The lifespan of men is increasing and this is associated with an increased prevalence of osteoporosis in men. Osteoporosis increases the risk of bone fracture. Fractures are associated with increased disability and mortality, and public health problems. We review here the study of osteoporosis in men as obtained from a longitudinal cohort of community-based older men, the Osteoporotic Fractures in Men Study (MrOS).

Hyponatremia may be a risk factor for fracture. To determine the relationship between hyponatremia and fracture we conducted cross-sectional and longitudinal analyses using data from the Osteoporotic Fractures in Men (MrOS) study. The MrOS study enrolled 5122 community dwelling men aged ≥65 years from six centers across the United States. We excluded men taking bisphosphonates, those with unknown medication history, those without serum sodium measures, or those with out of range assays for serum sodium. Serum sodium was measured at study entry. Subjects were followed for fractures (nonspine [including hip], hip, incident morphometric, and prevalent morphometric) for up to 9 years. We used Cox proportional hazards models to analyze the association between serum sodium levels (<135 mmol/L versus ≥135 mmol/L) and risk of nonspine and hip fractures, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We examined the association between morphometric vertebral fractures and serum sodium using logistic regression models, presented as odds ratios (ORs) and 95% CI. Hyponatremia was observed in 64 men (1.2% of the cohort). After adjusting for age, BMI, study center, and other covariates, we found that, compared to men with serum sodium ≥135 mmol/L, those with serum sodium <135 mmol/L, had an increased risk of hip fracture (HR = 3.04; 95% CI, 1.37 to 6.75), prevalent morphometric spine fracture (OR = 2.46; 95% CI, 1.22 to 4.95), and incident morphometric spine fracture (OR = 3.53; 95% CI, 1.35 to 9.19), but not nonspine fracture (OR = 1.44; 95% CI, 0.85 to 2.44). Adjusting for bone mineral density (BMD) did not change our findings. Our data show that hyponatremia is associated with up to a doubling in the risk of hip and morphometric spine fractures, independent of BMD. Further studies, to determine how hyponatremia causes fractures and if correction of hyponatremia decreases fractures, are needed.

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.

The last five years have witnessed a remarkable renaissance in vitamin D research and a complete re-evaluation of its benefits to human health. Two key factors have catalyzed these changes. First, it now seems likely that localized, tissue-specific, conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) drives many of the newly recognized effects of vitamin D on human health. The second key factor concerns the ongoing discussion as to what constitutes adequate or optimal serum vitamin D (25OHD) status, with the possibility that vitamin D-deficiency is common to communities across the globe. These two concepts appear to be directly linked when low serum concentrations of 25OHD compromise intracrine generation of 1,25(OH)2D within target tissues. But, is this an over-simplification? Pro-hormone 25OHD is a lipophilic molecule that is transported in the circulation bound primarily to vitamin D binding protein (DBP). While the association between 25OHD and DBP is pivotal for renal handling of 25OHD and endocrine synthesis of 1,25(OH)2D, what is the role of DBP for extra-renal synthesis of 1,25(OH)2D? We hypothesize that binding to DBP impairs delivery of 25OHD to the vitamin D-activating enzyme 1α-hydroxylase in some target cells. Specifically, it is unbound, 'free' 25OHD that drives many of the non-classical actions of vitamin D. Levels of 'free' 25OHD are dependent on the concentration of DBP and alternative serum binding proteins such as albumin, but will also be influenced by variations in DBP binding affinity for specific vitamin D metabolites. The aim of this review will be to discuss the merits of 'free 25OHD' as an alternative marker of vitamin D status, particularly in the context of non-classical responses to vitamin D. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Study objectives

To determine the association between common genetic variation in the clock gene pathway and objectively measured acti-graphic sleep and activity rhythm traits.

Design

Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study.

Setting

Population-based.

Participants

SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data.

Interventions

N/A.

Measurements and results

Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene GNB3, the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 PADD = 2 × 10(-5), rs2238114 PADD = 5 × 10(-5)) and lower LRRC23 gene expression (rs1047776: ρ = -0.22, P = 0.02; rs2238114: ρ = -0.50, P = 5 × 10(-8)). In MrOS participants, SNPs in ARNTL and NPAS2, genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: ARNTL rs3816358 P2DF = 1 × 10(-4), NPAS2 rs3768984 P2DF = 5 × 10(-5); wake onset time: rs3816358 P2DF = 3 × 10(-3), rs3768984 P2DF = 2 × 10(-4)) and the SNP interaction was significant (sleep onset time PINT = 0.003, wake onset time PINT = 0.001). A SNP association in the CLOCK gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations.

Conclusions

These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly.

Citation

Evans DS; Parimi N; Nievergelt CM; Blackwell T; Redline S; Ancoli-Israel S; Orwoll ES; Cummings SR; Stone KL; Tranah GJ. Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. SLEEP 2013;36(3):431-446.

Background

Muscle mass declines with age, while body adiposity increases. Sarcopenic obesity has been proposed to be particularly deleterious. However, previous methods for estimating muscle mass have been inadequate, and the relative contributions of total body fat versus muscle fat to adverse outcomes have been unclear.

Method

In a large cohort of older men (N = 1 017), we measured muscle mass (D3-creatine dilution), muscle density (high-resolution peripheral quantitative computed tomography in the diaphyseal tibia) as a proxy of muscle fat, and total body fat (dual-energy x-ray absorptiometry). We examined their associations with physical performance (walking speed, grip strength, chair stand time), the risk of mobility outcomes (mobility limitations, mobility disability), and the risk of death over ~5 years.

Results

In combined models, lower muscle mass and muscle density were independently associated with worse physical performance and the risk of adverse outcomes, while total body fat was minimally related to physical performance and not related to mobility outcomes or mortality. For example, the relative risks for mortality per 1 standardized unit increase in muscle density, muscle mass, and total body fat were 0.84 (95% confidence interval: 0.74, 0.96), 0.70 (0.57, 0.86), and 0.90 (0.64, 1.25), respectively.

Conclusions

Muscle mass and muscle density were associated with physical performance and adverse outcomes, and had independent, additive effects. There was little additional contribution of total body fat.

Low serum 25-hydroxy vitamin D (25(OH)D) concentrations are associated with increased hip fracture risk and decreased femoral areal bone mineral density (BMD) among elderly men. Structural dimensions of the proximal femur and volumetric BMD in cortical and trabecular compartments are also associated with hip fracture risk. However, associations of volumetric BMD or structural dimensions with serum 25(OH)D concentrations among older men remain unclear. In a random sample of 1608 men aged ≥65 years from the Osteoporotic Fractures in Men Study (MrOS), baseline serum 25(OH)D concentrations were measured by liquid chromatography/mass spectrometry assays. Femoral neck geometry and volumetric BMD derived from quantitative computed tomography included integral, cortical, and trabecular volumetric BMD; cross-sectional area; integral and cortical volume; and cortical volume as a percent of integral volume. We studied 888 men with vitamin D, parathyroid hormone (PTH), femoral neck geometry, and BMD measures. Whole-bone femoral strength and load-strength ratio from finite element (FE) analysis were also available for 356 men from this sample. Multivariable linear regression was used to estimate least square means of each femoral measure within quartiles of 25(OH)D adjusted for age, race, body mass index, height, latitude, and season of blood draw. Tests of linear trend in the means were performed across increasing quartile of serum 25(OH)D levels. Mean cortical volume (p trend = 0.006) and cortical volume as a percent of integral volume (p trend < 0.001) increased across increasing quartile of 25(OH)D level. However, overall femoral neck size (area and integral volume) did not vary by 25(OH)D level. Femoral neck volumetric BMD measures increased in a graded manner with higher 25(OH)D levels (p trend < 0.001). Femoral strength, but not load-strength ratio, increased with increasing 25(OH)D. Adjustment for PTH did not materially change these associations. We conclude that in older men, higher levels of endogenous 25(OH)D may increase whole-bone strength by increasing femoral volumetric BMD and cortical volume.

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.

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.

Muscle strength and physical performance are associated with incident fractures and mortality. However, their role in the risk of subsequent fracture and postfracture mortality is not clear. We assessed the association between muscle strength (grip strength) and performance (gait speed and chair stands time) and the risk of subsequent fracture and mortality in 830 men with low-trauma index fracture, who participated in the Osteoporotic Fractures in Men (MrOS) USA Study and had their index measurements assessed within 5 years prior to the index fracture. The annual decline in muscle strength and performance following index fracture, estimated using linear mixed-effects regression, was also examined in relation to mortality. The associations were assessed using Cox proportional hazards models adjusted for age, femoral neck bone mineral density (FN BMD), prior fractures, falls, body mass index (BMI), index fracture site, lifestyle factors, and comorbidities. Over a median follow-up of 3.7 (interquartile range [IQR], 1.3-8.1) years from index fracture to subsequent fracture, 201 (24%) men had a subsequent fracture and over 5.1 (IQR, 1.8-9.6) years to death, and 536 (65%) men died. Index measurements were not associated with subsequent fracture (hazard ratios [HRs] ranging from 0.97 to 1.07). However, they were associated with postfracture mortality. HR (95% confidence interval [CI]) per 1 standard deviation (1-SD) decrement in grip strength: HR 1.12 (95% CI, 1.01-1.25) and gait speed: HR 1.14 (95% CI, 1.02-1.27), and 1-SD increment in chair stands time: HR 1.08 (95% CI, 0.97-1.21). Greater annual declines in these measurements were associated with higher mortality risk, independent of the index values and other covariates. HR (95% CI) per 1-SD annual decrement in change in grip strength: HR 1.15 (95% CI, 1.01-1.33) and in gait speed: HR 1.38 (95% CI, 1.13-1.68), and 1-SD annual increment in chair stands time: HR 1.28 (95% CI, 1.07-1.54). Men who were unable to complete one or multiple tests had greater risk of postfracture mortality (24%-109%) compared to those performed all tests. It remains to be seen whether improvement in these modifiable factors can reduce postfracture mortality. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).