Imatinib mesylate does not increase bone volume in vivo.
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.
Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. s.osullivan@auckland.ac.nz
Susannah
S
O'Sullivan
Dorit
D
Naot
Karen E
KE
Callon
Maureen
M
Watson
Greg D
GD
Gamble
Marianne
M
Ladefoged
Morten A
MA
Karsdal
Peter
P
Browett
Jillian
J
Cornish
Andrew
A
Grey
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D000068877:Imatinib Mesylate; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D015675:Osteocalcin / Q000097:blood / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D010879:Piperazines; D011743:Pyrimidines; D015675:Osteocalcin; D000068877:Imatinib Mesylate