Bone Metabolism Effects of Medical Therapy in Advanced Renal Cell Carcinoma

Tyrosine kinase inhibitors and immune checkpoint inhibitors have substantially prolonged survival in patients affected by advanced renal cell carcinoma. However, their impact on bone metabolism is less studied than in other malignancies. Nevertheless, the bone is the second site of metastatic spread in these patients, and chronic renal insufficiency, a condition associated with bone dysmetabolism, is frequently seen in patients who underwent nephrectomy due to renal cancer. Indeed, tyrosine kinase inhibitors may lead to hypophosphatemia and increased parathyroid hormone levels, with low-normal calcium levels, while immune checkpoint inhibitors may cause hypocalcemia and hypercalcemia. Remarkably, jaw osteonecrosis is a bone complication of tyrosine kinase inhibitors occurring more frequently in patients affected by renal cell carcinoma than other malignancies. The reasons for this prevalence are still unknown. In the literature, studies on epidemiology and pathogenetic mechanisms of bone dysmetabolism induced by those anticancer drugs are sparse. More robust studies are necessary to clarify these issues. In the meantime, Clinicians should consider the risk of bone dysmetabolism in patients affected by renal cell carcinoma on treatment with the agents mentioned above, particularly in those receiving antiresorptive medications (i.e., biphosphonates and denosumab), which can increase the risk of hypocalcemia and jaw osteonecrosis. The medical therapy of advanced renal cell carcinoma (RCC) is based on the use of targeted therapies, such as tyrosine kinase inhibitors (TKI) and immune-checkpoint inhibitors (ICI). These therapies are characterized by multiple endocrine adverse events, but the effect on the bone is still less known. Relatively few case reports or small case series have been specifically focused on TKI and ICI effects on bone metabolism. However, the importance to consider these possible side effects is easily intuitable because the bone is one of the most frequent metastatic sites of RCC. Among TKI used in RCC, sunitinib and sorafenib can cause hypophosphatemia with increased PTH levels and low-normal serum calcium levels. Considering ICI, nivolumab and ipilimumab, which can be used in association in a combination strategy, are associated with an increased risk of hypocalcemia, mediated by an autoimmune mechanism targeted on the calcium-sensing receptor. A fearsome complication, reported for TKI and rarely for ICI, is osteonecrosis of the jaw. Awareness of these possible side effects makes a clinical evaluation of RCC patients on anticancer therapy mandatory, especially if associated with antiresorptive therapy such as bisphosphonates and denosumab, which can further increase the risk of these complications.