**8. Other animal models**

has been achieved [111, 112]. However, the length and frequency of intervals to allow catchup growth in children on TKI treatment still have to be defined and at least in our rat model,

**Figure 9.** Disorganization of the femoral epiphyseal line by long-term imatinib exposure. 2 μm sections of decalcified femora were stained with hematoxylin-eosin (magnification 100 ×). Controls show the typical "column" structure of the epiphyseal line and its physiological narrowing with increasing age. However, under imatinib exposure, the cellular

The established juvenile rat model mimics to a gross extent side effects of long-term TKI exposure on the growing bone in a developmental stage-dependent fashion. Impairment of longitudinal growth, as observed in children under imatinib treatment, could be unequivo-

this approach did not recover the biomechanical strength of the long bones.

architecture is more disorganized in a dose- and time-dependent manner.

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

**7.2. Clinical relevance**

cally modeled and confirmed.

The aim of the animal model described in this chapter was to evaluate side effects on bone remodeling rather than gaining further insight into the biology of CML (e.g., to study elementary mechanisms of CML disease progression) or on a more efficient antileukemic treatment exerted by new drugs (e.g., exploring why resistance develops under TKI therapy) [114, 115]. For these essential questions, the reader is kindly referred to the detailed body of literature on establishing and maintaining acute lymphatic or myeloid leukemic cells in xenograft models, transgenic models, and syngeneic models using a broad range of species [116–119], whereas mice are used mostly in orthotopic animal models [120–123].

Our research described, focused on the question how bone metabolism is affected by TKI treatment as an off-targeted side effect and therewith induced structural and mechanical osseous changes in healthy not-outgrown animals [124]. Bone remodeling has been studied in many species and resulted in the current available knowledge [125–131]. Evidently, the financial burden of animal maintenance and drug doses to be administered when sequelae of chronic exposure are investigated are much lower using small animals like mice and rats. Especially in these species, the time periods concerning defined stages of development are shorter, thus requiring drug exposure only for 2–3 months in order to mimic one to two decades in humans [132].

Most importantly, any intervention on the bone during chronic TKI exposure of the animals was minimized. Bone growth and repair is governed by regulatory mechanisms other than that of the outgrown organism. Therefore, the model described here differs principally from experiments investigating bone healing and growth after surgical procedures performed on the skeleton (for a comprehensive review see Refs. [131, 133, 134]).

**Author details**

Josephine T. Tauer1

Quebec, Canada

Dresden, Germany

Dresden, Germany

**References**

Lysann Kroschwald<sup>4</sup>

\*, Bernadette A. S. Jäger2

and Meinolf Suttorp<sup>3</sup>

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

, Anna Ulmer<sup>3</sup>

Studying Side Effects of Tyrosine Kinase Inhibitors in a Juvenile Rat Model with Focus on Skeletal...

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

2 Department of Gynecology and Obstetrics, University Hospital, Düsseldorf, Germany 3 Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital,

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

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[2] Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. The New England Journal of

[3] Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. The New England journal of Medicine. 2006;**354**:2006-2013.

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, Paula Geidel<sup>3</sup>

, Vera Girke<sup>3</sup>

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,

331

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 growth and in addition on other developing organs.
