title: Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis.
abstract: Though osteonecrosis of the jaw (ONJ) is temporally-associated with the use of nitrogen-containing bisphosphonates (N-BPs), a cause-and-effect relationship has not yet been established. We hypothesize that ONJ is a two-stage process in which: (1) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis; and (2) powerful antiresorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis. At age 28 days, rats (n = 15/group) were placed on a high-sucrose and casein diet to exacerbate the development of periodontitis. Animals were injected subcutaneously (SC) biweekly with vehicle or alendronate (ALN, 15 µg/kg), or IV once monthly with vehicle, a low dose (LD) of zoledronic acid (ZOL), or a high dose (HD) of ZOL and sacrificed after 6, 12, 18, and 24 weeks. Mandibles and maxillae were analyzed to determine the effects on the: (1) progression of periodontitis; (2) integrity of alveolar bone; (3) status of bone resorption and formation; (4) vascularity; and (5) osteocyte viability. We found that only HD-ZOL induced ONJ-like lesions in mandibles of rice rats after 18 and 24 weeks of treatment. These lesions were characterized by areas of exposed necrotic alveolar bone, osteolysis, a honeycomb-like appearance of the alveolar bone, presence of bacterial colonies, and periodontal tissue destruction. In addition, inhibition of bone formation, a paradoxical abolition of the antiresorptive effect of only HD-ZOL, increased osteocyte necrosis/apoptosis, and decreased blood vessel number were found after 18 and/or 24 weeks. Our study suggests that only HD-ZOL exacerbates the inflammatory response and periodontal tissue damage in rice rats, inducing bone lesions that resemble ONJ.
authors.affiliation: Department of Physiological Sciences, University of Florida, Gainesville, FL, USA. aguirrej@ufl.edu
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.forename: Mohammed P
authors.initials: MP
authors.lastname: Akhter
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Pingel
authors.forename: Alyssa
authors.initials: A
authors.lastname: Williams
authors.forename: Marda
authors.initials: M
authors.lastname: Jorgensen
authors.forename: Lakshmyya
authors.initials: L
authors.lastname: Kesavalu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000150:complications* / Q000473:pathology*; D002452:Cell Count; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D008334:Mandible / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010518:Periodontitis / Q000150:complications* / Q000473:pathology*; D016205:Sigmodontinae; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D019386:Alendronate