calcitriol and Hyperparathyroidism

Dysregulated mineral metabolism is a nearly universal sequalae of acute kidney injury (AKI). Abnormalities in circulating mineral metabolites observed in patients with AKI include hypocalcemia, hyperparathyroidism, hyperphosphatemia, decreased vitamin D metabolite levels, and increased fibroblast growth factor 23 levels. We review the pathophysiology of dysregulated mineral metabolism in AKI with a focus on calcium, phosphate, parathyroid hormone, and vitamin D metabolites. We discuss how mineral metabolite levels can serve as novel prognostic markers for incident AKI and other related outcomes in various clinical settings. Finally, we discuss how vitamin D metabolites potentially could be used as novel therapeutic agents for AKI prevention and treatment.

Topics: Acute Kidney Injury; Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Hyperphosphatemia; Hypocalcemia; Klotho Proteins; Membrane Proteins; Minerals; Parathyroid Hormone; Renal Replacement Therapy; Vitamin D; Vitamin D Deficiency

Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Hyperparathyroidism; Hyperphosphatemia; Kidney; Klotho Proteins; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Vitamin D

Vitamin D plays an important role in regulation of calcium homeostasis and bone metabolism. Among vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) can be used for the evaluation of vitamin D nutritional status. In contrast, 1,25-dihydroxyvitamin D (1,25 [OH] 2D) can be used for the diagnosis of hyperparathyroidism, renal malfunctions, and other calcium metabolism-related diseases. Serum 25-OH-D concentration can be measured with radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), chemiluminescence protein-binding assay (CLPBA), high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS) methods. Likewise, serum 1,25 (OH) 2D can be measured with RIA, EIA, radioreceptorassay (RRA) and ELISA methods. Clinicians are required to recognize the characteristics of each method and use serum concentrations of 25-OH-D and 1,25 (OH) 2D as biochemical markers for the diagnosis of bone diseases.

Topics: Bone Diseases; Humans; Hyperparathyroidism; Kidney Diseases; Vitamin D

Topics: Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibrous Dysplasia, Polyostotic; Humans; Hyperparathyroidism; Hypoparathyroidism; Hypophosphatemia; Parathyroid Hormone; Parathyroid Hormone-Related Protein; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphorus; Thyrotoxicosis; Vitamin D

Primary hyperparathyroidism manifests biochemically as a disturbance in serum calcium homeostasis. The central organ setting serum calcium level is the kidney. It not only has the highest rate of active calcium transport, but the kidney also modulates serum calcium homeostasis by virtue of its endocrine role in 1,25-hydroxyvitamin D secretion. Receptors for PTH are widely expressed throughout the renal tubule and are involved in both calcium transport and endocrine function. Biochemical manifestations of primary hyperparathyroidism by the kidney include increased tubular reabsorption of calcium, decreased reabsorption of phosphate and bicarbonate, and hypercalciuria. A reduction in glomerular filtration may occur in some patients with primary hyperparathyroidism, which perturbs the diagnostic relationships among biochemical variables and induces further increases in PTH secretion. Parathyroidectomy rapidly restores the biochemical abnormalities to normal apart from chronic reduced glomerular filtration. Clinical manifestations are nephrolithiasis, which is common, and nephrocalcinosis, which is uncommon. Nephrocalcinosis may occur with or without nephrolithiasis. Risk factors for nephrolithiasis are oversaturation of urine with calcium phosphate and with calcium oxalate. Risk factors for nephrocalcinosis are not clearly defined. Parathyroidectomy greatly reduces the incidence of nephrolithiasis but has little effect on nephrocalcinosis.

Topics: Bicarbonates; Calcium; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism; Kidney; Kidney Diseases; Phosphates; Renal Insufficiency; Vitamin D

Vitamin D's biologically active metabolite, 1,25(OH)2D3, has important effects upon the parathyroid cell that are relevant to both the physiology of mineral metabolism and the regulation of the secondary hyperparathyroidism of chronic renal failure. 1,25(OH)2D3 markedly decreases parathyroid hormone (PTH) gene transcription and thus PTH synthesis and secretion. It also acts to decrease parathyroid cell proliferation. Nonhypercalemic analogs of 1,25(OH)2D3 are being developed that may have a wider therapeutic window than 1,25(OH)2D3 itself. In the situations of chronic hypocalcemia and hypophosphatemia, there are interesting interrelationships between 1,25(OH)2D3 and the post-transcriptional regulation of the PTH gene. In nodular secondary hyperparathyroidism, there is down-regulation of the vitamin D receptor in the parathyroid. Different vitamin D receptor genotypes may be associated with higher levels of serum PTH and a predisposition to autonomous hyperplasia.

