Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy

Abstract

Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life-threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia.

Figure 1

Mechanism of hypercalcaemia from paraneoplastic syndrome and bone metastasis.

Figure 2

Case 1: Adjusted calcium levels from diagnosis (day 1) until present day. Note blue arrows denote intravenous fluids±zoledronic acid. Green arrow indicates treatment with denosumab. Dashed red line shows upper limit of normal for adjusted serum calcium. Orange arrow denotes where patient received calcitonin 200 units subcutaneous injection as inpatient three times daily increased to four times daily, but stopped on starting denosumab.

Figure 3

Case 2: Adjusted calcium levels from diagnosis of relapse (day 1) until present day. Note blue arrows denote hospital admissions for intravenous fluids and zoledronic acid. Green arrow indicates treatment with denosumab. Dashed red line shows upper limit of normal for adjusted serum calcium.