Long-term imatinib therapy promotes bone formation in CML patients.
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.
Fitter
Stephen
S
Bone and Cancer Research Laboratories, and Division of Haematology, Institute of Medical and Veterinary Science (IMVS), The Hanson Institute, Adelaide, SA 5000, Australia.
Dewar
Andrea L
AL
Kostakis
Panagiota
P
To
L Bik
LB
Hughes
Timothy P
TP
Roberts
Marion M
MM
Lynch
Kevin
K
Vernon-Roberts
Barrie
B
Zannettino
Andrew C W
AC
D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001549:Benzamides; D002113:Calcification, Physiologic / Q000187:drug effects; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010710:Phosphates / Q000097:blood; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010710:Phosphates; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium