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1.  Estimated GFR and Risk of Hip Fracture in Older Men: Comparison of Associations Using Cystatin C and Creatinine 
Higher serum cystatin C is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data in men. Whether an estimated GFR (eGFR) based on cystatin C (eGFRcys) is superior in predicting hip fracture risk to an eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-cys) is also uncertain.
Study Design
Nested case-cohort.
Setting & Participants
Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥65 years from six U.S. centers) including a random subcohort of 1602 men and 168 men with incident hip fractures (51 of whom were in the subcohort).
eGFRcys, eGFRcr and eGFRcr-cys computed using the CKD-EPI equations and expressed in categories of <60, 60–74, and ≥75 mL/min/l.73 m2 (referent group).
Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports.
Median eGFRcys was 72.9 (IQR, 60.5–85.7) mL/min/1.73 m2. In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site and BMI, the association of lower eGFRcys (but not lower eGFRcr or lower eGFRcr-cys) with higher hip fracture risk remained: for <60 vs. ≥75 mL/min/l.73 m2, HRs were 1.96 [95% CI, 1.25–3.09], 0.84 [95% CI, 0.52–1.37], and 1.08 [95% CI, 0.66–1.77] for eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site and BMI, eGFR of <60 ml/min/1.73 m2 defined by eGFRcys but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys and hip fracture was not explained by levels of calcitropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs. ≥75 mL/min/l.73 m2: HR, 1.43; 95% CI, 0.88–2.34) after consideration of additional clinical risk factors and bone mineral density.
Findings not generalizable other populations; residual confounding may exist.
Older community-dwelling men with lower eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys were not associated with a higher age-adjusted hip fracture risk.
PMCID: PMC3833961  PMID: 23890927
kidney function; cystatin C; creatinine; hip fracture; elderly; men
2.  Cystatin C and Frailty Status in Older Men 
Declining kidney function and frailty are common with aging, but the association between these conditions remains uncertain. We hypothesized that higher cystatin C would be associated with greater frailty status in men age 65 years and older.
Cross-sectional cohort study
Men ≥65 years from six U.S. sites
Serum cystatin C and creatinine were measured along with frailty status in a random sample of 1602 community-dwelling men age ≥65 years enrolled in the MrOS study. Frailty status was analyzed as an ordinal outcome of robust, intermediate stage, and frail using a multinomial logistic regression model and the base model was adjusted for age, race, and clinical site.
The mean age of the cohort was 73.8 years; 9.8% were frail and 47.2% were intermediate stage. Higher cystatin C was associated with a 7-fold higher odds of frail vs. robust status (OR quartile 4 vs. 1; 7.12, 95% CI 3.76–13.46) and a 2.4-fold higher odds of intermediate vs. robust status (OR quartile 4 vs. 1; 2.38, 95% CI 1.70–3.32). The association was attenuated but persisted after adjusting for multiple possible confounders. In contrast, neither higher serum creatinine (OR quartile 4 vs. 1; 1.36, 95% CI 0.78–2.40) nor lower creatinine-based eGFR (OR quartile 4 vs. 1; 1.01, 95% CI 0.54–1.87) was associated in a graded manner with higher odds of frailty.
Higher cystatin C, but not creatinine-based measures, was associated with increased odds of frailty status in this cohort of older men.
PMCID: PMC3773269  PMID: 24001352
Cystatin C; creatinine; frailty; elderly; kidney function
3.  A Comparison of Frailty Indexes for the Prediction of Falls, Disability, Fractures and Mortality in Older Men 
To compare validity of a parsimonious frailty index (components: weight loss, inability to rise from a chair, and poor energy [SOF index]) with that of the more complex CHS index (components: unintentional weight loss, low grip strength, poor energy, slowness, and low physical activity) for prediction of adverse outcomes in older men.
Prospective cohort study
Six U.S. centers
3132 men ≥67 years
Men classified as robust, intermediate stage or frail using SOF index and criteria similar to those used in CHS index. Falls reported tri-annually for 1 year. Disability (≥1 new impairment in performing IADL) ascertained at 1 year. Fractures and deaths ascertained during 3 years of follow-up. Area under the curve (AUC) statistics from receiver operating characteristic curve analysis compared for models containing SOF index versus CHS index.
Greater evidence of frailty as defined by either index was associated with increased risks of adverse outcomes. Frail men had a higher age-adjusted risk of recurrent falls (odds ratio [OR] 3.0–3.6), disability (OR 5.3–7.5), nonspine fracture (hazards ratio [HR] 2.2–2.3), and death (HR 2.5–3.5) (P<0.001 for all models). AUC comparisons revealed no differences between models with SOF index versus models with CHS index in discriminating falls (AUC=0.63, P= 0.97), disability (AUC=0.68, P=0.86), nonspine fracture (AUC=0.63, P=0.90), or death (AUC=0.71 for model with SOF index and 0.72 for model with CHS index, P=0.19).
The simple SOF index predicts risk of falls, disability, fracture and mortality in men as well as the more complex CHS index.
PMCID: PMC2861353  PMID: 19245414
frailty; older men; hip fracture; mortality
4.  Excessive Antibiotic Utilization in Men with Prostatitis 
The American journal of medicine  2008;121(5):444-449.
Prostatitis accounts for two million outpatient visits annually. The vast majority of prostatitis cases fit the definition of chronic pelvic pain syndrome for which routine antibiotic use is not indicated.
Inpatient, Outpatient, and Pharmacy Datasets from the Veterans Health Administration were used to quantify the magnitude of antibiotic use attributable to chronic pelvic pain syndrome. Specifically, men with a diagnosis of infectious/acute prostatitis, and/or a urinary tract infection were excluded, and the remaining men with a diagnosis of prostatitis were defined as having chronic pelvic pain syndrome.
Annual prevalence of chronic pelvic pain syndrome was 0.5%. Prescriptions for fluoroquinolone antibiotics were filled in 49% of men with a diagnosis of chronic pelvic pain syndrome compared to five percent in men without chronic pelvic pain syndrome. Men with chronic pelvic pain syndrome were greater than seven times more likely to receive a fluoroquinolone prescription independent of age, race/ethnicity and comorbid conditions. Increased use of other antibiotics was also observed. High utilization was similar in men with either infectious/acute prostatitis or chronic pelvic pain syndrome.
Despite evidence that antibiotics are not effective in the large majority of men with chronic pelvic pain syndrome, they were prescribed in 69% of men with this diagnosis. Some increased use is probably due to uncontrolled confounding by comorbid conditions or inaccurate diagnostic coding. However, a seven-fold higher rate of fluoroquinolone usage suggests strategies to reduce unnecessary antibiotic use in men with prostatitis are warranted.
PMCID: PMC2409146  PMID: 18456041
5.  Cystatin C and Risk of Hip Fractures in Older Women 
To test the hypothesis that older women with higher cystatin C are at increased risk of hip fracture independent of traditional risk factors including hip bone mineral density (BMD), we performed a case-cohort analysis nested in a cohort of 4709 white women attending a Year 10 (1997–1998) examination of the Study of Osteoporotic Fractures that included a random sample of 1170 women and the first 300 women with incident hip fracture occurring after Year 10 examination. Serum cystatin C and creatinine were measured in Year 10 sera. In a model adjusted for age, clinical site, body mass index and total hip BMD, higher cystatin C was associated with an increased risk of hip fracture (p for linear trend 0.008) with women in quartile 4 having a 1.9-fold higher risk (hazard ratio (HR) 1.91, 95% confidence (CI) 1.24–2.95) compared with those in quartile 1 (referent group). Further adjustment for additional risk factors only slightly attenuated the association; the risk for hip fracture was 1.7-fold (HR 1.74, 95% CI 1.11–2.72) higher in women in quartile 4 compared with those in quartile 1. In contrast, neither serum creatinine nor creatinine-based estimated glomerular filtration rate (eGFRCr) were associated with risk of hip fracture. Older women with higher cystatin C, but not higher serum creatinine or lower eGFRCr, have an increased risk of hip fracture independent of traditional risk factors. These findings suggest that cystatin C may be a promising biomarker for identification of older adults at high risk of hip fracture.
PMCID: PMC3646079  PMID: 23300153
renal function; cystatin C; hip fracture; elderly; women
6.  The Association of Body Size and Composition with Erectile Dysfunction in Older Men: Osteoporotic Fractures in Men (MrOS) Study 
To examine the association of body size and composition with erectile dysfunction (ED) in older men.
Cross-sectional analysis of the Osteoporotic Fractures in Men study.
Six U.S. clinical sites.
Community-dwelling men aged 65 years and older.
Body composition measures using anthropometry (body weight, body mass index [BMI]) and dual x-ray absorptiometry (total body fat percent, trunk fat percent, ratio of trunk and total body fat). Erectile dysfunction was assessed using the single item Massachusetts Male Aging Study (MMAS) scale and the International Index of Erectile Function questionnaire (IIEF-5).
Among men completing the MMAS scale (n=4108), prevalence of complete ED was 42%. Among sexually active men completing the IIEF-5 questionnaire (n=1659), prevalence of moderate to severe ED was 56%. In multivariate-adjusted analyses reporting prevalence ratios (PR) and 95% confidence intervals (CI), the prevalence of MMAS-defined complete ED was significantly increased in men in the highest quartile of increased body weight PR = 1.24, 95% CI = 1.16-1.34), total body fat percentage (PR = 1.25, 95% CI = 1.13-1.40), and trunk fat percentage (PR = 1.24, 95% CI = 1.15-1.38), and in men with BMI >30.0 kg/m2 compared to those with BMI 22.0-24.9 kg/m2 (PR = 1.17, 95% CI = 1.05-1.31). Associations appeared similar for IIEF-5 defined moderate to severe ED in analyses adjusted for age and study site.
