Receptor activator of nuclear κB ligand and osteoprotegerin: Where are we now and what about future treatment uses?

Purpose of review: Since the discovery of the RANK, its ligand, and osteoprotegerin as the final effectors of osteoclastogenesis and bone resorption, there has been an aggressive effort to develop a biologic antagonist of this pathway as a therapeutic for metabolic bone disease. While the early candidate osteoprotegerin molecules failed to meet clinical expectations, a human monoclonal antibody that recognizes RANKL (AMG162; Amgen, Inc., Thousand Oaks, California) is showing tremendous promise in phase II and phase III clinical trials. Here we review the trials and tribulations of RANK blockade for osteoporosis, tumor metastasis to bone, hypercalcemia of malignancy, inflammatory arthritis, and periprosthetic osteolysis. Recent findings: Although in-vitro studies have demonstrated RANKL-independent osteoclastogenesis and bone resorption, there is no evidence that this can occur in vivo. Furthermore, there are no preclinical models of metabolic bone disease that are refractory to RANK blockade. These studies have also demonstrated two critical advantages over bisphosphonate therapy. The first is that bone formation is not inhibited by RANK blockade such that anti-RANKL can be effectively used in combination with anabolic agents like parathyroid hormone, which is not true for alendronate. Second, RANK blockade is very effective in preventing erosions in the setting of inflammatory arthritis, and potentially aseptic loosening. Summary: Enrollment of the pivotal phase III clinical trial of AMG162 in women after menopause has been completed, and the results will be out in the next few years. If it is approved, the effective dosing regimen for patients will be subcutaneous injection of 60 mg every 6 months, which overcomes the gastrointestinal complications of oral bisphosphonates and should dramatically improve compliance. Moreover, anti-RANKL therapy may prove to be the long sought after intervention to prevent aseptic loosening in patients with established periprosthetic osteolysis.