Bisphosphonates and vascular endothelial growth factor-targeted drugs in the treatment of patients with renal cell carcinoma metastatic to bone

Skeletal involvement is common in patients with renal cell carcinoma (RCC): ∼30% of patients with metastatic RCC (mRCC) will develop bone metastases. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear-cell RCC (m-ccRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and the monoclonal antibody bevacizumab, became the therapy of choice for patients with m-ccRCC. Besides the undisputed efficacy of TKI in the treatment of m-ccRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, a relatively common practice in the treatment of such patients is bone-directed therapy with bisphosphonates (BPs). Recent evidence shows a potentially synergistic effect on efficacy but also the potential for increased toxicity of combining TKIs and BPs. This review article highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients.