Denosumab for management of parathyroid carcinoma-mediated hypercalcemia

Abstract

Context: Most of the morbidity and mortality from parathyroid cancer is due to PTH-mediated hypercalcemia. Classically, management mainly consists of surgical resection, chemotherapy, and alleviation of hypercalcemia using bisphosphonates and calcium receptor agonists. The use of denosumab in the treatment of parathyroid cancer-mediated hypercalcemia has not been reported.

Objective: The aim of this report is to describe the effect of denosumab on parathyroid cancer-induced hypercalcemia. SUBJECT, MEASURES, AND RESULT: The patient is a 39-year-old man with metastatic parathyroid cancer who presented at age 35. His calcium levels initially responded to surgery, bisphosphonates, calcium receptor agonist, and chemotherapy (dacarbazine). However, his disease progressed, and his hypercalcemia became refractory to these measures in the setting of rising PTH levels. The addition of denosumab, a humanized monoclonal antibody inhibiting receptor activator of nuclear factor κB ligand resulted in successful management of his hypercalcemia for an additional 16 months.

Conclusions: Denosumab can be effective in the treatment of refractory hypercalcemia in parathyroid cancer. It may also be of potential use in settings of benign hyperparathyroid-related hypercalcemia such as parathyromatosis, where hypercalcemia is not amenable to surgery or medical therapy with bisphosphonates and calcium receptor agonists.

Figure 1.

Graphic illustration of the time course of Ca levels (continuous line, scale on the left axis), PTH levels (dotted line, scale on the right axis) in relation to the administration of denosumab (illustrated by the letter D for 60 mg and DD for 120 mg), and iv bisphosphonates (zoledronic acid or pamidronate) (illustrated by the letter B).

Figure 2.

Role of denosumab in lowering Ca levels. Elevated PTH levels in parathyroid cancer increase osteoclast activity by increasing expression of RANKL on osteoblasts. RANKL then binds to receptor activator of nuclear factor κB (RANK) on the surface of osteoclasts and causes increased bone resorption. Osteoprotegerin (OPG) is a soluble protein that inhibits the binding of RANKL to RANK. Denosumab acts similarly to OPG and decreases osteoclast activity by inhibiting the binding to RANKL to RANK. Through this mechanism, denosumab decreases Ca release from the bone.