The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males

Objective Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males. Patients and measurements The number of CAGRs in 110 healthy men aged 20-50 years was determined by sequence analysis. We assessed BD by the radiation-free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone-specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined. Results In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = -0.286, P=0.001), whereas it was positively associated with markers of bone turnover (for BAP: partial r=0.32, P=0.001; for DPD: partial r=0.241, P=0.013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. ANOVA in groups according to age and the CAGR length suggested an increased age-dependent bone loss in subjects with a CAGR length of 22-31 compared with 14-21 CAGRs (overall P<0.01). Conclusions A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age-dependent bone loss.