Effect of Aerobic or Resistance Exercise,or Both,on Bone Mineral Density and Bone Metabolism in Obese Older Adults While Dieting: A Randomized Controlled Trial

Weight loss therapy of older adults with obesity is limited by weight loss–induced decrease in bone mineral density (BMD), which could exacerbate ongoing age-related bone loss and increase the risk for fractures. Therefore, it is recommended that weight loss therapy of older adults with obesity should include an intervention such as regular exercise to reduce the concomitant bone loss. However, the most appropriate exercise types to combine with weight loss therapy in this older population is unknown. In a randomized controlled trial, we performed a head-to-head comparison of aerobic or resistance exercise, or both, during matched ~10% weight loss in 160 older adults with obesity. We measured changes in BMD (total hip, femoral neck, trochanter, intertrochanter, one-third radius, lumbar spine) and bone markers. Changes between groups were analyzed using mixed-model repeated measures analyses of variance. After 6 months of intensive lifestyle interventions, BMD decreased less in the resistance group (−0.006 g/cm² [−0.7%]) and combination group (−0.012 g/cm² [−1.1%]) than in the aerobic group (−0.027 g/cm² [−2.6%]) (p = 0.001 for between-group comparisons). Serum C-telopeptide, procollagen type 1 N-propeptide, and osteocalcin concentrations increased more in the aerobic group (33%, 16%, and 16%, respectively) than in the resistance group (7%, 2%, and 0%, respectively) and combination group (11%, 2%, and 5%, respectively) (p = 0.004 to 0.048 for between-group comparisons). Multiple regression analyses revealed that the decline in whole body mass and serum leptin were the independent predictors of the decline in hip BMD (multiple R = 0.45 [p < .001]). These findings indicate that compared with aerobic exercise, resistance and combined aerobic and resistance exercise are associated with less weight loss–induced decrease in hip BMD and less weight loss–induced increase in bone turnover. Therefore, both resistance and combined aerobic and resistance exercise can be recommended to protect against bone loss during weight loss therapy of older adults with obesity. (LITOE ClinicalTrials.gov number NCT01065636.) © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.     

Effect of Oral Vitamin D3 Supplementation in Exclusively Breastfed Newborns: Prospective,Randomized, Double-Blind,Placebo-Controlled Trial

Exclusively breastfed infants are at a high risk of vitamin D deficiency. Few studies have evaluated the effects of vitamin D supplementation. Hence, we conducted a prospective randomized controlled trial investigating the effects of oral vitamin D3 400 IU/d supplementation in exclusively breastfed newborns. Serum 25-hydroxy-vitamin D (25[OH]D) levels in pregnant women and their newborns were evaluated. Breastfed newborns were randomized to one of two regimens at age 10 days. One group received vitamin D3 supplementation at a dose of 400 IU/d (vD-400 group), whereas the placebo group received a liquid product without vitamin D3. Outcomes were assessed at 4 months of age. A total of 92 pregnant women and their infants were enrolled, and the data of 72 infants (37 in the vD-400 group and 35 in the placebo group) who completed the study at 4 months of age were assessed. The results showed severe vitamin D deficiency in 15.2% of mothers before delivery, while 54.3% had vitamin D deficiency. Moreover, 15.2% of newborns presented with severe vitamin D deficiency at birth, while 52.2% had vitamin D deficiency. Maternal vitamin D levels were significantly correlated with infant vitamin D levels at birth (r = 0.816, p < 0.001). At 4 months of age, weight, head circumference, serum 25(OH)D, phosphorus, and intact parathyroid hormone levels significantly differed between the vD-400 and placebo groups. However, the body length and bone mineral density of the two groups did not differ significantly. Regardless of vitamin D supplementation, participants with severe vitamin D deficiency had significantly higher intact parathyroid hormone levels and lower bone mineral content. In conclusion, among exclusively breastfed infants, oral supplementation with vitamin D3 at a dose of 400 IU/d from age 10 days increased 25(OH)D concentrations at 4 months of age, but it did not affect bone mineralization. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Sequential Therapy With Recombinant Human IGF-1 Followed by Risedronate Increases Spine Bone Mineral Density in Women With Anorexia Nervosa: A Randomized,Placebo-Controlled Trial

