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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2538-2547.
Prepublished online as a Blood First Edition Paper on November 27, 2007; DOI 10.1182/blood-2007-07-104281.
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Submitted July 30, 2007
Accepted November 24, 2007
Long term imatinib therapy promotes bone formation in CML patients
Stephen Fitter, Andrea L Dewar, Panagiota Kostakis, L. Bik To, Timothy P Hughes, Marion M Roberts, Kevin Lynch, Barrie Vernon-Roberts, and Andrew CW Zannettino*
Division of Haematology, Bone and Cancer Research Laboratories, Institute of Medical and Veterinary Science, The Hanson Institute, Adelaide, SA, Australia
Division of Haematology, Institute of Medical and Veterinary Science, The Hanson Institute, Adelaide, SA, Australia
Medical Oncology, Novartis Pharmaceuticals Pty Ltd, Sydney, NSW, Australia
Adelaide Centre for Spinal Research, Institute of Medical and Veterinary Science, The Hanson Institute, Adelaide, SA, Australia
* Corresponding author; email: andrew.zannettino{at}imvs.sa.gov.au.
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.
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