Risk factors of medication-related osteonecrosis of the jaw in preventive tooth extraction before bone resorption inhibitor administration: A multicenter nested case–control study
Corresponding Author
Taro Saito
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Correspondence
Taro Saito, Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
Email: [email protected]
Search for more papers by this authorAtsushi Nishikawa
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorYuko Hara-Saito
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorAndrea Rei Estacio Salazar
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorAkira Kurokawa
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorAkihiko Iida
Department of Dentistry and Oral Maxillofacial Surgery, Nagaoka Red Cross Hospital, Niigata, Japan
Search for more papers by this authorMasahiro Yamaga
Department of Dentistry and Oral Maxillofacial Surgery, Nagaoka Chuo General Hospital, Niigata, Japan
Search for more papers by this authorHiroyuki Kano
Clinic of Oral and Maxillofacial Surgery, Niigata Prefectural Community Medicine Institute Uonuma Kikan Hospital, Niigata, Japan
Search for more papers by this authorYusuke Kato
Department of Oral and Maxillofacial Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorYoshiyuki Takata
Department of Dentistry and Oral Maxillofacial Surgery, Niigata City General Hospital, Niigata, Japan
Search for more papers by this authorHideyoshi Nishiyama
Division of Oral and Maxillofacial Radiology, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorNobutaka Kitamura
Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorTakahiro Tanaka
Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorRitsuo Takagi
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorCorresponding Author
Taro Saito
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Correspondence
Taro Saito, Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
Email: [email protected]
Search for more papers by this authorAtsushi Nishikawa
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorYuko Hara-Saito
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorAndrea Rei Estacio Salazar
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorAkira Kurokawa
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorAkihiko Iida
Department of Dentistry and Oral Maxillofacial Surgery, Nagaoka Red Cross Hospital, Niigata, Japan
Search for more papers by this authorMasahiro Yamaga
Department of Dentistry and Oral Maxillofacial Surgery, Nagaoka Chuo General Hospital, Niigata, Japan
Search for more papers by this authorHiroyuki Kano
Clinic of Oral and Maxillofacial Surgery, Niigata Prefectural Community Medicine Institute Uonuma Kikan Hospital, Niigata, Japan
Search for more papers by this authorYusuke Kato
Department of Oral and Maxillofacial Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorYoshiyuki Takata
Department of Dentistry and Oral Maxillofacial Surgery, Niigata City General Hospital, Niigata, Japan
Search for more papers by this authorHideyoshi Nishiyama
Division of Oral and Maxillofacial Radiology, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Search for more papers by this authorNobutaka Kitamura
Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorTakahiro Tanaka
Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorRitsuo Takagi
Division of Oral and Maxillofacial Surgery, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
Search for more papers by this authorAbstract
Introduction
Medication-related osteonecrosis of the jaw (MRONJ) occurs even after teeth with poor prognosis had been preventively extracted and medication had been initiated. In this nested case–control study, we focused on tooth extraction before bone resorption inhibitor administration for the treatment of malignant tumors.
Materials and Methods
A total of 180 teeth of 58 patients who were treated with zoledronic acid and/or denosumab from April 2012 to December 2016 at our hospital or partner institutions were included in this multicenter study. All participants underwent tooth extraction within 1 year before initiating therapy and were followed up for at least 1 year or at most 3 years after initiating bone resorption inhibitor administration. We evaluated the systemic and local risk factors: sex, age, cancer type, overweightness/obesity, anemia, undernutrition, diabetes, smoking, concomitant drugs, tooth extraction site, use of antibacterial drugs, wound closure, and waiting period between tooth extraction and medication.
Results
MRONJ occurred in 18 teeth of 10 patients and not in 162 teeth of 48 patients. Based on the Cox proportional hazards model, concomitant administration of angiogenesis inhibitors, mandibular molar, periapical radiolucency, and osteosclerosis of the surrounding areas were considered essential risk factors for MRONJ.
Conclusions
Chronic inflammation of the bone surrounding extracted teeth may be an essential risk factor for MRONJ when preventive tooth extraction is performed before the administration of bone resorption inhibitors for patients with malignant tumors.
CONFLICT OF INTERESTS
The authors declare no conflicts of interest associated with this manuscript.
REFERENCES
- 1Marx RE. Pamidronate (Aredia) and Zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003; 61: 1115–7.
- 2Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012; 23: 1341–7.
- 3Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg. 2014; 72: 1938–56.
- 4Green JR, Rogers MJ. Pharmacologic profile of zoledronic acid: a highly potent inhibitor of bone resorption. Drug Dev Res. 2002; 55: 210–24.
- 5Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011; 48: 677–92.
