Imatinib mesylate disturbs bone growth and remodellation in postnatal rats
Mirja Nurmio1, Henna Joki1, Jenny Kallio1, Jorma Määttä1, Kalervo Väänänen1, Jorma Toppari1, Kirsi Jahnukainen2,3 & Tiina Laitala-Leinonen1
Imatinib mesylate is a well-tolerated receptor tyrosine kinase inhibitor that has gained interest as a potential treatment for osteoporosis and other metabolic bone diseases. It is clinically approved for the treatment of chronic myelogenous leukaemia (CML), Philadelphia-positive acute lymphoblastic leukaemia and gastrointestinal stromal tumors (GIST), and targets the receptors for PDGFs, ABL-related gene, c-Abl, c-Kit and c-Fms. Altered bone and mineral metabolism has been described in patients receiving imatinib mesylate, and recent clinical data show that treating children with imatinib may result in bone loss. However, the precise effects on the bone microenvironment are unclear. We therefore exposed young rats to imatinib (150 mg/kg) on postnatal days 57, and studied the effects of tyrosine kinase inhibition on bone physiology on postnatal days 8 and 77.
Short-term imatinib treatment disturbed growth plate organization and eliminated all osteoclasts from the endochrondral junction. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that short-term imatinib treatment lead to a long-term resorption arrest at the growth plate and simultaneous bone loss at distal bone trabeculi. The impaired bone remodellation observed on postnatal day 8 remained significant until adulthood. The adverse effects were even more pronounced in another series of 14-day old animals that were given 100 mg/kg of imatinib on postnatal days 513. Therefore, clinicians prescribing tyrosine kinase inhibitors of receptors for c-Kit, c-Fms, PDGF-α or PDGF-β for children, should monitor their cancer patients also for possible adverse effects on bone growth and remodelling.