Osteoprotegerin (OPG) is a new member of the TNFR superfamily that functions solely as a secreted cytokine antagonist or decoy receptor. The structure and function of OPG is highly conserved during evolution, involves the binding to, and neutralization of RANKL during the regulation of bone metabolism. OPG is secreted by expressing cells, and can bind tightly to extracellular matrix proteins via a C-terminal heparin-binding domain.Overexpression of OPG, or systemic administration of recombinant protein, blocks osteoclast differentiation and activation in mice, rats, primates, and humans. The resulting effect is to negatively regulate bone resorption, which leads to increases in bone mass. Loss of OPG results in early onset osteoporosis in mice, leading to brittle bone structure and accumulation of long bone fractures. OPG recombinant protein can block the pathological bone loss that occurs following estrogen loss, during adjuvant-induced arthritis, and during the growth of lytic tumors, indicating a possible use in the treatment of osteopenic disorders characterized by increased osteoclast activity.