Percentage Change In Bone Mineral Density Research Articles

The efficacy and safety of bisphosphonate analogs for treatment of osteoporosis after spinal cord injury: a systematic review and meta-analysis of randomized controlled trials.

Rapid bone loss in the early stages of spinal cord injury (SCI) leads to an increased risk of osteoporotic fracture. A meta-analysis was conducted to assess the efficacy and safety of bisphosphonates for the treatment of osteoporosis after SCI. A literature search of the PubMed, EMBASE, Cochrane Library, and Web of Science databases identified nine randomized controlled trials with 206 individuals. This meta-analysis was performed using a random-effects model. The primary outcome was the percent change in bone mineral density (BMD) of the total hip, distal femur, and lumbar spine from baseline to 12 months. Bone turnover markers were secondary outcomes. The incidences of adverse events were assessed in order to evaluate safety. There were significant differences in BMD of the total hip and lumbar spine or serum C-terminal telopeptide between the bisphosphonate and control groups but no difference in adverse events. The percent change in BMD of the distal femur and serum type 1 procollagen N-terminal peptide from baseline to 12 months was not superior in the treatment groups. Osteoclast-mediated bone resorption was inhibited by bisphosphonate administration. Subgroup analyses of participants treated with zoledronate at different sites revealed a beneficial effect on BMD of the total hip and lumbar spine but not the distal femur. Early bisphosphonate administration after SCI was safe and beneficial to the BMD of the total hip and lumbar spine at 12 months.

The Impact of Observation Versus Parathyroidectomy on Bone Mineral Density and Fracture Risk Determined by FRAX Tool in Patients With Primary Hyperparathyroidism

To study impact of observation (OBV) vs parathyroidectomy (PTX) on biochemistry, bone mineral density (BMD) and fracture risk calculated by Fracture Risk Assessment (FRAX) tool in primary hyperparathyroidism (PHPT). Retrospective study of 60 patients (OBV – 26; PTX – 34 patients). Mean adjusted calcium improved in both groups [OBV - 2.76 ± 0.07 vs 2.51 ± 0.20 mmol/L; p < 0.00001, PTX - 2.87 ± 0.21 vs 2.36 ± 0.12 mmol/L; p < 0.00001]. Mean parathyroid hormone level declined in both but more in PTX group [OBV - 11.4 ± 5.2 vs. 9.7 ± 5.6 pmol/L; p = 0.04, PTX - 14.3 ± 8.2 vs 4.6 ± 2.2 pmol/L; p < 0.00001]. In OBV group, BMD and T scores declined at all sites. Mean percentage change of BMD was -5.8 % at femoral neck (FN), -4.9 % at total hip (TH), -6.2 % at lumbar spine (LS) and -10.0 % at lower 1/3rd radius (LR). PTX led to stabilization of BMD at FN (3.0 %), TH (-0.6 %) and LS (2.2 %) but significant improvement at LR (13.9 %; p = 0.0005). In OBV group, 10 year risk of hip fracture (HF) (7.5 ± 9.0 % vs. 8.6 ± 9.0; p = 0.01) and major osteoporotic fracture (OF) (16.6 ± 10.9 % vs 18.3 ± 10.8 %; p = 0.002) worsened with time whereas in PTX group, risk of both type of fractures remained stable (HF; p = 0.48 and OF; p = 0.43). Comparison between groups showed greater improvement in median % change of fracture risk for both HF and OF in PTX group. OBV in PHPT lead to greater decline in BMD at all skeletal sites and imparted significant risk of HF and major OF. PTX offered stabilization of BMD at most sites but improvement at LR with unchanged fracture risk. FRAX tool should be used more frequently and universally.

Effects of Bisphosphonates on Osteoporosis Induced by Duchenne Muscular Dystrophy: A Prospective Study

Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neuromuscular disease that brings a significantly increased risk of osteoporosis and bone fractures. We prospectively evaluated the effects of oral and intravenous bisphosphonates on the bones of children with DMD. This study included a total of 52 children with DMD. They were divided into zoledronic acid (ZOL), alendronate (ALN), and control groups according to bone mineral density (BMD) and history of fragility fractures. For 2 years, all patients took calcium, vitamin D, and calcitriol. Meanwhile, 17 patients received infusions of ZOL, and 18 patients received ALN. BMD, serum levels of alkaline phosphatase (ALP) and the cross-linked C-telopeptide of type I collagen (β-CTX) were evaluated. After 24 months of treatment, the percentage changes in lumbar spine BMD were 23.2 ± 9.7% and 23.6 ± 8.8% in the ZOL and ALN groups (all P<.01 vs. baseline). The increases did not differ between the ZOL and ALN groups, but were significantly larger than those of the control group (P<.01). Serum β-CTX and ALP levels, respectively, were decreased by 44.4 ± 18.0% and 31.9 ± 26.7% in the ZOL group and by 36.0 ± 20.3% and 25.8 ± 14.4% in the ALN group (all P<.01 vs. baseline). Zoledronic acid and alendronate had similar protective effects to increase bone mineral density and reduce bone resorption in children with DMD, which were superior to treatment of calcium, vitamin D, and calcitriol. 25OHD = 25 hydroxyvitamin D; ALN = alendro-nate; ALP = alkaline phosphatase; ALT = alanine aminotransferase; BMD = bone mineral density; BP = bisphosphonate; Ca = calcium; β-CTX = cross-linked C-telopeptide of type I collagen; DMD = Duchenne muscular dystrophy; FN = femoral neck; GC = glucocorticoid; LS = lumbar spine; ZOL = zoledronic acid.

Efficacy of once-weekly teriparatide in patients with glucocorticoid-induced osteoporosis: the TOWER-GO study.

Bisphosphonates are the standard treatment for glucocorticoid-induced osteoporosis (GIOP) with teriparatide being another option. While daily teriparatide has been shown to be effective in increasing bone mineral density (BMD), the efficacy of once-weekly teriparatide (56.5µg) has not yet been evaluated. The TOWER-GO study, a 72-week, multicenter, open-label, randomized controlled trial, was conducted in patients with GIOP to compare the effects of once-weekly teriparatide and once-weekly alendronate 35mg on BMD. Patients (N = 180) with GIOP for whom drug treatment was indicated according to the 2004 guidelines in Japan were randomized to receive once-weekly teriparatide (n = 89) or once-weekly alendronate (n = 91). The primary endpoint was the non-inferiority of percentage change in lumbar spine BMD at final follow-up. The secondary endpoints were the percentage change in BMD from baseline, incidence of bone fractures, and changes in bone turnover markers. While the non-inferiority of teriparatide to alendronate was not confirmed, BMD increased significantly from baseline with teriparatide and alendronate by 5.09% and 4.04%, respectively (both p < 0.05), at 72weeks. The incidence of vertebral and non-vertebral fractures was similar in both groups. Bone formation markers increased in the teriparatide group and decreased in the alendronate group. The non-inferiority of once-weekly teriparatide versus once-weekly alendronate in BMD change at 72weeks was not shown, but the increase in bone formation markers over time and the increase of BMD in GIOP patients treated with once-weekly teriparatide were confirmed.

Pharmacologic intervention for prevention of fractures in osteopenic and osteoporotic postmenopausal women: Systemic review and meta-analysis

ObjectivesEmerging evidence has indicated a role for pharmacologic agents in the primary prevention of osteoporotic fracture, but have not yet been systematically reviewed for meta-analysis. We conducted a meta-analysis to evaluate the efficacy of pharmacologic interventions in reducing fracture risk and increasing bone mineral density (BMD) in postmenopausal women with osteopenia or osteoporosis but without prevalent fragility fracture. MethodThe Medline, EMBASE, and CENTRAL databases were searched from inception to September 30, 2019. Only randomized placebo-controlled trials evaluating postmenopausal women with −1.0 > bone mineral density (BMD) T-score > −2.5 (low bone mass) and those with BMD T-score ≤ −2.5 (osteoporosis) but without baseline fractures, who were receiving anti-osteoporotic agents, providing quantitative outcomes data and evaluating risk of vertebral and/or non-vertebral fragility fracture at follow-up. The PRISMA guidelines were followed, applying a random-effects model. The primary endpoint was the effect of anti-osteoporotic regimens in reducing the incidence of vertebral fractures. Secondary endpoints were percentage changes in baseline BMD at the lumbar spine and total hip at 1 and 2 years follow up. ResultsFull-text review of 144 articles yielded, 20 for meta-analysis. Bisphosphonates reduced the risk of vertebral fracture (pooled OR = 0.50, 95%CIs = 0.36–0.71) and significantly increased lumbar spine BMD after 1 year, by 4.42% vs placebo (95%CIs = 3.70%–5.14%). At the hip, this value was 2.94% (95%CIs = 2.13%–3.75%). Overall results of limited studies for non-bisphosphonate drugs showed increased BMD and raloxifene significantly decreases the risk of subsequent clinical vertebral fractures. ConclusionThe bisphosphonates are efficacious and most evident for the primary prevention of osteoporotic vertebral fractures, reducing their incidence and improving BMD in postmenopausal women with osteopenia or osteoporosis.

