Abstract 3289: Skeletal consequences of bone resorption inhibitors (zoledronic acid and RANKL blocking antibody) injections during growth: mouse strain disparities and synergic effect

Abstract

Abstract Abstract Background: High doses of bone resorption inhibitors are currently evaluated for the treatment of malignant primary bone tumors. The impact of such an intensive treatment on growing skeleton is a critical question in the context of pediatric oncology. Methods: Protocols adapted from pediatric treatments were developed for mice (a total of 4 or 5 injections of Zoledronic acid (50 μg/kg) or IKK-22.5 antibody (50 μg/injection) every two or three days). Their impact on tibias, skull bones and teeth growth was analyzed by micro-CT and histology up to 3 months after the last injection. Potential disparities between mouse strains were evaluated using both CD1 and C57BL/6J mice, as was the possible synergic effect of the two inhibitors. Results: In both mouse strains, bone resorption inhibitors administrations induced a transient delay of tibia and skull bone growth. Indeed, three months after the last injection all bone parameters were back to normal. Regarding tooth eruption and root elongation, both were severely impaired in C57BL/6J mouse whatever the inhibitor considered while in CD1 mouse highly more important doses are necessary to observe similar effects. Combination of both inhibitors, at half-doses in CD1 mouse, induced severe delay of tooth eruption demonstrating the existence of synergic effect between the two inhibitors. Conclusions: In mouse, high doses of bone resorption inhibitors disturbed teeth eruption and elongation, and delayed tibias and skull bone formation. Difference of sensitivity to these inhibitors was observed between mouse strains which understanding will require further studies. A synergic effect was also observed for these inhibitors. In human, similar treatments may impact the permanent teeth eruption. These observations are crucial for the follow-up of pediatric patients treated with high doses of bone resorption inhibitors in ongoing European and American protocols. Citation Format: Frederic P. Lezot, Benjamin Navet, YongWon Choi, Hideo Yagita, Ariane Berdal, Christopher G. Mueller, Francoise Redini, Dominique Heymann. Skeletal consequences of bone resorption inhibitors (zoledronic acid and RANKL blocking antibody) injections during growth: mouse strain disparities and synergic effect. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3289. doi:10.1158/1538-7445.AM2015-3289