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Treatment of postmenopausal osteoporosis patients with teriparatide for 24 months reverts forming bone quality indices to premenopausal healthy control values.
Paschalis, EP, Gamsjaeger, S, Klaushofer, K, Shane, E, Cohen, A, Stepan, J, Pavo, I, Eriksen, EF, Taylor, KA, Dempster, DW
Bone. 2022;:116478
Abstract
Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 μg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 μm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p < 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels.
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Hypercalcemia: A Review.
Walker, MD, Shane, E
JAMA. 2022;(16):1624-1636
Abstract
IMPORTANCE Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. OBSERVATIONS Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. CONCLUSIONS AND RELEVANCE Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.
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Effect of vitamin D3 and calcium carbonate supplementation on muscle strength in postmenopausal women living with HIV.
Yin, MT, Bucovsky, M, Williams, J, Brunjes, D, RoyChoudhury, A, Colon, I, Ferris, DC, Olender, S, Schulze, PC, Sharma, A, et al
Antiviral therapy. 2020;(8):411-418
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Abstract
BACKGROUND Both falls and fractures are increased in older persons living with HIV (PLWH). Low serum total 25-hydroxyvitamin D (25-OHD) levels have been associated with falls, fractures and poor muscle strength. We hypothesized that vitamin D (VitD) supplementation would improve muscle strength in postmenopausal PLWH. METHODS In a 12-month prospective, randomized, double-blind, study of 69 African American and Hispanic postmenopausal PLWH on antiretroviral therapy with 25-OHD ≥10 ng/ml and ≤32 ng/ml, we investigated the effects of daily low (1,000 IU; n=31) and moderate (3,000 IU; n=38) cholecalciferol doses on lean mass and strength. Change in lean body mass was assessed by dual-energy X-ray absorptiometry (DXA), and isometric and isokinetic muscle strength in the dominant lower extremity was assessed using the Biodex System 4 Pro. RESULTS Mean age was 56 ±5 years, median CD4+ T-cell count 722 cells/mm3 and 74% had HIV RNA≤50 copies/ml. Serum 25-OHD did not differ at baseline, but was higher in the moderate than low VitD group at 6 and 12 months. In both groups, there were significant increases in lower extremity isokinetic torque, work and power at 12 months, with no change in lean mass. CONCLUSIONS VitD supplementation was associated with a modest increase in lower extremity strength in postmenopausal PLWH, without a concomitant increase in muscle mass. Magnitude of increase in strength were similar with 3,000 IU and 1,000 IU daily. Future larger studies will be required to determine the optimal dose of VitD to improve muscle strength and to determine whether supplementation reduces the risk of falls and fractures in PLWH.
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A Randomized Placebo-Controlled Trial of Low- Versus Moderate-Dose Vitamin D3 Supplementation on Bone Mineral Density in Postmenopausal Women With HIV.
Yin, MT, RoyChoudhury, A, Bucovsky, M, Colon, I, Ferris, DC, Olender, S, Agarwal, S, Sharma, A, Zeana, C, Zingman, B, et al
Journal of acquired immune deficiency syndromes (1999). 2019;80(3):342-349
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Prevalence of fracture is 2 to 3-fold higher in women with HIV over age 50 than in the general population. The aim of this study was to compare the effects of two doses of vitamin D3 repletion (3000 IU Vs 1000 IU) on bone turnover and change in bone mass and microarchitecture in postmenopausal women with HIV. The study is a randomised placebo-controlled study which recruited women with HIV aged between 40 and 70 years. The participants were randomised to 3000 vs 1000 IU vitamin D3 daily together with 500mg calcium carbonate twice daily. Results indicate that moderate dose vitamin D3 (3000 IU) supplementation in minority postmenopausal women with HIV on established antiretroviral therapy (treatment for HIV) did not appear to have a greater impact on bone mineral density or bone turnover than low dose vitamin D3 supplementation (1000 IU). Authors conclude that further studies are required to determine whether vitamin D3 supplementation is beneficial in this patient population, and if so, what dose provides the maximum benefit in terms of musculoskeletal health in persons aging with HIV.
