Temporal Trends in Obesity,Osteoporosis Treatment,Bone Mineral Density,and Fracture Rates: A Population‐Based Historical Cohort Study

Diverging international trends in fracture rates have been observed, with most reports showing that fracture rates have stabilized or decreased in North American and many European populations. We studied two complementary population‐based historical cohorts from the Province of Manitoba, Canada (1996–2006) to determine whether declining osteoporotic fracture rates in Canada are attributable to trends in obesity, osteoporosis treatment, or bone mineral density (BMD). The Population Fracture Registry included women aged 50 years and older with major osteoporotic fractures, and was used to assess impact of changes in osteoporosis treatment. The BMD Registry included all women aged 50 years and older undergoing BMD tests, and was used to assess impact of changes in obesity and BMD. Model‐based estimates of temporal changes in fracture rates (Fracture Registry) were calculated. Temporal changes in obesity and BMD and their association with fracture rates (BMD Registry) were estimated. In the Fracture Registry (n = 27,341), fracture rates declined 1.6% per year (95% confidence interval [CI], 1.3% to 2.0%). Although osteoporosis treatment increased from 5.6% to 17.4%, the decline in fractures was independent of osteoporosis treatment. In the BMD Registry (n = 36,587), obesity increased from 12.7% to 27.4%. Femoral neck BMD increased 0.52% per year and lumbar spine BMD increased 0.32% per year after covariate adjustment (p < 0.001). Major osteoporotic fracture rates decreased in models that did not include femoral neck BMD (fully adjusted annual change –1.8%; 95% CI, –2.9 to –0.5), but adjusting for femoral neck BMD accounted for the observed reduction (annual change –0.5%; 95% CI, –1.8 to +1.0). In summary, major osteoporotic fracture rates declined substantially and linearly from 1996 to 2006, and this was explained by improvements in BMD rather than greater rates of obesity or osteoporosis treatment. © 2014 American Society for Bone and Mineral Research.     

Contribution of Quadriceps Weakness to Fragility Fracture: A Prospective Study

The association between muscle weakness and fracture is not well understood. This study sought to examine the contribution of muscle strength at baseline and change in muscle strength to the observed risk of fragility fracture in older people. The study involved 595 men and 1066 women aged 60+ years (median 69 years) who had been followed for a median of 11 years (range, 4 to 22 years). Quadriceps isometric muscle strength (MS) measured at baseline and biennially was adjusted for height. Femoral neck bone mineral density (FNBMD) was measured by DXA. Low‐trauma fracture was ascertained from X‐ray reports and interview. The relationship between baseline MS and serial MS and fracture assessed by time‐invariant and time‐variant Cox's regression models was expressed as hazard ratio (HR) and 95% confidence interval (CI). During the follow‐up period, 282 (26%) women and 89 (15%) men sustained a fragility fracture. From age 60 years, women lost 0.28 kg/m (1.6%) of MS per year, whereas men lost 0.39 kg/m (1.5%) of MS per year. In the time‐variant model, using serial MS, each 1 SD (4.7 kg/m) lower MS was associated with a 27% increase in the risk of fracture in women (HR 1.27; 95% CI, 1.11 to 1.43); and 46% increase in men (HR 1.46; 95% CI, 1.22 to 1.75). After adjusting for FNBMD, age and prior fracture, history of fall and smoking, HR per SD of lower MS was 1.13 (95% CI, 0.99 to 1.28) for women and 1.35 (95% CI, 1.18 to 1.64) for men. These data indicate that muscle weakness is an independent determinant of fracture risk in men, but not in women. This sex difference suggests that apart from mechanical load effect of muscle on bone, there are other muscle‐bone interactions that need to be investigated in future studies. The accuracy of fracture risk prediction for men may be improved by incorporating muscle strength. © 2015 American Society for Bone and Mineral Research.     

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine–bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.     

