RANK Ligand: A Key Role in Cancer-Induced Bone Destruction?

Abstract

Abstract Context Prostate cancer (PCa) is associated with a high risk of bone metastases; androgen-deprivation therapy is associated with significant bone loss. Bone metastases and bone loss are both linked to an increased risk of skeletal-related events, which in turn can reduce quality of life and life expectancy. Understanding of the pathophysiology underlying bone disease in patients with cancer is therefore important for the development of new treatments that can prevent or reverse it as well as for the improvement of patient outcomes. Objective To provide an overview of bone metabolism in the normal state and to describe recent developments in our understanding of the pathophysiology underlying bone disease induced by cancer as well as cancer treatment–induced bone loss (CTIBL). Evidence acquisition This article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009. Evidence synthesis Skeletal integrity is maintained by a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The proteins osteoprotegerin and RANK Ligand play key roles in preserving this balance by preventing and promoting osteoclast activity, respectively. In bone disease associated with cancer, however, the balance shifts in favour of RANK Ligand, resulting in a vicious cycle of osteoclast activation and tumour growth; the same may be true in CTIBL. Denosumab, a fully human monoclonal antibody that binds to and inhibits RANK Ligand, has been shown to block osteoclast-mediated bone resorption and is currently under development as a potential treatment for bone abnormalities associated with cancer and its treatment. Conclusions Inhibition of the RANK Ligand pathway by the human monoclonal antibody denosumab may provide a novel treatment option for bone disease in PCa. Further studies are underway.