Certain primary tumours including breast and prostate cancers have a particular propensity for metastasis to bone. Metastatic bone disease can have significant impact on morbidity and mortality of cancer patients. Skeletal-morbidity (spinal cord compression, hypercalcaemia, fracture, need for radiotherapy and surgery to bone) can be effectively reduced by bisphosphonates, a class of anti-resorptive drugs. They are also effective in relieving pain from bone metastases, and may improve survival in patients with accelerated bone resorption. Additionally, there is an exciting body of evidence that suggest these drugs may have anti-tumor effects that may be exploited to prevent or delay the development of bone metastases. Reported effects include inhibition of cancer cell migration, adhesion and invasion as well as anti-angiogenic and immunomodulating effects. The pre-clinical evidence is compelling, and some recently reported randomised clinical studies go part way to support their use in clinical practice at earlier stages of the disease to prevent bone metastases. However, further results are awaited before routine clinical use in the adjuvant setting can be recommended.
Metastatic bone disease has a major impact on both the morbidity and mortality of patients. Antiresorptive bisphosphonates have revolutionized treatment and outcomes for patients with bone metastases, but pain and other skeletal complications still occur, adversely affecting quality of life and survival. Recent understanding of the bone microenvironment has highlighted the importance of RANK, its ligand (RANKL) and the decoy receptor OPG in the vicious cycle of bone resorption and destruction. Exploiting this triad led to the development of denosumab, a fully-human monoclonal antibody to RANKL. The success of this bone-directed agent in early clinical trials and favorable safety and tolerability profile led to the conduct of large multi-center randomized trials in breast, prostate, myeloma and other advanced cancers. In this review, we discuss the development of denosumab, the data that led to its licensing for patients with bone metastases and the future for bone-directed therapies. Keywords: bisphosphonate • bone-directed therapy • bone metastases • denosumab• OPG • RANK • RANKL. Metastatic bone diseaseDenosumab in the treatment of bone metastases
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