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Denosumab-Induced Hypocalcemia and Hyperparathyroidism in de novo Kidney Transplant Recipients.
Cianciolo, G, Tondolo, F, Barbuto, S, Iacovella, F, Zavatta, G, Altieri, P, Grandinetti, V, Comai, G, Cozzolino, M, La Manna, G
American journal of nephrology. 2021;(8):611-619
Abstract
INTRODUCTION Denosumab represents a realistic treatment option to increase bone mineral density in kidney transplant recipients (KTRs). It is still unknown how and at what extent posttransplantation bone disease and graft function influence the effects of denosumab on mineral metabolism indexes. In this study, we analyze risk factors of hypocalcemia and parathyroid hormone (PTH) increase after denosumab administration in eighteen de novo KTRs and its management before and after this treatment. METHODS We conducted a monocentric, observational, prospective study on de novo KTRs. All KTRs enrolled received a single 60 mg subcutaneous dose of denosumab every 6 months. Before kidney transplantation, no patients were treated with calcio-mimetic. After kidney transplantation and before antiresorptive therapy, no patients were treated with calcio-mimetic drugs and/or vitamin D receptor agonists, while all patients received nutritional vitamin D supplementation (from 1,000 IU to 1,500 IU daily). RESULTS Hypocalcemia was related to the degree of lumbar osteoporosis (p = 0.047); the increase in the PTH level was correlated to baseline bone turnover markers (bone alkaline phosphatase, serum osteocalcin, and β-C-terminal telopeptide), the 25 OH status, and eGFR. The introduction of calcitriol, after the PTH increase, in addition to cholecalciferol was necessary to ensure an adequate control of serum calcium and PTH during a follow-up of 15 months. Following the treatment with denosumab, it was observed an improvement of areal bone mineral density both at lumbar and femoral sites with a mean percentual increase of 1.74% and 0.25%, respectively. CONCLUSIONS Denosumab is an effective treatment for bone disease in KTRs. In our study, the increase in PTH is not a transient event but prolonged throughout the follow-up period and requires continuous supplementation therapy with calcitriol.
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The use of activated vitamin D and risks of hospitalization for infection and amputation in incident hemodialysis patients in Taiwan: a nationwide population-based cohort study.
Chao, JY, Li, CY, Wang, MC, Kao Yang, YH
BMC nephrology. 2020;(1):331
Abstract
BACKGROUND Hemodialysis patients have a high risk of mortality. The most common causes of death are cardiovascular disease and infection. The potential hazard or benefit associated with vitamin D use and cardiovascular or infection outcome is poorly characterized. METHODS We conducted a retrospective observational cohort study by recruiting 52,757 patients older than 20 years from Taiwan National Health Insurance Research Database (NHIRD) who initiated maintenance hemodialysis between 2001 and 2009. Patients who were prescribed activated vitamin D before the 360th day from hemodialysis initiation were defined as vitamin D users. The primary outcome of interest includes occurrence of acute myocardial infarction (AMI), ischemic stroke, lower limb amputation, and hospitalization for infection, respectively, while death events are treated as competing events. We conducted competing risk analysis using subdistribution hazard regression model to estimate subdistribution hazard ratios (SHRs) in relation to various outcomes. RESULTS During the median follow-up of 1019 days, the vitamin D users had a lower crude mortality rate, lower incidences of AMI, ischemic stroke, amputation, and hospitalization for infection compared with non-users. Taking into consideration competing events of death, vitamin D users were associated with a lower hazard of lower limb amputation (SHR 0.84 [95% CI, 0.74-0.96]) and hospitalization for infection (SHR 0.90 [95% CI, 0.87-0.94]), but not AMI or ischemic stroke, after adjustment for potential confounders. Subgroup analyses and dose response evaluation both showed a consistent association of activated vitamin D treatment with decreased risk of amputation and infection. CONCLUSION The findings suggest that therapeutic activated vitamin D use in hemodialysis patients may be beneficial for decreasing infection events and amputation, of which the latter is a complication of peripheral vascular disease, rather than reducing major atherosclerotic cardiovascular events such as AMI or ischemic stroke.
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Fitting Marginal Structural and G-Estimation Models Under Complex Treatment Patterns: Investigating the Association Between De Novo Vitamin D Supplement Use After Breast Cancer Diagnosis and All-Cause Mortality Using Linked Pharmacy Claim and Registry Data.
