Cinacalcet for the Treatment of Humoral Hypercalcemia of Malignancy: An Introductory Case Report with a Pathophysiologic and Therapeutic Review

Abstract

Hypercalcemia is an ominous development in the course of malignancy associated with a mean survival of only several months. A majority of cases of hypercalcemia are related to humoral hypercalcemia of malignancy (HHM), where hypercalcemia is caused by increased levels of circulating parathyroid hormone-related protein (PTHrP). Mainstay treatments in the management of HHM are intravenous fluids, intravenous bisphosphonates, and subcutaneous denosumab, although hypercalcemia oftentimes recurs despite these efforts. We present a case of advanced non-small cell lung cancer with PTHrP-mediated hypercalcemia that proved resistant to standard therapy. A trial of oral cinacalcet was initiated and improved calcium levels for 2 months despite a progressive rise in PTHrP and prior to subsequent disease progression. Based on the current body of literature, we propose that this calcium-lowering effect of cinacalcet occurs due to a potential effect on renal calcium excretion.

Keywords: Cinacalcet; Humoral hypercalcemia of malignancy; Pathophysiology.

Fig. 1.

Normal calcium homeostasis (A) and abnormal calcium homeostasis (B) in humoral hypercalcemia of malignancy. A If/when extracellular calcium (Ca²⁺ [e]) decreases (A), the calcium-sensing receptor (CaSR) on the parathyroid C cells is inhibited, resulting in increased parathyroid hormone (PTH) secretion (B). Increased PTH acts in the bones and kidneys. The effect of PTH in bone increases osteoclast (OC) function (C). In the kidneys, PTH increases calcium reabsorption in the distal convoluted tubule (D). In addition, PTH increases the activity of 1-α-hydroxylase in the kidneys (E), which in turn increases 1,25-OH vitamin D, thus increasing calcium absorption from the intestines (F). All of these mechanisms are designed to restore/maintain normal serum calcium levels. B PTH-related protein (PTHrP) is secreted by malignant cells (A). Because of its homology with PTH, it interacts with the PTH receptor (PTH-1r) in the bones and kidneys, resulting in increased bone resorption (B) and increased calcium reabsorption (C), respectively. This, in turn, raises extracellular calcium (D), which stimulates CaSR (E), resulting in lower PTH levels (F) [1, 2, 3, 4, 9, 13].

Fig. 2.

Effect of parathyroid hormone (PTH), PTH-related protein (PTHrP), bisphosphonates (BPs), and denosumab on bone metabolism. PTH and/or PTHrP bind to the PTH-1r receptor on osteoblasts (A), increasing the production of RANKL (B). RANKL binds to RANK receptors on osteoclasts (C), activating bone resorption, leading to calcium efflux into the extracellular space (D). Denosumab inhibits this process by binding to RANKL to prevent its binding to the RANK receptor (E). BPs in the bone matrix directly inhibit osteoclast function (F). Both of these actions decrease calcium efflux into the extracellular space [1, 2, 9, 15, 16].

Fig. 3.

Calcium handling in the distal convoluted tubule (A) and thick ascending loop of Henle (B). A In the distal convoluted tubule, parathyroid hormone (PTH) and PTH-related protein (PTHrP) promote the reabsorption of calcium via activation of the PTH-1r receptor on the luminal membrane. Calcium first enters from the lumen via the TRPV5 channel and is transported by calbindin-D28k to the basolateral membrane, where it is reabsorbed via activity of PMCA1b and NCXl. Activation of calcium-sensing receptor (CaSR) inhibits this process by inhibiting PMCA1b, the primary mechanism of calcium transport across the basolateral membrane. Additionally, activation of CaSR decreases the number of TRPV5 channels. B In the thick ascending loop of Henle, coordinated activity of the NKCC2, ROMK, CLCNKB, and Na-K ATPase channels leads to a lumen-positive potential, which in turn favors the reabsorption of Ca²⁺ via the claudin-16 channel. Activation of CaSR via several mechanisms inhibits the generation of this lumen-positive potential, thus leading to decreased calcium reabsorption and subsequently increased calcium excretion [3, 4, 5, 6, 10, 11, 13, 14].