Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project

Abstract

The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005)(2006)(2007), 2 years follow-up (2007)(2008)(2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (b ¼ -0.071), FSH (b ¼ -0.085), LH (b ¼ -0.070), and E1 (b ¼ 0.107) remained significantly associated with BMD loss in multivariate-adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n ¼ 171; hip, n ¼ 44; and nonvertebral, n ¼ 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.

Sex hormones, sex hormone binding globulin, and vertebral fractures in older men

“…We adjusted for these covariates, but other factors such as bone strength or complex measures of health status were not included in our multivariate models. Other reports that have found an association between SHBG and bone loss have postulated that SHBG is a biomarker for bone health (12), rather than a direct intermediate, and our data support this theory.…”

“…(3, 4) Low levels of testosterone (and estradiol) have been linked to non-vertebral fractures and osteoporosis, as well as frailty in older adults. (5–12) A recent report from the MrOS Swedish and Hong Kong cohorts of older men reported an association between higher levels of SHBG, but not testosterone or estradiol, and an increased risk of incident, clinically identified vertebral fractures (13); radiographic vertebral fractures were only ascertained in the Hong Kong men, but results were similar to those for clinical vertebral fractures. A few other smaller studies have also investigated this association in men and women, but these were limited to case-control studies(5, 14); small clinical populations (6); or cohort studies with relatively few fractures (11, 15).…”

Age-specific population centiles for androgen status in men

“…In this study, we utilize an illustrative response metameter to define net androgen status (53), defined as the sum of testosterone and DHT concentrations, using a weighting for DHT to reflect its higher androgenic potency. DHT is between two and ten times more potent than testosterone as an androgen, as measured by various mammalian and yeast AR bioassays (17,18) and reflecting its higher affinity for, and greater stability of, AR binding with a slower dissociation rate compared with testosterone (19).…”

Aging and sex hormones in males

“…42,48,121 Thus, low circulating levels of T result in parallel in low serum E 2 42,48 . Differently from the majority of studies, the CHAMP study did not find any association among serum T, E2, SHBG, and bone health, 122 on one hand, and, on the other hand, the Tromsø did not find any association between sex steroids and both BMD 71 and fracture risk. 72 Low total T levels were associated with lower hemoglobin levels in the InCHianti study similarly to EMAS, 89 suggesting that the effects of low T on hemoglobin should be carefully evaluated in older men due to the fact that anemia is one of the strongest markers of frailty 69 Not all studies investigated physical performance and both the muscular mass and strength in relation to circulating sex steroids.…”