Bone mineral density increases with fat body mass, and obesity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and directly related to fat body mass. We report here the effects of leptin administration compared with estrogen therapy on ovariectomy-induced bone loss in rats. Leptin was effective at reducing trabecular bone loss, trabecular architectural changes, and periosteal bone formation. Interestingly, the combination of estrogen and leptin further decreased bone turnover compared with that in estrogen-treated ovariectomized rats. Leptin also significantly increased osteoprotegerin mRNA steady state levels and protein secretion and decreased RANK ligand mRNA levels in human marrow stromal cells in vitro. Our findings suggest that leptin could modulate bone remodeling in favor of a better bone balance in rats. This study is the first evidence that leptin therapy has a significant effect in preventing ovariectomy-induced bone loss, and this effect may at least in part be mediated by the osteoprotegerin/RANK ligand pathway.