Interaction of RANKL and its cognate receptor, RANK, has been shown to play a critical role in osteoclast formation, activation, and survival. Endogenous osteoprotegerin (OPG) has been elucidated as a soluble decoy receptor for RANKL and serves as the key physiologic regulator of osteoclastic bone resorption. Binding of OPG to RANKL prevents RANK¿RANKL interaction and effectively inhibits bone resorption. The therapeutic potential of RANKL inhibitors, such as exogenous OPG (OPG-Fc), to decrease bone resorption has to be evaluated in various pathological situations. The hypothesis that inhibiting RANKL with OPG-Fc will prevent pathologic bone resorption and preserve the structural integrity of the femoral head after ischemic osteonecrosis was tested by Kim et al. [1] in piglets.

Radiographic assessment showed significantly better preservation of the femoral head structure in the group of animals receiving OPG-Fc compared with the saline group. Epiphyseal quotient (the ratio of epiphyseal height to diameter) was significantly higher in the OPG-Fc group. The number of osteoclasts was significantly reduced by OPG and trabecular bone volume, number, and separation were significantly better preserved in the OPG-Fc group. Immunostaining revealed the presence of OPG-Fc only within the blood vessels, with no apparent staining of bone matrix or trabecular bone surfaces.

This study shows that RANKL inhibition decreases bone resorption and femoral head deformity after ischemic osteonecrosis. Because RANKL inhibitors do not bind to bone, their effects on resorption are reversible as the drug is cleared from circulation. The reversible nature of RANKL inhibitors might be useful for treating pediatric bone diseases.

1. Kim HKW et al. J Bone Miner Res. 2006;21:1946-1954.