Denosumab for the Treatment of Bisphosphonate-Refractory Hypercalcemia

Case Report A 52-year-old man with a history of metastatic renal cell carcinoma to the lungs presented with confusion and dehydration to the outpatient oncology department. The corrected-for-albumin serum calcium level was 13.9 mg/dL after treatment with zoledrenic acid for 4 months. The patient had no known bone metastasis, and the parathyroid hormone–related protein in his serum was 67 pg/mL, which was consistent with humoral hypercalcemia of malignancy, a frequent syndrome in renal cell cancer. The patient was admitted to the inpatient service, started on hydration, and a dose of zoledronic acid was administrated. The patient improved clinically, and a moderate reduction in the calcium levels was achieved. However, 1 week later, the patient worsened again clinically, and his calcium levels were rising. His hypercalcemia was responding only minimally to aggressive hydration and calcitonin administration when it was decided to use denosumab, which is a novel agent, off-label to treat the bisphosphonate-refractory hypercalcemia of the patient. Denosumab is currently approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors. After the initiation of denosumab, the calcium level of the patient fell rapidly to normal levels within 2 days, which was durable for at least 1 month (Fig 1). Unfortunately, the patient experienced rapid disease progression and no additional treatments were administered. Discussion Zoledronic acid incorporates rapidly into the bone and is taken up by the resorptive activity of mature osteoclasts. Intracellularly, as a nitrogen-containing bisphosphonate, zoledronic acid acts principally as an inhibitor of farnesyl-pyrophosphate synthase, which reduces the prenylationand, therefore, theactivityofguanosine5 -triphosphate-binding proteins, which are critical to osteoclast function and survival. However, denosumabisanovel, fullyhumanmonoclonalantibody,whichprevents the receptor activator of nuclear factor kappa B ligand from binding to its receptor and inhibits osteoclast development, activation, and survival. Therefore, it is conceivable that denosumab has a more pronounced effect. Indeed, this notion was supported by data from phase III clinical trialsinwhichamorepronouncedsuppressionofbone-turnovermarkers was seen. At the same time, the propensity to cause significant hypocalcemia, presumably as a result of reduced osteoclast function, was significantly increased in patients treated with denosumab compared with patients treated with zoledronic acid. Hypocalcemia has emerged as one of the main adverse effects of this agent. Interestingly, Fizazi et al showed that a calcium decrease of grade 3 or higher occurred in 48 patients (5%) receiving denosumab and 13 patients (1%) receiving zoledronic acid, which demonstrated the potentially more potent effect of denosumab in malignant hypercalcemia. Other studies by Stopeck et al and Henry et al demonstrated similar effects. To our knowledge, this is the first reported case of management of malignant hypercalcemia in a solid tumor with denosumab. Currently, there is one ongoing clinical trial studying the use of denosumab for refractory hypercalcemia, and the results are pending.