Glucocorticoid therapy, especially at higher doses, is associated with significant adverse side effects including osteoporosis. Leptin, secreted from adipose tissue, has diverse effects on bone tissue regulation. As glucocorticoids stimulate leptin synthesis and secretion directly in adipose tissue we hypothesised that dexamethasone (DEX) induced osteoporosis may, in part, be mediated by an osteoblast dependent leptin-leptin receptor pathway. Human bone cells expressed leptin and leptin receptors (Ob-Ra and Ob-Rb). DEX increased leptin, Ob-Ra and Ob-Rb expression in a dose-dependent manner while decreasing expression of osteocalcin. In the presence of leptin, Cbfa1 and osteonectin expression showed no significant change, whereas osteocalcin expression was decreased. Recombinant human quadruple antagonist leptin suppressed DEX-induced osteocalcin downregulation. The signaling pathway involved up-regulation of JAK2. In conclusion, upregulation of leptin and Ob-Rb in human bone cells by DEX is associated with down-regulation of osteocalcin expression. The down regulation of osteocalcin by DEX was partially through a leptin autocrine/paracrine loop. Adverse effects of DEX on the skeleton may be modified by targeting leptin signaling pathways.