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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 Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Source Citation: LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387:299-309. 35939577.

Importance: Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk., Objective: To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture., Design, Setting, and Participants: This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA2DS2-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167 275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019., Exposures: Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban)., Main Outcomes and Measures: Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes., Results: In the study population of 167 275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score-matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis., Conclusions and Relevance: In this real-world population of 167 275 patients with AF, use of DOACs-particularly apixaban-compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

Our objective was to determine the associations of peripheral bone strength and microarchitecture with incident clinical and major osteoporotic fracture among older men after adjusting for major clinical risk factors. We used a prospective cohort study design with data from 1794 men (mean age 84.4 years) in the Osteoporotic Fractures in Men (MrOS) study. Eligible men attended the year 14 visit, had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia, DXA measured BMD, and were followed for mean 1.7 years for incident fracture. Failure load was estimated using finite element analysis. We used Cox proportional hazards models with standardized HR-pQCT parameters as exposure variables. Primary outcome was clinical fracture (n = 108). Covariates included either Fracture Risk Assessment Tool (FRAX) major osteoporotic fracture probability calculated with BMD (FRAX-BMD), or individual clinical risk factors (CRF) including age, total hip BMD, race, falls, and prevalent fracture after age 50 years. Lower failure load was associated with higher risk of incident clinical fracture and incident major osteoporotic fracture. For clinical fracture with FRAX-BMD adjustment, the associations ranged from hazard ratio (HR) 1.58 (95% CI, 1.25 to 2.01) to 2.06 (95% CI, 1.60 to 2.66) per SD lower failure load at the diaphyseal tibia and distal radius. These associations were attenuated after adjustment for individual CRFs, but remained significant at the distal sites. Associations of volumetric BMD with these outcomes were similar to those for failure load. At the distal radius, lower trabecular BMD, number, and thickness, and lower cortical BMD, thickness, and area were all associated with higher risk of clinical fracture, but cortical porosity was not. Among community-dwelling older men, HR-pQCT measures including failure load, volumetric BMD, and microstructure parameters at peripheral sites (particularly distal radius) are robust independent predictors of clinical and major osteoporotic fracture. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Prior studies suggest that increased urine albumin is associated with a heightened fracture risk in women, but results in men are unclear. We used data from Osteoporotic Fractures in Men (MrOS), a prospective cohort study of community-dwelling men aged ≥65 years, to evaluate the association of increased urine albumin with subsequent fractures and annualized rate of hip bone loss. We calculated albumin/creatinine ratio (ACR) from urine collected at the 2003-2005 visit. Subsequent clinical fractures were ascertained from triannual questionnaires and centrally adjudicated by review of radiographic reports. Total hip BMD was measured by DXA at the 2003-2005 visit and again an average of 3.5 years later. We estimated risk of incident clinical fracture using Cox proportional hazards models, and annualized BMD change using ANCOVA. Of 2982 men with calculable ACR, 9.4% had ACR ≥30 mg/g (albuminuria) and 1.0% had ACR ≥300 mg/g (macroalbuminuria). During a mean of 8.7 years of follow-up, 20.0% of men had an incident clinical fracture. In multivariate-adjusted models, neither higher ACR quintile (p for trend 0.75) nor albuminuria (HR versus no albuminuria, 0.89; 95% CI, 0.65 to 1.20) was associated with increased risk of incident clinical fracture. Increased urine albumin had a borderline significant, multivariate-adjusted, positive association with rate of total hip bone loss when modeled in ACR quintiles (p = 0.06), but not when modeled as albuminuria versus no albuminuria. Macroalbuminuria was associated with a higher rate of annualized hip bone loss compared to no albuminuria (-1.8% more annualized loss than in men with ACR <30 mg/g; p < 0.001), but the limited prevalence of macroalbuminuria precluded reliable estimates of its fracture associations. In these community-dwelling older men, we found no association between urine albumin levels and risk of incident clinical fracture, but found a borderline significant, positive association with rate of hip bone loss. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Context: We hypothesize that endogenous sex steroids are associated with fracture risk independent of race/ethnicity., Design and Setting: We performed a nested case-control study within the prospective Women's Health Initiative Observational Study. Incident nonspine fractures were identified in 381 black, 192 Hispanic, 112 Asian, and 46 Native American women over an average of 8.6 years. A random sample of 400 white women who experienced an incident fracture was chosen. One control was selected per case and matched on age, race/ethnicity, and blood draw date. Bioavailable estradiol (BioE2), bioavailable testosterone (BioT), and sex hormone-binding globulin (SHBG) were measured using baseline fasting serum. Conditional logistic regression models calculated the odds ratio (OR) and 95% confidence interval (CI) of fracture across tertiles of hormone., Results: In multivariable and race/ethnicity-adjusted models, higher BioE2 (>8.25 pg/mL) and higher BioT (>13.3 ng/dL) were associated with decreased risk of fracture (OR, 0.65; 95% CI, 0.50 to 0.85; P trend = 0.001 and OR, 0.76; 95% CI, 0.60 to 0.96; P trend = 0.02, respectively). The interaction term between race/ethnicity and either BioE2 or BioT was not significant. There was no association between SHBG and fracture risk. In models stratifying by race/ethnicity, higher BioE2 was associated with a lower risk of fracture in both white women (OR, 0.56; 95% CI, 0.36 to 0.87) and black women (OR, 0.61; 95% CI, 0.39 to 0.96). Higher BioT was associated with a significantly lower fracture risk in only black women (OR, 0.65; 95% CI, 0.43 to 1.00), P trend = 0.03., Conclusions: Serum BioE2 and BioT are associated with fracture risk in older women irrespective of race/ethnicity and independent of established risk factors for fracture., (Copyright © 2017 by the Endocrine Society)

To determine the association of weight loss with risk of clinical fractures at the hip, spine, and pelvis (central body fractures [CBFs]) in older men with and without accounting for the competing risk of mortality, we used data from 4523 men (mean age 77.5 years). Weight change between baseline and follow-up (mean 4.5 years between examinations) was categorized as moderate loss (loss ≥10%), mild loss (loss 5% to <10%), stable (<5% change) or gain (gain ≥5%). Participants were contacted every 4 months after the follow-up examination to ascertain vital status (deaths verified by death certificates) and ask about fractures (confirmed by radiographic reports). Absolute probability of CBF by weight change category was estimated using traditional Kaplan-Meier method and cumulative incidence function accounting for competing mortality risk. Risk of CBF by weight change category was determined using conventional Cox proportional hazards regression and subdistribution hazards models with death as a competing risk. During an average of 8 years, 337 men (7.5%) experienced CBF and 1569 (34.7%) died before experiencing this outcome. Among men with moderate weight loss, CBF probability was 6.8% at 5 years and 16.9% at 10 years using Kaplan-Meier versus 5.7% at 5 years and 10.2% at 10 years using a competing risk approach. Men with moderate weight loss compared with those with stable weight had a 1.6-fold higher adjusted risk of CBF (HR 1.59; 95% CI, 1.06 to 2.38) using Cox models that was substantially attenuated in models accounting for competing mortality risk and no longer significant (subdistribution HR 1.16; 95% CI, 0.77 to 1.75). Results were similar in analyses substituting hip fracture for CBF. Older men with weight loss who survive are at increased risk of CBF, including hip fracture. However, ignoring the competing mortality risk among men with weight loss substantially overestimates their long-term fracture probability and relative fracture risk. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Trabecular bone score (TBS) has been proposed as a dual-energy X-ray absorptiometry (DXA) derived measure of underlying quality of trabecular bone; however, TBS is not considered valid for those with body mass index (BMI) >37 kg/m 2 . Our objective was to determine the association between TBS and lumbar spine (trabecular) volumetric BMD (LS-VBMD) and to examine whether the association varied by BMI and body composition among older men below this clinical threshold. We used regression models to study 3479 men age ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study who had TBS from spine DXA scans, LS-VBMD from central quantitative computed tomography, measures of trunk fat and lean mass from DXA, and BMI <37 kg/m 2 . TBS was categorized as normal (n = 925), partially degraded (n = 1747), and degraded (n = 807). TBS was inversely related to BMI, trunk fat mass, and trunk lean mass (all p < 0.001). The relationship between TBS and LS-VBMD was nonlinear with magnitude of effect (slope of regression line using standardized variables) ranging from 0.07 (95% CI, -0.02 to 0.15) among those with degraded TBS up to 0.71 (95% CI, 0.54 to 0.89) among those with normal TBS. The relationship was still nonlinear after adjusting for age, clinical site, and either BMI, trunk lean mass, or trunk fat mass. The magnitude of effect relating TBS and LS-VBMD also decreased with increasing BMI (interaction, p = 0.090) and increasing trunk lean mass (interaction, p = 0.001), but not with increasing trunk fat mass (interaction, p = 0.224). In summary, the strength of the association between TBS and LS-VBMD among older men was variable and dependent on BMI and body composition, particularly trunk lean mass. The clinical utility of TBS among older men may be somewhat limited among men with high BMI or high trunk lean mass. © 2016 American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2016 American Society for Bone and Mineral Research.)

