Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Replacing sedentary time for physical activity: Does intensity matter for body composition in oldest-old adults?

To assess the independent and combined relationships among objectively measured sedentary time (ST), light intensity PA (LPA), and moderate-to-vigorous intensity PA (MVPA) with muscle mass and fat mass (FM) and how theoretical displacement of these inter-dependent behaviours relates to body composition in oldest-old men. A total of 1046 men participating in the year 14 visit of the prospective Osteoporotic Fractures in Men (MrOS) cohort study with complete data for accelerometry, dual x-ray absorptiometry, and deuterated creatine dilution (D3Cr) muscle mass were included in the analysis (84.0 ± 3.8 yrs.). Single, partition, and isotemporal substitution models were used to assess the interrelationships between PA intensities and ST with body composition measures, while controlling for relevant confounders. Replacing 30-min of ST with 30-min of MVPA was associated with lower FM (ß =-0.17, p < 0.001) and higher D3Cr muscle mass, although this was of borderline significance (ß = 0.07, p = 0.05). Replacing 30-min of ST for LPA was associated with lower FM (ß =-0.15, p < 0.001), but there was no effect on D3Cr muscle mass (p > 0.05). Exchanging ST with any intensity of PA is associated with benefits for FM in oldest-old adult men, although substitution with MVPA may be more beneficial than LPA for maintaining/improving skeletal muscle mass.

Relation Between Dietary Protein Intake and Gut Microbiome Composition in Community-Dwelling Older Men: Findings from the Osteoporotic Fractures in Men Study (MrOS).

BACKGROUND: Little is known about the association of specific nutrients, especially proteins, on age-related gut dysbiosis. OBJECTIVES: To determine the associations between the quantity and sources (vegetable and animal) of dietary protein intake and gut microbiome composition in community-dwelling older men. METHODS: We performed a cross-sectional analysis on 775 older men from the Osteoporotic Fractures in Men Study (MrOS) (age 84.2 ± 4.0 y) with available dietary information and stool samples at visit 4 (2014-2016). Protein intake was estimated from a brief FFQ and adjusted to total energy intake. The gut microbiome composition was determined by 16S (v4) sequencing (processed by DADA2 and SILVA). A total of 11,534 amplicon sequence variants (ASVs) were identified and assigned to 21 phyla with dominance of Firmicutes (45%) and Bacteroidetes (43%). We performed α-diversity, ß-diversity, and taxa abundance (by Analysis of Compositions of Microbiomes with Bias Correction [ANCOM-BC]) to determine the associations between protein intake and the gut microbiome. RESULTS: Median protein intake was 0.7 g/(kg body weight · d). Participants with higher energy-adjusted protein intakes had higher Shannon and Chao1 α-diversity indices (P < 0.05). For ß-diversity analysis, participants with higher protein intakes had a different center in weighted and unweighted UniFrac Principal Co-ordinates Analysis (PCoA) compared with those with lower intake (P < 0.05), adjusted for age, race, education, clinical center, batch number, fiber and energy intake, weight, height, and medications. Similarly, higher protein consumptions from either animal or vegetable sources were associated with higher gut microbiome diversity. Several genus-level ASVs, including Christensenellaceae, Veillonella, Haemophilus, and Klebsiella were more abundant in participants with higher protein intakes, whereas Clostridiales bacterium DTU089 and Desulfovibrio were more abundant in participants with lower protein intake (Bonferroni corrected P < 0.05). CONCLUSIONS: We observed significant associations between protein intake and gut microbiome diversity in community-living older men. Further studies are needed to elucidate the mediation role of the gut microbiome on the relation between protein intake and health outcomes in older adults.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

BACKGROUND: The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. OBJECTIVE: To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. DESIGN: Cohort study. SETTING: UK Biobank prospective cohort. PARTICIPANTS: Community-dwelling men aged 40 to 69 years. MEASUREMENTS: Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. RESULTS: Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). LIMITATION: Observational study; single baseline measurement of testosterone and SHBG. CONCLUSION: Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. PRIMARY FUNDING SOURCE: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Lower serum testosterone concentrations are associated with a higher incidence of dementia in men: The UK Biobank prospective cohort study.

