Increased bone remodeling with estrogen deficiency is mediated by the production of cytokines such as TNFalpha and interleukin (IL)-1. Recent data have indicated that the p38 pathway mediates cytokines effects on enhanced bone turnover in postmenopausal osteoporosis. Thus, in this study, we investigated the effect of a selective p38alpha inhibitor, SD-282, on the prevention of bone loss induced by estrogen deficiency in an adult ovariectomized (OVX) rat model. Results indicate that oral administration of SD-282 for 8 wk dose-dependently blunted the increase in the bone resorption marker DPD/Cr induced by OVX in adult rats. Associated with this effect, SD-282 did not reduce but significantly enhanced by 2-fold the rise in the bone formation marker serum osteocalcin observed in OVX animals. In addition, SD-282 completely blocked vertebral bone loss associated with estrogen deficiency. Furthermore, a partial preventive effect was observed in long bones with reduction of trabecular bone loss and enhancement of cross-sectional area of the diaphysis. Prevention of trabecular bone loss and increased in cortical bone area were associated with improvement of biomechanical resistances. In conclusion, chronic administration of a selective p38alpha inhibitor effectively prevented trabecular bone loss and alteration of bone microarchitecture induced by estrogen deficiency. Prevention of bone loss was associated with inhibition of bone resorption with uncoupled changes in bone formation. These data strongly suggest that the p38 pathway is important for regulation of bone resorption induced by estrogen deficiency, and selective inhibitors of this pathway have potential for prevention of bone loss in postmenopausal osteoporosis.