Abstract
BACKGROUND Prevalence of osteoporosis and fracture is increased among older people with HIV. We compared the effects of low (1000 IU) vs moderate (3000 IU) vitamin D3 (VitD) supplementation on areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) in African American and Hispanic postmenopausal women with HIV on antiretroviral therapy. METHODS We performed a 12-month prospective, randomized, double-blind, placebo-controlled study with primary outcomes of change in aBMD by dual-energy X-ray absorptiometry (DXA) and secondary outcomes of change in vBMD by quantitative computed tomography and bone turnover markers. An intent-to-treat analysis was performed on 85 randomized subjects (43 low and 42 moderate) for primary DXA outcomes, and complete case analysis was performed for secondary outcomes. RESULTS Mean age was 56 ± 5 years, median CD4 count was 722 cells/mm, and 74% had HIV RNA ≤ 50 copies/mL. Serum 25-OHD was higher in the moderate than low VitD group at 6 months (33.1 ± 10.3 vs 27.8 ± 8.1 ng/mL, P = 0.03) and 12 months, but parathyroid hormone levels remained similar. Percent change in aBMD, vBMD, and bone turnover markers did not differ between low and moderate VitD groups before or after adjustment for baseline aBMD. CONCLUSIONS VitD supplementation at 3000 IU daily increased mean total 25-OHD levels in postmenopausal women with HIV, but we did not find evidence of an effect on BMD beyond those observed with 1000 IU daily. Future studies are necessary to determine whether VitD supplementation is beneficial in this patient population, and if so, what dose is optimal for skeletal health.
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Low-Magnitude Mechanical Stimulation to Improve Bone Density in Persons of Advanced Age: A Randomized, Placebo-Controlled Trial.
Kiel, DP, Hannan, MT, Barton, BA, Bouxsein, ML, Sisson, E, Lang, T, Allaire, B, Dewkett, D, Carroll, D, Magaziner, J, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015;(7):1319-28
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Nonpharmacologic approaches to preserve or increase bone mineral density (BMD) include whole-body vibration (WBV), but its efficacy in elderly persons is not clear. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (VIBES) trial, a randomized, placebo-controlled trial of 10 minutes of daily WBV (0.3g at 37 Hz) in seniors recruited from 16 independent living communities. The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography (QCT) and biochemical markers of bone turnover. We randomized 174 men and women (89 active, 85 placebo) with T-scores -1 to -2.5 who were not taking bone active drugs and had no diseases affecting the skeleton (mean age 82 ± 7 years, range 65 to 102). Participants received daily calcium (1000 mg) and vitamin D (800 IU). Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring; placebo platforms resembled the active platforms. In total, 61% of participants in the active arm and 73% in the placebo arm completed 24 months. The primary outcomes, median percent changes (interquartile range [IQR]) in total volumetric femoral trabecular BMD (active group (2.2% [-0.8%, 5.2%]) versus placebo 0.4% [-4.8%, 5.0%]) and in mid-vertebral trabecular BMD of L1 and L2 (active group (5.3% [-6.9%, 13.3%]) versus placebo (2.4% [-4.4%, 11.1%]), did not differ between groups (all p values > 0.1). Changes in biochemical markers of bone turnover (P1NP and sCTX) also were not different between groups (p = 0.19 and p = 0.97, respectively). In conclusion, this placebo-controlled randomized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers; however, the high variability in vBMD changes limited our power to detect small treatment effects. The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals.
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Effect of supplementation with cholecalciferol and calcium on 2-y bone mass accrual in HIV-infected children and adolescents: a randomized clinical trial.
Arpadi, SM, McMahon, DJ, Abrams, EJ, Bamji, M, Purswani, M, Engelson, ES, Horlick, M, Shane, E
The American journal of clinical nutrition. 2012;(3):678-85
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BACKGROUND Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved. OBJECTIVE The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV-infected youth. DESIGN Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits. RESULTS Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH)D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis. CONCLUSION One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178.
