title: Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.
abstract: Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.|Department of Diagnosis and Surgery, School of Dentistry at Araraquara, Sao Paulo State University, Araraquara, Brazil.
authors.forename: Rafael Scaf
authors.initials: RS
authors.lastname: de Molon
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
authors.forename: Chingyun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Bezouglaia
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.affiliation: Division of Constitutive & Regenerative Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
authors.forename: Flavia Q
authors.initials: FQ
authors.lastname: Pirih
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
authors.forename: Akrivoula
authors.initials: A
authors.lastname: Soundia
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Fernando Queiroz
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Diagnosis and Surgery, School of Dentistry at Araraquara, Sao Paulo State University, Araraquara, Brazil.
authors.forename: Joni Augusto
authors.initials: JA
authors.lastname: Cirelli
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Aghaloo
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.|Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D021621:Imaging, Three-Dimensional; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008437:Maxilla / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008811:Mice, Inbred DBA; D012720:Severity of Illness Index; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: ANTIRESORPTIVE; BISPHOSPHONATES; COLLAGEN-INDUCED ARTHRITIS; ONJ; OSTEOCLASTS; OSTEONECROSIS OF THE JAWS; RHEUMATOID ARTHRITIS