I Van Pottelbergh

Differential contribution of testosterone and estradiol in the determination of cholesterol and lipoprotein profile in healthy middle-aged men.

The role of endogenous sex steroids in the association between male gender and cardiovascular risk remains unclear. We performed a cross-sectional analysis of the role of endogenous testosterone (T) and estradiol (E2), as well as their respective biologically active fractions, in the determination of lipids and lipoproteins in an occupation-based cohort of 715 healthy middle-aged men. Serum T, sex hormone binding globulin (SHBG) and E(2) were measured by immunoassays; free T (FT) and free E2 (FE2) were calculated using a validated equation. Serum total cholesterol (Chol), HDL-cholesterol (HDL-Chol), apolipoproteins A1 (ApoA1), B (ApoB), E (ApoE), ApoE phenotype, lipoprotein a (Lpa), fibrinogen, C-reactive protein (CRP), systolic (SBP) and diastolic blood pressure (DBP) were assessed. Serum levels of T and FT, correlated positively with HDL-Chol and ApoA1 with Spearman correlation coefficients, partialised for age and body mass index (BMI), ranging between 0.14 and 0.17 (P<0.001); FT was associated with total Chol and ApoB levels (r=0.12 for both T and FT; P<0.01). After adjustment for age and BMI, both serum E2 and FE2 levels correlated significantly with ApoE (r=0.25 and r=0.26 for E2 and FE2, respectively; P<0.001). Free and total E2 were associated with both SBP and DBP with correlation coefficients partialised for age and BMI ranging between 0.11 and 0.13 (P<0.01). No correlation was found between any of the studied sex steroids, fibrinogen, Lpa or CRP. In multiple linear regression analyses, T was the most important independent hormonal determinant of HDL-Chol levels, when E2, SHBG and exogenous factors were considered in the model (P<0.01), whereas E2 contributed mostly in the determination of ApoE levels (P<0.001) and SBP (P<0.01). When FT and FE2 were considered in multivariate analyses as independent hormonal variables, FT was the most significant predictor of HDL-Chol (P<0.01) and ApoB (P<0.01) concentrations. Moreover, in the same multivariate model, ApoE (P<0.001) concentration as well as SBP (P<0.001) was most affected by FE2 levels in comparison with FT. In conclusion, our findings do suggest a differential role of T and E2 in the determination of traditional cardiovascular risk factors in healthy middle-aged men. In the determination of both HDL-Chol and ApoB levels endogenous (F)T may be involved, whereas (F)E2 may contribute to the determination of ApoE levels in this study group of 715 healthy middle-aged men. Regarding the observational design of the study, the physiological relationship of the observed associations between sex steroids and cardiovascular risk factors remains to be unravelled.

Deficient Acquisition of Bone During Maturation Underlies Idiopathic Osteoporosis in Men: Evidence From a Three-Generation Family Study†‡

To address the issue whether deficient acquisition of bone during maturation or adult‐onset bone loss is primarily to blame for idiopathic osteoporosis in men, we assessed indices of bone mineral density and size, as well as biochemical markers of bone turnover in 61 probands (ages 20–65 years) with idiopathic osteoporosis (z‐score ≤ −2.0 at the spine or hip), their first‐degree relatives (n = 130), and age‐matched controls. There was no indication of accelerated bone loss. Indeed, in probands, the observed bone deficit versus controls was unrelated to the age of probands, and indices of bone turnover were not significantly different from controls. On the other hand, a specific deficit in bone acquisition was suggested by findings of lower bone mineral density values in three generations of male and female relatives of the probands, including their offspring; bone turnover in relatives was not different from controls. The bone mineral density deficit was more pronounced in male compared with female relatives; approximately 60% of the sons had a spinal bone mineral density z‐score of less than −2.0. There also was a skeletal site‐specificity in probands and their male relatives with a larger areal bone mineral density deficit at the spine compared with the hip and the forearm. The deficit at the spine corresponded to a reduction of both volumetric bone mineral density and bone size; a similar less pronounced deficit in volumetric bone mineral density, but not in bone size, was observed at the femoral neck. These findings in probands and their first‐degree relatives point toward a major contributory role of a genetically determined maturational defect in bone acquisition in the pathogenesis of idiopathic osteoporosis in men.

Telomere length versus hormonal and bone mineral status in healthy elderly men.

Telomeres, the termini of linear chromosomes, exert a key role in the process of cellular ageing. Progressive telomere shortening is implicated in senescence in vitro and ample evidence exists to support the hypothesis that telomere length is correlated with chronological age and ageing phenotypes in vivo. In this study, we assessed whether mean telomere length of peripheral blood leukocytes predicts age-associated bone loss and/or is related to sex steroid status in an elderly healthy male population (71-86 years). Out of this population, we selected 110 samples for telomere restriction fragment (TRF) length analysis. Fasting blood was analysed for testosterone, estradiol, sex hormone binding globulin and biochemical markers of bone turnover. Also, the bioavailable fractions of sex steroids were calculated. Bone mineral density was measured at baseline and longitudinal follow-up was available for 84 men. We found that mean TRF length was inversely correlated with age (r=-0.19; P=0.049). Although no correlations were found with sex steroids or BMD at baseline, age corrected mean TRF length was associated with longitudinal bone loss for different distal forearm sites (P<0.05). Further studies are required to confirm our results, yet in this study, the predictive value of telomere length for bone loss appears to be substantial, hence underscoring the role of telomere length as a biomarker of ageing phenotypes.

Association of the Type I Collagen alpha1 Sp1 Polymorphism, Bone Density and Upper Limb Muscle Strength in Community-Dwelling Elderly Men

Abstract: A polymorphic binding site of the Sp1 transcription factor in the gene encoding the alpha1 chain of type I collagen is associated with bone mineral density (BMD) and, independently, with fracture risk in postmenopausal women. The aim of this study is to examine whether in community-dwelling men over age 70 years, the COL1A1 Sp1 polymorphism is associated with BMD (by dual-energy X-ray absorptiometry) and/or with bone turnover and muscle strength – factors related to both BMD and fracture risk. The COL1A1 Sp1 genotype (SS, Ss and ss) was determined using polymerase chain reaction and MscI restriction digestion. Presence of the s allele was significantly associated with lower BMD at the distal forearm (p= 0.03) and different distal radius subregions, with Z-score differences between extreme genotype groups (SS vs ss) ranging from 0.87 (ultradistal radius; p= 0.17) to 1.31 (mid-region of distal radius; p= 0.03). Presence of the s allele was also associated with lower BMD at the hip, with differences between genotypes not approaching statistical significance. There were no differences between genotype groups for any of the assessed markers of bone formation and resorption. Presence of the s allele was associated with lower grip (p= 0.03) and biceps strength (p= 0.04) at the dominant arm, with the difference between extreme genotype groups amounting to 21% and 30%, respectively. In a multivariate analysis, the association between COL1A1 Sp1 polymorphism and forearm BMD Z-score was no longer significant after adjustment for height, percentage lean mass, level of physical activity and upper limb strength (p= 0.18), whereas the genotype-specific difference for grip and biceps strength remained significant after adjustment for age, height and percentage lean mass (p= 0.04 and p = 0.05, respectively). In conclusion, the COL1A1 Sp1 polymorphism is associated with BMD at the forearm and upper limb muscle strength in elderly men, the findings of multivariate analyses suggesting that the genotype-specific differences for BMD might be mediated, at least in part, by differences in muscle strength.

Inverse association between bone turnover rate and bone mineral density in community-dwelling men >70 years of age: no major role of sex steroid status.

Bone loss is accelerated in elderly men. Little is known about the pathophysiology of senile bone loss or about the role played by relative sex steroid deficiency in the determination of bone turnover in elderly men. In a population-based sample of 283 healthy, ambulatory men, aged 71-86 years, we sought to determine whether lower bone mineral density (BMD; using dual-energy X ray absorptiometry at the hip and the forearm) is associated with higher bone turnover, and we assessed the impact of sex steroid status on bone turnover. Indices of bone formation, serum osteocalcin (s-Oc), and bone-specific alkaline phosphatase (s-bAP) and indices of bone resorption, serum and urinary telopeptide of type I collagen (s-CTx and u-CTx), and urinary free deoxypyridinoline (u-Dpd) were intercorrelated (r = 0.29-0.76, p < 0.001). Bone turnover indices were negatively associated with BMD (r = -0.17 to -0.34, p < 0.01). In univariate analyses, there was a trend toward weak negative associations of bone turnover markers with serum free testosterone (FT), significant only for s-Oc and s-CTx (r = -0.16 and -0.14, p < 0.01), and with serum free estradiol (FE(2)), significant only for u-CTx and s-CTx (r = -0.18 and -0.19; p < 0.01). The lower quartile for FE(2) was associated with higher values of u-CTx (p = 0.003) and s-CTx (p < 0.001). However, in multivariate models, for the individual markers of bone turnover a negative association between estradiol (E(2)) or FE(2) and s-CTx was the only remaining (marginally) significant association (p < 0.05) for the relationship between sex steroids and any of the bone turnover indices assessed. In community-dwelling men age >70 years, bone turnover rate, as determined by biochemical markers, is a significant negative determinant of prevalent BMD. However, the findings do not support the view that relative differences in sex steroid status, as observed among healthy elderly men, have a major impact on bone turnover.

Complex Segregation Analysis Accounting for GxE of Bone Mineral Density in European Pedigrees Selected Through a Male Proband with Low BMD

Osteoporosis is a common multifactorial disorder characterized by low bone mass (BMD) and high susceptibility to low‐trauma fractures. Family and twin studies have found a strong genetic component in the determination of BMD, but the mode of inheritance of this trait is not yet fully understood. BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. Detection of potential gene‐environment interactions is of great interest in the determination of bone health status. Here we have conducted segregation analyses, using the regressive class D models, in a sample of 100 European pedigrees (NEMO) with 713 subjects (524 measured for phenotypes) identified via a male with low BMD values at either the Lumbar Spine or the Femoral Neck. Segregation analyses were conducted on the residuals of LS‐BMD and FN‐BMD adjusted for gender, age and BMI. We tested for gene‐covariate (GxE) interactions, and investigated the impact of significant GxE interactions on segregation results. Without GxE a major effect was found to be marginally significant in LS‐BMD and highly significant in FN‐BMD. For both traits the Mendelian hypothesis was rejected. Significant Age × gene and BMI × gene interactions were revealed. Accounting for GxE increased statistical evidence for a major factor in LS‐BMD, and improved the fit of the data to the Mendelian transmission model for both traits. The best fitting models suggested a codominant major gene accounting for 45% (LS‐BMD) and 44% (FN‐BMD) of the adjusted BMDs. However, substantial residual correlations were also found, and these remained highly significant after accounting for the major gene.