Gender and Age Differences in the Associations Between Cortical Thickness and Hand Osteoarthritis Severity: Data from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate gender differences in the association between metacarpal cortical thickness - a surrogate for bone density - and severity of radiographic hand osteoarthritis (HOA) in a longitudinal observational study. METHOD: Hand radiographs of 3,575 participants (2039 F/1536 M) from the Osteoarthritis Initiative were assessed at baseline and 48 months. A reader used a semi-automated software tool to calculate Tcort, a measurement of the cortical thickness, for metacarpals 2-4. Average Tcort at baseline and change in Tcort from baseline to 48 months was determined and stratified by gender and age for 7 5-year age groups. Spearman's rank correlation coefficients were calculated for the association of baseline Tcort and 2 measures of baseline HOA severity: the sum of Kellgren and Lawrence (KL) grade and total number of joints with radiographic HOA. Longitudinally, logistic regression was used to assess the relationship of Tcort loss to new finger joint radiographic HOA, increase in KL grades, and incident hand pain. RESULTS: Male Tcort was higher than females. Significant correlations between Tcort and radiographic severity were noted for women but not men, with stronger associations among women >60 years (rho=-0.25; 95% CI= -0.31- -0.19). Statistically significant associations were seen between Tcort change and radiographic osteoarthritis change among women but not men, with substantial gender differences for Tcort change, particularly ages 50 to 70 years (p<0.01; e.g.Tcort change ages 55 to <60: Males=-0.182(0.118), Females=-0.219(0.124). CONCLUSION: We found significant HOA-related gender differences in cortical thickness, suggesting the involvement of female bone loss during and after menopause.

The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

The American Society for Bone and Mineral Research Task Force on clinical algorithms for fracture risk report.

Using race and ethnicity in clinical algorithms potentially contributes to health inequities. The American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee convened the ASBMR Task Force on Clinical Algorithms for Fracture Risk to determine the impact of race and ethnicity adjustment in the US Fracture Risk Assessment Tool (US-FRAX). The Task Force engaged the University of Minnesota Evidence-based Practice Core to conduct a systematic review investigating the performance of US-FRAX for predicting incident fractures over 10 years in Asian, Black, Hispanic, and White individuals. Six studies from the Women's Health Initiative (WHI) and Study of Osteoporotic Fractures (SOF) were eligible; cohorts only included women and were predominantly White (WHI > 80% and SOF > 99%), data were not consistently stratified by race and ethnicity, and when stratified there were far fewer fractures in Black and Hispanic women vs White women rendering area under the curve (AUC) estimates less stable. In the younger WHI cohort (n = 64 739), US-FRAX without bone mineral density (BMD) had limited discrimination for major osteoporotic fracture (MOF) (AUC 0.53 (Black), 0.57 (Hispanic), and 0.57 (White)); somewhat better discrimination for hip fracture in White women only (AUC 0.54 (Black), 0.53 (Hispanic), and 0.66 (White)). In a subset of the older WHI cohort (n = 23 918), US-FRAX without BMD overestimated MOF. The Task Force concluded that there is little justification for estimating fracture risk while incorporating race and ethnicity adjustments and recommends that fracture prediction models not include race or ethnicity adjustment but instead be population-based and reflective of US demographics, and inclusive of key clinical, behavioral, and social determinants (where applicable). Research cohorts should be representative vis-à-vis race, ethnicity, gender, and age. There should be standardized collection of race and ethnicity; collection of social determinants of health to investigate impact on fracture risk; and measurement of fracture rates and BMD in cohorts inclusive of those historically underrepresented in osteoporosis research.

