Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease.
Osteonecrosis of the jaws (ONJ) is a complication of antiresorptive medications, such as denosumab or bisphosphonates, prescribed to patients with bone malignancy or osteoporosis. The most common instigating local factor in ONJ pathogenesis is tooth extraction. However, in adults the great majority of teeth are extracted due to dental disease. Here, we have investigated alveolar bone healing after extraction of healthy teeth or teeth with naturally occurring periradicular disease in mice treated with high dose zoledronic acid (ZA), a potent bisphosphonate, or OPG-Fc, a RANKL inhibitor. C57BL/6 mice were treated for eight weeks and in vivo micro-CT was performed to identify spontaneously occurring periradicular lesions around the roots of maxillary molars. Then, extractions of molars with and without dental disease were performed in all groups. Four weeks later, animals were euthanized and maxillae were dissected and analyzed. Clinically, all vehicle animals with extraction of healthy or diseased teeth, and most OPG-Fc or ZA animals with extraction of healthy teeth showed normal mucosal healing. On the contrary, most animals with OPG-Fc or ZA treatment and extraction of diseased teeth demonstrated impaired healing with visible mucosal defects. Radiographically, bone socket healing was significantly compromised in OPG-Fc and ZA-treated mice with periradicular disease in comparison to other groups. Histologically, all vehicle animals showed normal mucosal healing and socket remodeling. OPG-Fc and ZA animals with extraction of healthy teeth showed normal mucosal healing, woven bone formation in the socket, and decreased remodeling of the original socket confines. OPG-Fc and ZA animals with extraction of diseased teeth showed mucosal defects, persistent prominent inflammatory infiltrate, bone exposure and areas of osteonecrosis. These findings support that dental disease is critical in the pathogenesis of ONJ, not only as the instigating cause for tooth extraction, but also as a compounding factor in ONJ development and pathophysiology.
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Akrivoula
A
Soundia
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Danny
D
Hadaya
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Navid
N
Esfandi
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Diagnosis and Surgery, School of Dentistry at Araraquara, Sao Paulo State University, Araraquara 14801-903, Brazil.
Rafael Scaf
RS
de Molon
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Olga
O
Bezouglaia
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Sarah M
SM
Dry
Division of Constitutive & Regenerative Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Flavia Q
FQ
Pirih
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA. Electronic address: taghaloo@dentistry.ucla.edu.
Tara
T
Aghaloo
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Electronic address: stetradis@dentistry.ucla.edu.
Sotirios
S
Tetradis
D000539:Alveolar Process / Q000000981:diagnostic imaging / Q000473:pathology; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008963:Molar / Q000000981:diagnostic imaging / Q000473:pathology; D009061:Mouth Mucosa / Q000473:pathology; D010510:Periodontal Diseases / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D014081:Tooth Extraction / Q000009:adverse effects*; D014945:Wound Healing; D055114:X-Ray Microtomography
Dental disease; ONJ; OPG-Fc, extraction; Zoledronic acid