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.Abnormal Renal Calcium Handling Related to PTHrP HHM is the most common etiology of malignancy-related calcium dysregulation and accounts for ∼80% of HCM cases [1,2]. Most often, it occurs in solid tumors of the lung, head and neck, esophagus, skin, cervix, breast, kidneys, prostate, and bladder [1, 2]. These patients do not have bone metastases, and hypercalcemia occurs via PTHrP actions in both the bones and kidneys [1,2]. PTHrP has some homology with PTH, especially at the amino-terminus, and binds to the PTH-1 receptor, resulting in increased skeletal efflux of calcium and increased renal reabsorption of calcium by the mechanisms described earlier for PTH ( Fig. 1A, 2, 3A).The relative contribution of each of these processes to hypercalcemia is unknown, but it is estimated that up to 1,000 mg of calcium per day may be mobilized from the skeleton in HHM [2]. Additionally, there is an underappreciated renal contribution to HHM, as evidenced by studies in both animals and humans. In rats with HHM refractory to bone resorption inhibitors, anti-PTHrP antibodies resulted in a marked decrease in blood calcium coinciding with a 2-to 3-fold increase in fractional excretion of calcium [13]. Furthermore, in normal human subjects infused with PTHrP, the fractional excretion of calcium (control group: ∼2%) increased by ∼50% less (∼2.5-3.7%) than the increase induced by a similar rise in serum

Management of Primary Hyperparathyroidism With Severe Hypercalcemia During the COVID-19 Pandemic

“… 39 Moreover, numerous case reports have described cinacalcet use in the treatment of humoral hypercalcemia of malignancies mediated by PTH-related protein, such as metastatic renal cell carcinoma, metastatic breast cancer, and lung cancer. 43 , 44 …”

“…In addition, cinacalcet may reduce calcium levels through its effects on calcium-sensing receptor in the distal nephron and enhancing renal calcium excretion. 44 …”

Refractory paraneoplastic hypercalcaemia responding to cinacalcet

“…Cinacalcet is used for the reduction of hypercalcaemia in those with severe primary hyperparathyroidism who are unable to undergo parathyroidectomy, for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy, and additionally, to treat hypercalcaemia in those suffering from parathyroid carcinoma 8. Cinacalcet has been used very rarely to treat hypercalcaemia of malignancy, and there are only a handful of case reports available with regard to the same 9. CaSR is expressed in bone cells as well (contributing to bone homeostasis), in addition to the parathyroid glands and kidneys.…”

Evaluation of Diagnostic Workup and Etiology of Hypercalcemia of Malignancy in a Cohort of 167 551 Patients Over 20 Years

“…Toward this end, the recent publication showing recalcitrant HCM in solid tumors with an elevated 1,25-OH vitamin D with or without concomitant PTHrP elevation is but 1 example [ 16 ]. Also recent case reports have shown the potential utility of oral cinacalcet in the management of HCM caused by both PTHrP [ 33 ] and 1,25-OH vitamin D [ 34 ]. Although the exact mechanism of this effect is unknown, it may involve actions of cinacalet at the nonparathyroid calcium-sensing receptor in the bone, kidney, and intestine [ 34 ].…”