INTRODUCTION: The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. METHODS: Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. RESULTS: In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P = .001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13-1.81), and AD (P = .017, HR = 1.80, CI = 1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P < .001, HR = 0.66, CI = 0.51-0.85) and AD (P = .012, HR = 0.53, CI = 0.34-0.84). DISCUSSION: Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.

Oxylipins Associated with D3-Creatine Muscle Mass/Weight and Physical Performance among Community-Dwelling Older Men.

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography-mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men.

Sociodemographic, lifestyle and medical influences on serum testosterone and sex hormone-binding globulin in men from UK Biobank.

OBJECTIVE: Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years. DESIGN: Cross-sectional analysis of 208,677 community-dwelling men from the UK Biobank. MEASUREMENTS: We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates. RESULTS: Median (interquartile range) for serum testosterone was 11.6 (9.4-14.1) nmol/L, SHBG 36.9 (27.9-48.1) nmol/L and cFT 213 (178-255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P < .001). Living with a partner, (South) Asian ethnicity, never or previous smoker and some medical conditions were associated with lower testosterone. Poultry or fish eater, and higher physical activity were associated with higher testosterone (all P < .001). Testosterone was lowered by ~0.5 nmol/L across ages, ~1.5 nmol/L for BMI 30 vs 25 kg/m2 , ~2 nmol/L for (South) Asian ethnicity, living with partner, college/university qualifications, low red meat eater, insufficient physical activity and 0.3-1.0 nmol/L with cardiovascular disease or diabetes. Different combinations of these factors varied serum testosterone by ~4 nmol/L, SHBG by ~30 nmol/L and cFT by ~60 pmol/L. CONCLUSIONS: The identified modifiable risk factors support lifestyle-based interventions in men with low testosterone concentrations. Considering sociodemographic, lifestyle and medical factors facilitates more personalized interpretation of testosterone testing results with respect to existing reference ranges.

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Individual and joint trajectories of change in bone, lean mass and physical performance in older men.

BACKGROUND: Declines in bone, muscle and physical performance are associated with adverse health outcomes in older adults. However, few studies have described concurrent age-related patterns of change in these factors. The purpose of this study was to characterize change in four properties of muscle, physical performance, and bone in a prospective cohort study of older men. METHODS: Using repeated longitudinal data from up to four visits across 6.9 years from up to 4681 men (mean age at baseline 72.7 yrs. ±5.3) participating in the Osteoporotic Fractures in Men (MrOS) Study, we used group-based trajectory models (PROC TRAJ in SAS) to identify age-related patterns of change in four properties of muscle, physical performance, and bone: total hip bone mineral (BMD) density (g/m2) and appendicular lean mass/ht2 (kg/m2), by DXA; grip strength (kg), by hand dynamometry; and walking speed (m/s), by usual walking pace over 6 m. We also described joint trajectories in all pair-wise combinations of these measures. Mean posterior probabilities of placement in each trajectory (or joint membership in latent groups) were used to assess internal reliability of the model. The number of trajectories for each individual factor was limited to three, to ensure that the pair-wise determination of joint trajectories would yield a tractable number of groups as well as model fit considerations. RESULTS: The patterns of change identified were generally similar for all measures, with three district groups declining over time at roughly similar rates; joint trajectories revealed similar patterns with no cross-over or convergence between groups. Mean posterior probabilities for all trajectories were similar and consistently above 0.8 indicating reasonable model fit to the data. CONCLUSIONS: Our description of trajectories of change with age in bone mineral density, grip strength, walking speed and appendicular lean mass found that groups identified by these methods appeared to have little crossover or convergence of change with age, even when considering joint trajectories of change in these factors.

Rest-activity patterns and falls and fractures in older men.

