Preclinical evidence of potential craniofacial adverse effect of zoledronic acid in pediatric patients with bone malignancies

• High-dose zoledronic acid is given to osteosarcoma pediatric patients.
• It may affect tooth eruption and craniofacial developmental growth.
• Corresponding high-dose protocols were tested in growing mice.
• High-dose zoledronic acid altered irreversibly tooth eruption in young mice.
• High-dose zoledronic acid reversibly delayed skull bone formation.

High doses of zoledronic acid (ZOL), one of the most potent inhibitors of bone resorption, are currently evaluated in phase III clinical trials in Europe for the treatment of malignant pediatric primary bone tumors. The impact of such an intensive treatment on the craniofacial skeleton growth is a critical question in the context of patients with actively growing skeleton; in particular, in light of our previous studies evidencing that endochondral bone formation was transiently disturbed by high doses of ZOL. Two protocols adapted from pediatric treatments were developed for newborn mice (a total of 5 or 10 injections of ZOL 50 μg/kg every two days). Their impact on skull bones and teeth growth was analyzed by X-rays, microCT and histology up to 3 months after the last injection.ZOL administrations induced a transient delay of skull bone growth and an irreversible delay in incisor, first molar eruption and root elongation. Other teeth were affected, but most were erupted by 3 months. Root histogenesis was severely impacted for all molars and massive odontogenic tumor-like structures were observed in all mandibular incisors.High doses of ZOL irreversibly disturbed teeth eruption and elongation, and delayed skull bone formation. These preclinical observations are essential for the follow-up of onco-pediatric patients treated with ZOL.