title: Mandibular necrosis in beagle dogs treated with bisphosphonates.
abstract: OBJECTIVES - To test the effect of bisphosphonate (BP) treatment for up to 3 years on bone necrosis and osteocyte death in the mandible using a canine model. MATERIALS AND METHODS - Dogs were treated with clinical doses of oral alendronate (ALN, 0.2 or 1.0 mg/kg/day) for 1 or 3 years. In a separate study, dogs were treated with i.v. zoledronate (ZOL) at 0.06 mg/kg/day for 6 months. En bloc staining was used to identify necrotic areas in the mandible; viable osteocytes were identified using lactate dehydrogenase. RESULTS - None of the treatments was associated with exposed bone, but 17-25% of dogs treated for 1 year and 25-33% of dogs treated for 3 years with ALN showed pockets of dead bone. Necrotic areas had no viable osteocytes and were void of patent canaliculi. No control animals demonstrated necrotic bone. ZOL treatment for 6 months was associated with osteocyte death greater than that seen in animals treated with ALN or saline. It is not clear whether osteocyte death occurs because of direct toxic effects of BPs, or because suppressed remodelling fails to renew areas that naturally undergo cell death. Necrotic areas are also associated with bone other than the mandible, e.g. the rib, which normally undergo high rates of remodelling. CONCLUSIONS - Reduced remodelling rate using BPs may contribute to the pathogenesis of bone matrix necrosis. The development of an animal model that mimics important aspects of BP-related osteonecrosis of the jaw is important to understanding the pathogenesis of osteonecrosis.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dburr@iupui.edu
authors.forename: D B
authors.initials: DB
authors.lastname: Burr
authors.forename: M R
authors.initials: MR
authors.lastname: Allen
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000009:adverse effects; D000539:Alveolar Process / Q000187:drug effects / Q000473:pathology; D000818:Animals; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D001857:Bone Matrix / Q000187:drug effects / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006253:Haversian System / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008336:Mandibular Diseases / Q000139:chemically induced* / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects; D010020:Osteonecrosis / Q000139:chemically induced* / Q000473:pathology; D012272:Ribs / Q000187:drug effects; D012394:Rosaniline Dyes; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004396:Coloring Agents; D004164:Diphosphonates; D007093:Imidazoles; D012394:Rosaniline Dyes; C025485:basic fuchsin; D000077211:Zoledronic Acid; D007770:L-Lactate Dehydrogenase; D019386:Alendronate