Hypercalcemia of malignancy (HCM) is the most common cause of elevated serum calcium in hospitalized patients and is found with varying frequency in patients with various types of cancer. Calcium homeostasis is finely regulated with day-to-day variations of less than 2%, and the development of HCM stems from various anomalies in homeostatic mechanisms. Hypercalcemia often produces a number of clinical symptoms, including alterations in central nervous system function, symptoms of dehydration and renal dysfunction. Whenever possible and appropriate, the goals of treatment of HCM should therefore be to return the patient to a euvolemic state, to normalize serum calcium and to treat the underlying cause. Almost invariably, however, HCM is a particularly adverse complication for patients with cancer and is almost always associated with a dismal prognosis. Older treatments like mithramycin and calcitonin have recently been replaced with newer management strategies, mostly involving bisphosphonates. These agents are potent inhibitors of osteoclasts which have been found to normalize serum calcium levels in a high proportion of patients with HCM. Emerging therapeutic approaches include monoclonal antibodies to parathyroid hormone related peptide (PTHrP), inhibition of RANK ligand through the use of a soluble form of its receptor osteoprotegerin, analogues of Vitamin D and selective inhibiton of the Ras-Raf-MAPK-ERK signalling pathway. In this article, we review the pathophysiology of tumour osteolysis leading to hypercalcemia of malignancy, and we discuss the physiological basis for the clinical symptoms of hypercalcemia. Past, current and future therapeutic approaches are also reviewed.
