Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond

Bone metastases are a major cause of morbidity for men with prostate cancer. Although typical bone metastases from prostate cancer appear osteoblastic by radiographic imaging, excess number and activity of both osteoblasts and osteoclasts characterize most "osteoblastic" bone metastases. Additionally, pathological osteoclast activation is associated with increased risk of skeletal complications, disease progression, and death. Zoledronic acid, a potent intravenous bisphosphonate, reduces markers of osteoclast activity and significantly decreases the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Additional studies are needed to determine the optimal timing, schedule, and duration of bisphosphonate treatment in men with bone metastases as well as the potential role of bisphosphonates in other settings, including the prevention of bone metastases. Denosumab is a human monoclonal antibody that binds and neutralizes human receptor activator of NF-kappaB ligand (RANKL), a critical mediator of osteoclast activation, differentiation, and survival. Three ongoing pivotal studies involving more than 4,500 subjects will evaluate the role of denosumab for prevention of treatment-related fractures, bone metastases, and disease-related skeletal complications in men with prostate cancer.