title: Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat.
abstract: Bisphosphonates (BPs) are medications used commonly to treat primary and metastatic bone cancer, as well as osteoporosis. Although BPs improve bone mineral density, reduce fracture risk, and reduce hypercalcemia of malignancy, some patients develop BP-related osteonecrosis of the jaws (BRONJ). This devastating complication is defined as clinically exposed bone in the maxillofacial region for more than 8 weeks. Despite an increasing number of BRONJ cases since first reported, the disease pathophysiology remains largely unknown. Since published studies suggest a significant role for dental disease in the pathophysiology of BRONJ, we developed a BRONJ animal model where aggressive periodontal disease is induced by ligature placement around the crown of the right maxillary first molar in the presence of vehicle (veh) or zoledronic acid (ZA), a potent BP. Ligature placement induced significant alveolar bone loss, which was attenuated by ZA treatment. Osteonecrosis was observed associated with ligature-induced periodontitis in the ZA-treated group. This was seen as sequestration and extensive periosteal alveolar bone formation on micro-computed tomography (µCT) in the ligated site of BP-treated animals. Histologic examination confirmed these findings, seen as necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and exposure to the oral cavity. Importantly, the rat lesions were strikingly similar to those of BRONJ patients. Our data suggest that dental disease and potent BP therapy are sufficient for BRONJ development in the rat.
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095-1668, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Aghaloo
authors.forename: Ben
authors.initials: B
authors.lastname: Kang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Sung
authors.forename: Michael
authors.initials: M
authors.lastname: Shoff
authors.forename: Matthew
authors.initials: M
authors.lastname: Ronconi
authors.forename: Jack E
authors.initials: JE
authors.lastname: Gotcher
authors.forename: Olga
authors.initials: O
authors.lastname: Bezouglaia
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000009:adverse effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007571:Jaw Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D008297:Male; D008437:Maxilla / Q000000981:diagnostic imaging / Q000473:pathology; D008954:Models, Biological; D010011:Osteocytes / Q000473:pathology; D010012:Osteogenesis; D010020:Osteonecrosis / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D010510:Periodontal Diseases / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055114:X-Ray Microtomography
chemical_list: D004164:Diphosphonates