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate (“rhIGF-1/Risedronate”) (n = 33), 12 months of risedronate (“Risedronate”) (n = 33), or double placebo (“Placebo”) (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF-1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF-1 was well tolerated. Therefore, sequential therapy with rhIGF-1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Effect of ONO‐5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2‐Year Results From the OCEAN Study

Cathepsin K inhibitors, such as ONO‐5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24‐month treatment with ONO‐5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO‐5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO‐5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO‐5334 300 mg significantly suppressed the bone‐resorption markers urinary (u) NTX and serum and uCTX‐I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO‐5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO‐5334 doses). Levels of B‐ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO‐5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX‐I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO‐5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation. © 2014 American Society for Bone and Mineral Research.     

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy,a Randomized Trial

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual‐energy X‐ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent‐to‐treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow‐up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non‐white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow‐up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow‐up, immediate ART resulted in greater BMD declines than deferred ART at the hip (–2.5% versus –1.0%; difference –1.5%, 95% confidence interval [CI] –2.2 to –0.8, p < 0.001) and spine (–1.9% versus –0.4%; difference –1.6%, 95% CI –2.2 to –1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV‐related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer‐term consequences of the observed reductions in BMD is needed. Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.     

Predictors of Fracture in Older Women With Osteopenic Hip Bone Mineral Density Treated With Zoledronate

A recent analysis has found that during treatment with denosumab, women attaining higher bone densities (BMD) are less likely to have incident fractures. We have reexamined this important question using data from our recent trial of zoledronate in osteopenic women. One thousand women randomized to treatment with zoledronate were followed for 6 years. Of those, 122 sustained fragility fractures during follow-up. Baseline age, nonvertebral fracture history, total hip BMD, and calculated fracture risk were all significantly different between those who had fractures during the study and those who did not. BMDs achieved during the study were higher in those without incident fractures. However, achieved BMDs were very closely related to baseline values (r = 0.93, p < 0.0001). The increase in BMD during zoledronate treatment was not different between those who had incident fractures and those who did not (0.15 < p < 0.78), and change in BMD was not predictive of fracture (univariate logistic regression analysis). Stepwise regression analysis of all baseline variables showed the best independent predictors of fracture to be age (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04–1.13, p = 0.0003), baseline spine BMD (OR = 0.81, 95% CI 0.67–0.96, p = 0.016), and history of nonvertebral fracture (OR = 1.69, 95% CI 1.06–2.69, p = 0.028). Addition of change in BMD to this model did not improve its predictive power. If changes in BMD were included in the stepwise regression analysis of baseline variables, they did not emerge as significant predictors of fracture. It is concluded that age, fracture history, and baseline BMD determine the risk of new fractures. Differences in achieved BMD between those who do or do not fracture arise from the close relationship between baseline and achieved BMDs. These findings suggest that targeting any particular BMD during treatment is unlikely to be a useful or valid strategy. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Denosumab Prevents Early Periprosthetic Bone Loss After Uncemented Total Hip Arthroplasty: Results from a Randomized Placebo-Controlled Clinical Trial

