title: Periosteal microcirculatory reactions in a zoledronate-induced osteonecrosis model of the jaw in rats.
abstract: OBJECTIVE
  Nitrogen-containing bisphosphonates induce osteonecrosis mostly in the jaw and less frequently in other bones. Because of the crucial role of periosteal perfusion in bone repair, we investigated zoledronate-induced microcirculatory reactions in the mandibular periosteum in comparison with those in the tibia in a clinically relevant model of bisphosphonate-induced medication-related osteonecrosis of the jaw (MRONJ).
  
  
  METHODS
  Sprague-Dawley rats were treated with zoledronate (ZOL; 80 i.v. μg/kg/week over 8 weeks) or saline vehicle. The first two right mandibular molar teeth were extracted after 3 weeks. Various systemic and local (periosteal) microcirculatory inflammatory parameters were examined by intravital videomicroscopy after 9 weeks.
  
  
  RESULTS
  Gingival healing disorders (∼100%) and MRONJ developed in 70% of ZOL-treated cases but not after saline (shown by micro-CT). ZOL induced significantly higher degrees of periosteal leukocyte rolling and adhesion in the mandibular postcapillary venules (at both extraction and intact sites) than at the tibia. Leukocyte NADPH-oxidase activity was reduced; leukocyte CD11b and plasma TNF-alpha levels were unchanged.
  
  
  CONCLUSIONS
  Chronic ZOL treatment causes a distinct microcirculatory inflammatory reaction in the mandibular periosteum but not in the tibia. The local reaction in the absence of augmented systemic leukocyte inflammatory activity suggests that topically different, endothelium-specific changes may play a critical role in the pathogenesis of MRONJ.
  
  
  CONCLUSIONS
  This model permits for the first time to explore the microvascular processes in the mandibular periosteum after chronic ZOL treatment. This approach may contribute to a better understanding of the pathomechanism and the development of strategies to counteract bisphosphonate-induced side effects.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Szeged, Szeged, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Janovszky
authors.forename: Andrea
authors.initials: A
authors.lastname: Szabó
authors.forename: Renáta
authors.initials: R
authors.lastname: Varga
authors.forename: Dénes
authors.initials: D
authors.lastname: Garab
authors.forename: Mihály
authors.initials: M
authors.lastname: Boros
authors.forename: Csilla
authors.initials: C
authors.lastname: Mester
authors.forename: Nikolett
authors.initials: N
authors.lastname: Beretka
authors.forename: Tamás
authors.initials: T
authors.lastname: Zombori
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Wiesmann
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bernhardt
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.forename: Péter
authors.initials: P
authors.lastname: Balázs
authors.forename: József
authors.initials: J
authors.lastname: Piffkó
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D008334:Mandible / Q000098:blood supply / Q000000981:diagnostic imaging; D008833:Microcirculation / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D010521:Periosteum / Q000098:blood supply*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014081:Tooth Extraction; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid