calcitriol and Fractures--Bone

Chronic kidney disease (CKD) is associated with mineral and bone disorders (MBD) that are now considered as a syndrome. Bone fragility and a four to tenfold increased rate of skeletal fractures are often reported in CKD patients. The evaluation of the risk of these fractures in CKD patients should explore the same risk factors identified for the general population including low body weight, menopause, personal and familial history of osteoporosis, chronic inflammatory diseases, and corticosteroid therapy. The aim of this article is to provide a critical review of the tools used for the evaluation of bone loss and the risk of fracture in CKD patients, ranging from the measurement of bone mineral density (BMD), fracture risk assessment (Frax™), quantitative computed tomography (QCT), high-resolution peripheral quantitative computed tomography (HRpQTC), to circulating biomarkers of bone metabolism including vitamin D, parathyroid hormone (PTH), bone-specific alkaline phosphatase, osteocalcin, and some collagen type 1-related molecules indicators of bone remodeling.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Biomarkers; Bone Density; Chronic Kidney Disease-Mineral and Bone Disorder; Fractures, Bone; Humans; Osteocalcin; Parathyroid Hormone; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Tomography, X-Ray Computed; Vitamin D

This article succinctly summarizes the available evidence on the risk of bone fractures with sodium-glucose co-transporter-2 inhibitors. The US Food and Drug Administration has strengthened the warning for canagliflozin related to the increased risk of bone fractures, and added new information about decreased bone mineral density. The agency has also said that it will evaluate the risk of bone fractures with other drugs in the sodium-glucose co-transporter-2 inhibitor class. Increases in parathyroid hormone levels and decreases in 1,25-dihydroxyvitamin D levels have been postulated as possible mechanisms. In contrast, some studies with dapagliflozin have shown no effects on bone health. Because a consensus has not been reached, we believe that an expert opinion on how to interpret the available evidence would be of great benefit for clinicians.

Topics: Animals; Benzhydryl Compounds; Bone Density; Canagliflozin; Drug Labeling; Fractures, Bone; Glucosides; Humans; Hypoglycemic Agents; Parathyroid Hormone; Risk; Sodium-Glucose Transporter 2 Inhibitors; United States; United States Food and Drug Administration; Vitamin D

Recent studies have added new dimensions to the fund of knowledge on vitamin D. In addition to the classic role of vitamin D in preventing rickets and osteomalacia, a preventive effect against osteoporotic fractures has been convincingly established, and abundant evidence suggests a role in preventing malignancies and autoimmune diseases. Serum 25-OH-vitamin D assay is a simple test for evaluating vitamin D status. However, recent review articles indicate that current reference ranges for serum 25-OH-vitamin D are too low. An appropriate lower normal limit may be between 50-100 nmol/l (20-40 ng/ml). Standard supplement dosages may fail to provide concentrations above this range.

Topics: Fractures, Bone; Humans; Osteomalacia; Osteoporosis; Rickets; Risk Factors; Vitamin D; Vitamin D Deficiency

Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health.. We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours.. Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23.. Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk.. ClinicalTrial.gov (NCT02404870).. Supported by the Intramural Program of NIDDK.

Topics: Adult; Canagliflozin; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fractures, Bone; Healthy Volunteers; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Placebos; Sodium-Glucose Transporter 2 Inhibitors; Vitamin D

The authors' previous investigations have disclosed low serum 25-hydroxyvitamin D (25-OHD) concentrations in 45 patients during long-term hospitalization following stroke (mean 5.9 ng/mL). This 25-OHD deficiency resulted from sunlight deprivation.. To evaluate the efficacy of sunlight exposure in increasing serum 25-OHD, in reducing the severity of osteoporosis in bone mineral density (BMD), and in decreasing the risk of hip fractures in chronically hospitalized, disabled stroke patients.. In a 12-month randomized and prospective study of stroke patients, 129 received regular sunlight exposure for 12 months, and the remaining 129 (sunlight-deprived) did not.. At baseline, patients of both groups showed vitamin D deficiency. BMD increased by 3.1% in the sunlight-exposed group and decreased by 3.3% in the sunlight-deprived group (p = 0.0001). 25-OHD level increased by fourfold in the sunlight-exposed group. Six patients sustained hip fractures on the hemiplegic side in the sunlight-deprived group, and one hip fracture occurred among the sunlight-exposed group (p = 0421; odds ratio = 6.1).. Sunlight exposure can increase the BMD of vitamin D-deficient bone by increasing 25-OHD concentration.