Dysregulated rest-activity rhythm (RAR) patterns have been associated with several health conditions in older adults. This study showed that later acrophase was associated with a modestly greater risk of falls but not fractures in elderly men. Associations between dysregulated RAR patterns and osteoporosis risk warrant further investigation. PURPOSE: The purpose of this study was to investigate the relationship between rest-activity rhythm (RAR) patterns and risk of falls/fractures in older men. We hypothesized that dysregulated RAR would be associated with incident falls/fractures. METHODS: We used wrist-worn actigraphy to measure RAR over 4.8 ± 0.8 24-h periods in men (≥67 years) enrolled in the multicenter Outcomes of Sleep Disorders in Men (MrOS Sleep) Study (n = 3001). Men were contacted every 4 months to report occurrence of falls/fractures. RAR parameters included amplitude (difference between peak and nadir activity in counts/minute), mesor (activity counts/minute), acrophase (time of day of peak activity), and pseudo-F statistic (rhythm robustness) and were evaluated as continuous variables with associations reported per SD increase/decrease in models adjusted for confounders. Logistic regression was used to estimate the likelihood (odds ratio, OR) of recurrent falls in the year after the visit. Proportional hazards models were used to estimate the risk (hazard ratio, HR) of fractures. RESULTS: One year after the visit, 417 men (14%) had recurrent (≥2) falls. Later acrophase (OR 1.18, 95% CI 1.06-1.32) was associated with a modestly greater likelihood of falls. In 8.6 years (SD 2.6 years) of >97% complete follow-up, 256 men (8.53%) had a major osteoporotic fracture, 85 (2.8%) had a clinical spine fracture, and 110 (3.7%) had a hip fracture. No consistent, significant associations were observed between RAR patterns and fractures. CONCLUSIONS: Later acrophase was associated with a modestly greater risk of falls; this association did not translate into a higher fracture risk in this cohort of elderly men.

Screening for Osteoporosis in Older Men: Operating Characteristics of Proposed Strategies for Selecting Men for BMD Testing.

BACKGROUND: The optimal approach for selecting men for bone mineral density (BMD) testing to screen for osteoporosis is uncertain. OBJECTIVE: To compare strategies for selecting older men for screening BMD testing. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 4043 community-dwelling men aged ≥70 years at four US sites. MAIN MEASURES: BMD at the total hip, femoral neck, and lumbar spine using dual-energy x-ray absorptiometry (DXA). Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and area under the receiver operating curve (AUC) of the Osteoporosis Self-Assessment Tool (OST) and Fracture Risk Assessment Tool (FRAX) without BMD to discriminate between those with and without osteoporosis as defined by World Health Organization (WHO) diagnostic criteria, and between those recommended and not recommended for pharmacologic therapy based on the National Osteoporosis Foundation (NOF) guidelines. KEY RESULTS: Among the cohort, 216 (5.3%) had a BMD T-score ≤ -2.5 at the femoral neck, total hip, or lumbar spine, and 1184 (29.2%) met criteria for consideration of pharmacologic therapy according to NOF guidelines. The OST had better discrimination (AUC 0.68) than the FRAX (AUC 0.62; p = 0.004) for identifying T-score-defined osteoporosis. Use of an OST threshold of <2 resulted in sensitivity of 0.83 and specificity of 0.36 for the identification of osteoporosis, compared to sensitivity of 0.59 and specificity of 0.59 for the use of FRAX with a cutoff of 9.3% 10-year risk of major osteoporotic fracture. CONCLUSIONS: The OST performs modestly better than the more complex FRAX in selecting older men for BMD testing to screen for osteoporosis; the use of either tool substantially reduces the proportion of men referred for BMD testing compared to universal screening. Of 1000 men aged 70 and older in this community-based cohort, the use of an OST cutoff of <2 to select men for BMD testing would result in 654 men referred for BMD testing, of whom 44 would be identified as having osteoporosis, and nine with osteoporosis would be missed.

Comparison of Associations of DXA and CT Visceral Adipose Tissue Measures With Insulin Resistance, Lipid Levels, and Inflammatory Markers.

Visceral adipose tissue (VAT) measured by computed tomography (CT) is related to insulin resistance, lipids, and serum inflammatory markers. Our objective was to compare the strength of the associations of VAT measured using dual-energy X-ray absorptiometry (DXA-VAT) and CT (CT-VAT) with insulin resistance, serum lipids, and serum markers of inflammation. For 1117 men aged 65 and older enrolled in the Osteoporotic Fractures in Men Study, the cross-sectional associations of DXA-VAT and CT-VAT with homeostasis model assessment of insulin resistance (homa2ir), C-reactive protein, and high-density lipoprotein (HDL) cholesterol were estimated with regression models and compared using a Hausman test. Adjusted for age and body mass index, DXA-VAT was moderately associated with homa2ir (effect size 0.38, 95% confidence interval [CI]: 0.28-0.47) and modestly associated with HDL cholesterol (DXA effect size -0.29, 95% CI: -0.38 to -0.21). These associations were significantly greater than those for CT-VAT with homa2ir (0.30, 95% CI: 0.24-0.37; p value for effect size difference 0.03) and CT-VAT with HDL cholesterol (-0.22, 95% CI: -0.29 to -0.15; p value for difference 0.005). Neither DXA-VAT nor CT-VAT was associated with C-reactive protein after adjustment for age and body mass index (DXA-VAT effect size 0.14, 95% CI: -0.04 to 0.32; CT-VAT effect size 0.08, 95% CI: -0.08 to 0.25; p value for difference 0.35). DXA-VAT has similar or greater associations with insulin resistance and HDL cholesterol as does CT-VAT in older men, confirming the concurrent validity of DXA-VAT. Investigations of how well DXA measurements of VAT predict incident cardiovascular disease events are warranted.

Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1-FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1-FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1-FGFR1 and FN1-FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1-FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins.

Lower Urinary Tract Symptoms and Risk of Nonspine Fractures among Older Community Dwelling U.S. Men.

PURPOSE: Among older men, moderate and severe lower urinary tract symptoms are associated with increased fall risk compared to mild lower urinary tract symptoms. Falls are a major risk factor for fractures. Therefore, we assessed associations of lower urinary tract symptoms with fracture risk in community dwelling U.S. men age 65 years or older. MATERIALS AND METHODS: We conducted a prospective study in the MrOS (Osteoporotic Fractures in Men Study) cohort. Men were enrolled at 6 U.S. sites. The AUA-SI, lower urinary tract symptoms medication use, fracture risk factors and potential confounders were recorded at baseline and every 2 years thereafter for 4 assessments. Lower urinary tract symptom severity was categorized from the AUA-SI as mild (0 to 7 points), moderate (8 to 19 points) or severe (20 or more points). Associations of lower urinary tract symptom severity with fracture rate were estimated with HRs and 95% CIs from extended proportional hazards regression. RESULTS: Among 5,989 men with baseline AUA-SI score and hip bone mineral density measures, 745 incident nonspine fractures occurred during 43,807 person-years of followup. In a multivariable model adjusted for age, enrollment site, baseline hip bone mineral density, falls in the last year and prevalent fracture before baseline, there were no significant associations of moderate (HR 0.9, 95% CI 0.8-1.1) or severe (HR 1.0, 95% CI 0.8-1.3) lower urinary tract symptoms with fracture risk. None of the individual lower urinary tract symptoms assessed on the AUA-SI, including nocturia and urgency, was associated with increased fracture risk. CONCLUSIONS: In this cohort of older U.S. men, lower urinary tract symptoms were not independently associated with fracture risk.

Actigraphy- and Polysomnography-Measured Sleep Disturbances, Inflammation, and Mortality Among Older Men.

