Managing bone metastases and reducing skeletal related events in prostate cancer

Advanced-stage prostate cancer is associated with skeletal complications related to metastatic disease and its treatment. On the one hand, metastatic disease to bone is commonly associated with skeletal-related events (SREs); on the other hand, treatment with androgen-deprivation therapy (ADT) leads to loss in bone mineral density (BMD) and increased risk of fracture. Despite osteoblastic appearance on radiography, bone metastases from prostate cancer are associated with increased osteoblast and osteoclast activity providing the rationale for treatment with osteoclast-targeted agents. The bisphosphonate zoledronic acid and the monoclonal antibody denosumab reduce the incidence of SREs in metastatic castration-resistant prostate cancer (mCRPC). A number of agents prevent loss of BMD associated with ADT, but only denosumab is approved to reduce fractures in patients with non-metastatic prostate cancer. Another recently approved agent-radium-223-improves survival and delays SREs in mCRPC. The inhibitors of androgen receptor signalling, abiraterone and enzalutamide, improve survival in mCRPC and delay SREs, although the latter is likely related to control of disease rather than a direct effect on bone. Finally, the tyrosine kinase inhibitor cabozantinib shows promising activity in bone metastases from mCRPC. This Review addresses the skeletal morbidity associated with prostate cancer and the therapeutic options that exist to treat it.