title: Absence of exposed bone following dental extraction in beagle dogs treated with 9 months of high-dose zoledronic acid combined with dexamethasone.
abstract: OBJECTIVE
  Factors contributing to osteonecrosis of the jaw with anti-remodeling drug treatment are unclear. Epidemiologic and experimental studies have suggested the combination of bisphosphonates and dexamethasone results in osteonecrosis of the jaw more often than either agent alone. The goal of this study was to assess the combination of these 2 drugs in a large animal model previously shown to be susceptible to exposed bone in the oral cavity when treated with bisphosphonates.
  
  
  METHODS
  Skeletally mature beagle dogs were untreated controls or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL plus DEX. ZOL and DEX were given at doses based on those used in humans. All animals underwent single molar extraction at 7 and 8 months after the start of the study. Extraction sites were obtained at month 9 for assessment of osseous healing using micro-computed tomography and histology.
  
  
  RESULTS
  No animals were observed to have exposed bone after dental extraction, yet 1 animal treated with ZOL and 1 treated with ZOL plus DEX had severely disrupted extraction sites as viewed by computed tomography and histology. These 2 animals had an intense periosteal reaction that was less obvious but still present in all ZOL-treated animals and absent from untreated animals. There was no significant difference in bone volume within the socket among groups at 4 or 8 weeks after healing, yet the ratio of surface to volume was significantly higher in animals treated with ZOL plus DEX at 8 weeks compared with control animals.
  
  
  CONCLUSIONS
  These findings suggest a more complex pathophysiology to osteonecrosis of the jaw than is implied by previous epidemiologic studies and those in rodents and raise questions about the potential role of DEX in its etiology.
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. matallen@iupui.edu
authors: Matthew R
authors: MR
authors: Allen
authors: Tien-Min Gabriel
authors: TM
authors: Chu
authors: Salvatore L
authors: SL
authors: Ruggiero
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology* / Q000503:physiopathology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004285:Dogs; D004338:Drug Combinations; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D008334:Mandible / Q000187:drug effects; D023421:Models, Animal; D010521:Periosteum / Q000187:drug effects; D014081:Tooth Extraction / Q000009:adverse effects*; D020390:Tooth Socket / Q000187:drug effects*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004338:Drug Combinations; D007093:Imidazoles; D000077211:Zoledronic Acid; D003907:Dexamethasone
references: J Clin Periodontol. 2003 Sep;30(9):809-18
references: 12956657
references: J Oral Maxillofac Surg. 2010 Nov;68(11):2730-4
references: 20869151
references: J Bone Miner Res. 1987 Dec;2(6):595-610
references: 3455637
references: Mayo Clin Proc. 2006 Aug;81(8):1047-53
references: 16901028
references: J Oral Maxillofac Surg. 2011 Feb;69(2):418-27
references: 21122971
references: Oral Oncol. 2009 Feb;45(2):164-72
references: 18715819
references: J Bone Miner Res. 2010 Jan;25(1):98-105
references: 19580463
references: J Oral Maxillofac Surg. 2007 Mar;65(3):415-23
references: 17307586
references: Development. 1996 Oct;122(10):3151-62
references: 8898228
references: J Bone Miner Res. 2008 Jun;23(6):826-36
references: 18558816
references: J Bone Miner Res. 2006 Oct;21(10):1503-5
references: 16995804
references: Skeletal Radiol. 2012 Jul;41(7):861-5
references: 22526880
references: J Clin Oncol. 2006 Oct 20;24(30):4895-900
references: 17001071
references: J Oral Maxillofac Surg. 2008 May;66(5):987-94
references: 18423290
references: N Engl J Med. 2009 Jan 1;360(1):53-62
references: 19118304
references: N Engl J Med. 2007 Nov 22;357(21):2133-42
references: 18032763
references: Arthritis Res Ther. 2003;5(3):R163-73
references: 12723988
references: J Bone Miner Res. 2011 Aug;26(8):1871-82
references: 21351151
references: Exp Cell Res. 2002 Oct 1;279(2):227-38
references: 12243748
references: J Oral Maxillofac Surg. 2010 May;68(5):959-63
references: 20149510
references: Osteoporos Int. 2011 Feb;22(2):693-702
references: 20458574
references: Orthod Craniofac Res. 2010 Nov;13(4):214-22
references: 21040464
references: Ann Intern Med. 2006 May 16;144(10):753-61
references: 16702591