Malignant hypercalcemia.

Malignancy-associated hypercalcemia (MAH) is one of the clinical emergencies in medical oncology, arising early or, more often, during the late phases of disease. Prevalence cannot be estimated accurately because previous figures of 5-30% of all cancer patients have progressively reduced thanks to the widespread use of bisphosphonates for the prevention of skeletal events. The classic distinction of humoral vs. osteolytic hypercalcemia is still relevant from an etiological point of view, but should not be considered as a rigid alternative since both mechanisms may be active in the same patients and the activation of the RANKL pathway is a common pathogenetic mechanism. Parathyroid hormone-related protein mimics the effects of PTH on the bone and kidney (tubular calcium resorption) and may represent an attractive druggable target, but additional agents (cytokines or other mediators) as well as ectopic production of 1,25(OH)₂D₃ may give an important contribution to humoral hypercalcemia. Conversely, bone invasion by cancer cells determines massive bone reabsorption due to the release of proteolytic enzymes and pro-osteolytic agents with paracrine activity on adjacent bone and stromal cells. When cancer patients develop headache, confusion, de-hydration and tremors hypercalcemia should be suspected although slow rise of calcium levels may produce more indolent symptoms. Bisphosphonates (with or without hydration and diuretics) may efficiently control MAH but only if an active treatment for the underlying cancer is promptly started. The anti-RANKL monoclonal antibody denosumab represents a novel agent able to revert the vicious cycle of bone metastases and data from phase III studies are currently showing promising activity in reverting bone resorption with manageable toxicity.