vitamin-d-2 and Hyperparathyroidism--Secondary

Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia.. The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD).. A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting.. Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed.. This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.

Topics: Calcifediol; Calcium; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Network Meta-Analysis; Parathyroid Hormone; Phosphates; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of SHPT treatment in (chronic kidney disease) CKD.. The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness and side effects of calcifediol, ergocaliferol, calcitriol, paricalcitol, and cinacalcet were compared and analyzed.. Extended-release (ER) calcifediol raised the total serum 25-hydroxyvitamin D level over the threshold of 30 ng/mL in 80% of the patients analyzed in the study. It is the level required for intact PTH (iPTH) suppression. ER calcifediol reduced the iPTH level by 30% in about 30% of the patients, whereas only 2.1% of them had hypercalcemia. Calcitriol significantly decreased the iPTH values. It was the cause of hypercalcemia in 1.7% of the patients. The reduction of the iPTH level by more than 30% was observed in 85.7% of the patients in the paracalcitol group after 48-week supplementation. Paricalcitol was the cause of hypercalcemia in 1.9% of the patients. The cinacalcet therapy resulted in the highest percentage of patients with the iPTH level within the limits recommended by the KDOQI (70-110 ng/L for stage 4 CKD and 150-300 ng/L for stage 5 CKD). 92% of the patients met the KDOQI guidelines and the mean decrease in the serum iPTH level was 68%.. Calcifediol ER, paricalcitol, and cinacalcet significantly decreased the iPTH level in the patients under study. Paricalcitol increased the serum calcium concentration the most of all the drugs under analysis. It is noteworthy that only cinacalcet does not carry the risk of hypercalcemia.

Topics: Calcitriol; Calcium; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic

Paricalcitol and calcitriol are widely used for the treatment of secondary hyperparathyroidism in dialysis patients. We conducted a systematic review and meta-analysis to compare the efficacy and safety of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients. PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCT) assessing the efficacy of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients are included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Meta-analysis was carried out using the random-effect model. Six randomized controlled trials are included in the meta-analysis. Overall, compared with calcitriol treatment for secondary hyperparathyroidism in dialysis patients, paricalcitol treatment has comparable ≥50% reduction of parathyroid hormone (risk ratio [RR] = 1.33; 95% CI = 0.93-1.91; P = 0.12), calcium concentration (standard mean difference [Std. MD] = -0.21; 95% CI = -0.94 to 0.52; P = 0.58), phosphate concentration (Std. MD = -0.17; 95% CI = -0.58 to 0.24; P = 0.42), calcium phosphate (Std. MD = -0.08; 95% CI = -0.49-0.34; P = 0.71), alkaline phosphatase (Std. MD = -0.21; 95% CI = -0.73-0.31; P = 0.43), hypercalcemia (RR = 1.43; 95% CI = 0.51 to 3.98; P = 0.49), adverse events (RR = 0.79; 95% CI = 0.42-1.49; P = 0.47), and serious adverse events (RR = 0.78; 95% CI = 0.47-1.30; P = 0.33). Paricalcitol and calcitriol result in similar ≥50% reduction of parathyroid hormone, calcium concentration, phosphate concentration, calcium phosphate, alkaline phosphatase, hypercalcemia, adverse events, and serious adverse events for secondary hyperparathyroidism in dialysis patients.

Topics: Bone Density Conservation Agents; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Treatment Outcome

Vitamin D deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common among patients with chronic kidney disease (CKD) or undergoing dialysis. In addition to nutritional and sunlight exposure deficits, factors that affect vitamin D deficiency include race, sex, age, obesity and impaired vitamin D synthesis and metabolism. Serum 1,25(OH)₂D levels also decrease progressively because of 25(OH)D deficiency, together with impaired availability of 25(OH)D by renal proximal tubular cells, high fibroblast growth factor (FGF)-23 and decreased functional renal tissue. As in the general population, this condition is associated with increased morbidity and poor outcomes. Together with the progressive decline of serum calcitriol, vitamin D deficiency leads to secondary hyperparathyroidism (SHPT) and its complications, tertiary hyperparathyroidism and hypercalcemia, which require surgical parathyroidectomy or calcimimetics. Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts have recognized that vitamin D insufficiency and deficiency should be avoided in CKD and dialysis patients by using supplementation to prevent SHPT. Many vitamin D supplementation regimens using either ergocalciferol or cholecalciferol daily, weekly or monthly have been reported. The benefit of native vitamin D supplementation remains debatable because observational studies suggest that vitamin D receptor activator (VDRA) use is associated with better outcomes and it is more efficient for decreasing the serum parathormone (PTH) levels. Vitamin D has pleiotropic effects on the immune, cardiovascular and neurological systems and on antineoplastic activity. Extra-renal organs possess the enzymatic capacity to convert 25(OH)D to 1,25(OH)₂D. Despite many unanswered questions, much data support vitamin D use in renal patients. This article emphasizes the role of native vitamin D replacement during all-phases of CKD together with VDRA when SHPT persists.

Topics: Cholecalciferol; Dialysis; Dietary Supplements; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Parathyroid Hormone; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Vitamin D Deficiency

Secondary hyperparathyroidism (SHPT) is a severe complication for dialysis patients. Vitamin D receptor activators (VDRAs) are used to treat SHPT, but the comparative efficacy and safety between paricalcitol and other vitamin D receptor activators for management of SHPT in dialysis patients has been unproven.. We searched PubMed, Embase, and the Cochrane Library for the time period through June 2017 to identify randomized controlled trials that evaluated paricalcitol compared with other VDRAs for treatment of SHPT. The primary outcome was the percentage of patients with target reduction of intact parathyroid hormone (iPTH) from baseline. Secondary outcomes included incidences of hypercalcemia and hyperphosphatemia. The random-effects model was used to estimate relative risks (RRs) with 95% confidence intervals (CIs).. Eight studies (N = 759) were eligible for final inclusion. Compared with other VDRAs, no significant differences were found in the percentage of patients with target reduction of intact parathyroid hormone (iPTH) from baseline for paricalcitol treatment of SHPT in dialysis patients (RR, 1.01; 95% CI, 0. 87-1.18; p = 0.85). There were no differences in the incidence of hypercalcemia (RR, 0.95; 95% CI, 0.74-1.21; p = 0. 65) and hyperphosphatemia (RR, 0.94; 95% CI, 0.77-1.16; p = 0.58).. The presently available evidence is insufficient to draw a conclusion regarding whether paricalcitol therapy has a comparative efficacy and safety over other VDRAs for treating dialysis patients with SHPT. Large-sample, well-conducted, high-quality RCTs with patient-level outcomes (i.e., mortality) are urgently needed.

Topics: Bone Density Conservation Agents; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Renal Dialysis; Treatment Outcome

Deranged vitamin D metabolism represents an active trigger of secondary hyperparathyroidism (SHPT) in CKD. Correction of 25(OH)D deficiency by nutritional Vitamin D administration is suggested by KDIGO guidelines, to prevent and treat SHPT in CKD stage G3-G5 and G1T-G5T patients, although with a still inconsistent background. Nutritional vitamin D is available as cholecalciferol, ergocalciferol, or calcifediol. Superiority of calcifediol in increasing 25(OH)D levels has been suggested due to its better bioavailability. The safer pharmacokinetic of the recent modified-release (MR) formulation of calcifediol was effective in replenishing 25(OH)D levels with minimal impact on vitamin D catabolism and fibroblast-growth factor-23 (FGF-23) activation. Areas covered: the review discusses utility of calcifediol for treating SHPT in different CKD stages under physiology driven approach, focusing on vitamin D metabolism, guidelines suggestions and comparison between clinical effects on SHPT elicited by calcifediol, cholecalciferol and ergocalciferol. Expert commentary: although optimal targets of 25(OH)D and parathormone remain uncertain, calcifediol, especially in its newer MR formulation, may represent an intriguing option to combine an efficacious correction of 25(OH)D deficit and SHPT, with a limited impact on vitamin D catabolism and FGF-23 activation. Newer data are required to better explore the role of MR calcifediol in treating SHPT.

Topics: Animals; Biological Availability; Calcifediol; Cholecalciferol; Delayed-Action Preparations; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hyperparathyroidism, Secondary; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Vitamin D; Vitamins

Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD.

Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Minerals; Parathyroid Hormone; Phosphorus; Renal Insufficiency, Chronic

The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients.. PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2.. A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium × phosphorus products, and bone metabolism index.. Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research.

Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Renal Insufficiency, Chronic

The present review aims to assess the state-of-the-art regarding cost-effectiveness of therapy for secondary hyperparathyroidism in order to identify the best treatment and review methodological issues. PubMed and the Cochrane Library were searched to identify papers performing comparative analysis of costs and effects of treatment for secondary hyperparathyroidism in adult patients. Among the 66 papers identified, only 10 were included in the analysis. Treatment strategies evaluated in the selected papers were: cinacalcet in addition to vitamin D and phosphate binders versus vitamin D and phosphate binders only (seven papers), paricalcitol versus non-selective vitamin D (two papers), early and late introduction of cinacalcet in addition to vitamin D and phosphate binders (one paper) and paricalcitol versus cinacalcet (one paper). The high degree of heterogeneity among alternative treatments and methodological limits related to cost items considered, resource valuation methods and so on, make it unfeasible to reach a definite conclusion regarding cost-effectiveness but allow for future research opportunities.

Topics: Adult; Chelating Agents; Cinacalcet; Cost-Benefit Analysis; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Phosphates; Vitamin D

Compared to such native vitamin D agents as cholecalciferol (D3), egocalciferol (D2), and calcifediol (25- hydroxy vitamin D3, which need 1-alpha hydroxylase to be activated, 1-alpha-ergocalciferol, also known as doxercalciferol, is a synthetically manufactured vitamin D analog used for treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Doxercalciferol exhibits more structural similarities to plant-based vitamin D2, ergocalciferol, than with animal-based vitamin D3, cholecalciferol. Because doxercalciferol does not have a 25-hydroxy group, it requires 25-hydroxylation by the liver to be activated, a process independent of kidneys. Doxercalciferol shares these features with its D3 equivalent, 1-alpha-hydroxy-cholecalciferol (alphacalcidol), both of which are activated hepatically and independent of renal or extra-renal 1-alpha hydroxylase. In experimental and clinical studies of CKD and SHPT, doxercalciferol effectively reduces parathyroid hormone levels and restores abnormal bone pathology. The efficacy of doxercalciferol is similar to other vitamin D analogs including calcitriol, alphacalcidol, paricalcitol (19-nor-1,25-dihydroxyvitamin D2 ) and maxacalcitol (1,25-dihydroxy-22-oxa-vitamin D3). The frequency and magnitude of hypercalcemia or hyperphosphatemia observed with doxercalciferol treatment may be less than calcitriol or alphacalcidol therapy but not less than such vitamin D-mimetics as paricalcitol or maxacalcitol. Doxercalciferol can be used for the treatment of SHPT across all ranges of CKD, particularly if hypercalcemia is of concern. There are limited data as to whether doxercalciferol confers greater efficacy or better outcome and survival than other vitamin D analogs and D-mimetics. Whereas further studies are warranted, doxercalciferol can safely be used for correction of SHPT in the entire spectrum of CKD.

Topics: Animals; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Molecular Structure; Renal Dialysis; Renal Insufficiency, Chronic

The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.

Topics: Animals; Calcium; Ergocalciferols; Heart; Humans; Hyperparathyroidism, Secondary; Kidney; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic

Previous studies have demonstrated the safety and efficacy of using Paricalcitol for the treatment of secondary hyperparathyroidism (SHPT) in patients on dialysis. The aim of the current meta-analysis was to assess the safety and efficacy of Paricalcitol for the management of SHPT in patients with chronic kidney disease (CKD) not yet on dialysis. A secondary aim was to determine if sufficient data was available to assess the effect of Paricalcitol for the management of proteinuria.. A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software.. Paricalcitol is effective in lowering PTH in patients with CKD not yet on dialysis and is also effective in lowering proteinuria in diabetic CKD patients. However, we uncovered a safety signal identifying an elevated calcium phosphate product and a trend towards the development of hypercalcemia. A phosphate elevation was not demonstrated because the target used in the clinical studies was a P > 5.5 mg/dl, a value appropriate for dialysis patients and not CKD patients.. Although Paricalcitol is effective in lowering PTH, we advise caution in the use of any active Vitamin D analogues in patients with CKD because of the potential risk of exacerbating vascular calcification.

Topics: Bone Density Conservation Agents; Ergocalciferols; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Vitamin D

Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD). Beyond skeletal complications, uncontrolled SHPT is associated with cardiovascular mortality. Vitamin D receptor activators (VDRAs) are a mainstay of therapy for SHPT; however, use is limited by hypercalcemia, though less so with calcitriol analogs such as paricalcitol and there is emerging experience with oral formulations for non-SHPT indications. The role of VDRAs in the treatment of SHPT becomes a complex question as alternative strategies have developed.. This review summarizes trials that established the safety and efficacy of paricalcitol for SHPT. Comparative experience with paricalcitol as against other VDRAs will be reviewed as will the experience with paricalcitol in non-dialysis CKD and comparative experience with non-VDRA-based therapy.. VDRA therapy is considered first-line therapy for treatment of SHPT. Paricalcitol has demonstrated superiority to calcitriol with respect to parathyroid hormone suppression and calcium-phosphorus balance. Oral formulations of paricalcitol appear to be similarly effective for SHPT. While there is evidence to suggest adjunctive antiproteinuria benefit with the use of VDRAs, efficacy of these agents to slow the progression of CKD or to reduce cardiovascular risk has not yet been demonstrated.

Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Receptors, Calcitriol; Renal Insufficiency, Chronic

The treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited.. Two randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism. The primary end point (death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) in an unadjusted intention-to-treat analysis was not significant [hazard ratio 0.93; 95% confidence interval (CI) 0.85-1.02, P=0.11]. However, the pre-specified secondary end points of an adjusted intention-to-treat analysis (hazard ratio 0.88; 95% CI 0.79-0.97, P=0.008) were significant. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial, 227 patients with CKD stage 3-4 and left ventricular hypertrophy by echocardiography were randomized to paricalcitol or placebo. The primary end point of change in left ventricular mass index by MRI after 12 months was not different between the two groups, but the prespecified end point of cardiovascular-related hospitalizations was reduced in the paricalcitol-treated group (P=0.04).. The results of these two randomized controlled trials have negative primary end points but significant secondary end points and thus require physicians to individualize therapies for the treatment of secondary hyperparathyroidism.

Topics: Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcimimetic Agents; Cardiovascular Diseases; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Naphthalenes; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs).. MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes.. Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval [95% CI], 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58).. We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality.

Topics: Biomarkers; Chi-Square Distribution; Chronic Disease; Ergocalciferols; Evidence-Based Medicine; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Diseases; Odds Ratio; Parathyroid Hormone; Proteinuria; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome

The involvement of vitamin D deficiency in cardiovascular morbidity and mortality is attracting great interest. In patients with chronic kidney disease this association is stronger because vitamin D levels decrease as a result of renal progressive impairment. In chronic kidney disease secondary hyperparathyroidism commonly occurs in response to persistent hypocalcemia and hyperphosphatemia; moreover, parathyroid gland volume increases, vascular calcification is accelerated, and structural and functional modifications of the left ventricle are observed. These alterations entail both cardiac and renal involvement, resulting in cardio-renal syndrome. Recent studies concluded that vitamin D administration seems to have cardioprotective and renoprotective effects and improve peripheral vascular disease, vascular calcification, cardiac outcome, and blood pressure control. In clinical practice, therefore, the use of this hormone may play an important role in cardio-renal syndrome prevention.

Topics: Cardio-Renal Syndrome; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Kidney; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin D; Vitamin D Deficiency

Vitamin D deficiency is widespread in both the pediatric and adult chronic kidney disease (CKD) population. CKD is characterized by dysregulation of vitamin D and mineral metabolism. Secondary hyperparathyroidism and its management puts patients with CKD at increased cardiovascular risk. Emergence of experimental and some clinical data suggesting beneficial effects of vitamin D on proteinuria, blood pressure, inflammation and cardiovascular outcomes has pushed it to the center stage of CKD research. Pediatric data on vitamin D dysregulation and its consequences are still in its infancy. Ongoing prospective studies such as Chronic Kidney disease in Children (CKiD) and the Cardiovascular Comorbidity in Children with CKD (4 C) should help to delineate the evolution of disturbances in mineral metabolism and its adverse effects on growth, CKD progression and cardiovascular outcomes.

Topics: Child; Cholecalciferol; Dietary Supplements; Ergocalciferols; Growth Disorders; Humans; Hyperparathyroidism, Secondary; Kidney; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

Chronic kidney disease (CKD), and chronic renal failure in particular, is associated with vitamin D deficiency and with a disorder of all metabolic processes that are associated with vitamin D. Calcidiol levels are often low. At present, efforts are made to test and to pharmacologically modulate its levels and thus to contribute to greater availability of the substrate for external calcitriol production. Calcitriol production is reduced in CKD patients not only as a consequence of diminishing functional renal parenchyma but also as a consequence of 1-α-hydroxylase inhibition by FGF-23 and other factors. On the other hand, although parathormone (PTH) increases renal production of calcitriol, it also causes secondary hyperparathyroidism. Synthetic calcitriol (or α-calcidiol) supresses PTH production and is used to treat secondary hyperparathyroidism. This approach is often associated with adverse increase in calcaemia and phosphataemia as the effect on parathyroid glands is associated with an effect on the gastrointestinal tract where calcium and phosphor absorption is increased by calcitriol. Synthetic analogues of vitamin D inhibit parathyroid gland but have significantly lower effect on gastrointestinal tract. Paricalcitol is a selective VDR (vitamin D receptor) activator, used for targeted suppression of parathyroid glands. Vitamin D deficiency in general population is associated, at least in epidemiological studies, with a range of medical complications and the same also applies to patients with renal disease. Although randomised studies are not available, clinical observational studies repeatedly showed treatment with VDR activators to be associated with better prognosis. As other fields of medicine, nephrology currently pays a great attention to vitamin D and vitamin D receptor activation.

Topics: Calcitriol; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vitamin D-Binding Protein

At present, new compounds are available to treat secondary hyperparathyroidism, namely calcimimetics, novel phosphorus binders and also novel vitamin D receptor activators. Calcimimetics increase the sensitivity of the parathyroid gland to calcium through spatial configurational changes of the calcium-sensing receptor. In addition, experimental studies have demonstrated that calcimimetics also upregulate both the calcium-sensing receptor and the vitamin D receptor. They are efficacious in children, though the experience in paediatric chronic kidney disease is still limited. Sevelamer, lanthanum carbonate and magnesium iron hydroxycarbonate are novel phosphorus binders available on the market. Several studies have demonstrated their efficacy and safety up to 6 years, though costs are the main limitation for a wider use. Since almost all the experience available on the new phosphorus binders comes from its use in adults, studies on children are needed in order to confirm the efficacy and safety of these products. Other new salts and polymers are also being developed. New vitamin D receptor activators, such as paricalcitol, are as effective at suppressing parathyroid hormone (PTH) as the traditional vitamin D receptor activators used for the past two decades, but they have a better and safer profile, showing fewer calcaemic and phosphoraemic effects while preserving the desirable effects of the vitamin D receptor activators on the cardiovascular system, hypertension, inflammation and fibrosis. Their use in children with chronic kidney disease has revealed similar responses to those of adults. The novel compounds discussed in this review should facilitate and improve the management of mineral and bone disorders in children with chronic kidney disease.

Topics: Bone Density Conservation Agents; Calcium; Chelating Agents; Child; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Parathyroid Glands; Phosphates; Polyamines; Protein Binding; Receptors, Calcitriol; Receptors, Calcium-Sensing; Sevelamer

Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.

Topics: Alkaline Phosphatase; Calcinosis; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Hypophosphatemia; Kidney Failure, Chronic; Minerals; Osteoporosis; Parathyroid Hormone; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

The fields for clinical employment of vitamin D analogs are growing and under active evaluation in different medical specialties, ranging from dermatology to immunology and oncology. In this review we provide a brief description of the drugs that have been developed more specifically for the treatment of secondary hyperparathyroidism (SH) associated with uremia.

Topics: Calcitriol; Dihydroxycholecalciferols; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Uremia; Vitamin D

Decline in renal function is related directly to cardiovascular mortality. However, traditional risk factors do not fully account for the high mortality in these patients. Activated vitamin D, a hormone produced by the proximal convoluted tubule of the kidney, appears to have beneficial effects beyond suppressing parathyroid hormone (PTH). However, activated vitamin D also can cause hypercalcemia and hyperphosphatemia in chronic kidney disease. Newer agents such as vitamin D receptor activators (eg, paricalcitol) suppress PTH with reduced risk of hypercalcemia and hyperphosphatemia. Recent evidence from animal and preliminary human studies supports an association between vitamin D receptor activators and reduced risk of cardiovascular disease deaths, irrespective of PTH levels. New pathways of vitamin D regulation also have been discovered, involving fibroblast growth factor-23 and klotho. Although considerable work has been performed to advance our understanding of the effects of vitamin D in health and chronic kidney disease, more investigations and randomized trials need to be performed to elucidate the mechanistic underpinnings of these effects.

Topics: Animals; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Prognosis; Renal Dialysis; Vitamin D

Modern strategies to prevent secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients give great relevance to vitamin D replacement therapy. However, a sound approach to treatment requires taking into account many factors, including stage of CKD, underlying renal disorder, levels of circulating PTH, bone status, vitamin D deposits, and serum calcium (Ca) and phosphate (P) levels. The aim of vitamin D replacement therapy should be to prevent SHPT from the early stages of CKD, because once parathyroid hyperplasia and osteodystrophy develop, they cannot be completely reverted. The therapeutic strategies for SHPT are now changing. The availability of VDRAs allows inhibition of parathyroid glands with less effect on calcium and phosphate levels, and perhaps reduces the mortality of dialysis patients. Actual objectives for treating CKD patients with new generation VDRAs are to retain or amplify the effects of calcitriol on PTH suppression, with no effects on serum Ca and P levels. Paricalcitol is such a new VDRA with minimal impact on serum Ca and P levels. Since cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients, these data suggest that the beneficial effect associated with paricalcitol injection on patient survival is at least partially related to its effect on the cardiovascular system.

Topics: Calcium; Cinacalcet; Clinical Trials as Topic; Comorbidity; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Parathyroid Hormone; Phosphorus; Receptors, Calcitriol; Treatment Outcome; Vitamins

Alfacalcidol (1alpha-hydroxyvitamin D(3)) has been widely used since 1981 as a prodrug for calcitriol (1alpha,25-dihydroxyvitamin D(3)) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1alpha-hydroxyvitamin D(2)) has been used since 1999 as a prodrug for 1alpha,25-dihydroxyvitamin D(2) for the treatment of secondary hyperparathyroidism. Currently, six forms of vitamin D are known. They range from vitamin D(2) to vitamin D(7 )and are distinguished by their differing side chains. Only vitamin D(2) and vitamin D(3) have been found to be biologically active based on the elucidation of activation pathways. Alfacalcidol and osteoporosis/doxercalciferol and secondary hyperparathyroidism are discussed, with a new look at old compounds including their practical syntheses.

Topics: Drug Design; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Prodrugs; Rickets; Vitamin D; Vitamins

Chronic kidney disease is a growing public health concern, and secondary hyperparathyroidism is one of the most serious associated comorbidities. In healthy individuals, precisely controlled feedback loops dynamically modulate parathyroid hormone (PTH) levels. As kidney function declines, phosphate retention, decreased 1a,25-dihydroxyvitamin D3, and a tendency to hypocalcemia leads to overstimulation of PTH production and parathyroid hyperplasia. Vitamin D receptor (VDR) ligands are essential tools for controlling parathyroid activity. This review highlights the current clinical and biochemical VDR ligand studies, focusing on the differences between selective and nonselective VDR ligands. It is apparent that VDR ligands have important roles in the management of secondary hyperparathyroidism. Selective VDR ligands, in particular, may offer additional benefits in the treatment of bone disease, and may potentially reduce adverse effects related to cardiovascular disease.

Topics: Bone Density Conservation Agents; Calcitriol; Ergocalciferols; Gene Expression; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Receptors, Calcitriol; Vitamin D Deficiency

The articles providing answers to the questions on vascular calcification of most interest from a clinical point of view were selected. 1. How is it measured?: Studies showing the clinical utility of different tools to quantify it were analyzed. 2. What does it measure?: Both in dialysis patients and the general population, vascular calcification and arterial stiffness are prognostic factors for morbidity and mortality. Other markers such as fetuin-A are associated with mortality in patients on hemodialysis but not in patients in early stages of chronic kidney disease. 3. What causes it?: In two selected studies, it was demonstrated again that low bone turnover and diabetes cause cardiovascular disease and vascular calcification, respectively. 4. How is it treated?: There is still no clinical evidence of regression of vascular calcification. However, a prospective study in new hemodialysis patients showed that sevelamer compared to calcium compounds slows the progression of vascular calcification and confers greater survival. A study comparing both compounds in chronic hemodialysis patients showed that sevelamer only had a benefit on survival in patients older than 65 years. It remains to be demonstrated whether the good experimental results of paricalcitol and cinacalcet are confirmed in prospective clinical studies.

Topics: Aged; Animals; Atherosclerosis; Calcinosis; Chronic Disease; Cinacalcet; Coronary Artery Disease; Diabetes Complications; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Naphthalenes; Polyamines; Randomized Controlled Trials as Topic; Renal Artery; Sevelamer; Tomography, Spiral Computed; Tomography, X-Ray Computed; Vascular Diseases

Secondary hyperparathyroidism (SHPT) is common in chronic kidney disease (CKD) patients. Classically, SHPT is induced by hypocalcemia, hyperphosphatemia, and calcitriol deficiency, that cause not only renal osteodystrophy but also systemic toxicity, particularly cardiovascular disease.. Treatment with calcitriol, the active form of vitamin D, reduces serum parathyroid hormone (PTH) levels but may result in both hypercalcemia and hyperphosphatemia, increasing the risk of vascular calcification in CKD. Are the new vitamin D receptor activators (VDRAs) more useful in the treatment of SHPT for their reduced risk of hypercalcemia and hyperphosphatemia in haemodialysis (HD) patients?. In this review, we describe the new VDRA, paricalcitol (1,25-dihydroxy-19-nor-vitamin D2), which suppresses PTH secretion with minimal increases on serum calcium and phosphate levels.. In some animal models of CKD paricalcitol does not cause vascular calcification, while other VDRAs do. These data may account for the results seen in observational studies of HD patients, in which paricalcitol is associated with improved survival compared to calcitriol.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Kidney Failure, Chronic; Receptors, Calcitriol; Renal Dialysis

Hemodialysis (HD) patients are commonly affected by secondary hyperparathyroidism (SHPT), in which 3 well-known factors are usually involved: hypocalcemia, hyperphosphatemia and calcitriol deficiency. Classically, high parathyroid hormone (PTH) levels cause bone-associated diseases, such as osteitis fibrosa and renal osteodystrophy, but more recently it has been demonstrated the link between SHPT and a systemic toxicity, with a major role in determining cardio-vascular disease, including arterial calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis. Treatment with calcitriol (CT), the active form of vitamin D, reduces parathyroid hormone (PTH) levels, but may result in elevations in serum calcium (Ca) and phosphorus (P), increasing the risk of cardio-vascular calcification in the HD population. Several new vitamin D analogs have been developed and investigated with the rationale to treat SHPT with a reduced risk of hypercalcemia and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin D(2), 19-Nor-D(2)) is a vitamin D analog that suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. It was demonstrated that paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. Furthermore, 19-Nor-D(2) is the first analog approved for use in HD patients and is available for i.v. and oral administration, commonly 3 times weekly after HD. The purpose of the present review is to analyze the pathogenesis and treatment of SHPT in HD patients, and the role of paricalcitol in the prevention of arterial calcification.

Topics: Bone Density Conservation Agents; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin D

Despite the enormous cardiovascular disease epidemic and poor survival among individuals with chronic kidney disease (CKD), traditional risk factors such as hypercholesterolemia, hypertension, and obesity appear not as relevant as was previously thought, nor would their management improve survival in patients with CKD who are undergoing dialysis. On the contrary, kidney disease wasting (KDW) (also known as the malnutrition-inflammation complex), renal anemia, and kidney bone disease (KBD) appear to be the 3 most important nontraditional risk factors associated with cardiovascular disease in CKD. KBD-associated hyperparathyroidism may contribute to worsening refractory anemia and KDW/inflammation. The main cause of secondary hyperparathyroidism is active vitamin D deficiency. Hence, treatment of patients with KBD with vitamin D analogs, especially those with lesser effects on calcium and phosphorus such as paricalcitol, may be the most promising option for improving CKD outcomes. By conducting survival analyses in a 2-year (7/2001 to 6/2003) cohort of 58,058 patients on hemodialysis, we recently found that associations between high serum parathyroid hormone and increased death risk were masked by the demographic and clinical characteristics of patients, and that alkaline phosphatase had an incremental association with mortality. Administration of paricalcitol was associated with improved survival in time-varying models. We now present additional subgroup analyses that show that administration of any dose of paricalcitol, when compared with no paricalcitol, is associated with better likelihood of survival in virtually all subgroups of patients on hemodialysis. Because these associations may be secondary to bias by indication, randomized clinical trials are necessary to verify the findings of this and similar observational studies.

Topics: Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Renal Dialysis; Risk Factors; Survival Analysis; Vitamin D

Topics: Bone Density Conservation Agents; Dose-Response Relationship, Drug; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Treatment Outcome

New vitamin D derivatives were introduced to clinical use for the treatment of secondary hyperparathyroidism. Patients who were treated by paricalcitol survived more than patients who were treated by calcitriol. Doxercalciferol and paricalcitriol could maintain suppressed parathyroid hormone (PTH) with less frequent hypercalcemic accidents. Cinacalcet suppressed serum PTH levels in dialysis patients and decreased serum calcium and phosphate concentrations. We must further investigate these new drugs' outcomes, by measuring mortality and morbidity.

Topics: Bone Density Conservation Agents; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Vitamin D

There has been an emphasis over the last several years to identify and treat chronic kidney disease (CKD) and its complications as they evolve rather than waiting until the patient reaches end-stage renal disease (ESRD), also known as CKD stage 5. The number of patients who will be identified and prescribed therapies for complications such as secondary hyperparathyroidism (SHPT) is greater than initially proposed.. To review the pathways, complications, management, and estimated treatment costs of CKD-related SHPT.. An electronic literature search of MEDLINE (January 1980 through January 2007) was conducted for English-language publications using the base search term secondary hyperparathyroidism. To refine subsequent searches, the authors added Boolean operators to the following secondary and tertiary search terms: parathyroid hormone, chronic kidney disease, renal osteodystrophy, adynamic bone disease, vascular calcification, cardiovascular disease, vitamin D, vitamin D analogs, hypercalcemia, hyperphosphatemia, calcimimetics, costs, prevalence, and economics.. The initial MEDLINE search produced 278 relevant articles. After refining the search terms, the authors triaged the results for English-language publications relevant to the discussion of SHPT and its complications in CKD, eliminating 149 publications. The remaining 129 publications were accepted for review. These articles represent a growing body of primarily observational evidence that demonstrates that elevated intact parathyroid hormone (PTH) levels cause deleterious physiological results across a variety of organ systems, including the cardiovascular and skeletal systems. Specific complications associated with SHPT are left ventricular hypertrophy (LVH), renal osteodystrophy (ROD), and extraskeletal calcification. Medical management of the PTH/vitamin D/calcium and phosphorus imbalances in SHPT focus on regulating PTH levels via vitamin D therapy. The class of calcimimetics is a newer treatment modality that has favorable effects on biochemical laboratory values, such as serum calcium and phosphorus levels, but current data do not show differences on hard endpoint patient-oriented outcomes compared with standard generic agents. The direct drug costs in April 2007 U.S. dollars of treating CKD-associated elevations in PTH in predialysis patients range from $8.40 per patient per week ($437 per year) for oral generic calcitriol to $88.90 per patient per week ($4,623 per year) for oral paricalcitol (expressed as 85% of average wholesale price [AWP] for brand drugs or 70% of AWP for generic drugs). The direct drug costs of treating SHPT in hemodialysis patients range from $80.20 per patient per week ($4,170 per year) for generic calcitriol (IV) to $278.46 per patient per week ($14,480 per year) for oral cinacalcet.. SHPT causes skeletal and cardiovascular complications in CKD patients. Calcitriol therapy is effective in managing PTH levels, but efforts to reduce the associated hypercalcemia and hyperphosphatemia have led to the development of newer, yet more expensive, vitamin D analogs. With the lack of evidence to support comparative superior outcomes in end-organ disease among SHPT therapy alternatives, future research is still needed to clearly identify which newer agents are most competitive with the historical gold standard of calcitriol therapy.

Topics: Calcitriol; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Cost-Benefit Analysis; Drug Costs; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Naphthalenes; Parathyroid Hormone; Parathyroidectomy; Renal Insufficiency, Chronic; Vitamin D; Vitamins

Secondary hyperparathyroidism (SHPT) is a common and serious consequence of chronic kidney disease (CKD). SHPT is a complex condition characterised by a decline in 1,25-dihydroxyvitamin D and consequent vitamin D receptor (VDR) activation, abnormalities in serum calcium and phosphorus levels, parathyroid gland hyperplasia, elevated parathyroid hormone (PTH) secretion, and systemic mineral and bone abnormalities. There are three classes of drugs used for treatment of SHPT: (i) nonselective VDR activators or agonists (VDRAs); (ii) selective VDRAs; and (iii) calcimimetics. The VDRAs act on the VDR, whereas the calcimimetics act on the calcium-sensing receptor. Calcimimetics are commonly used in conjunction with VDRA therapy. By virtue of the differences in their chemical structure, the nonselective and selective VDRAs differ in their effects on gene expression, and ultimately parathyroid gland, bone and intestine function. Medications in all three classes are effective in suppression of PTH; however, clinical studies show that calcimimetics are associated with an unfavourable tolerability profile and hypocalcaemia, whereas nonselective VDRAs, and to a lesser extent selective VDRAs, are associated with dose-limiting hypercalcaemia and hyperphosphataemia. Selective VDRAs also have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs. Calcium load in patients with CKD can lead to vascular calcification, accelerated progression of cardiovascular disease and increased mortality. High serum phosphorus levels are also associated with adverse effects on cardiorenal function and survival. Recent evidence suggests that VDRAs are associated with a survival benefit in CKD patients, with a more favourable effect with selective VDRAs than nonselective VDRAs. Paricalcitol, a selective VDRA, is reported to exert specific effects on gene expression in various cell types that are involved in vascular calcification and the development of coronary artery disease. This article examines the molecular mechanisms that determine selectivity of VDRAs, and reviews the evidence for clinical efficacy, safety and survival associated with the three drug classes used for treatment of SHPT in CKD patients.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Chronic Disease; Cinacalcet; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Naphthalenes; Receptors, Calcitriol; Vitamin D

The 'classical' effects of vitamin D receptor activator or agonist (VDRA) therapy for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease primarily involves suppressive effects on the parathyroid gland, and regulation of calcium and phosphorus absorption in the intestine and mobilisation in bone. Observational studies in haemodialysis patients report improved cardiovascular and all-cause survival among those receiving VDRA therapy compared with those not on VDRA therapy. Among VDRAs, the selective VDRA paricalcitol has been associated with greater survival than nonselective VDRAs, such as calcitriol (1,25-dihydroxyvitamin D(3)). The survival benefits of paricalcitol appear to be linked, at least in part, to 'nonclassical' actions of VDRAs, possibly through VDRA-mediated modulation of gene expression. In cardiovascular tissues, VDRAs are reported to have beneficial effects such as anti-inflammatory and antithrombotic effects, inhibition of vascular smooth muscle cell proliferation, inhibition of vascular calcification and stiffening, and regression of left ventricular hypertrophy. VDRAs are also reported to negatively regulate the renin-angiotensin system, which plays a key role in hypertension, myocardial infarction and stroke. The selective VDRAs, paricalcitol and maxacalcitol, are associated with direct protective effects on glomerular architecture and antiproteinuric effects in response to renal damage. Paricalcitol regulates several cardiovascular and renal parameters more favourably than nonselective VDRAs. Complex nonclassical effects, which are not clearly understood, possibly contribute to the improved survival seen with VDRAs, especially paricalcitol.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Receptors, Calcitriol; Survival Rate

Secondary hyperparathyroidism is a common complication of patients with chronic kidney disease. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus. New vitamin D analogues have been developed to reduce parathyroid hormone secretion without concomitant hypercalcaemia and hyperphosphataemia. Recent data from studies with paricalcitol capsules, the oral formulation of 19-nor-1,25(OH)2D2, show a significant reduction in parathyroid hormone levels with no change in calcium and phosphorus levels when compared with placebo. Paricalcitol also compares favourably to other oral vitamin D analogues, effectively decreasing parathyroid secretion with less hypercalcaemia and hypercalciuria than other agents.

Topics: Capsules; Chronic Disease; Drug Administration Schedule; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Randomized Controlled Trials as Topic; Vitamin D; Vitamins

To review the pharmacology, pharmacokinetics, effectiveness, safety, and therapeutic considerations related to the use of doxercalciferol in the treatment of secondary hyperparathyroidism.. A MEDLINE search (1966-June 2006) was conducted using the key words vitamin D, ergocalciferols, and secondary hyperparathyroidism. Text word searches were also performed for the terms 1-alpha-hydroxy-vitamin D(2), 1-alpha-hydroxyergocalciferol, Hectorol, and doxercalciferol. Searches were limited to studies published in English and conducted in human subjects.. All published clinical studies evaluating the safety and effectiveness of doxercalciferol in secondary hyperparathyroidism were reviewed, and anecdotal patient reports were also evaluated. Selected clinical studies involving the use of calcitriol and/or paricalcitol in the treatment of secondary hyperparathyroidism were also included.. Doxercalciferol effectively reduces parathyroid hormone levels in patients with chronic kidney disease (CKD). Both oral and intravenous administration can significantly increase serum calcium and/or phosphorus levels as evidenced by placebo-controlled clinical trials. This agent has not been studied comparatively with calcitriol or paricalcitol to assess relative safety.. Doxercalciferol is approved for and effective in the treatment of secondary hyperparathyroidism related to CKD, both before and during dialysis, but has not demonstrated a lower incidence of hypercalcemia and/or hyperphosphatemia in relation to other vitamin D therapies. The drug is available in both oral and intravenous dosage forms. Doxercalciferol should be maintained as a formulary alternative for patients unresponsive to or intolerant of other vitamin D therapies, but comparative randomized studies are needed to differentiate its place in therapy.

Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone

This study evaluated the health-economic consequences of use of intravenous paricalcitol (Zemplar), oral calcitriol or oral and intravenous alfacalcidol for the treatment of patients with secondary hyperparathyroidism, focusing on a third-party payer perspective through inclusion of medication and hospital costs, survival rates and utilities. Cost values were based on German treatment recommendations and prices. Reference values for survival rates and utilities were based on the results of a MEDLINE search. The analysis showed a clear advantage for intravenous paricalcitol with respect to costs, effectiveness and utilities compared with treatment with oral calcitriol or intravenous alfacalcidol. Since the results were very cost sensitive with respect to selected diagnosis-related groups (DRGs) for kidney disease with dialysis, a sensitivity analysis was performed. This demonstrated first-order dominance of intravenous paricalcitol for a wide range of hospitalisation costs. In conclusion, this analysis suggested a clear benefit from the perspective of a third-party payer for intravenous paricalcitol compared with oral calcitriol and intravenous alfacalcidol in the treatment of patients with secondary hyperparathyroidism.

Topics: Calcitriol; Cost of Illness; Cost-Benefit Analysis; Ergocalciferols; Health Care Costs; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Quality-Adjusted Life Years; Renal Dialysis; Survival Rate

Paricalcitol (Zemplar) is a synthetic vitamin D(2) analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.

Topics: Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic

Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver, and 25-hydroxyvitamin D3-1alpha-hydroxylase in the kidney, to form the active metabolite, 1,25-dihydroxyvitamin D3. Chronic kidney disease (CKD) is characterized by reduced synthesis of 1,25-dibydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, secondary hyperparathyroidism (SHPT) and bone disease. CKD patients encounter a much higher risk of cardiovascular disease (CVD) than the general public. The cardiovascular risk factors for CKD patients include conventional factors such as age, gender, hypertension, diabetes, dyslipidemia and smoking, and non-conventional factors, such as anemia, uremia, reduced vascular compliance, inflammation and various hormonal factors. Several vitamin D analogs are currently available for the treatment of SHPT, and recent clinical data show that these analogs provide survival benefit for CKD patients in the order of paricalcitol > calcitriol > no vitamin D analog, independent of parathyroid hormone and calcium. Moreover, the survival benefit seems to be associated with cardiovascular causes. The observations made from these clinical studies raised intriguing questions about the involvement of the vitamin D receptor locus (VDR) in the cardiovascular system. This review discusses recent data regarding the role of vitamin D and its analogs in the CVD associated with CKD.

Topics: Calcitriol; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Failure, Chronic; Vitamin D

Paricalcitol (Zemplar) is a synthetic vitamin D2 analog that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US pediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.

Topics: Adult; Child; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone

Secondary hyperparathyroidism (SHP) is a frequent complication of dialysis patients. In this second article we will analyze the new vitamin D analogs, capable of decreasing parathyroid hormone (PTH) levels with a lower effect on intestinal calcium and phosphorus absorption. Among other advantages described in the experimental setting, paricalcitol shows a survival benefit in dialysis patients as compared to calcitriol, at least in retrospective studies, and thus it became our first-line vitamin D derivative. Calcimimetics are unique since they decrease PTH levels without increasing serum calcium and phosphorus. Actually, calcium and phosphorus decrease in a significant number of patients. These drugs will soon be authorized in Spain, and we describe the better achievement of K/DOQI guidelines as well as other beneficial effects observed in the experimental animal with them. Finally, we mention the potential benefit of mild metabolic acidosis, the use of bisphosphonates, the role of bone morphogenetic protein BMP-7, and the use of teriparatide. The future treatment of SHP will probably require the independent management of calcium, phosphorus, vitamin D and PTH. Thus, low-dose combined treatments with selective drugs may prove more effective than sequential therapies.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcium; Cinacalcet; Diphosphonates; Drug Therapy, Combination; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Parathyroid Hormone; Phosphorus; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Renal Dialysis; Retrospective Studies; Teriparatide; Transforming Growth Factor beta; Vitamin D

Bone metabolism is very frequently disturbed in end stage renal failure hemodialyzed, with secondary hyperparathyroidism development but also serious potential cardiovascular consequences. New treatments will be available very soon in Europe such as new phosphate binders, vitamin D2 analogues or calcimimetics to fight against such medical diseases, with the hope of less risk for vascular complications. The real place of such new medical opportunities needs to be determined. Moreover, studies with morbidity and mortality end-points are waited before estimating the real importance of these new therapeutic tools.

Topics: Calcium; Chelation Therapy; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Phosphorus; Renal Dialysis

A strict control of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) is indicated to avoid serious complications linked to osteitis fibrosa and other parathyroid-hormone (PTH)-related bodily disturbances. However, such a control is often achieved only at the price of unacceptably high plasma calcium and phosphorus levels and the risk of soft tissue calcification, even when using the novel, so-called 'non-hypercalcemic' vitamin D analogs. The advent of a new class of drugs, the calcimimetics, should allow a more adequate control of the disturbed calcium-phosphorus metabolism in CKD patients. In my opinion, the calcimimetics will not replace currently used medications but will be a valuable supplement to presently available treatment options for this major complication in patients with renal failure.

Topics: Calcitriol; Cinacalcet; Clinical Trials as Topic; Drug Synergism; Ergocalciferols; Humans; Hydroxycholecalciferols; Hypercalcemia; Hyperparathyroidism, Secondary; Intestinal Absorption; Kidney Failure, Chronic; Liver; Naphthalenes; Phosphates; Receptors, Calcitriol; Receptors, Calcium-Sensing; Vitamin D; Vitamin D Deficiency

Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver and 25-hydroxyvitamin D3-1 alpha-hydroxylase in the kidney to form the active metabolite 1 alpha,25-dihydroxyvitamin D3. The binding of 1 alpha,25-dihydroxyvitamin D3 to the vitamin D receptor (VDR), a nuclear receptor, activates VDR to interact with retinoid X receptor (RXR) and form the VDR/RXR/co-factor complex, which binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. 1 alpha,25-dihydroxyvitamin D3 regulates the homeostasis of calcium and phosphorus, and also controls the expression of parathyroid hormone. Chronic renal disease is characterized by reduced synthesis of 1 alpha,25-dihydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, over-stimulation of the parathyroid gland, and increased parathyroid hormone synthesis. This secondary hyperparathyroidism (HPT) can cause renal osteodystrophy unless treated. Several vitamin D analogs are currently available or under investigation for the treatment of secondary HPT, psoriasis and osteoporosis. Additional clinical studies are being conducted for a variety of indications, including bone diseases, cell proliferation disorders and autoimmune diseases. Different vitamin D analogs seem to exhibit differential effects as exemplified by the survival benefit provided by paricalcitol over 1 alpha,25-dihydroxyvitamin D3 for end-stage renal disease patients on hemodialysis. Elucidation of the mechanism of action for the different vitamin D analogs will enhance our understanding of the vitamin D pathway and improve therapeutic uses of these analogs. This review discusses recent progress on the use of vitamin D and its analogs in the management of HPT secondary to chronic renal disease.

Topics: Calcitriol; Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Failure, Chronic; Vitamin D

Topics: Calcitriol; Cholecalciferol; Drug Design; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Vitamin D

We examined 21 clinical trials (16 articles and 5 abstracts) that compared intravenous (i.v.) and oral vitamin D analogs for the treatment of secondary hyperparathyroidism in hemodialysis patients. Nearly all the studies had severe limitations, especially study size. Only 2 studies utilized more than 25 patients per treatment arm; 11 of the 16 articles and 4 of the 5 abstracts had less than 15 patients per arm. Calcitriol and/or alpha-calcidol were studied in 20 trials of the 21 studies (15 of the 16 articles) while 1 article examined doxercalciferol.. No difference of efficacy between i.v. and oral dosing was found in 10 of the 15 articles in which efficacy was assessed. The i.v. route provided significantly faster suppression of elevated parathyroid hormone (PTH) and/or a greater degree of suppression in 5 of 15 applicable articles, but in 2 of these 5 studies the i.v. dose was substantially greater than the oral dose. Side effects, chiefly hypercalcemia, were noted in half of the articles. Six of 9 articles with detailed results found no significant difference; only 2 found significantly increased hypercalcemia with oral dosing, and 1 found significantly increased hypercalcemia with i.v. dosing. Only 3 articles reported on hyperphosphatemia and no difference was found for mode of administration. One factor influencing 19 of the 21 comparisons was the use of oral doses that were therapeutically equivalent to about half or less the i.v. dose given the lower bioavailability of oral D hormones. One larger study (70 patients) that compared equipotent dosing of the 2 administration routes found 4 times more hypercalcemia using oral than i.v. dosing (p < 0.001). Another factor complicating interpretation is that the treatment periods were short, with half being 16 weeks or less and only 2 lasting 36 weeks.. Conclusions about the comparative efficacy and safety of the 2 administration routes require larger studies of longer duration that utilize therapeutically equivalent doses.

Topics: Administration, Oral; Drug Administration Routes; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Renal Dialysis

Secondary hyperparathyroidism is a well known complication of chronic renal insufficency. It is not only a state of increased parathyroid hormone secre-tion but also a state of parathyroid gland hyperplasia. Prevention and treatment of secondary hyperpara-thyroidism is a huge challenge for the nephrologist, despite new agents for the treatment of hyperphos-phataemia, new vitamin D analogues and calci-mimetics. The importance of parathyroid gland hyperplasia and the possibility of its reduction frequently are neglected issues. Ultrasonography could be very useful in detection of parathyroid gland size and shape and in the management of secondary hyperparathyroidism.

Topics: Drug Therapy, Combination; Epoxy Compounds; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Nephrology; Polyamines; Polyethylenes; Risk Assessment; Sevelamer; Severity of Illness Index; Treatment Outcome; Ultrasonography, Doppler

Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol). Replacement therapy with calcitriol or its precursor 1alpha-hydroxyvitamin D(3) (1alphaOHD(3), alfacalcidol) often produces hypercalcaemia, especially when combined with calcium-based phosphate binders. In addition, these vitamin D compounds can aggravate the hyperphosphataemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands but have less calcaemic activity, thereby offering a safer and more effective means of controlling 2HPT. 1,25-Dihydroxy-19-norvitamin D(2) (19-norD(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the US and 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) (1,25(OH)(2)26,27F6 D(3), falecalcitriol) have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-norD(2) have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcaemic and phosphataemic activities. The low calcaemic activity of OCT has been attributed to its rapid clearance, which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcaemic activity of 19-norD(2) diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared with 1alphaOHD(3), has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from an altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.

Topics: Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Vitamin D

Secondary hyperparathyroidism complicating chronic kidney disease requires therapy to minimize the effects of parathyroid hormone (PTH) on bone and other tissues. Low levels of calcitriol in blood play a major role in the initiation and maintenance of hyperparathyroidism. Accordingly, administration of calcitriol has been demonstrated to be an effective form of therapy. While this therapy is effective in controlling hyperparathyroidism, side effects of calcitriol, including increased intestinal absorption of calcium and phosphate, often complicate therapy by giving rise to hypercalcemia and hyperphosphatemia, which may be important risk factors for extraskeletal calcifications. Over the last several years, interest has turned toward vitamin D analogs, which may be able to affect parathyroid function with lesser effects on calcium and phosphorus in serum, and thereby, minimizing the undesirable toxicities of vitamin D therapy. Two vitamin D analogs are available in this country for the control of hyperparathyroidism in the setting of advanced kidney disease, and include 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), and more recently, 1-alpha-hydroxyvitamin D(2) (doxercalciferol). 19-nor-1,25-dihydroxyvitamin D(2) is widely used and was evaluated extensively in animals, revealing that this vitamin D sterol had a selective effect on increasing PTH suppression, with lesser effects on calcium and phosphorus metabolism. These studies lead to clinical trials which showed the efficacy of this therapy in that PTH could be lowered satisfactorily in patients with calcium and phosphorus values within the normal range. The selectivity of 19-nor-1,25-dihydroxyvitamin D(2) seen in animals has also been found in humans, such that therapy with this sterol can achieve control of hyperparathyroidism with a wider therapeutic window than the predecessor, calcitriol. 1-alpha-hydroxyvitamin D(2) has recently been introduced, but in contrast to paracalcitol, there is little reason to believe that there is any selectivity in its actions in terms of suppressing PTH, compared with its ability to raise serum calcium or phosphorus in serum. However, this vitamin D sterol can effectively decrease PTH levels in patients with advanced renal failure. Comparative studies of paricalcitol and doxercalciferol have not been undertaken at the present time. Further studies on the mechanism of actions might explain the differences between these sterols and their effects on the intestinal abs

Topics: Animals; Bone and Bones; Calcitriol; Calcium; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Vitamin D

Topics: Drug Costs; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Patient Selection; Renal Dialysis

Calcitriol and alfacalcidol are useful in suppressing parathyroid hormone (PTH) in haemodialysis patients, but hypercalcaemia and hyperphosphataemia are frequent. The vitamin D analogue, 1alpha-hydroxyvitamin D2 (1alphaD2), has a higher therapeutic index in animal models. Previously, 1alphaD2, 4 microg/day or 4 microg/haemodialysis, lowered iPTH to the target range in 87.5% of 24 haemodialysis patients with moderate to severe secondary hyperparathyroidism (plasma iPTH, 359-1521 pg/ml). The incidences of hypercalcaemia (serum Ca>2.8 mM) or hyperphosphataemia (serum P>2.23 mM) were low. Later, 10 of these patients were re-treated with 1alphaD2, initial dose, 10 microg, thrice weekly with haemodialysis. The iPTH was suppressed as readily, and there was no greater incidence of hypercalcaemia and hyperphosphataemia. Based on these data, a large, multicentre study is ongoing in California and Tennessee/Mississippi, using 1alphaD2 in haemodialysis patients with iPTH >400 pg/ml. In this and the earlier studies, only calcium-based phosphate binders were used to control serum phosphorus. The initial dose, 10 microg thrice weekly with haemodialysis, is adjusted to maintain a target iPTH within the range of 150-300 microg/ml; the final dose range is 2.5-20 microg per haemodialysis. The protocol includes 8 weeks of wash-out with no vitamin D, 16 weeks of open label treatment period with 1alphaD2, and finally 8 weeks of randomized double blinded treatment with either continued 1alphaD2 or placebo. Forty two patients from California and 38 from Tennessee/Mississippi have completed 16 weeks of open label treatment. In California, iPTH declined from 832+/-95 pg/ml at baseline to 222+/-71 pg/ml at the nadir and to 477+/-117 pg/ml at week 16 of the treatment. In Tennessee/Mississippi, the iPTH declined from 977+/-65 pg/ml to 286+/-42 pg/ml at the lowest point and to 493+/-79 at the end of the treatment. Plasma iPTH reached or fell below the target range in 84% of the 80 patients completing open treatment. Asymptomatic hypercalcaemia (serum Ca>2.8 mM) increased from 0.3 episodes/100 weeks during wash-out to 3.6 episodes/100 treated weeks in California and from 0 to 3.7 episodes in Tennessee/Mississippi. In California and Tennessee, the episodes of hyperphosphataemia (serum P>2.2 mM) increased from 5.0 and 5.0 episodes per 100 patient/week during wash-out to 10.1 and 10.9 episodes/100 treatment weeks, respectively, with 1alphaD2 treatment. There were no adverse events in asso

Topics: Administration, Oral; Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Phosphorus; Renal Dialysis

Calcitriol is effective in suppressing PTH levels in haemodialysis patients with hyperparathyroidism but has a low therapeutic index. There is a search for other vitamin D sterols that suppress PTH but cause less hypercalcaemia. We review evidence that 1 alpha-hydroxy-vitamin D2 (1 alpha-D2) may be an effective and safer alternative to calcitriol. In vitamin D-deficient rats, 1 alpha-D2 is equipotent to 1 alpha-D3, which is converted to calcitriol before it acts; but, in normal rats, 1 alpha-D2 is much less toxic at high doses. In osteopenia models, either steroid-induced or following ovariectomy, 1 alpha-D2 is equal to or more effective than 1 alpha-D3 in preventing bone loss but causes less hypercalciuria. Studies in osteoporotic women reveal minimal hypercalciuria with 1 alpha-D2 at doses up to 4 micrograms/day, data suggesting greater safety than reported with calcitriol or 1 alpha-D3. Preliminary data in haemodialysis patients with secondary hyperparathyroidism demonstrate the efficacy of 1 alpha-D2 in suppressing PTH levels with minimal untoward effects on serum Ca and no effects on serum P. Taken together, these observations suggest that 1 alpha-D2 deserves strong consideration as a therapeutic agent for secondary hyperparathyroidism associated with end-stage renal disease.

Topics: Animals; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Osteoporosis, Postmenopausal; Parathyroid Hormone; Phosphates; Rats; Renal Dialysis

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Topics: Chronic Disease; Combined Modality Therapy; Dihydroxycholecalciferols; Ergocalciferols; Female; Homeostasis; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Mesenchymoma; Middle Aged; Osteomalacia; Phosphates; Soft Tissue Neoplasms

Topics: 25-Hydroxyvitamin D 2; Animals; Calcifediol; Calcitriol; Calcium; Cyclic AMP; Ergocalciferols; Glomerular Filtration Rate; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Hypoparathyroidism; Mathematics; Methods; Parathyroid Diseases; Parathyroid Hormone

Current status of our understanding of the metabolism of vitamin D and its implications in metabolic bone disease is reviewed. The details of metabolism of vitamin D3 to 25-hydroxyvitamin D3 in the liver and its further conversion in the kidneys to either 1,25-dihydroxyvitamin D3 or 24,25-dihydroxyvitamin D3 are presented. The latter conversions are regulated by the vitamin D status, serum calcium through the parathyroid gland system, and serum inorganic phosphorus concentration. The 1,25-dihydroxyvitamin D3 can now be regarded as a calcium- and a phosphate-mobilizing hormone and must be considered as one of the most important serum calcium-regulating hormones. Disruption of the vitamin D metabolic sequence or the signal system for 1,25-dihydroxyvitamin D3 results in several bone and calcium metabolism disorders such as renal osteodystrophy, hypoparathyroidism, pseudohypoparathyroidism, and vitamin D-dependency rickets. The use of the synthetic analogs of 1,25-dihydroxyvitamin D3 as well as 1,25-dihydroxyvitamin D3 itself in the management of these disease states is discussed.

Topics: Animals; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Endocrine Glands; Ergocalciferols; Homeostasis; Humans; Hyperparathyroidism, Secondary; Intestinal Absorption; Kidney; Phosphates; Vitamin D

Topics: Bone Diseases; Calcinosis; Chronic Kidney Disease-Mineral and Bone Disorder; Diet Therapy; Ergocalciferols; Fibrous Dysplasia of Bone; Fractures, Spontaneous; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Kidney Transplantation; Metabolic Diseases; Osteomalacia; Osteosclerosis; Parathyroid Glands; Phosphates; Renal Dialysis; Tendon Injuries; Vitamin D

Topics: Aged; Aged, 80 and over; Calcifediol; Cardiovascular Diseases; Cost-Benefit Analysis; Delayed-Action Preparations; Ergocalciferols; Female; Fractures, Bone; Health Expenditures; Humans; Hyperparathyroidism, Secondary; Male; Markov Chains; Medicare; Quality-Adjusted Life Years; Renal Insufficiency, Chronic; Risk Factors; United States

Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD.. Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis.. In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 μg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children.. Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 μg paricalcitol 3 times weekly in children aged 10-16 years.

Topics: Adolescent; Bone Density Conservation Agents; Calcium; Child; Double-Blind Method; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Male; Parathyroid Hormone; Phosphorus; Renal Dialysis; Treatment Outcome

Management of secondary hyperparathyroidism (SHPT) in dialysis population includes the use of active vitamin D forms, among which paricalcitol was shown to be more effective at reducing parathyroid hormone (PTH) concentrations. A prospective randomized study comparing the effectiveness and safety of peroral paricalcitol and calcitriol in suppressing PTH concentrations in 20 hemodialysis patients was performed comparing the influence of agents on PTH suppression, calcium (Ca) and phosphate (P) level and calcium-phosphorus product (C×P). The study was performed in an "intent to treat" manner with primary end point in reduction of PTH level in the target area of 150 > PTH < 300 ng/L after 3 months. At the time point 3 months after therapy induction paricalcitol and calcitriol were equally efficient at correcting PTH levels, with paricalcitol showing significantly less calcemic effect than calcitriol.

Topics: Administration, Oral; Calcitriol; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prospective Studies; Renal Dialysis; Time Factors; Treatment Outcome

Many patients with chronic kidney disease are prescribed vitamin D receptor agonists (VDRAs) for the management of secondary hyperparathyroidism. Oral phosphate binders may interact with, and potentially reduce the therapeutic activity of, oral VDRAs. This post hoc analysis of a Phase 3 study evaluated the pharmacodynamic effects of the iron-based phosphate binder sucroferric oxyhydroxide (SFOH) and sevelamer (SEV) carbonate on VDRA activity in dialysis patients.. One thousand and fifty nine patients were randomized to SFOH 1.0-3.0 g/day (n = 710) or SEV 2.4-14.4 g/day (n = 349) for up to 52 weeks. Potential interactions of SFOH and SEV with VDRAs were assessed using serum intact parathyroid hormone (iPTH) concentrations as a pharmacodynamic biomarker. Three populations of SFOH- and SEV-treated patients were analyzed: Population 1 (n = 187), patients taking concomitant stable doses of oral VDRAs only; Population 2 (n = 250), patients taking no concomitant VDRAs; Population 3 (n = 68), patients taking concomitant stable doses of intravenous paricalcitol only. Populations were compared using a mixed-effects model to obtain the least squares mean change in iPTH from baseline to Week 52. Differences between treatment groups were also compared.. In Population 1, iPTH decreased from baseline to Week 52 in the SFOH group (-25.3 pg/ml) but increased in the SEV group (89.8 pg/ml) (p = 0.02). In Population 2, iPTH increased to a similar extent in both treatment groups. In Population 3, iPTH concentrations in both treatment groups decreased to a similar degree (-29.6 and -11.4 pg/ml for SFOH and SEV, respectively; p = 0.87).. In contrast with SEV, SFOH did not appear to impact the iPTH-lowering effect of oral VDRAs.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Biomarkers, Pharmacological; Bone Density Conservation Agents; Chelating Agents; Drug Combinations; Drug Interactions; Ergocalciferols; Female; Ferric Compounds; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Male; Middle Aged; Parathyroid Hormone; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sucrose

Active Vitamin D analogues are used clinically for prevention and treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. Nutritional vitamin D supplementation is used for additional local parathyroid (PTH) suppression, with lower incidence of hypercalcemia and hyperphosphatemia. This study evaluates the possible beneficial effects of combined vitamin D treatment (paricalcitol and cholecalciferol).. Sixty HD patients with serum parathyroid hormone (iPTH) >300 pg/mL were enrolled. All patients administered 2 mcg/day of paricalcitol and were randomly allocated into control group (placebo) or study group (cholecalciferol) for 16 weeks. Serum 25(OH)D₃, iPTH and human cathelicidin (hCAP-18) were measured at baseline and during follow-up.. iPTH levels decreased in the study group appropriately and were more significantly decreased at 16 weeks. Study group had significantly increased 25(OH)D₃ levels. In addition, the study group had significantly increased serum hCAP-18 levels compared with control group. Correlation analysis showed a significant correlation between the percentage increase in serum hCAP-18 and 25(OH)D₃ levels.. Cholecalciferol, in combination with paricalcitol, additively lowers the iPTH levels in a significant number of patients after 16 weeks of supplementation. A dose of 5000 IU/week of cholecalciferol could maintain serum 25(OH)D₃ levels above 30 ng/dL as early as 8 weeks after beginning supplementation. Doubling of serum cathelicidin levels were noted after 16 weeks of cholecalciferol supplementation in 40% of study patients.

Topics: Aged; Antimicrobial Cationic Peptides; Calcifediol; Cathelicidins; Cholecalciferol; Drug Interactions; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Placebos; Renal Dialysis; Treatment Outcome; Vitamin D

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.

Topics: Adult; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Calcium; Creatinine; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Phosphates; Postoperative Complications; Prospective Studies; Proteinuria; Vitamin D

Secondary hyperparathyroidism (SHPT) is one of the major complications of chronic kidney disease (CKD) and is associated with elevated serum intact parathyroid hormone (iPTH). Calcitriol, a non-selective vitamin D receptor agonist (VDRA) that suppresses iPTH is used for SHPT treatment, but its use is frequently complicated by hypercalcemia. Paricalcitol, a selective VDRA, demonstrated efficacy in iPTH suppression compared to maxacalcitol in a Phase 2 study (M11-609) in Japanese subjects. The current larger Phase 3 study (M11-517), evaluated the efficacy of intravenous paricalcitol injection compared to intravenous maxacalcitol injection with respect to iPTH and calcium control using a non-inferiority primary endpoint. In this double-blind, double-dummy, parallel-group study, eligible Japanese CKD subjects with SHPT on hemodialysis were randomized 1:1 to receive intravenous paricalcitol or intravenous maxacalcitol injections for 12 weeks. Dynamic allocation of subjects on the basis of screening iPTH levels was used to ensure equal distribution of subjects with iPTH <500 pg/mL and ≥500 pg/mL into the two treatment groups. 255 subjects were randomized to receive paricalcitol (N = 127) or maxacalcitol (N = 128). Primary efficacy analysis indicated that 27.7% in the paricalcitol group vs. 30.5% in the maxacalcitol group (95% CI -14.34% to 8.79%, P = 0.353) achieved target iPTH in the last 3 weeks without hypercalcemia during treatment, failing to achieve the non-inferiority margin of -5% that was set based upon agreement with the PMDA. Both intravenous paricalcitol and maxacalcitol were effective in reducing iPTH and provided similar safety profiles; however, non-inferiority for paricalcitol vs. maxacalcitol was not demonstrated.

Topics: Aged; Calcitriol; Calcium; Double-Blind Method; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Injections, Intravenous; Male; Middle Aged; Parathyroid Hormone; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic

Vitamin D deficiency/insufficiency is common in chronic kidney disease (CKD) patients and it contributes to secondary hyperparathyroidism, which occurs early in CKD. It is not clear whether the Kidney Disease Outcomes Quality Initiative (K/DOQI) recommended doses of ergocalciferol are adequate for correction of vitamin D insufficiency and hyperparathyroidism.. To evaluate the parathyroid hormone (PTH)-lowering effect, safety, and tolerability of high-dose ergocalciferol compared with conventional-dose ergocalciferol in CKD subjects.. We enrolled CKD stage III-IV patients who had 25-hydroxyvitamin D (25-OH-D) level <30 ng/mL. The patients were randomized into two groups, control group treated with ergocalciferol as recommended by K/DOQI guidelines, and treatment group treated with double dosage of ergocalciferol from the recommendation. We compared serum 25-OH-D, intact-PTH, phosphate, calcium, and bone biomarker levels, during the 8-week intervention.. Sixty-eight patients were included (34 controls and 34 treatments). Baseline characteristics of both groups were similar except calcium level 9.12 ± 0.56 mg/dL in control group and 9.44 ± 0.38 mg/dL in treatment group (p = 0.009), but not clinically significant. At the end of the 8-week, the mean 25-OH-D level significantly increased from 20.99 ± 6.68 to 33.41 ± 8.92 ng/mL in the treatment group (p = 0.001) and increased from 20.84 ± 7.21 to 23.42 ± 7.89 ng/mL in the control group (p = 0.026). There was also a significantly greater increase of 25-OH-D levels in the treatment group. Additionally, PTH levels significantly decreased from 90.75 ± 67.12 to 76.40 ± 45.97 at 8 weeks (p = 0.024) in the treatment group, and there was no change in the control group (97.14 ± 83.52 vs. 101.13 ± 95.03 pg/mL, p = 0.546). Serum calcium, phosphate, and adverse effects did not significantly change in either group throughout the study.. In addition to improving vitamin D levels, oral high-dose ergocalciferol was safe and had a beneficial effect in decreasing PTH in patients with stage III-IV of CKD.

Topics: Aged; Aged, 80 and over; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

Secondary hyperparathyroidism (SHPT) is common in end-stage renal disease. Our primary objective was to evaluate the efficacy of oral paricalcitol versus oral calcitriol on serum intact parathyroid hormone (iPTH) and mineral bone parameters in continuous ambulatory peritoneal dialysis (CAPD) patients with SHPT. The secondary objective was to analyze highly sensitive C-reactive protein (hsCRP) and peritoneal membrane function in both groups.. This was a prospective randomized control trial. CAPD patients with SHPT were randomized to paricalcitol or calcitriol for 15 weeks. Serum intact iPTH, calcium, phosphate and alkaline phosphatase (ALP) were measured at baseline and every 3 weeks. Serum hsCRP and peritoneal membrane functions were measured at baseline and at week 15.. A total of 26 patients were enrolled and randomized-12 to paricalcitol and 14 to calcitriol. Serum iPTH reduced significantly in both groups and there was no difference in the incidence of ≥50 % reduction of iPTH between both groups. There was a significant increase in serum calcium in both groups but there were no differences in serum phosphorus across the visits. The incidence of hypercalcemia was the same in both groups. Serum calcium-phosphorus (Ca × P) product increased in the paricalcitol group but decreased in the calcitriol group. Serum ALP decreased significantly in both groups. There were also no differences in pre- and post-treatment serum hsCRP and peritoneal function test (PFT) in both groups.. Both oral paricalcitol and calcitriol were equally efficacious in reducing serum iPTH but were associated with significantly higher serum calcium. Serum Ca × P product increased in the paricalcitol group and decreased in the calcitriol group. Serum hsCRP level and PFT were not affected by either treatment. A larger randomized controlled trial is indicated to confirm these initial findings.

Topics: Administration, Oral; Adult; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcitriol; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Prospective Studies; Treatment Outcome

Prevalence of secondary hyperparathyroidism (SHPT), a renal disease complication, is increasing in China. Available therapies may not optimally control SHPT, particularly in patients with hypercalcemia, hyperphosphatemia, and parathyroid hyperplasia. This study examined efficacy and safety of two dosing regimens of selective vitamin D receptor activator paricalcitol.. Subjects with SHPT (n = 216) undergoing hemodialysis were treated with paricalcitol i.v. for 12 weeks. One group was treated according to the EU paricalcitol package insert (PI) (initial μg dose based on iPTH/80), and the other was treated according to the US PI (initial dose of 0.04 μg/kg). Dose titration was based on iPTH and serum calcium (Ca) and phosphorus (P) levels.. The primary endpoint of two consecutive ≥ 30% iPTH decreases was achieved by 88.6% and 55.9% of subjects in the EU and US PI groups, respectively. Noninferiority of the EU PI group vs. the US PI group was demonstrated (lower bound of the 1-sided 97.5% CI = 21.3%). Superiority of the EU PI group was shown (lower limit > 0%) and confirmed by Fisher's exact test (p < 0.001); both groups showed similar achievement of recommended KDIGO iPTH levels. Ca and P levels were relatively constant.. Both EU and US PI paricalcitol dosing strategies effectively reduced iPTH levels in Chinese subjects with SHPT, with minimal impact on Ca and P levels.

Topics: Adult; Aged; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Single-Blind Method

The IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments.. The aim of this study was to compare the cost effectiveness of a paricalcitol-based regimen versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients from a US payer perspective, using a 1-year time horizon.. This was a post hoc cost-effectiveness analysis of data collected for US patients enrolled in the IMPACT SHPT study-a 28-week, randomized, open-label, phase 4, multinational study (ClinicalTrials.gov identifier: NCT00977080). Patients eligible for the IMPACT SHPT study were aged≥18 years with stage 5 chronic kidney disease, had been receiving maintenance haemodialysis three times weekly for at least 3 months before screening and were to continue haemodialysis during the study. Only US patients who reached the evaluation period (weeks 21-28) were included in this secondary analysis. US subjects in the IMPACT SHPT study were randomly assigned to receive intravenous paricalcitol, or oral cinacalcet plus fixed-dose intravenous doxercalciferol, for 28 weeks. Patients in the paricalcitol group could also receive supplemental cinacalcet for hypercalcaemia. The primary effectiveness endpoint in the IMPACT SHPT study was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) level of 150-300 pg/mL during the evaluation period. In this secondary analysis, we estimated the incremental cost-effectiveness ratio (ICER), comparing paricalcitol-treated patients with cinacalcet-treated patients on the basis of this primary endpoint and several secondary endpoints. Costs were estimated by examining the dosage of the study drug (paricalcitol or cinacalcet) and phosphate binders used by each participant during the trial. Nonparametric bootstrap analysis was used to examine the accuracy of the ICER point estimates.. The percentages of patients achieving the treatment goal of a mean iPTH level between 150-300 pg/mL during weeks 21-28 of therapy were 56.9% in the paricalcitol group and 34.0% in the cinacalcet group (a difference of 23%, p=0.0235). Paricalcitol was also more effective for each of the secondary endpoints. When annualized, the total drug costs were US$10,153 in the paricalcitol group and US$15,967 in the cinacalcet group, a difference of US$5,814 (57.3%, p=0.0053). Because the paricalcitol-based treatment was less expensive and more effective, it was 'dominant', compared with cinacalcet, in this cost-effectiveness analyses. In our bootstrap analysis, 99.1% of bootstrap replicates for the ICER of the primary endpoint fell within the lower right quadrant of the cost-effectiveness plane-where paricalcitol is considered dominant. For all of the other endpoints, paricalcitol was dominant in 100% of replicates.. On the basis of dosing and effectiveness data from US patients in the IMPACT SHPT study, we found that a regimen of intravenous paricalcitol was more cost effective than cinacalcet plus low-dose vitamin D in the management of iPTH in patients with SHPT requiring haemodialysis.

Topics: Administration, Intravenous; Administration, Oral; Aged; Bone Density Conservation Agents; Cinacalcet; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Naphthalenes; Renal Dialysis; Treatment Outcome; United States; Vitamin D

In this Phase 4 international study, efficacy and safety of paricalcitol-centred therapy were compared with that of cinacalcet-centred therapy for the treatment of chronic kidney disease (CKD)-associated secondary hyperparathyroidism (SHPT) in patients undergoing haemodialysis (ClinicalTrials.gov identifier NCT00977080).. Patients ≥ 18 years of age with Stage 5 CKD and SHPT [intact parathyroid hormone (iPTH) level of 300-800 pg/mL, calcium level of 8.4-10.0 mg/dL and phosphate concentration of ≤ 6.5 mg/dL] who were undergoing haemodialysis were included. Patients were randomized by mode of paricalcitol administration [i.e. intravenous (IV) or oral strata] to receive paricalcitol- or cinacalcet-centred therapy for ≤ 28 weeks. Changes in metabolic markers [total alkaline phosphatase (AP), bone-specific AP and fibroblast growth factor-23 (FGF-23)] and the proportion of patients in each treatment group who achieved an iPTH level of 150-300 pg/mL during Weeks 8, 16 and 21-28 as a composite value were evaluated.. Compared with cinacalcet-centred therapy, levels of both bone turnover markers were significantly reduced from baseline with IV and oral paricalcitol-centred treatment (P < 0.05 for both dosing strata) at Weeks 8, 16 and 28. Levels of FGF-23 were increased with paricalcitol versus cinacalcet-centred treatment. A greater proportion of patients receiving paricalcitol-centred therapy achieved target iPTH levels (i.e. 150-300 pg/mL) throughout the study in the IV and oral dosing strata compared with patients receiving cinacalcet-centred treatment.. In patients with CKD and SHPT undergoing haemodialysis, paricalcitol-centred therapy reduced circulating bone turnover markers and iPTH levels and increased FGF-23 levels compared with cinacalcet-centred treatment.. ClinicalTrials.gov identifier NCT00977080.

Topics: Aged; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Cinacalcet; Dose-Response Relationship, Drug; Ergocalciferols; Female; Fibroblast Growth Factor-23; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%.. Patients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.. Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.. These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Topics: Aged; Calcitriol; Ergocalciferols; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Incidence; Kidney Failure, Chronic; Middle Aged

Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease and frequently persists after kidney transplantation. Paricalcitol, a selective vitamin D receptor activator, is indicated in the management of this disorder and recent evidences have suggested that this drug has other beneficial effects. Aiming to elucidate these effects, our study included 52 stable kidney transplant recipients randomized 2:1 to treatment with paricalcitol or to no treatment. Bone mineral parameters, kidney function and inflammatory status were assessed at baseline, at 3 and at 12 months. Moreover, a proteomic approach, based on magnetic beads technology coupled to MALDI-TOF mass spectrometry readout, was used to determine changes in patients' plasma peptidome. Patients treated with paricalcitol showed a significant decrease in parathyroid hormone and alkaline phosphatase levels, and an increase of bone mineral density and glomerular filtration rate. The proteomic analysis revealed a decrease in bradykinin after paricalcitol treatment, whereas 2 peptides identified as fragments of the complement factor C4 decreased only in those patients not treated with paricalcitol. These findings suggest that paricalcitol may offer additional benefits due to immunomodulatory effects via the kallikrein-kinin and complement systems.

Topics: Aged; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Resorption; Bradykinin; Complement C4; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Phenomena; Male; Microspheres; Middle Aged; Peptide Fragments; Proteomics; Receptors, Calcitriol; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Postkidney transplant hyperparathyroidism is a significant problem. Vitamin D receptor agonists are known to suppress parathyroid hormone (PTH) secretion. We examined the effect of oral paricalcitol on posttransplant secondary hyperparathyroidism by conducting an open label randomized trial in which 100 incident kidney transplant recipients were randomized 1:1 to receive oral paricalcitol, 2 μg per day, for the first year posttransplant or no additional therapy. Serial measurements of serum PTH, calcium and bone alkaline phosphatase, 24-h urine calcium and bone density were performed. The primary endpoint was the frequency of hyperparathyroidism 1-year posttransplant. Eighty-seven patients completed the trial. One-year posttransplant, 29% of paricalcitol-treated subjects had hyperparathyroidism compared with 63% of untreated patients (p = 0.0005). Calcium supplementation was discontinued in two control and 15 treatment patients due to mild hypercalcemia or hypercalcuria. Paricalcitol was discontinued in four patients due to hypercalcuria/hypercalcemia and in one for preference. Two subjects required decreasing the dose of paricalcitol to 1 μg daily. Hypercalcemia was asymptomatic and reversible. Incidence of acute rejection, BK nephropathy and renal function at 1 year were similar between groups. Moderate renal allograft fibrosis was reduced in treated patients. Oral paricalcitol is effective in decreasing posttransplant hyperparathyroidism and may have beneficial effects on renal allograft histology.

Topics: Administration, Oral; Bone Density Conservation Agents; Dose-Response Relationship, Drug; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Minnesota; Prevalence; Prospective Studies; Treatment Outcome

The objective of this analysis was to compare costs of paricalcitol or cinacalcet plus low dose vitamin D, and of phosphate binders, in patients in the IMPACT SHPT study; and to extrapolate those to estimate expected annual maintenance costs.. IMPACT SHPT was a 28-week, randomized, open-label trial. Subjects from 12 countries received intravenous (IV) or oral paricalcitol, or oral cinacalcet plus fixed IV doxercalciferol or oral alfacalcidol. The primary end-point was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) value of 150-300 pg/mL during weeks 21-28 (evaluation period). This study compares the costs of study drugs and phosphate binders among participants during the study and annualized. This analysis includes only those subjects that reached the evaluation period (134 in each group).. The mean total drug costs over the study period were €2606 (SD = €2000) in the paricalcitol group and €3034 (SD = €3006) in the cinacalcet group (difference €428, p = 0.1712). The estimated annualized costs were €5387 (SD = €4139) in the paricalcitol group and €6870 (SD = €6256) in the cinacalcet group (difference €1492, p = 0.0395). In addition, a significantly greater proportion (p = 0.010) of subjects in the paricalcitol arm (56.0%) achieved an iPTH of 150-300 pg/mL during the evaluation period compared to the cinacalcet arm (38.2%).. This was a secondary analysis of the IMPACT SHPT study which was not designed or powered for costs as an outcome. The dosing of study drugs and phosphate binders in the IMPACT study may not reflect actual practice, and patients were followed for 28 weeks, while the treatment of SHPT is long-term.. Patients with SHPT requiring hemodialysis who were treated with a paricalcitol-based regimen for iPTH control had lower estimated annual drug costs compared to those treated with cinacalcet plus low-dose vitamin D.

Topics: Administration, Oral; Aged; Cinacalcet; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Ergocalciferols; Female; Follow-Up Studies; Health Care Costs; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Naphthalenes; Prospective Studies; Renal Dialysis; Treatment Outcome; Vitamin D

Existing treatment of proteinuria is not sufficient to halt the chronic kidney disease (CKD) epidemic. Therefore the aim of our study was to evaluate the effect of paricalcitol on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Forty-one non-dialysis CKD patients with secondary hyperparathyroidism (iPTH >65 pg/mL), serum calcium <2.6 mmol/L, serum phosphate <1.8 mmol/L and proteinuria (>150 mg/day) were treated with paricalcitol 1 μg/day. Most were treated for 6 months, with the exception of three patients having iPTH <30 pg/mL after 3 months, in whom therapy was stopped. All patients were followed for 6 months. 24-h ambulatory blood pressure (24hABP) monitoring was performed at 0 and 6 months. Fixed doses of ACE inhibitors and/or ARBs and/or statins were kept for 3 months before and during the study. Forty-one patients (30 men, 11 women; age 62.44 ± 11.93 years) with different primary causes of CKD were enrolled in the study. Urinary albumin/creatinine ratio (UACR), 24-h urinary albuminuria (24hUA) and 24-h urinary quantitative proteinuria (24hUQP) were measured. Values at 0 and 6 months of these parameters were log-transformed for statistical analysis. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) were found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 μg paricalcitol daily according to clinical practice in non-dialysis CKD patients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Bone Density Conservation Agents; Creatinine; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Practice Guidelines as Topic; Proteinuria; Renal Insufficiency, Chronic; Time Factors

The objective of the study was to compare the efficacy and safety of oral paricalcitol with oral calcitriol for treating secondary hyperparathyroidism.. We conducted the first multicenter open-labelled parallel group randomized controlled trial in 66 patients on dialysis. Patients were randomized to paricalcitol or calcitriol at a 3:1 dose ratio and adjusted to maintain intact parathyroid hormone (iPTH) level between 150-300 pg/mL, serum calcium ≤2.74 mmol/L and calcium-phosphate product ≤5.63 mmol(2) /L(2). The primary end point was the proportion of patients who achieved >30% reduction in iPTH.. At 24 weeks, 22 (61.1%) patients in the paricalcitol and 22 (73.3%) in the calcitriol group had achieved the primary end-point (P-value = 0.29). The cumulative proportion of patients who achieved the end-point at 6 weeks, 12 weeks and 24 weeks were 50%, 80.6% and 86.1%, respectively, in paricalcitol and 53.3%, 86.7% and 86.7%, respectively, in the calcitriol group (P-value = 0.67). Median time to the end-point was 6 weeks in both groups. There were no significant differences in iPTH level at any time during the study. The median reduction in iPTH at 24 weeks was 48.4% in the paricalcitol group and 41.9% in the calcitriol group (P-value = 0.6). The median maximal iPTH reduction was 77.1% (paricalcitol) and 83.7% (calcitriol), P-value = 0.3. Serum calcium and incidence of hypercalcaemia did not differ between groups. 16.7% of patients in both groups had at least one episode of hypercalcaemia (serum calcium >2.74 mmol/L). Other adverse events were similar between groups.. Our study suggests that oral paricalcitol has similar efficacy and safety to oral calcitriol.

Topics: Administration, Oral; Adult; Alkaline Phosphatase; Analysis of Variance; Biomarkers; Calcitriol; Calcium; Chi-Square Distribution; Down-Regulation; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kaplan-Meier Estimate; Kidney Failure, Chronic; Malaysia; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis; Time Factors; Treatment Outcome

The efficacy of 25-hydroxyvitamin D (25[OH]D) supplementation versus vitamin D receptor activators for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stages 3 or 4 and vitamin D deficiency is unclear.. Randomized controlled trial.. 80 patients with CKD stages 3 or 4, 25(OH)D level <30 ng/mL, and SHPT in a single medical center.. Ergocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL versus paricalcitol, 1 or 2 μg/d, for 16 weeks.. The occurrence of 2 consecutive parathyroid hormone (PTH) levels decreased by at least 30% from baseline. All analyses were intention to treat.. Baseline characteristics in the 2 groups were similar. 21 patients (53%) on paricalcitol and 7 patients (18%) on ergocalciferol treatment achieved the primary outcome measure (P = 0.002). After 16 weeks, PTH levels did not decrease significantly in patients receiving ergocalciferol, but were decreased significantly in those treated with paricalcitol (mean estimate of between-group difference over 16 weeks of therapy, 43.9 pg/mL; 95% CI, 11.2-76.6; P = 0.009). Serum 25(OH)D levels increased significantly after 16 weeks in only the ergocalciferol group, but not the paricalcitol group (mean estimate of between-group difference over 16 weeks of therapy, 7.08 ng/mL; 95% CI, 4.32-9.85; P < 0.001). Episodes of hyperphosphatemia and hypercalcemia were not significantly different between the 2 groups.. Lack of blinding and use of surrogate end points.. Paricalcitol is more effective than ergocalciferol at decreasing PTH levels in patients with CKD stages 3 or 4 with vitamin D deficiency and SHPT.

Topics: Aged; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Renal Insufficiency, Chronic; Severity of Illness Index; Vitamins

Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT.. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300-800 pg/mL, calcium 8.4-10.0 mg/dL (2.09-2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150-300 pg/mL during Weeks 21-28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint.. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%).. The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Bone Density Conservation Agents; Calcimimetic Agents; Cinacalcet; Cohort Studies; Disease Management; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Naphthalenes; Practice Guidelines as Topic; Renal Dialysis; Treatment Outcome; Vitamin D

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Biological Availability; Calcium; Capsules; Double-Blind Method; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Injections; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

Fibroblast growth factor 23 (FGF23) increases renal phosphate excretion and decreases the formation of 1,25 dihydroxyvitamin D. In patients with chronic kidney disease, plasma FGF23 levels are markedly elevated by unknown mechanisms. We explored the changes in FGF23 during treatment of secondary hyperparathyroidism (SHPT) with alfacalcidol or paricalcitol in haemodialysis patients.. Intravenous alfacalcidol and paricalcitol were compared in haemodialysis patients with SHPT in a randomized 2 × 16-week cross-over study, with 6 weeks washout period preceding treatment and between treatment periods. In 57 of the enrolled patients, blood samples were frozen before and after each treatment period and available for measurement of FGF23.. Treatment with both analogues increased FGF23 (P < 0.05 in all treatment periods). The magnitude of increase was similar for alfacalcidol and paricalcitol (Period 1: 223 versus 314%; P = 0.384 and Period 2: 174 versus 227%; P = 0.510) and the levels returned to pre-treatment levels during the washout period. Independent predictors of rise in FGF23 were baseline levels of FGF23 (P < 0.01), changes in ionized calcium (P < 0.01) and phosphate (P < 0.01) and cumulative dose of vitamin D analogues (P = 0.024).. Alfacalcidol and paricalcitol increase the plasma levels of FGF23 equally and substantially in haemodialysis patients.

Topics: Aged; Bone Density Conservation Agents; Calcium; Cross-Over Studies; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis

Data are limited regarding the use of paricalcitol in calcitriol-resistant patients with secondary hyperparathyroidism (SHPT). We aimed to evaluate the effects of paricalcitol in calcitriol-resistant hemodialysis patients with SHPT.. This is a 12-month, open-label, prospective study. Forty patients with calcitriol-resistant and/or calcitriol-intolerant SHPT were included. After a washout period, all patients converted to paricalcitol with a 1:3 conversion ratio. Serum calcium and phosphorus were monitored monthly, while serum intact parathyroid hormone (iPTH) once in every 3 months. Paricalcitol dose was reduced or discontinued in case of hypercalcemia and/or hyperphosphatemia. Pre- and posttreatment electrolyte and iPTH values were compared with Student's t-test and Wilcoxon signed-rank test, respectively.. Forty patients completed the study. Mean initiation dose of paricalcitol was 23 ± 7 μg/week. Mean serum calcium was 8.9 ± 0.8 mg/dL at baseline and 9.4 ± 0.7 mg/dL at study end (p = 0.07). Mean monthly serum phosphorus levels stayed stable. Paricalcitol was effective in reducing iPTH levels when compared with pretreatment values (747.9 ± 497.2 pg/mL, 307.3 ± 417.1 pg/mL, respectively; p < 0.001). Thirty-two patients had to discontinue intravenous (IV) paricalcitol at some time during their treatment. Main reasons for discontinuation were as follows: hyperphosphatemia (58%), hypercalcemia (25%), and iPTH < 150 pg/mL (17%).. Paricalcitol was found to be effective in reducing iPTH levels in calcitriol-resistant patients with SHPT despite relatively frequent drug discontinuation rates.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Density Conservation Agents; Calcitriol; Dose-Response Relationship, Drug; Drug Resistance; Drug Tolerance; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Renal Dialysis; Time Factors; Treatment Outcome; Young Adult

Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism.. A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism.. Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median follow-up was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels >100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D.. Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.

Topics: Adolescent; Analysis of Variance; Biomarkers; Chi-Square Distribution; Child; Child, Preschool; Chronic Disease; Dietary Supplements; Double-Blind Method; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kaplan-Meier Estimate; Kidney Diseases; London; Male; Odds Ratio; Placebos; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Vitamin D analogs are used for treatment of secondary hyperparathyroidism in patients with chronic kidney disease in order to prevent renal osteodystrophy, bone fracture and pain. Calcium and phosphate levels increase with increasing doses of vitamin D analogs and are associated with increased risk of vascular calcification and cardiovascular morbidity and mortality. Therefore, in everyday clinical practice, hypercalcemia and hyperphosphatemia often limits the ability to suppress secondary hyperparathyroidism in patients with chronic kidney disease. In Denmark, alfacalcidol and paricalcitol are the most frequently used vitamin D analogs. The present thesis describes the first comparative study of alfacalcidol and paricalcitol and their ability to control the disturbances in the mineral metabolism in hemodialysis patients. In a multicenter randomised 2 × 16-week cross-over study (n = 86), with a 6-week wash out period preceding and between treatment periods, intravenous alfacalcidol and paricalcitol were given by forced titration (50% dose increase) every second week, until parathyroid hormone were sufficiently suppressed or ionised calcium and/or phosphate levels were elevated. Due to the presence of a period effect, only data from the initial 16-week intervention period (n = 80) were available for statistical tests of effect on parathyroid hormone. The proportion of patients achieving a 30% decrease in parathyroid hormone over the last four weeks was similar in the two groups (alfacalcidol 82%, paricalcitol 93% (p = 0.180)). A significant interaction effect between baseline parathyroid hormone and treatment was found (p = 0.012), suggesting the effects of alfacalcidol to be independent of baseline parathyroid hormone level, whereas paricalcitol to be more efficient at low than at high baseline levels. There were no differences in incidence of hypercalcemia and hyperphosphatemia. FGF23 increases renal phosphate excretion and decreases levels of 1,25-dihydroxyvitamin D. FGF23 is elevated in hemodialysis patients by mechanisms not fully understood. We explored the influence of alfacalcidol and paricalcitol on FGF23 in stored blood samples from the beginning and the end of each treatment period. FGF23 increased significantly and equally during treatment with alfacalcidol and paricalcitol. Furthermore, we found baseline FGF23 to predict PTH levels after 16 weeks of vitamin D analog treatment. Overall, alfacalcidol and paricalcitol are equal candidates

Topics: Aged; Animals; Bone Density Conservation Agents; Cross-Over Studies; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Middle Aged; Parathyroid Hormone; Renal Dialysis

Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking.. To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2).. Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010.. Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112).. Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function.. Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.. Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease.. clinicaltrials.gov Identifier: NCT00497146.

Topics: Aged; Chronic Disease; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Treatment Outcome; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Optimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT (ClinicalTrials.gov identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis.. In this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150-300 pg/mL during Weeks 21-28.. Of 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21-28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P = 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P = 0.260). Cochran-Mantel-Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P = 0.010) in achieving iPTH 150-300 pg/mL during Weeks 21-28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively.. Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.

Topics: Administration, Intravenous; Administration, Oral; Aged; Bone Density; Bone Density Conservation Agents; Calcium; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Vitamin D

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcifediol; Calcium; Drug Therapy, Combination; Ergocalciferols; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Phosphorus; Renal Dialysis

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

Topics: Adolescent; Bone and Bones; Bone Density Conservation Agents; Calcitriol; Calcium Carbonate; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Therapy, Combination; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Longitudinal Studies; Male; Osteogenesis; Parathyroid Hormone; Polyamines; Sevelamer

Vitamin D receptor activator (VDRA) therapy has been shown to be associated with reduced mortality rates in chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT). However, differences between VDRAs in their ability to reduce both all-cause and cardiovascular-related mortality rates are not yet fully elucidated.. The objective of the current analysis was to determine the effect of VDRA therapy on mortality in an Italian dialysis population, observed prospectively every 6 months for 18 months. Patients were investigated for all-cause and cardiovascular-related mortality risk adjusted for various demographic, clinical, and/or SHPT treatment variables.. The cumulative probabilities of all-cause and cardiovascular-related mortality were lower for patients who received any VDRA treatment compared with those who did not (p < 0.001) regardless of all measured variables. Additionally, patients who received paricalcitol and/or cinacalcet (with or without VDRAs) compared with calcitriol showed a significant improvement in both all-cause and cardiovascular-related mortality (p < 0.001). Cinacalcet with or without VDRAs was not associated with a further decrease of mortality hazard ratios compared with paricalcitol monotherapy.. VDRA therapy (associated or not with cinacalcet) was associated with improved survival in dialysis patients, independent of demographic and clinical variables.

Topics: Aged; Calcitriol; Cardiovascular Diseases; Cinacalcet; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Italy; Kidney Failure, Chronic; Male; Middle Aged; Naphthalenes; Odds Ratio; Prospective Studies; Renal Dialysis; Risk Factors; Survival Rate; Vitamins

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.

Topics: Adult; Aged; Calcium; Cross-Over Studies; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis

The optimal treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) is unknown.. We conducted a randomized, blinded, 3-month trial in vitamin D-deficient CKD stage 3 and 4 patients with parathyroid hormone (PTH) values above the Kidney Disease Outcomes Quality Initiative target, comparing cholecalciferol (4000 IU/d x 1 month, then 2000 IU/d; n = 22) to doxercalciferol (1 microg/d; n = 25).. There was no difference in baseline demographics or lab tests, except a slightly higher estimated GFR (eGFR) in the doxercalciferol group. There was a significant increase in vitamin D level in the cholecalciferol group (14 +/- 6 to 37 +/- 10 ng/ml; P < 0.001) but no change in the doxercalciferol group. The PTH decreased by 27% +/- 34% in the doxercalciferol group (P = 0.002) and decreased by 10% +/- 31% in the cholecalciferol group (P = 0.16), but the difference between treatments was NS (P = 0.11). Similar results were found when absolute PTH change from baseline to end point was analyzed in a repeated-measures ANOVA model. The serum calcium and urine calcium excretions were not different. Additional non-mineral-related end points, albuminuria, and BP were evaluated, and although trends were present, this did not reach significance.. This prospective, randomized trial demonstrated a within-group reduction in PTH in the doxercalciferol-treated patients but no significant difference between the doxercalciferol and cholecalciferol patients. Larger, long-term studies are needed to demonstrate efficacy of mineral-related and non-mineral-related end points and safety.

Topics: Aged; Biomarkers; Calcium; Cholecalciferol; Chronic Disease; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Single-Blind Method; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer analogs (paricalcitol or doxercalciferol), along with dietary phosphorus restriction and phosphate binding agents. Published reports have suggested that treatment with paricalcitol in hemodialyzed (HD) patients offers a morbidity or mortality advantage in comparison with treatment with calcitriol. We have recently reported that switching from calcitriol to paricalcitol resulted in a lower serum calcium and calcium-phosphorus product (Ca x P product), as well as lower parathyroid hormone (PTH) and alkaline phosphatase during 6 months of serial treatment. We converted all HD patients in our large urban dialysis center from calcitriol to paricalcitol using a 1:3 conversion ratio, on the basis of published data. Comparisons of individual patient mean biochemical values, as well as episodes of hypercalcemia and elevated Ca x P product, were made after adjusting for equivalent doses. In addition, we recorded the number of missed doses during two years of therapy. No patient in this study had received a calcimimetic before or during the study period. Fifty-nine patients were treated with calcitriol for at least 12 months and then completed 12 months of paricalcitol. Conversion from calcitriol to paricalcitol resulted in lower serum calcium (P=0.0003), lower serum phosphorus (P=0.027), lower Ca x P product (P=0.003), reduced PTH (P=0.001) and reduced serum alkaline phosphatase (P=0.0005). Most dramatically, there was a highly significant difference in the number of missed doses (P<0.0001) during the treatments. This 2-year single-center study, comparing long-term calcitriol with paricalcitol treatment in the same HD patients, extends our previous findings, offers new information regarding single episodes of potentially adverse biochemical effects related to vitamin D therapy, and provides several clues that may explain the outcome advantages suggested by previously published retrospective analyses of large dialysis provider-pooled databases.

Topics: Aged; Calcinosis; Calcitriol; Calcium; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies

Optimal dialysate calcium concentration (DCa) has not been determined under less hypercalcemic vitamin D analogues and Ca-free phosphate (P) binders.. Twelve hyperparathyroidic hemodialysis patients under sevelamer hydrochloride were treated with paricalcitol in three periods (A, B and C) under DCa of 3.5, 3 and 2.5 mEq/l, respectively, in a 3-way open-label randomized crossover study.. Serum parathyroid hormone decreased in all periods. Under DCa = 2.5 mEq/l, there was a need for longer treatment duration, higher paricalcitol doses and increased sevelamer doses for higher serum P levels. No differences in serum Ca were observed. Ca x P values followed P changes. Episodes of Ca x P >55 mg(2)/dl(2) were more frequent in the C period.. Under paricalcitol and sevelamer, serum parathyroid hormone decreased without Ca increase under any DCa. DCa of 2.5 mEq/l resulted in higher paricalcitol doses, increased serum P levels and more frequent high Ca x P episodes and may not be optimal with the new medications.

Topics: Adult; Aged; Calcium; Dialysis Solutions; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Polyamines; Renal Dialysis; Sevelamer

Secondary hyperparathyroidism (SHPT) is common among haemodialysis patients. Intensive treatment with calcitriol is often complicated by hypercalcaemia, hyperphosphataemia and elevated calcium phosphorus (Ca X PO(4)) product. Paricalcitol is a vitamin D analogue developed to overcome some of the limitations of calcitriol therapy. The study objectives were to compare the response of intact parathyroid hormone (iPTH) and the incidence of hypercalcaemia, hyperphosphataemia and elevated Ca X PO(4) product in patients with severe SHPT treated with either i.v. calcitriol or i.v. paricalcitol.. This was a single centre randomized open label study. Patients with serum intact iPTH of 50 pmol/L or more were randomized to receive either i.v. calcitriol (0.01 ug/kg) or i.v. paricalcitol (0.04 ug/kg) during every haemodialysis treatment. Serum iPTH, calcium, phosphorus and alkaline phosphatase were measured at the beginning of the study and every 3 weeks for 12 weeks.. Twenty-five patients were enrolled into the study - 12 were randomized into the calcitriol group and 13 into the paricalcitol group. There were no differences in the baseline study parameters between both groups. Serum iPTH levels were significantly reduced (P = 0.003) only in the paricalcitol group but not in the calcitriol group (P = 0.101). On the other hand, serum calcium levels were significantly increased only in the calcitriol group (P = 0.004 vs P = 0.242). Serum phosphorus, alkaline phosphatase and Ca X PO(4) product were not different.. Intravenous paricalcitol may be superior to i.v. calcitriol for the treatment of severe SHPT in our chronic haemodialysis population. A larger randomized controlled trial is indicated to confirm these initial findings.

Topics: Adult; Aged; Calcitriol; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Male; Middle Aged; Phosphates; Renal Dialysis

Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.In Denmark alfacalcidol is the primary choice of vitamin D analog.A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia.. This is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks.. Hyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients.. ClinicalTrials.gov NCT00469599.

Topics: Adult; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Renal Dialysis; Treatment Outcome

Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD).. Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca x P product levels. The primary end points were efficacy (two consecutive iPTH decreases of >or=30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed.. Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH 500 pg/ml were 3.9 and 7.6 microg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive >or=30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo.. Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis; Phosphorus; Placebos; Receptors, Calcitriol; Renal Dialysis; Treatment Outcome

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34-1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01-1.34); Ca x P product from 58 to 48 (p = 0.001, 95% CI 4.2-15.7); and intact PTH (iPTH) from 426 +/- 274 to 300 +/- 228 pg/ml (p = 0.03, 95% CI 19.3-401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).

Topics: Black or African American; Bone and Bones; Bone Density Conservation Agents; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Naphthalenes

The safety and efficacy of paricalcitol injection have been well established for the prevention and treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 5. The capsule form of paricalcitol was developed to provide a convenient dosage form for patients with stages 3 and 4 CKD.. Three randomized, placebo-controlled, phase-3 trials were conducted in patients with stages 3 and 4 CKD with SHPT. Enrollment criteria included an estimated glomerular filtration rate between 15 and 60 mL/min/1.73 m2 (0.25 and 1.00 mL/s/1.73 m2), an average of 2 consecutive intact parathyroid hormone (iPTH) levels greater than 150 pg/mL (ng/L), 2 consecutive serum calcium levels between 8.0 and 10.0 mg/dL (2.00 and 2.50 mmol/L), and 2 consecutive serum phosphorus levels of 5.2 mg/dL or less (< or = 1.68 mmol/L). Two studies used a thrice-weekly dosing regimen and 1 study used a once-daily dosing regimen for 24 weeks. Dosing was based on serum iPTH, calcium, and phosphorus levels. The primary efficacy end point is 2 consecutive decreases in iPTH levels greater than 30% from baseline.. Two hundred twenty patients participated (n = 107, paricalcitol; n = 113, placebo). At least 2 consecutive decreases in iPTH levels of 30% or greater from baseline occurred in 91% of paricalcitol versus 13% of placebo patients (P < 0.001). Incidences of hypercalcemia, hyperphosphatemia, and elevated calcium-phosphorus product levels were not significantly different between groups. Similarly, no significant differences in urinary calcium and phosphorus excretion or deterioration in kidney function were detected in patients administered paricalcitol compared with placebo.. Paricalcitol capsule was well tolerated and effectively decreased iPTH levels with minimal or no impact on calcium levels, phosphorus balance, and kidney function in patients with stages 3 and 4 CKD.

Topics: Adult; Aged; Aged, 80 and over; Capsules; Disease Progression; Double-Blind Method; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies

Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing.. Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects.. Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive > or = 30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca x P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens.. QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive > or = 30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca x P product as compared with placebo or intermittent dosing.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Capsules; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Vitamins

Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D(3)) to suppress parathyroid hormone (PTH), but dosing of 1,25D(3) is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1alpha-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca x P, while still suppressing PTH.. We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h.. Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 +/- 0.11 mmol/l) than paricalcitol (1.85 +/- 0.07 mmol/l; p = 0.025). Ca x P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 +/- 0.26 vs. 4.54 +/- 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol).. Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca x P.

Topics: Adult; Aged; Bone Density Conservation Agents; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Phosphorus; Prospective Studies; Renal Dialysis

Proteinuria is a marker of cardiovascular and renal disease in patients with chronic kidney disease (CKD), and reduction in proteinuria has been associated with improved cardiovascular and renal outcomes. While active vitamin D and its analogs have been shown to have renal protective effects in animals, these hormones have not been shown to reduce proteinuria in CKD patients.. In three double-blind, randomized, placebo-controlled studies to evaluate the safety and efficacy of oral paricalcitol, 220 CKD stage 3 and 4 patients with secondary hyperparathyroidism (SHPT) were randomized to oral paricalcitol (N= 107, mean dose 9.5 microg/week) or placebo (N= 113) and followed for up to 24 weeks. In conjunction with other safety measures, proteinuria was measured by dipstick and read by an automated reader at the beginning and end of trial. We subsequently analyzed the dipstick data to evaluate the effect of paricalcitol on proteinuria.. At baseline, proteinuria was present in 57 patients randomized to oral paricalcitol and 61 patients randomized to placebo (NS). At the final visit, 29/57 (51%) of the paricalcitol patients compared to 15/61 (25%) placebo patients had reduction in proteinuria, P= 0.004 (odds for reduction in proteinuria 3.2 times greater for paricalcitol patients, 95% CI 1.5-6.9). For the patients who had both proteinuria at baseline and parathyroid hormone (PTH) suppression (end point defined as 2 consecutive > or =30% decreases in iPTH from baseline), 27/51 (53%) patients had a reduction in the proteinuria in the paricalcitol group and 0/7 (0%) had a reduction in proteinuria in the placebo group. Reduction of proteinuria favored patients on paricalcitol, regardless of age, sex, race, diabetes mellitus, hypertension, or use of therapies to block the renin-angiotensin-aldosterone system (RAAS).. Our results demonstrate that the reduction in proteinuria was associated with paricalcitol treatment, and the reduction in proteinuria was independent of concomitant use of agents that block the RAAS. Paricalcitol as a potential pharmacologic means of reducing proteinuria in CKD patients warrants further investigation.

Topics: Administration, Oral; Aged; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

Calcitriol lowers parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) stages 3 and 4, but its use is limited by a low therapeutic index and concerns regarding hypercalcemia and acceleration of kidney disease. We evaluated doxercalciferol (1alpha-hydroxyvitamin D2) as an alternative therapy in a randomized, double-blinded, placebo-controlled, multicenter trial.. Fifty-five adults with stage 3 or 4 CKD and an intact PTH (iPTH) level greater than 85 pg/mL (ng/L) completed 8 baseline weeks, followed by 24 weeks of oral therapy with doxercalciferol or placebo. Pretreatment demographics and biochemical features did not differ between groups. Dosages were increased gradually if iPTH level was not decreased by 30% or greater and serum calcium and phosphorus levels were stable. Regular monitoring included plasma iPTH, serum calcium and phosphorus, urinary calcium, bone-specific serum markers, and serum lalpha,25-dihydroxyvitamin D levels. Glomerular filtration rate (GFR) was measured before and after treatment.. Mean plasma iPTH level decreased by 46% from baseline after 24 weeks of doxercalciferol treatment (P <0.001), but was unchanged with placebo. After 6 weeks, iPTH level reductions with doxercalciferol treatment exceeded those with placebo at all subsequent intervals (P <0.001). No clinically significant differences in mean serum calcium or phosphorus or urinary calcium levels or incidence of hypercalcemia, hyperphosphatemia, or hypercalciuria were noted between groups. Serum C- and N-telopeptide and bone-specific alkaline phosphatase levels decreased with doxercalciferol treatment relative to both baseline and placebo (P <0.01). Adverse-event rates and changes in GFR did not differ between groups.. Doxercalciferol is safe and effective in controlling secondary hyperparathyroidism of patients with CKD stages 3 and 4.

Topics: Aged; Calcium; Chronic Disease; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus

Management of secondary hyperparathyroidism has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or elevations in the calcium-phosphorus (Ca x P) product. In clinical studies, paricalcitol was shown to be effective at reducing PTH concentrations without causing significant hypercalcemia or hyperphosphatemia as compared to placebo. A comparative study was undertaken in order to determine whether paricalcitol provides a therapeutic advantage to calcitriol.. A double-blind, randomized, multicenter study comparing the safety and effectiveness of intravenous paricalcitol and calcitriol in suppressing PTH concentrations in hemodialysis patients was performed. A total of 263 randomized patients were enrolled at domestic and international sites. Following the baseline period, patients with serum Ca x P < 75, and a PTH level > or =300 pg/mL were randomly assigned to receive either paricalcitol or calcitriol in a dose-escalating fashion for up to 32 weeks. Dose adjustments were based on laboratory results for PTH, calcium, and Ca x P. The primary end point was the greater than 50% reduction in baseline PTH. Secondary end points were the occurrence of hypercalcemia and elevated Ca x P product.. Paricalcitol-treated patients achieved a > or =50% reduction from baseline PTH significantly faster than did the calcitriol-treated patients (P = 0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/mL) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Ca x P product than calcitriol patients (P = 0.008).. Paricalcitol treatment reduced PTH concentrations more rapidly with fewer sustained episodes of hypercalcemia and increased Ca x P product than calcitriol therapy.

Topics: Adult; Aged; Calcitriol; Calcium Channel Agonists; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Incidence; Male; Middle Aged; Parathyroid Hormone

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Topics: Administration, Oral; Adult; Aged; Double-Blind Method; Drug Administration Routes; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Middle Aged; Renal Dialysis

Paricalcitol is a vitamin D analog approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure. This study was designed to evaluate the long-term efficacy and safety of paricalcitol. Additional analysis evaluated the effects of paricalcitol in hypocalcemic and hyperphosphatemic subpopulations.. One hundred sixty-four end-stage renal disease (ESRD) patiesnts on hemodialysis were treated in an open-label, multicenter study lasting up to 13 months in duration. After a baseline or washout period, an initial starting dose of 0.04-0.393 microg/kg was given 2-3 times per week. This dose was adjusted at the discretion of the investigator according to the patient's intact parathyroid hormone level (iPTH), calcium level, and calcium-phosphorus (Ca x P) product. The therapy was intended to reproduce expected clinical use of paricalcitol. Patients represented a wide cross-section of the ESRD population, and were not excluded from the study based on age or underlying disease.. The mean paricalcitol dose level throughout the study was 0.10 microg/kg. The mean iPTH levels (baseline mean 628.3 +/- 27.65 pg/ml) decreased rapidly during the first 4 months of therapy, and reached the designated target range (100-300 pg/ml) by month 5 (mean 295.3 +/- 25.69 pg/ml). A maximum mean decrease in iPTH level of 409 +/- 35.01 pg/ml was seen at month 13. Throughout the course of the study, the mean normalized calcium level was maintained well within the normal range (9.44-9.94 mg/dl). The mean phosphorus level was maintained in an acceptable range throughout the study (5.92-6.53 mg/dl). Mean Ca x P product was maintained between 52 and 65. Mean alkaline phosphatase levels decreased significantly from baseline with a maximum mean decrease of 62 +/- 17.3 U/l observed at month 9. In 34 initially hypocalcemic patients (mean of 7.7 mg/dl) iPTH levels decreased from baseline, on average, by 443 +/- 81.86 pg/ml while mean calcium levels rose by 1.2 +/- 0.23 mg/dl to reach the normal range. In 35 initially hyperphosphatemic patients (mean of 8.0 mg/dl) iPTH levels decreased, on average, by 515 +/- 103.31 pg/ml with an associated mean decrease in phosphorus of 0.57 +/- 0.52 mg/dl. Adverse events that were considered by the investigator to have a possible. probable, or definite relationship to study drug occurred in 26% of patients. Other than expected temporary effects of hypercalcemia and hyperphosphatemia. the only possible trends for causally-related adverse events were for nausea/vomiting and metallic taste.. This long-term study of paricalcitol demonstrates that it rapidly and effectively suppresses iPTH levels in a wide spectrum of ESRD patients and caused no unexpected adverse events.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Kidney Failure, Chronic; Male; Middle Aged; Nausea; Parathyroid Hormone; Phosphorus; Taste Disorders; Time Factors; Vomiting

Vitamin D therapy for patients with end-stage renal disease (ESRD) on hemodialysis therapy has relied on patient dry weight to determine the initial dose of medication. Obtaining a patient's dry weight can be difficult, and no correlation has been established between a patient's body weight and severity of secondary hyperparathyroidism. We conducted a double-blind, double-dummy, randomized, 12-week, multicenter trial to compare the incidence of hypercalcemia (single occurrence) between two dosing regimens: one regimen based on baseline intact parathyroid hormone (iPTH; PTH/80) level, and the other regimen based on patient body weight (0.04 microgram/kg). One hundred twenty-five adult patients with ESRD on maintenance hemodialysis therapy were enrolled at multiple sites. Before treatment, all patients were required to have PTH levels of 300 pg/mL or greater, calcium levels of 8.0 mg/dL or greater and 10.5 mg/dL or less, and a calcium x phosphorus (Ca x P) product of 70 or less. Patients were randomized to one of two regimens: the nonrandomized treatment was also administered as a placebo dummy. No incidence of hypercalcemia occurred in either treatment group during the study. Patients treated according to the formula iPTH/80 required fewer dose adjustments and achieved the first of four consecutive reductions from baseline PTH level of 30% or greater more rapidly than patients treated based on body weight (P = 0.0306). Incidences of elevated Ca x P product levels were similar between treatment groups. Treatment with paricalcitol injection based on degree of secondary hyperparathyroidism incurred no greater risk for hypercalcemia and achieved meaningful therapeutic results with fewer dose adjustments than dosing based on patient body weight.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Body Weight; Calcium; Confidence Intervals; Double-Blind Method; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Topics: Adult; Aged; Alkaline Phosphatase; Calcium; Double-Blind Method; Drug Administration Schedule; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Phosphorus

Calcitriol and alfacalcidol are useful in suppressing parathyroid hormone (PTH) in haemodialysis patients, but hypercalcaemia and hyperphosphataemia are frequent. The vitamin D analogue, 1alpha-hydroxyvitamin D2 (1alphaD2), has a higher therapeutic index in animal models. Previously, 1alphaD2, 4 microg/day or 4 microg/haemodialysis, lowered iPTH to the target range in 87.5% of 24 haemodialysis patients with moderate to severe secondary hyperparathyroidism (plasma iPTH, 359-1521 pg/ml). The incidences of hypercalcaemia (serum Ca>2.8 mM) or hyperphosphataemia (serum P>2.23 mM) were low. Later, 10 of these patients were re-treated with 1alphaD2, initial dose, 10 microg, thrice weekly with haemodialysis. The iPTH was suppressed as readily, and there was no greater incidence of hypercalcaemia and hyperphosphataemia. Based on these data, a large, multicentre study is ongoing in California and Tennessee/Mississippi, using 1alphaD2 in haemodialysis patients with iPTH >400 pg/ml. In this and the earlier studies, only calcium-based phosphate binders were used to control serum phosphorus. The initial dose, 10 microg thrice weekly with haemodialysis, is adjusted to maintain a target iPTH within the range of 150-300 microg/ml; the final dose range is 2.5-20 microg per haemodialysis. The protocol includes 8 weeks of wash-out with no vitamin D, 16 weeks of open label treatment period with 1alphaD2, and finally 8 weeks of randomized double blinded treatment with either continued 1alphaD2 or placebo. Forty two patients from California and 38 from Tennessee/Mississippi have completed 16 weeks of open label treatment. In California, iPTH declined from 832+/-95 pg/ml at baseline to 222+/-71 pg/ml at the nadir and to 477+/-117 pg/ml at week 16 of the treatment. In Tennessee/Mississippi, the iPTH declined from 977+/-65 pg/ml to 286+/-42 pg/ml at the lowest point and to 493+/-79 at the end of the treatment. Plasma iPTH reached or fell below the target range in 84% of the 80 patients completing open treatment. Asymptomatic hypercalcaemia (serum Ca>2.8 mM) increased from 0.3 episodes/100 weeks during wash-out to 3.6 episodes/100 treated weeks in California and from 0 to 3.7 episodes in Tennessee/Mississippi. In California and Tennessee, the episodes of hyperphosphataemia (serum P>2.2 mM) increased from 5.0 and 5.0 episodes per 100 patient/week during wash-out to 10.1 and 10.9 episodes/100 treatment weeks, respectively, with 1alphaD2 treatment. There were no adverse events in asso

Topics: Administration, Oral; Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Phosphorus; Renal Dialysis

Paricalcitol (19-nor-1alpha-25-dihydroxyvitamin D2), a new vitamin D analog developed for the treatment of secondary hyperparathyroidism, was evaluated in three double-blind, placebo-controlled, dose-escalating, randomized multicenter trials. A total of 78 patients (40 Paricalcitol injection, 38 placebo) achieved treatment phase eligibility, which included intact parathyroid hormone (iPTH) > or = 400 pg/ml, normalized serum calcium levels between 8.0 and 10.0 mg/dl, and calcium x phosphorus product values less than 75. Study end points included a decrease in iPTH of at least 30% or a maximum of five dose escalations. After a 4-wk washout, paricalcitol or placebo was administered intravenously three times per week after dialysis for 12 wk. Study drug was started at a dose of 0.04 microg/kg and was increased by 0.04 microg/kg every 2 wk to a maximal allowable dose of 0.24 microg/kg or until at least a 30% decrease in serum iPTH was achieved. The dose of paricalcitol that decreased iPTH by at least 30% became the maintenance dose. Of 40 patients receiving paricalcitol, 27 (68%) had at least a 30% decrease in serum iPTH for 4 consecutive weeks, compared with three of 38 patients (8%) receiving placebo (P < 0.001). For patients who received 12 wk of treatment with paricalcitol, the levels of iPTH decreased significantly from 795+/-86 to 406+/-106 pg/ml (P < 0.001), whereas the values for PTH were 679+/-41 pg/ml before and 592+/-41 pg/ml after 12 wk of therapy in patients receiving placebo (P=NS). Also, there was a significant difference between treatment groups for the change from baseline PTH levels (P < 0.001). Paricalcitol treatment resulted in a significant reduction in serum alkaline phosphatase from 148+/-23 U/L to 101+/-14 U/L (P < 0.001) in patients treated for 12 wk compared with 120+/-9 U/L to 130+/-11 U/L (P=NS) in patients receiving placebo for 12 wk. Importantly, hypercalcemia did not occur before achieving target serum iPTH levels in any of the paricalcitol-treated patients. There was no significant difference for the change from baseline in serum phosphorus within or between treatment groups. There was no significant difference in adverse events between the paricalcitol and placebo-treated groups. These studies demonstrate that paricalcitol safely and effectively suppresses iPTH levels in hemodialysis patients. This second generation vitamin D analog may have a wider therapeutic window than current vitamin D preparations, and thus may allow redu

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Calcium; Double-Blind Method; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Safety

In this double-blind, placebo-controlled, randomized, multicenter study, 35 patients with end-stage renal disease undergoing maintenance hemodialysis were treated three times weekly for 4 weeks with either 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) intravenously at doses ranging from 0.04 to 0.24 microg/kg or placebo. Eligible patients with secondary hyperparathyroidism (HPT; intact parathyroid hormone [iPTH] level > 300 pg/mL) were initially withdrawn from any existing vitamin D therapy over a 4-week washout period and then randomized to treatment for 4 weeks with either paricalcitol or placebo. Overall, there was a clinically and statistically significant reduction in iPTH level for patients receiving paricalcitol compared with placebo (P = 0.006). The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH level for 75% of the patients receiving paricalcitol per dosing group. The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH for 75% of patients receiving paricalcitol per dosing group. Sixty-eight percent (15 of 22) of patients receiving paricalcitol attained this efficacy end point regardless of dosage received (0.04, 0.08, 0.16, and 0.24 microg/kg). Eighty-three percent (5 of 6) of the patients in each of the paricalcitol groups receiving 0.16- and 0.24-microg/kg dosages attained the efficacy end point. Only two patients receiving placebo attained the iPTH end point. There were no clinically relevant differences in serum calcium (Ca) or phosphorus (P) levels between the group treated with paricalcitol and that treated with placebo. Although there was a statistically significant difference between the change from baseline to final-visit Ca levels in the paricalcitol group and the placebo group (P < 0.001), the final-visit mean Ca level in the paricalcitol group was within the normal range (9.44 mg/dL). There was no statistically significant difference between groups for the change from baseline in P level (P = 0.625). Only one patient treated with paricalcitol developed hypercalcemia before or coincident with the iPTH end point. Three other patients receiving paricalcitol experienced elevated serum Ca levels subsequent to reaching the iPTH end point, with iPTH reductions of 83% to 98%. There were no significant differences between patients treated with paricalcitol and patients treated with placebo in adverse reactions. These results show that paricalcitol safely and effectiv

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcium; Double-Blind Method; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis; Vitamin D

Secondary hyperparathyroidism contributes to significant morbidity in patients with chronic renal failure. The treatment of this disorder with vitamin D compounds, such as calcitriol, although effective at suppressing parathyroid hormone (PTH) secretion, may promote the development of hypercalcemia and hyperphosphatemia, thus increasing the risk for metastatic calcification. A new vitamin D analogue, 19-nor-1alpha,25-(OH)2D2 (paricalcitol; Zemplar, Abbott Laboratories, Inc, Chicago, IL) has recently been developed for the treatment of secondary hyperparathyroidism, and, in experimental animals, it was found to be less calcemic and phosphatemic than calcitriol. In double-blind clinical trials, paricalcitol effectively decreased the levels of PTH by 60%, yet the mean serum calcium values remained within the normal range. The few episodes of hypercalcemia that occurred in the paricalcitol-treated patients (8 of 400 determinations > or =11.0 mg/dL in 7 patients) were associated with marked decreases in PTH levels (87% +/- 2% less than baseline) and absolute values of PTH less than 100 pg/mL in four of the seven patients. PTH values less than 100 pg/mL, however, occurred in 15 patients, but were not invariably associated with frank hypercalcemia, although serum calcium levels increased to 10.63 +/- 0.3 mg/dL, slightly greater than the upper limits of normal. Additional studies to evaluate the conversion from calcitriol to paricalcitol therapy showed that a dose ratio of 1:4 (calcitriol:paricalcitol) could maintain control of high levels of PTH without significant alterations in serum calcium and phosphorus levels. These studies indicate that effective control of hyperparathyroidism can be achieved with paricalcitol therapy with minimal perturbation of serum calcium and phosphorus levels, and may have a therapeutic advantage over current treatment strategies.

Topics: Calcium; Double-Blind Method; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Phosphorus

Topics: Bone Density Conservation Agents; Calcium; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Pain; Parathyroid Hormone; Renal Dialysis

Obesity increases the risk of vitamin D insufficiency, which exacerbates secondary hyperparathyroidism in chronic kidney disease. Recent studies suggest that serum total 25-hydroxyvitamin D (25OHD) levels of ≥50 ng/mL are necessary to produce significant reductions in elevated parathyroid hormone levels in nondialysis patients. Data from real-world and randomized controlled trials (RCTs) involving these patients were examined for (1) relationships between vitamin D treatments and the achieved levels of serum 25OHD and between serum 25OHD and body weight (BW)/body mass index (BMI); and (2) the impact of BW/BMI on achieving serum 25OHD levels ≥50 ng/mL with extended-release calcifediol (ERC) treatment or vitamin D supplementation (cholecalciferol or ergocalciferol).. Data obtained from nondialysis patients participating in two real-world studies, one conducted in Europe (Study 1) and the other (Study 2) in the USA, and in two US RCTs (Studies 3 and 4) were analyzed for serum 25OHD outcomes after treatment with ERC, vitamin D supplements, or placebo.. More than 50% of subjects treated with vitamin D supplements in both real-world studies (Studies 1 and 2) failed to achieve serum 25OHD levels ≥30 ng/mL, a level widely viewed by nephrologists as the threshold of adequacy; only 7.3-7.5% of subjects achieved levels ≥50 ng/mL. Data from the European study (Study 1) showed that serum 25OHD levels had significant and nearly identical inverse relationships with BW and BMI, indicating that high BW or BMI thwarts the ability of vitamin D supplements to raise serum 25OHD. One RCT (Study 3) showed that 8 weeks of ERC treatment (60 μg/day) raised serum 25OHD levels to ≥30 and 50 ng/mL in all subjects, regardless of BW, while cholecalciferol (300,000 IU/month) raised serum 25OHD to these thresholds in 56% and 0% of subjects, respectively. The other RCT (Study 4) showed that ERC treatment (30 or 60 μg/day) successfully raised mean serum 25OHD levels to at least 50 ng/mL for subjects in all BW categories, whereas no increases were observed with placebo treatment.. Real-world studies conducted in Europe and USA in nondialysis patients (Studies 1 and 2) showed that vitamin D supplements (cholecalciferol or ergocalciferol) were unreliable in raising serum total 25OHD to targets of 30 or 50 ng/mL. In contrast, ERC was demonstrated to be effective in one real-world study (Study 2) and two RCTs (Studies 3 and 4) conducted in US nondialysis patients in raising serum 25OHD to these targeted levels irrespective of BW.

Topics: Calcifediol; Cholecalciferol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Overweight; Parathyroid Hormone; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT.

Topics: Age Factors; Aged; Alleles; Calcitriol; Calcium; Calcium-Regulating Hormones and Agents; Cinacalcet; Ergocalciferols; Female; Gene Expression; Genotype; Heterozygote; Homozygote; Humans; Hyperparathyroidism, Secondary; Logistic Models; Male; Middle Aged; Parathyroid Hormone; Phosphates; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies

In chronic kidney disease, the activation of the renin-angiotensin-aldosterone system (RAAS) and renal inflammation stimulates renal fibrosis and the progression to end-stage renal disease. The low levels of vitamin D receptor (VDR) and its activators (VDRAs) contribute to worsen secondary hyperparathyroidism and renal fibrosis.. The 7/8 nephrectomy model of experimental chronic renal failure (CRF) was used to examine the anti-fibrotic effects of treatment with two VDRAs, paricalcitol and calcitriol, at equivalent doses (3/1 dose ratio) during 4 weeks.. CRF increased the activation of the RAAS, renal inflammation and interstitial fibrosis. Paricalcitol treatment reduced renal collagen I and renal interstitial fibrosis by decreasing the activation of the RAAS through renal changes in renin, angiotensin receptor 1 (ATR1) and ATR2 mRNAs levels and renal inflammation by decreasing renal inflammatory leucocytes (CD45), a desintegrin and metaloproteinase mRNA, transforming growth factor beta mRNA and protein, and maintaining E-cadherin mRNA levels. Calcitriol showed similar trends without significant changes in most of these biomarkers.. Paricalcitol effectively attenuated the renal interstitial fibrosis induced by CRF through a combination of inhibitory actions on the RAAS, inflammation and epithelial/mesenchymal transition.

Topics: Animals; Biomarkers; Calcitriol; Ergocalciferols; Fibrosis; Hyperparathyroidism, Secondary; Inflammation; Kidney; Kidney Failure, Chronic; Receptors, Calcitriol; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

Topics: Calcitriol; Cinacalcet; Cost-Benefit Analysis; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D. We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.. A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%;. Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.

Topics: Administration, Intravenous; Administration, Oral; Aged; Biomarkers; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Substitution; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome; United States; Vitamins

Topics: Calcimimetic Agents; Calcitriol; Chelating Agents; Cholecalciferol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Parathyroidectomy; Phosphates; Phosphorus, Dietary; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency

Left ventricular hypertrophy (LVH) is common in renal transplant recipients (RTRs), and persistent secondary hyperparathyroidism (SHPT) is considered to be one of the main causes of its pathogenesis. In this study we evaluated if the control of SHPT with paricalcitol is associated with a reduction of LVH in RTRs.. For this purpose we selected 24 RTRs with LVH and SHPT. Secondary hyperparathyroidism was defined as PTH levels 1.5 times higher than the high normal limits, while LVH was defined as a left ventricular mass index (LVMi) >95g/m2 in females, and >115g/m2 in males. Treatment with paricalcitol started at mean dose of 1µg/day and lasted 18 months. The dose of paricalcitol was reduced to 1µg on the other day when serum calcium was >10.5mg/dl and/or fractional excretion of calcium was >0.020%; administration was temporarily stopped when serum calcium was >11 mg/dl.. At follow-up PTH levels decreased from 198 ± 155 to 105 ± 43pg/ml, and LVMi decreased from 134 ± 21 to 113 ± 29g/m2; the presence of LVH decreased from 100% at baseline to 54% at F-U. Serum calcium levels showed a modest and not significant increase. Renal function was stable in all patients.. Secondary hyperparathyroidism seems to play an important role in the development and maintenance of LVH and its correction with paricalcitol has a favorable impact on its progression.

Topics: Adult; Aged; Bone Density Conservation Agents; Calcium; Drug Administration Schedule; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Sex Factors; Time Factors

To evaluate monthly percentage changes of intact parathyroid hormone (iPTH) and other major bone marker levels in patients with secondary hyperparathyroidism (SHPT) undergoing hemodialysis (HD) and receiving paricalcitol.. A total of 493 (F/M 244/249) adult patients with SHPT who were undergoing HD in 22 HD units and receiving paricalcitol treatment, with iPTH > 300 mg/mL, adjusted serum levels of calcium (Ca) < 10.2 mg/dL, and serum levels of inorganic phosphorus (iP) < 6 mg/dL were included in this multi-center, national, prospective, observational study. Data regarding efficacy, safety, and adverse events of paricalcitol treatment were collected during a 12-month follow-up period through monthly visits along with serum iPTH, Ca, iP, alkaline phosphatase (ALP) and other required biochemistry tests as necessary. Mortality data until 6 months after the end of the study were also investigated.. The mean age was 58.3 ± 15.8 years and the mean duration of HD was 6.2 ± 5.5 years, respectively. As of 12th month, mean iPTH values decreased from 646 ± 424 pg/mL to 473 ± 387 pg/mL (p < 0.001); no statistically significant changes were observed in Ca levels (p > 0.05). Serum ALP levels also significantly decreased (p = 0.001) and serum phosphorus levels significantly increased (p < 0.001) during the study observation period. Reasons for early terminations were being lost to follow-up (n = 119, 24.1%), hyperphosphatemia (iP > 6 mg/dL, n = 108, 21.9%), low iPTH levels (iPTH < 150 mg/dL, n = 97, 19.7%), and withdrawal of consent (n = 41, 8.3%). In total 32 patients (6.5%) were prematurely terminated the study with hypercalcemia (Ca > 10.2 mg/dL). 46.9% of those hypercalcemic patients had other anomalies with iP and iPTH levels along with hypercalcemia.. Paricalcitol treatment, resulted in successful iPTH control. In approximately 6.5% of the patients paricalcitol treatment was discontinued since Ca levels reached > 10.2 mg/dL in those patients. No unfavorable effects on serum phosphorus and Ca-phosphorus (Ca × P) product were observed.

Topics: Bone Density Conservation Agents; Calcium; Drug Monitoring; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Turkey

The complex pathophysiology of progressive chronic kidney disease (CKD) and the development of mineral and bone disorder, abbreviated as CKD-MBD, is of vital importance to a pediatric patient. Paricalcitol, the 19 nor-1,25(OH)

Topics: Adolescent; Child; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic

The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

Topics: Adult; Calcimimetic Agents; Calcitriol; Cell Transdifferentiation; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Oxyphil Cells; Parathyroid Glands; Parathyroidectomy; Receptors, Calcium-Sensing; Renal Insufficiency, Chronic; Uremia; Vitamin D

Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation were observed in both etelcalcetide- and paricalcitol-treated rats. Serum calcium and phosphorus were significantly lower in etelcalcetide-treated uremic rats and was unchanged in paricalcitol-treated rats. Both serum FGF23 and aortic calcium content were significantly lower in etelcalcetide-treated uremic rats compared with either vehicle- or paricalcitol-treated uremic rats. The degree of aortic calcium content for etelcalcetide-treated rats was similar to that in nonuremic controls and corroborated findings of lack of histologic aortic mineralization in those groups. In conclusion, etelcalcetide and paricalcitol similarly attenuated progression of SHPT in an adenine rat model of CKD. However, etelcalcetide differentially prevented vascular calcification, at least in part, due to reductions in serum FGF23, calcium, and phosphorus levels.

Topics: Animals; Disease Models, Animal; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Peptides; Rats; Rats, Wistar; Renal Insufficiency; Vascular Calcification

INTRODUCTION    Secondary hyperparathyroidism (SHPT) is a common hormonal disorder associated with chronic kidney disease (CKD). The treatment of SHPT should lead to a reduction in parathormone concentrations by calcimimetics or active vitamin D administration and stabilization of calciumand phosphate metabolism. In the event of failure of conservative treatment, complete or partial parathyroid resection should be considered. OBJECTIVES    The aim of the study was to assess the beneficial effects of a combination treatment with paricalcitol and cinacalcet in comparison with paricalcitol alone. PATIENTS AND METHODS    A total of 64 hemodialyzed patients (mean [SD] age, 58 [16] years) with inadequate control of serum parathyroid hormone levels were treated with intravenous paricalcitol, while 16 patients simultaneously received oral cinacalcet. Laboratory tests (intact parathormone [iPTH], calcium, phosphorus) were performed on a monthly basis. In the study, iPTH, calium, phosphorus, and alkaline phosphatase levels were assessed at baseline and after 24 weeks of treatment with paricalcitol alone or in combination with cinacalcet. RESULTS    In both groups, a significant decrease in the iPTH level was observed. Although paricalcitol affects calcium levels, no hypercalcemia was observed. The combination treatment did not result in a significant lowering of iPTH levels in comparison with paricalcitol alone. CONCLUSIONS    Treatment of SHPT with intravenous paricalcitol in patients on hemodialysis is effective and has a good safety profile. The combination of paricalcitol and cinacalcet does not improve the outcomes. Moreover, the combined treatment does not affect calcium and phosphorus concentrations. The cost‑effectiveness of therapy should also be considered.

Topics: Adult; Aged; Calcium-Regulating Hormones and Agents; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

The Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines on the management of bone disease in patients with chronic kidney disease recommend periodic measurement of serum calcium, phosphorus, vitamin D, and parathyroid hormone levels after kidney transplantation, with the frequencies that will vary according to the severity of bone disease and graft function. Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism.. We retrospectively evaluated the effect of treatment with paricalcitol among our kidney transplant recipients. We monitored the effect of paricalcitol on bone density; the plasma levels of parathyroid hormone, calcium, and phosphorus; and proteinuria and calciuria. Comparisons were made between these parameters before treatment and 12 months after treatment.. Eighty-eight kidney transplant recipients with a mean age at the time of transplantation of 47.1 ± 10.5 years were receiving paricalcitol. On average, paricalcitol was included into the treatment for 48 months from transplantation (median, 27 months). The patients had significantly improved bone density (P < .001), significantly lower parathyroid hormone levels (P < .001), and significantly decreased proteinuria (P = .02) after 12 months of treatment. During the treatment with paricalcitol, the immunosuppressive therapy, dose of prednisone, body mass index, and vitamin D levels had not significantly changed. Nor had any significant change occurred to graft function.. Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients.

Topics: Adult; Biomarkers; Bone Density; Bone Density Conservation Agents; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Slovakia; Time Factors; Treatment Outcome

Topics: Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Renal Dialysis

The management of hyperparathyroidism in hemodialysis patients involves the administration of phosphate binders, vitamin D receptor activators, and calcimimetics. Intravenous paricalcitol has been preferred over oral calcitriol as it may cause less hypercalcemia and hyperphosphatemia. However, there is little data looking at the efficacy and tolerability of oral calcitriol in the calcimimetic era particularly in a real practice-based experience. The University of California, Irvine free-standing dialysis center converted from routine intravenous paricalcitol to oral calcitriol due to pharmacy purchasing preferences. We report the efficacy, safety, and cost of such a change.. Ninety-three preconversion intravenous paricalcitol and 91 postconversion oral calcitriol.. Conversion to in-center, pulse, oral calcitriol (0.25 mcg = 1 mcg paricalcitol) 3 times a week from intravenous paricalcitol. Additional dose adjustments were made by the nephrologists based on clinical indications.. Five-month average serum calcium, phosphorous, and intact parathyroid hormone levels and cardiovascular events pretransition and posttransition.. There were 93 patients on intravenous paricalcitol between April 2013 and August 2013, of which 74 converted to oral calcitriol and were included in the postconversion group evaluated between October 2013 and February 2014. An additional 17 new patients had initiated calcitriol such that 91 patients were on oral therapy in the postconversion period. Sevelamer use increased from 41 (44.1%) patients preconversion to 48 (52.7%) postconversion, whereas calcium acetate use significantly dropped from 62 (66.7%) to 46 (50.5%) (P = .026). Cinacalcet use dropped slightly from 37 (39.7%) patients preconversion to 35 (38.4%) postconversion. Average serum calcium, phosphorus, and intact parathyroid hormone levels remained unchanged after conversion. Percent of values within Kidney Disease Outcome Quality Initiative guidelines were similarly maintained. Estimated vitamin D cost savings were $564 per person/year. No increase in the incidence of cardiovascular events was observed.. We conclude that in-center distributed pulse oral calcitriol may be an effective, safe, and economical treatment option for the management of hyperparathyroidism in hemodialysis patients.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Alkaline Phosphatase; Calcitriol; Calcium; Disease Management; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Parenteral Nutrition; Phosphorus; Receptors, Calcitriol; Renal Dialysis; Retrospective Studies; Treatment Outcome

To investigate the effects of Vitamin D Analogs, paricalcitol and alphacalcidol, on hemoglobin levels and erythropoietin-stimulating agents' dosage in hemodialysis patients with chronic renal failure. A total of 310 patients under hemodialysis treatment for chronic renal failure were included in this retrospective multicenter study. Data on serum parathormone and hemoglobin levels, erythropoietin-stimulating agents' doses, C-reactive protein, calcium and phosphate levels were collected from medical records to comparatively evaluate paricalcitol, alphacalcidol and no treatment groups. Apart from significantly higher levels for hematocrit in patients treated with paricalcitol compared to pre-treatment values (32.3(3.8) vs. 34.1(3.1) p=0.007), pre-treatment and post-treatment values for biochemical parameters were similar in paricalcitol and alphacalcidol groups including ESA dose. A significant increase in parathormone levels (p=0.000 for each) while a significant decrease in calcium (p=0.003 and 0.040, respectively), Hb (p=0.001 and 0.009, respectively) and hematocrit (p=0.001 and 0.021, respectively) levels were determined in paricalcitol and alphacalcidol treated patients compared with untreated patients. Also, phosphate levels in alphacalcidol treated patients were significantly higher (p=0.018) than untreated patients. Our findings revealed insufficient suppression of parathormone levels and there of lower hemoglobin and hematocrit levels, but similar ESA dosage among CRF patients treated with Vitamin D analogs compared with untreated patients.

Topics: Aged; Anemia; Ergocalciferols; Female; Hematinics; Hemoglobins; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Retrospective Studies

Paricalcitol decreases intact parathyroid hormone and the frequency of secondary hyperparathyroidism after kidney transplantation. This proof-of-concept study aimed to assess the effect of paricalcitol on fibroblast growth factor-23/KLOTHO axis in renal transplants.. Twenty-nine subjects with secondary hyperparathyroidism received oral paricalcitol 1 μg/d for 3 months, and 8 patients matched by age, sex, and creatinine clearance, but with intact parathyroid hormone less than 100 pg/mL, were included as controls.. Intact parathyroid hormone decreased in paricalcitol-treated patients (P < 0.0001). Serum fibroblast growth factor-23 enhanced (P < 0.01), whereas KLOTHO concentrations showed a trend to increase (P = 0.067). KLOTHO gene expression in peripheral blood mononuclear cells increased by 45.7% in paricalcitol-treated patients (P < 0.01), without change in controls. Paricalcitol administration resulted in a median percent decrease of 56% in methylated DNA levels of KLOTHO promoter (P < 0.001). The ratio of the unmethylated/methylated KLOTHO promoter DNA did not change in controls, but it increased by 177% in paricalcitol-treated subjects (P < 0.0001). The increase in this ratio was independently associated with the change in serum KLOTHO (r = 0.55, P < 0.01) and messenger RNA expression levels (r = 0.40, P < 0.05).. Paricalcitol administration to renal transplant patients significantly reduced intact parathyroid hormone and increased fibroblast growth factor-23, with a trend to increase in serum KLOTHO. Paricalcitol-treated patients showed a decrease in the methylation of the KLOTHO promoter with an increment in the ratio of un-methyated/methylated DNA, which was associated with an increase of KLOTHO gene expression levels and serum KLOTHO concentrations. Long-term studies are needed to assess whether paricalcitol-induced increase in KLOTHO gene expression and serum concentrations may translate into beneficial clinical effects.

Topics: Aged; DNA Methylation; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Klotho Proteins; Male; Middle Aged; Promoter Regions, Genetic; Prospective Studies

Secondary hyperparathyroidism (sHPT) is a common complication being a consequence of metabolic disorders associated with chronic kidney disease (CKD). Treatment of the sHPT should lead to calcium-phosphate management stabilization and parathyroid hormone levels reduction. The phosphate binders, synthetic vitamin D analogs and calcimimetics are used in sHPT treatment. In this paper we analyzed the results of three month paricalcitol treatment of 36 hemodialysis patients with sHPT (serum iPTH> 500 pg/ml). 11 patients have additionally received cinacalcet. Analysis of the results showes a statistically significant reduction in iPTH and alkaline phosphatase. Paricalcitol is effecitve in the tratment of SHPT with favourable profile of side effects. Alcaline phosphatase reduction may be a desirable additional therapeuctic effect. However, it appears that combined therapy with paricalcitol and cinacalcet shoud be offered to selected population of patients i.e. with hypocalcemia after calcimimetics.

Topics: Adult; Aged; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Chronic kidney disease (CKD) is a disorder with high morbidity and mortality worldwide whose complications generate multiple costs. In Ecuador, only a few healthcare institutions have implemented management protocols aimed to reduce costs and to improve the quality of life of patients. The aim of this study is to evaluate the short-term (1-year) and long-term (5-year) costs and savings in the management of secondary hyperparathyroidism (SHPT) of hemodialyzed CKD patients by comparing calcitriol and paricalcitol in a large social security hospital in Quito, Ecuador.. The estimation model assessed the resources used in the management of SHPT by comparing prospectively the cost savings within 1-year and 5-year time horizon with calcitriol and paricalcitol. Hospitalization, erythropoietin (EPO), treatment doses, intravenous iron consumption, and medical supplies were estimated according international references, based on the initial parathormone level (iPTH) of patients. The Ecuadorian National Reference costs (2014-2015) and institutional costs were used to calculate treatment costs. A statistical sensitivity analysis was also performed.. The study was based on data from 354 patients of whom 147 (41.4 %) had a value of iPTH in the range 300-600 pg/ml, 45 (12.8 %) in the range 601-800 pg/ml, and 162 (45.7 %) over 800 pg/ml. The 1-year estimated costs per patient for calcitriol and paricalcitol, respectively, were: medication, 63.88 USD and 1,123.44 USD; EPO, 19,522.95 USD and 16,478 USD; intravenous iron 143.21 USD and 187.76 USD. Yearly hospitalization costs per patient were 11,647.99 USD with calcitriol and 8,019.41 USD with paricalcitol. Total yearly costs per patient amounted to 31,378.02 USD with calcitriol and 25,809.50 USD with paricalcitol. Total savings using paricalcitol were 5,568.52 USD per patient compared with calcitriol. The 5-year cumulative medication costs were 319 USD for calcitriol and 2,403 USD for paricalcitol; EPO with calcitriol was 97,615 USD and with paricalcitol 82,394 USD; intravenous iron with calcitriol was 716 USD and paricalcitol 939 USD. Hospitalization costs for patients with calcitriol and paricalcitol were 43,095 USD and 62,595 USD, respectively. Total savings using paricalcitol amounted 32,414 USD per patient compared with calcitriol.. Paricalcitol use generated more cost savings than calcitriol after 1 and 5 years.

Topics: Bone Density Conservation Agents; Budgets; Calcitriol; Costs and Cost Analysis; Drug Costs; Ecuador; Ergocalciferols; Female; Hospitalization; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Medical Audit; Middle Aged; Quality of Life; Renal Dialysis; Retrospective Studies

Traditionally, secondary hyperparathyroidism (SHPT) due to low calcitriol synthesis in failing kidneys has been treated with synthetic vitamin D receptor (VDR) activators. Recently, also the importance of low native vitamin D status beyond the issue of SHPT has been recognized in these patients. The aim of this work was to evaluate the effect of cholecalciferol supplementation in haemodialysis patients with low vitamin D serum levels. Another aim was to evaluate dual vitamin D therapy (cholecalciferol supplementation plus paricalcitol) in haemodialysis patients with vitamin D deficiency and concomitant SHPT.. Ninety clinically stable maintenance haemodialysis patients were included. Supervised cholecalciferol supplementation was administered due to low vitamin D status. Patients with SHPT were also treated with synthetic VDR activator. Two pre hoc subgroups for statistical analysis were formed: patients treated solely with cholecalciferol (N=34; 5,000 IU once weekly) and patients treated with a combination of cholecalciferol (identical dose, i.e. 5,000 IU/week) plus paricalcitol (N=34, median dose 10 μg/week). Follow-up visit was scheduled 15 weeks later. Serum concentrations of calcidiol (25-D), parathyroid hormone (PTH) and beta-cross laps (CTX) were assessed at baseline and at follow-up. Serum calcium, phosphate and alkaline phosphatase (ALP) were monitored monthly. Only non-calcium gastrointestinal phosphate binders were administered. Dialysate calcium was 1.5 mmol/L in all patients, and no oral calcium-containing preparations were prescribed. Depending on data distribution, parametric or nonparametric statistical methods were used for comparison within each group (i.e. baseline vs. follow-up data) as well as between groups.. In the whole group of 90 patients, mean baseline 25-D serum level was 20.3 (standard deviation 8.7) nmol/L, and it increased to 66.8 (19) nmol/L (p<0.0001) after supplementation. In both preformed subgroups, the effect of vitamin D supplementation was almost identical. In cholecalciferol monotherapy, 25-D levels increased from 18.4 (8.2) to 68.6 (21.2) and in dual vitamin D therapy from 18.4 (5.0) to 67.6 (17.7) nmol/L (both p<0.0001). In addition, both treatment modalities decreased serum PTH levels importantly: from 21.7 (interquartile range 17.3; 35.4) to 18.1 pmol/L (15.3; 24.7) in monotherapy (p=0.05) and from 38.6 (31.8; 53.3) to 33.9 pmol/L (26.1; 47.5) in dual vitamin D therapy (p=0.01). Serum calcium, phosphate, ALP and CTX did not change. We have not observed any episode of hypercalcemia in any subject during the whole period of follow-up. At baseline, slightly lower 25-D levels were observed in diabetic than in non-diabetic patients. This difference disappeared after substitution. Vitamin D status and its changes were not related to the patient's age.. Low 25-D levels were very common in haemodialysis patients. They were safely and effectively corrected with supervised low-dose cholecalciferol supplementation. In patients with higher baseline PTH levels, dual vitamin D therapy (cholecalciferol plus paricalcitol) was safely and effectively used.

Topics: Aged; Alkaline Phosphatase; Bone Density Conservation Agents; Calcifediol; Calcium; Cholecalciferol; Dietary Supplements; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Receptors, Calcitriol; Renal Dialysis; Vitamin D Deficiency; Vitamins

Vitamin D deficiency has been linked to many different pathologies, especially with morbimortality in patients with chronic kidney disease. The progressive loss of renal function leads to calcitriol deficiency and homeostatic changes in calcium, phosphorus, FGF-23 and PTH, among others. All these changes can also influence vitamin D receptor (VDR) activation and the development of secondary hyperparathyroidism (SHPT). The biologic actions of both vitamin D and its synthetic analogues are mediated by binding to the same VDR, acting on different genes. There is a narrow relationship between low levels of calcitriol and SHPT. The combined approach of VDR activation and phosphate restriction, among others, plays an important role in the early treatment of the chronic kidney disease-mineral and bone disorder (CKD-MBD). The Spanish Society of Nephrology, in order to reduce the uniform and significant association with CKD-associated mortality, calcidiol and high phosphate levels suggests normalization of phosphate as well as calcidiol levels in both CKD and dialysis patients. Moreover, it considers that, in addition to selective/non selective activation of VDR for the prevention and treatment of SHPT, VDR could be activated in dialysis patients by native vitamin D or even low paricalcitol doses, independently of PTH levels, as some cohort studies and a recent metaanalysis have found an association between treatment with active vitamin D and decreased mortality in patients with CKD. In general it is considered reasonable to use all this information to individualise decision making.

Topics: Animals; Calcifediol; Calcimimetic Agents; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Substitution; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hyperparathyroidism, Secondary; Phosphates; Rats; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin D

Klotho plays an important role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Klotho is highly expressed in the kidney and parathyroid glands, but its presence in the vasculature is debated. Renal Klotho is decreased in CKD, but the effect of uremia on Klotho in other tissues is not defined. The effect of vitamin D receptor activator therapy in CKD on the expression of Klotho in various tissues is also in debate. In uremic rats (surgical 5/6th nephrectomy model), we compared 3 months of treatment with and without paricalcitol on Klotho immunostaining in the kidney, parathyroid glands, and aorta. With uremia, Klotho was unchanged in the parathyroid, significantly decreased in the kidney (66%) and the intimal-medial area of the aorta (69%), and significantly increased in the adventitial area of the aorta (67%) compared with controls. Paricalcitol prevented the decrease of Klotho in the kidney, increased expression in the parathyroid (31%), had no effect in the aortic media, but blunted the increase of Klotho in the aortic adventitia. We propose that fibroblasts are responsible for the expression of Klotho in the adventitia. In hyperplastic human parathyroid tissue from uremic patients, Klotho was higher in oxyphil compared with chief cells. Thus, under our conditions of moderate CKD and mild-to-moderate hyperphosphatemia in rats, the differential expression of Klotho and its regulation by paricalcitol in uremia is tissue-dependent.

Topics: Adventitia; Animals; Aorta; Bone Density Conservation Agents; Disease Models, Animal; Ergocalciferols; Female; Fibroblasts; Glucuronidase; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney; Klotho Proteins; Nephrectomy; Oxyphil Cells; Parathyroid Glands; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tunica Intima; Uremia

Secondary hyperparathyroidism is highly prevalent in kidney transplant recipients, and commonly results in hypercalcaemia; an association to osteopenia and bone fractures has also been observed. Paricalcitol has proved effective to control secondary hyperparathyroidism in chronic kidney disease in both dialysed and non-dialysed patients, with a low hypercalcaemia incidence. Currently available experience on paricalcitol use in kidney transplant recipients is scarce. Our main aim was to show the effect of paricalcitol on mineral bone metabolism in kidney transplant recipients with secondary hyperparathyroidism.. A retrospective multicentre study in kidney transplant recipients aged>18 years with a 12-month or longer post-transplantation course, stable renal function, having received paricalcitol for more than 12 months, with available clinical follow-up for a 24-month period.. A total of 69 patients with a 120 ± 92-month post-transplantation course were included. Baseline creatinine was 2.2 ± 0.9 mg/dl y GFR-MDRD was 36 ± 20 ml/min/1.73 m(2). Paricalcitol doses were gradually increased during the study: baseline 3.8 ± 1.9 μg/week, 12 months 5.2 ± 2.4 μg/week; 24 months 6.0 ± 2.9 μg/week (P<.001). Serum PTH levels showed a significant fast decline: baseline 288 ± 152 pg/ml; 6 months 226 ± 184 pg/ml; 12 months 207 ± 120; 24 months 193 ± 119 pg/ml (P<.001). Reduction from baseline PTH was ≥30% in 42.4% of patients at 12 months y in 65.2% of patients at 24 months. Alkaline phosphatase showed a significant decrease in first 6 months followed by a plateau: baseline 92 ± 50 IU/l; 6 months 85 ± 36 IU/l, 12 months 81 ± 39 IU/l (P<.001). Overall, no changes were observed in serum calcium and phosphorus, and in urine calcium excretion. PTH decline was larger in patients with higher baseline levels. Patients with lower baseline calcium levels showed significantly increased levels (mean increase was 0.5-0.6 mg/dl) but still within normal range, whereas patients with baseline calcium>10mg/dl showed gradually decreasing levels. Fifteen (21.7%) patients had received prior calcitriol therapy. When shifted to paricalcitol, such patients required paricalcitol doses significantly larger than those not having received calcitriol. Paricalcitol was used concomitantly to cinacalcet in 11 patients with significant PTH reductions being achieved; clinical course was similar to other patients and paricalcitol doses were also similar.. Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients. Overall, no significant changes were observed in calcium and phosphorus levels or urinary excretion. Patients having previously received calcitriol required higher paricalcitol doses. When used in patients receiving cinacalcet, paricalcitol results in a significant PTH fall, with paricalcitol doses being similar to those used in patients not receiving cinacalcet.

Topics: Adult; Aged; Alkaline Phosphatase; Bone and Bones; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitriol; Calcium; Cinacalcet; Drug Substitution; Drug Therapy, Combination; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Postoperative Complications; Retrospective Studies

Safety and efficacy of paricalcitol in hemodialysis patients with secondary hyperparathyroidism (sHPT) was investigated under routine clinical practice in German and Austrian dialysis centers.. Hemodialysis patients with sHPT initiating intravenous paricalcitol were enrolled in this noninterventional study regardless of concomitant sHPT treatment. Prior active vitamin D therapy was discontinued. Clinical laboratory values, including intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphorus (P), Ca × P product, and alkaline phosphatase (AP), were recorded for 6 months following initiation of paricalcitol treatment.. 1,313 patients (Austria, n = 280; Germany, n = 1,033) from 169 dialysis centers were enrolled. Most patients (n = 932; 79.1%) had received dialysis for ≥1 year. Median iPTH fell from 518.9 pg/ml [55.0 pmol/l] at baseline to 264.0 pg/ml [28.0 pmol/l] after 6 months (p < 0.0001). After 6 months of treatment, ≥30 and ≥60% reductions in iPTH were observed in 63.0 and 35.9% of patients, respectively. At 6 months, 27.2% of patients achieved iPTH levels between 150 and <300 pg/ml [15.9 and <31.8 pmol/l] compared with 9.7% at baseline. Ca, P, and Ca × P levels remained stable in the majority of patients. AP levels declined from a median of 98 U/l at baseline to 83 U/l (p < 0.0001) at 6 months. Monitoring of adverse events and clinical laboratory assessments identified no unexpected safety signals for paricalcitol.. Paricalcitol is an effective and well-tolerated treatment option for the control of iPTH levels in hemodialysis patients with sHPT. The results of this study support the results of previous trials under real-time clinical practice conditions in Austria and Germany.

Topics: Aged; Alkaline Phosphatase; Austria; Bone Density Conservation Agents; Calcimimetic Agents; Calcium; Cinacalcet; Ergocalciferols; Female; Germany; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic

Paricalcitol, a selective vitamin D receptor (VDR) activator used for treatment of secondary hyperparathyroidism in chronic kidney disease (CKD), has been associated with survival advantages, suggesting that this drug, beyond its ability to suppress parathyroid hormone, may have additional beneficial actions. In this prospective, nonrandomised, open-label, proof-of-concept study, we evaluated the hypothesis that selective vitamin D receptor activation with paricalcitol is an effective target to modulate inflammation in CKD patients. Eight patients with an estimated glomerular filtration rate between 15 and 44 mL/min/1.73 m(2) and an intact parathyroid hormone (PTH) level higher than 110 pg/mL received oral paricalcitol (1  μg/48 hours) as therapy for secondary hyperparathyroidism. Nine patients matched by age, sex, and stage of CKD, but a PTH level <110 pg/mL, were enrolled as a control group. Our results show that five months of paricalcitol administration were associated with a reduction in serum concentrations of hs-CRP (13.9%, P < 0.01), TNF-α (11.9%, P = 0.01), and IL-6 (7%, P < 0.05), with a nonsignificant increase of IL-10 by 16%. In addition, mRNA expression levels of the TNFα and IL-6 genes in peripheral blood mononuclear cells decreased significantly by 30.8% (P = 0.01) and 35.4% (P = 0.01), respectively. In conclusion, selective VDR activation is an effective target to modulate inflammation in CKD.

Topics: Adult; Anti-Inflammatory Agents; Case-Control Studies; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Inflammation; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Receptors, Calcitriol; Renal Insufficiency, Chronic; Treatment Outcome

Secondary hyperparathyroidism (SHPT) is a common feature in maintenance hemodialysis (MHD) patients. Inadequate treatment of SHPT has been associated with cardiovascular complications, and vitamin D therapy might influence the development of cardiovascular diseases. In the present study, we aimed to evaluate the effects of intravenous paricalcitol and calcitriol treatments on left ventricular mass index changes in MHD patients.. We conducted an observational study with a 12-month follow-up duration to compare the outcomes of intravenous paricalcitol and calcitriol treatments in MHD patients. Eighty patients with moderate to severe SHPT were enrolled in the study. All the patients had normalized total serum Ca concentration <10.5 mg/dL, serum calcium-phosphorus product (Ca × P) <75, and parathyroid hormone level (PTH) level ≥300 pg/mL at the begining of the follow-up period.. The patients were divided into a paricalcitol group (n = 40) and a calcitriol group (n = 40). The demographic, clinical, and biochemical characteristics of the patients were similar at baseline. We observed significantly superior control of SHPT; lesser frequency of hypercalcemia and hyperphosphatemia, and Ca × P level elevations; and interruption of vitamin D treatment in the paricalcitol group. Moreover, we found no significant change in left ventricular mass index in the paricalcitol group, but found a significantly increased left ventricular mass index in the calcitriol group during the follow-up period (from 136.6 ± 35.2 g/m2 to 132.9 ± 40.4 g/m2 vs. from 137.2 ± 30.1 g/m2 to 149.4 ± 31.0 g/m2; p<0.044).. We observed that, compared with calcitriol therapy, paricalcitol therapy reduced the PTH concentrations more effectively without causing hypercalcemia and hyperphosphatemia and might have a substantial beneficial effect on the development of left ventricular hypertrophy.

Topics: Adult; Calcitriol; Drug Monitoring; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Dialysis; Treatment Outcome; Vitamin D; Vitamins

Topics: Administration, Oral; Adult; Aged; Biomarkers; Ergocalciferols; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney; Kidney Transplantation; Logistic Models; Middle Aged; Multivariate Analysis; Odds Ratio; Parathyroid Hormone; Proteinuria; Risk Factors; Time Factors; Treatment Outcome

To assess the level of compliance and variability of mineral metabolism parameters over time in a sample of haemodialysis patients for the different ranges proposed (KDIGO guidelines/S.E.N recommendations) in both groups and individuals continuously.. Every four months, we collected data on calcium, phosphorus, PTH and treatment in a sample of 44 patients followed up continuously for 32 months. We established the percentages of patients who complied with the objectives set for each parameter in both ranges: optimal (KDIGO) and acceptable (S.E.N.) in each control and the percentage that individually complied with the objectives in at least 75% of the determinations.. Compliance with the objective using the optimal range improved, although PTH did not exceed 50%. Using the acceptable range, the objective was achieved in the three parameters in over 70% and over 50% of patients achieved the three simultaneously while using the optimal range, 30% was never achieved. Individually, compliance with the optimal range was continuously achieved in 52.3% (calcium), 45.5% (phosphorus) and in only one patient in PTH, while when using the acceptable range, compliance was achieved in 84.1% (calcium) and 70.5% (phosphorus and PTH).. The use of less stringent criteria than the KDIGO guidelines in calcium, phosphorus and PTH objectives allows patients to remain continuously within appropriate ranges with less intervention and less individual variability.

Topics: Aged; Calcium; Chelating Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Ergocalciferols; Female; Follow-Up Studies; Goals; Guideline Adherence; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Parathyroidectomy; Peritoneal Dialysis; Phosphorus; Postoperative Complications; Practice Guidelines as Topic; Renal Dialysis; Retrospective Studies

Topics: Artifacts; Bone Density Conservation Agents; Chromatography, Liquid; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Renal Insufficiency, Chronic; Sensitivity and Specificity; Tandem Mass Spectrometry; Vitamin D

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Renal Insufficiency, Chronic; Vitamins

The discovery of fibroblast growth factor-23 (FGF-23) as a key regulator of phosphate and vitamin D metabolism has forced a rethink about the mineral and bone disorder of chronic kidney disease (CKD). FGF-23 powerfully predicts adverse cardiovascular outcomes in patients with CKD and an important question is whether treatment regimens should now be tailored to address FGF-23 levels in addition to those of calcium, phosphate, parathyroid hormone and vitamin D. Nevertheless, despite the known action of active vitamin D therapies to increase FGF-23, this should probably still form an important part of the management of patients with hyperparathyroidism and perhaps at low doses of essentially all patients with advanced renal disease.

Topics: Bone Density Conservation Agents; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Male

Secondary hyperparathyroidism (SHPT) is a frequent complication of CKD with incidence, prevalence, and costs increasing worldwide. The objective of this analysis was to estimate therapy cost of SHPT in a sub-population of the FARO study.. In the FARO study, an observational survey aimed to evaluate patterns of treatment in patients with SHPT who had undergone hemodialysis, pharmacological treatments and biochemical parameters evolution data were collected in four surveys. Patients maintaining the same treatment in all sessions were grouped by type of treatment and evaluated for costs from the Italian National Health Service perspective.. Four cohorts were identified: patients treated with oral (PO) calcitriol (n=182), intravenous (IV) calcitriol (n=34), IV paricalcitol (n=62), and IV paricalcitol+cinacalcet therapy (n=20); the cinacalcet monotherapy group was not analysed due to low number of patients (n=9). Parathyroid hormone (PTH) level at baseline and effectiveness of treatments in suppressing PTH level were assessed to test comparability among cohorts: calcitriol PO patients were significantly less severe than others (PTH level at baseline lower than 300 pg/ml; p<0.0001); calcitriol IV patients did not reach significant reduction in PTH level. Paricalcitol and paricalcitol+cinacalcet treatment groups results were comparable, while only the IV paricalcitol cohort's PTH level, weekly dosage, and cost decreased significantly from the first to the fourth survey (p=0.020, p=0.012, and p=0.0124, respectively). Total costs per week of treatment (including calcium-based phosphate binder and sevelamer) were significantly lower in the paricalcitol vs paricalcitol+cinacalcet cohort (p<0.001). Major limitations of this study are related to the survey design: not controlled and lack of comparability between cohorts; however, reflective of true practice patterns.. The IV Paricalcitol cohort had significantly lower treatment costs compared with patients treated with paricalcitol+calcimemtics (p<0.001), without a significant difference in terms of baseline severity and PTH control.

Topics: Aged; Aged, 80 and over; Calcitriol; Cinacalcet; Comorbidity; Cost-Benefit Analysis; Drug Therapy, Combination; Ergocalciferols; Fees, Pharmaceutical; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic

Patients on peritoneal dialysis (PD) have protein loss through peritoneal membrane (PM) and experience changes in permeability of the membrane. Paricalcitol is a selective vitamin D receptor activator with an effect upon systemic inflammation and an inhibitory effect upon the renin-angiotensin-aldosterone system (RAAS).. This study explores the possible effect of paricalcitol upon the PM in 23 patients on PD with high iPTH levels. Peritoneal kinetic studies were performed before and after paricalcitol, measuring also ultrafiltration/ day, peritoneal protein losses and proteinuria. Results were compared with a control group of 15 patients not receiving any form of vitamin D.. With a mean dose of 1.3 μg/day, peritoneal protein loss decreased from 0.91 ± 0.35 to 0.76 ± 0.26 g/l (15.4%) (p = 0.007) and from 7.55 to 6.46 g/d (p < 0.033), and ultrafiltration increased from 844 to 1,002 ml/d (15.8%) (p = 0.037) and from 284 to 323 ml/4 h. (NS), with minimal change in the creatinine dialysate/plasma ratio 0.67 ± 0.12 vs. 0.65 ± 0.11. Proteinuria decreased from 1.65 to 1.25 g/l (21.9%) (p = 0.01) and iPTH decreased from 668 ± 303 to 291 ± 148 pg/ml (p < 0.001). In the control group, no changes in peritoneal membrane permeability and proteinuria were found.. The results of the study indicate that paricalcitol is effective in treating hyperparathyroidism in patients on PD, and suggest an effect upon proteinuria and PM permeability (not previously reported), with diminished peritoneal protein loss and increased ultrafiltration. The antiinflammatory, antifibrotic and RAAS-modulating actions described for paricalcitol may be responsible for these findings, and could be important for preserving the peritoneum as a dialyzing membrane.

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Permeability; Prospective Studies; Proteinuria

Pseudohypoparathyroidism type 1B (PHP1B) patients have PTH resistance at the renal proximal tubule and develop hypocalcemia and secondary hyperparathyroidism. Hyperparathyroid bone disease also develops in some patients. PHP1B patients are at theoretical risk of developing tertiary hyperparathyroidism.. Patients were studied in a clinical research center.. Five female PHP1B patients presented with hypercalcemia and elevated PTH.. Patients either underwent parathyroidectomy (n = 4) or received cinacalcet (n = 1).. Serum calcium and PTH were serially measured before and after intervention.. Five PHP1B patients developed concomitantly elevated serum calcium and PTH levels (range, 235-864 ng/liter) requiring termination of calcium and vitamin D therapy (time after diagnosis, 21-42 yr; median, 34 yr), consistent with tertiary hyperparathyroidism. Four patients underwent parathyroidectomy with removal of one (n = 2) or two (n = 2) enlarged parathyroid glands. Calcium and vitamin D therapy was reinstituted postoperatively, and at 93-month median follow-up, PTH levels ranged between 56 and 182 (normal, <87) ng/liter. One patient was treated with cinacalcet, resulting in resolution of hypercalcemia.. PHP1B patients are at risk of developing tertiary hyperparathyroidism and/or hyperparathyroid bone disease and should therefore be treated with sufficient doses of calcium and vitamin D to achieve serum calcium and PTH levels within or as close to the normal range as possible. Surgery is the treatment of choice in this setting. Cinacalcet may be a useful alternative in those who do not undergo surgery.

Topics: Adolescent; Age of Onset; Calcitriol; Calcium; Child, Preschool; Disease Progression; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Male; Middle Aged; Muscular Diseases; Osteitis Fibrosa Cystica; Parathyroid Glands; Parathyroid Hormone; Parathyroidectomy; Pseudohypoparathyroidism; Seizures; Syntaxin 16; Young Adult

Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone, a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses.. We examined mortality-predictability of low (>1 but <10 µg/week) versus high (≥10 µg/week) dose of administered paricalcitol over time in a contemporary cohort of 15 442 MHD patients (age 64 ± 15 years, 55% men, 44% diabetes, 35% African-Americans) from all DaVita dialysis clinics across the USA (7/2001-6/2006 with survival follow-ups until 6/2007) using conventional Cox regression, propensity score (PS) matching, and marginal structural model (MSM) analyses.. In our conventional Cox models and PS matching models, low dose of paricalcitol was not associated with mortality either in baseline (hazard ratio (HR): 1.03, 95% confidence interval (CI): (0.97-1.09)) and (HR: 0.99, 95%CI:(0.86-1.14)) or time-dependent (HR: 1.04, 95%CI: (0.98-1.10)) and (HR: 1.12, 95%CI: (0.98-1.28)) models, respectively. In contrast, compared to high dose of paricalcitol, low dose was associated with a 26% higher risk of mortality (HR: 1.26, 95%CI: (1.19-1.35)) in MSM. The association between dose of paricalcitol and mortality was robust in almost all subgroups of patients using MSMs.. Higher dose of paricalcitol appears causally associated with greater survival in MHD patients. Randomized controlled trials need to verify the survival effect of paricalcitol dose in MHD patients are indicated.

Topics: Aged; Bone Density Conservation Agents; Cohort Studies; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Models, Structural; Mortality; Parathyroid Hormone; Predictive Value of Tests; Propensity Score; Proportional Hazards Models; Receptors, Calcitriol; Renal Dialysis; Survival Analysis

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Naphthalenes; Renal Dialysis; Vitamin D

Parathyroidectomies are performed when medical therapy fails to control secondary hyperparathyroidism in hemodialysis patients. The objective of this study was to compare parathyroidectomy rates in secondary hyperparathyroidism patients treated with paricalcitol or cinacalcet.. Retrospective cohort study using health insurance claims from January 2001 through June 2007 for adult hemodialysis patients who were new users of paricalcitol or cinacalcet. Subjects had a minimum of 12 months' enrollment prior to initiation of treatment and at least 30-day follow-up.. We identified 1,387 paricalcitol- and 1,317 cinacalcet-treated patients. The parathyroidectomy incident rate was 74% lower in the paricalcitol (0.58 per 100 patient-years) compared to the cinacalcet (2.24 per 100 patient-years) cohort, with an unadjusted rate ratio of 0.26 (95% CI 0.12-0.52). The time to parathyroidectomy from medication initiation was longer for paricalcitol than cinacalcet; however, it was not statistically significant (535 vs. 443 days, p = 0.377). A Cox proportional hazard model that adjusted for age, gender, obesity, significantly different comorbidities, and duration of hemodialysis resulted in an adjusted risk reduction for parathyroidectomy of 79% (HR = 0.21, 95% CI 0.10-0.46) for paricalcitol compared to cinacalcet.. These data suggest that long-term treatment with paricalcitol is associated with fewer parathyroidectomies when compared to cinacalcet. Further comparative studies are needed to validate these results.

Topics: Cinacalcet; Cohort Studies; Comorbidity; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Illinois; Male; Middle Aged; Naphthalenes; Prevalence; Proportional Hazards Models; Renal Dialysis; Treatment Outcome

Paricalcitol is more effective than calcitriol in hemodialysis patients (HD) with secondary hyperparathyroidism (SHPT), but it is not effective in some of them. We have investigated the relationship between paricalcitol responsiveness and parathyroid gland (PTG) size. Thirty HD with SHPT treated previously with calcitriol for at least 6 months were switched to paricalcitol (1:4 conversion ratio). Parathyroid gland number and size (maximum longitudinal diameter [MLD] of largest PTG) was measured by ultrasonography. Patients were divided into 2 groups: group A (MLD ≤9.0 mm [17 HD]); and group B (MLD >9.0 mm [13 HD]). They were defined responder if both the last 2 monthly determinations of inhibit parathyroid hormone (iPTH) were within the target (<300 pg/mL) according to National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommendations. Twenty-six and 20 HD completed 6-month and 12-month paricalcitol therapy, respectively. After 6 months of paricalcitol treatment, 23.5% HD of group A and 7.7% of group B were responders. At 12 months, 41.2 % of group A and 7.7% of group B were responders. Throughout paricalcitol therapy, serum calcium and phosphorus concentrations slightly increased in all HD but more significantly in group B. The baseline iPTH and MLD of the largest PTG were significantly correlated with final iPTH levels. Paricalcitol is more effective than calcitriol in SHPT, but the responsiveness to paricalcitol and hypercalcemia are related to PTG size. The measurement of MLD by ultrasonography may be useful for predicting responsiveness to paricalcitol, avoiding an unnecessary and expensive therapy.

Topics: Aged; Bone Density Conservation Agents; Calcitriol; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Glands; Renal Dialysis

A dyshomeostasis of macro- and micronutrients, including vitamin D and oxidative stress, are common pathophysiologic features in patients with congestive heart failure (CHF). In African Americans (AA) with CHF, reductions in plasma 25(OH)D are of moderate-to-marked severity (<20 ng/mL) and may be accompanied by ionized hypocalcemia with compensatory increases in serum parathyroid hormone (PTH). The management of hypovitaminosis D in AA with CHF has not been established.. Herein, a 14-week regimen: an initial 8 weeks of oral ergocalciferol (50,000 IU once weekly); followed by a 6-week maintenance phase of cholecalciferol (1400 IU daily); and a CaCO₃ (1000 mg daily) supplement given throughout was designed and tested. Fourteen AA patients having a dilated (idiopathic) cardiomyopathy with reduced ejection fraction (EF, <35%) were enrolled: all completed the initial 8-week course; and 12 complied with the full 14 weeks. At baseline, 8 and/or 14 weeks, serum 25(OH)D and PTH; serum 8-isoprostane, a biomarker of lipid peroxidation, and echocardiographic EF were monitored.. Reduced 25(OH)D at entry (14.4 ± 1.3 ng/mL) was improved (P < 0.05) in all patients at 8 weeks (30.7 ± 3.2 ng/mL) and sustained (P < 0.05) at 14 weeks (30.9 ± 2.8 ng/mL). Serum PTH, abnormally increased in 5 patients at baseline (104.8 ± 8.2 pg/mL), was reduced at 8 and 14 weeks (74.4 ± 18.3 and 73.8 ± 13.0 pg/mL, respectively). Plasma 8-isoprostane at entry (136.1 ± 8.8 pg/mL) was reduced at 14 weeks (117.8 ± 7.8 pg/mL; P < 0.05), whereas baseline EF (24.3 ± 1.7%) was improved (31.3 ± 4.3%; P < 0.05).. Thus, the 14-week course of supplemental vitamin D and CaCO₃ led to healthy 25(OH)D levels in AA with heart failure having vitamin D deficiency of moderate-to-marked severity. Albeit a small patient population, the findings suggest that this regimen may attenuate the accompanying secondary hyperparathyroidism and oxidative stress and improve ventricular function.

Topics: Black or African American; Calcium Carbonate; Calcium, Dietary; Cardiomyopathy, Dilated; Cholecalciferol; Dietary Supplements; Dinoprost; Ergocalciferols; Female; Heart Failure; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Stroke Volume; Vitamin D; Vitamin D Deficiency

Secondary hyperparathyroidism (SHPT) is a common problem among patients with chronic kidney disease (CKD) on haemodialysis. This study was conducted to assess the use, effectiveness and safety of intravenous paricalcitol in haemodialysis patients with various degrees of SHPT.. This observational, multicentre, prospective study was conducted in 14 Swedish dialysis centres from May 2007 to June 2008 and included 92 haemodialysis patients with a diagnosis of SHPT associated with CKD. The decision to initiate treatment with intravenous paricalcitol was made by the treating physician. No treatment algorithms were provided.. Mean patient age was 64 years. Of the 92 patients included, 74 had an intact parathyroid hormone (iPTH) level of >300 pg/ml at baseline. Median iPTH was 584 pg/ml in patients with a baseline PTH of >300 pg/ml. During follow-up there was a decrease in iPTH to 323 pg/ml at 6 months (-45%, p < 0.0001). In parallel, there was a small increase in serum calcium, but serum phosphorus and the calcium × phosphorus product remained unchanged.. This study showed that intravenous paricalcitol substantially and safely decreased iPTH in haemodialysis patients with a baseline iPTH above the Kidney Disease Outcomes Quality Initiative recommended target range (150-300 pg/ml) and had minimal impact on serum minerals.

Topics: Aged; Biomarkers, Pharmacological; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Chronic Disease; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Observation; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Sweden

Secondary hyperparathyroidism is a characteristic feature of chronic kidney disease, which develops early in the course of chronic kidney disease, often in a progressive way. It occurs as the renal function continues to decline and is encountered following a series of biochemical abnormalities, which are responsible for initiation and maintenance of increased parathyroid hormone (PTH) secretion. Several agents are used in the management of secondary hyperparathyroidism. Paricalcitol is a new generation selective vitamin D receptor activator that lowers PTH levels by exerting a less hypercalcaemic and hyperphosphataemic effect. In addition, there is emerging evidence of the benefit of paricalcitol in preventing intravascular calcification and proteinuria.

Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Renal Dialysis; Renal Insufficiency, Chronic; Survival Analysis; Vitamins

Two new clinical trials highlight refinements in the use of vitamin D and its analogs in the treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD), and the treatment of proteinuria in diabetics. In patients with ESRD, alfacalcidol is as effective as paricalcitol in suppressing parathyroid hormone; the occurrence of hypercalcemia and hyperphosphatemia is infrequent and similar with the two analogs. Oral cholecalciferol reduces albuminuria and urinary transforming growth factor-β1 in patients with type 2 diabetes mellitus and proteinuria.

Topics: Albuminuria; Cholecalciferol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Male; Renal Dialysis; Renin-Angiotensin System; Transforming Growth Factor beta1

Severe secondary hyperparathyroidism is a complication of chronic kidney disease. Paricalcitol is a vitamin D receptor activator with efficacy in the treatment of hyperparathyroidism that also has the minor side effects of hypercalcemia and hyperphosphatemia. As a pleiotropic effect, paricalcitol reduces proteinuria in patients with chronic kidney disease stages 2-4. Oral paricalcitol offers an alternative way to treat hyperparathyroidism and proteinuria in peritoneal dialysis patients. Our prospective study enrolled 18 patients with hyperparathyroidism (6 with diabetes also) who were given oral paricalcitol at initial dose of 1-2 microg daily, depending on their level of intact parathyroid hormone (iPTH). In the 1st month, iPTH levels declinedsignificantly to 295 +/- 147 pg/mL from 670 +/- 318 pg/mL, and by the 3rd month, they declined to 192 +/- 340 pg/mL (p < 0.001). Without modifications to doses of angiotensin converting-enzyme inhibitor or angiotensin II receptor blocker, proteinuria declined in the 1st month to 1.41 +/- 1.5 g/L from 1.68 +/- 1.7 (p = 0.006) and, in the 3rd month, without statistical significance. In some patients, the dose of paricalcitol was reduced because of iPTH levels that were too low at 1 month. The patients whose doses of paricalcitol were maintained at 3 months showed a reduction in proteinuria to 2.1 +/- 2.1 g/L daily from 3.1 +/- 2. 7 g/L (p = 0.04) and to 2.3 +/- 2.1 g/day from 5.0 +/- 6.1 g/day (p = 0.012). In conclusion, paricalcitol is effective for treating hyperparathyroidism in patients on peritoneal dialysis and seems also to have an antiproteinuric effect in these patients.

Topics: Administration, Oral; Adult; Aged; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis; Proteinuria

Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease. Treatment with paricalcitol, a selective vitamin D receptor (VDR) activator, has shown benefits in these patients by adequately reducing PTH levels with minimal changes in serum calcium and phosphorus. The aim of this study was to assess the effectiveness and safety of paricalcitol in chronic renal disease patients (CKD grades 3 and 4).. A study of our experience with paricalcitol was conducted in normal clinical practice in patients over 18 years diagnosed with grade 3 or 4 chronic kidney disease. Patients were periodically evaluated every 3 months. The primary endpoint of effectiveness was to obtain two consecutive decreases of ≥30% in iPTH with respect to baseline values. The secondary endpoints were fulfilment of the objectives in accordance with the Spanish Society of Nephrology (SEN) and Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, as well as the relationship between the effectiveness of the treatment and different patient variables. Safety was studied by means of hypercalcaemia events.. The primary study endpoint was achieved in 54.3% of patients. In addition, another 16.3% of patients had reduced iPTH by more than 30% at the 3rd visit. Therefore, 70.6% of patients reduced their iPTH levels by more than 30% in 6 months. The relationship between treatment success and both glomerular filtration rate and body mass index was significant. There were few adverse events, although hypercalcaemia was found in 5.4% of patients.. Treatment with paricalcitol is effective in controlling secondary hyperparathyroidism in non-dialysed patients with a wide safety margin.

Topics: Aged; Aged, 80 and over; Body Mass Index; Calcium; Chronic Disease; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Evaluation; Endpoint Determination; Ergocalciferols; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3-hour daily hemodialysis (3 hours x 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321-1983]-472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium x phosphorus product (80.3 +/- 26.8-48.9 +/- 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 +/- 2.34-4.75 +/- 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 +/- 2.04-9.62 +/- 0.93 mg/dL, P<0.01). Three-hour daily hemodialysis with the use of high-dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.

Topics: Adult; Appointments and Schedules; Biomarkers; Bone Density Conservation Agents; Calcinosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Ergocalciferols; Female; Heart Valve Diseases; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Minerals; Phosphates; Renal Dialysis; Severity of Illness Index

secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) and a frequent cause of clinically significant bone disease. Non-selective vitamin D receptor (VDR) activator treatment has been used to treat the condition but is ineffective for many patients with hypercalcaemia and hyperphosphataemia and may precipitate worsening of their condition. Compared with non-selective VDR activator treatment, use of the VDR ligand paricalcitol may increase survival and reduce the risk of morbidities in patients with SHPT, which may have health economic consequences.. the objective of this study was to determine the cost effectiveness of paricalcitol versus a non-selective VDR activator for the treatment of SHPT in patients with CKD in the UK setting.. A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials and observational studies, official UK price/tariff lists and national population statistics. The comparator was alfacalcidol, a non-selective VDR activator medication. The primary perspective of the study was that of the UK National Health Service (NHS). The efficacy outcomes (reductions in SHPT, proteinuria, complications and mortality) were extrapolated to: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3.5%. The year of costing for costs determined in the study was 2006.. the reference case analysis was a 10-year time horizon, based on a comparison of paricalcitol with a non-selective VDR activator, which is started in CKD stage 3 (moderate reduction in glomerular filtration rate [GFR] with kidney damage) and continued in CKD stage 4 (severe reduction in GFR) and CKD stage 5 (established kidney failure). The use of paricalcitol leads to an additional medical cost of pound3224 ($US5970). The health benefits of paricalcitol lead to an increase in LYG of 0.52 and a gain in QALYs of 0.465. Therefore the use of paricalcitol results in an incremental cost-effectiveness ratio of pound6933/QALY ($US12 840/QALY) from the primary perspective of the NHS. One-way sensitivity analyses and probabilistic sensitivity analyses confirmed the robustness of the model.. this model showed that the favourable clinical benefit of paricalcitol results in positive short- and long-term health economic benefits. This study suggests that the use of paricalcitol in patients with early CKD may be cost effective from the UK NHS perspective versus non-selective VDR activator medication.

Topics: Chronic Disease; Cost-Benefit Analysis; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Markov Chains; Quality-Adjusted Life Years; Receptors, Calcitriol

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Renal Dialysis; Time Factors; Treatment Outcome; Up-Regulation

Treatment options for secondary hyperparathyroidism were significantly amended with the introduction of cinacalcet and paricalcitol. Limitations of resources in public health systems demand detailed analyses of accruing costs. The aim of this study was to compare the costs of these new treatment modalities to surgery.. Patients who underwent initial parathyroidectomy (n = 91) and patients treated with cinacalcet or paricalcitol (n = 100) at an ambulatory dialysis center between 01/2003 and 12/2006 were analyzed. The revenues of both therapies for the funding agencies were calculated by a cost-cost analysis. The real arising costs of the supplier were analyzed and compared to the revenues.. Treatment costs for cinacalcet (60 mg/day/year) were 5828.40€ and 4485.20€ for paricalcitol (15 μg/week/year). Revenues for inpatient surgical treatment according to the German DRG system were 3755.38€/case. Additionally, costs for postoperative ambulatory therapies were 545.05€ for the first year and 384.97€ for the following.. Due to linearly increases, expenses of medical treatment with cinacalcet for more than 9 months or paricalcitol for more than 12 months exceeded the costs of surgical therapy. The indication of these new medical therapies should be restricted to patients as an interim solution ahead of surgery or in patients considered unfit for surgery.

Topics: Bone Density Conservation Agents; Cinacalcet; Cost Control; Costs and Cost Analysis; Ergocalciferols; Germany; Humans; Hyperparathyroidism, Secondary; Naphthalenes; Parathyroidectomy

National Kidney Foundation's Kidney Disease Outcome Quality Initiative (KDOQI) guidelines offer an outline for providing standardized care for best outcomes in chronic kidney disease (CKD). It is unknown whether real-world treatment practices follow these guidelines.. The Hectorol Registry Outcome in Chronic Kidney Disease (HeROICkd), an observational patient registry, captured information on adult patients with CKD Stage 3 or 4 throughout US clinics during a 9-month observation period. Data were collected quarterly from patients' medical records, throughout each patient's normal treatment course. The proportion of patients with intact parathyroid hormone (iPTH) levels within KDOQI guidelines, change in iPTH, Ca, P, and Ca x P product over the 9-month observation period, incidence of hypercalcemia and hyperphosphatemia, and predictors of change in iPTH were examined.. 1,339 CKD Stage 3 and 4 patients from 78 nephrology and internal medicine clinics were included. 40% of CKD Stage 3 participants and 45% of Stage 4 had a 30% or greater reduction in iPTH levels from baseline to 9 months follow-up. While the proportion of CKD Stage 3 and 4 participants with iPTH levels within the KDOQI recommendations improved significantly over the 9 months, it was still modest, at 28% and 23%, respectively. Mean doxercalciferol dose was below that recommended in the package insert and a minority of patients had all mineral metabolism parameters (iPTH, Ca, P) regularly recorded in their medical records.. The results of this registry, which examined iPTH treatment with doxercalciferol in CKD Stage 3 and 4, suggest that in the real-world treatment setting, the adherence to KDOQI guidelines is not optimal.

Topics: Aged; Aged, 80 and over; Bone Density Conservation Agents; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Phosphorus; Practice Guidelines as Topic; Registries

The objective of this study was to determine the cost effectiveness of paricalcitol versus calcitriol for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease in the United States setting.. A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials and observational studies, official US price/tariff lists and national population statistics. The comparator was calcitriol, a non-selective vitamin D receptor activator (VDRA) medication. The primary perspective of the study was that of the third-party payer in the US. The efficacy outcomes (reduction in secondary hyperparathyroidism (SHPT), reduction in proteinuria, complications and mortality) were extrapolated to: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3.5%.. The reference case analysis was a 10-year time horizon based on a comparison of paricalcitol with calcitriol, which is started in chronic kidney disease (CKD) stage 3 and continued in CKD stage 4 and CKD stage 5. The use of paricalcitol leads to a cost saving of US$1941. The inclusion of indirect costs leads to a cost saving of US$2528. The use of paricalcitol leads to an increase in life-years gained (0.47 years) and a gain in QALYs (0.43). The use of paricalcitol results in a dominant outcome from the perspective of the third-party payer, as well as from the societal perspective. One-way sensitivity analyses and probabilistic sensitivity analyses confirmed the robustness of the model.. This model showed that the favorable clinical benefit of paricalcitol results in positive short and long-term health economic benefits. This study suggests that the use of paricalcitol in patients with early chronic kidney disease may be cost-effective from the third-party payer perspective in the US versus calcitriol. Additional comparative studies are necessary to validate these results.

Topics: Algorithms; Calcitriol; Case-Control Studies; Cost-Benefit Analysis; Decision Support Techniques; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Markov Chains; Models, Biological; Renal Insufficiency, Chronic; Sensitivity and Specificity; United States

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) health in the general population and those at high risk of CV disease, as well as in patients with chronic kidney disease (CKD). In CKD patients, a lack of VDR activation is one of the main pathophysiological factors contributing to secondary hyperparathyroidism (SHPT). However, this lack of VDR activation has numerous additional implications on CV and renal function, with SHPT being only one symptom of a much more extensive disorder. VDRs are widely expressed throughout the body with manifold activities that involve feedback loops within the CV, immune, and renal systems. Modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and vascular calcifi cation, as well as a number of other endpoints in cardiac and renal pathology. Among compounds available for the treatment of SHPT, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the PTH gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond PTH control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.

Topics: Bone Density Conservation Agents; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Receptors, Calcitriol

Secondary hyperparathyroidism is a serious complication of chronic renal disease when function decline and is characterized by abnormalities in serum calcium and phosphate profile, along with a decline in calcitriol synthesis. A reduced density of specific receptors for vitamin D and calcium in several tissues and organs are also present, thus contributing to parathyroid hyperplasia and abnormal parathyroid hormone synthesis and secretion. This metabolic derangement is observable early in the course of chronic renal failure (stages 3 and 4) and on this basis it should also be treated early in order to avoid important clinical consequences. To afford secondary hyperparathyroidism, several strategies should be considered: phosphate oral intake control (diet and phosphate binders), adequate calcium oral intake, vitamin D receptor activation. More specifically, the concept of selective vitamin D receptor activation will be considered as well as its biological effects, the use of paricalcitol (a selective vitamin D receptor activator) given orally to patients on peritoneal dialysis, and stages 3 and 4 of chronic renal failure. Finally, we will consider a series of nonclassical interesting potential mechanisms of selective vitamin D receptor activation leading to reduced cardiovascular and all-cause mortality.

Topics: Bone Density Conservation Agents; Calcitriol; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Peritoneal Dialysis; Phosphates; Receptors, Calcitriol

Vascular calcification is associated with an increase in cardiovascular mortality in stage 5 chronic kidney disease. To determine if vitamin D receptor activators (VDRAs) have differential effects in the pathogenesis of aortic calcification, we assessed the effects of paricalcitol and doxercalciferol in vivo using 5/6 nephrectomized (NX) rats. To quantify the functional consequences of vascular calcification, pulse wave velocity (PWV), an aortic compliance index, was measured.. NX rats were fed a diet containing 0.9% phosphorous and 0.6% calcium 4 weeks prior to and throughout the study. On Day 0, rats received vehicle or VDRA (0.083, 0.167 and 0.333 microg/kg, i.p.) three times per week for 6 weeks. At Day 0 and Weeks 2 and 6, blood was drawn and PWV was measured by Doppler ultrasound.. VDRAs (0.167 and 0.333 microg/kg) consistently lowered PTH at Weeks 2 and 6. All doses of paricalcitol increased serum calcium at Week 6 but not at Week 2, while the two higher doses of doxercalciferol increased serum calcium at both Weeks 2 and 6. Treatment with paricalcitol (0.333 microg/kg) increased serum phosphorus at Weeks 2 and 6; these changes were not different from those observed in 5/6 NX rats. All doses of doxercalciferol increased serum phosphorus at Week 6. Paricalcitol had no effect on Ca x P; however, the two highest doses of doxercalciferol increased Ca x P at Weeks 2 and 6 above that observed in the 5/6 NX vehicle-treated group. There were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with the two higher doses of doxercalciferol caused a significant elevation in aortic calcium and phosphorus contents. Measurements of PWV demonstrated differential effects of VDRAs on vascular compliance. Paricalcitol produced no effects on PWV, while the two highest doses of doxercalciferol increased PWV at Week 6.. In uraemic rats with established secondary hyperparathyroidism, we demonstrate differential effects of paricalcitol and doxercalciferol on aortic calcification and PWV, independent of serum Ca, P and Ca x P, suggesting different mechanisms of action between VDRAs.

Topics: Animals; Aorta; Blood Flow Velocity; Calcinosis; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Renal Insufficiency, Chronic; Uremia; Vascular Resistance

Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients; however, patients with higher serum parathyroid hormone (PTH), indicative of a more severe secondary hyperparathyroidism and higher death risk, are usually given higher VDRA dosages, which can lead to confounding by medical indication and attenuated survival advantage of high VDRA dosages. It was hypothesized that the ratio of the administered paricalcitol dosage to serum PTH level discloses better the underlying dosage-survival association.. The 3-yr mortality predictability of the administered paricalcitol during the first 3 mo of the cohort divided by averaged serum intact PTH during the same period was examined in 34,307 MHD patients from all DaVita dialysis clinics across the United States using Cox regression.. MHD patients were 60.8 +/- 15.4 yr of age and included 47% women, 34% black patients, and 47% patients with diabetes. Initially, the ratio of paricalcitol (mircrog/wk) to PTH (pg/ml) was divided into four groups: 0 (reference), 1 to <30, 30 to <60, and >60 x 10(-3). Unadjusted, case mix-adjusted (demographics, comorbidity, and Kt/V), and malnutrition-inflammation complex syndrome-adjusted models, the death rate ratio for the paricalcitol/PTH index groups, were 0.99, 0.95, and 0.92. Restricted cubic splines analyses were consistent with a linear relation.. Higher weekly paricalcitol dosage per each unit of serum PTH seems to have an incremental association with greater survival in MHD patients. The observed dosage-response phenomenon needs to be confirmed in clinical trials.

Topics: Aged; Biomarkers; Chronic Disease; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Proportional Hazards Models; Receptors, Calcitriol; Renal Dialysis; Risk Assessment; Time Factors; Treatment Outcome; United States

Topics: Calcinosis; Calcium; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Molecular Mimicry; Receptors, Calcitriol; Renal Dialysis

Calciphylaxis (calcific uremic arteriolopathy) is a severe complication of hemodialysis characterized by subcutaneous calcification of the small arteries and tissue necrosis. Our case report is focused on a woman receiving hemodialysis (HD) with diabetes mellitus for 20 years and severe secondary hyperparathyroidism, who presented painful subcutaneous nodules, skin necrosis and ulcerations. As the treatment of calciphylaxis is mainly empirical and controversial, we decided to administer cinacalcet with paricalcitol for the control of hyperparathyroidism and sodium thiosulfate to improve the calcification of the arterioles. Two months after the start of the therapy, parathyroid hormone (PTH) decreased significantly and the skin lesions nearly disappeared. Thus, we believe that the combination of sodium thiosulfate with cinacalcet and paracalcitol is effective for the treatment of calciphylaxis with secondary hyperparathyroidism.

Topics: Aged; Calciphylaxis; Chelating Agents; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Naphthalenes; Renal Dialysis; Thiosulfates; Treatment Outcome

Doxercalciferol and paricalcitol are used to treat hyperparathyroidism in chronic kidney disease. This study was conducted to define equivalent dose requirements to convert patients from intravenous paricalcitol to intravenous doxercalciferol.. Following a 4-week baseline period using a fixed dose of paricalcitol, 42 adult hemodialysis subjects were assigned to receive a fixed dose of doxercalciferol for 4 weeks using a conversion factor of either 50 or 65% of the prior paricalcitol dose. During a 12-week titration period the doxercalciferol dose was adjusted to optimize iPTH levels into the range of 150 - 300 pg/ml. Annual costs to achieve equivalent iPTH control were calculated for both vitamin D analogs.. During the doxercalciferol fixed-dose period, the average dose of doxercalciferol was 2.1 +/- 1.3 microg and 3.1 +/- 1.8 microg in the 50 and 65% dose conversion groups, respectively. During this period mean iPTH in the 50% dose conversion group increased by 24 pg/ml (p = 0.017). During the dose titration period, doxercalciferol was increased to bring iPTH within the target range. Calcium control was maintained with both conversion factors, while slightly better phosphorus control was seen in the 65% dose conversion group. Annualized treatment cost for doxercalciferol was 28% less expensive per patient than paricalcitol.. Patients can be managed safely and effectively with conversion and dose titration from paricalcitol to doxercalciferol. Both conversion strategies maintained iPTH at clinically satisfactory levels. Furthermore, doxercalciferol therapy resulted in drug acquisition cost-savings.

Topics: Bone Density Conservation Agents; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Treatment Outcome

Vitamin D compounds are effective in managing elevated PTH levels in secondary hyperparathyroidism (SHPT) of renal failure. However, undesired increases in serum calcium and phosphorus associated with compounds such as calcitriol [1,25(OH)2D3] has prompted a search for compounds with improved safety profiles. 1alpha,24(S)(OH)2D2 (1,24(OH)2D2) is a vitamin D2 metabolite with low calcium-mo bilizing activity in vivo. We studied the efficacy of 1,24(OH)2D2 in mice lacking the CYP27B1 enzyme [25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase)], a novel vitamin D deficiency model with SHPT.. 1alpha-OHase-deficient (-/-) mice and normal (+/-) heterozygous littermates re ceived 1,24(OH)2D2 (100, 300, 1000, and 3000 pg/g/day) or 1,25(OH)2D3 (30, 300, and 500 pg/g/day) for 5 weeks via daily sc injection. Control groups received vehicle.. Vehicle-treated 1alpha-OHase-deficient mice were hypocalcemic and had greatly elevated serum PTH. 1,24(OH)2D2 at doses above 300 pg/g/day normalized serum calcium, serum PTH, bone growth plate morphology, and other bone parameters. No hy percalcemia was observed at any dose of 1,24(OH)2D2 in normal or 1alpha-OHase-deficient animals. In contrast, 1,25(OH)2D3 at only 30 pg/g/day normalized calcemia, serum PTH, and bone parameters, but at higher doses completely suppressed PTH and caused hypercalcemia in both 1alpha-OHase-deficient and normal mice. Treatment with 500 pg/g/day of 1,25(OH)2D3 also induced osteomalacia in normal animals.. 1,25(OH)2D3 was maximally active at 10-fold lower doses than 1,24(OH)2D2, but induced hypercalcemia and osteomalacia at high doses. 1,24(OH)2D2 normalized serum calcium, serum PTH, and bone histomorphometry without hypercalcemia in 1alpha-OHase-deficient mice with SHPT.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Bone and Bones; Calcinosis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ergocalciferols; Femur; Hypercalcemia; Hyperparathyroidism, Secondary; Mice; Mice, Transgenic; Parathyroid Hormone; Vitamin D Deficiency

Vitamin D derivatives and calcimimetics are used to treat secondary hyperparathyroidism in patients with chronic renal failure. We investigated the effect of calcitriol, paricalcitol, and the calcimimetic AMG 641 on soft-tissue calcification in uremic rats with secondary hyperparathyroidism. Control and uremic rats were treated with vehicle, calcitriol, paricalcitol, AMG 641, or a combination of AMG 641 plus calcitriol or paricalcitol. Parathyroid hormone levels were reduced by all treatments but were better controlled by the combination of paricalcitol and AMG 641. The calcimimetic alone did not induce extraosseous calcification but co-administration of AMG 641 reduced soft-tissue calcification and aortic mineralization in both calcitriol- and paricalcitol-treated rats. Survival was significantly reduced in rats treated with calcitriol and this mortality was attenuated by co-treatment with AMG 641. Our study shows that extraskeletal calcification was present in animals treated with calcitriol and paricalcitol but not with AMG 641. When used in combination with paricalcitol, AMG 641 provided excellent control of secondary hyperparathyroidism and prevented mortality associated with the use of vitamin D derivatives without causing tissue calcification.

Topics: Animals; Aorta; Calcinosis; Calcitriol; Calcium; Calcium Channel Agonists; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Phosphorus; Rats; Rats, Wistar; Uremia

Abnormalities in vitamin D metabolism play a major role in the pathogenesis of secondary hyperparathyroidism in chronic kidney disease. The gradual and progressive decline in 1,25-dihydroxyvitamin D in the course of chronic kidney disease is the result of several mechanisms that limit the ability of the failing kidney to maintain the levels of 1,25-dihydroxyvitamin D despite increasing levels of parathyroid hormone. Recent observations have indicated that chronic kidney disease seems to be associated with a high incidence of nutritional vitamin D insufficiency or deficiency as manifested by decreased levels of 25-hydroxyvitamin D. This contributes to the inability to maintain the levels of 1,25-dihydroxyvitamin D; therefore, current practice guidelines suggest repleting vitamin D status by the administration of native vitamin D as a first step in the therapy of the abnormalities of bone and mineral metabolism in chronic kidney disease. The efficacy of this therapy is extremely variable, and active vitamin D sterols may be required, especially as kidney disease progresses. The importance of the abnormal vitamin D metabolism is being investigated vigorously in view of the observations that vitamin D may have important biologic actions in many tissues in addition to bone and parathyroid. Thus, observational data have suggested potential survival benefits of vitamin D sterol administration in this clinical setting, and experimental data have suggested a potential beneficial effect of vitamin D sterols on the progression of kidney disease. Further work is required to define the mechanisms involved and to examine the effects of vitamin D therapy on outcomes in randomized, controlled trials.

Topics: Chronic Disease; Ergocalciferols; Evidence-Based Medicine; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Practice Guidelines as Topic; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

A 17-year-old Filipino male hemodialysis patient presented for renal transplant evaluation. He had significant skeletal abnormalities characterized by bone pain, an inability to walk, and secondary hyperparathyroidism despite therapy with an active vitamin D sterol (paricalcitol).. The patient underwent a physical examination, and his serum levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, aluminum and 25-hydroxycholecalciferol (25OH-vitamin D) were determined. X-rays of hips and lower extremities, MRI, and bone histomorphometry after double tetracycline labeling were performed.. Osteomalacia associated with low 25OH-vitamin D levels.. Monthly therapy with ergocalciferol (vitamin D2) and discontinuation of paricalcitol.

Topics: Adolescent; Bone Density Conservation Agents; Ergocalciferols; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Osteomalacia; Renal Dialysis; Vitamin D Deficiency

Topics: Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Renal Dialysis

Vitamin D is essential for intestinal calcium absorption, bone mineralisation and plays an important role in neuromuscular functions. Vitamin D insufficiency is highly prevalent among postmenopausal women with osteoporosis and in the elderly. In turn, supplements of vitamin D3 (cholecalciferol), and to a lesser extent vitamin D2 (ergocalciferol), may decrease falls and fracture risk by 25%. Despite some recent negative studies, the actual question is not to know whether vitamin D is necessary, but rather how much vitamin D is sufficient to prevent secondary hyperparathyroidism, falls and fractures. Moreover, the risk of osteoporosis and of fragility fractures may be influenced by genetic variation in the vitamin D receptor (VDR).

Topics: Accidental Falls; Aged; Bone Density Conservation Agents; Calcification, Physiologic; Calcium; Cholecalciferol; Ergocalciferols; Female; Fractures, Bone; Humans; Hyperparathyroidism, Secondary; Intestinal Absorption; Neuromuscular Junction; Osteoporosis; Osteoporosis, Postmenopausal; Receptors, Calcitriol; Vitamin D; Vitamins

The effects of calcitriol and paricalcitol on circulating levels of intact parathyroid hormone, parathyroid hormone-(1-84), the large carboxy-terminal-parathyroid hormone fragments, and the parathyroid hormone-(1-84)/carboxy-terminal-parathyroid hormone fragments were studied.. In the longitudinal study, 31 hemodialysis patients who were receiving intravenous calcitriol or paricalcitol were followed for 6 to 8 wk. After a washout period, patients were treated with the other vitamin D compound for 6 to 8 wk. Plasma intact parathyroid hormone and parathyroid hormone-(1-84) were measured, and the parathyroid hormone ratio was calculated. In the cross-sectional study, results of intact parathyroid hormone, parathyroid hormone-(1-84), and parathyroid hormone ratio were compared between patients who were treated with paricalcitol (n = 49) versus no vitamin D therapy (n = 44).. In the longitudinal study, the parathyroid hormone ratio was significantly lower in patients who were treated with calcitriol and higher with paricalcitol treatment compared with values that were obtained during washout. In the cross-sectional study, intact parathyroid hormone levels were identical in both groups, whereas parathyroid hormone-(1-84) and thus parathyroid hormone ratio values were higher in patients who were given paricalcitol than in patients who were not receiving vitamin D.. These data show that at similar intact parathyroid hormone values, the active parathyroid hormone-(1-84) compound is lower with calcitriol than with paricalcitol treatment. This finding might be relevant for choice of vitamin D compound in patients with stage 5 chronic kidney disease.

Topics: Adult; Aged; Calcitriol; Chronic Disease; Cross-Sectional Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Parathyroid Hormone; Peptide Fragments; Renal Dialysis

Vitamin D has various actions in skeletal muscle. The purpose of this study was to compare lower-limb muscle size and strength in hemodialysis (HD) patients being treated with 1,25-dihydroxyvitamin D (calcitriol) or a 1,25-dihydroxyvitamin D analogue (paricalcitol) with lower-limb muscle size and strength in HD patients who were receiving none.. This was a retrospective, cross-sectional study.. This study was performed in outpatient HD centers.. Hemodialysis patients receiving calcitriol or paricalcitol (active vitamin D) for control of secondary hyperparathyroidism (VitD, n = 49) were compared with HD patients who were not (n = 30).. The main outcome measures included the cross-sectional areas (CSAs) of the thigh and tibialis anterior muscles by magnetic resonance imaging, and three measures of strength: the three-repetition maximum (3RM) for knee extension (isotonic), the peak torque of knee extensors (isokinetic), and maximal voluntary contraction of the ankle dorsiflexor muscles (isometric).. There were no differences in age, weight, dialysis vintage, or intact parathyroid hormone levels between groups, although serum albumin was higher in the VitD group (P < .05). Patients in the VitD group had a larger thigh-muscle CSA (P < .05) and were stronger across all strength measures (P < .05) after controlling for age and gender (by analysis of covariance). When all analyses were subsequently adjusted for serum albumin concentration, only the difference in 3RM knee-extension strength lost significance. There were no significant differences in any measurements between patients who received calcitriol or paricalcitol.. Treatment with active vitamin D was associated with greater muscle size and strength in this cohort of HD patients.

Topics: Calcitriol; Cohort Studies; Cross-Sectional Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Parathyroid Hormone; Renal Dialysis; Retrospective Studies; Serum Albumin; Vitamin D

Topics: Calcitriol; Ergocalciferols; Germany; Health Care Costs; Hospitalization; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Models, Economic; Renal Dialysis; Research Design; Survival Rate

Topics: Acetates; Calcitriol; Calcium; Calcium Compounds; Chronic Disease; Cinacalcet; Clinical Trials, Phase III as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Naphthalenes; Parathyroid Hormone; Phosphorus; Randomized Controlled Trials as Topic

Secondary hyperparathyroidism (SHPT) remains a treatment dilemma in pediatric dialysis patients. Recent experience with paricalcitol (P), a vitamin D analogue, in adults with SHPT has shown equal efficacy and improved survival compared to traditional treatment with calcitriol (C). We present our experience with (C) compared to (P) treatment in our pediatric dialysis patients with SHPT. Twenty-one patients (mean age 11.5+/-5 years) with SHPT (intact parathyroid hormone (iPTH) averaging 1,228+/-496 pg/ml) were studied. Seventeen received (C) followed by (P); while an additional four were treated with either (C=1) or (P=3) alone. After 26+/-8 weeks, average percent (%) decrease in iPTH was similar with (C) and (P) (-60.4+/-34% versus -65.4+/-28%, respectively; p=0.6). In the (P) group, the effective dose in children was greater than in adult trials based on kilogram weight. Episodes of hypercalcemia between the treatment groups were not different. However, episodes of elevated calcium x phosphorus product (CaxP)> or =70 mg(2)/dl(2) occurred more frequently in the (C) group (odds ratio=1.5; p=0.01). Paricalcitol appears to be safe and effective in pediatric patients. Data suggest that dosing should be gauged according to degree of SHPT. This should serve as impetus for future pharmacokinetic studies in pediatric dialysis patients.

