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 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.
Vandyke
Kate
K
Myeloma and Mesenchymal Research Laboratory, Division of Haematology, Centre for Cancer Biology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, Australia.
Fitter
Stephen
S
Dewar
Andrea L
AL
Hughes
Timothy P
TP
Zannettino
Andrew C W
AC
D001549:Benzamides; D016723:Bone Remodeling / Q000187:drug effects*; D046152:Gastrointestinal Stromal Tumors / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate