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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. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2007-07-104281v1 111/5/2538    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Fitter, S. Articles by Zannettino, A. C. W. PubMed PubMed Citation Articles by Fitter, S. Articles by Zannettino, A. C. W. Related Collections Free Research Articles Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Long-term imatinib therapy promotes bone formation in CML patients Stephen Fitter1, Andrea L. Dewar1, Panagiota Kostakis1, L. Bik To2, Timothy P. Hughes2, Marion M. Roberts2, Kevin Lynch3, Barrie Vernon-Roberts4, and Andrew C. W. Zannettino1 1 Bone and Cancer Research Laboratories, and 2 Division of Haematology, Institute of Medical and Veterinary Science (IMVS), The Hanson Institute, Adelaide; 3 Medical Oncology, Novartis Pharmaceuticals, Sydney; and 4 Adelaide Centre for Spinal Research, IMVS, The Hanson Institute, Adelaide, Australia 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Imatinib and the neoplastic bone microenvironment Paul Mathew Blood 2008 111: 2495-2496. [Full Text] [PDF] This article has been cited by other articles: S. Jonsson, B. Olsson, C. Ohlsson, M. Lorentzon, D. Mellstrom, and H. Wadenvik Increased cortical bone mineralization in imatinib treated patients with chronic myelogenous leukemia Haematologica, July 1, 2008; 93(7): 1101 - 1103. [Full Text] [PDF]

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