Implant loosening is the most common indication for revision surgery after total hip arthroplasty (THA). Although bone resorption around the implants plays a pivotal role in the pathophysiology of loosening, it is unknown whether potent early inhibition of osteoclasts could mitigate this process and thus reduce the need for revision surgery. We performed a randomized, double-blind, placebo-controlled phase 2 trial in 64 patients aged 35 to 65 years with unilateral osteoarthritis of the hip. They underwent surgery with an uncemented THA and were randomized to either two subcutaneous doses of denosumab (n = 32) or placebo (n = 32) given 1 to 3 days and 6 months after surgery. Patients were followed for 24 months. Primary outcome was periprosthetic bone mineral density (BMD) of the hip at 12 months as measured by dual-energy X-ray absorptiometry (DXA). In addition, [¹⁸F] sodium fluoride positron emission tomography/CT (F-PET) was performed in half of the patients for analysis of periprosthetic standardized uptake value (SUV). Analyses were made according to intention-to-treat principles. The trial was registered at ClinicalTrials.gov 2011-001481-18, NCT01630941. Denosumab potently inhibited early periprosthetic bone loss. After 12 months, BMD in the denosumab group was 32% (95% confidence interval [CI] 22–44) higher in Gruen zone 7 and 11% (95% CI 8–15) higher in zones 1 to 7. After 24 months, the difference in BMD between groups had decreased to 15% (95% CI 4–27) in zone 7 and 4% (95% CI 0–8) in zones 1 to 7. In both groups, SUV increased after surgery, but the increase was less pronounced in the denosumab group. Biochemical markers of bone metabolism decreased in the denosumab group in the first 12 months, but a rebound effect with marker concentrations above baseline was observed after 24 months. Denosumab potently prevents early periprosthetic bone loss after uncemented THA; however, the effect diminishes after discontinuation of treatment. Further research is needed to determine whether this bone loss will prove to be of clinical importance and, if so, whether the positive effect observed in this study could be preserved by either prolonged treatment with denosumab or additional antiresorptive treatment. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.     

Dietary Inflammatory Index,Bone Mineral Density,and Risk of Fracture in Postmenopausal Women: Results From the Women's Health Initiative

Previous studies suggest that bone loss and fracture risk are associated with higher inflammatory milieu, potentially modifiable by diet. The primary objective of this analysis was to evaluate the association of the dietary inflammatory index (DII), a measure of the inflammatory potential of diet, with risk of hip, lower‐arm, and total fracture using longitudinal data from the Women's Health Initiative Observational Study and Clinical Trials. Secondarily, we evaluated changes in bone mineral density (BMD) and DII scores. DII scores were calculated from baseline food frequency questionnaires (FFQs) completed by 160,191 participants (mean age 63 years) without history of hip fracture at enrollment. Year 3 FFQs were used to calculate a DII change score. Fractures were reported at least annually; hip fractures were confirmed by medical records. Hazard ratios for fractures were computed using multivariable‐adjusted Cox proportional hazard models, further stratified by age and race/ethnicity. Pairwise comparisons of changes in hip BMD, measured by dual‐energy X‐ray absorptiometry from baseline, year 3, and year 6 were analyzed by quartile (Q1 = least inflammatory diet) of baseline DII scores in a subgroup of women (n = 10,290). Mean DII score improved significantly over 3 years (p < 0.01), but change was not associated with fracture risk. Baseline DII score was only associated with hip fracture risk in younger white women (HR Q4,1.48; 95% CI, 1.09 to 2.01; p = 0.01). There were no significant associations among white women older than 63 years or other races/ethnicities. Women with the least inflammatory DII scores had less loss of hip BMD (p = 0.01) by year 6, despite lower baseline hip BMD, versus women with the most inflammatory DII scores. In conclusion, a less inflammatory dietary pattern was associated with less BMD loss in postmenopausal women. A more inflammatory diet was associated with increased hip fracture risk only in white women younger than 63 years. © 2016 American Society for Bone and Mineral Research.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Effect of Low‐Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo‐Controlled Trial

Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low‐magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12‐month randomized double‐blind placebo‐controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak‐to‐peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual‐energy X‐ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex‐specific Z‐scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12‐month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention‐to‐treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z‐score was +0.22 in the active arm and –0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z‐score. Treatment response did not vary according to baseline body mass index (BMI) Z‐score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research.     

