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|Title:||Long-term imatinib therapy promotes bone formation in CML patients|
|Citation:||Blood, 2008; 111(5):2538-2547|
|Publisher:||Amer Soc Hematology|
|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|
|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.|
|Keywords:||Humans; Phosphates; Calcium; Piperazines; Pyrimidines; Platelet-Derived Growth Factor; Antineoplastic Agents; Organ Size; Cell Proliferation; Gene Expression Regulation, Leukemic; Calcification, Physiologic; Enzyme Activation; Osteogenesis; Time Factors; Adult; Aged; Middle Aged; Female; Male; Adipogenesis; Proto-Oncogene Proteins c-crk; Proto-Oncogene Proteins c-akt; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mesenchymal Stromal Cells|
|Description:||Copyright © 2007 by American Society of Hematology|
|Provenance:||Prepublished online Nov 27, 2007|
|Appears in Collections:||Pathology publications|
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