OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice.
Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-κB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by μCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a "drug holiday" in managing the ONJ patient.
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.|Department of Diagnosis and Surgery, School of Dentistry at Araraquara, S, ã, o Paulo State University, Araraquara, Brazil.
Rafael Scaf
RS
de Molon
Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, Osaka, Japan.
Hiroaki
H
Shimamoto
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
Olga
O
Bezouglaia
Division of Associated Specialties, UCLA School of Dentistry, Los Angeles, CA, USA.
Flavia Q
FQ
Pirih
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Sarah M
SM
Dry
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Paul
P
Kostenuik
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Rogely W
RW
Boyce
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Denise
D
Dwyer
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.
Tara L
TL
Aghaloo
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA.|Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
Sotirios
S
Tetradis
D000038:Abscess; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000188:drug therapy* / Q000473:pathology*; D001862:Bone Resorption; D000069448:Denosumab / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging; D008437:Maxilla / Q000000981:diagnostic imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000494:pharmacology; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D007141:Immunoglobulin Fc Fragments; D007527:Isoenzymes; C000608353:OPG-Fc fusion protein, rat; D053244:Osteoprotegerin; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; D000069448:Denosumab; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
ALVEOLAR BONE; ANTIRESORPTIVES; BISPHOSPHONATES; DENOSUMAB; OSTEOCLASTS; OSTEONECROSIS OF THE JAW (ONJ); ZOLEDRONIC ACID