Madden, JM, Leacy, FP, Zgaga, L, Bennett, K
American journal of epidemiology. 2020;(3):224-234
Abstract
Studies have shown that accounting for time-varying confounding through time-dependent Cox proportional hazards models may provide biased estimates of the causal effect of treatment when the confounder is also a mediator. We explore 2 alternative approaches to addressing this problem while examining the association between vitamin D supplementation initiated after breast cancer diagnosis and all-cause mortality. Women aged 50-80 years were identified in the National Cancer Registry Ireland (n = 5,417) between 2001 and 2011. Vitamin D use was identified from linked prescription data (n = 2,570). We sought to account for the time-varying nature of vitamin D use and time-varying confounding by bisphosphonate use using 1) marginal structural models (MSMs) and 2) G-estimation of structural nested accelerated failure-time models (SNAFTMs). Using standard adjusted Cox proportional hazards models, we found a reduction in all-cause mortality in de novo vitamin D users compared with nonusers (hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.73, 0.99). Additional adjustment for vitamin D and bisphosphonate use in the previous month reduced the hazard ratio (HR = 0.45, 95% CI: 0.33, 0.63). Results derived from MSMs (HR = 0.44, 95% CI: 0.32, 0.61) and SNAFTMs (HR = 0.45, 95% CI: 0.34, 0.52) were similar. Utilizing MSMs and SNAFTMs to account for time-varying bisphosphonate use did not alter conclusions in this example.
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Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.
Bliuc, D, Tran, T, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, et al
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2019;(4):817-828
Abstract
UNLABELLED In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.
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The efficacy of pharmacotherapy in postmenopausal osteoporosis: a longitudinal observational study.
Pluskiewicz, W, Adamczyk, P, Franek, E, Sewerynek, E, Wichrowska, H, Napiórkowska, L, Stuss, M, Rozwandowicz, A, Drozdzowska, B
Endokrynologia Polska. 2019;(6):473-477
Abstract
INTRODUCTION The aim of the study was an assessment of longitudinal changes in fracture probability in postmenopausal women. MATERIAL AND METHODS A group of 226 postmenopausal women at baseline mean age 66.46 ± 7.96 years were studied. There were 21 women without therapy, 102 taking calcium + vitamin D, and 103 women on antiresorptive therapy, in the study group. Data concerning clinical risk factors for osteoporosis and hip BMD were gathered. Fracture probability for major and hip fractures was established using FRAXTM. RESULTS Mean follow-up time was 2.43 ± 0.59 years. Baseline FRAX value in the whole group for major fracture was 7.1 ± 4.18, and at follow-up it was 7.44 ± 4.04. Respective results for FRAX for hip fracture were 3.17 ± 2.69 and 3.02 ± 2.35. In the whole group the probability for major fractures significantly increased during follow-up (p < 0.05) and for hip fracture did not change. In non-treated patients and patients taking calcium + vitamin D the fracture probability increased significantly. In patients on antiresorptive therapy the fracture probability did not change, which was connected with an improvement in bone status assessed by DXA. Femoral neck T-score in the whole group did not change, in those not treated and taking calcium + vitamin D it decreased significantly (p < 0.05), while in treated women it increased significantly (p < 0.05). In patients with improved bone status the FRAX values for major and hip fractures decreased by 0.44 ± 1.62 and 0.36 ± 1.19, respectively. Conversely, in patients with worsening T-score value the FRAX values increased by 1.33 ± 1.42 and 0.66 ± 1.25, respectively. CONCLUSION Antiresorptive therapy stabilises fracture probability in postmenopausal women due to improvement in bone status.
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Hypercalcemia and acute kidney injury induced by eldecalcitol in patients with osteoporosis: a case series of 32 patients at a single facility.
