Dysregulation of bone remodeling by imatinib mesylate

Imatinib mesylate is a rationally designed tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Although the efficacy and tolerability of imatinib are a vast improvement over conventional chemotherapies, the drug exhibits of...

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Bibliographic Details
Published in:Blood 2010-01, Vol.115 (4), p.766-774
Main Authors: Vandyke, Kate, Fitter, Stephen, Dewar, Andrea L., Hughes, Timothy P., Zannettino, Andrew C.W.
Format: Article
Language:English
Subjects:
Benzamides
Biological and medical sciences
Bone Remodeling - drug effects
Gastrointestinal Stromal Tumors - complications
Gastrointestinal Stromal Tumors - drug therapy
Hematologic and hematopoietic diseases
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - complications
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Medical sciences
Osteoclasts - drug effects
Osteolysis - drug therapy
Osteolysis - etiology
Piperazines - therapeutic use
Protein Kinase Inhibitors - therapeutic use
Pyrimidines - therapeutic use
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Summary:Imatinib mesylate is a rationally designed tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Although the efficacy and tolerability of imatinib are a vast improvement over conventional chemotherapies, the drug exhibits off-target effects. An unanticipated side effect of imatinib therapy is hypophosphatemia and hypocalcemia, which in part has been attributed to drug-mediated changes to renal and gastrointestinal handling of phosphate and calcium. However, emerging data suggest that imatinib also targets cells of the skeleton, stimulating the retention and sequestration of calcium and phosphate to bone, leading to decreased circulating levels of these minerals. The aim of this review is to highlight our current understanding of the mechanisms surrounding the effects of imatinib on the skeleton. In particular, it examines recent studies suggesting that imatinib has direct effects on bone-resorbing osteoclasts and bone-forming osteoblasts through inhibition of c-fms, c-kit, carbonic anhydrase II, and the platelet-derived growth factor receptor. The potential application of imatinib in the treatment of cancer-induced osteolysis will also be discussed.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2009-08-237404