Vitamin D and Muscle Health: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials

The objective of this study was to investigate the effects of vitamin D supplementation versus placebo on muscle health. For this systematic review and trial-level meta-analysis of placebo-controlled trials, a systematic search of randomized controlled trials published until October 2020 was performed in Medline, Embase, and Google Scholar. We included studies in humans (except athletes) on supplementation with vitamin D2 or D3 versus placebo, regardless of administration form (daily, bolus, and duration) with or without calcium co-supplementation. The predefined endpoints were physical performance reported as timed up and go test (TUG; seconds), chair rising test (seconds), 6-minute walking distance (m), and Short Physical Performance Battery (SPPB; points). Furthermore, endpoints were maximum muscle strength (Newton) measured at handgrip, elbow flexion, elbow extension, knee flexion, and knee extension, as well as muscle (lean tissue) mass (kg). Falls were not included in the analysis. Cochrane Review Manager (version 5.4.1.) calculating mean difference (MD) using a random effect model was used. In total, 54 randomized controlled trials involving 8747 individuals were included. Vitamin D versus placebo was associated with a significantly longer time spent performing the TUG (MD 0.15 [95% confidence interval (CI) 0.03 to 0.26] seconds, N = 19 studies, I² = 0%, n = 5223 participants) and a significant lower maximum knee flexion strength (MD –3.3 [−6.63 to −0.03] Newton, N = 12 studies, I² = 0%, n = 765 participants). Total score in the SPPB showed a tendency toward worsening in response to vitamin D compared with placebo (MD −0.18 [−0.37 to 0.01] points, N = 8 studies, I² = 0%, n = 856 participants). Other measures of muscle health did not show between-group differences. In subgroup analyses, including studies with low vitamin D levels, effects of vitamin D supplementation did not differ from placebo. Available evidence does not support a beneficial effect of vitamin D supplementation on muscle health. Vitamin D may have adverse effects on muscle health, which needs to be considered when recommending vitamin D supplementation. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Single‐ and Multiple‐Dose Randomized Studies of Blosozumab,a Monoclonal Antibody Against Sclerostin,in Healthy Postmenopausal Women

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject‐ and investigator‐blind, placebo‐controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single‐dose study (12 to placebo) and up to 12 subjects to each arm in the multiple‐dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose‐dependent responses were observed in sclerostin, N‐terminal propeptide of procollagen type 1, bone‐specific alkaline phosphatase, osteocalcin, C‐terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.     

The Effect of Discontinuing Treatment With Blosozumab: Follow‐up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1‐year randomized, placebo‐controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow‐up; 88 women completed 1 year of follow‐up. At the beginning of follow‐up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow‐up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow‐up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C‐terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti‐drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized Trials

The cardiovascular safety of denosumab has not yet been evaluated in a systematic review. This systematic review and meta-analysis sought to quantify the number of randomized controlled trials (RCTs) of denosumab (against comparators) reporting cardiovascular adverse events (CAEs) and examine the balance of CAEs between treatment arms. MEDLINE, Embase, and clinicaltrials.gov were searched from inception to October 26, 2019, for RCTs of denosumab versus comparators for any indication. Included trials were randomized, enrolled ≥100 participants, and reported bone-related outcomes. Primary outcome for analysis was all CAEs, a composite endpoint representing summation of all CAEs as reported by included trials. Secondary outcomes included major adverse cardiovascular events (MACE). Data were pooled using a fixed effects model to determine relative risk (RR) and 95% confidence interval (95% CI). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 554 records screened, 49 were included, while 36 reported CAEs. Twenty-seven included trials (12 eligible for meta-analysis) were conducted in 13,202 postmenopausal women. Compared with bisphosphonates, there was a 46% (95% CI 1.05 to 2.02) increase in CAEs (85/2136 events in denosumab-treated versus 58/2131 events in bisphosphonate-treated; seven trials). There was a similar imbalance in a five-point (stroke, myocardial infarction, cardiovascular death, heart failure, atrial fibrillation) MACE endpoint (28/2053 versus 12/2050; RR = 2.33 [1.19 to 4.56]). Compared with placebo-treated women, there was no imbalance in total CAEs (439/4725 events in denosumab versus 399/4467 in placebo; RR = 0.79 [0.41 to 1.52]; seven trials). No imbalance in total AEs (versus bisphosphonates: 0.98 [0.92 to 1.04]; versus placebo: 0.99 [0.98 to 1.01]) occurred. Other indications showed no statistically significant results. The excess CAEs in postmenopausal women treated with denosumab compared with bisphosphonates, but not placebo, indirectly supports claims that bisphosphonates may suppress CAEs. Future trials should use standardized CAE reporting to better describe cardiovascular effects of bone active medications. (PROSPERO: CRD42019135414.) © 2020 American Society for Bone and Mineral Research (ASBMR).     

