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Imatinib Mesylate Does Not Increase Bone Volume In Vivo

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Abstract

Imatinib mesylate is a tyrosine kinase inhibitor used in the management of disorders in which activation of c-Abl, PDGFR, or c-Kit signaling plays a critical role. In vitro, imatinib stimulates osteoblast differentiation, inhibits osteoblast proliferation and survival, and decreases osteoclast development. Patients treated with imatinib exhibit altered bone and mineral metabolism, with stable or increased bone mass. However, recovery from the underlying disease and/or weight gain might contribute to these effects. We therefore investigated the skeletal effects of imatinib in healthy rats. We evaluated the effects of imatinib on bone volume, markers of bone turnover, and bone histomorphometry in mature female rats treated for 5 weeks with either vehicle, imatinib 40 mg/kg daily, or imatinib 70 mg/kg daily. Compared to vehicle, imatinib reduced trabecular bone volume/tissue volume (mean [SD]: vehicle 26.4% [5.4%], low-dose imatinib 24.8% [4.9%] [P = 0.5], high-dose imatinib 21.1% [5.7%] [P = 0.05]), reduced osteoblast surface (mean [SD]: vehicle 12.8% [5.8%], low-dose 6.8% [1.9%] [P < 0.01], high-dose 7.8 [3.1%] [P < 0.05]), and reduced serum osteocalcin (mean change from baseline [95% CI]: vehicle −8.2 [−26.6 to 10.2] ng/ml, low dose −79.7 [−97.5 to −61.9] ng/ml [P < 0.01 vs. vehicle], high-dose −66.0 [−82.0 to −50.0] ng/ml [P < 0.05 vs. vehicle]). Imatinib did not affect biochemical or histomorphometric indices of bone resorption. These results suggest that, in healthy animals, treatment with imatinib does not increase bone mass and that the improvements in bone density reported in patients receiving imatinib may not be a direct effect of the drug.

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Acknowledgments

This work was funded by the Health Research Council of New Zealand. S. O. is the recipient of postgraduate scholarships from the Australia and New Zealand Bone and Mineral Society and the University of Auckland and a postdoctoral fellowship from the Auckland Medical Research Foundation. A. G. is the recipient of a University of Auckland Early Career Excellence Award. The work at Nordic Bioscience was supported by the Danish research foundation (Den Danske forskningsfond). We thank Novartis for the gift of imatinib and Juerg Gasser (Novartis Institute for BioMedical Research, Basel Area, Switzerland) for his assistance in developing the study protocol.

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Authors and Affiliations

  1. Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Susannah O’Sullivan, Dorit Naot, Karen E. Callon, Maureen Watson, Greg D. Gamble, Jillian Cornish & Andrew Grey

  2. Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Peter Browett

  3. Nordic Bioscience, Herlev, Denmark

    Marianne Ladefoged & Morten A. Karsdal

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  1. Susannah O’Sullivan
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  2. Dorit Naot
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Correspondence to Susannah O’Sullivan.

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P. Browett has received research funding and consulting fees from Novartis.

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O’Sullivan, S., Naot, D., Callon, K.E. et al. Imatinib Mesylate Does Not Increase Bone Volume In Vivo. Calcif Tissue Int 88, 16–22 (2011). https://doi.org/10.1007/s00223-010-9429-1

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