This article is part of the supplement: Basic science, rationale, background and future of denosumab: a RANK ligand inhibitor
Clinical development of anti-RANKL therapy
1 The Center for Musculoskeletal Research, University of Rochester Medical Center, Elmwood Avenue, Rochester, New York 14642, USA
2 Department of Medicine, University of Rochester Medical Center, Elmwood Avenue, Rochester, New York 14642, USA
Arthritis Research & Therapy 2007, 9(Suppl 1):S7 doi:10.1186/ar2171Published: 29 June 2007
The receptor activator of nuclear factor-κB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer).