**Author details**

experiments investigating bone healing and growth after surgical procedures performed on

Ethical concerns in the last decades resulted in the establishment of studying bone growth and development preclinically in *ex vivo* cultures mostly making use of embryonic bone of mouse or rat strains [135, 136]. For an overview on conventional versus static versus 3D dynamic bioreactor models as well as a chorioallantoic membrane (CAM)-culture systems, the reader is kindly referred to a comprehensive review by Abubakar et al [137]. The composition of the nursing cell culture medium in these models is a crucial step. However, concerning TKIs whose metabolism in juvenile rodents is still poorly characterized and pleiotropically influences bone remodeling (e.g., impact on synthesis of growth hormone and insulin-like growth factor, liver metabolism, vitamin D metabolism, renal function, etc.) evidently not all components can be added to a cell culture medium mimicking correctly the *in vivo* situation. Therefore, our investigations had to be restricted to a genetically unchanged—"healthy" animal model to study the side effects of long-term TKI exposure on bone remodeling during

Long-term toxicity resulting from off-target effects of TKIs can be assessed conveniently by administering TKIs via the drinking water to juvenile male Wistar rats over a prolonged period. During all developmental phases (prepubertal, puberty, postpubertal, and adult), drug blood levels are obtained corresponding to data in humans. The juvenile animal model disclosed reduced long bone length and diminished vertebral height combined with reduced bone mass density and reduced breaking strength dose-dependently after chronic exposure to imatinib. Thus, the juvenile animal model depicted here mimics perfectly clinical observations on osseous changes observed in pediatric patients with CML. Furthermore, intermittent exposure of the high TKI dose mitigated the skeletal side effect and therefore represented a possible treatment option for pediatric patients suffering from longitudinal growth retardation under imatinib therapy. The juvenile animal model might also be of value to predict

sequelae of TKI treatment in other human organs following exposure over decades.

MS has received research funding and lecture honoraria from Novartis Pharmaceuticals (Nürnberg, Germany), Bristol-Myers Squibb (Munich, Germany), and Pfizer (Berlin, Germany). Funding: Continuous financial support was provided by unrestricted research grants from Novartis Pharmaceuticals (Nürnberg, Germany), Sonnenstrahl e. V. (Dresden, Germany), and Stiftung Mitteldeutsche Kinderkrebsforschung (Leipzig, Germany). Additional financial support was given by a research grant from the Deutsche Forschungsgemeinschaft (#SU122/3-1;

Disclosures: JTT, BASJ, AU, PG, VG, and LK have nothing to disclose.

the skeleton (for a comprehensive review see Refs. [131, 133, 134]).

330 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

growth and in addition on other developing organs.

**9. Conclusion**

**Acknowledgements**

Bonn, Germany).

Josephine T. Tauer1 \*, Bernadette A. S. Jäger2 , Anna Ulmer<sup>3</sup> , Paula Geidel<sup>3</sup> , Vera Girke<sup>3</sup> , Lysann Kroschwald<sup>4</sup> and Meinolf Suttorp<sup>3</sup>

\*Address all correspondence to: jtauer@shriners.mcgill.ca

1 Department of Pediatrics, Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada

2 Department of Gynecology and Obstetrics, University Hospital, Düsseldorf, Germany

3 Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital, Dresden, Germany

4 Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
