Bisphosphonates cause osteonecrosis of the jaw-like disease in mice.
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a morbid bone disease linked to long-term bisphosphonate use. Despite its broad health impact, mechanistic study is lacking. In this study, we have established a mouse model of BONJ-like disease based on the equivalent clinical regimen in myeloma patients, a group associated with high risk of BONJ. We demonstrate that the murine BONJ-like disease recapitulates major clinical and radiographical manifestations of the human disease, including characteristic features of osseous sclerosis, sequestra, avascular, and radiopaque alveolar bone in the jaw that persists beyond a normal course of wound healing following tooth extraction. We find that long-term administration of bisphosphonates results in an increase in the size and number of osteoclasts and the formation of giant osteoclast-like cells within the alveolar bone. We show that the development of necrotic bone and impaired soft tissue healing in our mouse model is dependent on long-term use of high-dose bisphosphonates, immunosuppressive and chemotherapy drugs, as well as mechanical trauma. Most importantly, we demonstrate that bisphosphonate is the major cause of BONJ-like disease in mice, mediated in part by its ability to suppress osseous angiogenesis and bone remodeling. The availability of this novel mouse model of BONJ-like disease will help elucidate the pathophysiology of BONJ and ultimately develop novel approaches for prevention and treatment of human BONJ.
Bi
Yanming
Y
University of Maryland School of Medicine, 800 W. Baltimore Street, Baltimore, MD 21201, USA.
Gao
Yamei
Y
Ehirchiou
Driss
D
Cao
Chunzhang
C
Kikuiri
Takashi
T
Le
Anh
A
Shi
Songtao
S
Zhang
Li
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000494:pharmacology; D016723:Bone Remodeling / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology; D000077143:Docetaxel; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology; D007571:Jaw Diseases / Q000139:chemically induced* / Q000473:pathology; D008334:Mandible / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010020:Osteonecrosis / Q000139:chemically induced* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid; D003907:Dexamethasone
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