Osteoprotegerin (OPG) is a recently identified citokine with an important role in bone remodeling, that acts as a decoy receptor for RANKL; OPG was shown to be an important inhibitor of osteoclast differentiation and activation. Leptin influences bone metabolism by acting on differentiated osteoblasts, having an anabolic effect on bone. The relationship between circulating OPG levels and osteoporosis in postmenopausal women is controversial. Thus, one of the aims of our study was to investigate the relationships between OPG levels and biochemical markers of bone turnover and bone density in women with and without osteoporosis. We have investigated 135 postmenopausal women, including a group with osteoporosis (n=76, mean age 59+/-8 years) and a group with severe osteoporosis (n=31, mean age 64+/-8 years), using healthy postmenopausal women (n=28, mean age 48+/-9 years) as controls. The serum concentrations of OPG were determinated by ELISA. Serum estradiol was measured by Enzyme Immunoassay (EIA). The markers of bone formation and resorption were measured by standard methods. Leptin was measured by ELISA. Bone mineral density at lumbar spine and femoral neck was measured by dual energy x-ray absorptiometry (DEXA). There was a significant positive association between serum OPG levels and age (r=0.27; p<0.001), both in the postmenopausal women as a whole and in the cohort with osteoporosis. Circulating OPG levels were significantly higher in both osteoporotic groups (p<0.005 and p<0.01, respectively) than in the control group. There were no significant associations between serum OPG levels and bone density, bone markers and serum estradiol. Serum leptin levels were significantly associated with age (r=0.18, p<0.03), estradiol (r=0.2, p<0.05) and BMD (r=0.25, p<0.008); there was no significant relationship between leptin and bone turnover markers. We conclude that serum OPG levels increase with age, both in healthy and osteoporotic postmenopausal women. This could represent a possible protective mechanism against bone loss. Serum leptin levels also increase with age and are positively associated with estradiol and BMD and not significantly associated with bone turnover markers.