Topics: Aged; Bone Density; Calcium; Female; Fractures, Bone; Heliotherapy; Humans; Male; Osteoporosis; Parathyroid Hormone; Prospective Studies; Stroke; Vitamin D; Vitamin D Deficiency

Bone disease contributes to relevant morbidity after solid organ transplantation. Vitamin D has a crucial role for bone metabolism. Activation of vitamin D depends on the endocrine function of both, liver and kidney. Our study assessed key markers of bone metabolism at time of transplantation and 6 months after transplantation among 70 kidney and 70 liver recipients. In 70 kidney recipients 25-OH vitamin D levels did not differ significantly between peri-transplant (median 32.5nmol/l) and 6 months post-transplant (median 41.9nmol/l; P = 0.272). Six months post-transplant median 1, 25-(OH)2 vitamin D levels increased by >300% (from 9.1 to 36.5ng/l; P<0.001) and median intact parathyroid hormone levels decreased by 68.4% (from 208.7 to 66.0 ng/l; P<0.001). Median β-Crosslaps (CTx) and total procollagen type 1 amino-terminal propeptide (P1NP) decreased by 65.1% (from 1.32 to 0.46ng/ml; P<0.001) and 60.6% (from 158.2 to 62.3ng/ml; P<0.001), respectively. Kidney recipients with incident fractures had significantly lower levels of 1, 25-(OH)2 vitamin D at time of transplantation and of intact parathyroid hormone 6 months post-transplant. Among 70 liver recipients, 25-OH vitamin D, 1, 25-(OH)2 vitamin D and intact parathyroid hormone levels were not significantly altered between peri-transplant and 6 months post-transplant. Contrary to kidney recipients, median CTx increased by 60.0% (from 0.45 to 0.72 ng/ml; P = 0.002) and P1NP by 49.3% (from 84.0 to 125.4ng/ml; P = 0.001) in the longitudinal course. Assessed biomarkers didn't differ between liver recipients with and without fractures. To conclude, the assessed panel of biomarkers proved highly dynamic after liver as well as kidney transplantation in the early post-transplant period. After kidney transplantation a significant gain in 1, 25-(OH)2 vitamin D combined with a decline in iPTH, CTx and P1NP, whereas after liver transplantation an increase in CTx and P1NP were characteristic.

Topics: Adult; Biomarkers; Bone and Bones; Bone Density; Bone Remodeling; Collagen Type I; Female; Fractures, Bone; Glomerular Filtration Rate; Humans; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Parathyroid Hormone; Peptide Fragments; Peptides; Phosphates; Procollagen; Prospective Studies; Vitamin D

Topics: Bone Demineralization, Pathologic; Bone Density; Canagliflozin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fractures, Bone; Humans; Parathyroid Hormone; Phosphorus; Sodium-Glucose Transporter 2 Inhibitors; Vitamin D

The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.

Topics: Animals; Cartilage; Chondrocytes; Fracture Healing; Fractures, Bone; Mice; Mice, Knockout; Osteogenesis; Vitamin D; Vitamin D3 24-Hydroxylase

Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED-discordant, twin and sibling matched-pair approach, and assessed clinically relevant subgroups: AED polytherapy; longer-duration AED; and falls history.. Twenty-nine same-sex (mean age 44.9 years, 59% female), ambulatory, community-dwelling twin and sibling pairs, discordant for AED exposure (and AED-indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum samples for 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and immunoreactive parathyroid hormone (iPTH) levels were taken.. There were significant mean within-pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within-pair differences were seen in fasting serum levels of 1,25(OH)(2)D, 25OHD and iPTH after Bonferroni correction.. Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.

Topics: Accidental Falls; Adult; Anticonvulsants; Diseases in Twins; Drug Therapy, Combination; Epilepsy; Female; Fractures, Bone; Gait; Humans; Male; Muscle Strength; Parathyroid Hormone; Postural Balance; Risk Factors; Siblings; Vitamin D; Vitamin D Deficiency

