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.

OBJECTIVE: To test the hypothesis that lower 25-hydroxyvitamin D [25(OH)D] levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline. METHODS: We measured 25(OH)D and assessed cognitive function using the Modified Mini-Mental State Examination (3MS) and Trail Making Test Part B (Trails B) in a cohort of 1,604 men enrolled in the Osteoporotic Fractures in Men Study and followed them for an average of 4.6 years for changes in cognitive function. RESULTS: In a model adjusted for age, season, and site, men with lower 25(OH)D levels seemed to have a higher odds of cognitive impairment, but the test for trend did not reach significance (impairment by 3MS: odds ratio [OR] 1.84, 95% confidence interval [CI] 0.81-4.19 for quartile [Q] 1; 1.41, 0.61-3.28 for Q2; and 1.18, 0.50-2.81 for Q3, compared with Q4 [referent group; p trend = 0.12]; and impairment by Trails B: OR 1.66, 95% CI 0.98-2.82 for Q1; 0.96, 0.54-1.69 for Q2; and 1.30, 0.76-2.22 for Q3, compared with Q4 [p trend = 0.12]). Adjustment for age and education further attenuated the relationships. There was a trend for an independent association between lower 25(OH)D levels and odds of cognitive decline by 3MS performance (multivariable OR 1.41, 95% CI 0.89-2.23 for Q1; 1.28, 0.84-1.95 for Q2; and 1.06, 0.70-1.62 for Q3, compared with Q4 [p = 0.10]), but no association with cognitive decline by Trails B. CONCLUSION: We found little evidence of independent associations between lower 25-hydroxyvitamin D level and baseline global and executive cognitive function or incident cognitive decline.

Context: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown. Objective: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women. Design: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD. Results: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD. Conclusions: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.

BACKGROUND: Estrogen plus progestin therapy increases breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain. METHODS: We analyzed data from the Women's Health Initiative Estrogen + Progestin Trial, which randomized postmenopausal women with an intact uterus to receive daily conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg (n = 8506), or placebo (n = 8102). At baseline and annually, participants underwent mammography and clinical breast examination. Self-reported breast tenderness was assessed at baseline and at 12 months. The incidence of invasive breast cancer was confirmed by medical record review (mean follow-up of 5.6 years). RESULTS: Of women without baseline breast tenderness (n = 14,538), significantly more assigned to receive conjugated equine estrogens plus medroxyprogesterone vs placebo experienced new-onset breast tenderness after 12 months (36.1% vs 11.8%, P <.001). Of women in the conjugated equine estrogens plus medroxyprogesterone group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared with those without (hazard ratio, 1.48; 95% confidence interval, 1.08-2.03; P =.02). In the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness (P =.97). CONCLUSIONS: New-onset breast tenderness during conjugated equine estrogens plus medroxyprogesterone therapy was associated with increased breast cancer risk. The sensitivity and specificity of the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model. Trial Registration clinicaltrials.gov Identifier: NCT00000611.

Context: Fetuin-A inhibits the insulin receptor in vitro. Higher serum fetuin-A concentrations are associated with type 2 diabetes longitudinally and greater adiposity in cross-sectional analyses. Whether higher fetuin-A concentrations are associated with accumulation of adiposity over time is unknown. Objective: To determine the association of fetuin-A levels with changes in body composition over 5 yr. Study Design: Observational cohort study nested in the Health Aging and Body Composition Study. Predictor: Serum fetuin-A levels. Outcomes: Visceral adipose tissue (VAT), abdominal sc adipose tissue, and thigh muscle area by computed tomography, and waist circumference and body mass index were measured at baseline and again after 5 yr. Percent change and extreme change (>1.5 SDs) in each measure were calculated. Results: Over 5 yr, subjects lost body mass in each measure, including 6% decline in VAT. Yet each SD (0.42 g/liter) higher fetuin-A concentration was associated with a 5.5% increase in VAT over 5 yr (95% confidence interval 1.9-9.2%; P = 0.003) in models adjusted for age, sex, race, clinical site, diabetes, physical activity, triglycerides, kidney function, and the baseline VAT score. Similarly, higher fetuin-A concentrations were associated with extreme VAT gain (relative risk 1.70, 95% confidence interval 1.12-2.60, P = 0.01). Fetuin-A concentrations were not statistically significant associated with change in any other measures of body composition (P > 0.20). Conclusions: Higher fetuin-A concentrations are associated with the accumulation of VAT in well-functioning, community-living older persons. The mechanisms linking fetuin-A, VAT, and insulin resistance remain to be determined.

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<or=0.05 was considered to denote significance. RESULTS: There were 498 incident non-vertebral fractures (15.5/1000 person-years) and 121 incident hip fractures (3.6/1000 person-years). Compared with men who had had no falls, the risk of non-vertebral and lower extremity fractures was significantly higher in men with one fall (HR = 1.54 (95% CI 1.22 to 1.96) and 1.91 (95% CI 1.36 to 2.67), respectively) and men with two or more falls (HR = 1.81 (95% CI 1.40 to 2.34) and 1.79 (95% CI 1.23 to 2.61), respectively). The risk of head/chest, upper extremity and hip fractures (HR = 2.22 (95% CI 1.42 to 3.49), 2.08 (95% CI 1.01 to 4.28) and 1.79 (95% CI 1.07 to 2.98), respectively) was significantly higher for two or more falls than no falls; however, equivalent risks were not significantly higher (HR = 1.36 (95% CI 0.88 to 2.20), 1.55 (95% CI 0.74 to 3.25) and 1.41 (95% CI 0.87 to 2.27), respectively) comparing men with one fall versus no falls. CONCLUSION: Expanding clinical screens to include an assessment of fall frequencies may improve prediction of older men at risk of head/chest, upper extremity and hip fractures.

PURPOSE: To estimate the incidence of age-related macular degeneration (AMD) and the association of smoking and alcohol in a population of older women. DESIGN: Prospective cohort study. METHODS: Subjects were women who attended the Study of Osteoporotic Fractures year-10 and year-15 follow-up clinic visits and had fundus photographs taken at both visits (n = 1,958; 245 Black and 1,713 White subjects; mean age at year 10 visit, 78.2 years). Forty-five degree stereoscopic fundus photographs were graded for AMD. Logistic regression was used to test whether risk factors were associated with incident AMD. RESULTS: The overall 5-year AMD incidence was 24.1%(95% confidence interval [CI], 21.7 to 26.6) for early and 5.7%(95% CI, 4.6 to 6.8) for late. Early AMD incidence in White subjects ranged from 21.9% in those aged 74 to 79 years to 33.2% in those 80 to 84 years, but was observed at the slightly lower rate of 29.0% in subjects >/=85 years (trend P <.0001). After confounder adjustment, alcohol consumption was significantly associated with an elevated risk of incident early AMD (odds ratio [OR], 1.57; 95% CI, 1.18 to 2.11). There was an increased risk of early AMD among subjects aged 80 years or older who were smoking compared to those younger than 80 years who were not smoking (OR, 5.49; 95% CI, 1.57 to 19.20; P for interaction =.026). CONCLUSIONS: The magnitude of the greater-than-additive effect of smoking on the age-adjusted risk of AMD reinforces recommendations to quit smoking even for older individuals.

Abstract 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) vitamin D] levels are associated with an increased risk of fracture we performed a case-cohort study of 436 men with incident non-spine fractures including 81 hip fractures and a random subcohort of 1608 men; average follow-up time 5.3 years. Serum 25(OH) vitamin D(2) and 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. Multivariable models included age, clinic, season, race, height, weight and physical activity. The mean (standard deviation, SD) total 25(OH) vitamin D (ng/ml) was 24.6(7.8) in non-spine cases, 21.5(7.9) in hip fracture cases and 25.2(7.8) in non-cases (non-spine fracture cases versus non-cases, p = 0.14; hip fracture cases versus non-cases; p<0.0001). 25(OH) vitamin D levels were unrelated to non-spine fractures. One SD decrease in total 25(OH) vitamin D was associated with an increased risk of hip fracture (multivariate HR=1.60 (1.18-2.17). Compared to men in the top quartile of total 25(OH) vitamin D (>/=28), the HR of hip fracture was 2.36 (1.08, 5.15) for men in the lowest quartile (< 20), p trend=0.009. Adjusting for hip bone mineral density attenuated the association by > 50%, p trend = 0.065. Low serum 25(OH) vitamin D concentrations are associated with a higher risk of hip fracture in older men. Measurement of 25(OH) vitamin D may be useful in identifying men at high risk of hip fracture.

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.

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.