Aihara, S, Yamada, S, Oka, H, Kamimura, T, Nakano, T, Tsuruya, K, Harada, A
Renal failure. 2019;(1):88-97
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Abstract
BACKGROUND Eldecalcitol (ELD) is an active vitamin D3 analog that is widely used in Japan for the treatment of osteoporosis. The most common adverse drug reaction of ELD is hypercalcemia. However, few reports have focused on acute kidney injury (AKI) associated with ELD-induced hypercalcemia. MATERIALS AND METHODS We retrospectively reviewed the medical records at our hospital for cases of hypercalcemia-induced AKI between April 2013 and February 2018. Among them, we focused on patients who developed AKI secondary to ELD-induced hypercalcemia. RESULTS Among 69 patients who developed hypercalcemia-induced AKI, 32 patients (46.4%) developed AKI associated with ELD-induced hypercalcemia. Their mean age was 82 ± 5 years, 97% of them were female, mean corrected serum calcium level was 12.2 ± 1.5 mg/dL, serum creatinine level was 2.5 ± 2.2 mg/dL, and estimated glomerular filtration rate was 23.9 ± 14.4 ml/min/1.73 m2 on admission. ELD administration was discontinued in all patients and some of them were treated with hydration with or without calcitonin, which was followed by a normalization of serum calcium level. Corrected serum calcium level on admission was significantly higher (p < .05) in patients treated with magnesium oxide. Although there were no significant differences, serum calcium and creatine levels on admission tended to be higher in patients who were treated with other drugs that affect renal hemodynamics and renal calcium metabolism than those not taking these drugs. CONCLUSIONS Prescribers of ELD should regularly monitor serum calcium levels and kidney function to prevent hypercalcemia and AKI associated with ELD and pay more attention to concomitant drugs especially magnesium oxide.
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Prescribing and adherence to bone protection medications following hip fracture in the United Kingdom: results from the World Hip Trauma Evaluation (WHiTE) cohort study.
Cehic, M, Lerner, RG, Achten, J, Griffin, XL, Prieto-Alhambra, D, Costa, ML
The bone & joint journal. 2019;(11):1402-1407
Abstract
AIMS: Bone health assessment and the prescription of medication for secondary fracture prevention have become an integral part of the acute management of patients with hip fracture. However, there is little evidence regarding compliance with prescription guidelines and subsequent adherence to medication in this patient group. PATIENTS AND METHODS The World Hip Trauma Evaluation (WHiTE) is a multicentre, prospective cohort of hip fracture patients in NHS hospitals in England and Wales. Patients aged 60 years and older who received operative treatment for a hip fracture were eligible for inclusion in WHiTE. The prescription of bone protection medications was recorded from participants' discharge summaries, and participant-reported use of bone protection medications was recorded at 120 days following surgery. RESULTS Of 5456 recruited patients with baseline data, 2853 patients (52%) were prescribed bone protection medication at discharge, of which oral bisphosphonates were the most common, 4109 patients (75%) were prescribed vitamin D or calcium, and 606 patients (11%) were not prescribed anything. Of those prescribed a bone protection medication, only 932 patients (33%) reported still taking their medication 120 days later. CONCLUSION These data provide a reference for current prescription and adherence rates. Adherence with oral medication remains poor in patients with hip fracture. Cite this article: Bone Joint J 2019;101-B:1402-1407.
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Rush Fracture Liaison Service for capturing "missed opportunities" to treat osteoporosis in patients with fragility fractures.
Gupta, MJ, Shah, S, Peterson, S, Baim, S
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018;(8):1861-1874
Abstract
UNLABELLED In spite of being a public health problem of pandemic proportions, osteoporosis continues to be underdiagnosed and undertreated especially in older adults with fragility fractures. Confirmation of this hypothesis resulted in the development of a novel Fracture Liaison Service (Rush FLS). Results of the first 12 months of operation revealed that patients with confirmed fragility fracture do not have a timely diagnosis at fracture occurrence or treatment of their disease. The Rush FLS is an effective fracture liaison model. INTRODUCTION Determining the prevalence of undiagnosed and untreated osteoporosis in fragility fracture patients, either admitted to an academic tertiary care center or treated and discharged from the center's emergency department to be followed in the endocrinology bone clinic, using an innovative, educational, low-cost, physician-run Fracture Liaison Service (FLS). METHODS An automated alert was integrated into the electronic medical record at Rush University Medical Center (RUMC), triggered by historical and/or acute fracture(s) in patients 50 years or older, in patients that were either admitted to the hospital or in patients evaluated in the emergency department and discharged to be followed in the endocrinology bone clinic. We report the results of the first 12 months of operation in patients admitted to the hospital. RESULTS First acute fragility fracture(s) were identified in 36% (80/223), only historical fragility fracture(s) in 28% (63/223) and both acute and historical fragility fracture(s) in 36% (80/223). The cumulative subgroup with historical fragility fractures with/without new fractures included 67% (96/143) without a previous diagnosis of osteoporosis. First acute fragility fracture group included 83.8% (67/80) without a previous diagnosis of osteoporosis. Rush FLS "captured missed opportunities" in 73.1% (163/223) of previously undiagnosed and 77.1% (172/223) of previously untreated osteoporosis patients. Dual-energy x-ray absorptiometry (DXA) prior to FLS consult was confirmed in 30% (67/223). Vitamin D deficiency (25-hydroxy vitamin D < 20 ng/ml) in 41.9% (78/186) including undetectable levels in 16.6% (31/186) and secondary hyperparathyroidism in 43.3% (78/180) were the most common laboratory confirmed secondary etiologies for bone loss. CONCLUSIONS This study reported undiagnosed, uninvestigated, and untreated osteoporosis in the majority of fragility fracture patients seen by the Rush FLS in the first 12 months of operation.
