Hypercalcemia of malignancy

Hypercalcemia of malignancy (HM) is the most common metabolic disorder in cancer patients, representing the second cause of hypercalcemia in the general population. HM is observed in 10-15% of patients with malignancy, especially in those with advanced cancer, usually indicating a poor prognosis1. In patients with HM, tumor cells may activate osteoclasts through several pathways, and the disruption of the balance between osteoblast and osteoclast activity in the bone marrow results in osteolysis, calcium loss and hypercalcemia. Two different mechanisms may lead to HM. Osteolytic hypercalcemia is directly induced by cancer cells invading the bone, leading to the degradation of mineral matrix and involving various cytokines, including interleukin (IL)-1β, IL-3, IL-6, tumor necrosis factor (TNF)-α, TNF-β, MIP, prostaglandins and chemokines, locally produced by tumor cells2. Both normal and malignant bone marrow cells interact with this network of cytokines, increasing receptor activator of nuclear factor-kappaB ligand (RANKL) and other mediators, ultimately leading to osteoclast activation adjacent to cancer cells. The secretion of parathyroid hormone-related protein (PTHrP) by the malignant cells represents the main cause of HM: the so-called humoral hypercalcemia. 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 hypercalcemia3. Up to 80% of patients with HM exhibit elevated PTHrP serum levels, which is usually observed in the presence of advanced or metastatic solid tumors, thus predicting short survival. Drugs that are capable of inhibiting osteoclast activity, such as bisphosphonates, 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, may decrease osteoclast-related bone resorption, normalizing or reducing serum calcium levels in most patients with HM. References: (1) Hu et al., J Natl Cancer Inst 105:1417-20, 2013; (2) Lumachi et al., Curr Med Chem 18:3529-36, 2011; (3) Lumachi et al., Med Chem 8:551-5, 2012.