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Background Exercise is an effective strategy to improve quality of life and physical fitness in breast cancer survivors; however, few studies have focused on the early survivorship period, minorities, physically inactive and obese women, or tested a combined exercise program and measured bone health. Here, we report the effects of a 16-week aerobic and resistance exercise intervention on patient-reported outcomes, physical fitness, and bone health in ethnically diverse, physically inactive, overweight or obese breast cancer survivors. Methods One hundred breast cancer survivors within 6 months of completing adjuvant treatment were assessed at baseline, post-intervention, and 3-month follow-up (exercise group only) for physical fitness, bone mineral density, serum concentrations of bone biomarkers, and quality of life. The exercise intervention consisted of moderate-vigorous (65–85% heart rate maximum) aerobic and resistance exercise thrice weekly for 16 weeks. Differences in mean changes for outcomes were evaluated using mixed-model repeated measure analysis. Results At post-intervention, the exercise group was superior to usual care for quality of life (between group difference: 14.7, 95% CI: 18.2, 9.7; p  < 0.001), fatigue (p < 0.001), depression (p < 0.001), estimated VO 2max (p < 0.001), muscular strength (p < 0.001), osteocalcin ( p  = 0.01), and BSAP ( p  = 0.001). At 3-month follow-up, all patient-reported outcomes and physical fitness variables remained significantly improved compared to baseline in the exercise group ( p  < 0.01). Conclusions A 16-week combined aerobic and resistance exercise program designed to address metabolic syndrome in ethnically-diverse overweight or obese breast cancer survivors also significantly improved quality of life and physical fitness. Our findings further support the inclusion of supervised clinical exercise programs into breast cancer treatment and care. Trial registration This trial is registered on ClinicalTrials.gov: NCT01140282 as of June 9, 2010.

Summary We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication. Introduction Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers. Methods Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53–84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35–40 years). Results Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI −63 % (difference 13 %, 95 % CI 0 to 27.1, P  = 0.049) and good compliance −67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P  = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P  = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate. Conclusions Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39–0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of −1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31–0·64], p<0·0001) and in those with a bone mineral density T-score of less than −1 already at baseline (n=1548, HR 0·57 [95% CI 0·40–0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. Amgen.

Summary Thyrotoxicosis leads to loss of bone mass. Vitamin D is important to bone health. In this randomized, placebo-controlled trial, we showed that bone restoration did not improve when adding vitamin D supplementation to standard care of Graves’ disease thyrotoxicosis. Bone density and microarchitecture improved markedly with treatment of thyrotoxicosis. Purpose Vitamin D is important to skeletal health and ensuring a replete vitamin D status is recommended. In thyrotoxicosis, bone turnover is increased and bone mass density (BMD) reduced. We examined whether vitamin D supplementation improves bone recovery in thyrotoxicosis caused by Graves’ disease (GD). Methods Using a double-blinded design, hyperthyroid patients with GD were randomized to vitamin D3 70 µg/day (2800 IU) or similar placebo as add-on to antithyroid drugs (ATD). At baseline and 9 months, we measured BMD and bone architecture using DXA and high resolution peripheral quantitative computerized tomography. Bone turnover markers (BTM) were measured at 3 months also. Effect of vitamin D versus placebo and the response to ATD treatment were analyzed using linear mixed modelling. Results Eighty-six GD patients were included (age 41 ± 14 years, 86% females). Compared to placebo, vitamin D3 did not improve BMD or microarchitecture. In response to ATD, BMD increased in the hip by 2% (95%CI: 1–4%). Cortical porosity decreased in tibia (− 7% [95%CI: − 12 to − 2%]) and radius [− 14% [95%CI: − 24 to − 3%]), and trabecular thickness increased (tibia (5% [95%CI: 2 − 9%]) and radius (4% [95%CI: 1–7%]). Changes in BTM, but not thyroid hormones, were associated with changes in BMD by DXA and with changes in the cortical compartment. Conclusion In newly diagnosed GD, 9 months of high dose vitamin D3 supplementation does not offer benefit by improving skeletal health. Treatment of thyrotoxicosis is associated with the recovery of BMD and microarchitecture. Clinicaltrial.gov identifier NCT02384668

Abstract Context Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. Objective Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). Design We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. Results We identified 14 independent loci associated (P < 5 × 10−8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10−11) and females (P = 7.48 × 10−6). Conclusion Our findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.

There are limited comparative studies between one-anastomosis gastric bypass (OAGB) vs Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on body composition and musculoskeletal health. To compare changes in body composition, areal bone mineral density (aBMD), muscle strength, and physical function in the first year following OAGB, RYGB, and SG within a UK-based healthcare setting. This is a secondary analysis of the BARI-LIFESTYLE trial in 119 adults (77% women; mean ± SD age 45.9 ± 10.3 years; body mass index 43.6 ± 5.5 kg/m2) who underwent OAGB (n = 19), RYGB (n = 39), and SG (n = 61). Body composition and aBMD by dual energy x-ray absorptiometry, handgrip strength, sit to stand (STS) test and 6-minute walking test (6MWT) were assessed presurgery and at 12 months postsurgery. OAGB, RYGB, and SG exhibited similar reductions in body weight, body fat, and lean mass (within-group comparisons, P < .001). All surgery types were associated with reductions in aBMD at the total hip, femoral neck, and lumbar spine, which were more pronounced after OAGB and RYGB than after SG (all P < .03), though there was no difference between OAGB and RYGB. Despite reductions in absolute handgrip strength, relative handgrip strength, STS test, and 6MWT improved postsurgery (all P < .02), with no differences by surgical procedure. OAGB, RYGB, and SG resulted in comparable weight loss, changes in body composition and improvements in relative muscle strength and physical function. OAGB and RYGB, compared with SG, led to greater BMD reductions at clinically relevant sites. Future long-term studies should explore whether these BMD reductions translate into a greater fracture risk.

SummaryEarly PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents.IntroductionWe evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an “uncoupling index” (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups.MethodsBlood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient.ResultsEarly BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P < 0.0001) with abaloparatide (r = 0.561) than teriparatide (r = 0.198). The mean UI at 1 month was greater for abaloparatide versus teriparatide (1.743 and 1.493, respectively; P = 0.03) but was similar at 3 months or later time points.ConclusionsEarly s-PINP changes correlate with percentage change in lumbar spine BMD 18 months after treatment with both abaloparatide and teriparatide, though the correlation with abaloparatide was greater. The UI was similar between abaloparatide and teriparatide suggesting that the balance between formation and resorption markers was similar.

Summary We report the results of alendronate ingestion plus exercise in preventing the declines in bone mass and strength and elevated levels of urinary calcium and bone resorption in astronauts during 5.5 months of spaceflight. Introduction This investigation was an international collaboration between NASA and the JAXA space agencies to investigate the potential value of antiresorptive agents to mitigate the well-established bone changes associated with long-duration spaceflight. Methods We report the results from seven International Space Station (ISS) astronauts who spent a mean of 5.5 months on the ISS and who took an oral dose of 70 mg of alendronate weekly starting 3 weeks before flight and continuing throughout the mission. All crewmembers had available for exercise a treadmill, cycle ergometer, and a resistance exercise device. Our assessment included densitometry of multiple bone regions using X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and assays of biomarkers of bone metabolism. Results In addition to pre- and post-flight measurements, we compared our results to 18 astronauts who flew ISS missions and who exercised using an early model resistance exercise device, called the interim resistance exercise device, and to 11 ISS astronauts who exercised using the newer advanced resistance exercise device (ARED). Our findings indicate that the ARED provided significant attenuation of bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate attenuated the expected decline in essentially all indices of altered bone physiology during spaceflight including: DXA-determined losses in bone mineral density of the spine, hip, and pelvis, QCT-determined compartmental losses in trabecular and cortical bone mass in the hip, calculated measures of fall and stance computed bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium. Conclusions The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.

Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.

Insulin resistance is an adverse health outcome that accompanies obesity. Fat mass is negatively associated with the bone mass after adjustment for confounders. Insulin resistance might be an intermediary in this relationship. To determine whether insulin resistance is an intermediary in the relationship between adiposity and bone mass in adolescents. Cross-sectional secondary analysis of baseline data from a previous randomized trial. University research facility. A total of 240 adolescents (68% female), aged 7 to 15 years. Using dual energy x-ray absorptiometry, bone mineral content (BMC), areal bone mineral density, lean mass, and fat mass were measured. Skeletal sites of interest included the total body and lumbar spine (LS). Waist circumference was measured using an anthropometric tape measure. Insulin and glucose were measured in fasting sera, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Path analysis was performed to determine whether the relationship between adiposity and bone was mediated through insulin resistance. Fat mass (r = 0.467; P < 0.001) and waist circumference (r = 0.487; P < 0.001) correlated positively with HOMA-IR. Controlling for race, sex, maturation, lean mass, and height, fat mass, waist circumference, and HOMA-IR were negatively associated with LS BMC and total body areal bone mineral density (P < 0.05 for all). Additionally, path models for fat mass (95% CI, -5.893 to -0.956) and waist circumference (95% CI, -15.473 to -2.124) showed a negative relationship with LS BMC via HOMA-IR. These results support an intermediary role of insulin resistance in the relationship between adiposity and LS bone mass.