Tricyclic antidepressant use and risk of fractures: A meta‐analysis of cohort and case‐control studies

Because studies of the association between tricyclic antidepressant (TCA) treatment and risk of fracture have shown inconsistent findings, we sought to assess whether people who take TCAs are at increased risk of fracture. Relevant studies published by June 2012 were identified through database searches of Scopus, MEDLINE, EMBASE, PsycINFO, ISI Web of Science, and WorldCat Dissertations and Theses from their inception, and manual searching of reference lists. Only original studies that examined the association between TCA treatment and risk of fracture were included. Two investigators independently conducted literature searches, study selection, study appraisal, and data abstraction using a standardized protocol. Disagreements were resolved by consensus. Twelve studies met inclusion criteria. Because of the heterogeneity of these studies, random‐effects models were used to pool estimates of effect. Overall, TCA use was associated with significantly increased fracture risk (relative risk [RR], 1.45; 95% confidence interval [CI], 1.31–1.60; p < 0.001). Increased fracture risk associated with TCA use was also observed in studies that adjusted for bone mineral density (RR, 1.54; 95% CI, 1.24–1.90; p < 0.001) or depression (RR, 1.49; 95% CI, 1.28–1.67; p < 0.001). Strength of association with TCA exposure duration ≥6 weeks (RR, 1.13; 95% CI, 1.00–1.28) was substantially weaker than association with TCA exposure duration <6 weeks (RR, 2.40; 95% CI, 1.41–4.08). Prior TCA exposure had no significant effect on fracture risk (RR, 1.04; 95% CI, 0.86–1.26; p = 0.70). After accounting for publication bias, we found the overall association between TCA use and fracture risk to be slightly weaker (RR, 1.36; 95% CI, 1.24–1.50) but still significant (p < 0.001). Findings of this meta‐analysis indicate that treatment with TCAs may convey an increased risk of fracture, independent of depression and bone mineral density. © 2013 American Society for Bone and Mineral Research.     

Association of Bone Density Monitoring in Routine Clinical Practice With Anti-Osteoporosis Medication Use and Incident Fractures: A Matched Cohort Study

Routine bone mineral density (BMD) monitoring of individuals during the initial 5 years of anti-osteoporosis treatment is controversial. Using a registry-based cohort from the Province of Manitoba, Canada, we compared anti-osteoporosis medication use and fracture outcomes in women with versus without BMD monitoring receiving anti-osteoporosis medication. We identified 4559 women aged 40 years and older receiving anti-osteoporosis therapy with serial BMD testing (monitoring) within 5 years (mean interval 3.2 years) and 4559 propensity score–matched women without BMD monitoring. We assessed anti-osteoporosis medication use over 5 years from a population-based retail pharmacy database. Incident fractures to 10 years from health services data. During median 10 years observation, 1225 (13.4%) women developed major osteoporotic fracture, including 382 (4.2%) with hip fractures. Monitored women had significantly better fracture-free survival for major osteoporotic fracture (p = 0.040; 10-year cumulative risk 1.9% lower, 95% confidence interval [CI] 0.3–3.6%) and hip fracture ( p = 0.001; 10-year cumulative risk 1.8% lower, 95% CI 0.7–2.8%) compared with women who were not monitored. Hazard ratios (HRs) were significantly lower in monitored versus not monitored women for major osteoporotic fracture (HR = 0.89, 95% CI 0.80–0.98) and hip fracture (HR = 0.74, 95% CI 0.63–0.87). Days of medication use, medication persistence ratio, and treatment switching over 5 years were greater in monitored versus not monitored women. At the end of 5 years, more women in the monitored group persisted on treatment and more switched treatment, with switching behavior associated with an observed interval reduction in BMD. In conclusion, our findings suggest a possible role for BMD monitoring after initiating anti-osteoporosis therapy in the routine clinical practice setting. © 2019 American Society for Bone and Mineral Research.     

Long‐term cadmium exposure and the association with bone mineral density and fractures in a population‐based study among women

All people are exposed to cadmium (Cd) via food; smokers are additionally exposed. High Cd exposure is associated with severe bone damage, but the public health impact in relation to osteoporosis and fractures at low environmental exposure remains to be clarified. Within the population‐based Swedish Mammography Cohort, we assessed urinary Cd [U‐Cd, µg/g of creatinine (cr)] as a marker of lifetime exposure and bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) among 2688 women. Register‐based information on fractures was retrieved from 1997 to 2009. Associations were evaluated by multivariable regression analyses. In linear regression, U‐Cd was inversely associated with BMD at the total body (p < .001), femoral neck (p = .025), total hip (p = .004), lumbar spine (p = .088), and volumetric femoral neck (p = .013). In comparison with women with U‐Cd < 0.50 µg/g of cr, those with U‐Cd ≥ 0.75 µg/g of cr had odds ratios (ORs) of 2.45 [95% confidence interval (CI) 1.51–3.97] and 1.97 (95% CI 1.24–3.14) for osteoporosis at the femoral neck and lumbar spine, respectively. Among never‐smokers, the corresponding ORs were 3.47 (95% CI 1.46–8.23) and 3.26 (95% CI 1.44–7.38). For any first fracture (n = 395), the OR was 1.16 (95% CI 0.89–1.50) comparing U‐Cd ≥ 0.50 µg/g of cr with lower levels. Among never‐smokers, the ORs (95% CIs) were 2.03 (1.33–3.09) for any first fracture, 2.06 (1.28–3.32) for first osteoporotic fracture, 2.18 (1.20–3.94) for first distal forearm fracture, and 1.89 (1.25–2.85) for multiple incident fractures. U‐Cd at low environmental exposure from food in a general population of women showed modest but significant association with both BMD and fractures, especially in never‐smokers, indicating a larger concern than previously known. © 2011 American Society for Bone and Mineral Research.     

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1–SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm²), total hip (800 versus 876 mg/cm²), and lumbar spine (1024 versus 1062 mg/cm²); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2–SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1–SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Changes in Bone Marrow Adipose Tissue One Year After Roux-en-Y Gastric Bypass: A Prospective Cohort Study

Bone marrow adipose tissue (BMAT) has been postulated to mediate skeletal fragility in type 2 diabetes (T2D) and obesity. Roux-en-Y gastric bypass (RYGB) induces a substantial weight loss and resolution of comorbidities. However, the procedure induces increased bone turnover and fracture rates. No previous study has evaluated biopsy-measured BMAT fraction preoperatively and after RYGB. In this study, we aimed to investigate BMAT fraction of the hip in participants with and without T2D preoperatively and 1 year after RYGB and explore factors associated with BMAT change. Patients with morbid obesity scheduled for RYGB were examined preoperatively and 1 year after RYGB. Forty-four participants were included and preoperative examinations were possible in 35. Of these, 33 (94%) met for follow-up, 2 were excluded, and BMAT estimation was not possible in 1. Eighteen (60%) of the participants were females and 11 (37%) had T2D. Preoperative BMAT fraction was positively associated with glycosylated hemoglobin and negatively associated with areal bone mineral density (aBMD). After RYGB, BMAT fraction decreased from 40.4 ± 1.7% to 35.6 ± 12.8%, p = 0.042, or with mean percent change of 10.7% of preoperative BMAT fraction. Change in BMAT fraction was positively associated with change in body mass index (BMI) and total body fat. In females, we observed a mean percent reduction of 22.4 ± 19.6%, whereas in males BMAT increased with a mean percent of 6.8 ± 37.5%, p = 0.009. For males, changes in estradiol were associated with BMAT change; this was not observed for females. In participants with and without T2D, the mean percent BMAT reduction was 5.8 ± 36.9% and 13.5 ± 28.0%, respectively, p = 0.52. We conclude that a high BMAT seems to be associated with lower aBMD and poorer glycemic control in obese subjects. After RYGB, we observed a significant decrease in BMAT. The reduction in BMAT did not differ between participants with and without T2D, but appeared sex specific. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

A Mendelian Randomization Study of the Effect of Type‐2 Diabetes and Glycemic Traits on Bone Mineral Density

Type‐2 diabetes (T2D) is associated in observational studies with both higher bone mineral density (BMD) and higher fracture risk for given BMD. These relationships may however be confounded by factors such as body mass index (BMI). Here we used Mendelian randomization (MR) to obtain non‐confounded estimates of the effect of T2D and glycemic traits on BMD. We identified genetic variants strongly associated with T2D risk (34,840 T2D cases and 114,981 controls) and fasting glucose (133,010 nondiabetic individuals), but not associated with BMI, and determined the effects of these variants on BMD (up to 83,894 individuals). Using these variants as instrumental variables, we found that a genetically‐increased risk of T2D increased femoral neck BMD (+0.034 SD in BMD per unit increase in log‐odds of T2D [95% CI, 0.001 to 0.067; p = 0.044]). Genetically‐increased fasting glucose also increased femoral neck BMD (+0.13 SD in BMD per mmol/L increase in fasting glucose [95% CI, 0.01 to 0.25; p = 0.034]). Similar nonsignificant trends were observed for the effects of T2D and fasting glucose on lumbar spine BMD. Our results indicate that both genetically‐increased T2D risk and genetically‐increased fasting glucose have weak positive effects on BMD. © 2016 American Society for Bone and Mineral Research.     

Trabecular Bone Score: A Noninvasive Analytical Method Based Upon the DXA Image

The trabecular bone score (TBS) is a gray‐level textural metric that can be extracted from the two‐dimensional lumbar spine dual‐energy X‐ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross‐sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment. © 2014 American Society for Bone and Mineral Research.     

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized,Double‐Blind,Phase 2, Parallel Group Study

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T‐score ≤–2.0 and ≥–3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open‐label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β‐CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β‐CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Causal Associations of Anthropometric Measurements With Fracture Risk and Bone Mineral Density: A Mendelian Randomization Study

Uncovering additional causal clinical traits and exposure variables is important when studying osteoporosis mechanisms and for the prevention of osteoporosis. Until recently, the causal relationship between anthropometric measurements and osteoporosis had not been fully revealed. In the present study, we utilized several state-of-the-art Mendelian randomization (MR) methods to investigate whether height, body mass index (BMI), waist-to-hip ratio (WHR), hip circumference (HC), and waist circumference (WC) are causally associated with two major characteristics of osteoporosis, bone mineral density (BMD) and fractures. Genomewide significant (p ≤ 5 × 10⁻⁸) single-nucleotide polymorphisms (SNPs) associated with the five anthropometric variables were obtained from previous large-scale genomewide association studies (GWAS) and were utilized as instrumental variables. Summary-level data of estimated bone mineral density (eBMD) and fractures were obtained from a large-scale UK Biobank GWAS. Of the MR methods utilized, the inverse-variance weighted method was the primary method used for analysis, and the weighted-median, MR-Egger, mode-based estimate, and MR pleiotropy residual sum and outlier methods were utilized for sensitivity analyses. The results of the present study indicated that each increase in height equal to a single standard deviation (SD) was associated with a 9.9% increase in risk of fracture (odds ratio [OR] = 1.099; 95% confidence interval [CI] 1.067–1.133; p = 8.793 × 10⁻¹⁰) and a 0.080 SD decrease of estimated bone mineral density (95% CI −0.106–(−0.054); p = 2.322 × 10⁻⁹). We also found that BMI was causally associated with eBMD (beta = 0.129, 95% CI 0.065–0.194; p = 8.113 × 10⁻⁵) but not associated with fracture. The WHR adjusted for BMI, HC adjusted for BMI, and WC adjusted for BMI were not found to be related to fracture occurrence or eBMD. In conclusion, the present study provided genetic evidence for certain causal relationships between anthropometric measurements and bone mineral density or fracture risk. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Skin Autofluorescence,a Noninvasive Biomarker for Advanced Glycation End-Products,Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant’s grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08–2.35; p = .02); OR 1.30 (95% CI, 0.89–1.97; p = .20), and OR 1.40 (95% CI, 0.95–2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08–2.64; p = .02), OR 1.74(95% CI, 1.11–2.71; p = .01), and OR 1.73 (95% CI, 1.12–2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04–2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18–2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Time to onset of antifracture efficacy and year-by-year persistence of effect of zoledronic acid in women with osteoporosis

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years.     

Relationship Between Low Bone Mineral Density and Fractures With Incident Cardiovascular Disease: A Systematic Review and Meta‐Analysis

An increasing evidence base suggests that low bone mineral density (BMD) and fractures are associated with cardiovascular disease (CVD). We conducted a systematic review and meta‐analysis summarizing the evidence of low BMD and fractures as risk factors for future CVD. Two independent authors searched major databases from inception to August 1, 2016, for longitudinal studies reporting data on CVD incidence (overall and specific CVD) and BMD status and fractures. The association between low BMD, fractures, and CVD across longitudinal studies was explored by calculating pooled adjusted hazard ratios (HRs) ±95% confidence intervals (CIs) with a random‐effects meta‐analysis. Twenty‐eight studies (18 regarding BMD and 10 fractures) followed a total of 1,107,885 participants for a median of 5 years. Taking those with higher BMD as the reference, people with low BMD were at increased risk of developing CVD during follow‐up (11 studies; HR = 1.33; 95%CI, 1.27 to 1.38; I² = 53%), after adjusting for a median of eight confounders. This finding was confirmed using a decrease in one standard deviation of baseline BMD (9 studies; HR = 1.16; 95% CI, 1.09 to 1.24; I² = 69%). The presence of fractures at baseline was associated with an increased risk of developing CVD (HR = 1.20; 95% CI, 1.06 to 1.37; I² = 91%). Regarding specific CVDs, low BMD was associated with an increased risk of developing coronary artery disease, cerebrovascular conditions, and CVD‐associated death. Fractures at baseline was associated with an increased risk of cerebrovascular conditions and death due to CVD. In conclusion, low BMD and fractures are associated with a small, but significant increased risk of CVD risk and possibly death. © 2017 American Society for Bone and Mineral Research.     

