Impact of Long-Term Exposure to the Tyrosine Kinase Inhibitor Imatinib on the Skeleton of Growing Rats

The tyrosine kinase (TK) inhibitor imatinib provides a highly effective therapy for chronic myeloid leukemia (CML) via inhibition of the oncogenic TK BCR-ABL1. However, off-target TKs like platelet-derived growth factor receptors (PDGF-R) and colony-stimulating factor-1 receptor (c-fms), involved in bone remodeling, are also inhibited. Thus, pediatric patients with CML on imatinib exhibit altered bone metabolism, leading to linear growth failure. As TKI treatment might be necessary for a lifetime, long-term effects exerted on bone in children are of major concern. Therefore, we studied the skeletal long-term effects of continuous and intermittent imatinib exposure in a juvenile rat model.Four-weeks-old male Wistar rats were chronically exposed to imatinib via drinking water over a period of 10 weeks. Animals were exposed to a standard and high imatinib dosage continuously and to the high imatinib dose intermittently. Bone mass and strength were assessed using pQCT, micro-computed tomography (μCT), and biomechanical testing at the prepubertal, pubertal, and postpubertal age. Bone length and vertebral height as well as biochemical markers of bone turnover were analyzed.Femoral and tibial bone length were dose-dependently reduced by up to 24% (pIn conclusion, imatinib mainly impaired longitudinal growth of long bones rather than the vertebrae of growing rats. Interestingly, intermittent imatinib exposure has less skeletal side effects, which may be beneficial in pediatric patients taking imatinib.酪氨酸激酶（tyrosine kinase, TK）抑制剂伊马替尼可通过抑制致癌性酪氨酸激酶BCR-ABL1，为慢性髓性白血病（chronic myeloid leukemia, CML）提供高效治疗方案。然而，该药物同时也会抑制参与骨重塑的脱靶酪氨酸激酶，例如血小板衍生生长因子受体（platelet-derived growth factor receptors, PDGF-R）与集落刺激因子-1受体（colony-stimulating factor-1 receptor, c-fms）。因此，接受伊马替尼治疗的慢性髓性白血病儿科患者会出现骨代谢异常，进而引发线性生长障碍。鉴于酪氨酸激酶抑制剂治疗往往需要终身进行，其对儿童骨骼的长期影响已成为学界重点关注的问题。因此，我们在幼年大鼠模型中探究了持续与间歇暴露于伊马替尼对骨骼的长期效应。将4周龄的雄性Wistar大鼠通过饮用水持续暴露于伊马替尼，时长共计10周。实验设置了标准剂量与高剂量的持续给药组，以及高剂量间歇给药组。在青春期前、青春期及青春期后三个时间节点，我们通过外周定量计算机断层扫描（peripheral quantitative computed tomography, pQCT）、显微计算机断层扫描（micro-computed tomography, μCT）以及生物力学测试评估骨量与骨强度，并同步分析骨长度、椎骨高度以及骨转换生化标志物。股骨与胫骨长度呈剂量依赖性降低，最高可达24%（P<0.05）。综上，伊马替尼主要损害生长大鼠的长骨纵向生长，而非椎骨。值得注意的是，间歇暴露于伊马替尼的骨骼副作用更轻，这或许可为接受伊马替尼治疗的儿科患者带来获益。