In a cohort of older men, increased body weight, BMI, and total body fat percent were independently associated with increased prevalence of moderate to severe and complete ED. Future studies should investigate whether interventions to promote weight loss and fat loss will improve erectile function in older men.
PMCID: PMC4028028  PMID: 23311552
obesity; erectile dysfunction; men; aged
7.  Association Between Serum 25(OH) Vitamin D and the Risk of Cognitive Decline in Older Women 
Results of prospective studies examining the association between 25 hydroxyvitamin D (25[OH]D) levels and cognitive decline have been inconsistent. We tested the hypothesis that lower 25(OH)D levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline.
The study is a cross-sectional and longitudinal analysis of a prospective cohort of 6,257 community-dwelling elderly women followed for 4 years. Global cognitive function was measured by the Modified Mini-Mental State Examination and executive function was measured by Trail Making Test Part B (Trails B). Cognitive impairment at baseline was defined as a score >1.5 SD below the sample mean; cognitive decline was defined as decline from baseline to follow-up >1 SD from mean change in score.
Women with very low vitamin D levels had an increased odds of global cognitive impairment at baseline: odds ratio (95% confidence interval), 1.60 (1.05–2.42) for women with 25(OH)D <10 ng/mL (25 nmol/L) compared with those with 25(OH)D levels ≥30 ng/mL (75 nmol/L). Compared with women with baseline 25(OH)D level ≥30 ng/mL (75 nmol/L), women with lower levels had an increased risk of global cognitive decline: odds ratio (95% confidence interval), 1.58(1.12–2.22) for women with levels <10 ng/mL (25 nmol/L), and 1.31 (1.04–1.64) for those with levels 10–19.9 ng/mL (25–49 nmol/L). Levels of 25(OH)D were not associated with executive cognitive function.
Low 25(OH)D levels among older women were associated with a higher odds of global cognitive impairment and a higher risk of global cognitive decline.
PMCID: PMC3437964  PMID: 22454371
Vitamin D; Cognitive decline; Executive function; Cohort studies; Risk factors in epidemiology
8.  Metabolic Syndrome and Physical Performance In Elderly Men: The Osteoporotic Fractures in Men (MrOS) Study 
To examine the association of metabolic syndrome (MetS) with objective measures of physical performance.
Cross-sectional analysis of the cohort study, the Osteoporotic Fractures in Men Study.
Six clinical sites in the US.
5,457 ambulatory men (mean (±SD), age, 73.6 (5.9) years).
Physical performance assessed by grip strength, narrow walk speed, walking speed, and time to complete five repeated chair stands. Individual scores were converted to quintiles (worst [1] to best [5]; unable to complete=0) and summed for an overall score (mean (±SD), 11.6 (4.3), range, 1–20). MetS was defined by World Health Organization criteria that include evidence of glucose dysregulation (insulin resistance, diabetes, or hyperinsulinemia), and at least two additional characteristics: high blood pressure, low high density lipoprotein cholesterol, high triglycerides, or obesity.
26.3% of participants met criteria for MetS. In separate linear regression models, four of five MetS components were related to performance (P<.001); only high blood pressure was unrelated. Men with MetS had a 1.11-point lower performance score (mean (95% confidence interval (CI)) =10.81 (10.61, 11.00)) than men without MetS (mean (95% CI) =11.92 (11.81, 12.03)) (P<.001), adjusting for age, race, education and site. With further covariate adjustment this difference was reduced but remained significant (β=−0.78, P<.001). A graded association was observed between number of MetS components (0, 1, 2, or 3+) and performance (P for trend <.001). Findings were similar excluding men with diabetes or obese men.
Metabolic dysregulation is related to objectively-assessed poorer physical performance among relatively healthy older men.
PMCID: PMC3545517  PMID: 21806561
aged; men; metabolic syndrome; physical function; physical performance
9.  Effect of Nurse Case Management Compared With Usual Care on Controlling Cardiovascular Risk Factors in Patients With Diabetes 
Diabetes Care  2011;34(8):1689-1694.
To determine whether nurse case management with a therapeutic algorithm could effectively improve rates of control for hypertension, hyperglycemia, and hyperlipidemia compared with usual care among veterans with diabetes.
A randomized controlled trial of diabetic patients that had blood pressure (BP) >140/90 mmHg, hemoglobin A1c (HbA1c) >9.0%, or LDL >100 mg/dL. Intervention patients received case management (n = 278) versus usual care (n = 278) over a 1-year period. The primary outcome was the percentage of patients achieving simultaneous control of all three parameters (defined by BP <130/80 mmHg, HbA1c <8.0%, and LDL <100 mg/dL) at 1 year. Secondary outcomes included improvements within each individual component of the composite primary outcome. Differences between groups were analyzed using t tests, Pearson χ2 tests, and linear and logistic regression.