BPS804 Anti‐Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial

This 21‐week, open‐label, phase 2a trial aimed to evaluate the pharmacodynamics and safety of multiple, escalating infusions of BPS804, a neutralizing, anti‐sclerostin antibody, in adults with moderate osteogenesis imperfecta (OI). Patients received BPS804 (three escalating doses each separated by 2 weeks [5, 10, and 20 mg/kg]) or no treatment (reference group). The primary efficacy endpoints were mean changes from baseline to day 43 in: procollagen type 1 N‐terminal propeptide (P1NP), procollagen type 1 C‐terminal propeptide (P1CP), bone‐specific alkaline phosphatase (BSAP), osteocalcin (OC), and type 1 collagen cross‐linked C‐telopeptide (CTX‐1). Mean change from baseline to day 141 in lumbar spine areal bone mineral density (aBMD) was also assessed. BPS804 safety and tolerability were assessed every 2 weeks. Overall, 14 adults were enrolled (BPS804 group: n = 9, mean age 30.7 years, mean aBMD Z‐score –2.6; reference group, n = 5, mean age 27.4 years, mean aBMD Z‐score –2.2). In the BPS804 group, P1NP, P1CP, BSAP, and OC were increased by 84% (p < 0.001), 53% (p = 0.003), 59% (p < 0.001), and 44% (p = 0.012), respectively, versus baseline (reference: P1NP, +6% [p = 0.651]; P1CP, +5% [p = 0.600]; BSAP, –13% [p = 0.582]; OC, –19% [p = 0.436]). BPS804 treatment downregulated CTX‐1 by 44% from baseline (reference: –7%; significance was not tested for this biomarker), and increased aBMD by 4% (p = 0.038; reference group: +1%; p = 0.138). BPS804 was generally well tolerated. There were 32 adverse events reported in nine patients; none was suspected to be treatment‐related. There were no treatment‐related fractures. BPS804 stimulates bone formation, reduces bone resorption, and increases lumbar spine aBMD in adults with moderate OI. This paves the way for a longer‐term, phase 3 trial into the efficacy, safety, and tolerability of BPS804 in patients with OI. © 2017 American Society for Bone and Mineral Research.     

Effect of Two‐Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non‐Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two‐hundred eighteen non‐obese (body mass index [BMI] 25.1 ± 1.7 kg/m²), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone‐active hormones, nutrient intake, and physical activity. Body weight (–7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (–5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat‐free mass (–2.2 ± 0.2 versus –0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (–0.013 ± 0.003 versus 0.007 ± 0.004 g/cm²; p < 0.001), total hip (–0.017 ± 0.002 versus 0.001 ± 0.003 g/cm²; p < 0.001), and femoral neck (–0.015 ± 0.003 versus –0.005 ± 0.004 g/cm²; p = 0.03). Changes in bone markers were greater at 12 months for C‐telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate‐resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone‐specific alkaline phosphatase (BSAP) (–1.4 ± 0.4 versus –0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N‐propeptide; at 24 months, only BSAP differed between groups (–1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25‐hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF‐1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ～31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long‐term studies are needed to determine if CR‐induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise. © 2015 American Society for Bone and Mineral Research.     

