title: Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone.
abstract: BACKGROUND
  Bisphosphonate-related osteonecrosis of the jaw was first described to start with sterile osteocyte death, similar to osteonecrosis in other parts of the skeleton. The typical chronic osteomyelitis was thought to develop when the dead bone was exposed to the oral cavity. An alternative explanation would be that the chronic osteomyelitis is a result of a bisphosphonate-related inability of infected bony lesions to heal. We tested the hypothesis that primary osteocyte death is not necessary for the development of jaw osteonecrosis.
  
  
  METHODS
  Forty rats were randomly allocated to four groups of 10. All animals underwent unilateral molar extraction and received the following drug treatments: Group I, controls with no drug treatment; Group II, 200 μg/kg per day alendronate; Groups III and IV, 200 μg/kg per day alendronate and 1 mg/kg of dexamethasone. All rats were euthanized after 14 days. Presence of osteonecrosis was determined by clinical and histological observations for groups I-III. For group IV, osteocyte viability at the contralateral uninjured site was examined using lactate dehydrogenase histochemistry (LDH).
  
  
  RESULTS
  All animals in the alendronate plus dexamethasone groups developed large ONJ-like lesions. Lactate dehydrogenase staining showed viable osteocytes in the contralateral jaw with no tooth extraction. No signs of osteonecrosis were seen in the other groups.
  
  
  CONCLUSIONS
  Bisphosphonates and dexamethasone caused no osteocyte death in uninjured bone, but large ONJ-like lesions after tooth extraction. Osteonecrosis of the jaw appears to arise first after the bone has been exposed. Possibly, bisphosphonates hamper the necessary resorption of bone that has become altered because of infection.
authors.affiliation: Orthopaedics, Department of Clinical and Experimental Medicine, Faculty of Medicine, Linköping University, Linköping, Sweden. jahan.abtahi@lio.se
authors.forename: Jahan
authors.initials: J
authors.lastname: Abtahi
authors.forename: Fredrik
authors.initials: F
authors.lastname: Agholme
authors.forename: Olof
authors.initials: O
authors.lastname: Sandberg
authors.forename: Per
authors.initials: P
authors.lastname: Aspenberg
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D005882:Gingival Diseases / Q000209:etiology; D005890:Gingivectomy / Q000379:methods; D005938:Glucocorticoids / Q000008:administration & dosage; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D008437:Maxilla / Q000601:surgery; D008963:Molar / Q000601:surgery; D019226:Oral Ulcer / Q000209:etiology; D010011:Osteocytes / Q000187:drug effects / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014081:Tooth Extraction / Q000009:adverse effects*; D020390:Tooth Socket / Q000187:drug effects / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D007770:L-Lactate Dehydrogenase; D019386:Alendronate