Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with intraperitoneal leptin at two different doses or vehicle for 14 days. In tail suspended rats, low leptin dose compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by 3D microtomography). In contrast, high leptin-dose inhibited femoral bone-growth and reduced bone-mass by decreasing bone formation rate and increasing bone-resorption in both tail suspended and unsuspended groups. High and low dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High leptin dose (but not low), induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone-changes at high leptin dose are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by further studies.