The effects of tyrosine kinase inhibition on bone remodelling.

Imatinib is a rationally-designed tyrosine kinase inhibitor that is a highly-successful treatment for chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours. In a retrospective study, it was previously shown that imatinib therapy is associated with an increase in trabecular bone volume. In this current study, a prospective analysis of bone indices in imatinib-treated CML patients was carried out to determine the mechanism responsible for this altered bone remodelling. Imatinib therapy resulted in an increase in trabecular bone volume and trabecular thickness in iliac crest trephines, relative to prior to treatment. This was associated with a significant decrease in osteoclast numbers, assessed histologically, and in serum levels of a marker of osteoclast activity. Osteoblast numbers were not altered by up to 12 months of treatment. These data suggest that imatinib dysregulates bone remodelling by inhibiting osteoclast activity. It was next examined whether a second-generation tyrosine kinase inhibitor, dasatinib, which is successfully used to treat CML in imatinib-resistant patients, could similarly alter bone remodelling. Dasatinib treatment significantly increased trabecular bone volume and trabecular thickness in a rat model of normal bone remodelling. This was primarily attributable to inhibition of osteoclast activity, at least in part through inhibition of Fms. These studies show for the first time that dasatinib treatment is associated with a decrease in osteoclast formation and activity in vitro and in vivo, suggesting that decreased bone resorption is a likely side-effect of dasatinib therapy. Additionally, these studies highlight the possibility that both imatinib and dasatinib may represent potential treatments for diseases characterised by aberrant bone loss. While imatinib is well-tolerated in children, emerging data suggest that long-term therapy may result in decelerated growth in juvenile CML patients. To date, there are no reports suggesting a mechanism for altered growth in imatinib-treated paediatric patients. In a normal mature rat model, we found that daily treatment with imatinib or dasatinib significantly decreased growth plate thickness at the proximal tibia, with a complete fusion of the growth plate by 12 weeks of treatment in imatinib-treated animals. Furthermore, chondrocyte proliferation and activity were significantly decreased by imatinib and dasatinib treatment in vitro, through a mechanism that may involve inhibition of PDGFRβ. The dramatic effect of imatinib and dasatinib on growth plate morphology in rats suggests that growth plate closure should be investigated as a potential mechanism for inhibited growth in pre-pubescent patients receiving imatinib.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201