-Melanocyte-stimulating hormone (-MSH), a 13-amino acid peptide produced in the brain and pituitary gland, is a regulator of appetite and body weight, and its production is regulated by leptin, a factor that affects bone mass when administered centrally. -MSH acts via melanocortin receptors. Humans deficient in melanocortin receptor 4 (MC4-R) have increased bone mass, and MC4-R has been identified in an osteoblast-like cell line. Thus -MSH may act directly on the skeleton, a question addressed by the present studies. In primary cultures of osteoblasts and chondrocytes, -MSH dose dependently (10⁹ M) stimulated cell proliferation. In bone marrow cultures, -MSH (>10⁹ M) stimulated osteoclastogenesis. Systemic administration of -MSH to mice (20 injections of 4.5 µg/day) decreased the trabecular bone volume in the proximal tibiae from 19.5 ± 1.8 to 15.2 ± 1.4% (P = 0.03) and reduced trabecular number (P = 0.001). Radiographic indexes of trabecular bone, assessed by phase-contrast X-ray imaging, confirmed the bone loss. It is concluded that -MSH acts directly on bone, increasing bone turnover, and, when administered systemically, it decreases bone volume. The latter result may also be contributed to by -MSH effects elsewhere, such as the adipocyte, pancreatic -cell, or central nervous system.