Oral cinacalcet responsiveness in non-parathyroid hormone mediated hypercalcemia of malignancy

Hypercalcemia of malignancy develops in approximately 20-30% of patients with advanced cancer and is an ominous sign. This condition is subdivided into three categories: i) humoral hypercalcemia of malignancy (80% of cases), mediated by systemic parathyroid hormone-related protein; ii) osteolytic metastases (20% of cases), mediated by inflammatory cytokines locally released by tumor cells and/or peri-tumor macrophages; and iii) ectopic production of 1,25-dihydroxyvitamin D (<1% of cases), leading to intestinal hyperabsorption of calcium and increased osteoclastic bone resorption. Humoral hypercalcemia of malignancy is seen in a variety of solid tumors, while osteolytic metastases are most common in breast cancer and multiple myeloma. Hypercalcemia of malignancy mediated by 1,25-dihydroxyvitamin D is primarily seen in lymphomas, having only rarely been reported in solid tumors. Pharmacologic management of humoral hypercalcemia of malignancy and osteolytic metastases mainly involves inhibition of bone resorption with intravenous bisphosphonates, subcutaneous denosumab, and subcutaneous calcitonin. Glucocorticoid therapy is the mainstay for management of increased 1,25-dihydroxyvitamin D. Unfortunately, management of hypercalcemia of malignancy often requires inpatient admission in the acute setting, and loss of effectiveness of antiresorptive therapy is common. We propose oral cinacalcet may be an efficacious therapy for hypercalcemia of malignancy related to elevated 1,25-dihydroxyvitamin D, and we present supporting data from two cases involving solid tumors. Furthermore, we hypothesize that this effect is primarily mediated by cinacalcet's interaction with the calcium-sensing receptor in the intestine with lesser effects at bone and kidney. Lastly, the role of 1,25-dihydroxyvitamin D in hypercalcemia malignancy may be underappreciated in solid tumors.