Topics: Cell Division; Chronic Kidney Disease-Mineral and Bone Disorder; Gene Expression Regulation; Genotype; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Parathyroid Glands; Receptors, Calcitriol; Tretinoin; Vitamin D

Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23.. Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks.. ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events.. Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Calcifediol; Calcium; Creatinine; Delayed-Action Preparations; Double-Blind Method; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities.. The objective of the study was to suppress elevated PTH levels in XLH patients.. This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later.. PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit.. Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less.. The intervention for this study was the use of paricalcitol or placebo for 1 year.. Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans.. PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject.. Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Bone Density Conservation Agents; Child; Double-Blind Method; Ergocalciferols; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Placebos; Prospective Studies; Treatment Outcome; Vitamin D; Young Adult

Hyperphosphataemia is almost inevitable in end stage renal disease (ESRD) patients and is associated with increased morbidity and mortality. In this study we examined whether oral activated charcoal (oAC) reduces serum phosphate level in haemodialysis patients.. This was an open-label, prospective, uncontrolled study. One hundred and thirty-five haemodialysis patients were included in this study, with cessation of treatment with any phosphate binders during a 2 week washout period. Patients with serum phosphate levels greater than 5.5 mg/dL during the washout period were included for treatment with oAC. oAC was started at a dose of 600 mg three times per day with meals and was administered for 24 weeks. oAC dose was titrated up during the 24 week period to achieve phosphate control (3.5-5.5 mg/dL). A second 2 week washout period followed the end of oAC treatment.. In the 114 patients who successfully completed the trial, the mean dose of activated charcoal was 3190 ± 806 mg/day. oAC reduced mean phosphate levels to below 5.5 mg/dL, with mean decreases of 2.60 ± 0.11 mg/dL (P < 0.01) and 103 (90.4%) of the patients reached the phosphate target. After the second washout period the phosphate levels increased to 7.50 ± 1.03 mg/dL (P < 0.01). Serum intact parathyroid hormone (iPTH) levels declined from 338.75 ± 147.77 pg/mL to 276.51 ± 127.82 pg/mL (P < 0.05) during the study. oAC had no influence on serum prealbumin, total cholesterol, triglycerides, serum ferritin, haemoglobin or platelet levels and the levels of 1,25-dihydroxyvitamin D were stable during the study.. In this open-label uncontrolled study, oAC effectively controls hyperphosphataemia and hyperparathyroidism in haemodialysis patients. The safety and efficacy of oAC needs to be assessed in a randomized controlled trial.

Topics: Administration, Oral; Aged; Analysis of Variance; Biomarkers; Charcoal; China; Drug Administration Schedule; Female; Ferritins; Hemoglobins; Humans; Hyperparathyroidism; Hyperphosphatemia; Lipids; Male; Middle Aged; Parathyroid Hormone; Phosphates; Platelet Count; Prealbumin; Prospective Studies; Renal Dialysis; Time Factors; Treatment Outcome; Vitamin D

GH may improve phosphate balance and height in X-linked hypophosphatemic rickets (XLH). This study evaluated the impact of exclusive rhGH therapy on phosphate homeostasis and growth.. Ten children (median age 12.2 years) with XLH were included in a 12-month trial with GH. Conventional treatment was discontinued 1 month prior GH (0.033 mg/kg/day); 1alpha-hydroxyvitamin D was added at 6 months and oral phosphate at 12 months, when GH was discontinued. Patients were followed 1-3 monthly until 18 months for clinical, biochemical and radiographic parameters.. Serum phosphate Z-score increased significantly from baseline at 6 months (p = 0.005) and 9 months (p = 0.009) but returned to baseline by 12 months. Serum 1,25-dihydroxyvitamin D also increased significantly. Parathyroid function normalized. The median height Z-score was -2.2 (-2.7 to +0.4) at GH onset and -1.7 (-2.3 to +0.3) at 12 months. One patient showed a significant increase in radiographic rickets activity and 3 patients aggravation of lower limb deformity; the others showed no changes or improvement in these parameters.. GH treatment improved serum phosphate and 1,25-dihydroxyvitamin D, normalized parathyroid function and improved longitudinal growth in XLH. It may however aggravate pre-existing skeletal deformities.

Topics: Adolescent; Body Height; Bone and Bones; Bone Density Conservation Agents; Bone Development; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Familial Hypophosphatemic Rickets; Female; Genetic Diseases, X-Linked; Growth Hormone; Homeostasis; Humans; Hydroxycholecalciferols; Hyperparathyroidism; Male; Parathyroid Glands; Phosphates; Radiography; Vitamin D

Calcitriol therapy is the mainstay of therapy for the treatment of secondary hyperparathyroidism. Oral administration of calcitriol is necessary in CAPD patients, but no studies have directly compared different routes of administration in this patient population.. To determine if the peak serum calcitriol level (pulse therapy) is more important than the total delivered dose, we randomized CAPD patients with mild to moderate secondary hyperparathyroidism to receive either pulse (3.0 microg twice a week, n = 10) or daily (0.75 microg a day, n = 8) oral calcitriol in comparable weekly doses. The main comparison was the rate of decline of serum intact parathyroid hormone (PTH) levels to reach the desired end-point of 100 pg/ml. The patients were dialysed with low-calcium dialysate and received only calcium-containing phosphate binders.. Pharmacokinetic analysis after a single dose of 3.0 microg (pulse) vs 0.75 microg (daily) revealed 1,25(OH)2-vitamin D levels to be higher in the pulse group at 3 and 6 h, but equivalent by 12 h. The area under the curve for 1 week of daily and 1 week of pulse therapy was equal. The patients in the 2 arms had equivalent basal serum levels of PTH (pulse = 562 +/- 291 vs daily = 454 +/- 113 pg/ml), calcium (pulse = 2.32 +/- 0.20 vs daily = 2.32 +/- 0.12 mmol/l) and phosphorus (pulse = 1.32 +/- 0.52 vs daily = 1.35 +/- 0.26 mmol/l). The time required for the PTH to decrease to 100 pg/ml and the rate of decline in PTH were similar (time: pulse = 14.2 +/- 6.8 weeks, daily = 12.2 +/- 7 weeks; rate: pulse = 7.4 +/- 4.2 vs daily = 8.4 +/- 4.2% PTH/week; P = NS). The serum calcium increased similarly in both groups. Hypercalcaemia (> 2.9 mmol/l) was rare (pulse = 3, daily = 2 episodes).. This study demonstrates that pulse and daily calcitriol are similarly effective and safe for the treatment of mild to moderate secondary hyperparathyroidism in CAPD patients despite higher peak levels of 1,25(OH)2-vitamin D with pulse therapy.

Topics: Adult; Aged; Calcitriol; Calcium; Female; Humans; Hyperparathyroidism; Male; Middle Aged; Osmolar Concentration; Parathyroid Hormone; Peritoneal Dialysis, Continuous Ambulatory; Vitamin D

Opinions are conflicting about the epidemiology of vitamin D deficiency. This population-based study investigated cross-sectionally the associations of 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (calcitriol) with indices of mineral homeostasis. Study cohort consisted of 979 persons of the Moli-Sani study, both sexes, ages ≥35 years. Data collection included serum calcidiol by different assays, serum calcitriol, serum parathyroid hormone, serum and urine calcium, and phosphorus. Prevalence of mild-to-moderate calcidiol deficiency (10-19 ng/mL) was 36.4% and did not associate with hypocalcemia or hyperparathyroidism. Prevalence of severe calcidiol deficiency (<10 ng/mL) was 16.8% and associated with hyperparathyroidism only (odds ratio = 8.81, 95% confidence interval = 2.4/32.9). Prevalence of calcitriol deficiency (<18 pg/mL) was 3.1% and associated with hypocalcemia (29.1, 7.4/114.5) but not hyperparathyroidism. In ANOVA along concentration strata, lower calcidiol associated with higher parathyroid hormone only (

Topics: Adult; Aged; Biomarkers; Calcium; Cross-Sectional Studies; Female; Homeostasis; Humans; Hyperparathyroidism; Hypocalcemia; Italy; Male; Middle Aged; Parathyroid Hormone; Prevalence; Prospective Studies; Severity of Illness Index; Vitamin D; Vitamin D Deficiency

Reports of clinical rickets are particularly evident in minority infants and children, but only limited analyses of vitamin D are available in this demographic group.. We sought to characterize circulating 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and their determinants, including circulating parathyroid hormone (PTH), total alkaline phosphatase activity (ALP), calcium, and phosphorus, in minority infants and children.. We obtained demographic information and blood samples for measurement of PTH, ALP, 25(OH)D, and 1,25(OH)(2)D in >750 6-mo- to 3-y-old children. Dietary intake data were obtained and analyzed.. The mean (±SD) 25(OH)D concentration was 66 ± 22 nmol/L (26.3 ± 8.7 ng/dL). A total of 15% of children had 25(OH)D concentrations less than the recommended target threshold of 50 nmol/L. Combined elevations of PTH and ALP occurred in only 2.5% of children. Determinants of 25(OH)D included vitamin D intake, age (decreasing with age), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), formula use (higher intakes), season (greater concentrations in the summer and fall than in the winter and spring), and, inversely, PTH. The mean 1,25(OH)(2)D concentration was 158 ± 58 pmol/L (60.6 ± 22.5 pg/mL), which was consistent with a reference range of 41-274 pmol/L or 15.7-105.5 pg/mL. Determinants for 1,25(OH)(2)D were age (decreasing with age), sex (greater concentrations in girls than in boys), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), and, inversely, serum calcium and phosphorus.. Although 15% of subjects were vitamin D insufficient, only 2.5% of subjects had elevations of both PTH and ALP. The greater 25(OH)D concentrations observed with formula use confirm that dietary vitamin D fortification is effective in this demographic group. Circulating 1,25(OH)(2)D is higher in infants than in older children and adults and, in contrast to 25(OH)D, is not directly correlated with nutrient intakes.

Topics: Age Factors; Alkaline Phosphatase; Calcium; Catchment Area, Health; Child, Preschool; Diet; Female; Humans; Hyperparathyroidism; Infant; Male; Minority Groups; Parathyroid Hormone; Phosphorus; Prevalence; Reference Values; Seasons; Sex Factors; Skin Pigmentation; Urban Population; Vitamin D; Vitamin D Deficiency; Vitamins

This retrospective data analysis was undertaken to examine the biochemical differences between renal stone formers with normocalcemic hyperparathyroidism (NHPT) and those with normal parathyroid hormone (PTH) levels. Our goal was to ascertain whether 25-hydroxyvitamin D (25(OH)D) status related to PTH levels in this patient cohort. Our findings among 74 patients with NHPT indicate that stone formers with NHPT had significantly lower 25(OH)D levels compared to 192 controls (p = 0.0001) and that 25(OH)D is positively correlated with 1,25-dihydroxyvitamin D values (R = 0.736, p = 0.015). Sequential measurements (after 3 - 5 years), among 11 patients with NHPT who did not receive vitamin D (VitD) preparations, showed a significant increase in urinary calcium (3.43 ± 1.96 vs. 5.72 ± 3.95, p = 0.0426) without a significant change in PTH levels. VitD supplementation, to 3 patients resulted in significant PTH decrease (11.8 ± 1.8 vs. 9.8 ± 1.3, p = 0.003). Prospective studies are needed to confirm the role of vitamin supplementation in renal stone formers with NHPT.

Topics: Biomarkers; Calcium; Chi-Square Distribution; Dietary Supplements; Female; Humans; Hyperparathyroidism; Kidney Calculi; Male; Middle Aged; Ontario; Parathyroid Hormone; Recurrence; Retrospective Studies; Time Factors; Vitamin D; Vitamin D Deficiency; Vitamins

Elderly men and women with protein deficiencies have low levels of circulating IGF-I, and it is likely this contributes to reduced bone formation and increased bone resorption. We hypothesized that calcitropic hormones are involved in this effect and are affected by dietary protein. We therefore investigated the influence of a low-protein diet on the PTH-1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] axis and IGF-I in rats, using pamidronate to block resorption that normally contributes to mineral homeostasis. We fed 6-month-old Sprague Dawley female rats isocaloric diets containing 2.5% or 15% casein for 2 wk. Pamidronate was then administered sc (0.6 mg/kg/) for 5 d. Blood samples were collected at different time points. Serum 1,25(OH)₂D₃, IGF-I, PTH, calcium, and phosphorus were determined in all rats; vertebral bone strength and histomorphometric analysis were performed in rats subject to the longest low-protein diets. We found 2 wk of low protein increased PTH levels, decreased 1,25(OH)₂D₃, calcium, and IGF-I, suggesting that increased PTH compensates for low-protein-induced decreases in 1,25(OH)₂D₃. Pamidronate augmented the increased PTH after 8 wk of low protein and prevented the 1,25(OH)₂D₃ decrease. IGF-I remained low. Protein malnutrition induced decreases in relative bone volume and trabecular thickness, which was prevented by pamidronate. Maximal load was reduced by protein restriction, but rescued by pamidronate. In summary, the low protein diet resulted in hyperparathyroidism, a reduction in circulating levels of IGF-I, and reduced 1,25(OH)₂D₃ despite hyperparathyroidism. Blocking resorption resulted in further increases in PTH and improved microarchitecture and biomechanical properties, irrespective of vitamin D status or protein intake.

Topics: Animals; Bone and Bones; Bone Resorption; Calcitriol; Calcium; Caseins; Dietary Proteins; Diphosphonates; Dose-Response Relationship, Drug; Female; Hyperparathyroidism; Immunoassay; Insulin-Like Growth Factor I; Lumbar Vertebrae; Pamidronate; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Time Factors; Vitamin D

The objective of this study was to characterize changes in metabolic bone parameters following bariatric surgery. Seventy-three obese adult patients who underwent either gastric banding (GB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD/DS) were followed prospectively for 18 months postoperatively. Changes in the calcium-vitamin D axis (25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), calcium, parathyroid hormone (PTH)), markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) and resorption (urinary N-telopeptide (NTx)), as well as bone mineral density (BMD) were assessed at 3-month intervals during this time period. Bariatric surgery resulted in significant and progressive weight loss over 18 months. With supplementation, 25OHD levels increased 65.3% (P < 0.0001) by 3 months, but leveled off and decreased <30 ng/ml by 18 months. PTH initially decreased 21.4% (P = 0.01) at 3 months, but later approached presurgery levels. 1,25(OH)(2)D increased significantly starting at month 12 (50.3% increase from baseline, P = 0.008), and was positively associated with PTH (r = 0.82, P = 0.0001). When stratified by surgery type, median PTH and 1,25(OH)(2)D levels were higher following combined restrictive and malabsorptive operations (RYGB and BPD/DS) compared to GB. Bone formation/resorption markers were increased by 3 months (P < 0.05) and remained elevated through 18 months. Radial BMD decreased 3.5% by month 18, but this change was not significant (P = 0.23). Our findings show that after transient improvement, preoperative vitamin D insufficiency and secondary hyperparathyroidism persisted following surgery despite supplementation. Postoperative secondary hyperparathyroidism was associated with increased 1,25(OH)(2)D levels and increased bone turnover markers.

Topics: Adult; Bariatric Surgery; Biomarkers; Bone Density; Bone Resorption; Dietary Supplements; Female; Humans; Hyperparathyroidism; Male; Middle Aged; Obesity; Parathyroid Hormone; Postoperative Complications; Prospective Studies; Vitamin D; Vitamin D Deficiency; Weight Loss

The objectives were to determine the prevalence of vitamin D deficiency [25(OH)D < 10 ng/ml] in pediatric renal transplant (RTx) recipients, compared with controls and identify correlates of changes in 25(OH)D and intact parathyroid hormone (iPTH) levels following transplantation. Serum 25(OH)D, 1,25(OH)(2)D, and iPTH were measured once in 275 healthy controls and at transplantation, and 3 and 12 months posttransplantation in 58 RTx recipients. Multivariate logistic regression models determined the odds ratio (OR) of vitamin D deficiency in RTx recipients vs. controls adjusted for age, sex, race, and season. Generalized estimating equations were used to assess changes following transplantation. At transplantation, 22% of nonblack and 27% of black RTx recipients were vitamin D deficient. The adjusted OR of vitamin D deficiency was greater in RTx recipients (p < 0.001) compared with controls; however, the transplant association was greater in nonblack vs. black individuals (interaction p = 0.02). Overall, 25(OH)D levels did not change significantly following transplantation. Younger age (p < 0.01), nonblack race (p < 0.001), visits in nonwinter months (p < 0.001), and supplementation with ≥400 IU/day ergo/cholecalciferol (p < 0.001) were associated with increases (or lesser declines) in 25(OH)D following transplantation. Increases in 25(OH)D levels (p < 0.001) and vitamin D supplementation (p < 0.01) were associated with greater reductions in iPTH levels following transplantation, independent of 1,25(OH)(2)D levels.

Topics: Adolescent; Age Factors; Biomarkers; Black or African American; Case-Control Studies; Chi-Square Distribution; Child; Child, Preschool; Dietary Supplements; Female; Humans; Hyperparathyroidism; Kidney Transplantation; Logistic Models; Male; Odds Ratio; Ohio; Parathyroid Hormone; Philadelphia; Prevalence; Risk Assessment; Risk Factors; Seasons; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Young Adult

Disturbances in bone and mineral metabolism are common in chronic kidney disease (CKD) patients. Most studies have been performed in hemodialysis and there is less information on non-dialysis patients, on the coexistence of other risk factors and on the achievement of more recent and stringent guidelines. Cross sectional study of analytical mineral and bone parameters in 125 incident patients (creatinine clearance <60 ml/min) in a monographic CKD clinic. Evaluation after one year of follow-up in 69 patients. Progression of CKD was associated with significant increased levels of phosphate, calcium x phosphate and iPTH and decreased calcium and 1,25 dihydroxyvitamin D. Levels of 25-hydroxyvitamin D were unchanged, but lower than recommended. Phosphate correlated negatively with 1,25-dihydroxivitamin D and creatinine clearance, and positively with iPTH. At every stage of CKD, most patients had PTH values outside recommended limits. More than 69% CKD 3 and CKD 4 patients had higher than recommended PTH levels. Above recommended phosphate levels were present in 25% of CKD 4 and 47% of CKD 5 patients. Most of these had associated high LDL-cholesterol. Higher than recommended calcium levels were more prevalent than low calcium and there was a high prevalence (31%) of vascular calcification. One year of intervention improved the percentage of patients with controlled calcium or iPTH, but not phosphate.. In incident CKD patients there is a high prevalence of out-of-target mineral and bone analytical parameters. The currently authorized therapeutic arsenal for these patients may not be adequate to deal with the problem.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Chronic Disease; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Hyperparathyroidism; Hyperphosphatemia; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prevalence; Vitamin D

Oncogenic osteomalacia is a rare condition characterized by a low serum phosphate, reduced tubular reabsorption of phosphate and a low or inappropriately normal 1,25 dihydroxyvitamin D and is usually secondary to a phosphaturic mesenchymal tumor. Complete tumor resection results in resolution of all features. We report a patient with oncogenic osteomalacia and concurrent secondary hyperparathyroidism. Serum phosphate failed to normalize preoperatively with octreotide therapy, although this treatment did suppress serum FGF23. The postoperative course was distinguished by marked hyperphosphatemia that was associated with elevated serum 1,25 dihydroxyvitamin D concentrations.

