The correlations between the serum levels of OPG, RANKL with age, menopause, bone markers, and bone mineral densities (BMDs) at the lumbar spine and proximal femur were studied in 504 pre- and postmenopausal Chinese women aged 20-75 years. We found that age was positively and negatively correlated with serum concentrations of OPG (r = 0.442, P < 0.001) and RANKL (r = -0.263, P < 0.001), respectively. Compared with premenopausal women, postmenopausal women showed higher serum OPG levels (107.6 +/- 3.0 vs 72.0 +/- 1.8 pg/ml, P < 0.001), lower serum RANKL concentrations (4.7 +/- 0.4 vs. 5.8 +/- 0.3 pg/ml, P < 0.001) and RANKL/OPG ratios (0.045 +/- 0. 004 vs. 0.099 +/- 0.008, P < 0.001). Neither serum levels of OPG nor RANKL or RANKL/OPG ratio correlated with BMDs after adjustment of age and menopause. They also showed no differences among normal, osteopenic and osteoporotic postmenopausal women. Serum levels of OPG were positively correlated with urinary excretion of NTx (r = 0.1453, P = 0.006). Serum levels of RANKL (r = -0.1928, P < 0.001) and RANKL/OPG ratio (r = -0.1303, P = 0.013) were inversely correlated with serum concentrations of OC. In multiple regression analysis, up to 20% variance (R(2) = 0.106-0.224) of the OPG-RANKL system in peripheral circulation can be explained by age, menopause and bone markers. These results suggest that although serum OPG and RANKL concentrations were unrelated with BMDs, the age- and menopause- dependent changes of serum OPG and RANKL might be a protective mechanism against the accelerated bone loss in postmenopausal women.