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Prevention of fractures after solid organ transplantation: a meta-analysis.
Stein, EM, Ortiz, D, Jin, Z, McMahon, DJ, Shane, E
The Journal of clinical endocrinology and metabolism. 2011;(11):3457-65
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Abstract
CONTEXT Bone loss and fracture are serious sequelae of organ transplantation, particularly in the first posttransplant year. Most interventional studies have been inadequately powered to detect effects on fracture. OBJECTIVE The objective of the study was to determine whether treatment with bisphosphonates (BP) or active vitamin D analogs (vitD) during the first year after transplantation reduces fracture risk and estimate the effect of these interventions on bone loss. DATA SOURCES Sources included PUBMED, MEDLINE, Cochrane Library, and abstracts from scientific meetings (presented 2003-2010). STUDY SELECTION Randomized controlled clinical trials of BP or vitD in solid organ transplant recipients were included if treatment was initiated at the time of transplantation and fracture data were collected. DATA EXTRACTION Two investigators independently extracted data and rated study quality. Fixed effect and random-effects models were used to obtain pooled estimates. DATA SYNTHESIS Eleven studies of 780 transplant recipients (134 fractures) were included. Treatment with BP or vitD reduced the number of subjects with fracture [odds ratio (OR) 0.50 (0.29, 0.83)] and number of vertebral fractures, [OR 0.24 (0.07, 0.78)]. An increase in bone mineral density at the lumbar spine [2.98% (1.31, 4.64)] and femoral neck [3.05% (2.16, 3.93)] was found with treatment. When BP trials (nine studies, 625 subjects) were examined separately, there was a reduction in number of subjects with fractures [OR 0.53 (0.30, 0.91)] but no significant reduction in vertebral fractures [OR 0.34 (0.09, 1.24)]. CONCLUSIONS Treatment with BP or vitD during the first year after solid organ transplant was associated with a reduction in the number of subjects with fractures and fewer vertebral fractures.
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Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss.
Conroy, R, Girotra, M, Shane, E, McMahon, DJ, Pavlovich, KH, Leibel, RL, Rosenbaum, M, Korner, J
Metabolism: clinical and experimental. 2011;(9):1222-6
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The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt(initial)] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt(-10%P)] or replacement doses of leptin [Wt(-10%L)]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt(initial) and Wt(-10%P) and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt(initial) to Wt(-10%L) (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.
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Vitamin D in organ transplantation.
Stein, EM, Shane, E
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2011;(7):2107-18
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Abstract
Vitamin D deficiency is prevalent among patients with end-stage organ failure awaiting transplant. Low serum 25-hydroxyvitamin D (25-OHD) levels in these patients may be related to many disease-specific factors, as well as decreased sunlight exposure and limited intake of foods containing vitamin D. Low serum 25-OHD levels are also extremely common following solid organ transplantation, both during the immediate postoperative period and in long-term graft recipients. Demographic and lifestyle factors are important in determining D status in transplant recipients. Worse vitamin D status is associated with poorer general health, lower albumin, and even decreased survival among these patients. Although several studies have demonstrated that active forms of vitamin D and its analogues prevent bone loss following transplantation, the data do not show consistent benefit. These therapies may have particular utility after renal transplantation. However, given the narrow therapeutic window with respect to hypercalcemia and hypercalciuria, and the demonstrated efficacy of bisphosphonates to prevent post-transplantation bone loss, we regard these agents as adjunctive rather than primary therapy for transplantation osteoporosis. The effects of 1,25(OH)(2)D on the immune system, which are still being elucidated, may have potential for reducing infections and preventing allograft rejection after transplantation.
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Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate.
Seeman, E, Delmas, PD, Hanley, DA, Sellmeyer, D, Cheung, AM, Shane, E, Kearns, A, Thomas, T, Boyd, SK, Boutroy, S, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;(8):1886-94
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The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (-2.1% to -0.8%) at the distal radius after 12 months. Alendronate prevented the decline (-0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p < or = .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.