Using race or ethnicity when calculating disease risk may contribute to health disparities. The ASBMR Task Force on Clinical Algorithms for Fracture Risk was created to understand the impact of the US Fracture Risk Assessment Tool (US-FRAX) race and ethnicity adjustments. The Task Force reviewed the historical development of FRAX, including the assumptions underlying selection of race and ethnicity adjustment factors. Furthermore, a systematic review of literature was conducted, which revealed an overall paucity of data evaluating the performance of US-FRAX in racially and ethnically diverse groups. While acknowledging the existence of racial and ethnic differences in fracture epidemiology, the Task Force determined that currently there is limited evidence to support the use of race and ethnicity­specific adjustments in US-FRAX. The Task Force also concluded that research is needed to create generalizable fracture risk calculators broadly applicable to current US demographics, which do not include race and ethnicity adjustments. Until such population­based fracture calculators are available, clinicians should consider providing fracture risk ranges for Asian, Black, and/or Hispanic patients and should engage in shared decision-making with patients about fracture risk interpretation. Future studies are required to evaluate fracture risk tools in populations inclusive of those historically underrepresented in research.

Balancing fracture risk versus risk of mortality before fracture among women aged 80 years or older.

BACKGROUND: Most fractures occur in women aged ≥80 years but competing mortality unrelated to fracture may limit the benefit of osteoporosis drug therapy for some women in late life. Our primary aim was to develop separate prediction models for non-spine fracture (NSF) and mortality before fracture to identify subsets of women with varying fracture versus mortality risks. METHODS: Separate prediction models were developed for NSF and mortality before NSF for 4895 women aged ≥80 years enrolled in the Study of Osteoporotic Fractures (SOF) or the Health Aging and Body Composition (HABC) study. Proportional hazards models modified to account for competing mortality were used to identify candidate risk factors for each outcome. Predictors associated with NSF or mortality (p < 0.2) were included in separate competing risk models to estimate the cumulative incidence of NSF and mortality before NSF during 5 years of follow-up. This process was repeated to develop separate prediction models for hip fracture and mortality before hip fracture. RESULTS: Significant predictors of NSF (race, total hip BMD, grip strength, prior fracture, falls, and use of selective serotonin reuptake inhibitors, benzodiazepines, or oral/transdermal estrogen) differed from predictors of mortality before NSF (age, walking speed, multimorbidity, weight change, shrinking, smoking, self-rated health, dementia, and use of warfarin). Within nine subsets of women defined by tertiles of risk, 5-year outcomes varied from 28% NSF and 8% mortality in the high-risk NSF/low-risk mortality subset, to 9% NSF and 22% mortality in the low-risk NSF/high-risk mortality subset. Similar results were seen for predictors of hip fracture and mortality before hip fracture. CONCLUSION: Considerable variation in 5-year competing mortality risk is present among women in late life with similar 5-year NSF risk. Both fracture risk and life expectancy should inform shared clinical decision-making regarding initiation or continuation of osteoporosis drug therapy for women aged ≥80 years.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Associations between hypertension with reproductive and menopausal factors: An integrated women's health programme (IWHP) study.

BACKGROUND: Women are less likely to have classic cardiovascular risk factors than men, and events during their reproductive and menopausal years may increase hypertension risk. The aim of this study is to examine woman-specific factors, including menstrual, reproductive and pregnancy complications, in relation to the prevalence of hypertension in mid-life Asian women. METHODS: This is a cross-sectional study of 1146 healthy women aged 45-69 years, from a multi-ethnic Asian cohort. The women completed an extensive questionnaire that included their sociodemographic details, medical history, lifestyle and physical activity, and reproductive and menopausal history. They also underwent objectively measured physical performance tests and a dual X-ray absorptiometry scan. Hypertension was defined as a systolic BP ≥140 and/or diastolic BP ≥90mm Hg, past diagnosis by a physician, or use of antihypertensive medications. Multivariable logistic regression was used to assess the independent risk factors for hypertension. RESULTS: The average age of the 1146 women analysed was 56.3 (SD 6.2) years, and 55.2 percent of them were hypertensive. The prevalence of gestational diabetes and gestational hypertension was 12.6% and 9.4%, respectively. Besides age, abnormal menstrual cycle length at 25 years of age (OR:2.35, CI:1.34-4.13), preeclampsia (OR:2.46, CI:1.06-5.74), increased visceral adiposity (OR:4.21, CI:2.28-7.79) and reduced physical performance (OR:2.83, CI:1.46-5.47) were independently associated with hypertension in Asian women. CONCLUSIONS: Our findings highlight the necessity of including features of menstrual and reproductive history as possible indicators of hypertension risk in cardiovascular disease risk assessment and prevention among Asian women. Reducing visceral adiposity and exercise to improve physical performance may help women avoid developing hypertension.

Physical function trajectory after wrist or lower arm fracture in postmenopausal women: results from the Women's Health Initiative Study.

Long-term physical functioning trajectories following distal forearm fracture are unknown. We found that women with versus those without distal forearm fracture were more likely to experience a 5-year decline in physical functioning, independent of initial physical functioning level. This association was most evident among women 80 years and older. INTRODUCTION: Physical functioning trajectory following lower arm or wrist fracture is not well understood. PURPOSE: This study is to evaluate physical functioning trajectory before vs. after lower arm or wrist fracture, stratified by age. METHODS: We performed a nested case-control study of prospective data from the Women's Health Initiative Study (n = 2097 cases with lower arm or wrist fracture, 20,970 controls). Self-reported fractures and the physical functioning subscale of the RAND 36-item Short-Form Health Survey were assessed annually. We examined three physical functioning trajectory groups: stable, improving, and declining. RESULTS: Mean (SD) number of physical functioning measurements was 5.2 (1.5) for cases and 5.0 (1.4) for controls. Declining physical functioning was observed among 20.4% of cases and 16.0% of controls. Compared to women without lower arm or wrist fracture, women with lower arm or wrist fracture were 33% more likely to experience declining physical functioning (adjusted odds ratio [aOR] 1.33 95% confidence interval [CI] 1.19-1.49, reference group stable or improving physical functioning trajectory). Associations varied by age: age ≥ 80 years aOR 1.56 (95% CI 1.29-1.88); age 70-79 years aOR 1.29 (95% CI 1.09-1.52); age < 70 years aOR 1.15 (95% CI 0.86-1.53) (pinteraction = 0.06). Associations between lower arm or wrist fracture and odds of declining physical functioning did not vary by baseline physical functioning or physical activity level. CONCLUSIONS: Women with lower arm or wrist fracture, particularly those aged 80 and older, were more likely to experience declines in physical functioning than women without such fractures, independent of baseline physical functioning level.

More rapid bone mineral density loss in older men with diabetes: The Osteoporotic Fractures in Men (MrOS) Study.

CONTEXT: Type 2 diabetes mellitus (T2D) is associated with more rapid bone loss in women, but less evidence is available for men or those with prediabetes. OBJECTIVE: To determine whether bone loss rate is affected by diabetes status in older men, we analyzed data from the Osteoporotic Fractures in Men (MrOS) study. METHODS: The multisite MrOS study enrolled 5,994 men aged ≥65 years. Diabetes status was defined by self-report, diabetes medication use, or elevated fasting serum glucose at baseline. Hip bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA) at baseline and a follow-up visit after 4.6 ± 0.4 years. This analysis included 4095 men, excluding those without a follow-up DXA or with unknown diabetes status. Changes in hip BMD in participants with normoglycemia (NG), prediabetes, or T2D, excluding thiazolidinedione (TZD) users, were evaluated using generalized linear models (GLM). Diabetes medication use and BMD loss among those with T2D were also evaluated with GLM. RESULTS: In adjusted models, loss in hip BMD was greater in men with T2D (- 2.23%: 95% CI: -2.54 to -1.91; p<0.001) but not in men with prediabetes (-1.45%; 95% CI -1.63 to -1.26; p=0.33) compared to NG (-1.57%: 95% CI -1.73 to -1.41). Among men with T2D, TZD, insulin and sulfonylurea use were associated with greater hip BMD loss. CONCLUSIONS: Men with T2D, but not prediabetes, experienced an accelerated bone loss compared to participants with normoglycemia. More rapid bone loss predicts increased risk of fractures and mortality in broader populations.

