The Limited Clinical Utility of Testosterone, Estradiol, and Sex Hormone Binding Globulin Measurements in the Prediction of Fracture Risk and Bone Loss in Older Men.

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 (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG (>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.

Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations.

CONTEXT: Normocalcemic primary hyperparathyroidism is typically identified after referral to a specialty clinic. At diagnosis, patients demonstrate features seen in hypercalcemic primary hyperparathyroidism. Normocalcemic hypoparathyroidism has been discovered after hypocalcemia unmasked after bisphosphonate administration. OBJECTIVE: We hypothesized that screening unselected, nonreferral populations, such as The Osteoporotic Fractures in Men (MrOS) study and Dallas Heart Study (DHS), would identify asymptomatic subjects with normocalcemic hyperparathyroidism and hypoparathyroidism. METHODS: Normocalcemic hyperparathyroidism was defined as serum PTH greater than the upper reference range with normal albumin-adjusted serum calcium, excluding common secondary causes (renal failure [estimated glomerular filtration rate <60 mL/min], 25-hydroxyvitamin D <20 ng/mL, and thiazide use), and normocalcemic hypoparathyroidism as PTH below the reference range with normocalcemia. Cross-sectional data were obtained from MrOS, and longitudinal data (baseline and 8 years) from DHS. RESULTS: In 2364 men from MrOS, we identified 9 with normocalcemic hyperparathyroidism (prevalence 0.4%) and 26 with normocalcemic hypoparathyroidism (1.1%). In 3450 men and women from DHS, we identified 108 with normocalcemic hyperparathyroidism (3.1%) and 68 with normocalcemic hypoparathyroidism (1.9%). Of the 108 normocalcemic hyperparathyroid subjects, 64 had follow-up data. Hypercalcemic primary hyperparathyroidism developed in 1 subject whereas 13 (0.6% of the follow-up cohort) showed persistently elevated PTH levels with normocalcemia. Of the 26 normocalcemic hypoparathyroid subjects with follow-up data, none developed overt hypoparathyroidism and 2 (0.09%) had persistent evidence of normocalcemic hypoparathyroidism. CONCLUSIONS: This study documents normocalcemic primary hyperparathyroidism and hypoparathyroidism identified among community-dwelling individuals. Larger studies are needed to determine the true prevalence and natural history of these parathyroid disorders.

The burden of urinary incontinence and urinary bother among elderly prostate cancer survivors.

BACKGROUND: Data describing urinary health in elderly, community-dwelling prostate cancer (PCa) survivors are limited. OBJECTIVE: To elucidate the prevalence of lower urinary tract symptoms, urinary bother, and incontinence in elderly PCa survivors compared with peers without PCa. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of 5990 participants in the Osteoporotic Fractures in Men Research Group, a cohort study of community-dwelling men ≥ 65 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We characterized urinary health using self-reported urinary incontinence and the American Urological Association Symptom Index (AUA-SI). We compared urinary health measures according to type of PCa treatment in men with PCa and men without PCa using multivariate log-binomial regression to generate prevalence ratios (PRs). RESULTS AND LIMITATIONS: At baseline, 706 men (12%) reported a history of PCa, with a mean time since diagnosis of 6.3 yr. Of these men, 426 (60%) reported urinary incontinence. In adjusted analyses, observation (PR: 2.11; 95% confidence interval [CI], 1.22-3.65; p=0.007), surgery (PR: 4.41; 95% CI, 3.79-5.13; p<0.0001), radiation therapy (PR: 1.49; 95% CI, 1.06-2.08; p=0.02), and androgen-deprivation therapy (ADT) (PR: 2.02; 95% CI, 1.31-3.13; p=0.002) were each associated with daily incontinence. Daily incontinence risk increased with time since diagnosis independently of age. Observation (PR: 1.33; 95% CI, 1.00-1.78; p=0.05), surgery (PR: 1.25; 95% CI, 1.10-1.42; p=0.0008), and ADT (PR: 1.50; 95% CI, 1.26-1.79; p<0.0001) were associated with increased AUA-SI bother scores. Cancer stage and use of adjuvant or salvage therapies were not available for analysis. CONCLUSIONS: Compared with their peers without PCa, elderly PCa survivors had a two-fold to five-fold greater prevalence of urinary incontinence, which rose with increasing survivorship duration. Observation, surgery, and ADT were each associated with increased urinary bother. These data suggest a substantially greater burden of urinary health problems among elderly PCa survivors than previously recognized.

Abdominal myosteatosis is independently associated with hyperinsulinemia and insulin resistance among older men without diabetes.

OBJECTIVE: Skeletal muscle adipose tissue (AT) infiltration (myosteatosis) increases with aging and may contribute to the development of Type 2 diabetes mellitus (T2DM). It remains unclear if myosteatosis is associated to glucose and insulin homeostasis independent of total and central adiposity. DESIGN AND METHODS: The association between intermuscular AT (IMAT) in the abdominal skeletal muscles (total, paraspinal, and psoas) and fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 393 nondiabetic Caucasian men aged 65+ was evaluated. Abdominal IMAT, visceral AT (VAT), and subcutaneous AT (SAT) (cm(3) ) were measured by quantitative computed tomography at the L4-L5 intervertebral space. RESULTS: In age, study site, height, and muscle volume adjusted regression analyses, total abdominal and psoas (but not paraspinal) IMAT were positively associated with glucose, insulin, and HOMA-IR (all P < 0.003). The associations between total abdominal and psoas IMAT and insulin and HOMA-IR remained significant after further adjusting for lifestyle factors, as well as duel-energy x-ray absorptiometry (DXA) measured total body fat, VAT, or SAT in separate models (all P < 0.009). CONCLUSIONS: A previously unreported, independent association between abdominal myosteatosis and hyperinsulinemia and insulin resistance among older Caucasian men was indicated. These associations may be specific for particular abdominal muscle depots, illustrating the potential importance of separately studying specific muscle groups.

