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Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men. © 2016 American Society for Bone and Mineral Research.

ObjectivesThe goal of this study was to evaluate the prospective association of fetuin-A levels with cardiovascular disease (CVD) mortality.BackgroundFetuin-A is a circulating inhibitor of calcium deposition in the vasculature and of insulin action in muscle and fat, and may be involved in the pathogenesis of CVD.MethodsThis is a population-based prospective study of 633 men and 1,025 women (median age = 73 years) who had fetuin-A levels and CVD risk factors evaluated in 1992 to 1996 and were followed for vital status through 2010.ResultsPlasma fetuin-A (g/l ± SD) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI]: 1.34 to 2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI: 0.19 to 0.98; p = 0.046) for participants with diabetes.ConclusionsLow fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms leading to CVD death in those with versus without diabetes.

The purpose of this study was to determine the association between neutrophil gelatinase-associated lipocalin (NGAL) levels and cardiovascular and all-cause mortality in community-dwelling older adults.NGAL is a novel marker best known for its role in rapidly identifying acute kidney injury. Although expressed in atherosclerosis, its association with cardiovascular disease (CVD) in the community has not been reported.We measured plasma NGAL levels in 1,393 Rancho Bernardo Study participants without CVD, mean age 70 years. Participants were followed for a mean time period of 11 years.During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and creatinine clearance, NGAL was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase: 1.33, 95% confidence interval [CI]: 1.12 to 1.57), all-cause mortality (HR: 1.19, 95% CI: 1.07 to 1.32), and a combined cardiovascular endpoint (HR: 1.26, 95% CI: 1.10 to 1.45). After further adjusting for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), NGAL remained an independent predictor of each outcome. NGAL improved the C-statistic (0.835 to 0.842) for prediction of CVD death (p = 0.001). Net reclassification improvement (0) with the addition of NGAL was 18% (p = 0.02); the integrated discrimination index was also significant (p = 0.01). Participants with NGAL and NT-proBNP above the median had increased risk of CVD death versus those with only NT-proBNP elevated (HR: 1.43, 95% CI: 1.12 to 1.82).Plasma NGAL is a significant predictor of mortality and CVD in community-dwelling older adults, independent of traditional risk factors and kidney function, and adds incremental value to NT-proBNP and CRP. The potential impact of these results includes providing insight into new mechanisms of CVD and the possibility of improving screening, intervention, and prevention.

Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.05 mg/dl lower serum phosphorus when adjusted for age, ethnicity, testosterone, sex hormone-binding globulin, calcium, estimated glomerular filtration rate, intact parathyroid hormone, 25(OH) vitamin D, bone mineral density, and alkaline phosphatase. These results were similar in individuals with or without chronic kidney disease. Serum testosterone concentrations were also statistically significantly associated with lower serum phosphorus levels. We confirmed these results in an independent sample of 2555 older men, wherein these associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Hence, our study of community-living older men suggests that estradiol may directly or indirectly induce phosphaturia in humans. The mechanism responsible for the association of testosterone with serum phosphorus remains to be determined.

Background Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. Interpretation Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Despite overwhelming biological plausibility, evidence for a protective effect of oestrogen on cognitive function in postmenopausal women is inconsistent. This study examines the association between endogenous oestrogen levels and subsequent 4-year decline in cognitive function test performance in community-dwelling older women.Longitudinal cohort study.Three hundred and forty-three postmenopausal women (median age 70 years).Between 1984 and 1987, serum for measurement of sex hormones was obtained along with relevant covariates. Cognitive function was assessed in 1988-1991 and again in 1992-1996 using the Category Fluency test, the Mini-Mental Status Exam (MMSE) and Trail Making Test B (Trails B).Women in the highest tertile of oestrone and bioavailable oestradiol had respectively 1.75 (95% CI 1.02, 3.07) and 1.79 (95% CI 1.04, 3.10) higher odds of 4 year decline in Category Fluency, a test of frontal lobe function, compared to those in the lowest tertile, independent of age and education. The 20% of women with highest tertile levels of both oestrone and bioavailable oestradiol had a twofold higher odds of verbal fluency loss (OR = 2.17; 95% CI 1.21, 3.89). Adjustment for testosterone levels or for obesity-related factors associated with high endogenous oestrogens (higher body mass index, waist girth, and triglycerides and lower high-density lipoprotein cholesterol) did not alter results. Neither oestrogen was associated with change in MMSE or Trails B scores.Higher endogenous oestrogen levels were associated with a greater decline in verbal fluency in postmenopausal women. This association was not explained by elevated androgens or by obesity or obesity-related factors.

This study investigated the prognostic value of detectable cardiac troponin T (TnT) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in a population of community-dwelling older adults.Minimally elevated levels of TnT, a marker of cardiomyocyte injury, have been found in small subsets of the general population, with uncertain implications. A marker of ventricular stretch, NT-proBNP has clinical utility in many venues, but its long-term prognostic value in apparently healthy older adults and in conjunction with TnT is unknown.Participants were 957 older adults from the Rancho Bernardo Study with plasma NT-proBNP and TnT measured at baseline (1997 to 1999) and followed up for mortality through July 2006.Participants with detectable TnT (/=0.01 ng/ml, n = 39) had an increased risk of all-cause and cardiovascular death (adjusted hazard ratio [HR] by Cox proportional hazards analysis: 2.06; 95% confidence interval [CI]: 1.29 to 3.28, p = 0.003 for all-cause mortality; HR: 2.06, 95% CI: 1.03 to 4.12, p = 0.040 for cardiovascular mortality); elevated NT-proBNP also predicted an increased risk of all-cause and cardiovascular mortality (adjusted HR per unit-log increase in NT-proBNP: 1.85, 95% CI: 1.36 to 2.52, p0.001 for all-cause mortality; HR: 2.51, 95% CI: 1.55 to 4.08, p0.001 for cardiovascular mortality). Those with both elevated NT-proBNP and detectable TnT had poorer survival (HR for high NT-proBNP and detectable TnT vs. low NT-proBNP and any TnT: 3.20, 95% CI: 1.91 to 5.38, p0.001). Exclusion of the 152 participants with heart disease at baseline did not materially change the TnT mortality or NT-proBNP mortality associations.Apparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.