Topics: Aged; Antineoplastic Agents, Hormonal; Biomarkers; Bone and Bones; Combined Modality Therapy; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Octreotide; Osteomalacia; Phosphates; Tomography, X-Ray Computed; Treatment Outcome; Vitamin D

Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. To investigate the relation between blood levels of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) with hemodialysis outcomes, we measured baseline vitamin D levels in a cross-sectional analysis of 825 consecutive patients from within a prospective cohort of incident US hemodialysis patients. Of these patients, 78% were considered vitamin D deficient with 18% considered severely deficient. Calcium, phosphorus, and parathyroid hormone levels correlated poorly with 25D and 1,25D concentrations. To test the association between baseline vitamin D levels and 90-day mortality, we selected the next 175 consecutive participants who died within 90 days and compared them to the 750 patients who survived in a nested case-control analysis. While low vitamin D levels were associated with increased mortality, significant interaction was noted between vitamin D levels, subsequent active vitamin D therapy, and survival. Compared to patients with the highest 25D or 1,25D levels who received therapy, untreated deficient patients were at significantly increased risk for early mortality. Our study shows that among incident hemodialysis patients, vitamin D deficiency is common, correlates poorly with other components of mineral metabolism and is associated with increased early mortality.

Topics: Aged; Calcium; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Risk Factors; Survival Analysis; Vitamin D; Vitamin D Deficiency

We aimed to determine the serum level of fibroblast growth factor-23 (FGF-23) in patients with primary hyperparathyroidism (pHPT) to understand its physiological role in the disorder.. Ninety-eight patients with pHPT who underwent parathyroidectomy formed the study group. We also measured serum FGF-23 in 11 of these patients on postoperative day 6.. Serum FGF-23 levels was significantly higher in pHPT patients than in healthy controls (35.6+/-17.8 ng/l vs 28.9+/-11.2 ng/l (mean+/-s.d.); P<0.001 (Pearson's correlation coefficient)), but there was no significant difference in the serum FGF-23 level between pHPT patients with normal renal function (creatinine clearance (Ccr) of >or=70 ml/min) and healthy controls. Serum FGF-23 correlated positively with serum calcium (P<0.0001) and intact parathyroid hormone (PTH) (P<0.01), and negatively with Ccr (P<0.001), serum phosphate (P<0.05), and serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (P<0.05). Multiple linear regression analysis of factors potentially determining serum FGF-23 levels in pHPT patients showed serum calcium (P<0.01) and Ccr (P<0.001) to be significant predictors. The serum levels of FGF-23 did not change after parathyroidectomy despite the normalization of serum calcium values. Multiple linear regression analysis revealed that serum FGF-23 was not a significant predictor of serum phosphate or 1,25(OH)(2)D in pHPT patients.. FGF-23 may not play a significant role in regulating phosphate or 1,25(OH)(2)D in pHPT patients, especially in those with normal renal function. Further studies are warranted to determine the role of FGF-23 in renal insufficiency or failure.

Topics: Adult; Aged; Calcium; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Linear Models; Male; Middle Aged; Phosphates; Renal Insufficiency; Vitamin D

The role of albumin in bone metabolism was studied in Nagase analbuminemic (NA) rats. Serum calcium (Ca), inorganic phosphate (Pi) and magnesium (Mg) concentrations did not differ between female NA and control Sprague-Dawley (SD) rats at the time of ovariectomy (ovx), although serum ionized Ca was significantly lower in NA rats than in SD rats. Serum parathyroid hormone (PTH) and osteocalcin (OC) concentrations and urinary Ca excretion were significantly greater in NA rats than in SD rats, suggesting hyperparathyroidism and the resultant enhanced bone turnover in NA rats. Paradoxically, ovx increased serum PTH and OC in NA rats but not in SD rats. Ovx-induced exacerbation of hyperparathyroidism was confirmed by significantly greater conversion of 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D in ovx NA rats even after normalization to vitamin D-binding protein. Bone mineral density (BMD) in proximal tibia increased similarly in a time-dependent manner in sham-operated NA and SD rats. However, ovx ablated the time-dependent increase of BMD in SD rats and significantly decreased BMD in NA rats by 2 wk after ovx, resulting in a significantly lower BMD in ovx NA rats than in ovx SD rats. In summary, NA rats, which are analbuminemic with compensatory increases in lipid and protein synthesis, developed hyperparathyroidism, possibly due to an increase in serum Pi and a reduction of ionized Ca, and ovx induced a greater BMD reduction in NA rats than in SD rats, probably by exacerbating hyperparathyroidism.

Topics: Albumins; Analysis of Variance; Animals; Body Weight; Bone and Bones; Bone Density; Calcium; Female; Hyperparathyroidism; Magnesium; Osteocalcin; Ovariectomy; Parathyroid Hormone; Protein Biosynthesis; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Vitamin D

Primary hyperparathyroidism (PHP) during pregnancy is well known to confer an increased risk of complications to both the mother and the fetus. However, the risks and optimal management of patients with mild, asymptomatic disease during pregnancy are much less clear. We observed a patient with mild, asymptomatic PHP who was diagnosed before conception through pregnancy. The patient remained asymptomatic through the first 22 weeks of pregnancy, and her calcium levels remained under 11 mg/dL. This occurred despite a dramatic elevation in the level of 1,25-dihydroxyvitamin D and marked hypercalciuria. Parathyroid surgery was performed at 22 weeks of gestation and a parathyroid adenoma was removed. Postoperatively, the patient's calcium level normalized and the rest of the pregnancy was uncomplicated. The patient delivered a healthy baby at 40 weeks of gestation. The neonatal course was unremarkable. We conclude that mild, asymptomatic PHP during early pregnancy is compatible with normal fetal development and an uncomplicated pregnancy and that the serum calcium level in such patients can remain stable with medical management alone, despite the marked changes in maternal calcium metabolism that characterize normal pregnancy.

Topics: Adenoma; Adult; Calcium; Disease Progression; Embryonic and Fetal Development; Female; Humans; Hypercalcemia; Hyperparathyroidism; Infant, Newborn; Parathyroid Hormone; Parathyroid Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Diagnosis; Prospective Studies; Ultrasonography, Prenatal; Vitamin D

Mutations in the vitamin D receptor (VDR) gene have been shown to cause hereditary vitamin D-resistant rickets (HVDRR). The patient in this study is a young French-Canadian boy with no known consanguinity in his family. The child exhibited the clinical characteristics of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) levels as well as total alopecia. Fibroblasts were cultured from a skin biopsy of the patient and used to assess the VDR. Northern blot analysis showed that a normal size VDR transcript was expressed; however, [3H]1,25(OH)2D3-binding levels were very low and Western blot analysis failed to detect any VDR protein. Total resistance to 1,25(OH)2D3 was demonstrated by the failure of the cultured fibroblasts to induce the transcription of the 25-hydroxyvitamin D-24-hydroxylase gene when treated with high concentrations of 1,25(OH)2D3. Analysis of the DNA sequence revealed a unique C to T base change corresponding to nucleotide 218 of the VDR cDNA. This single base substitution changes the codon for arginine (CGA) to an opal stop codon (TGA), resulting in the truncation of the VDR at amino acid 30. The Arg30stop mutation prematurely terminates translation and deletes 398 amino acids including most of the zinc fingers as well as the entire ligand-binding domain. Restriction fragment length polymorphism analysis of a DdeI restriction site created by the mutation showed that the parents were heterozygous for the mutant allele. In conclusion, the Arg30stop mutation truncates the VDR and leads to a hormone-resistant condition which is the molecular basis of HVDRR in this patient.

Topics: Alopecia; Calcitriol; Cells, Cultured; Cytochrome P-450 Enzyme System; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Hyperparathyroidism; Hypocalcemia; Hypophosphatemia, Familial; Male; Mutation; Polymorphism, Restriction Fragment Length; Receptors, Calcitriol; Rickets; Skin; Steroid Hydroxylases; Vitamin D; Vitamin D3 24-Hydroxylase

Measurement of serum 1,25-dihydroxyvitamin D levels is important for diagnosis of various calcium metabolism disorders. Conventional assays for 1,25-dihydroxyvitamin D employed specific 1,25-dihydroxyvitamin D receptor as binding site for the ligand and thus, biologically active 1,25-dihydroxyvitamin D ligand, which is labeled with 3H, was required. Usage of 3H made assays cumbersome works. A new assay which uses specific antibody as the binding site and the radioligand labeled with 125I is now available as a commercial kit. Using these kits, we first studied basically the reproducibility, recovery, cross-reactivity and comparison with conventional assays. All of those results were satisfactory. Secondly, we measured clinically in 111 healthy adults and in patients with various disorders such as renal failure, primary hyperparathyroidism, hypoparathyroidism and sarcoidosis. This newly available kit for measurement of circulating 1,25-dihydroxyvitamin D is proved to be useful in clinical evaluation of calcium metabolic disorders.

