Abstract

Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. Tumour derived factors stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its receptor RANK on precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption and destruction of bone resulting in disruption of structural integrity and skeletal complications. This biological pathway provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents to reduce the risk of these complications.

In advanced metastatic cancer, multiple, randomised controlled trials over the past two decades have clearly demonstrated that bisphosphonates are effective in reducing skeletal morbidity. Zoledronic acid is the most potent bisphosphonate, with efficacy across the range of tumour types associated with metastatic bone disease. More recently denosumab, a fully human monoclonal antibody that specifically inhibits RANKL has become available. Denosumab has been shown in large randomised studies to be more effective than zoledronic acid, with a significant delay in both first and subsequent skeletal events. Denosumab was also easier to administer and has some safety advantages. Prevention of skeletal morbidity is associated with pain relief, improved quality of life and, in some settings, the potential to extend survival.