title: Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw.
abstract: OBJECTIVE
  The aim of this study was to investigate the potential role of microcrack accumulation in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (ONJ) through an animal model.
  
  
  METHODS
  Twenty-four ovariectomized rats were randomly divided into a bisphosphonate group (n = 19) and control group (n = 5) and weekly injected with zoledronic acid and normal saline, respectively. After 6 weeks, surgical intervention was performed, and the injections were continued for eight additional weeks. Then, the animals were sacrificed, and ONJ lesions were inspected for the presence of microcracks using scanning electron microscopy. Measurements included bone dimension, number of cracks, crack length, and normalized indices; crack density (Cr.Dn) and crack surface density (Cr.S.Dn) were used for group comparison.
  
  
  RESULTS
  Both number of cracks and crack length in the bisphosphonate group were greater than those in the control group (P < 0.05). Of the 19 rats injected with bisphosphonates, 13 rats (68.4 %) were classified into the ONJ group. Cr.Dn and Cr.S.Dn were significantly greater in the ONJ group than in the non-ONJ group, indicating accumulation of unrepaired microcracks (P < 0.05). Seventy-two percent of microcracks in the ONJ group conformed to the defined length that was considered significant according to a previous literature (30-80 μm); whereas 12 % of microcracks in the non-ONJ group were considered significant (P < 0.05).
  
  
  CONCLUSIONS
  Accumulation of unrepaired microcracks was significantly associated with the development of bisphosphonate-related ONJ. Further research is required to determine the role of microcracks in the pathogenesis of bisphosphonate-related ONJ.
  
  
  CONCLUSIONS
  Long-term bisphosphonates use may deteriorate the biomechanical and physiological bone integrity, contributing to the pathogenesis of bisphosphonate-related ONJ.
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea.|Department of Oral & Maxillofacial Surgery, Ewha Womans University Medical Center, Anyangcheon-ro 1071, Yangcheon-gu, Seoul, 158-710, South Korea.
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea.
authors.forename: Maria Erika A
authors.initials: ME
authors.lastname: Landayan
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea.|Department of Oral & Maxillofacial Surgery, Ewha Womans University Medical Center, Anyangcheon-ro 1071, Yangcheon-gu, Seoul, 158-710, South Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea.
authors.forename: Jacquiline Czar I
authors.initials: JC
authors.lastname: Tatad
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea. oralsurgeonsj@gmail.com.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea. oralsurgeonsj@gmail.com.|Department of Oral & Maxillofacial Surgery, Ewha Womans University Medical Center, Anyangcheon-ro 1071, Yangcheon-gu, Seoul, 158-710, South Korea. oralsurgeonsj@gmail.com.
authors.forename: Sun-Jong
authors.identifier: http://orcid.org/0000-0003-2347-3516
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, South Korea.|Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, South Korea.
authors.forename: Myung-Rae
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Department of Oral and Maxillofacial Surgery, Yonsei University, Seoul, South Korea.
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Cha
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000633:toxicity; D004164:Diphosphonates / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000633:toxicity; D007571:Jaw Diseases / Q000139:chemically induced / Q000473:pathology*; D008855:Microscopy, Electron, Scanning; D010052:Ovariectomy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Bisphosphonate-related osteonecrosis of the jaw; Bisphosphonates; Microarchitecture; Microcrack; Rat