Testosterone Treatment and Fractures in Men with Hypogonadism.

BACKGROUND: Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed. METHODS: In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated. RESULTS: The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points. CONCLUSIONS: Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Associations Between Walking Speed and Gut Microbiome Composition in Older Men From the MrOS Study.

BACKGROUND: Gut dysbiosis has been linked to frailty, but its association with early mobility decline is unclear. METHODS: First, we determined the cross-sectional associations between walking speed and the gut microbiome in 740 older men (84 ±â€…4 years) from the MrOS cohort with available stool samples and 400 m walking speed measured in 2014-2016. Then, we analyzed the retrospective longitudinal associations between changes in 6 m walking speed (from 2005-2006 to 2014-2016, calculated by simple linear equation) and gut microbiome composition among participants with available data (702/740). We determined gut microbiome composition by 16S sequencing and examined diversity, taxa abundance, and performed network analysis to identify differences in the gut microbiome network of fast versus slow walkers. RESULTS: Faster 400 m walking speed (m/s) was associated with greater microbiome α-diversity (R = 0.11; p = .004). The association between a slower decline in 6 m walking speed and higher α-diversity (R = 0.07; p = .054) approached borderline significance. Faster walking speed and less decline in walking speed were associated with a higher abundance of genus-level bacteria that produce short-chain fatty acids, and possess anti-inflammatory properties, including Paraprevotella, Fusicatenibacter, and Alistipes, after adjusting for potential covariates (p < .05). The gut microbiome networks of participants in the first versus last quartile of walking speed (≤0.9 vs ≥1.2 m/s) exhibited distinct characteristics, including different centrality measures (p < .05). CONCLUSIONS: Our findings suggest a possible relationship between gut microbiome diversity and mobility function, as indicated by the associations between faster walking speed and less decline in walking speed over 10 years with higher gut microbiome diversity in older men.

The Vitamin D Metabolite Ratio Is Associated With Volumetric Bone Density in Older Men.

CONTEXT: Serum 25-hydroxyvitamin D (25(OH)D) is the current marker of vitamin D adequacy, but its relationship with bone health has been inconsistent. The ratio of 24,25-dihydroxyvitamin D3 to 25(OH)D3 (vitamin D metabolite ratio or VMR) is a marker of vitamin D that has been associated with longitudinal changes in bone mineral density (BMD) and fracture risk. OBJECTIVE: High-resolution peripheral quantitative computed tomography (HR-pQCT) provides information on bone health beyond standard dual-energy x-ray absorptiometry, in that it measures volumetric BMD (vBMD) as well bone strength. The relationship of the VMR with vBMD and bone strength remains unknown. METHODS: We evaluated the associations of the VMR and 25(OH)D3 with vBMD and bone strength in the distal radius and tibia, assessed by HR-pQCT in 545 older men participating in the Osteoporotic Fractures in Men (MrOS) Study. Primary outcomes were vBMD and estimated failure load (EFL, a marker of bone strength) at the distal radius and tibia. RESULTS: The mean age was 84 ± 4 years, 88.3% were White, and 32% had an estimated glomerular filtration rate <60 mL/min/1.73 m2. In adjusted models, each twofold higher VMR was associated with a 9% (3%, 16%) higher total vBMD and a 13% (5%, 21%) higher EFL at the distal radius. Results were similar at the distal tibia. 25(OH)D3 concentrations were not associated with any of the studied outcomes. CONCLUSION: Among older men, a higher VMR was associated with greater vBMD and bone strength while 25(OH)D3 was not. The VMR may serve as a valuable marker of skeletal health in older men.

The effect of starting metformin on bone mineral density among women with type 2 diabetes in the Study of Women's Health Across the Nation (SWAN).

