Rebound hypercalcaemia timing is associated with cumulative weight-based denosumab dose for central giant cell granuloma treatment in children despite a dose weaning regimen.

Central giant cell granulomas (CGCG) are locally destructive, non-neoplastic lesions that express receptor activator of nuclear factor-kappaB (RANK) and RANK ligand. Denosumab, a monoclonal antibody against RANK ligand, is licensed in skeletally mature patients, with less experience in children who are at risk of rebound hypercalcaemia. We describe the response to denosumab in five skeletally immature children with CGCG. Denosumab was started aged 2.1 to 11.6 years, for 8 to 22 months, with a cumulative dose of 9.6 to 58.8 mg/kg. Three patients followed a weaning protocol (using reducing dose frequency and zoledronic acid). Denosumab ossified all lesions. Three patients had subsequent surgery, and one had recurrence. All had rebound hypercalcaemia, 8.9-47 weeks (median 23.3 weeks) after the last treatment dose. Four presented with symptomatic hypercalcaemia and acute kidney injury. Cumulative denosumab treatment dose/kg positively correlated with (1) time to rebound after the last treatment dose (r(2) = 0.94, p = 0.006); and (2) length of admission for hypercalcaemia treatment (r(2) = 0.87, p = 0.02). All patients had increased bone mineral density and metaphyseal sclerosis that improved after stopping denosumab. One had a clavicular fracture at the intersection of normal and high-density bone. We propose that rebound hypercalcaemia should be an anticipated consequence of stopping denosumab in skeletally immature patients and exists on a spectrum. A higher cumulative denosumab dose/kg increases the time to rebound hypercalcaemia and its severity. Further work is needed to establish the lowest dose and the shortest treatment duration to balance effective treatment with minimising side effects.