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ObjectivesTo determine the association of the frailty phenotype with subsequent healthcare costs and utilization.DesignProspective cohort study (Study of Osteoporotic Fractures (SOF)).SettingFour U.S. sites.ParticipantsCommunity-dwelling women (mean age 80.2) participating in SOF Year 10 (Y10) examination linked with their Medicare claims data (N=2,150).MeasurementsAt Y10, frailty phenotype defined using criteria similar to those used in the Cardiovascular Health Study frailty phenotype and categorized as robust, intermediate stage, or frail. Participant multimorbidity burden ascertained using claims data. Functional limitations assessed by asking about difficulty performing instrumental activities of daily living. Total direct healthcare costs and utilization ascertained during 12 months after Y10.ResultsMean total annualized cost±standard deviation (2014 dollars) was $3,781±6,920 for robust women, $6,632±12,452 for intermediate stage women, and $10,755 ± 16,589 for frail women. After adjustment for age, site, multimorbidity burden, and cognition, frail women had greater mean total (cost ratio (CR)=1.91, 95% confidence interval (CI)=1.59-2.31) and outpatient (CR=1.55, 95% CI=1.36-1.78) costs than robust women and greater odds of hospitalization (odds ratio (OR)=2.05, 95% CI=1.47-2.87) and a skilled nursing facility stay (OR=3.85, 95% CI=1.88-7.88). There were smaller but significant effects of the intermediate stage category on these outcomes. Individual frailty components (shrinking, poor energy, slowness, low physical activity) were also each associated with higher total costs. Functional limitations partially mediated the association between the frailty phenotype and total costs (CR further adjusted for self-reported limitations=1.32, 95% CI=1.07-1.63 for frail vs robust; CR=1.35, 95% CI=1.18-1.55 for intermediate stage vs robust women).ConclusionIntermediate stage and frail older community-dwelling women had higher subsequent total healthcare costs and utilization after accounting for multimorbidity and functional limitations. Frailty phenotype assessment may improve identification of older adults likely to require costly, extensive care.

BackgroundFew studies have examined whether change in cognition is linked to mortality. This study examined the relationship between cognitive trajectories in older age and risk of death.MethodsWe studied community-dwelling, nondemented women aged 65+ (mean age = 71) enrolled in a prospective study of aging and followed up to 25 years. A modified Mini-Mental State Examination (mMMSE) and Trail Making Task Part B (TMTB) were administered at multiple visits during follow-up. We examined the association between cognitive trajectories (analyzed by quintiles) from baseline to age 80 (n = 7,477 for mMMSE and n = 6,503 for TMTB) and all-cause mortality after age 80 using Cox regression models, both unadjusted and adjusted for education, physical activity, alcohol, depression score, current smoking and history of hypertension and diabetes. Cause of death was determined from death certificates, classified as cardiovascular, cancer and other.ResultsWomen with greater rate of decline were older, less educated, less physically active, had higher depression score and were more likely to have a history of hypertension and diabetes (all p < .01). Participants with the greatest decline (quintile 1) had an increased risk of death (mMMSE hazard ratio [HR] = 1.28; TMTB HR = 1.43] and those with the least decline (quintile 5) had a decreased risk of death (mMMSE HR = 0.73; TMTB HR = 0.61) compared with intermediate decliners (quintiles 2-4). Cognitive trajectories were associated with cardiovascular mortality and other causes of death, but not cancer deaths.ConclusionsOur study suggests that greater decline in general cognition or executive function is associated with higher rates of mortality in oldest-old women.

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m(2) ) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m(2) was 0.87 (95% confidence interval [CI], 0.85-0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09-1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored.

Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.

BackgroundCurrently 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.MethodsPostmenopausal 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.ResultsBreast 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).ConclusionA 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p

ContextAdiponectin may influence the risk of coronary heart disease (CHD) independently of traditional cardiovascular risk factors.ObjectiveBecause body composition and adiponectin levels vary by race, we examined the relationship of adiponectin with prevalent and incident CHD in a cohort of older Black and White adults.Design and settingWe conducted a cross-sectional and prospective cohort study at two U.S. clinical centers.ParticipantsParticipants included 3075 well-functioning adults between ages 70 and 79 yr enrolled in the Health, Aging, and Body Composition study.Main outcome measuresPrevalent CHD was defined as history of myocardial infarction, coronary artery bypass graft, percutaneous coronary transluminal angioplasty, angina, or major electrocardiogram abnormalities. After excluding those with prevalent CHD, incident CHD was defined as hospitalized myocardial infarction or CHD death.ResultsAt baseline, 602 participants (19.6%) had CHD. During 6 yr of follow-up, 262 (10.6%) incident CHD events occurred. Whites had higher median adiponectin than Blacks (12 vs. 8 microg/ml, P < 0.001). Race modified the effect of adiponectin (P for interaction was 0.002 for prevalent CHD, and P = 0.02 for incident CHD). Among Whites, an inverse association of adiponectin with CHD was explained by high-density lipoprotein and glucose. Among Blacks, a doubling of adiponectin was associated with a 40% higher risk of both prevalent CHD (odds ratio, 1.41; 95% confidence interval, 1.11-1.78) and incident CHD (hazards ratio, 1.37; 95% confidence interval, 1.01-1.87) after adjusting for explanatory variables.ConclusionHigh circulating concentrations of adiponectin were associated with higher risk of CHD in older Blacks, even accounting for traditional CHD risk factors.

Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0: 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL ([beta] = 0.08 [+ or -] 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging. Key Words: Telomere--Survival--Life span--Health status--Years of healthy life.

Abstract Background Prediction of long-term survival in healthy adults requires recognition of features that serve as early indicators of successful aging. The aims of this study were to identify predictors of long-term survival in older women and to develop a multivariable model based upon longitudinal data from the Study of Osteoporotic Fractures (SOF). Methods We considered only the youngest subjects (n = 4,097) enrolled in the SOF cohort (65 to 69 years of age) and excluded older SOF subjects more likely to exhibit a "frail" phenotype. A total of 377 phenotypic measures were screened to determine which were of most value for prediction of long-term (19-year) survival. Prognostic capacity of individual predictors, and combinations of predictors, was evaluated using a cross-validation criterion with prediction accuracy assessed according to time-specific AUC statistics. Results Visual contrast sensitivity score was among the top 5 individual predictors relative to all 377 variables evaluated (mean AUC = 0.570). A 13-variable model with strong predictive performance was generated using a forward search strategy (mean AUC = 0.673). Variables within this model included a measure of physical function, smoking and diabetes status, self-reported health, contrast sensitivity, and functional status indices reflecting cumulative number of daily living impairments (HR ≥ 0.879 or RH ≤ 1.131; P < 0.001). We evaluated this model and show that it predicts long-term survival among subjects assigned differing causes of death (e.g., cancer, cardiovascular disease; P < 0.01). For an average follow-up time of 20 years, output from the model was associated with multiple outcomes among survivors, such as tests of cognitive function, geriatric depression, number of daily living impairments and grip strength (P < 0.03). Conclusions The multivariate model we developed characterizes a "healthy aging" phenotype based upon an integration of measures that together reflect multiple dimensions of an aging adult (65-69 years of age). Age-sensitive components of this model may be of value as biomarkers in human studies that evaluate anti-aging interventions. Our methodology could be applied to data from other longitudinal cohorts to generalize these findings, identify additional predictors of long-term survival, and to further develop the "healthy aging" concept.

Background: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition.Methods: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia.Results: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature.Conclusions: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities. [ABSTRACT FROM AUTHOR]

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; Pinteraction = .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. [ABSTRACT FROM PUBLISHER]

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3 ± 15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-α SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin. [ABSTRACT FROM AUTHOR]

The article presents a study regarding large-scale genome-wide linkage analysis for loci linked to bone mass density (BMD) at different skeletal sites in extreme selected sibships. The purpose of the study was to identify quantitative trait loci (QTLs) for BMD in a Chinese population which reveals 4 novel QTLs and suggests that BMD at different skeletal sites may also share common genetic causes.

