We have developed a rat model of inflammation-mediated osteopenia. Generalized loss of trabecular bone occurs in the rat after sc injection of nonspecific irritants such as talcum (magnesium silicate) and cotton wool (Cellulose). Although it appears likely that a systemic mediator of bone resorption is responsible for these effects, the loss of bone was not due to increased PTH secretion, since it occurred in parathyroidectomized rats, nor due to excessive 1,25-dihydroxyvitamin-D3 production. In parathyroidectomized rats, this inflammation was associated with significant increase in serum calcium within 4-7 days independent of its cause. Identification and characterization of this mechanism may provide insight into the bone loss associated with chronic inflammatory diseases such as rheumatoid arthritis and periodontal disease.