ESPE Yearbook of Paediatric Endocrinology

In brief: This 1-year, open-label, randomised controlled trial examined the effects and tolerability of denosumab, compared with zoledronic acid, on bone mineral density (BMD), spinal morphometry, and safety in a large cohort of children (n=84) with osteogenesis imperfecta. Treatment with denosumab increased BMD and improved spinal morphometry in children with OI, but was frequently associated with rebound hypercalcaemia (in 31%). This rebound hypercalcaemia could be alleviated by switching to zoledronic acid treatment.

Commentary: Osteogenesis imperfecta (OI) is a rare genetic skeletal disorder mainly caused by pathogenic variants in the type 1 collagen gene that results in bone fragility with fractures, bone deformities, and short stature. Patients may also present with extraosseous manifestations, including dentinogenesis imperfecta, hearing loss, joint hypermobility, blue sclerae, and cardiac/respiratory defects. To date, intravenous bisphosphonates, which inhibit bone resorption by promoting osteoclast apoptosis, are virtually the only treatment available for children with OI. However, it has been reported that bisphosphonates have poor efficacy in specific types of OI with different pathophysiology (e.g. OI type 5). Therefore, new antiresorptive drugs, such as denosumab, and anabolic agents need to be investigated in patients with bone fragility.

Denosumab, a humanised monoclonal antibody targeting receptor activator of nuclear factor κB ligand (RANKL), has been approved for the treatment of primary osteoporosis in adult patients. By binding to RANKL, a key mediator of osteoclast differentiation, function, and survival, denosumab works through a different pathway from bisphosphonates to increase BMD and reduce the fracture incidence in adult patients with osteoporosis. The current study showed that denosumab also significantly increased BMD and improved the spinal morphometry in children with OI. Regarding the tolerability, as previously reported, rebound hypercalcaemia was a quite common adverse event of denosumab in children with OI (31% of whom 46% even developed hypercalcaemic crisis) with an average of 4.7 months since the last denosumab injection. This rebound hypercalcaemia could be alleviated by switching to zoledronic acid treatment.

Treatment with denosumab appears to be a promising new option in the treatment of bone fragility in children. Further studies are needed to confirm its efficacy and to determine optimal treatment regimens and minimise risks.