The Potential Role of Preoperative Trabecular Bone Score in Predicting Changes in Bone Mineral Density After Parathyroidectomy.

The skeletal indication for parathyroidectomy for primary hyperparathyroidism (PHPT) is based on bone mineral density (BMD) T-score < - 2.5. Whether trabecular bone score (TBS) additionally identifies patients who benefit from parathyroidectomy in terms of bone health is unknown. We aimed to study changes in BMD and TBS among Chinese who underwent curative parathyroidectomy for PHPT, in relation to their preoperative parameters, especially in those with worst site BMD T-score ≥ - 2.5 (non-osteoporotic range). We included consecutive Chinese individuals who underwent curative parathyroidectomy during 2002-2015 for PHPT and completed preoperative and postoperative BMD and TBS measurements in Queen Mary Hospital. Correlations between preoperative parameters and changes in densitometric parameters were studied. 45 Chinese individuals (13 men, 32 women) were included (mean age 62.0 ± 10.0years and BMI 24.6 ± 4.7kg/m2). After parathyroidectomy, BMD at lumbar spine (LS) improved by 6.7% (p < 0.001) while TBS did not change. Among women, peak preoperative parathyroid hormone and calcium levels independently predicted LS BMD gain. Among women with BMD in non-osteoporotic range, LS BMD also improved after parathyroidectomy, where preoperative TBS was the only significant variable inversely correlating with percentage change in LS BMD (ρ - 0.775, p = 0.005). Particularly, those with preoperative TBS ≤ 1.25 gained 7.1% LS BMD post-parathyroidectomy (p = 0.003). LS BMD, but not TBS, improved after parathyroidectomy. Among non-osteoporotic PHPT women, preoperative TBS inversely correlated with postoperative BMD improvement. Hence, low preoperative TBS may be an additional indication for surgical benefit with parathyroidectomy in non-osteoporotic PHPT women, as those with worse preoperative TBS tend to benefit more from surgery.

Effects of bisphosphonates on osteoporosis induced by Duchenne muscular dystrophy: A prospective study

ABSTRACT Objective: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neuromuscular disease that brings a significantly increased risk of osteoporosis and bone fractures. We prospectively evaluated the effects of oral and intravenous bisphosphonates on the bones of children with DMD. Methods: This study included a total of 52 children with DMD. They were divided into zoledronic acid (ZOL), alendronate (ALN), and control groups according to bone mineral density (BMD) and history of fragility fractures. For 2 years, all patients took calcium, vitamin D, and calcitriol. Meanwhile, 17 patients received infusions of ZOL, and 18 patients received ALN. BMD, serum levels of alkaline phosphatase (ALP) and the cross-linked C-telopeptide of type I collagen (β-CTX) were evaluated. Results: After 24 months of treatment, the percentage changes in lumbar spine BMD were 23.2 ± 9.7% and 23.6 ± 8.8% in the ZOL and ALN groups (all P Conclusion: Zoledronic acid and alendronate had similar protective effects to increase bone mineral density and reduce bone resorption in children with DMD, which were superior to treatment of calcium, vitamin D, and calcitriol. Abbreviations: 25OHD = 25 hydroxyvitamin D; ALN = alendro-nate; ALP = alkaline phosphatase; ALT = alanine aminotransferase; BMD = bone mineral density; BP = bisphosphonate; Ca = calcium; β-CTX = cross-linked C-telopeptide of type I collagen; DMD = Duchenne muscular dystrophy; FN = femoral neck; GC = glucocorticoid; LS = lumbar spine; ZOL = zoledronic acid

Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials

The validation of bone mineral density (BMD) as a surrogate outcome for fracture would allow the size of future randomised controlled osteoporosis registration trials to be reduced. We aimed to determine the association between treatment-related changes in BMD, assessed by dual-energy x-ray absorptiometry, and fracture outcomes, including the proportion of treatment effect explained by BMD changes. We did a pooled analysis of individual patient data from multiple randomised placebo-controlled clinical trials. We included data from multicentre, randomised, placebo-controlled, double-blind trials of osteoporosis medications that included women and men at increased osteoporotic fracture risk. Using individual patient data for each trial we calculated mean 24-month BMD percent change together with fracture reductions and did a meta-regression of the association between treatment-related differences in BMD changes (percentage difference, active minus placebo) and fracture risk reduction. We also used individual patient data to determine the proportion of anti-fracture treatment effect explained by BMD changes and the BMD change needed in future trials to ensure fracture reduction efficacy. Individual patient data from 91 779 participants of 23 randomised, placebo-controlled trials were included. The trials had 1-9 years of follow-up and included 12 trials of bisphosphonate, one of odanacatib, two of hormone therapy (one of conjugated equine oestrogen and one of conjugated equine oestrogen plus medroxyprogesterone acetate), three of PTH receptor agonists, one of denosumab, and four of selective oestrogen receptor modulator trials. The meta-regression revealed significant associations between treatment-related changes in hip, femoral neck, and spine BMD and reductions in vertebral (r2 0·73, p<0·0001; 0·59, p=0·0005; 0·61, p=0·0003), hip (0·41, p=0·014; 0·41, p=0·0074; 0·34, p=0·023) and non-vertebral fractures (0·53, p=0·0021; 0·65, p<0·0001; 0·51, p=0·0019). Minimum 24-month percentage changes in total hip BMD providing almost certain fracture reductions in future trials ranged from 1·42% to 3·18%, depending on fracture site. Hip BMD changes explained substantial proportions (44-67%) of treatment-related fracture risk reduction. Treatment-related BMD changes are strongly associated with fracture reductions across randomised trials of osteoporosis therapies with differing mechanisms of action. These analyses support BMD as a surrogate outcome for fracture outcomes in future randomised trials of new osteoporosis therapies and provide an important demonstration of the value of public access to individual patient data from multiple trials. Foundation for National Institutes of Health.

The effect of calcium and vitamin D compounds on bone mineral density in patients undergoing glucocorticoid therapies: a network meta-analysis.

The objective of our systematic review and network meta-analysis (NMA) is to investigate which vitamin D and/or calcium regimen would yield the greatest increase in lumbar spine, femoral neck, and total hip bone mineral density (BMD) in adult patients undergoing glucocorticoid therapy. We performed NMAs based on a prospectively developed protocol. A database search of MEDLINE, EMBASE, Web of Science, CINAHL, CENTRAL and Chinese databases were conducted for relevant randomized controlled trials (RCTs). Outcomes were percentage change in lumbar spine, femoral neck, and total hip BMD from baseline. We included 16 RCTs containing 1073 eligible patients in our analysis. We found alfacalcidol+calcium to yield the greatest percentage increase in lumbar spine BMD (MD 6.05, 95% credible interval [CrI] - 4.18 to 16.18) compared to no treatment, and calcitriol+calcium to yield the greatest percentage increase in femoral neck BMD (MD 8.46, 95% CrI - 4.74 to 21.51) compared to no treatment. Cholecalciferol+calcium ranked first in terms of its ability to increase total hip BMD; however this finding needs to be interpreted with caution due to low sample sizes in the cholecalciferol+calcium treatment arm. None of the treatment arms ruled out the possibility of no effect for any outcome. Alfacalcidol and calcitriol were the most efficacious treatment arms for increasing lumbar spine and femoral neck BMD, respectively. Our findings need to be validated by further investigations using larger, better-designed RCTs. Key Points •The efficacy of calcium/vitamin D compounds was examined using network meta-analyses. •Alfacalcidol + calcium yielded the greatest increase in lumbar spine BMD, calcitriol + calcium yielded the greatest increase in femoral neck BMD. •Future guidelines should place greater emphasis on the efficacy of different vitamin D compounds.

Calcium supplementation for improving bone density in lactating women: a systematic review and meta-analysis of randomized controlled trials

Clinical trials evaluating the effect of calcium supplementation on bone loss in lactating women have been small, with inconsistent results. We aimed to determine the effect of calcium supplementation on bone mineral density (BMD) in lactating women. An electronic search of databases was conducted from inception to January 2020. Two authors screened studies, extracted data, and assessed the risk of bias of eligible studies. Percentage change in BMD was pooled using random-effects models and reported as weighted mean differences (WMDs) with 95% CIs. Risk of bias was assessed using the Cochrane risk of bias tool. Five randomized controlled trials including 567 lactating women were included. All had a high risk of bias. Mean baseline calcium intake ranged from 562 to 1333 mg/d. Compared with control groups (placebo/no intervention), calcium supplementation (600/1000 mg/d) had no significant effect on BMD at the lumbar spine (WMD: 0.74%; 95% CI: -0.10%, 1.59%; I2=47%; 95% CI: 0%, 81%; n=527 from 5 trials) or the forearm (WMD: 0.53%; 95% CI: -0.35%, 1.42%; I2=55%; 95% CI: 0%, 85%; n=415 from 4 trials). BMD at other sites was assessed in single trials: calcium supplementation had a small to moderate effect on total-hip BMD (WMD: 3.3%; 95% CI: 1.5%, 5.1%) but no effect on total body or femoral neck BMD. Overall, the meta-analysis indicates that calcium supplementation does not provide clinically important benefits for BMD in lactating women. However, there was adequate dietary intake before supplementation in some studies, and others did not measure baseline calcium intake. Advising lactating women to meet the current recommended calcium intakes (with supplementation if dietary intake is low) is warranted unless new high-certainty evidence to the contrary from robust clinical trials becomes available. More research needs to be done in larger samples of women from diverse ethnic and racial groups.This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42015022092.

Oral Bisphosphonate Therapy for Osteogenesis Imperfecta: A Systematic Review and Meta-Analysis of Six Randomized Placebo-Controlled Trials.

ObjectiveTo assess the effectiveness and safety of oral bisphosphonates in increasing bone mineral density (BMD), reducing fractures, and improving clinical function in patients with osteogenesis imperfecta (OI).MethodsStudies were eligible for inclusion if they were randomized controlled trials of directly comparing oral bisphosphonate therapy with placebo‐group in OI patients. Data synthesis regarding to bone mineral density as measured by dual‐energy X‐ray absorptiometry (DEXA), decreased fracture incidence, change in biochemical markers of bone and mineral metabolism, bone histology, growth, bone pain, quality of life, and others were assessed, and meta‐analysis done when possible.ResultsFrom 98 potential references and six randomized controlled studies a total of 263 participants receiving oral bisphosphonates and 143 placebo treatments contributed data to meta‐analysis. Pooled meta‐analysis of three studies suggested that there was significant difference between bisphosphonate treated group and placebo in number of patients with at least one fracture (mean difference 0.53, 95% confidence interval 0.32–0.89, P = 0.02). Pooled meta‐analysis of two studies suggested that significant difference was noted between bisphosphonate treated group and placebo in mean percentage change in spine BMD (T‐score) (mean difference 28.43, 95% confidence interval 7.09‐49.77, P = 0.009). The similar effect was shown in the term of mean change (Z‐score) in spine BMD.ConclusionsSignificant improvement in lumbar areal BMD in patients affected with OI has been shown when treated with oral bisphosphonates, even though only a small population was enrolled. We cannot draw a definite conclusion that the increase in BMD can be translated into fracture reduction and clinical functional improvement. The optimal method, dose, type, initiation, and duration of oral bisphosphonates therapy still remains unclear. Well‐designed, adequately‐powered, placebo‐controlled RCTs investigating the effects of oral bisphosphonates on fractures reduction and improvement in quality of life in both children and adults are studied here.

Alendronate use and bone mineral density gains in women with moderate-severe (stages 3B\u20135) chronic kidney disease: an open cohort multivariable and propensity score analysis from Funen, Denmark

SummaryBisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients.PurposeThis study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD).MethodsWe created a cohort of CKD stage 3B–5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD.ResultsUse of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B–5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users.ConclusionIn a real-world cohort of women with stage 3B–5 CKD, use of alendronate appears associated with a significant improvement of 2–3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.

0856 Relationship Between A Composite Measure Of Sleep Health And Bone Mineral Density In A Sample Of Older Women From The Study Of Osteoporotic Fractures

Abstract Introduction Observational studies suggest poor sleep is related to lower bone mineral density (BMD) and increased osteoporosis risk. Yet, many studies focus on sleep duration and lack inclusion of other sleep characteristics. The sleep health construct simultaneously recognizes multiple dimensions of sleep and is operationalized as a composite score. Thus, we examined whether a composite measure of sleep health was related to BMD in a sample of older women. Methods The sample included 1968 older women (mean age: 83.6 ± 3.1 years) from the Study of Osteoporotic Fractures. Six sleep health domains (regularity, duration, satisfaction, timing, efficiency, sleepiness/alertness) were dichotomized into either “good” or “poor” categories. The number of “good” characteristics were summed into a score ranging from 0 (poor) to 6 (good). BMD (g/cm2) was measured at the femoral neck, total hip, and trochanter sites with dual energy x-ray absorptiometry. Multiple linear regression was used to explore the association between sleep health (composite score and the individual domains) with BMD (cross-sectional) and annualized percent change in BMD (longitudinal). All models were adjusted for age, body mass index, alcohol consumption, smoking, physical activity, education, diabetes, hyperthyroidism, fracture history, and cardiovascular disease. Results Average sleep health score was 3.8±1.2. Cross-sectionally, better sleep health was associated with higher BMD at the femoral neck (β=.04, p=.04) and trochanter (β=.05, p=.02). Sleep health was not cross-sectionally associated with BMD at the total hip (β=.03, p=.09) or with change in BMD at any region (Each p &amp;gt;.13). The individual domain of sleep regularity was cross-sectionally related to BMD at the total hip and trochanter, respectively (β=.04, P=.04; β=.05, P=.02). Conclusion A multi-dimensional measure of sleep health was related to greater BMD cross-sectionally at the femoral neck and trochanter regions in a sample of older women. Future studies should focus on associations between sleep health and osteoporotic-related fractures. Support The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576

SUN-377 Efficacy of Low Dose Denosumab in Maintaining Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Real World, Prospective Observational Study

Introduction: Denosumab, a fully human monoclonal antibody to RANK-ligand, has been shown to increase bone mineral density (BMD) and reduce the risk of hip, vertebral and non-vertebral fractures in postmenopausal women with osteoporosis (1-3). Varying doses of denosumab including 30mg/3months have demonstrated a decrease in bone remodelling in a dose-dependent manner (2,4-6). The primary objective of this study is to evaluate the efficacy of low dose denosumab (30mg/6 months) in postmenopausal women with osteoporosis who are reluctant to consider or continue the full dose of denosumab due to adverse events (AE) or concerns of potential AE. Methods: Following informed consent, postmenopausal women with a T-score of ≤ -2.5 at the lumbar spine (LS) or at the total hip (TH) received denosumab 30mg/6months. Patients with an additional skeletal disorder, prior fragility fracture, or on oral steroids (daily in the past 12 months) were excluded. The primary endpoint was the percent change in BMD at the lumbar spine (LS), total hip (HP), femoral neck (FN) and 1/3 radius (1/3R) at 12 months. Secondary outcomes were 1) percent change in BMD at the LS, TH, FN, and 1/3R at 24 months and 2) AE. Results: We enrolled 183 patients. The mean age was 69 years (SD= 7.07), 80% of patients had a moderate fracture risk (CAROC tool), 3% were current smokers and 9% consumed alcohol daily. 14.4% of patients were on SSRI/SNRI, 9.6% were on PPI, and no patient was on an aromatase inhibitor. At 12 months (n=125), the mean BMD significantly increased by +2.0% (95% CI 2.8%-1.3%) at the LS (p<0.001). There was no significant change in BMD at the FN, TH, AND 1/3R. At 24 months (n=65), the percent change in BMD was +3.4% (95% CI 4.8%-2.0%: p<0.001) at the LS, +1.5% (95% CI 2.9%-0.15%: p=0.031) at the FN, +1.9% (95% CI 3.5%-0.24%: p=0.025) at the 1/3R. There was no significant change in BMD at the TH. Conclusion: Low dose denosumab appears to be effective in maintaining BMD in postmenopausal women with a moderate fracture risk and may be of benefit in individuals who are experiencing side effects or concerns of side effects. This may also be of value following 10 years of therapy in order to maintain BMD.

OR15-01 Blockers and Bones: Loss of Absolute Bone Mineral Density Is Common in Trans- and Gender- Diverse Adolescents Treated with GnRHa

Background: The expected pubertal accrual of bone mineral density (BMD) may be disrupted in trans and gender diverse (TGD) adolescents who undergo pubertal suppression with Gonadotropin Releasing Hormone agonists (GnRHa)1. The extent of this effect remains unclear and is confounded by varying methods used to assess BMD1.While BMD Z-scores in GnRHa-treated TGD adolescents may be expected to decline relative to pubertal peers, this measure provides no information on actual changes in BMD. Annualised, percent change in BMD (%BMD velocity, %BMDV) provides a standardised measure of accrual or loss, but has not been reported in this context. Aims: (1) To evaluate bone accrual or loss using %BMDV in a cohort of GnRHa-treated TGD adolescents; (2) to explore associations between baseline characteristics (BMD Z score, Vitamin D status and Tanner Stage) and %BMDV. Methods. Retrospective 10yr audit at tertiary pediatric gender service. Bone densitometry data were collected at baseline and 12-24monthly during GnRHa. Areal BMD values and Z-scores for lumbar spine (LS) and total hip (TH) were obtained. %BMDV between baseline and final scan was calculated for LS and TH. Population data for %BMDV before and during puberty were derived from the BMD in Childhood Study2. Results are reported as mean (±SD) or mean difference (MD; 95% confidence interval). Results. Data from 28 patients (20 transfemale; 8 transmale) who commenced GnRHa at 13.3 (±2.0) yrs and were observed over 23.2 (±11.5) mo were included. Mean (±SD) %aBMDV during GnRHa therapy was -0.66 (±4.54) %/yr for TH and +1.91 (±4.23) %/yr for LS, both substantially lower than %aBMDV in pre-pubertal population controls (~+3-4%/year). 53% of GnRHa-treated youth exhibited negative %aBMDV, indicating bone loss, at TH and/or LS. %aBMDV was lower in (i) Vitamin D deficient youth, with MD at TH (-6.07; -9.00, -3.13); and LS (-4.93; -9.56, -0.30) relative to Vitamin D sufficient peers and (ii) youth who were Tanner stage 4+ at baseline, with MD at TH (-4.1; -7.7, -0.44) and LS (-3.6; -7.2, 0.01) relative to Tanner stage 2-3 peers. Height-adjusted Z scores declined from baseline with GnRHa treatment in >95% of patients and were not predictive of %aBMDV. Conclusion. GnRHa-treated TGD adolescents in this cohort exhibited lower BMD accrual rates than pre-pubertal population controls. Over half of our cohort lost BMD, which is a significant concern in adolescence. Vitamin D deficiency and more advanced pubertal stage at GnRHa initiation were associated with greater bone loss during treatment. These data highlight the need to monitor and optimise bone health in GnRHa-treated TGD young people. We recommend routine annual densitometry and %BMDV evaluation regardless of baseline Z-scores as well as routine screening and treatment of vitamin D deficiency while on GnRHa.References.1.Chew D., et al., Pediatrics, 2018. 141: p.e20173742.2.Zemel B.S., et al., JCEM, 2011. 96 p.3160-9.

A randomized, open-label, controlled trial of monthly oral minodronate or semiannual subcutaneous injection of denosumab for bone loss by androgen deprivation in Asian men with prostate cancer: the PRevention of Osteopenia with Minodronate And DEnosumab (PROMADE) study.

To evaluate whether monthly oral minodronate or semiannual subcutaneous injection of denosumab improves bone mineral density (BMD) in Asian men with prostate cancer (PCa) receiving ADT. A multicenter, open-label, randomized, controlled study including patients with hormone-sensitive PCa without bone metastasis receiving ADT was performed. Patients were randomized (1:1:1) to minodronate, denosumab, or no agent control groups. The primary end point was the mean percentage change in BMD at the lumbar spine at 12months. Secondary end points were the mean percentage change in BMD at the femoral neck and total hip and changes in bone turnover markers. Statistical comparison was performed using analysis of covariance. Of the 147 subjects enrolled in this study, 102 were randomly assigned into the minodronate (n = 36), denosumab (n = 36), and control (n = 30) groups. The percentage change in BMD at the lumbar spine was significantly improved in the minodronate (2.5%, p < 0.05) and denosumab groups (4.0%, p < 0.01) compared with that in the control group (- 0.1%). Denosumab increased BMD at the femoral neck and total hip at 12months, whereas minodronate only increased BMD at the total hip compared with controls (all p< 0.05). The percentage change in bone turnover markers at 12months was significantly lower in the minodronate and denosumab groups compared with that in the control group (both p < 0.01). Minodronate or denosumab can be used for preventing bone loss related to ADT in Asian patients with PCa.

Delayed Denosumab Injections and Bone Mineral Density Response: An Electronic Health Record-based Study.

Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response. We examined the association of delays in injections of denosumab with BMD change. We used electronic medical records from two academic hospitals from 2010 to 2017. Patients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%-93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%). Annualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck. We identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002). A longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed.

Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study.

Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results. To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo. Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration. 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment. One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student's t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed. Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95% confidence interval [CI] -0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95% CI -3.1 to 0.6, P = .19), total hip BMD (-0.2%: 95% CI -1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI -7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex. Over 1-year levothyroxine had no effect on bone health in older adults with SHypo. ClinicalTrial.gov NCT01660126 and NCT02491008.

Alendronate/Vitamin D for attenuating bone mineral density loss during antiretroviral initiation: a pilot randomized controlled trial

Background: Antiretroviral therapy (ART) initiation is associated with decreases in bone mineral density (BMD).Objectives: To plan for a larger trial, we sought to obtain preliminary estimates for the difference in the change in BMD at 48 weeks achieved with 24 weeks of prophylactic alendronate/vitamin D during ART initiation compared to no intervention, the within-group standard deviation of this change, and intra-patient correlation coefficient for repeated BMDs. Secondary objectives included assessing enrollment feasibility, treatment acceptability, adherence and safety.Methods: We randomized treatment-naïve HIV-positive adults initiating tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat or abacavir/lamivudine/dolutegravir 1:1:1 to immediate alendronate/vitamin D3 70 mg/5600 IU for 24 weeks (concomitant treatment arm, CTA), the same intervention starting 24 weeks after study entry (delayed treatment arm, DTA), or no bone anti-resorptive therapy (standard of care, SOC). We assessed BMD, acceptability, adverse events and drug adherence at baseline, week 24 and week 48.Results: Of 29 included participants, 72% initiated TDF/FTC/ELV/c and 28% initiated ABC/3TC/DTG. Median (IQR) CD4 count was 388 (303,525) cells/mm3 and median plasma HIV RNA was 4.45 (2.26, 4.84) log10 copies/mL. The mean (SD) percentage change in BMD for the CTA and DTA combined was 1.95% (2.53%), 0.38% (3.34%), and −0.57% (3.50%) at the lumbar spine, femoral neck and total hip respectively at 48 weeks. The ICC among repeated measurements of BMD was 0.978, 0.964, and 0.967 at these sites, respectively. Enrollment feasibility, drug acceptability, adherence, and tolerability were good.Conclusions: Our findings inform the sample size for a larger trial of bone anti-resorptive therapy during ART initiation and support feasibility.

Bone Mineral Density After Transitioning From Denosumab to Alendronate.

ContextThere are few studies on patients transitioning from denosumab to bisphosphonates.ObjectiveTo investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from denosumab to alendronate.DesignRandomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531).Setting25 study centers in the US and Canada.PatientsTreatment-naïve postmenopausal women with BMD T-scores from −2.0 to −4.0.InterventionsThis post hoc analysis evaluated women randomized to subcutaneous denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2.Main Outcome MeasureA 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate.ResultsOf 126 participants randomized to denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7% lost BMD at the lumbar spine, total hip, and femoral neck, respectively. Few participants fell below their pretreatment baseline BMD value; this occurred most often in those who lost BMD in year 2. Women who lost BMD with alendronate in year 2 also showed a greater percent change in BMD with denosumab in year 1. The BMD change in year 2 was similar regardless of baseline characteristics or adherence to oral alendronate.ConclusionAlendronate can effectively maintain the BMD gains accrued after 1 year of denosumab in most patients, regardless of baseline characteristics.