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The objective of this work was to estimate the incidence rate of cardiovascular disease (CVD) events (myocardial infarction, stroke, or CVD death) at 1 year among three cohorts of patients at high risk of fracture (osteoporosis, previous fracture, and anti-osteoporosis medication) and to identify the key risk factors of CVD events in these three cohorts. To do so, this prospective cohort study used data from the Clinical Practice Research Datalink, a primary care database from United Kingdom. Major adverse cardiovascular events (MACE, a composite outcome for the occurrence of either myocardial infarction [MI], stroke, or CVD death) were identified in patients aged 50 years or older at high or imminent fracture risk identified in three different cohorts (not mutually exclusive): recently diagnosed with osteoporosis (OST, n = 65,295), incident fragility fracture (IFX, n = 67,065), and starting oral bisphosphonates (OBP, n = 145,959). About 1.90%, 4.39%, and 2.38% of the participants in OST, IFX, and OBP cohorts, respectively, experienced MACE events. IFX was the cohort with the higher risk: MACE incidence rates (cases/1000 person-years) were 19.63 (18.54-20.73) in OST, 52.64 (50.7-54.5) in IFX, and 26.26 (25.41-27.12) in OBP cohorts. Risk of MACE events at 1 year was predicted in the three cohorts. Models using a set of general, CVD, and fracture candidates selected by lasso regression had a good discrimination (≥70%) and internal validity and generally outperformed the models using only the CVD risk factors of general population listed in QRISK tool. Main risk factors common in all MACE models were sex, age, smoking, alcohol, atrial fibrillation, antihypertensive medication, prior MI/stroke, established CVD, glomerular filtration rate, systolic blood pressure, cholesterol levels, and number of concomitant medicines. Identified key risk factors highlight the differences of patients at high risk of fracture versus general population. Proposed models could improve prediction of CVD events in patients with osteoporosis in primary care settings. © 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)., (© 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).)

Bone mineral density (BMD) is an established measure used to diagnose patients with osteoporosis. In clinical trials, change in BMD has been shown to provide a reliable estimate of fracture risk reduction, and achieved BMD T-score has been shown to reflect the near-term risk of fracture. We aimed to test the association between BMD T-score and fracture risk in patients treated for osteoporosis in a real-world setting. This retrospective, observational cohort study included Swedish females aged ≥55 years who had a total hip BMD measurement at one of three participating clinics. Patients were separated into two cohorts: bisphosphonate-treated and bisphosphonate-naïve prior to BMD measurement, stratified by age and prior nonvertebral fracture status. The primary outcome was cumulative incidence of clinical fractures within 24 months of BMD measurement, with other fracture types included as secondary outcomes. Associations between T-score and fracture risk were estimated using proportional hazards regression and restricted cubic splines. A total of 15,395 patients were analyzed: 11,973 bisphosphonate-naïve and 3422 bisphosphonate-treated. In the 24 months following BMD measurement, 6.3% (95% confidence interval [CI], 5.9-6.7) of bisphosphonate-naïve and 8.4% (95% CI, 7.5-9.4) of bisphosphonate-treated patients experienced a clinical fracture. Strong inverse relationships between BMD T-score and fracture incidence were observed in both cohorts. Among bisphosphonate-naïve patients, this relationship appeared to plateau around T-score -1.5, indicating smaller marginal reductions in fracture risk above this value; bisphosphonate-treated patients showed a more consistent marginal change in fracture risk across the evaluated T-scores (-3.0 to -0.5). Trends remained robust regardless of age and prior fracture status. This real-world demonstration of a BMD-fracture risk association in both bisphosphonate-naïve and bisphosphonate-treated patients extends evidence from clinical trials and recent meta-regressions supporting the suitability of total hip BMD as a meaningful outcome for the clinical management of patients with osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

The rate of bone loss varies across the aging period via multiple complex mechanisms. Therefore, the role of genetic factors on bone loss may also change similarly. In this study, we investigated the effect of age on the genetic component of bone loss in a large twin-based longitudinal study. During 17 years of follow-up in TwinsUK and Healthy Ageing Twin Study (HATS), 15,491 hip and lumbar spine dual-energy X-ray absorptiometry (DXA) scans were performed in 7056 twins. Out of these subjects, 2716 female twins aged >35 years with at least two scans separated for >4 years (mean follow-up 9.7 years) were included in this analysis. We used a mixed-effects random-coefficients regression model to predict hip and spine bone mineral density (BMD) values for exact ages of 40, 45, 50, 55, 60, 65, 70, 75, and 80 years, with adjustment for baseline age, weight, height, and duration of hormone replacement therapy. We then estimated heritability of the changes in BMD measures between these age ranges. Heritability estimates for cross-sectional hip and spine BMD were high (ranging between 69% and 88%) at different ages. Heritability of change of BMD was lower and more variable, generally ranging from 0% to 40% for hip and 0% to 70% for spine; between age 40 and 45 years genetic factors explained 39.9% (95% confidence interval [CI], 25%-53%) of variance of BMD loss for total hip, 46.4% (95% CI, 32%-58%) for femoral neck, and 69.5% (95% CI, 59%-77%) for lumbar spine. These estimates decreased with increasing age, and there appeared to be no heritability of BMD changes after the age of 65 years. There was some evidence at the spine for shared genetic effects between cross-sectional and longitudinal BMD. Whereas genetic factors appear to have an important role in bone loss in early postmenopausal women, nongenetic mechanisms become more important determinants of bone loss with advanced age., (Copyright © 2012 American Society for Bone and Mineral Research.)

Although quantitative ultrasound (QUS) is known to be correlated with BMD and bone structure, its long-term predictive power for fractures in comparison with DXA is unclear. We examined this in a sample of men and women in the European Prospective Investigation into Cancer (EPIC)-Norfolk who had both heel QUS and hip DXA between 1995 and 1997. From 1455 participants (703 men) 65-76 yr of age at baseline, 79 developed a fracture over 10.3 +/- 1.4 yr of follow-up. In a sex-stratified Cox proportional-hazard model including age, height, body mass index, prior fracture, smoking, alcohol intake, and total hip BMD, a 1 SD decrease in BMD was associated with a hazard ratio (HR) for fracture of 2.26 (95% CI: 1.74-2.95). In the multivariable model with heel broadband ultrasound attenuation (BUA) in place of BMD, HR for a 1 SD decrease in BUA was 2.04 (95% CI: 1.55-2.69). Global measures of model fit showed relative superiority of the BMD model, whereas the area under the receiving operator characteristic (ROC) curve was slightly higher for the BUA model. Using both Cox models with BMD and BUA measures, we calculated exact 10-yr absolute risk of fracture for all participants and categorized them in groups of <5%, 5% to <15%, and >or=15%. Comparison of groupings based on two models showed a total reclassification of 28.8% of participants, with the greatest reclassification (approximately 40%) among the intermediate- and high-risk groups. This study shows that the power of QUS for prediction of fractures among the elderly is at least comparable to that of DXA. Given the feasibility and lower cost of ultrasound measurement in primary care, further studies to develop and validate models for prediction of 10-yr risk of fracture using clinical risk factors and QUS are recommended.

Identification of those at high risk of osteoporosis and fractures using clinically available tests beyond BMD measures is a major clinical challenge. We examined forced expiratory volume in 1 s (FEV1), an easily obtainable measure of respiratory function, as a clinical measure for fracture prediction. In the context of the European Prospective Investigation into Cancer-Norfolk Study, 8304 women and 6496 men 42-81 yr of age underwent a health check including spirometry and heel quantitative ultrasonography between 1997 and 2000 and were followed up for incident hip fractures until 2007. The main outcome measures were broadband ultrasound attenuation (BUA) of the heel (cross-sectional analysis) and hip fracture risk (prospective analysis). In multivariate regression models, a 1-liter increase in FEV1 was associated with a statistically significant 2.2-dB/MHz increase in BUA, independent of age, smoking, height, body mass index, history of fracture, and use of corticosteroids. Mean FEV1 was significantly lower among 84 women and 36 men with hip fracture compared with other participants. In multivariate proportional-hazard regression models, the relative risk (RR) of hip fracture associated with a 1-liter increase in FEV1 was 0.5 (95% CI, 0.3-0.9; p < 0.001) for both men and women. RR of hip fracture for a 1 SD increase in FEV1 was approximately equivalent to a 0.5 SD increase in BUA among women (1 SD among men) and an 5-yr decrease in age among both men and women. Middle-aged and older people with low respiratory function are at increased risk of osteoporosis and hip fracture. FEV1, an easy, low-cost, and feasible clinical measure, may help improve the identification of high-risk groups.

Identifying factors affecting BMD precision and interindividual heterogeneity in BMD change can help optimize BMD monitoring. BMD change for the lumbar spine and total hip for short-term reproducibility (n = 328) and long-term clinical monitoring (n = 2720) populations were analyzed with heteroscedastic regression using linear prediction for mean (monitoring population only) and log-linear prediction for SD (both populations). For clinical monitoring, male sex, baseline body mass index (BMI), and systemic corticosteroid use were associated with greater SD of BMD change. Weight gain was negatively associated with SD for the hip, whereas height change was positively associated with SD for the spine. Each additional year of monitoring increased the SD by 6.5-9.2%. Osteoporosis treatment affected mean change but did not increase dispersion. For short-term reproducibility, performing scans on a different day increased the SD of measurement error by 38-44%. Baseline BMD, difference in bone area, and a repeat scan performed by different technologists were associated with higher measurement error only for the hip. For both samples, heteroscedastic regression outperformed models that assumed homogeneous variance. Heteroscedastic regression techniques are powerful yet underused tools in analyzing longitudinal BMD data and can be used to generate individualized predictions of BMD change and measurement error.

Unlabelled: In this large population-based prospective study among middle-aged and older men and women, we found that height loss of >2 cm over a period of 4 yr is a significant predictor of future fractures. Serial measurement of height is, therefore, recommended among the elderly people., Introduction: Height change can be easily measured and may contribute to fracture risk prediction. We assessed measured height loss and fracture incidence in a prospective population study., Materials and Methods: Height was measured in participants in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) between 1993 and 1997 and repeated between 1997 and 2000. Incident fractures to 2006 were ascertained by hospital record linkage., Results: In 14,921 men and women 42-82 yr of age, during a mean follow-up period of 7.1 yr, there were 390 fractures, including 122 hip fractures. Prior annual height loss in those who had an incident fracture (1.8 +/- 0.3 [SD] mm) was significantly greater than other participants (0.9 +/- 0.2 mm; p < 0.001). Participants with annual height loss >0.5 cm had an age- and sex-adjusted hazard ratio of any fracture of 1.76 (95% CI, 1.16-2.67) and of hip fracture of 2.08 (95% CI, 1.07-4.05) compared with those with no height loss. Each 1 cm/yr height loss was associated with a hazard ratio of 1.86 (95% CI, 1.28-2.72) for all fractures and 2.24 (95% CI, 1.23-4.09) for hip fracture after adjustment for age, sex, past history of fracture, smoking, body mass index, alcohol intake, and heel ultrasound measures. Annual height loss of 1 cm was comparable to having a past history of fracture and equivalent to being approximately 14 yr older in chronological age in terms of the magnitude of relationship with fracture risk., Conclusions: Middle-aged and older men and women with annual height loss >0.5 cm are at increased risk of hip and any fracture. Serial height measurements can contribute to fracture risk prediction.