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Treatment of Hypovitaminosis D in an Orthopaedic Trauma Population.
Andres, BA, Childs, BR, Vallier, HA
Journal of orthopaedic trauma. 2018;(4):e129-e133
Abstract
OBJECTIVES To determine the incidence of hypovitaminosis D and to evaluate a supplementation intervention. We hypothesized that patients would exhibit high adherence with a free sample, and levels would become sufficient. DESIGN Prospective observational study. SETTING Level 1 trauma center. PATIENTS One hundred forty-four consecutive, skeletally mature patients treated for acute fractures. INTERVENTION All were provided 600 mg calcium and 800 IU vitamin D3 capsules twice daily. MAIN OUTCOME MEASUREMENTS Serum 25(OH) D levels were obtained on presentation and after supplementation. Patient surveys determined adherence, vitamin D intake, and sun exposure. RESULTS Ninety-one men and 53 women, mean age 45 years, mean body mass index 28.1, were studied. Mean baseline 25(OH) D level was 20.2 ng/mL, including 9 patients taking vitamin D supplements before injury. All others (mean baseline 16.9 ng/mL) were prescribed calcium and vitamin D and were offered free supplements when discharged. Seventy-seven patients completed surveys, and mean 25(OH) D level was 36.7 ng/mL after a mean of 7.0 weeks of supplementation (P < 0.0001). Seventy-nine percent reported adherence to supplement recommendations. All adherent patients achieved normal levels. Sixteen patients were nonadherent, with 10 who forgot to take the supplement, 4 choosing not to use it, 1 choosing to sell the sample, and 1 losing the sample. CONCLUSION Hypovitaminosis D was present in 97% of orthopaedic trauma patients who were not already taking supplements. The intervention was effective in reducing hypovitaminosis D within several weeks, with all supplemented patients achieving normal levels. Seventy-nine percent of patients adhered to recommendations. Further study to determine the long-term cost-effectiveness of this strategy seems warranted. LEVEL OF EVIDENCE Therapeutic, Level II. See Instructions for Authors for a complete description of levels of evidence.
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Changes in blood and urinary cadmium levels and bone mineral density according to osteoporosis medication in individuals with an increased cadmium body burden.
Eom, SY, Yim, DH, Hong, SM, Kim, YD, Kim, H, Choi, BS, Park, JD, Park, CH, Kim, GB, Yu, SD
Human & experimental toxicology. 2018;(4):350-357
Abstract
The aim of this study was to assess changes in bone mineral density (BMD) and cadmium (Cd) levels in blood and urine in individuals living in a Cd-contaminated area according to the type of osteoporosis medication over a three-year period. This follow-up study included 204 residents living in the vicinity of a closed copper refinery, who had been found to have elevated urinary or blood Cd levels. Cd levels in the blood and urine, as well as BMD, were measured every 6 months. After the first BMD measurement, individuals were prescribed antiresorptives such as alendronate or vitamin D and calcium, according to their BMD. Subjects were classified according to the type of medicine provided over the previous 6 months. General linear models controlling for other factors were used to evaluate the effects of each type of medication on the participants' Cd levels and BMD. Spinal BMD showed a significant increase in the antiresorptive group compared to the nontreatment group. Significant decreases in blood Cd levels were found in the vitamin D and calcium group, in comparison to the nontreatment group, as well as a marginally significant decrease in the antiresorptive group. The vitamin D and calcium group showed a significantly greater decrease in urinary Cd levels than the nontreatment group. In contrast, antiresorptive medication was found to have a negative effect on urinary Cd excretion. These results suggest that vitamin D and calcium treatment for osteoporosis lowers blood Cd levels more effectively and improves urinary Cd excretion.