Background: Although older adults are disproportionately affected by painful musculoskeletal conditions and receive more opioid analgesics than persons in other age groups, insufficient evidence is available regarding opioid harms in this age group., Objective: To examine longitudinal relationships between opioid use and falls, clinical fractures, and changes in physical performance. We hypothesized that opioid use would be associated with greater risks of falling and incident clinical fractures and greater declines in physical performance., Design: We analyzed data from the Osteoporotic Fractures in Men Study (MrOS), a large prospective longitudinal cohort study. Participants completed baseline visits from 2000 to 2002 and were followed for 9.1 (SD 4.0) years., Participants: MrOS enrolled 5994 community-dwelling men ≥ 65 years of age. The present study included 2902 participants with back, hip, or knee pain most or all of the time at baseline., Main Measures: The exposure of interest was opioid use, defined at each visit as participant-reported daily or near-daily use of any opioid-containing analgesic. Among patients, 309 (13.4 %) reported opioid use at one or more visits. Participants were queried every 4 months about falls and fractures. Physical performance scores were derived from tests of grip strength, chair stands, gait speed, and dynamic balance., Key Results: In the main analysis, the adjusted risk of falling did not differ significantly between opioid use and non-use groups (RR 1.10, 95% CI 0.99, 1.24). Similarly, adjusted rates of incident clinical fracture did not differ between groups (HR 1.13, 95% CI 0.94, 1.36). Physical performance was worse at baseline for the opioid use group, but annualized change in physical performance scores did not differ between groups (-0.022, 95% CI -0.138, 0.093)., Conclusions: Additional research is needed to determine whether opioid use is a marker of risk or a cause of falls, fractures, and progressive impairment among older adults with persistent pain., Competing Interests: The authors report no potential conflicts of interest. Funding This material is based on work supported by the National Institutes of Health (NIH) National Institute on Aging (NIA #R03 AG042980) and with resources and facilities of the Minneapolis VA Health Care System. The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding from the following institutes: the NIA, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and the NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

To examine the degree of trauma in major osteoporotic fractures (MOF) in men versus women, we used data from 15,698 adults aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study (5994 men) and the Study of Osteoporotic Fractures (SOF) (9704 women). Participants were contacted tri-annually to ascertain incident fractures, which were confirmed by radiographic reports and coded according to degree of self-reported trauma. Trauma was classified as low (fall from ≤ standing height; fall on stairs, steps, or curb; minimal trauma other than fall [coughing, turning over]); moderate (collisions with objects during normal activity without associated fall); or high (fall from > standing height; severe trauma [motor vehicle accident, assault]). MOF included hip, clinical vertebral, wrist, and humerus fractures. Mean fracture follow-up was 9.1 years in SOF and 8.7 years in MrOS. A total of 14.6% of the MOF in men versus 6.3% of the MOF in women were classified as high trauma (p < 0.001); men versus women more often experienced fractures resulting from severe trauma as well as from fall > standing height. High-trauma fractures were more significantly common in men versus women at the hip (p = 0.002) and wrist (p < 0.001) but not at the spine or humerus. Among participants with MOF, the odds ratio of a fracture related to high-trauma fracture among men versus women was 3.12 (95% confidence interval [CI] 1.70-5.71) after adjustment for traditional risk factors. Findings were similar in analyses limited to participants with hip fractures (odds ratio [OR] = 3.34, 95% CI 1.04-10.67) and those with wrist fracture (OR = 5.68, 95% CI 2.03-15.85). Among community-dwelling older adults, MOF are more likely to be related to high trauma in men than in women. These findings are not explained by sex differences in conventional risk factors and may reflect a greater propensity among men to engage in risky behavior. © 2015 American Society for Bone and Mineral Research., (© 2015 American Society for Bone and Mineral Research.)

Context: The United States Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture (MOF) is at least 9.3% using the Fracture Risk Assessment Tool. In postmenopausal women age 50-64 years old, it is uncertain how the USPSTF screening strategy compares with the Osteoporosis Self-Assessment Tool and the Simple Calculated Osteoporosis Risk Estimate (SCORE) in discriminating women who will and will not experience MOF., Objective: This study aimed to assess the sensitivity, specificity, and area under the receiver operating characteristic curve of the three strategies for discrimination of incident MOF over 10 years of follow-up among postmenopausal women age 50-64 years., Setting and Design: This was a prospective study conducted between 1993-2008 at 40 US Centers., Participants: We analyzed data from participants of the Women's Health Initiative Observational Study and Clinical Trials, age 50-64 years, not taking osteoporosis medication (n = 62 492)., Main Outcome Measures: The main outcome was 10-year (observed) incidence of MOF., Results: For identifying women with incident MOF, sensitivity of the strategies ranged from 25.8-39.8%, specificity ranged from 60.7-65.8%, and AUC values ranged from 0.52-0.56. The sensitivity of the USPSTF strategy for identifying incident MOF ranged from 4.7% (3.3-6.0) among women age 50-54 years to 37.3% (35.4-39.1) for women age 60-64 years. Adjusting the thresholds to improve sensitivity resulted in decreased specificity., Conclusions: Our findings do not support use of the USPSTF strategy, Osteoporosis Self-Assessment Tool, or SCORE to identify younger postmenopausal women who are at higher risk of fracture. Our findings suggest that fracture prediction in younger postmenopausal women requires assessment of risk factors not included in currently available strategies.

Aims/hypothesis: Diabetes mellitus is associated with increased fracture risk in women but few studies are available in men. To evaluate the relationship between diabetes and prospective non-vertebral fractures in elderly men, we used data from the Osteoporotic Fractures in Men (MrOS) study., Methods: The MrOS enrolled 5,994 men (aged ≥65 years). Diabetes (ascertained by self-report, the use of medication for diabetes or an elevated fasting glucose level) was reported in 881 individuals, 80 of whom were using insulin. Hip and spine bone mineral density (BMD) was measured using dual x-ray absorptiometry (DXA). After recruitment, the men were followed for incident non-vertebral fractures using a triannual (3 yearly) questionnaire for an average of 9.1 (SD 2.7) years. The Cox proportional hazards model was used to assess the incident risk of fractures., Results: In models adjusted for age, race, clinic site and total hip BMD, the risk of non-vertebral fracture was higher in men with diabetes compared with normoglycaemic men (HR 1.30, 95% CI 1.09, 1.54) and was elevated in men using insulin (HR 2.46, 95% CI 1.69, 3.59). Men with impaired fasting glucose did not have a higher risk of fracture compared with normoglycaemic men (HR 1.04, 95% CI 0.89, 1.21). After multivariable adjustment, the risk of non-vertebral fracture remained higher only among men with diabetes who were using insulin (HR 1.74, 95% CI 1.13, 2.69)., Conclusions/interpretation: Men with diabetes who are using insulin have an increased risk of non-vertebral fracture for a given age and BMD.

Bone loss and structural damage with advancing age lead to skeletal fragility as manifested by low bone mass and deficits in bone geometry, microarchitecture, and material properties. Skeletal fragility, in combination with a greater propensity to fall, results in an increased susceptibility to fractures with aging, known as fragility fractures. Fragility fractures exceed 2 million per year in number and account for nearly 20 billion dollars per year in health care costs in the United States. Advanced age, low bone mass, and previous fracture are strong risk factors for fractures at nearly all skeletal sites, but each type of fracture also has its own set of unique risk factors. Hip fractures are most strongly associated with adverse consequences, but these account for only a minority of fragility fractures. Vertebral fractures comprise the most common manifestation of fragility fracture, but the majority of these fractures are asymptomatic. Most research has focused on the epidemiology of fractures at the hip, vertebrae, and wrist and less is known about other fracture types, which account for 40% of total fragility fractures that are clinically recognized. Future research focused on identification of older adults at high risk of disabling fractures is warranted.

Purpose: To explore the association between consumption of fruits and vegetables and the presence of glaucoma in older African-American women., Design: Cross-sectional study., Methods: Disc photographs and suprathreshold visual fields were obtained from the 662 African-American participants in the Study of Osteoporotic Fractures. Masked, trained readers graded all discs, and 2 glaucoma specialists reviewed photographs and visual fields. The Block Food Frequency Questionnaire assessed food consumption. Relationships between selected fruit/vegetable/nutrient consumption and glaucoma were evaluated using logistic regression models after adjusting for potential confounders., Results: After excluding women missing Food Frequency Questionnaire and disc data, 584 African-American women (88.2% of total African-American cohort) were included. Glaucoma was diagnosed in at least 1 eye in 77 subjects (13%). Women who ate 3 or more servings/day of fruits/fruit juices were 79% (odds ratio [OR] = 0.21; 95% confidence interval [CI]: 0.08-0.60) less likely to have glaucoma than women who ate less than 1 serving/day. Women who consumed more than 2 servings/week of fresh oranges (OR = 0.18; 95% CI: 0.06-0.51) and peaches (OR = 0.30; 95% CI: 0.13-0.67) had a decreased odds of glaucoma compared to those consuming less than 1 serving/week. For vegetables, >1 serving/week compared to ≤1 serving/month of collard greens/kale decreased the odds of glaucoma by 57% (OR = 0.43; 95% CI: 0.21-0.85). There was a protective trend against glaucoma in those consuming more fruit/fruit juices (P = .023), fresh oranges (P = .002), fresh peaches (P = .002), and collard greens/kale (P = .014). Higher consumption of carrots (P = .061) and spinach (P = .094) also showed some associations. Individual nutrient intake from food sources found protective trends with higher intakes of vitamin A (P = .011), vitamin C (P = .018), and α-carotene (P = .021), and close to statistically significant trends with β-carotene (P = .052), folate (P = .056), and lutein/zeaxanthin (P = .077)., Conclusion: Higher intake of certain fruits and vegetables high in vitamins A and C and carotenoids may be associated with a decreased likelihood of glaucoma in older African-American women. Randomized controlled trials are needed to determine whether the intake of specific nutrients changes the risk of glaucoma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine whether older postmenopausal women with a history of bilateral oophorectomy before natural menopause (surgical menopause) have a higher risk of nonvertebral postmenopausal fracture than women with natural menopause., Methods: We used 21 years of prospectively collected incident fracture data from the ongoing Study of Osteoporotic Fractures, a cohort study of community-dwelling women without previous bilateral hip fracture who were 65 years or older at enrollment, to determine the risk of hip, wrist, and any nonvertebral fracture. χ(2) and t tests were used to compare the two groups on important characteristics. Multivariable Cox proportional hazards regression models stratified by baseline oral estrogen use status were used to estimate the risk of fracture., Results: Baseline characteristics differed significantly among the 6,616 women within the Study of Osteoporotic Fractures who underwent either surgical (1,157) or natural (5,459) menopause, including mean age at menopause (44.3 ± 7.4 vs 48.9 ± 4.9 y, P < 0.001) and current use of oral estrogen (30.2% vs 6.5%, P < 0.001). Fracture rates were not significantly increased for surgical versus natural menopause, even among women who had never used oral estrogen (hip fracture: hazard ratio [HR], 0.87; 95% CI, 0.63-1.21; wrist fracture: HR, 1.10; 95% CI, 0.78-1.57; any nonvertebral fracture: HR, 1.11; 95% CI, 0.93-1.32)., Conclusions: These data provide some reassurance that the long-term risk of nonvertebral fracture is not substantially increased for postmenopausal women who experienced premenopausal bilateral oophorectomy, compared with postmenopausal women with intact ovaries, even in the absence of postmenopausal estrogen therapy.

Unlabelled: To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups., Introduction: The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups., Methods: A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c))., Results: Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women., Conclusion: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

Low 25-hydroxyvitamin D [25(OH)D] levels have been linked to hip fracture in white women. To study the association of 25(OH)D with risk of fracture in multiethnic women, we performed a nested case-control study within the prospective Women's Health Initiative (WHI) Observational Study. Incident fractures were identified in 381 black, 192 Hispanic, 113 Asian, and 46 Native American women over an average of 8.6 years. A random sample of 400 white women who fractured was chosen. One control individual was selected per case and matched on age, race/ethnicity, and blood draw date. 25(OH)D, parathyroid hormone, and vitamin D-binding protein (DBP) were measured in fasting baseline serum. Conditional logistic regression models were used to calculate the odds ratio (OR) and 95% CI. In multivariable models, higher 25(OH)D levels compared with levels less than 20 ng/mL were associated with a lower risk of fracture in white women (20 to <30 ng/mL: OR = 0.82, 95% CI 0.58-1.16; ≤30.0 ng/mL: OR = 0.56, 95% CI 0.35-0.90; p trend = 0.02). In contrast, higher 25(OH)D (≥20 ng/mL) compared with levels less than 20 ng/mL were associated with a higher risk of fracture in black women (OR = 1.45, 95% CI 1.06-1.98; p trend = 0.043). Higher 25(OH)D (≥30.0 ng/mL) was associated with higher fracture risk in Asian women after adjusting for DBP (OR = 2.78, 95% CI 0.99-7.80; p trend = 0.04). There was no association between 25(OH)D and fracture in Hispanic or Native American women. Our results suggest divergent associations between 25(OH)D and fracture by race/ethnicity. The optimal level of 25(OH)D for skeletal health may differ in white and black women., (Copyright © 2011 American Society for Bone and Mineral Research.)

Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture risk prediction, the World Health Organization recently developed a country-specific fracture risk index of clinical risk factors (FRAX) that estimates 10-year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women aged 65 or older in the Study of Osteoporotic Fractures using FRAX 10-year probabilities of hip and major osteoporotic fracture (ie, hip, clinical spine, wrist, and humerus) compared with incidence of fractures over 10 years of follow-up. Overall ability of FRAX to predict fracture risk based on initial BMD T-score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver-operating-characteristic (ROC) analyses using area under the curve (AUC). Over 10 years of follow-up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n = 3791, 61%); they developed many hip (n = 176, 48%) and major osteoporotic fractures (n = 569, 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (eg, age + prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX and simpler models predict 10-year risk of incident hip and major osteoporotic fractures in older US women with normal or low bone mass., (Copyright © 2011 American Society for Bone and Mineral Research.)

Use of antidepressant medications has been associated with increased risk of fracture, but prior studies have been limited by incomplete control of confounders or a limited number of fractures. Use of antidepressant medications by 8,217 community-dwelling women aged 69 and older from a population-based prospective cohort study at four US clinical centers was assessed by interview at four examinations over a 10-year period, beginning in 1992-1994. Use was coded as a time-dependent variable. Incident fractures occurring after the initial medication assessment until July 2007 were confirmed by radiographic reports. Potential confounders were included in multivariable models and updated at each follow-up visit. Compared to nonusers of antidepressant medications, women using SSRIs experienced a higher risk of nonspine fracture in age-adjusted models (HR = 1.36, 95% CI 1.11-1.67) and in multivariable models controlling for potential confounders (HR = 1.30, 95% CI 1.04-1.62). SSRI use was not associated with an increased risk of first hip fracture (HR = 1.01, 95% CI 0.71-1.44) but was associated with an increased risk of wrist fracture (HR = 1.54, 95% CI 1.01-2.36). TCA use was associated with an increased risk of nonspine fracture in age-adjusted models, but in multivariable models this risk was attenuated. SSRI use was associated with a higher risk of any nonspine fracture, but not hip fracture, in this cohort of older women. TCA use was associated with a higher risk of nonspine fracture, but this association was in part explained by confounding factors.

Background: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown., Methods: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided., Results: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04)., Conclusion: A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

The purpose of these analyses was to explore whether physical activity score, leg power or grip strength were associated with tibia and radius estimates of bone strength, cortical density, or total bone area. Peripheral quantitative computed tomography (pQCT) was used to compare tibial and radial bone volumetric density (vBMD, mg/cm(3)), total (ToA, mm(2)) and cortical (CoA, mm(2)) bone area, and estimates of bone compressive strength (bone strength index, BSI) and bending strength (polar strength strain index, SSIp) in a subset (n=1171) of men (> or = 65 years) who participated in the multi-site Osteoporotic Fractures in Men (MrOS) study. Physical activity was assessed by questionnaire (PASE), leg power by Nottingham Power Rig, and grip strength by a hand-held Dynamometer. Participants were categorized into quartiles of PASE, grip strength or leg power. The model was adjusted for age, race, clinic, weight, and limb length. In the tibia, BSI (+7%) and SSIp (+4%) were highest in the most active physically quartile compared to the least active (p<0.05). At the 4% site of the tibia, men with the greatest leg power had both greater ToA (+5%, p<0.001) and BSI (+5.3%, p=0.086) compared to men with the least leg power. At the 66% site of the tibia, the men with the highest leg power, compared to the men with the lowest leg power, had greater ToA (+3%, p=0.045) SSIp (+5%, p=0.008). Similar results were found at both the distal and midshaft of the radius. The findings of this study suggest the importance of maintaining levels of physical activity and muscle strength in older men to prevent bone fragility., (Copyright 2010. Published by Elsevier Inc.)

Background: A possible familial component to fracture risk may be mediated through a genetic liability to fall recurrently., Methods: Our analysis sample included 186 female sibling-ships (n=401) of mean age 71.9 yr (SD=5.0). Using variance component models, we estimated residual upper-limit heritabilities in fall-risk mobility phenotypes (e.g., chair-stand time, rapid step-ups, and usual-paced walking speed) and in recurrent falls. We also estimated familial and environmental (unmeasured) correlations between pairs of fall-risk mobility phenotypes. All models were adjusted for age, height, body mass index, and medical and environmental factors., Results: Residual upper-limit heritabilities were all moderate (P<0.05), ranging from 0.27 for usual-paced walking speed to 0.58 for recurrent falls. A strong familial correlation between usual-paced walking speed and rapid step-ups of 0.65 (P<0.01) was identified. Familial correlations between usual-paced walking speed and chair-stand time (-0.02) and between chair-stand time and rapid step-ups (-0.27) were both nonsignificant (P>0.05). Environmental correlations ranged from 0.35 to 0.58 (absolute values), P<0.05 for all., Conclusions: There exists moderate familial resemblance in fall-risk mobility phenotypes and recurrent falls among older female siblings, which we expect is primarily genetic given that adult siblings live separate lives. All fall-risk mobility phenotypes may be coinfluenced at least to a small degree by shared latent familial or environmental factors; however, up to approximately one-half of the covariation between usual-paced walking speed and rapid step-ups may be due to a common set of genes.

In the Fracture Intervention Trial (FIT) Long Term Extension (FLEX) Trial, 10 years of alendronate (ALN) did not significantly reduce the risk of nonvertebral fractures (NVFs) compared with 5 years of ALN. Continuing ALN reduced the risk of clinical but not morphometric vertebral fractures regardless of baseline vertebral fracture status. In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-scores of -2.5 or less. To determine whether the effect of long-term ALN on fracture differs by vertebral fracture status and femoral neck (FN) T-score, we performed a post hoc analysis using FLEX data, a randomized, double-blind, placebo-controlled trial among 1099 postmenopausal women originally randomized to ALN in the FIT with mean ALN use of 5 years. In the FLEX Trial, women were randomized to placebo (40%) or ALN 5 mg/day (30%) or ALN 10 mg/day (30%) for an additional 5 years. Among women without vertebral fracture at FLEX baseline (n = 720), continuation of ALN reduced NVF in women with FLEX baseline FN T-scores of -2.5 or less [relative risk (RR) = 0.50, 95% confidence interval (CI) 0.26-0.96] but not with T-scores of greater than -2.5 and -2 or less (RR 0.79, 95% CI 0.37-1.66) or with T-scores of greater than -2 (RR 1.41, 95% CI 0.75-2.66; p for interaction = .019). Continuing ALN for 10 years instead of stopping after 5 years reduces NVF risk in women without prevalent vertebral fracture whose FN T-scores, achieved after 5 years of ALN, are -2.5 or less but does not reduce risk of NVF in women whose T-scores are greater than -2., ((c) 2010 American Society for Bone and Mineral Research.)

The association between vitamin D levels and incident fractures in older men is uncertain. To test the hypothesis that low serum 25-hydroxyvitamin D [(25(OH)D] levels are associated with an increased risk of fracture, we performed a case-cohort study of 436 men with incident nonspine fractures, including 81 hip fractures, and a random subcohort of 1608 men; average follow-up time 5.3 years. Serum vitamin D(2) and vitamin D(3) were measured on baseline sera using mass spectrometry and summed for total vitamin D. Modified Cox proportional hazards models were used to estimate the hazard ratio (HR) of fracture with 95% confidence intervals (CIs). Multivariable models included age, clinic, season, race, height, weight, and physical activity. The mean (SD) total 25(OH)D was 24.6 (7.8) ng/mL in nonspine fracture subjects, 21.5 (7.9) ng/mL in hip fracture subjects, and 25.2 (7.8) ng/mL in controls (nonspine fracture subjects versus nonpatients, p = .14; hip fracture subjects versus controls, p < .0001). 25(OH)D levels were unrelated to nonspine fractures. One SD decrease in total 25(OH)D was associated with an increased risk of hip fracture (multivariate HR = 1.60; 95% CI 1.18-2.17). Compared with men in the top quartile of total 25(OH)D (> or =28), the HR of hip fracture was 2.36 (95% CI 1.08-5.15) for men in the lowest quartile (<20) (p = .009 for trend). Adjusting for hip bone mineral density attenuated the association by more than 50% (p = .065 for trend). Low serum 25(OH)D concentrations are associated with a higher risk of hip fracture in older men. Measurement of 25(OH)D may be useful in identifying men at high risk of hip fracture., (Copyright 2010 American Society for Bone and Mineral Research.)

The effects of type 2 diabetes mellitus (T2DM) on bone volumetric density, bone geometry, and estimates of bone strength are not well established. We used peripheral quantitative computed tomography (pQCT) to compare tibial and radial bone volumetric density (vBMD, mg/cm(3)), total (ToA, mm(2)) and cortical (CoA, mm(2)) bone area and estimates of bone compressive and bending strength in a subset (n = 1171) of men (> or =65 years of age) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study. Analysis of covariance-adjusted bone data for clinic site, age, and limb length (model 1) and further adjusted for body weight (model 2) were used to compare data between participants with (n = 190) and without (n = 981) T2DM. At both the distal tibia and radius, patients with T2DM had greater bone vBMD (+2% to +4%, model 1, p < .05) and a smaller bone area (ToA -1% to -4%, model 2, p < .05). The higher vBMD compensated for lower bone area, resulting in no differences in estimated compressive bone strength at the distal trabecular bone regions. At the mostly cortical bone midshaft sites of the radius and tibia, men with T2DM had lower ToA (-1% to -3%, p < .05), resulting in lower bone bending strength at both sites after adjusting for body weight (-2% to -5%, p < .05) despite the lack of difference in cortical vBMD at these sites. These data demonstrate that older men with T2DM have bone strength that is low relative to body weight at the cortical-rich midshaft of the radius despite no difference in cortical vBMD., (Copyright 2010 American Society for Bone and Mineral Research.)

Background: A Web-based risk assessment tool (FRAX) using clinical risk factors with and without femoral neck bone mineral density (BMD) has been incorporated into clinical guidelines regarding treatment to prevent fractures. However, it is uncertain whether prediction with FRAX models is superior to that based on parsimonious models., Methods: We conducted a prospective cohort study in 6252 women 65 years or older to compare the value of FRAX models that include BMD with that of parsimonious models based on age and BMD alone for prediction of fractures. We also compared FRAX models without BMD with simple models based on age and fracture history alone. Fractures (hip, major osteoporotic [hip, clinical vertebral, wrist, or humerus], and any clinical fracture) were ascertained during 10 years of follow-up. Area under the curve (AUC) statistics from receiver operating characteristic curve analysis were compared between FRAX models and simple models., Results: The AUC comparisons showed no differences between FRAX models with BMD and simple models with age and BMD alone in discriminating hip (AUC, 0.75 for the FRAX model and 0.76 for the simple model; P = .26), major osteoporotic (AUC, 0.68 for the FRAX model and 0.69 for the simple model; P = .51), and clinical fracture (AUC, 0.64 for the FRAX model and 0.63 for the simple model; P = .16). Similarly, performance of parsimonious models containing age and fracture history alone was nearly identical to that of FRAX models without BMD. The proportion of women in each quartile of predicted risk who actually experienced a fracture outcome did not differ between FRAX and simple models (P > or = .16)., Conclusion: Simple models based on age and BMD alone or age and fracture history alone predicted 10-year risk of hip, major osteoporotic, and clinical fracture as well as more complex FRAX models.

We used data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and an elevated risk of fracture. MrOS enrolled 5995 subjects >65 yr; hip BMD was measured at baseline and after a mean follow-up of 4.6 yr. Nonspine fractures were documented during a mean follow-up of 5.0 yr. Using fasting serum collected at baseline and stored at -190 degrees C, bone turnover measurements (type I collagen N-propeptide [PINP]; beta C-terminal cross-linked telopeptide of type I collagen [betaCTX]; and TRACP5b) were obtained on 384 men with nonspine fracture (including 72 hip fractures) and 947 men selected at random. Among randomly selected men, total hip bone loss was 0.5%/yr among those in the highest quartile of PINP (>44.3 ng/ml) and 0.3%/yr among those in the lower three quartiles (p = 0.01). Fracture risk was elevated among men in the highest quartile of PINP (hip fracture relative hazard = 2.13; 95% CI: 1.23, 3.68; nonspine relative hazard = 1.57, 95% CI: 1.21, 2.05) or betaCTX (hip fracture relative hazard = 1.76, 95 CI: 1.04, 2.98; nonspine relative hazard = 1.29, 95% CI: 0.99, 1.69) but not TRACP5b. Further adjustment for baseline hip BMD eliminated all associations between bone turnover and fracture. We conclude that higher levels of bone turnover are associated with greater hip bone loss in older men, but increased turnover is not independently associated with the risk of hip or nonspine fracture.

Objectives: To evaluate the associations between visual field loss and nonspine fractures., Design: Prospective cohort study., Setting: Community., Participants: Four thousand seven hundred seventy-three community-dwelling white and African-American women aged 65 and older with no previous history of hip fracture at the time of recruitment., Measurements: Radiographically confirmed hip and nonspine, nonhip fractures identified from September 1997 to April 2008. Visual field loss was measured using a Humphrey Field Analyzer suprathreshold screening test of the peripheral and central vision of each eye and was classified into an ordinal rating of no, mild, moderate, or severe binocular visual field (BVF) loss., Results: For hip and nonspine, nonhip fractures and in unadjusted and covariate-adjusted analyses, the highest incidence of fractures was seen in women with the most-severe BVF loss. In covariate-adjusted analysis, women with mild, moderate, and severe BVF loss had a 49% (hazard ratio (HR)=1.49, 95% confidence interval (CI)=1.18-1.88), 25% (HR=1.25, 95% CI=0.87-1.80), and 66% (HR=1.66, 95% CI=1.19-2.32) greater risk, respectively, for hip fractures than women without BVF loss. Similarly, women with mild visual field loss had a 12% (HR=0.88, 95% CI=0.75-1.04) lower risk for nonspine, nonhip fractures, whereas women with moderate and severe visual field loss had a 18% (HR=1.18, 95% CI=0.92-1.52) and 59% (HR=1.59, 95% CI=1.24-2.03) greater risk of nonspine, nonhip fractures than women without BVF loss., Conclusion: BVF loss is independently associated with hip and nonspine, nonhip fractures in older female volunteers.

Objective: To determine whether information on number of falls on a falls history screen predicts risk of non-vertebral and hip fracture., Methods: A cohort of 5995 community-dwelling men aged 65 years and older (mean 73.7) was followed over 7.2 years for incident non-vertebral fractures. Cox proportional hazard models were used to calculate hazard ratios (HRs) (95% CI) for incident fracture comparing a history of one and two or more falls with no falls. Models were adjusted for age, clinic, body mass index, height, femoral neck bone mineral density and whether the participant had a non-trauma fracture after the age of 50. p

Context: As men age, the prevalence of frailty increases whereas levels of androgens decline. Little is known about the relation between these factors., Objective: The aim of this study was to assess cross-sectional and longitudinal associations of estradiol, bioavailable estradiol, testosterone, bioavailable testosterone (bioT), and SHBG with frailty status., Design and Setting: The Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers., Participants: A total of 1469 community-dwelling men at least 65 yr old with baseline data participated; 1245 men had frailty status reassessed 4.1 yr later., Main Outcome Measure: Proportional odds models estimated the likelihood of greater frailty status. Frail men had at least three of the following: weakness, slowness, low activity, exhaustion, and shrinking/sarcopenia; intermediate men had one or two criteria; and robust men had none. At follow-up, death was included as an additional ordinal outcome. Sex hormones were assayed by spectrometry/chromatographic methods., Results: In cross-sectional analyses, men in the lowest quartile of bioT had 1.39-fold (95% confidence interval, 1.02, 1.91) increased odds of greater frailty status compared to men in the highest quartile after adjustment for covariates including age, body size, health status, and medical conditions. In age-adjusted longitudinal analyses, men in the lowest quartile of bioT had 1.51-fold (95% confidence interval, 1.10, 2.07) increased odds of greater frailty status 4.1 yr later. This association was largely attenuated by adjustment for covariates. No other hormones were associated in a cross-sectional or longitudinal manner with frailty status after adjustment., Conclusions: Low levels of bioT were independently associated with worse baseline frailty status. Frailty status should be considered as an outcome in trials of testosterone supplementation.