Topics: Acute Kidney Injury; Adult; Aged; Binding Sites; Calcium; Female; Humans; Hyperparathyroidism; Hypoparathyroidism; Male; Middle Aged; Radioimmunoassay; Radioligand Assay; Sarcoidosis; Vitamin D

The purpose of this study was to investigate whether dietary calcium intake in primary hyperparathyroidism is associated with differences in bone mineral density and biochemical parameters, and to determine whether these observations are related to 1,25-dihydroxyvitamin D.. Dietary calcium intake was determined from diet records in 71 unselected patients enrolled in an ongoing longitudinal study on the natural history of primary hyperparathyroidism. Subjects were placed into one of three dietary calcium groups based on their mean dietary calcium intake: very low (< 300 mg/day; mean = 199 +/- 14), low (300 to 800 mg/day; mean = 529 +/- 21), and US RDA (> 800 mg/day; mean = 1023 +/- 73). Biochemical indices were indicative of patients with modern day primary hyperparathyroidism, showing mild hypercalcemia (2.79 +/- 0.02 mmol/L), low normal serum phosphorus (0.90 +/- 0.03 mmol/L), elevated parathyroid hormone levels by midmolecule (764 +/- 69 pg/mL) and immunoradiometric (118 +/- 8 pg/mL) assays, and high normal 1,25-dihydroxyvitamin D (60 +/- 3 pg/mL) and urinary calcium excretion (6.3 +/- 0.4 mmol/day). Bone mineral density was measured by dual energy x-ray absorptiometry at the lumbar spine, right femoral neck and distal third of the nondominant radius for each subject.. Over the entire range, there was no significant effect of dietary calcium on serum parathyroid hormone levels, calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, urinary calcium excretion, or bone mineral density of the lumbar spine, femoral neck or distal one-third radius. Serum 1,25-dihydroxyvitamin D was elevated in 37 patients (52%). Despite similarly low dietary calcium intake among patients with normal and elevated levels of 1,25-dihydroxyvitamin D (477 +/- 50 mg/day vs. 533 +/- 40 mg/day), patients with elevated levels of 1,25-dihydroxyvitamin D had higher parathyroid hormone levels by immunoradiometric assay (136 +/- 11 pg/mL vs. 97 +/- 10 pg/mL; P < .05), and urinary calcium (7.4 +/- 0.05 mmol/day vs. 5.1 +/- 0.05 mmol/day; P < .05 or 0.82 +/- 0.04 mmol/mmol creatinine vs. 0.56 +/- 0.04 mmol/mmol creatinine; P < .01).. The data suggest that patients with normal levels of 1,25-dihydroxyvitamin D can liberalize their calcium intake without adverse consequences. However those with elevated levels of 1,25-dihydroxyvitamin D are advised to be more restrictive in order to prevent hypercalciuria.

Topics: Bone Density; Calcium, Dietary; Female; Humans; Hyperparathyroidism; Male; Middle Aged; Vitamin D

There has been controversy regarding the initial pathogenic events involved with the hyperparathyroidism of chronic renal failure (CRF). Low serum levels of 1,25-dihydroxyvitamin D in uremic patients are postulated by some as having a role in permitting higher parathyroid hormone (PTH) secretion. However, recent animal and in vitro studies strongly suggest that phosphate has a direct effect on parathyroid cells to enhance PTH secretion. To evaluate the relationships among serum phosphate, calcium, PTH, and 1,25-dihydroxyvitamin D in uremic humans, we performed a cross-sectional analysis of 84 patients with varying levels of CRF. Using stepwise regression analysis after adjusting for multiple comparisons, we found that serum phosphate correlated directly with serum PTH (r = 0.62, P < 0.01) in patients with mild to moderate CRF (creatinine < or = 3.0 mg/dL), independent of serum calcium and 1,25-dihydroxyvitamin D levels. In patients with more severe renal failure (creatinine > 3.0 mg/dL), only the serum calcium correlated with serum PTH (r = -0.47, P < 0.01). While serum 1 ,25-dihydroxyvitamin D showed no correlations with PTH, phosphate, or calcium at any stage of renal failure, the mean 1,25-dihydroxyvitamin D level in patients with mild CRF was lower than that in age-matched controls (24 +/- 3 pg/mL v 37 +/- 2 pg/mL; P < 0.01), suggesting that low 1,25-dihydroxyvitamin D was permissive for enhanced PTH secretion. These data demonstrate an independent association of serum phosphate with PTH in patients with CRF and suggest that phosphate may directly enhance PTH secretion in this setting. This study supports recent animal studies showing a direct parathyroid cell effect of phosphate on PTH secretion.

Topics: Aged; Calcium; Case-Control Studies; Creatinine; Cross-Sectional Studies; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Phosphates; Regression Analysis; Uremia; Vitamin D