Hypercalcemia: An Overview of its Pathology

Calcium is essential for several human physiological processes, including the function of cellular membranes, nerves and muscles, enzymatic activities, and blood clotting. The endocrine control of Ca2+ is achieved by a homeostatic mechanism involving PTH, 1,25-dihydroxyvitamin D, and calcitonin, but other factors, such as FGF-23, TRPV5, and Klotho, regulate calcium metabolism. Hypercalcemia is a relatively common disorder largely related to primary hyperparathyroidism that accounts for approximately 80% of cases. Malignancy-associated hypercalcemia (MAH) is the most common metabolic disorder in malignancy that can be observed in 10–15% of cancer patients. Two different mechanisms may lead to MAH. The so-called humoral hypercalcemia is largely caused by the secretion of parathyroid hormone-related protein (PTHrP) by the malignant cells. On the contrary, local osteolytic hypercalcemia is induced directly by cancer cells invading the bone leading to the degradation of mineral matrix. All patients with hypercalcemia require early diagnosis and treatment to prevent the development of serious mid- and long-term complications. These complications are now uncommon in patients with primary hyperparathyroidism, in whom effective parathyroidectomy leads to complete recovery, but they can be observed in cancer patients with cancer-related skeletal events.