A greater number of individuals assigned to case management achieved the primary study outcome of having all three outcome measures under control (61 [21.9%] compared with 28 [10.1%] in the usual care group [P < 0.01]). In addition, a greater number of individuals assigned to the intervention group achieved the individual treatment goals of HbA1c <8.0% (73.7 vs. 65.8%, P = 0.04) and BP <130/80 mmHg (45.0 vs. 25.4%, P < 0.01), but not for LDL <100 mg/dL (57.6 vs. 55.4%, P = 0.61), compared with those in the usual care group.
In patients with diabetes, nurse case managers using a treatment algorithm can effectively improve the number of individuals with control of multiple cardiovascular risk factors at 1 year.
PMCID: PMC3142048  PMID: 21636796
10.  Impact of Diastolic and Systolic Blood Pressure on Mortality: Implications for the Definition of “Normal” 
The National Heart, Lung and Blood Institute currently defines a blood pressure under 120/80 as “normal.”
To examine the independent effects of diastolic (DBP) and systolic blood pressure (SBP) on mortality and to estimate the number of Americans affected by accounting for these effects in the definition of “normal.”
Data on adults (age 25–75) collected in the early 1970s in the first National Health and Nutrition Examination Survey were linked to vital status data through 1992 (N = 13,792) to model the relationship between blood pressure and mortality rate adjusting for age, sex, race, smoking status, BMI, cholesterol, education and income. To estimate the number of Americans in each blood pressure category, nationally representative data collected in the early 1960s (as a proxy for the underlying distribution of untreated blood pressure) were combined with 2008 population estimates from the US Census.
The mortality rate for individuals over age 50 began to increase in a stepwise fashion with increasing DBP levels of over 90. However, adjusting for SBP made the relationship disappear. For individuals over 50, the mortality rate began to significantly increase at a SBP ≥140 independent of DBP. In individuals ≤50 years of age, the situation was reversed; DBP was the more important predictor of mortality. Using these data to redefine a normal blood pressure as one that does not confer an increased mortality risk would reduce the number of American adults currently labeled as abnormal by about 100 million.
DBP provides relatively little independent mortality risk information in adults over 50, but is an important predictor of mortality in younger adults. Conversely, SBP is more important in older adults than in younger adults. Accounting for these relationships in the definition of normal would avoid unnecessarily labeling millions of Americans as abnormal.
PMCID: PMC3138604  PMID: 21404131
blood pressure; hypertension; guidelines; mortality
11.  Chapter 12: Systematic Review of Prognostic Tests 
Journal of General Internal Medicine  2012;27(Suppl 1):94-101.
A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted.
PMCID: PMC3364355  PMID: 22648680
prognosis; predictive accuracy; reclassification; review
12.  Chapter 11: Challenges in and Principles for Conducting Systematic Reviews of Genetic Tests used as Predictive Indicators 
Journal of General Internal Medicine  2012;27(Suppl 1):83-93.
In this paper, we discuss common challenges in and principles for conducting systematic reviews of genetic tests. The types of genetic tests discussed are those used to 1). determine risk or susceptibility in asymptomatic individuals; 2). reveal prognostic information to guide clinical management in those with a condition; or 3). predict response to treatments or environmental factors. This paper is not intended to provide comprehensive guidance on evaluating all genetic tests. Rather, it focuses on issues that have been of particular concern to analysts and stakeholders and on areas that are of particular relevance for the evaluation of studies of genetic tests. The key points include:The general principles that apply in evaluating genetic tests are similar to those for other prognostic or predictive tests, but there are differences in how the principles need to be applied or the degree to which certain issues are relevant.A clear definition of the clinical scenario and an analytic framework is important when evaluating any test, including genetic tests.Organizing frameworks and analytic frameworks are useful constructs for approaching the evaluation of genetic tests.In constructing an analytic framework for evaluating a genetic test, analysts should consider preanalytic, analytic, and postanalytic factors; such factors are useful when assessing analytic validity.Predictive genetic tests are generally characterized by a delayed time between testing and clinically important events.Finding published information on the analytic validity of some genetic tests may be difficult. Web sites (FDA or diagnostic companies) and gray literature may be important sources.In situations where clinical factors associated with risk are well characterized, comparative effectiveness reviews should assess the added value of using genetic testing along with known factors compared with using the known factors alone.For genome-wide association studies, reviewers should determine whether the association has been validated in multiple studies to minimize both potential confounding and publication bias. In addition, reviewers should note whether appropriate adjustments for multiple comparisons were used.
PMCID: PMC3364361  PMID: 22648679
genetic test; systematic review methods; predictive tests; prognostic tests; risk
13.  Sleep-Disordered Breathing and Urinary Albumin Excretion in Older Men 
Sleep-disordered breathing(SDB) may be deleterious to the cardiovascular system and other organs, including the kidney. Although older men are at increased risk for both kidney disease and SDB, it is unknown whether SDB is associated with higher urinary albumin excretion in this population.