Topics: Adolescent; Adult; Bone Density Conservation Agents; Calcitriol; Calcium; Child; Child, Preschool; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Infant; Kidney Failure, Chronic; Male; Phosphates; Pilot Projects; Renal Dialysis; Retrospective Studies; Vitamin D

Intravenous vitamin D is standard therapy for secondary hyperparathyroidism in hemodialysis (HD) patients. In for-profit dialysis clinics, mortality was higher for patients on calcitriol compared to paricalcitol. Doxercalciferol, a second vitamin D2 analog, is currently available. We assessed mortality associated with each vitamin D analog and with lack of vitamin D therapy in patients who began HD at Dialysis Clinic Inc. (DCI), a not-for-profit dialysis provider. During the 1999-2004 study period we studied 7731 patients (calcitriol: n=3212; paricalcitol: n=2087; doxercalciferol: n=2432). Median follow-up was 37 weeks. Mortality rates (deaths/100 patient-years) were identical in patients on doxercalciferol (15.4, 95% confidence interval (13.6-17.1)) and paricalcitol (15.3 (13.6-16.9)) and higher in patients on calcitriol (19.6 (18.2-21.1)) (P<0.0001). In all models mortality was similar for paricalcitol versus doxercalciferol (hazard ratios=1.0). In unadjusted models, mortality was lower in patients on doxercalciferol (0.80 (0.66, 0.96)) and paricalcitol (0.79 (0.68, 0.92)) versus calcitriol (P<0.05). In adjusted models, this difference was not statistically significant. In all models mortality was higher for patients who did not receive vitamin D versus those who did (1.2 (1.1-1.3)). Mortality in doxercalciferol- and paricalcitol-treated patients was virtually identical. Differences in survival between vitamin D2 and D3 may be smaller than previously reported.

Topics: Adult; Aged; Aged, 80 and over; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitriol; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis; Retrospective Studies; Risk Factors; Survival Analysis; Vitamin D

Paricalcitol, a vitamin D analog, is commonly administered three times weekly to control secondary hyperparathyroidism in hemodialysis patients. Less frequent dosing would be more convenient, require less nursing time, and be an option in other dialysis modalities. No studies have examined the efficacy of once-weekly dosing of paricalcitol.. Chronic hemodialysis patients receiving a stable dose of paricalcitol three times weekly with intact PTH (iPTH) 100-500 ng/l were monitored during a two-week baseline, then were converted to a single mid-week paricalcitol dose equal to the previous cumulative weekly dose. Serum calcium and phosphorus were monitored weekly and iPTH levels determined during study Weeks 4 and 8. A single paricalcitol dose adjustment was made during study Week 5 based on iPTH to achieve a target value of 150-300 ng/l. Phosphate binders and calcium dialysate bath were kept constant during the study.. In the 25 patients, mean iPTH was 295 +/- 107 ng/l at baseline, and not significantly different at Week 4 (307 +/- 111 ng/l) or Week 8 (285 +/- 98 ng/l). Paricalcitol dose increases mid-study were almost exclusively in patients with iPTH > 300 ng/l. Calcium, phosphorus, and calcium x phosphorus product were not significantly different on weekly therapy. (Only one patient developed a calcium > 2.55 mmol/l during the study.). Once-weekly dosing of paricalcitol is an effective option in treatment of secondary hyperparathyroidism. Less frequent dosing may better allocate nursing time and potentially benefit other patient populations with CKD and ESRD.

Topics: Calcium; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Treatment Outcome

Abnormalities of serum calcium, phosphorous and intact parathyroid hormone (PTH) are associated with morbidity and mortality in haemodialysis patients. Pharmacologic parenteral vitamin D administration is used to correct these abnormalities; however, the relationship between vitamin D therapies and hospitalizations has never been addressed.. Healthcare data from January 1999 to November 2001 were analysed for 11,443 adult haemodialysis patients who received at least 10 doses of vitamin D therapy. Multivariate models were used to evaluate the effects of vitamin D therapy on: (i) total number of hospitalizations, (ii) total number of hospital days and (iii) risk of first hospitalization after initiation of vitamin D therapy.. When compared with the calcitriol group, the paricalcitol group had a lower risk of first all-cause hospitalization (14% less likely, P<0.0001), fewer hospitalizations per year (0.642 fewer, P<0.001) and fewer hospital days per year (6.84 fewer, P<0.001). In the paricalcitol and calcitriol groups, respectively, 5.6 and 41.3% patients switched to another vitamin D compound. For those patients who started and remained on the same vitamin D product, paricalcitol-treated patients experienced 0.846 fewer hospitalizations per year and 9.17 fewer hospital days per year, P<0.001 for both. The paricalcitol group also had a lower risk of first PTH-related hospitalizations, fewer PTH-related annual hospitalizations and fewer days per year.. Paricalcitol-treated patients experienced fewer hospitalizations and hospital days per year when compared with calcitriol-treated patients. Initiating vitamin D therapy with paricalcitol may result in overall savings of approximately 7600-11,000 US dollars per patient per year. A randomized, controlled, blinded study would be valuable in confirming and understanding these results.

Topics: Calcitriol; Ergocalciferols; Hospitalization; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Medical Records; Renal Dialysis; Retrospective Studies; Risk Assessment; Treatment Outcome

This is the first detailed pharmacokinetic report published on the administration of doxercalciferol [1alpha(OH)D(2)] recently introduced to treat secondary hyperparathyroidism.. 1alpha(OH)D(2) was administered in a range of single and multiple doses to volunteers with and without normal renal and/or hepatic function. Subsequent serial blood samples were assayed by HPLC/radioimmunoassay for the metabolite 1,25-dihydroxyvitamin D(2) [1,25(OH)(2)D(2)], the major active species.. Bioavailability of 1,25(OH)(2)D(2) from a single 5 micro g 1alpha(OH)D(2) oral-capsule dose was estimated to be normally approximately 42% of that from a 5 micro g intravenous injection. Steady-state serum concentrations of 1,25(OH)(2)D(2) were attainable within 8 day, and fluctuated approximately 2.5-fold from peak to trough when oral 1alpha(OH)D(2) doses were taken every second day, and the terminal half-life was 34+/-14 h. Mean steady-state serum concentrations rose less than proportionally (from 20 to 45 pg/ml) on increasing oral 1alpha(OH)D(2) doses from 5 to 15 micro g every 48 h. Renal patients showed 39+/-37% increase in serum 1,25(OH)(2)D(2) concentration during 3-4 h haemodialysis sessions, but no other difference in steady-state pharmacokinetics was found between these or hepatically impaired patients and normal subjects.. Given the sensitivity limits of current assays, the pharmacokinetics of this and other vitamin-D compounds is best elucidated from steady-state studies. The pharmacokinetics of 1,25(OH)(2)D(2) from 1alpha(OH)D(2) doses appears to be similar to that of 1,25(OH)(2)D(3) from 1alpha(OH)D(3) doses, albeit D(3) data have to date largely derived from single-dose studies. Deviation of 1,25(OH)(2)D(2) pharmacokinetics from linearity appears to be marginal enough to be clinically manageable with adequate precaution.

Topics: Administration, Oral; Adult; Aged; Biological Availability; Case-Control Studies; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Infusions, Intravenous; Kidney Failure, Chronic; Liver Diseases; Male; Maximum Tolerated Dose; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Reference Values; Risk Factors; Treatment Outcome; Vitamin D

To survey the medical nutrition therapy practices of renal dietitians for the treatment of bone mineral metabolism.. To obtain data on phosphorus diet prescription levels. To determine allied team involvement for phosphate binder and Vitamin D therapies. To assess the frequency and target levels for monitoring serum calcium, phosphorus, -phosphorus product, intact PTH and alkaline phosphatase.. Two renal dietitians from the National Kidney Foundation-Council on Renal Nutrition developed a 5-question survey. This was posted on both the RenalRD Listserv and the NKF-CRN website from January 1 through February 15, 2001. Dietitians were asked to respond using facsimile, e-mail or reply by mail.. One hundred and thirty-one surveys were received representing all major dialysis providers in the United States, the British Virgin Islands, and Japan. Results included information for peritoneal and hemodialysis patients. Five different methods for dosing phosphate binders were determined. Prescribed phosphate binders included calcium acetate, sevelamer hydrochloride, and calcium carbonate. 108 out of 131 dietitian respondents (82.5%) have a medical protocol in place for vitamin D therapy. Of the respondents, 47% were directly responsible for implementing the vitamin D protocol. Paricalcitol was the most widely used form of IV Vitamin D. Biochemistry results were as follows: calcium, 16 different ranges from 8.0 mg/dL to 11.5 mg/dL; phosphorus, 13 different ranges from 2.5 mg/dL to 6.5 mg/dL; calcium-phosphorus product, 13 different ranges from 55-75; iPTH, 20 different ranges from 50-300 pg/mL; alkaline phosphatase, 18 different ranges from no records being monitored to a level of 500 mg/dL.. The survey revealed a large variability in the treatment of bone mineral metabolism. Improved clinical practice guidelines for the health care team are being developed with the National Kidney Foundation (NKF)-Kidney Disease Outcomes and Quality Initiative (KDOQI) bone disease management workgroup.

Topics: Acetates; Bone and Bones; Calcium Carbonate; Calcium Compounds; Dietetics; Epoxy Compounds; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Phosphates; Phosphorus, Dietary; Polyamines; Polyethylenes; Renal Dialysis; Sevelamer; Surveys and Questionnaires; Vitamin D

The efficacy and safety of the vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D2, 1alphaD2) in the treatment of secondary hyperparathyroidism in hemodialysis patients has been previously reported. We report these effect of 16-week 1alphaD2 treatment on mineral metabolism and bone mineral density (BMD) in a hemodialysis patient with persistent secondary hyperparathyroidism post parathyroidectomy, resistant to previous calcitriol treatment. Levels of iPTH, bone-specific alkaline phosphatase and serum type I collagen C telopeptide were above normal at baseline and were substantially decreased with 1alphaD2 treatment (-92%, -63% and -53%, respectively). BMD increased in all areas: total skeleton (+6.5%), lumbar spine (+6.9%) and total femur (+4.3%). The patient showed no hypercalcemia, and phosphorus levels remained between 3.3 and 6.2 mg/dl.

Topics: Adult; Bone Density; Bone Remodeling; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Male; Parathyroid Hormone; Parathyroidectomy; Renal Dialysis

The efficacy of the vitamin D analog paricalcitol has mainly been shown in short-term studies. There are limited data regarding long-term treatment with this agent. This purpose of this study was to determine long-term effects of paricalcitol therapy on parathyroid hormone (PTH) suppression and serum levels of calcium, phosphorus and calcium-phosphorus product (Ca x P).. Patients who received paricalcitol for > or = 3 months had the following data collected: demographics, drug dosage, serum PTH, corrected serum calcium concentration, serum phosphorus concentrations and serum Ca x P values.. Sixteen patients received paricalcitol for a mean of 18 months. The mean +/- SD dose of paricalcitol was 0.13 +/- 0.12 mcg/kg. The mean +/- SD pre-paricalcitol serum PTH concentration was 705 +/- 423 pg/mL. PTH concentration did not change significantly over the duration of treatment (mean +/- SD: 821 +/- 480 pg/mL). The number of patients who had at least one corrected serum calcium concentration > or = 11.5 mg/dL, one serum phosphorus concentration > or = 6.5 mg/dL, or one Ca x P level > or = 70 were 75%, 94% and 82%, respectively. Hypercalcemia and elevated Ca x P value resulted in a mean of 17% of doses being withheld during therapy.. During the study, PTH was not adequately suppressed by paricalcitol. This was primarily attributed to withholding paricalcitol doses due to elevated serum calcium and Ca x P levels.

Topics: Adult; Calcium; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Phosphorus Metabolism Disorders; Renal Dialysis

Paricalcitol [Zemplar: Abbott Laboratories, Abbott Park, IL, U.S.A.] is efficient for treating secondary hyperparathyroidism in patients on maintenance hemodialysis (HD). Zemplar is thought to be more potent than calcitriol and has been reported to cause less hypercalcemia and hyperphosphatemia. Here, we report a 1-year follow-up on patients from one inner-city dialysis unit. We reviewed the charts of 100 patients and collected data for 1 year. Patients were stratified into four groups depending upon their intact parathormone (iPTH) levels. Hemoglobin (Hb) and erythropoietin (EPO) doses were determined. More than 50% of patients had iPTH levels greater than 300 pg/mL. Mean Ca and PO4 levels were not significantly different, but Zemplar doses were significantly different in all groups. None of the patients had symptomatic bone disease. Seven patients were changed to low-Ca dialysate (1.0 mEq/L) secondary to hypercalcemia (Ca > 11.5 mg/dL) and severe secondary hyperparathyroidism. Interestingly, patients with low iPTH (< 100 pg/microL) showed relative EPO resistance, and patients with high iPTH (> 600 pg/microL) required smaller EPO doses. An inverse relationship was observed between Zemplar and EPO dose. The effect of Zemplar on EPO responsiveness needs to be confirmed in a larger study. Our data suggest that severe secondary hyperparathyroidism is frequent despite aggressive paricalcitol therapy in our inner-city HD population. To control severe secondary hyperparathyroidism in these patients, dietary and medication compliance may need to be supplemented with more effective non-calcium phosphate binders or calcimimetic agents, or both.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Ergocalciferols; Erythropoietin; Hemoglobins; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Middle Aged; Parathyroid Hormone; Renal Dialysis

Control of hyperphosphatemia and the administration of vitamin D are the primary treatment modalities for the prevention and management of secondary hyperparathyroidism. Vitamin D therapy for secondary hyperparathyroidism has been limited by the development of hypercalcemia and/or hyperphosphatemia due to increased intestinal absorption of these minerals. Recently, selective vitamin D analogs specifically designed to suppress parathyroid hormone (PTH) without causing hypercalcemia or hyperphosphatemia have shown promise for the treatment of secondary hyperparathyroidism in uremia. This case report describes the successful use of doxercalciferol to treat severe secondary hyperparathyroidism in an adult male patient undergoing chronic peritoneal dialysis, with a follow-up period of 9 months. During this period, the patient's hyperparathyroidism was rapidly and easily controlled. Treatment was complicated by a single incident of over suppression of PTH, with concomitant hypercalcemia. This quickly resolved upon temporary discontinuation of doxercalciferol therapy, after which therapy was resumed without further incident.

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Male; Parathyroid Hormone; Peritoneal Dialysis

The process of managing SHPT requires ongoing evaluation and revision. Although A.M. presented a number of challenges in the course of managing her SHPT, the outcome goals were met. Throughout the course of treatment, the renal dietitian worked collaboratively with the other members of the multidisciplinary team and played an important role in educating the patient as well as monitoring the treatment plan and response to therapy. More aggressive paricalcitol dosing and close patient follow up was shown to be effective in the management of SHPT.

Topics: Aged; Calcium; Drug Monitoring; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Parathyroid Hormone; Phosphorus; Treatment Outcome

Paricalcitol was evaluated for the treatment of secondary hyperparathyroidism (SHPT) in a long-term, prospective, open-label study of 37 patients with end-stage renal failure resistant to intravenous calcitriol. All patients had an intact parathyroid hormone (iPTH) level of 600 pg/mL or greater before being converted from calcitriol to paricalcitol therapy. Paricalcitol therapy was initiated at a 1:4 calcitriol to paricalcitol dose conversion ratio for the initial 14 patients and a 1:3 dose ratio for the next 23 patients. Subsequent dosing was based on iPTH, calcium, and phosphorus determinations. All patients underwent hemodialysis three times weekly and received structured nutritional counseling. Mean iPTH level (baseline, 901 +/- 58 pg/mL) decreased rapidly during the initial 2 months and was 165 +/- 24 pg/mL at 16 months. Alkaline phosphatase levels decreased from 280 +/- 27 IU at baseline to 65 +/- 12 IU at 16 months. Mean calcium and phosphorus levels did not change significantly over the 16 months of paricalcitol therapy. The baseline mean calcium level of 9.4 +/- 0.2 mg/dL increased to 9.7 +/- 0.2 mg/dL (P = 0.86), and phosphorus level decreased from 6.1 +/- 0.2 to 5.8 +/- 0.2 mg/dL (P = 0.77). The greater paricalcitol doses afforded by the initial dose conversion ratio of 1:4 produced unacceptably rapid iPTH suppression and subsequent hypercalcemia. Mean doses of paricalcitol decreased six- to sevenfold throughout the course of therapy while maintaining acceptable iPTH suppression. Eight patients developed hypercalcemia, which successfully managed by dietary counseling, phosphate-binder adjustment, and paricalcitol dose reduction. Six patients developed hyperphosphatemia; 3 patients responded adequately to dietary manipulation and phosphate binders, but 3 patients had repeated episodes. Three patients did not respond adequately to paricalcitol therapy and required parathyroidectomy. In summary, paricalcitol was successful at controlling SHPT in patients resistant to calcitriol therapy with minimal impact on calcium and phosphorus homeostasis. The 1:3 initial dose conversion provided the smoothest iPTH control with only a single episode of hypercalcemia in patients treated with this initial dose. Doses of paricalcitol decreased over time.

Topics: Calcitriol; Calcium; Dietary Proteins; Drug Resistance; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Serum Albumin

Topics: Aged; Calcium; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Risk Factors; Vitamin D Deficiency

The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.

Topics: Animals; Calcitriol; Calcium; Cattle; Cells, Cultured; Dose-Response Relationship, Drug; Ergocalciferols; Female; Hyperparathyroidism, Secondary; Intestine, Small; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

A single-day large dose of vitamin D (stosstherapy) was given to 42 patients with nutritional vitamin D-deficiency rickets. Stosstherapy is safe and effective, obviates problems with compliance, and, by evoking a response in 4 to 7 days in nutritional rickets, becomes a valuable diagnostic aid for patients in whom initial findings do not clearly distinguish nutritional rickets from familial hypophosphatemic rickets.

Topics: Administration, Oral; Calcium; Capsules; Child; Child, Preschool; Drug Administration Schedule; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hypocalcemia; Hypophosphatemia, Familial; Infant; Phosphates; Rickets; Vitamin D; Vitamin D Deficiency

We reported a successful treatment of secondary hyperparathyroidism by intermittent oral administration of high dose of 1, 25 dihydroxycholecalciferol [1.25-(OH)2D3] in three patients on maintenance hemodialysis. Dialysis durations were 4 months in case 1, 6.5 years in case 2 and 12.5 years in case 3. The levels of c-PTH ranged from 4.7 ng/ml to 94.2 ng/ml. 1, 25-(OH)2D3 in dosages up to 8.0 micrograms was given once a week just after hemodialysis. Before the administration and after 48 hours, serum Ca, serum Pi, serum Mg, c-PTH and highly sensitive PTH were assayed. There was a significant correlation between max. plasma concentration of 1, 25-(OH)2D and logarithm of the dose in all patients. The max. plasma level of 1, 25-(OH)2D reached 25-(OH)2D reached to 200 pg/ml at 4 hours after the oral administration of 8.0 micrograms. Their thresholds of 1, 25-(OH)2D level which could decrease the PTH levels were elevated proportionally to their dialysis durations. Case 1 required 4.0 micrograms to suppress secondary hyperparathyroidism, whereas, case 2 and 3 did 8.0 micrograms of 1, 25-(OH)2D3. Severe hypercalcemia was not observed during a high dose treatment. In conclusion, we have succeeded in treating refractory secondary hyperparathyroidism by intermittent oral administration of high dose 1, 25-(OH)3D3. This therapy is recommended to start in the earlier stage of a long-term dialysis in order to prevent severe secondary hyperparathyroidism and bone disease.

Topics: Administration, Oral; Aged; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis

A marked improvement of renal osteodystrophy was achieved after a combined treatment with keto acids and vitamin D in patients with chronic renal failure. Results were checked by histological investigations. The biochemical background of the successful treatment was analysed. A regression of hyperparathyroidism and improvement in vitamin D status are the cause of this phenomenon.

Topics: Amino Acids; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Dietary Proteins; Ergocalciferols; Food, Fortified; Humans; Hyperparathyroidism, Secondary; Keto Acids; Kidney Failure, Chronic; Parathyroid Hormone; Phosphorus

A 25-yr-old black man with cystic fibrosis and cirrhosis developed symptoms of osteomalacia and hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and low circulating 25-hydroxyvitamin D (25-OHD). Serum 1,25-dihydroxyvitamin D (1,25-[OH]2D) was within the normal range. Iliac crest bone biopsy confirmed the diagnosis of osteomalacia. Oral administration of 50,000 IU of vitamin D2 failed to relieve symptoms or raise serum 25-OHD levels to normal. Intramuscular vitamin D2, 10,000 IU every 8-12 week, improved symptoms, raised serum 25-OHD to normal, and increased circulating 1,25-[OH]2D to values five times normal. Over the next 10 mo circulating 1,25-[OH]2D remained elevated despite normalization of serum calcium, phosphorus, and parathyroid hormone. Repeat bone biopsy 1 yr after parenteral vitamin D showed healing of the osteomalacia. Malabsorption of vitamin D appears secondary to profound steatorrhea due to pancreatic insufficiency and secondary biliary cirrhosis. Although extensive hepatocellular disease was present, hepatic conversion of vitamin D to 25-OHD was intact. Both high and low circulating 1,25-[OH]2D levels during active osteomalacia have been reported; initially, the level was in the normal range and higher values in this patient occurred with repletion of 25-OHD substrate. This study shows that symptomatic osteomalacia may be a major manifestation of cystic fibrosis in those patients surviving into adulthood. Measurements of serum 25-OHD in cystic fibrosis patients may identify those who should receive supplemental vitamin D.

Topics: Adult; Bone and Bones; Calcium; Cystic Fibrosis; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Hypocalcemia; Liver; Liver Cirrhosis; Magnesium; Malabsorption Syndromes; Male; Osteomalacia; Parathyroid Hormone; Phosphorus; Serum Albumin; Vitamin D

Five full-term infants with birth weights appropriate for gestational age presented with hypocalcemic tetany at 5 to 9 days of age. All infants had been fed Similac 20, a cow milk formula. Initial mean serum calcium (Ca), phosphorus (P), and magnesium (Mg) levels of the tetanic infants were 6.8, 9.5, and 1.6 mg/dL, respectively. The mean serum parathyroid hormone (PTH) level was elevated at 79 mu LEq/mL (adult normal values, less than or equal to 57 mu LEq/mL). Following restoration of normocalcemia with Ca supplements, feeding was reinstituted with Similac 20 in two infants and Similac PM 60/40 in three infants. Serum biochemical and hormonal values were compared with those of 18 exclusively breast-fed infants followed up from three weeks to six months and 14 Similac 20-fed full-term infants followed up from one week to six months. In tetanic infants, serum Ca concentrations became elevated (10.4 +/- 0.05 mg/dL; mean +/- SEM) by six weeks (vs 9.2 +/- 0.3 mg/dL in breast-fed infants) (P less than .001) and serum Mg concentrations (2.26 +/- 0.01 mg/dL) by four weeks (vs 1.92 +/- 0.07 mg/dL in breast-fed infants) (P less than .01). Mean serum P concentrations declined progressively. Mean serum PTH concentrations were elevated and ranged from 74 to 143 mu LEq/mL at two to 16 weeks (vs mean 28 to 35 mu LEq/mL in breast-fed infants (P less than .0001). In 14 formula-fed-nontetanic full-term infants, serum PTH concentrations were intermediate between formula-fed-tetanic and breast-fed infants, mean serum Ca concentrations ranged from 10.2 to 10.4 mg/dL, and mean serum P concentrations declined from 8.3 to 7.1 mg/dL. We speculate that acute hypocalcemic tetany in the study infants was induced by the relatively high P load in cow milk formulas (vs human milk); with the continued P load, secondary hyperparathyroidism continued, maintaining P, Ca, and Mg homeostasis.

Topics: 25-Hydroxyvitamin D 2; Animals; Breast Feeding; Calcitonin; Calcitriol; Calcium; Cattle; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Infant Food; Infant, Newborn; Longitudinal Studies; Magnesium; Milk; Parathyroid Hormone; Phosphorus; Tetany

Previous reports have suggested that secondary hyperparathyroidism is extremely uncommon in hepatic osteomalacia. This, together with other findings, has led to suggestions that in chronic liver disease there may be selective resistance of bone to vitamin D or a specific bone mineralization defect unrelated to Vitamin D. To examine these possibilities, twenty-five patients with chronic liver disease have been studied by bone biopsy, serum calcium and inorganic phosphate, plasma 25-hydroxyvitamin D, plasma immunoreactive parathormone (iPTH), fasting urine cAMP, fasting renal tubular maximal reabsorptive capacity for phosphate (TmP/GFR) and fine grain hand x-rays. Nine of the patients had osteomalacia on bone biopsy, eight of these had subnormal levels of plasma 25-hydroxyvitamin D and the other had a borderline result. Based on the consensus of all the tests, five of these had evidence of secondary hyperparathyroidism. Plasma iPTH was higher in patients with osteomalacia than in patients without osteomalacia (P less than 0.01) or controls (P less than 0.01). Urine cAMP was higher in patients with osteomalacia than in patients without osteomalacia (P less than 0.001) or controls (P less than 0.01). TmP/GFR was significantly lower in patients with osteomalacia than in controls (P less than 0.05) but not significantly different from patients without osteomalacia. The findings of this study indicate that hyperparathyroidism occurs in a substantial proportion of patients with the osteomalacia of chronic liver disease. Moreover, osteomalacia in chronic liver disease is clearly related to reduced levels of plasma 25-hydroxyvitamin D. We conclude that hepatic osteomalacia is a vitamin D deficiency state and there is no need to suggest an unusual aetiology.

Topics: 25-Hydroxyvitamin D 2; Chronic Disease; Cyclic AMP; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Liver Diseases; Osteomalacia; Parathyroid Hormone

Vitamin D appears to influence parathyroid function indirectly through its effects on calcium metabolism rather than by a direct action of its metabolites on the parathyroid glands. In states of both secondary and primary hyperparathyroidism, the quantitative production of 1,25-(OH)2D may be determined by the prevailing concentration of serum 25-(OH)D but there appears to be some constraint that limits the formation of 1,25-0(OH)2D when the provision of its precursor exceeds the physiological. From the absence of this constraint in 'type 2 vitamin D dependency' it is inferred that it may operate through 'self-inhibition' of the renal production of 1,25-(OH)2D. It is shown that the level of serum 25-(OH)D may always exert some influence on the production of 1,25-(OH)2D and that this effect is facilitated by hyperparathyroidism. In developing vitamin D deficiency the reactive secondary hyperparathyroidism may thus function as an adaptive mechanism that sustains the level of serum 1,25-(OH)2D in the face of a diminishing serum 25-(OH)D. Failure of this adaptation and the development of a critical deficiency of 1,25-(OH)2D is regarded as the direct cause of defective mineralisation of bone. This concept would explain the absence of osteomalacia in some patients with very low levels of serum 25-(OH)D and the occurrence of defective osseous mineralisation in hypoparathyroidism.

Topics: 25-Hydroxyvitamin D 2; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Hypocalcemia; Osteomalacia; Parathyroid Hormone; Vitamin D; Vitamin D Deficiency

Highly sensitive assays have been developed that enable 25-hydroxycholecalciferol (25-hydroxyvitamin D3) and 25-hydroxyergocalciferol (25-hydroxyvitamin D2) to be measured in the same serum sample. With these assays it has been shown that endogenously produced cholecalciferol (vitamin D3) is important in man; the findings further emphasize the role of vitamin D metabolites as hormones rather than vitamins in the traditional sense. Dietary sources of vitamin D appear to be inadequate and vitamin D deficiency has been shown to the cause of rickets and osteomalacia in Asian immigrants to Britain. This condition may be readily treated with small doses of vitamin D. In addition, sub-clinical deficiency was found in the Asian community. In the elderly, also, vitamin D deficiency was established as an important cause of osteomalacia and again evidence for the existence of a sub-clinical deficiency state was found. It is therefore suggested that the present prophylactic practices should be reviewed. Secondary hyperparathyroidism (reflected by elevated concentrations of circulating immunoassayable parathyroid hormone) was shown to be the rule rather than the exception in vitamin D deficiency. Some patients, however, had failed to respond to a hypocalcaemic stimulus. In others, there were high concentrations of parathyroid hormone despite normal serum calcium concentrations. Thus the relationship between parathyroid hormone and metabolites of vitamin D may not be mediated through changes in serum calcium alone, and it is postulated that metabolites of vitamin D may directly affect the secretion of parathyroid hormone.

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Animals; Asia; Asian People; Child; Cholecalciferol; Ergocalciferols; Ethnicity; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; London; Middle Aged; Osteomalacia; Parathyroid Hormone; Radioimmunoassay; Rats; Rickets; Submarine Medicine; United Kingdom; Vitamin D; Vitamin D Deficiency

Periosteal new bone formation in the pelvis is reported in five patients on maintenance haemodialysis for chronic renal failure. In two of the cases the shafts of long bones were also involved. The associated radiological and biochemical findings suggest that this unusual radiological feature may be a manifestation of secondary hyperparathyroidism. In one patient in whom the plasma phosphate and calcium X phosphate [Ca X P1] product were reduced there was partial incorporation of the periosteal new bone into the underlying cortex.

Topics: Adolescent; Adult; Calcium; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Ossification, Heterotopic; Pelvis; Periosteum; Phosphates; Radiography; Renal Dialysis

Topics: Adolescent; Adult; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Osteomalacia; Vitamin D Deficiency

Topics: Alkaline Phosphatase; Biopsy; Bone Resorption; Calcium; Calcium Isotopes; Chronic Disease; Dihydrotachysterol; Ergocalciferols; Glomerulonephritis; Humans; Hyperparathyroidism, Secondary; Intestinal Absorption; Nephritis; Osteitis Fibrosa Cystica; Renal Dialysis