Melanocortin is the downstream mediator of leptin signaling and absence of leptin signaling in ob/ob and db/db mice revealed the enhancement of bone formation through the central regulation. While α-melanocyte-stimulating hormone (α MSH) inhibits the secretion of interleukin-1 α and tumor necrosis factor-α from the inflammatory cells, α MSH can also enhance clonal expansion of pro B cells linked to stimulation of osteoclastogenesis. Therefore, we tested the effect of melanocortin on bones. α MSH analogues [⁶His] α MSH-ND and [⁶Asn] α MSH-ND were synthesized and the radio-ligand receptor binding- and cyclic AMP generating activity were analyzed in China Hamster Ovary cell line over-expressing melanocortin receptors. The EC₅₀ of [⁶His] α MSH-ND measured from melanocortin-1, 3, 4 and 5 receptors were 0.008±0.0045, 1.523±0.707, 0.780±0.405, and 250.320±42.234 nM, respectively, and the EC₅₀ of [⁶Asn] α MSH-ND were 16.8±6.94, 271.8±21.95, 8.0±1.21, and 1132.5±635.46 nM, respectively. Four weeks after the subcutaneous injection of the analogues, the body weights in the [⁶His] α MSH-ND and the [⁶Asn] α MSH-ND treated groups (346.0±20.63 g vs. 350.0±13.57 g) were lower than that of the vehicle treated group (375.8±17.31 g, p < 0.05). There was no difference in the total femoral BMD measured by dual x-ray absorptiometry among the three groups. Among the three groups, there were no differences in the total numbers of crystal violet positive- or alkaline phosphatase positive colonies, in the expression of Receptor Activator of Nuclear Factor Kappa-B ligand on the tibia and the total number of multinucleated osteoclast-like cells differentiated from primary cultured bone marrow cells. From the above results, no evidence of bone gain or loss was found after treatment of the α MSH analogues peripherally.