Genetic variants of the androgen receptor and klotho protein may contribute to variation in bone mass as well as to predisposition to osteoporosis. The relationship of a CAG repeat polymorphism of the androgen receptor gene (AR) and of a -395G-->A polymorphism of the klotho gene (KL) to bone mineral density (BMD) in Japanese women was examined in a population-based study. The subjects (1,101 and 1,110 women for AR and KL polymorphisms, respectively) were aged 40-79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases. BMD for the total body, lumbar spine, right femoral neck, right trochanter, and right Ward's triangle was measured by dual-energy X-ray absorptiometry. Genotypes for the AR and KL polymorphisms were determined by polymerase chain reaction based assays. The number of CAG repeats of AR was inversely correlated with BMD for the lumbar spine in premenopausal women but not in postmenopausal women. The (CAG)(n</=22) and (CAG)(n>/=23) alleles were designated S and L, respectively. Among premenopausal women, BMD for the total body was significantly lower in subjects with the LL genotype than in those with the SS genotype or those in the combined group of SS and SL genotypes. In contrast, BMD was not associated with AR genotype in postmenopausal women. Among all women, BMD for the lumbar spine was significantly lower in subjects with the GG genotype of the -395G-->A polymorphism of KL than in those with the AA genotype. BMD was not associated with -395G-->A genotype among premenopausal women. In postmenopausal women, BMD for the total body or lumbar spine tended to be lower in subjects with the GG genotype than in those with the AA genotype or those in the combined group of GA and AA genotypes. These results suggest that AR is a susceptibility gene for reduced BMD in premenopausal Japanese women, and that KL is a susceptibility gene for reduced BMD in all women.