ESPE Yearbook of Paediatric Endocrinology

In brief: This article reviews the evidence and provides expert opinion on the safe and appropriate use of denosumab in children and adolescents with RANKL-mediated disorders such as giant cell bone tumours, fibrous dysplasia and juvenile Paget’s disease.

Commentary: Receptor activator of nuclear factor κB ligand (RANKL) is expressed by osteogenic cells and induces osteoclast differentiation by binding to RANK on osteoclast precursors. Excessive production of RANKL, as seen in RANKL-mediated bone tumours, results in focal bone destruction or systemic unregulated bone turnover. Various therapies have been used to treat these disorders (including surgery and medical treatments such as bisphosphonates) with variable efficacy and generally high occurence rates.

Denosumab is a humanised monoclonal antibody that inhibits RANKL with potent anti-osteoclastic effects. Although efficacy has been demonstrated in large prospective studies in adults with RANKL-mediated bone tumours, there is limited experience with the use of denosumab in children and adolescents due to the rarity of these disorders. Published data suggest that denosumab is effective in reducing osteoclastic activity and the expansion of focal lesions in RANKL-mediated bone tumours and fibrous dysplasia, with subsequent ossification with continued treatment. However, the rate of lesion recurrence after treatment cessation is important, with some lesions requiring subsequent surgery or otherwise long-term denosumab treatment. In addition, rebound hypercalcemia between doses or after discontinuation of denosumab is common in children and adolescents and appears to be greater than in adults.

These authors provide expert opinion on the safe and appropriate use of denosumab in children and adolescents with RANKL-mediated disorders. It highlights the need for patients to be managed in a tertiary specialist centre by a multidisciplinary team with expertise in managing denosumab treatment and the rebound phenomenon. Expert recommendations are given on the indication for denosumab treatment, its implementation and monitoring (efficacy and safety). The authors also discuss the use of intravenous bisphosphonates to prevent rebound hypercalcaemia after discontinuation of denosumab or during dose or interval tapering. Further collaborative research is needed to determine optimal treatment regimens and minimise risks.