The Importance of Previous Fracture Site on Osteoporosis Diagnosis and Incident Fractures in Women

Previous fracture increases the risk of subsequent fractures regardless of the site of the initial fracture. Fracture risk assessment tools have been developed to guide clinical management; however, no discrimination is made as to the site of the prior fracture. Our objective was to determine which sites of previous nontraumatic fractures are most strongly associated with a diagnosis of osteoporosis, defined by a bone mineral density (BMD) T‐score of ≤ ?2.5 at the femoral neck, and an incident major osteoporotic fracture. Using administrative health databases, we conducted a retrospective historical cohort study of 39,991women age 45 years and older who had BMD testing with dual‐energy X‐ray absorptiometry (DXA). Logistic regression and Cox proportional multivariate models were used to test the association of previous fracture site with risk of osteoporosis and incident fractures. Clinical fractures at the following sites were strongly and independently associated with higher risk of an osteoporotic femoral neck T‐score after adjustment for age: hip (odds ratio [OR], 3.58; 95% confidence interval [CI], 3.04–4.21), pelvis (OR, 2.23; 95% CI, 1.66–3.0), spine (OR, 2.16; 95% CI, 1.77–2.62), and humerus (OR, 1.74; 95% CI, 1.49–2.02). Cox proportional hazards models, with adjustment for age and femoral neck BMD, showed the greatest increase in risk for a major osteoporotic fracture for women who had sustained previous fractures of the spine (hazard ratio [HR], 2.08; 95% CI, 1.72–2.53), humerus (HR, 1.70; 95% CI, 1.44–2.01), patella (HR, 1.54; 95% CI, 1.10–2.18), and pelvis (HR, 1.45; 95% CI, 1.04–2.02). In summary, our results confirm that nontraumatic fractures in women are associated with osteoporosis at the femoral neck and that the site of previous fracture impacts on future osteoporotic fracture risk, independent of BMD. © 2014 American Society for Bone and Mineral Research.     

Amino Acid Intakes Are Associated With Bone Mineral Density and Prevalence of Low Bone Mass in Women: Evidence From Discordant Monozygotic Twins

Although a higher protein intake, particularly from vegetable sources, has been shown to be associated with higher bone mineral density (BMD) the relative impact of specific amino acids on BMD and risk of osteoporosis remains to be determined. Mechanistic research suggests that a number of specific amino acids, including five nonessential amino acids—alanine, arginine, glutamic acid, glycine, and proline—may play a role in bone health, principally through improved production of insulin and insulin‐like growth factor 1 and the synthesis of collagen and muscle protein. However to date, no previous studies have examined the associations between habitual intake of amino acids and direct measures of BMD and prevalence of osteoporosis or osteopenia, and no studies have examined this relationship in discordant identical twin‐pairs. In these analyses of female monozygotic twin‐pairs discordant for amino acid intake (n = 135), twins with higher intakes of alanine and glycine had significantly higher BMD at the spine than their co‐twins with within‐pair differences in spine‐BMD of 0.012 g/cm² (SE 0.01; p = 0.039) and 0.014 g/cm² (SE 0.01; p = 0.026), respectively. Furthermore, in cross‐sectional multivariable analyses of 3160 females aged 18 to 79 years, a higher intake of total protein was significantly associated with higher DXA‐measured BMD at the spine (quartile Q4 to quartile Q1: 0.017 g/cm², SE 0.01, p = 0.035) and forearm (Q4 to Q1: 0.010 g/cm², SE 0.003, p = 0.002). Intake of six amino acids (alanine, arginine, glutamic acid, leucine, lysine, and proline) were associated with higher BMD at the spine and forearm with the strongest association observed for leucine (Q4 to Q1: 0.024 g/cm², SE 0.01, p = 0.007). When intakes were stratified by protein source, vegetable or animal, prevalence of osteoporosis or osteopenia was 13% to 19% lower comparing extreme quartiles of vegetable intake for five amino acids (not glutamic acid or proline). These data provide evidence to suggest that intake of protein and several amino acids, including alanine and glycine, may be beneficial for bone health, independent of genetic background. © 2015 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.