To investigate rates of bone turnover and calcium homeostasis in Gambian women, we recruited 103 peri- and postmenopausal women, aged 45 to 80+ years and 11 women of reproductive age. Fasting blood was analyzed for plasma osteocalcin, PTH, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], total- and bone-specific alkaline phosphatase. Plasma and urinary calcium, inorganic phosphate, sodium, potassium, creatinine, and albumin and urine free deoxypyridinoline (Dpd) was also measured. Samples from 20 premenopausal and 31 postmenopausal women from Cambridge, UK were analyzed, using the same methodology for comparison. For the Gambian women, peak calcium excretion occurred at around 50 years of age. For women aged > or =45 years, calcium excretion decreased by 3.0% per year of age (SE 1%; P < 0.005). In this age group, 25(OH)D also decreased with age (P < 0.005). Urinary sodium output, pH, and titratable acid output decreased (all P < 0.05) and total alkaline phosphatase (P < 0.005), osteocalcin (P < 0.005), and PTH (P < 0.05) increased with age. Comparisons were made between the following groups of Gambian and British women: premenopausal, early (age 55-64 years)- and late (age 65+ years)-postmenopausal. Gambian women of all ages were lighter (P < 0.001), shorter (P < 0.01), and had higher plasma bone-specific alkaline phosphatase activity (P < 0.05) and higher concentrations of osteocalcin (P < 0.05), PTH (P < 0.001), 1,25(OH)(2)D (P < 0.001), and 25(OH)D (P < 0.001). There were no consistent differences in calcitonin, while urinary free Dpd outputs were lower in the Gambians (P < 0.001). Plasma calcium, phosphate, and albumin (P < 0.01) were significantly lower. Urinary calcium, phosphate, sodium, and potassium excretion were lower, particularly in the postmenopausal group (P < 0.001). Although Gambian urine pH was more acidic, titratable acid output was lower (P < 0.01). These data show that Gambian women with low dietary calcium intakes and good vitamin D status have low urinary calcium excretion and that menopausal changes in calcium and bone metabolism among Gambian women are similar to those seen in other populations. In addition, they demonstrate that Gambian women of all ages have raised plasma PTH and 1,25(OH)(2)D concentrations and raised markers of osteoblast activity. We postulate that high endogenous PTH concentrations may be beneficial to bone health in Gambian women, removing fatigue damage and improving bone quality.

Topics: Bone Development; Calcitonin; Calcium; Creatinine; Female; Fractures, Bone; Gambia; Homeostasis; Humans; Incidence; Middle Aged; Parathyroid Hormone; Perimenopause; Potassium; Rural Population; Sodium; Vitamin D

Women are at higher risk for osteoporosis, but most of the literature examining the effect of alcohol abuse on bone mineral density (BMD) has been in men. The aim of this study was to determine differences in BMD and fracture prevalence among women in treatment for alcohol abuse, in recovery and non-alcohol-dependent women. This cross-sectional study was completed at two residential substance abuse centers in Iowa (USA). The patients were Caucasian women, aged 18-70 years, in treatment for alcohol abuse and dependence ( n=228); in recovery and abstaining from alcohol ( n=156); and women with no history of alcohol abuse ( n=447). The main outcome measures were femoral neck and lumbar spine BMD measured by dual-energy X-ray absorptiometry (DXA); self-reported lifetime fracture prevalence. After adjusting for age and menopausal status, women in treatment had BMDs that were 7.7% ( p<0.01) and 6.3% ( p<0.01) lower at the femoral neck and lumbar spine, respectively, than non-alcohol-abusing women, and 4.8% lower at both bone sites ( p<0.01) than women in recovery. Femoral neck BMD of women in recovery was 3.1% lower ( p<0.01) than in non-alcohol-dependent women; however, the difference was not significant following multivariate analysis. Women in treatment and recovery reported more fractures during childhood and early adolescence than non-alcohol-dependent women ( p<0.01). Women in recovery also reported significantly greater numbers of fractures following sobriety than their paired non-alcohol-dependent counterparts. Alcohol abuse and dependence was associated with lower femoral neck and lumbar spine BMD. Women with histories of alcohol dependence had a higher lifetime prevalence of fractures, including time periods before the onset of problem drinking and following abstinence, suggesting that factors other than acute intoxication contributed to the greater fracture prevalence.

Topics: Adolescent; Adult; Aged; Alcoholism; Amenorrhea; Body Mass Index; Bone Density; Contraceptives, Oral; Cross-Sectional Studies; Female; Fractures, Bone; Humans; Liver Diseases; Middle Aged; Pregnancy; Pregnancy in Adolescence; Smoking; Vitamin D