Background: Higher fat mass may be an independent risk factor for osteoporosis and osteoporotic fractures. Objective: We aimed to determine the independent contribution of fat mass to osteoporosis and to estimate the risk of osteoporotic fractures in relation to body weight, lean mass, and other confounders. Design: This was a community-based, cross-sectional study of 7137 men, 4585 premenopausal women, and 2248 postmenopausal women aged 25-64 y. Total-body and hip bone mineral content (BMC) and bone mineral density (BMD) and body composition were measured by dual-energy X-ray absorptiometry. Serum lipids were measured. Sex- and menopause-specific multiple generalized linear models were applied. Results: Across 5-kg strata of body weight, fat mass was significantly inversely associated with BMC in the whole body and total hip. When we compared the highest quartile with the lowest quartile of percentage fat mass in men, premenopausal women, and postmenopausal women, the adjusted odds ratios (95% CIs) of osteoporosis defined by hip BMD were 5.2 (2.1, 13.2), 5.0 (1.7, 15.1), and 6.9 (4.3, 11.2), respectively. Significant linear trends existed for higher risks of osteoporosis, osteopenia, and nonspine fractures with higher percentage fat mass. Significant negative relations were found between whole-body BMC and cholesterol, triacylglycerol, LDL, and the ratio of HDL to LDL in all groups. Conclusions: Risks of osteoporosis, osteopenia, and nonspine fractures were significantly higher for subjects with higher percentage body fat independent of body weight, physical activity, and age. Thus, fat mass has a negative effect on bone mass in contrast with the positive effect of weight-bearing itself. [ABSTRACT FROM AUTHOR]

Growing evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has also been correlated with visceral fat. Thus, we examined the relationship of oxLDL at baseline with adiposity and T2D among 3037 subjects from a prospective cohort study, the Health ABC Study. The mean level of serum oxLDL was higher in men than in women (1.34±.02 vs. 1.29±.02, p=.04), and in Blacks compared to Whites (1.37±.02 vs. 1:27±.02, p<.001). We examined 5 adiposity traits (BMI, % body fat measured by DEXA, fasting leptin, and abdominal visceral and subcutaneous fat mass area measured by CT scan), as well as 4 T2D-related traits (T2D status, HbA1c, fasting glucose and insulin). The regression models were adjusted for the effects of significant covariates. Using data from baseline, oxLDL was strongly and positively associated with 3 traits for overall obesity (β=.68± .12 for BMI, β=.95±. 14 for % body fat and β=. 13±.03 for leptin, all p<.001), while it had a weaker association with abdominal fat masses (β=.12±.05 for subcutaneous fat and β=.27±.05. for visceral fat, p=.02-.05). OxLDL was also positively associated with T2D (OR=1.26, 95% CI: 1.11-1.45), fasting glucose (β=.03±.006), HbA1c (β=.03±.004) and fasting insulin (β=.14±.02) (all p < .001). Moreover, we had data on BMI, % body fat, fasting glucose and HbA1c at Year 6 of follow-up. The association (in strength and magnitude) between oxLDL at baseline and these 4 traits at Year 6 remained virtually the same. The association between oxLDL and T2D traits (both at baseline and Year 6) remained significant after adjusting for BMI at baseline, and vice versa. Neither race nor sex modified these associations. OxLDL, a marker of systemic oxidative stress, was significantly associated with adiposity and T2D independently, using both cross-sectional and prospectively collected data. The role of oxidative stress in T2D merits further investigations. [ABSTRACT FROM AUTHOR]

Purpose: The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process., Methods: We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. The clinical community has become accustomed to a certain amount of adjudication and may criticize trials that lack adjudication., Limitations: It is difficult to document the value of adjudication in trials that have reported adjudicated and nonadjudicated event rates and related treatment effects. Making rationale decisions about when and how to adjudicate is hampered by the lack of published study of when and how central adjudication is helpful to improve the quality and validity of trials and at what cost., Conclusions: Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication - which trials, which outcomes, what methods - deserves scrutiny and further study.