We examined 507 community-dwelling men age ≥67 years(mean 76.0±5.3) enrolled in the MrOS Sleep study who underwent overnight polysomnography and gave a spot urine sample. SDB severity was categorized using the respiratory disturbance index and percent total sleep time <90% oxygen saturation(%time O2<90). Urinary albumin excretion was expressed using the albumin-to-creatinine ratio(ACR).
There was a graded association between respiratory disturbance index and ACR (age and race-adjusted mean ACR=9.35 mg/gCr for respiratory disturbance index≥30 versus 6.72 mg/gCr for respiratory disturbance index<5, p=0.007). This association was attenuated after further adjustment for body mass index(BMI), hypertension and diabetes and no longer reached significance(p=0.129). However, even after adjustment for age, race, BMI, hypertension and diabetes, greater %time O2<90 was associated with higher ACR(10.35 mg/gCr for ≥10%time O2<90 versus 7.45 mg/gCr for <1%time O2<90, p=0.046).
SDB, measured by elevated respiratory disturbance index or nocturnal hypoxemia, was associated with higher ACR. The relationship between respiratory disturbance index and ACR was partially explained by higher BMI and greater prevalence of hypertension and diabetes among men with SDB. However, greater nocturnal hypoxemia was independently associated with higher ACR, suggesting that the hypoxia component of SDB may mediate any detrimental effect of SDB on the kidney.
PMCID: PMC3272772  PMID: 20186573
Albuminuria; sleep-disordered breathing; chronic kidney disease; nocturnal hypoxemia
14.  Estimates of the Proportion of Older White Men Who Would Be Recommended for Pharmacologic Treatment by the New US National Osteoporosis Foundation Guidelines 
Journal of Bone and Mineral Research  2010;25(7):1506-1511.
The new US National Osteoporosis Foundation's (NOF's) Clinician's Guide to Prevention and Treatment of Osteoporosis includes criteria for recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck or spine bone mineral density (BMD) T-scores of −2.5 or less, and presence of low bone mass at the femoral neck or spine plus a 10-year risk of hip fracture of 3% or greater or of major osteoporotic fracture of 20% or greater. The proportion of men who would be recommended for treatment by these guidelines is not known. We applied the NOF criteria for treatment to men participating in the Osteoporotic Fractures in Men Study (MrOS). To determine how the MrOS population differs from the general US population of Caucasian men aged 65 years and older, we compared men in MrOS with men who participated in the National Health and Nutrition Examination Survey (NHANES) III on criteria included in the NOF treatment guidelines that were common to both cohorts. Compared with NHANES III, men in MrOS had higher femoral neck BMD values. Application of NOF guidelines to MrOS data estimated that at least 34% of US white men aged 65 years and older and 49% of those aged 75 years and older would be recommended for drug treatment. Application of the new NOF guidelines would result in recommending a very large proportion of white men in the United States for pharmacologic treatment of osteoporosis, for many of whom the efficacy of treatment is unknown. © 2010 American Society for Bone and Mineral Research.
PMCID: PMC3153995  PMID: 20200971
osteoporosis; men; treatment; guidelines; epidemiology; bone density
15.  Kidney Function and Cognitive Performance and Decline in Older Men 
To examine the association of kidney function with cognitive impairment and decline in elderly men.
Observational prospective cohort.
Community based.
5529 community dwelling men, aged 65 years or older (mean age 73.6 ± 5.9).
Estimated Glomerular filtration rate (eGFR) calculated using the standardized Modification of Diet in Renal Disease (MDRD) equation; cognitive function assessed with Modified Mini-Mental State Examination (3MS) and Trail Making Test B (Trails B).
At baseline, 148 (2.7%) and 494 (9.1%) men were classified as cognitively impaired and, in the 5-year prospective analysis, 931 (23%) and 432 (11.6%) met the criteria for cognitive decline at follow-up defined by 3MS and Trails B performance, respectively. In unadjusted analysis, the odds of prevalent cognitive impairment and risk of cognitive decline were significantly higher among men with eGFR of <45 and 45–59 mL/min/1.73m2, compared to men with eGFR ≥60 mL/min/1.73m2. These associations were largely explained by difference in age, race, and education between the eGFR categories, with the exception of the association between reduced renal function and higher odds of impairment based on Trails B test score which persisted despite adjustment for multiple potential confounders.
This study found evidence of an independent association between mild to moderate reductions in kidney function and poor executive function at baseline, but not with global cognitive impairment or risk of cognitive decline in older men.
PMCID: PMC3108463  PMID: 18795984
kidney function; cognition; elderly
16.  Rest/Activity Rhythms and Cardiovascular Disease in Older Men 
Chronobiology international  2011;28(3):258-266.
Prior studies have suggested an increased risk of CVD-related mortality in older adults with disturbed circadian rest/activity rhythms (RARs). The objective goal of this study was to examine the association between disrupted RARs and risk of cardiovascular disease (CVD) events in older men. A total of 2,968 men aged 67 yrs and older wore wrist actigraphs for 115±18 consecutive hours. RAR parameters were computed from wrist actigraphy data and expressed as quartiles (Q). CVD events consisted of a composite outcome of coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD) events. Secondary analyses examined associations between RARs and individual components of the composite outcome (CHD, stroke, and PVD). There were 490 CVD events over an average of 4.0±1.2 yrs. Overall, reduced amplitude (HR = 1.31, 95%CI 1.01–1.71 for Q2 vs. Q4) and greater minimum (HR = 1.33, 95%CI 1.01–1.73 for Q4 vs. Q1) were associated with an increased risk of CVD events in multivariable-adjusted models. In secondary analyses, there was an independent association between reduced amplitude (HR = 1.36, 95%CI 1.00–1.86) and greater minimum activity counts (HR = 1.39, 95%CI 1.02–1.91) with increased risk of CHD events. Reduced F-value (HR = 2.88, 95%CI 1.41–5.87 for Q1 vs. Q4 and HR = 2.71, 95%CI 1.34–5.48 for Q2 vs. Q4) and later occurring acrophase of the RAR (HR = 1.65, 95%CI 1.04–2.63 for Q4 vs. Q2–3) were associated with an increased risk of PVD events. Results were similar in men without a history of CVD events. The findings revealed among older men, measures of decreased circadian activity rhythm robustness (reduced amplitude and greater minimum activity) were associated with an increased risk of CVD events, primarily through increased risk of CHD or stroke events, whereas measures of reduced circadian activity rhythm robustness were not associated with risk of CVD events overall, but were associated with an increased risk of PVD events. These results should be confirmed in other populations.
PMCID: PMC3104399  PMID: 21452921
Rest/activity rhythm; Circadian rhythms; Sleep; Elderly; Cardiovascular disease
17.  Muscle power and physical activity are associated with bone strength in older men: The osteoporotic fractures in men study 
Bone  2010;47(2):205-211.
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/cm3), total (ToA, mm2) and cortical (CoA, mm2) 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 (≥ 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.
PMCID: PMC3073372  PMID: 20466088
Older men; Physical activity; Bone strength; Bone geometry; Peripheral quantitative computed tomography
18.  Bone Mass and Strength in Older Men With Type 2 Diabetes: The Osteoporotic Fractures in Men Study 
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/cm3), total (ToA, mm2) and cortical (CoA, mm2) bone area and estimates of bone compressive and bending strength in a subset (n = 1171) of men (≥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. © 2010 American Society for Bone and Mineral Research
PMCID: PMC3153385  PMID: 19594301
bone geometry; osteoporosis; peripheral quantitative computed tomography; diabetes mellitus
19.  A Comparison of Prediction Models for Fractures in Older Women: Is More Better 
Archives of internal medicine  2009;169(22):2087-2094.
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. Our objective is to determine whether prediction with FRAX® models is superior to that based on parsimonious models.
We conducted a prospective cohort study in 6252 women aged ≥65 years and compared the value of FRAX® models that include BMD to parsimonious models based on age and BMD alone for prediction of fractures. We also compared FRAX® models without BMD to 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 (ROC) curve analysis were compared between FRAX® models and simple models.
AUC comparisons revealed no differences between FRAX® models with BMD versus simple models with age and BMD alone in discriminating hip (AUC=0.75 for FRAX® model and 0.76 for simple model, p=0.26); major osteoporotic (AUC=0.68 for FRAX® model and 0.69 for simple model, p=0.51); or clinical fracture (AUC=0.64 for FRAX® model and 0.63 for simple model, p=0.16). 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≥0.16).
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.
PMCID: PMC2811407  PMID: 20008691
20.  Rest/Activity Rhythms and Mortality Rates in Older Men: MrOS Sleep Study 
Chronobiology international  2010;27(2):363-377.
An association between increased risk of mortality and disruptions in rest/activity circadian rhythms (RAR) has been shown among adults with dementia and with metastatic colorectal cancer. However the association among a more general population of older adults has not been studied.
Study population consisted of 2964 men aged 67 and older enrolled in the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study. Rest/activity patterns were measured with wrist actigraphy. RAR parameters were computed and expressed as quintiles, and included acrophase (time of peak activity level), amplitude (peak-to-nadir difference), mesor (middle of the peak), pseudo F-value (overall circadian rhythmicity), beta (steepness) and alpha (peak-to-trough width).
After adjustment for multiple potential confounders, men in the lowest quintile of pseudo F-value had a 57% higher mortality rate (Hazard ratio [HR]=1.57, 95%CI, 1.03–2.39) compared with men in the highest quintile. This association was even stronger with increased risk of cardiovascular disease-related mortality (CVD) (HR=2.32, 95%CI, 1.04–5.22). Additionally, men in the lowest quintile of acrophase had a 2.8-fold higher rate of CVD-related mortality (HR=2.84, 95%CI, 1.29–6.24). There was no evidence of independent associations with amplitude, mesor, alpha, beta and risk of mortality.
Older men with less robust RAR and earlier acrophase timing, have modestly higher all-cause and CVD-related mortality rates. Further research should examine potential biological mechanisms underlying this association.
PMCID: PMC2918381  PMID: 20370475
rest/activity rhythms; circadian rhythms; mortality; elderly; sleep
21.  Effect of Exercise on Disorders of Carbohydrate and Lipid Metabolism in Adults With Traumatic Spinal Cord Injury: Systematic Review of the Evidence 
Carbohydrate and lipid metabolism disorders may affect adults with spinal cord injuries (SCIs) differently than able-bodied individuals because of reduced physical activity in the SCI population. The objective of this study was to conduct a systematic review to determine the effectiveness of exercise to improve carbohydrate and lipid metabolism disorders in adults with chronic SCI.
Studies were identified in MEDLINE (1996–2008), Cochrane Library, bibliographies of identified articles, and expert recommendations. English language articles were included if they evaluated adults with chronic SCI; evaluated exercise; and reported carbohydrate-, lipid-, and/or cardiovascular disease-related outcomes.
Twenty-two studies met inclusion criteria, including 15 intervention case-series and 7 cross-sectional surveys using self-reported physical activity measures. Intervention protocols involved active (n  =  7) or electrically stimulated (n  =  7) exercise or an educational program (n  =  1) from 8 to 52 weeks in duration. Frequency of exercise was typically 2 to 3 sessions/week, lasting 30 to 60 minutes/session. Totals of 150 and 369 subjects participated in studies with carbohydrate (n  =  12) or lipid and cardiovascular (n  =  16) outcomes, respectively; 78% were men. Level of SCI ranged from C4 to L5 and included both incomplete and complete lesions. Outcomes measures included fasting and postload blood glucose and insulin concentrations and serum cholesterol levels. Small sample sizes and variations in study design, intervention, SCI characteristics, and reported outcomes precluded quantitative pooling of results or reliable assessment of metabolic efficacy. No intervention studies assessed cardiovascular outcomes.
Evidence is insufficient to determine whether exercise improves carbohydrate and lipid metabolism disorders among adults with SCI. Expert consensus, based on the preliminary evidence, is needed to inform future studies.
PMCID: PMC2830675  PMID: 19777857
Spinal cord injuries; Tetraplegia; Paraplegia; Exercise; Functional electrical stimulation; Lipid metabolism; Carbohydrate metabolism; Systematic review; Outcomes research
22.  Renal function and sleep-disordered breathing in older men 
Nephrology Dialysis Transplantation  2008;23(12):3908-3914.
Background. Sleep-disordered breathing (SDB) is common in severe chronic kidney disease (CKD) and may contribute to morbidity and mortality in this population. However, the association between mild to moderate CKD and likelihood of SDB is uncertain.
Methods. We studied 2696 men ≥65 years (mean 73.0 ± 5.5) enrolled in the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study who had serum creatinine (SCr) measured 3.4 years prior to overnight polysomnography (PSG). CKD was expressed as quartiles of estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD) formula. SDB was assessed using the respiratory disturbance index (RDI) with ≥4% oxygen desaturation.
Results. Mean SCr was 0.99 ± 0.20 mg/dl; 14.8% had eGFR <60 ml/min/1.73 m2. Median RDI was 7.4 events/hour (inter-quartile range 2.6–15.8). Lower eGFR was not associated with higher mean RDI in the unadjusted model (P for trend = 0.180). There was evidence of an interaction between eGFR and age for the prediction of RDI; an association between lower eGFR and higher RDI was evident only among men ≤72 (median) years. Among this age group, however, the association was not statistically significant after further adjustment for body mass index (BMI) (P for trend = 0.278).
Conclusions. In this cohort of older community-dwelling men, reduced renal function was not associated with greater evidence of SDB, except among younger old men. However, this association was largely explained by higher BMI at lower eGFR. Further prospective study in younger populations is needed to clarify our findings.
PMCID: PMC2587522  PMID: 18644799
chronic kidney disease; kidney dysfunction; sleep disorders
23.  Association of the ACTN3 Genotype and Physical Functioning With Age in Older Adults 
The purpose of this study was to examine the association of the alpha-actinin-3 (ACTN3) R577X polymorphism on muscle function and physical performance in older adults.
We measured knee extensor torque, midthigh muscle cross-sectional area, muscle quality, short physical performance battery score, and 400-meter walk time at baseline and after 5 years in white older adults aged 70–79 years in the Health, Aging and Body Composition Study cohort (n = 1367). Incident persistent lower extremity limitation (PLL) over 5 years was additionally assessed. We also examined white men in the Osteoporotic Fractures in Men Study, a longitudinal, observational cohort (n = 1152) of men 65 years old or older as a validation cohort for certain phenotypes.
There were no significant differences between genotype groups in men or women for adjusted baseline phenotypes. Male X-homozygotes had a significantly greater adjusted 5-year increase in their 400-meter walk time compared to R-homozygotes and heterozygotes (p = .03). In women, X-homozygotes had a ~35% greater risk of incident PLL compared to R-homozygotes (hazard ratio = 0.65, 95% confidence interval = 0.44–0.94). There were no other significant associations between any of the phenotypes and ACTN3 genotype with aging in either cohort.
The ACTN3 polymorphism may influence declines in certain measures of physical performance with aging in older white adults, based on longitudinal assessments. However, the influence of the ACTN3 R577X polymorphism does not appear to have a strong effect on skeletal muscle–related phenotypes based on the strength and consistency of the associations and lack of replication with regard to specific phenotypes.
PMCID: PMC2728123  PMID: 19038838
Genetics; Elderly; Sarcopenia; Skeletal muscle
24.  Peripheral Arterial Disease Is Associated With Higher Rates of Hip Bone Loss and Increased Fracture Risk in Older Men 
Circulation  2009;119(17):2305-2312.
Peripheral arterial disease (PAD) and osteoporosis are chronic illnesses that increase in prevalence with aging and certain metabolic disorders. The association between PAD, rates of bone loss, and fracture risk in older men is uncertain.
Methods and Results
We sought to test the hypothesis that PAD is associated with higher rates of bone loss and increased fracture risk. We analyzed data from a prospective cohort study involving 6 US centers and 5781 men at least 65 years of age. We assessed ankle-brachial index and hip bone mineral density, followed up prospectively for changes in hip bone mineral density and fractures. PAD was defined as a baseline ankle-brachial index <0.9. Hip bone mineral density was measured with dual x-ray absorptiometry at baseline and again an average of 4.6 years later. Incident nonspine fractures were ascertained by self-report and confirmed with radiography reports during an average of 5.4 years of follow-up. At baseline, the prevalence of PAD was 6.2%. After adjustment for age, race, site, and baseline bone mineral density, the mean annualized rate of bone loss at the total hip was −0.66% per year (95% confidence interval −0.78 to −0.54) in men with PAD compared with −0.34% per year (95% confidence interval −0.36 to −0.31) in men without PAD (P<0.001). After further adjustment for multiple potential confounders, the difference was attenuated (−0.49% in men with PAD versus −0.35% in men without PAD) but remained significant (P=0.02). Findings were similar at hip subregions. Twelve percent of men with PAD and 7.9% of those without PAD experienced an incident nonspine fracture (hazard ratio adjusted for age, race, and site=1.47, 95% confidence interval 1.07 to 2.04); this association was not altered substantially by further adjustment for multiple confounders.
In community-dwelling older men, PAD was associated with higher rates of hip bone loss and increased risk of nonspine fractures. Further research should examine the biological mechanisms underlying the association between reduced limb blood flow and fractures.
PMCID: PMC2766264  PMID: 19380619
peripheral arterial disease; bone loss; fractures
25.  Differences in Site-Specific Fracture Risk Among Older Women with Discordant Results for Osteoporosis at Hip and Spine: the Study of Osteoporotic Fractures 
To examine the fracture pattern in older women whose bone mineral density (BMD) T-score criteria for osteoporosis at hip and spine disagree, hip and spine BMD were measured in Study of Osteoporotic Fractures participants using dual energy x-ray absorptiometry (DXA). Hip osteoporosis was defined as T-score ≤-2.5 at femoral neck or total hip, and spine osteoporosis as T-score ≤-2.5 at lumbar spine. Incident clinical fractures were self-reported and centrally adjudicated. Incident radiographic spine fractures were defined morphometrically. Compared to women with osteoporosis at neither hip nor spine, those osteoporotic only at hip had a 3.0-fold age and weight-adjusted increased risk for hip fracture (95%CI 2.4-3.6), and smaller increases in risk of nonhip nonspine (HR=1.6), clinical spine (OR=2.2), and radiographic spine fractures (OR=1.5). Women osteoporotic only at spine had a 2.8-fold increased odds of radiographic spine fracture (95%CI 2.1-3.8), and smaller increases in risk of clinical spine (OR=1.4), nonhip nonspine (HR=1.6), and hip fractures (HR=1.2). Discordant BMD results predict different fracture patterns. DXA fracture risk estimation in these patients should be site-specific. Women osteoporotic only at spine would not have been identified from hip BMD measurement alone, and may have a sufficiently high fracture risk to warrant preventive treatment.
PMCID: PMC2724071  PMID: 18296090
Osteoporosis; bone density; fractures; prospective studies; DXA

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