Osteonecrosis of the jaw and rebound hypercalcaemia in young people treated with denosumab for giant cell tumour of bone

Context: Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand, is an approved treatment for giant cell tumour of bone (GCTB) in adults and ‘skeletally mature’ adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw [ONJ] and atypical femur fractures during treatment in adults, and rebound hypercalcaemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents.

Objectives: To describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients.

Patients: Two adolescents (14 and 15 years) and a young adult (40 years) received fixed denosumab for GCTB for 1.3 - 4years (cumulative dose 47-98 mg/kg), which was stopped due to development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcaemia with acute kidney injury 5.5 - 7 months after denosumab cessation.

Results: The ONJ necessitated surgical debridement. Rebound hypercalcaemia (serum calcium 3.1-4.3mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcaemia recurred in 2 patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naïve to chemotherapy, radiotherapy, bisphosphonates, corticosteroids and metastases free, confirming the causative role of denosumab in these complications.

Conclusion: These suppression-release effects of high-dose denosumab on bone remodelling raise questions about safety of fixed dosing and treatment duration. In young people weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.