Malignancy-related hypercalcemia

Malignancy-related hypercalcemia (MRH) is the second cause of hypercalcemia and the most common metabolic disorder in patients with advance cancer. In patients with MRH, the disruption of the balance between osteoblast and osteoclast activity in the bone marrow results in osteolysis and calcium loss. Local osteolytic hypercalcemia is induced directly by cancer cells invading the bone, leading to the degradation of mineral matrix, involving various cytokines, including interleukin (IL)-1β, IL-3, IL-6, tumor necrosis factor (TNF)-α, TNF-β, macrophage inflammatory protein, prostaglandins and chemokines, locally produced by the tumor cells. Both normal and malignant bone marrow cells interact together with this network of cytokines increasing receptor-activated nuclear factor-κ ligand (RANKL) and other mediators, ultimately leading to osteoclast activation adjacent to the cancer cells. Humoral hypercalcemia is the main cause of MRH. It is usually triggered by the secretion of parathyroid hormone-related protein (PTHrP) by the malignant cells and elevated PTHrP serum levels are usually observed in patients with advanced solid cancer, thus predicting short survival. PTHrP is a polypeptide exhibiting PTH-like activity that stimulates RANKL expression in bone marrow stromal cells and osteoblasts, resulting in osteoclast formation in the bone microenvironment and hypercalcemia. The drugs capable of inhibiting osteoclast activity, such as bisphosphonates, may lead to a reduction in progressive bone resorption and to the correction of hypercalcemia. The monoclonal antibody denosumab, mimicking the effects of osteoprotegerin that inhibits RANKL-RANK interactions by binding to RANKL, significantly decrease osteoclast-related bone resorption and subsequent hypercalcemia in most patients with MRH.