Higher testosterone levels are associated with less loss of lean body mass in older men.

CONTEXT: Little information exists about longitudinal changes in body composition and physical function in relation to sex hormone levels in older men. OBJECTIVE: The aim of the study was to determine associations of testosterone, estradiol, and SHBG with changes in body composition and physical function. DESIGN AND SETTING: We conducted a prospective cohort study within the Osteoporotic Fractures in Men (MrOS) study at six U.S. clinical centers. PARTICIPANTS: A total of 5994 ambulatory men aged 65 yr or older enrolled in the MrOS. We examined 1183 men with complete measures of sex steroid hormones, body composition, and some measure of physical function. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURE(S): Sex steroids were measured by mass spectrometry in serum collected at baseline. Measurements of body composition using dual-energy x-ray absorptiometry and physical performance (grip strength, leg power, timed chair stands, narrow walk, and 6-m walk) were performed at baseline and repeated 4.5 yr later. RESULTS: Overall, men lost 1.3 kg (±4.4 sd) weight between study visits. Lean mass, especially appendicular, declined less at higher baseline testosterone levels (P < 0.05). These associations were most evident in the 40% of men who lost more than 2.0 kg during follow-up. In weight losers, higher testosterone was associated with less decline in timed chair stands. Estradiol was not related to body composition or physical function changes. Higher SHBG was associated with less loss of appendicular lean mass and grip strength. CONCLUSIONS: Higher endogenous testosterone is associated with reduced loss of lean mass and lower extremity function in older men losing weight. Endogenous testosterone may contribute to healthy aging.

Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts.

CONTEXT: Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. METHODS: TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. RESULTS: In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. CONCLUSION: Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

Progression of lower urinary tract symptoms in older men: a community based study.

PURPOSE: Lower urinary tract symptom progression in community dwelling older men is not well described. MATERIALS AND METHODS: We evaluated 5,697 participants in Osteoporotic Fractures in Men, a prospective cohort study of community dwelling men 65 years old or older. We characterized lower urinary tract symptoms using the American Urological Association symptom index at 2 time points, including at study entry and at 2-year followup. Progression was examined in the overall cohort and within baseline symptom strata (symptom index 7 or less and 8 or greater) using descriptive statistics. RESULTS: At baseline mean +/- SD age was 73.5 +/- 5.8 years and mean symptom index score was 8.3 +/- 6.3 points. Mean and median total symptom index increased during followup by 1.1 +/- 5.0 and 1.0 points, respectively. Of the 3,092 men with a symptom index of 7 points or less at baseline 883 (29%) reported lower urinary tract symptoms progression (8 points or greater) at followup. The incidence of lower urinary tract symptom progression increased with advancing baseline age. Of the 2,605 men with a symptom index of 8 points or greater at baseline 622 (24%) reported progression of at least 4 points at followup. Of the 2,200 men with a baseline symptom index of 7 points or less and no history of benign prostatic hyperplasia or lower urinary tract symptom treatment 94% remained untreated, 2% reported benign prostatic hyperplasia surgery and 4% reported medication use at followup. CONCLUSIONS: Up to 29% of community dwelling older men with no or mild lower urinary tract symptoms will have clinically significant lower urinary tract symptoms within 2 years. These data help elucidate the natural history of lower urinary tract symptoms in the community and provide useful data to design clinical trials of lower urinary tract symptom prevention.

Association between sex steroids and cognition in elderly men.

OBJECTIVE: To examine the association of cognitive function with sex steroid and sex hormone binding globulin (SHBG) levels among elderly men. DESIGN: Prospective cohort study, The Osteoporotic Fractures in Men Study (MrOS), consisting of 5995 US community dwelling men of 65 years or older. PATIENTS: One thousand six hundred and two men were chosen randomly from MrOS cohort for sex steroid level measurements by Mass Spectrometry (MS) at baseline. Two thousand six hundred and twenty-three MrOS participants with sex steroids measured using RIA were also examined. MEASUREMENTS: Baseline and follow-up (4.5 years later) performance on two cognitive tests: Trails B (executive function and motor speed) and 3MS (global cognitive function). Baseline total testosterone and oestradiol were measured by MS. Free testosterone (free-T) and free oestradiol (free-E) were calculated. SHBG was measured by radioimmunoassay. Data were analysed using linear regression. RESULTS: Baseline free-T and free-E levels were not associated with cognitive performance or change in cognition, following adjustment for age, education, race, health status and alcohol use. Baseline SHBG levels were inversely associated with follow-up trails B (P = 0.03) and 3MS performance (P = 0.02). Higher SHBG was associated with an increased risk of cognitive decline. Total sex steroid levels were not associated with cognitive performance. CONCLUSIONS: Despite large numbers of participants and rigorous sex steroid measurements, we did not observe an association between cognition and either testosterone or oestradiol levels. We conclude that endogenous sex steroids in the normal range are not related to executive function or global cognitive function in elderly men. High SHBG deserves further examination as a risk factor for cognitive decline.