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Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for
Kate Vandyke1, Stephen Fitter, Jenny Drew
1Myeloma Research Laboratory, Division of Hematology, Centre for Cancer Biology, SA Pathology, GPO Box 14, Adelaide, SA, Australia 5000.
Context:
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.
Insights
Imatinib treatment for chronic myeloid leukemia (CML) decreases osteoclast activity, increasing bone volume. However, it also causes a site-specific decrease in bone mineral density, requiring further investigation.
Area of Science:
- Oncology
- Bone Biology
- Pharmacology
Background:
- Imatinib is a tyrosine kinase inhibitor used for Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit(+) gastrointestinal stromal tumors.
- Previous studies indicated imatinib therapy increases trabecular bone volume.
Purpose of the Study:
- To prospectively analyze bone indices in imatinib-treated CML patients.
- To determine the mechanism behind imatinib-induced bone remodeling changes.
Main Methods:
- Prospective analysis of 11 newly diagnosed CML patients on high-dose imatinib (600 mg/d).
- Quantification of serum bone remodeling markers, dual-energy x-ray absorptiometry (DXA) for bone mineral density (BMD), and bone biopsy analysis (histology, micro-CT) at baseline and 6, 12, 24 months.
- Assessment of bone parameters in the TIDEL II study.
Main Results:
- Imatinib treatment led to increased trabecular bone volume and thickness.
- A significant decrease in osteoclast numbers and serum osteoclast activity markers was observed.
- Osteoblast numbers remained unchanged, and a site-specific decrease in femoral neck BMD was noted.
Conclusions:
- Imatinib therapy dysregulates bone remodeling by reducing osteoclast activity without a corresponding decrease in osteoblast activity, resulting in increased trabecular bone volume.
- The site-specific decrease in femoral neck BMD warrants further long-term investigation to understand its causes and consequences.