Context: The relationship between sex steroids and fracture is poorly understood., Objective: The objective of the study was to examine associations between nonvertebral fracture risk and bioavailable estradiol (bioE2), bioavailable testosterone (bioT), and SHBG., Design: This was a case-cohort study., Setting: The Osteoporotic Fractures in Men Study (MrOS) was conducted in a prospective U.S. cohort in 5995 community-dwelling men 65 yr old or older., Participants: Participants included a subcohort of 1436 randomly chosen white men plus all 446 minorities and all those with incident hip and other nonvertebral fractures., Main Outcome Measures: Baseline testosterone and estradiol were measured by mass spectrometry (MS) and SHBG by RIA., Results: Men with the lowest bioE2 (<11.4 pg/ml) or highest SHBG (>59.1 nm) had greater risk of all nonvertebral fractures [adjusted hazard ratio (HR) [95% confidence interval]: 1.5 (1.2-1.9) and 1.4 (1.1-21.8), respectively]. Men with the lowest bioT (<163.5 ng/dl) had no increased fracture risk after adjustment for bioE2 [adjusted HR 1.16 (0.90-1.49)]. A significant interaction between SHBG and bioT (P = 0.03) resulted in men with low bioT and high SHBG having higher fracture risk [HR 2.1 (1.4-3.2)]. Men with low bioE2, low bioT, and high SHBG were at highest risk [HR 3.4 (2.2-5.3)]., Conclusions: Older men with low bioE2 or high SHBG levels are at increased risk of nonvertebral fracture. When SHBG levels are high, men with low bioT levels have higher risk. The strongest association occurred when all measures were considered in combination.

It is unknown whether caregivers who perform more caregiving tasks have a greater decline in health from higher stress or less decline because of better health, staying active, or psychological factors. This 1999-2004 US study examined caregiving intensity and 2-year change in performance-based functioning among 901 elderly women from the Caregiver-Study of Osteoporotic Fractures sample. Caregivers were categorized as high (n = 167) or low (n = 166) intensity based on how many activities of daily living they performed for the care recipient. Caregiving intensity status and physical performance score (sum of quartiles of walking pace, grip strength, and chair-stand speed; range, 0-9) were assessed at baseline and at 2 annual follow-up interviews. At baseline, high-intensity caregivers reported the most stress but had the best physical functioning; noncaregivers (n = 568) had the poorest physical functioning (adjusted scores = 5.09 vs. 4.54, P = 0.03). Low-intensity caregivers declined more than noncaregivers over 2 years, but high-intensity caregivers did not (adjusted difference = -0.33, P = 0.07 vs. 0.03, P = 0.89). Among respondents with the same caregiving status at baseline and 1-year interviews, high-intensity caregivers maintained the highest physical performance throughout follow-up. Higher levels of physical performance persisted over 2 years among high-intensity caregivers, which did not support the traditional stress hypothesis.

Successful aging is multidimensional, and many phenotypes have been proposed. We examined a biomarker of aging based on repeated measures of BMD for up to 15 yr and hypothesized that maintenance of BMD will be associated with low fracture risk and disability and improved survival. We studied 9704 women recruited at four U.S. clinical centers and enrolled in the Study of Osteoporotic Fractures, a longitudinal cohort study. Of these, 8224 women had at least one hip BMD measurement. Hip BMD was measured a maximum of five times over 15 yr. Random effects regression was used to determine a BMD slope for each subject. Three groups were formed-"maintained" BMD: slope >or=0, n = 724 (9%); "expected" BMD loss: slope <0 to <1 SD below mean, n = 6478 (79%); and "accelerated" BMD loss: slope >or=1 SD below mean, n = 1022 (12%). Cox proportional hazards models were used to compare the relative hazard (RH; 95% CI) of fracture, incident mobility disability, and mortality in the maintained and accelerated groups compared with the expected. A 1 SD decrease in the BMD slope was associated with an increased risk of all outcomes. In multivariate models, the RH of nonspine fracture was 0.81 (0.71-0.93) and of hip fracture was 0.36 (0.25-0.53) for women in the maintained compared with the expected group. The incidence of mobility disability was lower in the maintained versus expected group (RH = 0.70; 95% CI = 0.59-0.83), but this was largely explained by other factors. Women who experienced accelerated bone loss were more likely to develop disability (RH = 1.56; 95% CI: 1.33-1.84). Mortality risks were lower in the maintained compared with the expected group (RH = 0.49; 95% CI: 0.42-0.58). In conclusion, a subset of older women maintained their BMD up to 15 yr, suggesting that bone loss is not an inevitable consequence of aging. These women experienced a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging.

Introduction: Although wrist actigraphy-derived sleep indices correlate with adverse health outcomes, it is unclear whether these indices identify specific sleep disorders., Methods: Overnight polysomnography and > or = three 24-h periods of wrist actigraphy were performed in the Study of Osteoporotic Fractures (SOF) (n = 455, age: 73-96 y). Actigraphy identified those with reduced sleep efficiency (SE, < 70%) and decreased sleep duration (< or = 5 h). Sleep disorders considered were: (1) sleep-disordered breathing (SDB): respiratory disturbance index > or =15 and (2) periodic limb movement disorder (PLMD): periodic limb movement-arousal index > or =5. Multivariable logistic regression analyses modeled each sleep disorder as the dependent variable with wrist actigraphy measures, age, race, medication use, depression, body mass index, activity, mental status, and comorbidity as independent variables., Results: In multivariable models, poor SE derived from wrist actigraphy was associated with 2.4-fold higher odds of SDB (OR = 2.43, 95% CI: 1.43-4.14) and PLMD (OR = 2.36, 95% CI: 1.34-4.15). Reduced sleep duration was associated with 3.2-fold higher odds of SDB (OR = 3.18, 95% CI: 1.51-6.68), and a 3.8-fold higher odds of PLMD (OR = 3.77, 95% CI: 1.78-7.95)., Conclusions: In elderly women, wrist actigraphy-ascertained reduced SE and sleep duration are associated with objective measures of SDB and PLMD. Thus, although not able to discriminate between the different sleep disorders, variations in wrist actigraphy measures collected in epidemiologic studies may identify individuals at higher risk of SDB or PLMD.

Recent studies have suggested an increased fracture risk with acid-suppressive medication use. We studied two cohorts of men and women over age 65 who were enrolled in the Osteoporotic Fractures in Men Study (MrOS) and the Study of Osteoporotic Fractures (SOF), respectively. We used dual-energy X-ray absorptiometry and assessed baseline use of proton pump inhibitors (PPIs) and/or H2 receptor antagonists (H2RAs) in 5,755 men and 5,339 women. Medication use and bone mineral density (BMD) were assessed, and hip and other nonspine fractures were documented. On multivariate analysis, men using either PPIs or H2RAs had lower cross-sectional bone mass. No significant BMD differences were observed among women. However, there was an increased risk of nonspine fracture among women using PPIs (relative hazard [RH] = 1.34, 95% confidence interval [CI] 1.10-1.64). PPI use was also associated with an increased risk of nonspine fracture in men but only among those who were not taking calcium supplements (RH = 1.49, 95% CI 1.04-2.14). H2RA use was not associated with nonspine fractures, and neither H2RA use nor PPI use was associated with incident hip fractures in men or women. The use of PPIs in older women, and perhaps older men with low calcium intake, may be associated with a modestly increased risk of nonspine fracture.

Candidate osteoporosis gene variants were examined for associations with fracture risk and bone mineral density (BMD). A total of 9,704 white women were recruited at four U.S. clinical centers and enrolled into the Study of Osteoporotic Fractures, a longitudinal cohort study. Genotyping of 31 polymorphisms from 18 candidate osteoporosis genes was performed in 6,752 women. Incident radiographic fractures were identified at the third and eighth examinations compared with the baseline examination. BMD was measured at the total hip by dual-energy X-ray absorptiometry. Analyses were adjusted for age, clinic site, and self-reported ethnicity. During a mean follow-up of 14.5 years, a total of 849 hip, 658 vertebral, and 2,496 nonhip/nonvertebral fractures occurred in 6,752 women. Women carrying the ALOX15&#95;G48924T T/T genotype had a higher rate of hip fracture (hazard ratio [HR] = 1.33;95% confidence interval [95% CI] = 1.00-1.77) compared with the G/G genotype. Compared with those carrying the PRL&#95;T228C T/T genotype, women with either the C/C (HR = 0.80; 95% CI = 0.67-0.95) or C/T (HR = 0.81; 95% CI = 0.68-0.97) genotype had a lower rate of nonvertebral/nonhip fractures. Women carrying the BMP2&#95;A125611G G/G genotype had a higher rate of vertebral fracture (odds ratio [OR] = 1.51; 95% CI = 1.03-2.23) compared with the A/A genotype. Women with the ESR1&#95;C1335G G/G genotype had a higher rate of vertebral fracture (OR = 1.64; 95% CI = 1.07-2.50) compared with the C/C genotype. Compared with those with the MMP2&#95;C595T C/C genotype, women with the C/T (OR = 0.79; 95% CI = 0.65-0.96) or T/T (OR = 0.44; 95% CI = 0.27-0.72) genotype had a lower rate of vertebral fracture. In conclusion, polymorphisms in several candidate genes were associated with hip, vertebral, and nonhip/nonvertebral fractures but not with total hip BMD in this large population based cohort study.