Heart transplantation, with its attendant glucocorticoid and cyclosporine therapy, has deleterious effects on the skeleton. We have previously reported rapid bone loss and high fracture rates (36% of patients) during the first year after heart transplantation. The bone loss was accompanied by declines in serum 1,25-dihydroxyvitamin D and osteocalcin levels and increased urinary excretion of markers of bone resorption (hydroxyproline, pyridinoline, and deoxypyridinoline). We therefore investigated whether bone loss could be prevented by bisphosphonates, agents that inhibit bone resorption.. Serial measurements of bone mineral density (BMD) and biochemical indexes of mineral metabolism were compared in 18 group A patients who received a single intravenous infusion of pamidronate (60 mg) within 2 weeks of heart transplantation, followed by 4 cycles of oral etidronate (400 mg daily for 14 days every 3 months) and oral calcitriol 0.25 microg daily, to those of 52 patients who previously underwent transplantation (group B) who did not receive antiresorptive therapy. Both groups received elemental calcium 1000 mg and vitamin D 400 IU daily.. At 12 months after transplantation, there was virtually no lumbar spine bone loss in group A patients, whereas lumbar spine BMD had declined significantly in group B patients (0.2% +/- 0.9% vs 6.8% +/- 1.0%, respectively; P < .0001). Similarly, femoral neck BMD fell by 10.6% +/- 1.1% in group B patients and by only 2.7% +/- 1.4% in group A patients (P < .0001). Three incident vertebral fractures occurred in two group A patients, whereas 17 group B patients sustained 30 incident vertebral fractures, one hip fracture and three episodes of rib fractures (P < .02; test of proportions). With respect to markers of bone resorption, urinary deoxypyridinoline fell by 51% +/- 9% in group A patients and increased by 65% +/- 22% in group B patients by 3 months after transplantation (P < .0001).. In summary, heart transplant recipients treated with bisphosphonates and replacement doses of calcitriol sustained less bone loss and fewer fractures than those treated with calcium and vitamin D. We conclude that bisphosphonate therapy, in conjunction with calcitriol, shows promise for prevention of transplantation-related osteoporosis.

Topics: Absorptiometry, Photon; Amino Acids; Biomarkers; Bone Density; Bone Resorption; Calcitriol; Calcium; Creatinine; Diphosphonates; Drug Therapy, Combination; Etidronic Acid; Female; Fractures, Bone; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Osteoporosis; Pamidronate; Parathyroid Hormone; Pilot Projects; Vitamin D

The purpose of this study was to determine the prevalence of osteoporosis, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with end-stage liver disease who were referred for orthotopic liver transplantation. A prospective study was performed on 58 cirrhotic patients (6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis), who were referred for orthotopic liver transplantation. Patients, excluding those with primary biliary cirrhosis, were classified in Child-Pugh groups according to the severity of liver disease (class B [28 patients], class C [24 patients]). Biochemical parameters of bone mineral metabolism and standard liver function tests were measured in all patients. Additionally, serum osteocalcin, urinary hydroxyproline/creatinine ratio, serum intact parathyroid hormone, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, follicle-stimulating hormone, and luteinizing hormone levels were determined in patients and controls within the same age range. Plasma testosterone, sex hormone-binding globulin levels, and free testosterone index were obtained for all men included in the study. Bone mass of the lumbar spine and femur were measured by dual X-ray absorptiometry (DPX-L), and were expressed as a standard deviation of mean values (Z-score) from a sex and age-matched control group. Spinal X-rays were obtained to assess vertebral fractures. Osteoporosis was considered as a factor in spinal bone mineral density with a Z-score below 2 or at least one vertebral fracture. Twenty-five patients (43%) had osteoporosis, with lower bone mass measurements in the lumbar spine than in the femoral neck (P < 0.005). Alcoholic and Child-Pugh C patients showed the lowest femoral bone mineral density values. Cirrhotic patients showed lower osteocalcin levels than controls (14.3 +/- 5.9 vs. 18.2 +/- 8.1 ng/ml; P < 0.05) and showed increased urinary hydroxyproline (125.1 +/- 51.5 vs. 107.9 +/- 26.6 nM/mg creatinine; P < 0.05). Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone levels were significantly lower in cirrhotic patients than in controls (10.3 +/- 9.1 vs. 23.1 +/- 26.6 ng/ml; P = 0.000), (12.9 +/- 9.1 vs. 48.3 +/- 11.5 pg/ml; P = 0.000), (16.6 +/- 9.2 vs. 27.9 +/- 8.2 pg/ml; P = 0.000), with no differences between Child-Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-hydroxyvitamin D serum values (4.

Topics: Adult; Bone Density; Bone Diseases, Metabolic; Creatinine; Female; Fractures, Bone; Humans; Hydroxyproline; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Osteocalcin; Osteoporosis; Parathyroid Hormone; Prevalence; Prospective Studies; Risk Factors; Testosterone; Vitamin D