OBJECTIVES: To evaluate whether objectively measured sleep characteristics are associated with mortality risk independent of inflammatory burden and comorbidity. METHODS: The Osteoporotic Fractures in Men Sleep Study (conducted in 2003-2005) included community-dwelling older men (n = 2531; average [standard deviation {SD}] age = 76.3 (5.5) years). Sleep measures from in-home polysomnography and wrist actigraphy and assessments of serum inflammatory markers levels (C-reactive protein, interleukin-6, tumor necrosis factor α, tumor necrosis factor α soluble receptor II, and interferon-γ) were obtained. Vital status was ascertained over an average (SD) follow-up of 7.4 (1.9 SD) years. RESULTS: Three of the seven main sleep measures examined were independently associated with greater inflammatory burden. Mortality risk associated with prolonged (≥10% total sleep time) blood oxygen desaturation and short (<5 hours) sleep duration was attenuated to nonsignificance after adjusting for inflammatory burden or medical burden/lifestyle factors. Severe blood oxygen desaturation (adjusted hazard ratio [aHR] = 1.57, 95% confidence interval [CI] = 1.11-2.22), sleep fragmentation (aHR = 1.32, 95% CI = 1.12-1.57), and a lower percentage of sleep in rapid eye movement (aHR per SD = 0.90, 95% CI = 0.93-0.97) were independently associated with mortality. CONCLUSIONS: Short sleep duration and prolonged blood oxygen desaturation were independently associated with inflammatory burden, which attenuated associations between these sleep characteristics and mortality. Medical and life-style factors also substantially attenuated most sleep-mortality associations, suggesting complex relations between sleep, inflammation, and disease. Sleep fragmentation, severe blood oxygen desaturation, and the percentage of sleep time in rapid eye movement were independently related to mortality risk. Future studies with repeated measures of mediators/confounds will be necessary to achieve a mechanistic understanding of sleep-related mortality risk.

Sensorimotor Peripheral Nerve Function and Physical Activity in Older Men.

We determined whether sensorimotor peripheral nerve (PN) function was associated with physical activity (PA) in older men. The Osteoporotic Fractures in Men Study Pittsburgh, PA, site (n = 328, age 78.8 ± 4.7 years) conducted PN testing, including: peroneal motor and sural sensory nerve conduction (latencies, amplitudes: CMAP and SNAP for motor and sensory amplitude, respectively), 1.4g/10g monofilament (dorsum of the great toe), and neuropathy symptoms. ANOVA and multivariate linear regression modeled PN associations with PA (Physical Activity Scale for the Elderly [PASE] and SenseWear Armband). After multivariable adjustment, better motor latency was associated with higher PASE scores (160.5 ± 4.8 vs. 135.6 ± 6.7, p < .01). Those without versus with neuropathy symptoms had higher PASE scores (157.6 ± 5.3 vs. 132.9 ± 7.1, p < .01). Better versus worse SNAP was associated with slightly more daily vigorous activity (9.5 ± 0.8 vs. 7.3 ± 0.7, p = .05). Other PN measures were not associated with PA. Certain PN measures were associated with lower PA, suggesting a potential pathway for disability.

Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis.

OBJECTIVES: To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA. METHODS: The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis. RESULTS: The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation. CONCLUSIONS: Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

Fracture risk in diabetic elderly men: the MrOS study.

AIMS/HYPOTHESIS: Diabetes mellitus is associated with increased fracture risk in women but few studies are available in men. To evaluate the relationship between diabetes and prospective non-vertebral fractures in elderly men, we used data from the Osteoporotic Fractures in Men (MrOS) study. METHODS: The MrOS enrolled 5,994 men (aged ≥65 years). Diabetes (ascertained by self-report, the use of medication for diabetes or an elevated fasting glucose level) was reported in 881 individuals, 80 of whom were using insulin. Hip and spine bone mineral density (BMD) was measured using dual x-ray absorptiometry (DXA). After recruitment, the men were followed for incident non-vertebral fractures using a triannual (3 yearly) questionnaire for an average of 9.1 (SD 2.7) years. The Cox proportional hazards model was used to assess the incident risk of fractures. RESULTS: In models adjusted for age, race, clinic site and total hip BMD, the risk of non-vertebral fracture was higher in men with diabetes compared with normoglycaemic men (HR 1.30, 95% CI 1.09, 1.54) and was elevated in men using insulin (HR 2.46, 95% CI 1.69, 3.59). Men with impaired fasting glucose did not have a higher risk of fracture compared with normoglycaemic men (HR 1.04, 95% CI 0.89, 1.21). After multivariable adjustment, the risk of non-vertebral fracture remained higher only among men with diabetes who were using insulin (HR 1.74, 95% CI 1.13, 2.69). CONCLUSIONS/INTERPRETATION: Men with diabetes who are using insulin have an increased risk of non-vertebral fracture for a given age and BMD.