Unlabelled: Among community-dwelling older men, compared to those without Parkinson's disease (PD), over approximately 5 years, those with baseline PD had a significantly greater rate of annualized total hip bone loss (-1.1% vs. 0.4%), proportion of incident non-spine fractures (14.9% vs. 7.2%) and mortality (34.8% vs. 9.5%)., Introduction: The objective of this study was to examine the association of Parkinson's disease (PD) with bone loss and fractures in older men., Methods: This prospective cohort study analyzed data from 5,937 community dwelling men aged >or=65 years at six clinical centers of the Osteoporotic Fractures in Men (MrOS) Study. At baseline and visit two (mean interval 4.6 +/-0.4 SD years), community-diagnosed PD was ascertained by self-report and hip bone mineral density (BMD) was measured using dual energy x-ray absorptiometry (DXA). Incident fractures were self-reported. Fractures and deaths were centrally adjudicated., Results: At baseline, 46 (0.8%) men had PD. Age-adjusted mean annualized total hip bone loss was greater in men with vs. those without PD (-1.08% vs. -0.36%, p < 0.001). 15.2% of men with PD and 7.2% of men without PD experienced an incident non-spine fracture (age-adjusted HR 2.4, 95%CI 1.1-5.0). 34.8% of men with PD and 9.5% of men without PD died during follow-up (age-adjusted HR 3.5, 95%CI 2.2-5.5). Associations of PD with bone loss, fractures and mortality were modestly altered by additional individual adjustment for possible confounders., Conclusions: In community-dwelling older men, PD was associated with increased bone loss, fractures and mortality. In addition to implementing fall prevention measures, clinicians should consider osteoporosis screening in older men with PD.

Unlabelled: Among community-dwelling older women, compared to those without Parkinson's disease (PD), women with PD have 7.3% lower BMD and an increased risk for hip fracture (HR = 2.6)., Introduction: Studies reporting an association of Parkinson's disease (PD) with low bone mineral density (BMD) and increased fracture risk often have been prone to selection bias, and have not accounted for potentially important explanatory variables, including recent weight loss. Further, little is known about the association between PD and non-hip fractures. Consequently, we investigated the independent association of PD with hip BMD and long-term fracture risk., Methods: Associations of self-reported PD with hip BMD and incident hip and non-spine, non-hip fracture were analyzed using linear regression and Cox proportional hazards, respectively. This prospective cohort study analyzed 8,105 older women with known PD status (n = 73 with PD) at four US clinical centers of the Study of Osteoporotic Fractures., Results: Compared to women without PD, age-adjusted mean total hip BMD was 7.3% lower in women with PD. Women with PD had a 2.6-fold higher age-adjusted risk for incident hip fracture. Parkinson's disease was not significantly associated with non-spine, non-hip fractures., Conclusions: In age-adjusted models, women with PD had lower hip BMD and increased hip fracture risk, associations that were no longer significant after further weight and multivariate adjustment. Older women with PD should be considered for evaluation and treatment to reduce their fracture risk.

Purpose: To explore the association between the consumption of fruits and vegetables and the presence of glaucoma., Design: Cross-sectional cohort study., Methods: In a sample of 1,155 women located in multiple centers in the United States, glaucoma specialists diagnosed glaucoma in at least one eye by assessing optic nerve head photographs and 76-point suprathreshold screening visual fields. Consumption of fruits and vegetables was assessed using the Block Food Frequency Questionnaire. The relationship between selected fruit and vegetable consumption and glaucoma was investigated using adjusted logistic regression models., Results: Among 1,155 women, 95 (8.2%) were diagnosed with glaucoma. In adjusted analysis, the odds of glaucoma risk were decreased by 69% (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.11 to 0.91) in women who consumed at least one serving per month of green collards and kale compared with those who consumed fewer than one serving per month, by 64% (OR, 0.36; 95% CI, 0.17 to 0.77) in women who consumed more than two servings per week of carrots compared with those who consumed fewer than one serving per week, and by 47% (OR, 0.53; 95% CI, 0.29 to 0.97) in women who consumed at least one serving per week of canned or dried peaches compared with those who consumed fewer than one serving per month., Conclusions: A higher intake of certain fruits and vegetables may be associated with a decreased risk of glaucoma. More studies are needed to investigate this relationship.

Background: Frailty, as defined by the index derived from the Cardiovascular Health Study (CHS index), predicts risk of adverse outcomes in older adults. Use of this index, however, is impractical in clinical practice., Methods: We conducted a prospective cohort study in 6701 women 69 years or older to compare the predictive validity of a simple frailty index with the components of weight loss, inability to rise from a chair 5 times without using arms, and reduced energy level (Study of Osteoporotic Fractures [SOF index]) with that of the CHS index with the components of unintentional weight loss, poor grip strength, reduced energy level, slow walking speed, and low level of physical activity. Women were classified as robust, of intermediate status, or frail using each index. Falls were reported every 4 months for 1 year. Disability (> or =1 new impairment in performing instrumental activities of daily living) was ascertained at 4(1/2) years, and fractures and deaths were ascertained during 9 years of follow-up. Area under the curve (AUC) statistics from receiver operating characteristic curve analysis and -2 log likelihood statistics were compared for models containing the CHS index vs the SOF index., Results: Increasing evidence of frailty as defined by either the CHS index or the SOF index was similarly associated with an increased risk of adverse outcomes. Frail women had a higher age-adjusted risk of recurrent falls (odds ratio, 2.4), disability (odds ratio, 2.2-2.8), nonspine fracture (hazard ratio, 1.4-1.5), hip fracture (hazard ratio, 1.7-1.8), and death (hazard ratio, 2.4-2.7) (P < .001 for all models). The AUC comparisons revealed no differences between models with the CHS index vs the SOF index in discriminating falls (AUC = 0.61 for both models; P = .66), disability (AUC = 0.64; P = .23), nonspine fracture (AUC = 0.55; P = .80), hip fracture (AUC = 0.63; P = .64), or death (AUC = 0.72; P = .10). Results were similar when -2 log likelihood statistics were compared., Conclusion: The simple SOF index predicts risk of falls, disability, fracture, and death as well as the more complex CHS index and may provide a useful definition of frailty to identify older women at risk of adverse health outcomes in clinical practice.

Unlabelled: Using data from a randomized placebo-controlled trial of 10,101 postmenopausal women not selected on the basis of osteoporosis, we examined whether the effect of raloxifene treatment on fractures was consistent across categories of fracture risk. Treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of the presence or absence of risk factors for fracture., Introduction: In The Raloxifene Use for The Heart (RUTH) trial, women assigned to raloxifene had a lower risk of clinical vertebral fractures but not nonvertebral fractures. However, it is uncertain whether the effect of raloxifene on fractures in this population not selected for low BMD differs according to risk factors for fractures., Materials and Methods: We randomly assigned 10,101 postmenopausal women >or=55 yr of age with documented coronary heart disease or at high risk for coronary events to 60 mg raloxifene daily or placebo and followed them for a median of 5.6 yr. Fractures (nonvertebral and clinical vertebral) were prespecified secondary endpoints that were reported at semiannual visits. Fractures were adjudicated and confirmed using X-ray reports or medical records., Results: There was no difference between raloxifene and placebo groups in risk of nonvertebral fractures (428 versus 438 events; hazard ratio [HR], 0.96; 95% CI, 0.84-1.10), including hip/femur (89 versus 103 events; HR, 0.85; 95% CI, 0.64-1.13) and wrist (107 versus 111 events; HR, 0.95; 95% CI, 0.73-1.24) fractures. Women treated with raloxifene had a lower risk of clinical vertebral fractures (64 versus 97 events; HR, 0.65; 95% CI, 0.47-0.89). The effect of treatment with raloxifene on risk of nonvertebral and clinical vertebral fractures was consistent across fracture risk categories defined at baseline by age, smoking status, physical activity level, prior history of fracture, family history of hip fracture, diabetes mellitus, previous use of hormone therapy, thyroid hormone use, statin use, weight loss, body mass index, or fracture specific summary risk score., Conclusions: In older women with or at high risk of coronary heart disease not selected on the basis of osteoporosis or increased fracture risk, treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of presence or absence of risk factors for fracture.

Context: Osteoporotic fractures are common among elderly men., Objective: To evaluate among older men the cost-effectiveness of bone densitometry followed by 5 years of oral bisphosphonate therapy to prevent fractures for those found to have osteoporosis (femoral neck T score < or =-2.5), compared with no intervention., Design, Setting, and Population: Computer Markov microsimulation model using a societal perspective and a lifetime horizon. Simulations were performed for hypothetical cohorts of white men aged 65, 70, 75, 80, or 85 years, with or without prior clinical fracture. Data sources for model parameters included the Rochester Epidemiology Project for fracture costs and population-based age-specific fracture rates; the Osteoporotic Fractures in Men (MrOS) study and published meta-analyses for the associations among prior fractures, bone density, and incident fractures; and published studies of fracture disutility., Main Outcome Measures: Costs per quality-adjusted life-year (QALY) gained for the densitometry and follow-up treatment strategy compared with no intervention, calculated from lifetime costs and accumulated QALYs for each strategy., Results: Lifetime costs per QALY gained for the densitometry and follow-up treatment strategy were less than $50,000 for men aged 65 years or older with a prior clinical fracture and for men aged 80 years or older without a prior fracture. These results were most sensitive to oral bisphosphonate cost and fracture reduction efficacy, the strength of association between bone mineral density and fractures, fracture rates and disutility, and medication adherence., Conclusions: Bone densitometry followed by bisphosphonate therapy for those with osteoporosis may be cost-effective for men aged 65 years or older with a self-reported prior clinical fracture and for men aged 80 to 85 years with no prior fracture. This strategy may also be cost-effective for men as young as 70 years without a prior clinical fracture if oral bisphosphonate costs are less than $500 per year or if the societal willingness to pay per QALY gained is $100,000.

Background: Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of antidepressants that block the serotonin transporter. Osteoblasts and osteocytes express functional serotonin transporters; serotonin transporter gene disruption in mice results in osteopenia; and SSRI use has been associated with increased risk of hip fracture., Methods: To determine whether SSRI use is associated with lower bone mineral density (BMD) in older men and to compare the results for SSRIs with those of other antidepressants, we performed a cross-sectional analysis of data from 5995 men 65 years and older participating in the prospective cohort Osteoporotic Fractures in Men Study. Main outcome measures included medication use; BMD at the femoral neck, greater trochanter, and lumbar spine measured by dual-energy x-ray absorptiometry; and potential covariates., Results: In adjusted analyses, mean BMD among SSRI users (n=160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine compared with BMD in men reporting no antidepressant use (n=5708 [P=.002 for total hip; P<.001 for lumbar spine]). There was no significant difference among users of trazodone hydrochloride (n=52) or tricyclic antidepressants (n=99) compared with nonusers. Adjusting for variables that could be associated with BMD and/or SSRI use did not significantly alter these results. The observed difference in BMD for SSRIs is similar to that seen with glucocorticoids., Conclusions: In this population of men, BMD was lower among those reporting current SSRI use, but not among users of other antidepressants. Further research is needed to confirm this finding in light of widespread SSRI use and potentially important clinical implications.

Unlabelled: Quantitative ultrasound (QUS) is associated with fracture risk in women, but there are few data in men. We studied 5,607 older men and found that QUS predicts hip and any non-spine fracture risk nearly as well as BMD. Combined measurements of QUS and BMD are not superior to either measurement alone., Introduction: Quantitative ultrasound (QUS) predicts fracture risk among older women, but there are few prospective studies among older men. We studied the ability of QUS and BMD measurements to predict hip and other non-spine fractures in a population-based study of older men., Methods: Calcaneal QUS and hip BMD were measured in 5,607 men aged > or =65 years recruited from six US centers. At baseline duplicate QUS measurements with repositioning were obtained, and subsequent hip and other non-spine fractures were documented by review of x-rays or x-ray reports. The relationships between QUS and fractures were examined with proportional hazard models adjusted for age and clinic. We used receiver operating characteristic curves and predicted fracture risk models to determine the utility of QUS alone, BMD alone or the combination of QUS+BMD., Results: During a mean follow-up of 4.2 years with 99% complete follow-up, 239 men suffered a non-spine fracture, including 49 hip fractures. Each standard deviation reduction in broadband ultrasonic attenuation (BUA) was associated with an increased risk of hip (relative hazard=2.0, CI: 1.5, 2.8) and any non-spine fracture (relative hazard=1.6, CI: 1.4, 1.8). The area under the receiver operating characteristic curve and the predicted probability of fracture were similar for BUA alone, BMD alone and the combination of BUA+BMD, indicating that once BUA or BMD is known, the other measurement does not add useful information. Other QUS parameters gave similar results., Conclusions: QUS measurements predict the risk of hip and any non-spine fracture in older men, and do so nearly as well as hip BMD measurements. Combined measurements of QUS and BMD are not superior to either measurement alone.

Unlabelled: We evaluated the association between the VDR translation start site polymorphism and osteoporotic phenotypes among 6698 older white women. Women with the C/C genotype had lower wrist BMD and an increased risk of wrist and all non-spine/low-trauma fractures. The high frequency of this variant confers a population attributable risk that is similar to several established risk factors for fracture., Introduction: The vitamin D receptor (VDR) is a nuclear receptor that regulates bone formation, bone resorption, and calcium homeostasis. A common C to T polymorphism in exon 2 of the VDR gene introduces a new translation start site and a protein that differs in length by three amino acids (T = 427aa, C = 424aa; rs10735810)., Materials and Methods: We conducted genetic association analyses of this polymorphism, BMD, and fracture outcomes in a prospective cohort of 6698 white American women >or=65 years of age. Incident fractures were confirmed by physician adjudication of radiology reports. There were 2532 incident nontraumatic/nonvertebral fractures during 13.6 yr of follow-up including 509 wrist and 703 hip fractures., Results: Women with the C/C genotype had somewhat lower distal radius BMD compared with those with the T/T genotype (CC=0.358 g/cm(2), CT=0.361 g/cm(2), TT=0.369 g/cm(2), p=0.003). The C/C genotype was also associated with increased risk of non-spine, low traumatic fractures (HR: 1.18; 95% CI: 1.04, 1.33) and wrist fractures (HR: 1.33; 95% CI: 1.01, 1.75) compared with the T/T genotype in age-adjusted models. Further adjustments for distal radius BMD only slightly attenuated these associations. The VDR polymorphism was not associated with hip fracture. The population attributable risk (PAR) of the C/C genotype for incident fractures was 6.1%. The PAR for established risk factors for fracture were: low femoral neck BMD (PAR=16.3%), maternal history of fracture (PAR=5.1%), low body weight (PAR=5.3%), corticosteroid use (PAR=1.3%), and smoking (PAR=1.6%). Similar PAR results were observed for wrist fractures., Conclusions: The common and potentially functional VDR translation start site polymorphism confers a modestly increased relative risk of fracture among older white women. However, the high frequency of this variant confers a population attributable risk that is similar to or greater than several established risk factors for fracture.