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Medline ® Abstract for Reference 116

of 'Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia'

Long-term imatinib therapy promotes bone formation in CML patients.
Fitter S, Dewar AL, Kostakis P, To LB, Hughes TP, Roberts MM, Lynch K, Vernon-Roberts B, Zannettino AC
Blood. 2008;111(5):2538. Epub 2007 Nov 27.
Imatinib inhibits tyrosine kinases important in osteoclast (c-Fms) and osteoblast (platelet-derived growth factor receptor [PDGF-R], c-Abl) function, suggesting that long-term therapy may alter bone homeostasis. To investigate this question, we measured the trabecular bone volume (TBV) in iliac crest bone biopsies taken from chronic myeloid leukemia (CML) patients at diagnosis and again after 2 to 4 years of imatinib therapy. Half the patients (8 of 17) showed a substantive increase in TBV (>2-fold), after imatinib therapy, with the TBV in the posttreatment biopsy typically surpassing the normal upper limit for the patient's age group. Imatinib-treated patients exhibited reduced serum calcium and phosphate levels with hypophosphatemia evident in 53% (9 of 17) of patients. In vitro, imatinib suppressed osteoblast proliferation and stimulated osteogenic gene expression and mineralized-matrix production by inhibiting PDGF receptor function. In PDGF-stimulated cultures, imatinib dose-dependently inhibited activation of Akt and Crk-L. Using pharmacologic inhibitors, inhibition of PI3-kinase/Akt activation promoted mineral formation, suggesting a possible molecular mechanism for the imatinib-mediated increase in TBV in vivo. Further investigation is required to determine whether the increase in TBV associated with imatinib therapy may represent a novel therapeutic avenue for the treatment of diseases that are characterized by generalized bone loss.
Bone and Cancer Research Laboratories, and Division of Haematology, Institute of Medical and Veterinary Science (IMVS), The Hanson Institute, Adelaide, SA 5000, Australia.