Mechanisms and treatment of hypercalcemia of malignancy

Hypercalcemia of malignancy is a common paraneoplastic syndrome and a frequent complication of advanced breast and lung cancer, and multiple myeloma. The development of this malignancy complication often purports a poor prognosis. Thorough evaluation to establish the cause of hypercalcemia is essential because some patients may actually have undiagnosed primary hyperparathyroidism.

Production of humoral factors by the primary tumor, collectively known as humoral hypercalcemia of malignancy (HHM), is the mechanism responsible for 80% of cases. The vast majority of HHM is caused by tumor-produced parathyroid hormone-related protein followed by infrequent tumor production of 1,25-dihydroxyvitamin D and parathyroid hormone. The remaining 20% of cases are caused by bone metastasis with consequent bone osteolysis and release of skeletal calcium. Key therapies are saline hydration to promote calciuresis and bisphosphonates to reduce pathologic osteoclastic bone resorption. Calcitonin and glucocorticoids, especially in 1,25-dihydroxyvitamin D-mediated HHM, also have calcium-lowering effects.

Recent discoveries on mechanisms of malignancy-associated hypercalcemia highlight the critical role of the osteoclast. Bisphosphonates and other novel therapies being evaluated in clinical trial target this bone-resorbing cell type and provide effective and durable serum calcium reduction.