title: Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.
abstract: BACKGROUND
  Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit(+) gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume.
  
  
  OBJECTIVE
  In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. DESIGN, PATIENTS, AND INTERVENTION: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis.
  
  
  RESULTS
  Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck.
  
  
  CONCLUSIONS
  These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck.
authors.affiliation: Myeloma Research Laboratory, Division of Hematology, Centre for Cancer Biology, SA Pathology, GPO Box 14, Adelaide, SA, Australia 5000.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.forename: Stephen
authors.initials: S
authors.lastname: Fitter
authors.forename: Jenny
authors.initials: J
authors.lastname: Drew
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Schultz
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: David T
authors.initials: DT
authors.lastname: Yeung
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005260:Female; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005542:Forearm / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate