Long-term imatinib therapy promotes bone formation in CML patients

Abstract

Imatinib inhibits tyrosine kinases important in osteoclast (c-Fms) and osteoblast (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 CML patients at diagnosis and again following 2-4 years of imatinib therapy. Half the patients (8/17) showed a substantive increase in TBV (> 2 fold), following imatinib therapy, with the TBV in the post treatment 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% (9/17) of patients. In vitro, imatinib suppressed osteoblast proliferation and stimulated osteogenic gene expression and mineralised matrix production by inhibiting PDGF receptor function. In PDGF stimulated cultures, imatinib dose dependently inhibited activation of Akt and Crk L. Using pharmacological 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 if the increase in TBV associated with imatinib therapy may represent a novel therapeutic avenue for the treatment of diseases that are characterised by generalised bone loss.