We examined longitudinal changes in BMD among women in the mid-life starting metformin. Study subjects were 57 years old (mean), and 36% were White. Women initiating metformin were similar to noninitiators. During the 3-year follow-up, BMD loss at all anatomic areas was similar between groups and in subgroups including baseline fasting blood glucose. PURPOSE/INTRODUCTION: Women with type 2 diabetes have higher bone mineral density (BMD), experience slower BMD loss, but have increased fracture risk. Data regarding the effect of metformin on BMD remain discordant. We examined longitudinal changes in BMD among women in the mid-life starting metformin. METHODS: Participants in the Study of Women's Health Across the Nation (SWAN), a diverse community-based US cohort, with BMD measurements were evaluated. Propensity score matching helped balance baseline characteristics of metformin initiators versus noninitiators. Mixed model regression tested the change in BMD between groups. RESULTS: Subjects (n = 248) were 57.4 years old (mean), and 35.9% were White. Women initiating metformin (n = 124) were similar to noninitiators (n = 124) in age and race/ethnicity. During the median 3-year follow-up, BMD loss at all anatomic areas was similar between the metformin initiators and nonusers (all p > 0.3). Subgroup analyses including baseline fasting blood glucose showed no between-group differences. Initiation of metformin (vs. not) in peri-menopausal women was not associated with BMD changes. CONCLUSIONS: Women in the mid-life starting metformin had longitudinal changes in BMD very similar to other women not starting metformin.

Breaking Up Sedentary Time Reduces Recurrent Fall Risk, but Not Incident Fracture Risk in Older Men.

Apart from physical activity volume, frequent breaks from sedentary bouts and active bouts may differentially reduce fall and fracture risk. We assessed the longitudinal relationship between frequency of breaks from time spent sedentary and frequency of active bouts with recurrent falls and fractures. The sample included 2918 men aged 79.0 ± 5.1 years with free-living activity (SenseWear Armband) at the Osteoporotic Fractures in Men Study (MrOS) year 7 (2007-2009) visit. Men were divided into quartiles by the number of breaks from sedentary bouts (sedentary bout: 5+ minutes sedentary; <1.5 metabolic equivalents of task [METS]) and separately by active bout frequency (active bout: 5+ minutes of activity; ≥1.5 METS). Recurrent falls (2+ falls/year) and fractures were ascertained by self-report; fractures were radiographically confirmed. Generalized estimating equations estimated the recurrent fall odds, with restricted cubic splines applied to assess nonlinear relationships. Cox proportional hazards models estimated fracture risk. Over 4 years of follow-up after year 7, 1025 (35.1%) men were fallers. Over 8.40 ± 4.10 years of follow-up, 640 (21.9%) men experienced a fracture. There was a significant nonlinear U-shaped relationship between number of breaks from sedentary bouts and recurrent falls (p < 0.001); compared with men with few breaks from sedentary bouts (1.4-<13.6), the odds of recurrent falls were lower with a moderate number (13.6-<17.0, odds ratio [OR] = 0.82, 95% confidence interval [CI] 0.66, 1.01; 17.0-<20.4, OR = 0.79, 95% CI 0.64, 0.99), but not with the highest number of breaks from sedentary bouts (20.4-34.6, OR = 1.01, 95% CI 0.81, 1.27). Results remained borderline significant after adjusting for total sedentary time. Men with the highest compared with the lowest number of breaks from sedentary bouts had a lower fracture risk, but the association was attenuated after adjustment for total sedentary time. No associations were observed for active bout frequency. In conclusion, breaking up extended periods of sedentary time reduces fall risk regardless of total sedentary time. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Utility of HR-pQCT in detecting training-induced changes in healthy adult bone morphology and microstructure.

Healthy bone adjusts its traits in an exceptionally coordinated, compensatory process. Recent advancements in skeletal imaging via High-Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) allows for the in vivo 3-dimensional and longitudinal quantification of bone density, microarchitecture, geometry, and parameters of mechanical strength in response to varying strain stimuli including those resulting from exercise or military training. Further, the voxel size of 61 microns has the potential to capture subtle changes in human bone in as little as 8 weeks. Given the typical time course of bone remodeling, short-term detection of skeletal changes in bone microstructure and morphology is indicative of adaptive bone formation, the deposition of new bone formation, uncoupled from prior resorption, that can occur at mechanistically advantageous regions. This review aims to synthesize existing training-induced HR-pQCT data in three distinct populations of healthy adults excluding disease states, pharmacological intervention and nutritional supplementation. Those included are: 1) military basic or officer training 2) general population and 3) non-osteoporotic aging. This review aims to further identify similarities and contrasts with prior modalities and cumulatively interpret results within the scope of bone functional adaptation.

Comprehensive assessment of chrononutrition behaviors among nationally representative adults: Insights from National Health and Nutrition Examination Survey (NHANES) data.

BACKGROUND: Aligning the time of food intake, i.e., chrononutrition, with the body's circadian clock can have a significant impact on overall health, particularly cardiometabolic health. However, there is a lack of population-based information on various chrononutrition behaviors in the United States, where the prevalence of obesity is high. OBJECTIVE: Our primary aim was to characterize chrononutrition behaviors and their 15-year trends among US adults. We also explored the temporal associations between trends in chrononutrition behaviors and trends in obesity. DESIGN: We utilized data from 8 cycles (2003-2018) of the National Health and Nutrition Examination Survey (NHANES) on 34,470 adults (age >19 years). The clock time of food/beverage consumption was extracted from two 24-h food recalls. The following chrononutrition behaviors were defined: 1) The clock time of the first, last, and midpoint (when 50% of total daily energy was consumed) of food/beverage intake; 2) Eating window (the time elapsed between the first and last intake); 3) Late-night eating (food intake between 21:00-23:59); and 4) Eating frequency. Survey-weighted % or mean ± standard error (SE) was used to demonstrate chrononutrition behaviors and survey-weighted regression models were utilized to evaluate trends in chrononutrition behaviors, BMI, and obesity over a 15-year period. RESULTS: Thirty five percent of US adults had long eating windows lasting 13 h or more, with 59% of individuals consuming calories after 9 PM. The patterns of food intake among American adults were skewed, with the highest proportion of their daily energy intake (36%) being consumed during dinner meals. Notable differences in chrononutrition behaviors observed among different population subgroups. Young adults and men had longer eating windows with a higher prevalence of late-night eating compared to their age- and sex-counterparts. Black individuals had shorter eating periods due to delayed breakfast, the highest proportion (68%) of late-night eating, and obtained a greater amount of energy intake from snacks compared to other racial/ethnic groups. Over the 15-year span, there were only minor changes in a few aspects of chrononutrition behaviors, including 2% reduction in the time of eating window, while most other meal timing behaviors remained unchanged. Trends in chrononutrition behaviors were disproportionately smaller than the trends in obesity rates. CONCLUSIONS: US adults persistently consume higher amounts of daily energy intake later in the day. Despite calls for Americans to shift intake to earlier parts of the day, this study shows that there is little change in the overall population over the 15-year period reviewed.

Advantages and Disadvantages of Random Forest Models for Prediction of Hip Fracture Risk Versus Mortality Risk in the Oldest Old.

Targeted fracture prevention strategies among late-life adults should balance fracture risk versus competing mortality risk. Models have previously been constructed using Fine-Gray subdistribution methods. We used a machine learning method adapted for competing risk survival time to evaluate candidate risk factors and create models for hip fractures and competing mortality among men and women aged 80 years and older using data from three prospective cohorts (Study of Osteoporotic Fractures [SOF], Osteoporotic Fracture in Men study [MrOS], Health Aging and Body Composition study [HABC]). Random forest competing risk models were used to estimate absolute 5-year risk of hip fracture and absolute 5-year risk of competing mortality (excluding post-hip fracture deaths). Models were constructed for both outcomes simultaneously; minimal depth was used to rank and select variables for smaller models. Outcome specific models were constructed; variable importance was used to rank and select variables for inclusion in smaller random forest models. Random forest models were compared to simple Fine-Gray models with six variables selected a priori. Top variables for competing risk random forests were frailty and related components in men while top variables were age, bone mineral density (BMD) (total hip, femoral neck), and frailty components in women. In both men and women, outcome specific rankings strongly favored BMD variables for hip fracture prediction while frailty and components were strongly associated with competing mortality. Model discrimination for random forest models varied from 0.65 for mortality in women to 0.81 for hip fracture in men and depended on model choice and variables included. Random models performed slightly better than simple Fine-Gray model for prediction of competing mortality, but similarly for prediction of hip fractures. Random forests can be used to estimate risk of hip fracture and competing mortality among the oldest old. Modest gains in performance for mortality without hip fracture compared to Fine-Gray models must be weighed against increased complexity. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Self-Reported Sleep Disturbances over the Menopausal Transition and Fracture Risk: The Study of Women's Health Across the Nation.

Sleep disturbances are common and may impact fracture risk directly by influencing bone turnover or indirectly through shared risk factors or mediators. To investigate the association between self-reported sleep disturbances across the menopausal transition (MT) and fractures, we prospectively studied 3101 women enrolled in the Study of Women's Health Across the Nation (SWAN). At each of 14 study visits spaced approximately 18 months apart, a standardized validated scale ascertained trouble falling asleep, waking up several times during the night, and waking up earlier than planned. Two time-varying exposures were modeled: presence of any of the three disturbances at least three times per week and waking up several times during the night at least three times per week. Base models adjusted for fixed (race/ethnicity, study site) and time-varying characteristics (age, body mass index, and MT stage). Fully adjusted models also included time-varying bone beneficial and detrimental medications, smoking, alcohol, physical activity, diabetes, depression and sleep medications, and depressive symptoms. Women who experienced a fracture were more likely to report a greater frequency of having trouble falling asleep, waking up several times, and/or waking up earlier: 35% versus 30% at baseline, p = 0.02. In the base models, women who had any of the three sleep disturbances at least three times per week had a higher risk of any fracture, odds ratio (OR) = 1.23 (95% confidence intervals, 1.02, 1.48) and nontraumatic fracture, OR = 1.36 (1.03, 1.80). These associations were largely attenuated to nonsignificance in the fully adjusted model. Sensitivity analyses limiting our sample to 2315 SWAN women enrolled in the bone mineral density (BMD) centers yielded similar results. Additional adjustment for femoral neck BMD had no effect on our results. In conclusion, self-reported sleep disturbances were associated with an increased risk of fractures, but these associations likely reflect shared risk factors or factors in the causal pathway. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Alcohol intake and endogenous sex hormones in women: meta-analysis of cohort studies and Mendelian randomization.

Background: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. Methods: We investigated cross-sectional associations between self-reported alcohol intake and serum or plasma concentrations of oestradiol, oestrone, progesterone (in pre-menopausal women only), testosterone, androstenedione, DHEAS (dehydroepiandrosterone sulphate) and SHBG (sex hormone binding globulin) in 45 431 pre-menopausal and 173 476 post-menopausal women. We performed multivariable linear regression separately for UK Biobank, EPIC (European Prospective Investigation into Cancer and Nutrition) and EHBCCG (Endogenous Hormones and Breast Cancer Collaborative Group), and meta-analysed the results. For testosterone and SHBG, we also conducted two-sample Mendelian Randomization (MR) and colocalisation using the ADH1B (Alcohol Dehydrogenase 1B) variant (rs1229984). Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in pre-menopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal oestradiol to 6.6% for post-menopausal DHEAS. There was an inverse association of alcohol with SHBG in post-menopausal women but a small positive association in pre-menopausal women. MR identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI: 0.6%, 7.6%) and free testosterone (7.8%; 4.1%, 11.5%), and an inverse association with SHBG (-8.1%; -11.3%, -4.9%). Colocalisation suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (PP4: 0.81 and 0.97 respectively). Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women.

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy.