Biotargeting in Metastatic Bone Disease

Metastatic disease to bone in the setting of adenocarcinoma can be a devastating complication. It often leads to chronic pain, and limited mobility, and can cause significant disability for patients. In addition, many patients develop pathologic fractures which increase the risk of disability and lead to significant morbidity and mortality. Metastatic disease also puts patients at risk for hypercalcemia which can cause weakness, nausea, anorexia, confusion, dehydration, and constipation. Increased levels of circulating calcium also impair renal function and cause mental dysfunction. The receptor activator of nuclear factor kappa-B ligand (RANKL) pathway has been well elucidated in the development of bone metastasis, and specific drugs such as zoledronic acid and denosumab, which target this pathway, have shown success in their prevention and treatment. However, a significant number of patients continue to develop additional bony disease while on these agents, indicating the necessity for the identification of additional biotargets for the management and prevention of metastatic bone disease. Potential future biotargets for the treatment of metastatic bone disease are multifactorial. They include interleukins as well as members of the tumor necrosis factor alpha (TNF-α) family. In addition, bone morphogenic proteins may play an important role in the development of bone metastasis. The Wnt signaling pathway has been implicated in a variety of different cancers and may also be a potential target for the prevention of bony metastasis. Other potential targets include vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF). Other protein targets such as semaphorin-4D and plexin B1 may also be a potential target. Elucidation of the role these potential targets play in the development of metastatic disease to bone, with further increase in our understanding of the mechanisms of how bony metastasis occurs, allows us to potentially develop additional therapeutic agents to prevent bony metastasis from occurring, thereby improving patients’ functionality and hopefully decreasing morbidity and mortality.