Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy

Osteoprotegerin (OPG), a novel, secreted tumor necrosis factor receptor fam ily member that inhibits osteoclast formation and activity was examined for its activity in a syngeneic tumor model of humoral hypercalcemia of malign ancy. Normal mice bearing Colon-26 tumors develop increases in both parathy roid hormone-related protein (PTHrP) expression and plasma PTHrP, marked hy percalcemia, and increased bone resorption. OPG, given either at the onset of hypercalcemia or after it had occurred, blocked tumor-induced increases in bone resorption and hypercalcemia and rapidly normalized blood ionized c alcium. In tumor-bearing mice, OPG treatments reduced osteoclast activity f rom approximately 2-fold above normal into the subphysiological range but h ad no effects on tumor size, tumor-induced cachexia, or PTHrP levels. The p otent effects of OPG in this humoral hypercalcemia of malignancy model sugg est a potential therapeutic role for OPG in the prevention and treatment of this disorder.