- 6Ohnuki H, Izumi K, Terada M, Saito T, Kato H, Suzuki A, et al. Zoledronic acid induces S-phase arrest via a DNA damage response in normal human oral keratinocytes. Arch Oral Biol. 2012; 57: 906–17.
- 7Saito T, Izumi K, Shiomi A, Uenoyama A, Ohnuki H, Kato H, et al. Zoledronic acid impairs re-epithelialization through down-regulation of integrin αvβ6 and transforming growth factor beta signalling in a three-dimensional in vitro wound healing model. Int J Oral Maxillofac Surg. 2014; 43: 373–80.
- 8Lang M, Zhou Z, Shi L, Niu J, Xu S, Lin W, et al. Influence of zoledronic acid on proliferation, migration, and apoptosis of vascular endothelial cells. Br J Oral Maxillofac Surg. 2016; 54: 889–93.
- 9Gao SY, Zheng GS, Wang L, Liang YJ, Zhang SE, Li K, et al. Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB. PLoS ONE. 2017; 12:e0179248
- 10Hasegawa T, Kawakita A, Ueda N, Funahara R, Tachibana A, Kobayashi M, et al. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporos Int. 2017; 28: 2465–73.
- 11Heufelder MJ, Hendricks J, Remmerbach T, Frerich B, Hemprich A, Wilde F. Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 117: e429–35.
- 12Otto S, Tröltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, et al. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg. 2015; 43: 847–54.
- 13Nicolatou-Galitis O, Papadopoulou E, Vardas E, Kouri M, Galiti D, Galitis E, et al. Alveolar bone histological necrosis observed prior to extractions in patients, who received bone-targeting agents. Oral Dis. 2020; 26: 955–66.
- 14Ristow O, Rückschloß T, Moratin J, Müller M, Kühle R, Dominik H, et al. Wound closure and alveoplasty after preventive tooth extractions in patients with antiresorptive intake—a randomized pilot trial. Oral Dis. 2021; 27: 532–46.
- 15Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009; 20: 117–20.
- 16Kobashi H, Ishimoto S, Ishii S, Yakushiji N. Clinical study about dental treatment before applying BMA (Bone Modifying Agents) with the patients of bone metastatic cancer. J Jpn Stomatol Soc. 2017; 66: 221–8.
- 17Lee SH, Kim KJ, Yang DH, Jeong KW, Ye BD, Byeon JS, et al. Postpolypectomy fever, a rare adverse event of polypectomy: nested case-control study. Clin Endosc. 2014; 47: 236–41.
- 18Walter C, Laux C, Sagheb K. Radiologic bone loss in patients with bisphosphonate-associated osteonecrosis of the jaws: a case-control study. Clin Oral Investeig. 2014; 18: 385–90.
- 19Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M. Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev. 2018; 69: 177–87.
- 20Rogers SN, Palmer NO, Lowe D, Randall C. United Kingdom nationwide study of avascular necrosis of the jaws including bisphosphonate-related necrosis. Br J Oral Maxillofac Surg. 2015; 53: 176–82.
- 21Hallmer F, Andersson G, Götrick B, Warfvinge G, Anderud J, Bjørnland T. Prevalence initiating factor and treatment outcome of medication-related osteonecrosis of the jaw—a 4-year prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 126: 477–85.
- 22Fusco V, Porta C, Saia G, Paglino C, Bettini G, Scoletta M, et al. Osteonecrosis of the jaw in patients with metastatic renal cell cancer treated with bisphosphonates and targeted agents: results of an Italian multicenter study and review of the literature. Clin Genitourin Cancer. 2015; 13: 287–94.
- 23Guillot A, Joly C, Barthélémy P, Meriaux E, Negrier S, Pouessel D, et al. Denosumab toxicity when combined with anti-angiogenic therapies on patients with metastatic renal cell carcinoma: a GETUG study. Clin Genitourin Cancer. 2019; 17: e38–43.
- 24Pimolbutr K, Porter S, Fedele S. Osteonecrosis of the jaw associated with antiangiogenics in antiresorptive-naïve patient: a comprehensive review of the literature. Biomed Res Int. 2018; 2018:8071579. https://doi.org/10.1155/2018/8071579
- 25Aso K. Roentgenological and histopathological study on osteosclerosis of mandible. J Kyushu Dent Soc. 1980; 33: 672–91.
10.2504/kds.33.672 Google Scholar
- 26Miyamoto I, Ishikawa A, Morimoto Y, Takahashi T. Potential risk of asymptomatic osteomyelitis around mandibular third molar tooth for aged people: a computed tomography and histopathologic study. PLoS ONE. 2013; 8:e73897.
- 27Nicolatou-Galitis O, Schiødt M, Mendes RA, Ripamonti C, Hope S, Drudge-Coates L, et al. Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019; 127: 117–35.
Citing Literature
