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Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.

AbstractCONTEXT:
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.
AuthorsKate Vandyke, Stephen Fitter, Jenny Drew, Seiji Fukumoto, Christopher G Schultz, Natalie A Sims, David T Yeung, Timothy P Hughes, Andrew C W Zannettino
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 98 Issue 1 Pg. 67-76 (Jan 2013) ISSN: 1945-7197 [Electronic] United States
PMID23144472 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
Topics
  • Absorptiometry, Photon
  • Adult
  • Aged
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Benzamides
  • Bone Density (drug effects)
  • Bone Remodeling (drug effects, physiology)
  • Bone and Bones (diagnostic imaging, drug effects, pathology)
  • Female
  • Femur Neck (diagnostic imaging, drug effects, pathology)
  • Forearm (diagnostic imaging, pathology)
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (diagnostic imaging, drug therapy, metabolism, physiopathology)
  • Lumbar Vertebrae (diagnostic imaging, drug effects, pathology)
  • Male
  • Middle Aged
  • Organ Specificity (drug effects)
  • Piperazines (pharmacology, therapeutic use)
  • Protein Kinase Inhibitors (pharmacology, therapeutic use)
  • Pyrimidines (pharmacology, therapeutic use)

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