The Effect of an Exercise Intervention Program on Bone Health After Bariatric Surgery: A Randomized Controlled Trial

Exercise has been suggested as a therapeutic approach to attenuate bone loss induced by bariatric surgery (BS), but its effectiveness remains unclear. Our aim was to determine if an exercise-training program could induce benefits on bone mass after BS. Eighty-four patients, submitted to gastric bypass or sleeve gastrectomy, were randomized to either exercise (EG) or control group (CG). One month post-BS, EG underwent a 11-month supervised multicomponent exercise program, while CG received only standard medical care. Patients were assessed before BS and at 1, 6, and 12 months post-BS for body composition, areal bone mineral density (BMD), bone turnover markers, calciotropic hormones, sclerostin, bone material strength index, muscle strength, and daily physical activity. A primary analysis was conducted according to intention-to-treat principles and the primary outcome was the between-group difference on lumbar spine BMD at 12 months post-BS. A secondary analysis was also performed to analyze if the exercise effect depended on training attendance. Twelve months post-BS, primary analysis results revealed that EG had a higher BMD at lumbar spine (+0.024 g∙cm⁻² [95% confidence interval (CI) 0.004, 0.044]; p = .015) compared with CG. Among total hip, femoral neck, and 1/3 radius secondary outcomes, only 1/3 radius BMD improved in EG compared with CG (+0.013 g∙cm⁻² [95% CI 0.003, 0.023]; p = .020). No significant exercise effects were observed on bone biochemical markers or bone material strength index. EG also had a higher lean mass (+1.5 kg [95% CI 0.1, 2.9]; p = .037) and higher number of high impacts (+51.4 [95% CI 6.6, 96.1]; p = .026) compared with CG. In addition, secondary analysis results suggest that exercise-induced benefits may be obtained on femoral neck BMD but only on those participants with ≥50% exercise attendance compared with CG (+5.3% [95% CI 2.0, 8.6]; p = .006). Our findings suggest that an exercise program is an effective strategy to ameliorate bone health in post-BS patients. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Bone Adaptation in Adult Women Is Related to Loading Dose: A 12-Month Randomized Controlled Trial

Although strong evidence exists that certain activities can increase bone density and structure in people, it is unclear what specific mechanical factors govern the response. This is important because understanding the effect of mechanical signals on bone could contribute to more effective osteoporosis prevention methods and efficient clinical trial design. The degree to which strain rate and magnitude govern bone adaptation in humans has never been prospectively tested. Here, we studied the effects of a voluntary upper extremity compressive loading task in healthy adult women during a 12-month prospective period. A total of 102 women age 21 to 40 years participated in one of two experiments: (i) low (n = 21) and high (n = 24) strain magnitude; or (ii) low (n = 21) and high (n = 20) strain rate. Control (n = 16) no intervention. Strains were assigned using subject-specific finite element models. Load cycles were recorded digitally. The primary outcome was change in ultradistal radius integral bone mineral content (iBMC), assessed with QCT. Interim time points and secondary outcomes were assessed with high resolution pQCT (HRpQCT) at the distal radius. Sixty-six participants completed the intervention, and interim data were analyzed for 77 participants. Likely related to improved compliance and higher received loading dose, both the low-strain rate and high-strain rate groups had significant 12-month increases to ultradistal iBMC (change in control: −1.3 ± 2.7%, low strain rate: 2.7 ± 2.1%, high strain rate: 3.4 ± 2.2%), total iBMC, and other measures. “Loading dose” was positively related to 12-month change in ultradistal iBMC, and interim changes to total BMD, cortical thickness, and inner trabecular BMD. Participants who gained the most bone completed, on average, 128 loading bouts of (mean strain) 575 με at 1878 με/s. We conclude that signals related to strain magnitude, rate, and number of loading bouts contribute to bone adaptation in healthy adult women, but only explain a small amount of variance in bone changes. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.