Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males

OBJECTIVES The physiological effects of oestrogens on bone in men were larg ely unanticipated until recently, when oestrogen deficiency in males with a romatase deficiency and oestrogen resistance was found to cause osteoporosi s and delayed fusion of epiphyses despite sufficient serum testosterone. Th is raises the possibility that in normal men oestrogens rather than androge ns are of physiological importance in bone maturation. In the present study , we examined the association of serum oestradiol (E2) compared to that of free testosterone (FT) with bone mineral density (BMD) in normal men. The e ffect of oestrogen receptor (ER) gene polymorphism on BMD in men was also a ddressed. SUBJECTS Eighty-one Thai men aged 20-79 years. All were healthy and did not take medication which may affect calcium and bone metabolism. BMD was asse ssed by DEXA. Dietary calcium was assessed by a 3-day dietary record. Serum E2 and FT concentrations were measured by radioimmunoassay. Polymorphism a t intron 1 of the alpha isoform of ER gene was determined by PCR-RFLP. Smal l p represents the presence of the restriction site while capital P indicat es the absence of the restriction site. RESULTS Serum FT decreased with increasing age (r = -0.58, P < 0.0001) whil e E2 did not. However, there was a positive association between E2 and FT ( r = 0.28, P < 0.05). Serum FT was related to BMD at femoral neck (r = 0.26, P < 0.05) and Ward's triangle (r = 0.30, P < 0.01) while E2 was related to BMD at anteroposterior (AP) lumbar spine (r = 0.29, P < 0.05), femoral nec k (r = 0.23, P < 0.05) and femoral trochanter (r = 0.27, P < 0.05). Besides FT and E2, age, body weight, fat mass and fat-free mass were also correlat ed to BMD at various skeletal sites. Using stepwise multiple linear regress ion to control for the confounding effects among these factors, fat-free ma ss was found to be strongly associated with BMD at most skeletal sites. Ser um E2 was related to BMD independently of other factors including FT at AP lumbar spine (r = 0.22, P < 0.05), femoral neck (r = 0.26, P < 0.01), femor al trochanter (r = 0.22, P < 0.05) and Ward's triangle (r = 0.26, P < 0.01) while serum FT was not associated with BMD at any site after controlling f or E2 and other related factors. Concerning ER alpha gene polymorphism, 27 (33.3%) of the subjects had pp genotype, while 42 (51.9%) and 12 (14.8%) Pp and PP genotypes, respectively. After controlling for age, body weight, fa t mass, fat-free mass, calcium intake, FT and E2, the presence of P allele was associated with higher BMD at AP L2-L4 (P < 0.05). CONCLUSIONS Serum oestradiol is more related to bone mass than free testost erone in normal men. Oestrogen-receptor gene polymorphism is also associate d with bone mass in men independently of oestradiol levels. Serum oestradio l together with oestrogen-receptor genotype may partly determine bone mass in males.