Benefits of low-dose Denosumab for managing treatment-resistant rebound hypercalcaemia after cessation of Denosumab therapy for giant cell granulomas

Abstract

Background Denosumab is a monoclonal antibody against RANK-ligand, which is essential for osteoclast differentiation and activation. Noonan syndrome is a RAS-opathy with a propensity for giant cell granulomas (GCGs) which express RANK and respond well to treatment with denosumab. Adverse effects in children include metaphyseal sclerosis and post-cessation hypercalcaemia (1). Presenting problem A 17-year-old male with Noonan Syndrome was diagnosed with multiple GCGs of the maxilla and mandible at 6 years old. After repeated surgical debulking, denosumab was commenced at 12 years old: 120mg weekly for 3 weeks, monthly for 18 months, 3rd monthly for 6 months, then 4th monthly. Positron emission tomography (PET)-computed tomography (CT) and magnetic resonance imaging (MRI) scans performed at 1 and 3 years demonstrated complete metabolic response, with reduction in size and sclerosis. At 16 years old, after 4 years of denosumab therapy, he presented with a right distal femoral fracture, at the junction of a thick band of metaphyseal sclerosis and 'normal' bone. The fracture required surgical fixation, and calcium levels monitored weekly. He presented 3 weeks later with severe hypercalcaemia 3.08 mmol/L (2.20-2.65). Clinical Management Initial management with IV hyperhydration followed by 0.025 mg/kg Zoledronate resulted in normalisation of calcium. However, one week later his rebound hypercalcaemia returned (4.20 mmol/L), and did not resolve with hyperhydration, calcitonin, risedronate, and 5 doses of Zoledronate (total 0.15mg/kg) over a 2-week period. Denosumab (30mg; 0.85mg/kg) was subsequently given resulting in rapid normalisation of serum calcium. He now requires low doses of denosumab (10mg; 0.25mg/kg) every 6-7 weeks when hypercalcaemia recurs. Metaphyseal sclerosis at the proximal tibia has improved on plain x-ray. After 15 months on this low-dose regimen, PET-CT showed no evidence of GCG activation. Discussion Denosumab therapy significantly reduced morbidity from aggressive facial GCGs, but also resulted in a pathologic fracture and treatment-resistant hypercalcaemia in this patient. 15 months of low-dose denosumab has successfully managed rebound hypercalcaemia, whilst allowing remodelling of the metaphyseal sclerosis and supressing GCT activity on PET-CT. This case highlights the importance of exploring the utility of long-term low-dose denosumab therapy in patients with GCG, especially in the setting of a predisposing RAS-opathy.