title: Effect of different doses of zoledronic acid in establishing of bisphosphonate-related osteonecrosis.
abstract: OBJECTIVE
  To establish osteonecrosis of the jaws in rats treated with different doses of zoledronic acid (ZA).
  
  
  METHODS
  Male Wistar rats (n=6-7) received three consecutive weekly intravenous ZA infusions at doses of 0.04, 0.20 or 1.00mg/kg ZA or saline (control). Four weeks after the last administration, the animals were submitted to simple extraction of the lower left first molar. An additional dose of ZA was administered seven days later, and the animals were sacrificed 28 days after exodontia. Weight was measured and blood was collected weekly for analysis. The jaw was radiographically and microscopically examined along with the liver, spleen, kidney and stomach.
  
  
  RESULTS
  All ZA doses showed a higher radiolucent area than the control (p<0.0001), but the dose of 0.04mg/kg did not show BRONJ. Doses of 0.20 and 1.00mg/kg ZA showed histological evidence of bone necrosis (p=0.0004). Anaemia (p<0.0001, r(2)=0.8073) and leucocytosis (p<0.0001, r(2)=0.9699) are seen with an increase of lymphocytes (p<0.0001, r(2)=0.6431) and neutrophils and monocytes (p=0.0218, r(2)=0.8724) in all the animals treated with an increasing dose of ZA. Haemorrhage and ectasia were observed in the spleen (p=0.0004) and stomach (p=0.0168) in a dose-dependent manner, and the animals treated with ZA showed a lower rate of weight gain (p<0.0001).
  
  
  CONCLUSIONS
  We designed a bisphosphonate-related osteonecrosis of the jaw model that reproduces radiographic and histological parameters and mimics clinical alterations such as leucocytosis, anaemia and idiosyncratic inflammatory post infusion reactions.
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil. Electronic address: paulo_goberlanio@yahoo.com.br.
authors.forename: Paulo Goberlânio de Barros
authors.initials: PG
authors.lastname: Silva
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Antonio Ernando Carlos
authors.initials: AE
authors.lastname: Ferreira Junior
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Carolina Rodrigues
authors.initials: CR
authors.lastname: Teófilo
authors.affiliation: Department of Clinical Analysis, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Maritza Cavalcante
authors.initials: MC
authors.lastname: Barbosa
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Roberto César Pereira
authors.initials: RC
authors.lastname: Lima Júnior
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Fabrício Bitú
authors.initials: FB
authors.lastname: Sousa
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Mário Rogério Lima
authors.initials: MR
authors.lastname: Mota
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Ronaldo de Albuquerque
authors.initials: Rde A
authors.lastname: Ribeiro
authors.affiliation: Department of Dental Clinic, Division of Oral Pathology, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceara, Fortaleza, Ceara, Brazil.
authors.forename: Ana Paula Negreiros Nunes
authors.initials: AP
authors.lastname: Alves
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000633:toxicity*; D004164:Diphosphonates / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects; D013270:Stomach / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Acute-phase reaction; Anaemia; Bisphosphonate-associated osteonecrosis of the jaw; Leukocytosis; Zoledronic acid