Calcitonin gene-related peptide (CGRP) is a neuropeptide abundantly concentrated in sensory nerve endings innervating bone metaphysis and periosteum, which indicates that it plays a local role in bone metabolism. CGRP-alpha and -beta share structural and functional homology with calcitonin (CT) and have been shown to inhibit bone resorption in vitro and to induce hypocalcemia in vivo. We recently reported that CGRP stimulates the production of the growth factor insulin-like growth factor-I and inhibits that of the cytokine tumor necrosis factor-alpha by osteoblasts, suggesting that CGRP may control bone cell activity. To investigate this possibility, we used ovariectomized (ovx) rats as a high bone turnover model and compared the effects of CGRP to those of CT. ovx young female rats were injected daily starting the day after surgery with either phosphate-buffered saline, CGRP-alpha (1.15 mg/kg per day), or CT (3 micrograms/kg per day) for 28 days. Ovariectomy induced an increase in bone turnover associated with a 60% loss in trabecular bone volume of the proximal tibia. CGRP inhibited bone resorption but not bone formation, and was nevertheless less efficient than CT in preventing bone loss, since CGRP-treated rats had a loss of 46% of cancellous bone, whereas CT-treated rats had a loss of 21%. This suggests that CGRP is either less potent than CT at inhibiting bone resorption or else very rapidly degraded. These data indicate that CGRP can control bone cells through a mechanism that is in part different from that of CT, and further suggest that CGRP may play a local role in bone metabolism.