title: Preclinical evidence of potential craniofacial adverse effect of zoledronic acid in pediatric patients with bone malignancies.
abstract: 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 50μg/kg every two days). Their impact on skull bones and teeth growth was analyzed by X-rays, microCT and histology up to 3months 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 3months. 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.
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lézot
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesneau
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.affiliation: INSERM, UMR1138, Paris F-75006, France.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Castaneda
authors.affiliation: IGFL, CNRS UMR-5242, ENS de Lyon, Lyon F-69364, France; Université de Lyon 1, Faculté d'odontologie, Equipe odontoblastes et régénération du tissu dentaire, Lyon F-69372, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Farges
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR-957, Nantes, F-44035, France; Université de Nantes Nantes Atlantique Université, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France. Electronic address: francoise.redini@univ-nantes.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy*; D002648:Child; D019465:Craniofacial Abnormalities / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Osteosarcoma; Skull bone formation; Tooth eruption; Zoledronic acid