RANK Ligand Inhibition: A Novel Strategy for the Treatment of Bone Metastases

Context: Prostate cancer (PCa) is associated with bone metastases, which lead to disruption in the normally well-controlled process of bone remodelling. This disruption may lead to bone pain and fractures. Improvements in the assessment and management of bone metastases are therefore required. Objective: To assess the value of bone turnovermarkers, particularlyN-telopeptide in urine (uNTx), in predicting skeletal events and the potential of the novel agent denosumab to reduce the secondary disruption to bone in men with PCa. Evidence acquisition: This article is based on a presentation at an Amgen satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009. Evidence synthesis: High levels of uNTx in patients with bone metastases secondary to a range of cancers, including PCa, are associated with an increased risk of skeletal-related events (SRE) and death. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANK Ligand, currently under development as a potential new treatment for bone metastases associated with a broad range of tumours. Denosumab has been shown to reduce the level of uNTx in patients with bonemetastases resulting from breast cancer. Treatment with denosumab also has beneficial effects on other bone markers and the incidence of SRE in these patients. Similarly, denosumab reduces uNTx levels and the risk of SRE in patientswith other primary tumours, including PCa. Evidence from an active-comparator study involving patients previously unresponsive to bisphosphonates suggests a benefit of denosumab over continued bisphosphonate treatment. Conclusions: Measurement of uNTx levels may be a useful marker for identifying patientsmost at risk of skeletal complications. Denosumab suppresses uNTx levels, and trials evaluating the efficacy of denosumab in preventing and treating complications caused by bone metastases are continuing. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.