Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. Receptor activator of NF-kB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents. Recent studies indicate that the risk of skeletal complications is related to the rate of bone resorption.Multiple, randomised controlled trials over the past two decades have clearly demonstrated that bisphosphonates (BPs) are effective in reducing skeletal morbidity from metastatic cancer. Zoledronic acid is the most potent BP, and has shown superior efficacy to pamidronate in the prevention of skeletal complications in breast cancer, and is the only agent to show clear benefit in the management of metastatic bone disease from prostate cancer (castrate resistant), lung cancer and other solid tumours. Oral agents such as ibandronate and clodronate provide a useful alternative for some clinical situations.Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120mg 4 weekly administered by subcutaneous injection has been defined for the treatment of advanced malignancy. Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the BPs. Additionally, a randomised phase II study in patients with increased bone resorption, despite ongoing BPs, has compared changing to denosumab to continuation of the BP; rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a large phase III programme comparing denosumab to zoledronic acid in metastatic bone disease from a range of solid tumours (n=>5,000), denosumab was more effective, easier to administer and had some safety advantages.The bone-targeted agents are an important component of management in advanced malignancy. Combined with systemic cancer therapy, effective symptom control and appropriate surgical and radiological interventions, modern multi-disciplinary care has transformed the care of patients with metastatic bone disease. Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. Receptor activator of NF-kB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents. Recent studies indicate that the risk of skeletal complications is related to the rate of bone resorption. Multiple, randomised controlled trials over the past two decades have clearly demonstrated that bisphosphonates (BPs) are effective in reducing skeletal morbidity from metastatic cancer. Zoledronic acid is the most potent BP, and has shown superior efficacy to pamidronate in the prevention of skeletal complications in breast cancer, and is the only agent to show clear benefit in the management of metastatic bone disease from prostate cancer (castrate resistant), lung cancer and other solid tumours. Oral agents such as ibandronate and clodronate provide a useful alternative for some clinical situations. Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120mg 4 weekly administered by subcutaneous injection has been defined for the treatment of advanced malignancy. Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the BPs. Additionally, a randomised phase II study in patients with increased bone resorption, despite ongoing BPs, has compared changing to denosumab to continuation of the BP; rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a large phase III programme comparing denosumab to zoledronic acid in metastatic bone disease from a range of solid tumours (n=>5,000), denosumab was more effective, easier to administer and had some safety advantages. The bone-targeted agents are an important component of management in advanced malignancy. Combined with systemic cancer therapy, effective symptom control and appropriate surgical and radiological interventions, modern multi-disciplinary care has transformed the care of patients with metastatic bone disease.