Risk factors for dental findings of the development of medication-related osteonecrosis of the jaw: Investigation of 3734 teeth in cancer patients receiving high dose antiresorptive agents.

Introduction

Patients scheduled to receive antiresorptive agents (ARAs) should have dental work performed beforehand to prevent medication-related osteonecrosis of the jaw (MRONJ). 1 , 2 , 3 However, dental work is time-consuming, and it is sometimes difficult to complete all treatments before ARA administration. In cases of bone metastases from cancer or hypercalcemia, in particular, ARA administration often cannot be delayed until dental treatment has been completed.

Dental treatment includes a wide range of procedures, including periodontal, endodontic, and surgical procedures. Which of these should be prioritized when the time required to administer ARAs is limited? We conducted a study aimed at determining which dental findings put patients at higher risk of developing MRONJ. We examined the findings on panoramic radiographs taken during ARA administration that showed a high risk of patients developing MRONJ, tooth-by-tooth. We also examined the risk of developing MRONJ due to oral factors using the jaw-by-jaw method.

Materials and methods

A total of 172 patients (329 jaws and 3734 teeth) who received high-dose ARA (bisphosphonate and/or denosumab) treatment and were referred to the Oral and Maxillofacial Surgery or Oral Management Center of Nagasaki University Hospital between 2011 and 2020 were included in the study. Panoramic radiography was performed at the first visit. The following information was extracted from the medical records: Age, sex, MRONJ site (upper or lower jaw), smoking habit, diabetes, use of corticosteroids, white blood cell count, serum albumin and creatinine levels, type of ARA administered, local infection symptoms of the gingiva (pus discharge, pain, redness, and swelling), and number of remaining teeth. Patients in whom MRONJ had already developed were excluded. Panoramic radiography, apical lesions of ≥3 mm, enlargement of the periodontal space, thickening of the lamina dura, alveolar bone resorption of >1/3, and periapical osteosclerosis of each tooth were investigated ( Fig. 1 ). Follow-ups were performed for as long as possible, and when MRONJ developed, the time of onset was recorded. The extracted data were analyzed on a tooth-by-tooth, jaw-by-jaw, and patient-by-patient basis.

All statistical analyses were performed using SPSS software (version 26.0; Japan IBM Co., Ltd., Tokyo, Japan). Uni- and multivariate analyses were performed using Cox regression analysis. Covariates for the multivariate analysis were selected using a stepwise method. Cumulative incidence was calculated using the Kaplan–Meier method and analyzed using the log-rank test. Two-tailed P < 0.05 was considered significant. Receiver Operating Characteristic (ROC) curve analysis was also performed on the number of imaging events per tooth (total number of imaging events/number of remaining teeth) and the development of MRONJ on a jaw-by-jaw basis.

The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labor, and Welfare of Japan. Ethical approval was obtained from the Institutional Review Board (IRB) of Nagasaki University Hospital (2208080). As this was a retrospective study, informed consent was waived. The research plan, highlighting the guaranteed opt-out opportunity, was published on the homepage of the hospital, according to the instructions of the IRB.

Results

Patient characteristics and factors related to the development of MRONJ

The background characteristics of the 172 patients are listed in Table 1 . This study included 102 men and 70 women with a mean age of 62.3 years.

The primary tumors were breast cancer in 54 cases, lung cancer in 41 cases, multiple myeloma in 20 cases, prostate cancer in 17 cases, and other cancers in 40 cases; the ARA types were bisphosphonate in 77 cases, denosumab in 88 cases, and denosumab followed by bisphosphonate in 7 cases. MRONJ occurred in 32 of the 172 patients. The cumulative incidence rates from the start of treatment were 4.8% at 1 year, 13.8% at 2 years, 18.1% at 3 years, 25.6% at 4 years, and 31.2% at 5 years, with the incidence rate increasing as the duration of treatment increased ( Fig. 2 ).

Patient-by-patient analysis

Variables excluding individual tooth findings were examined in relation to MRONJ development. Older age and fewer remaining teeth were significant risk factors associated with the development of MRONJ in univariate analysis. In multivariate analysis, diabetes ( P = 0.009) and a low number of remaining teeth ( P < 0.001) were significant risk factors for development ( Table 2 ).

Tooth-by-tooth analysis

A total of 3734 teeth were registered. Apical lesions, enlargement of the periodontal space, thickening of the lamina dura, alveolar bone resorption of >1/3, periapical osteosclerosis, and local infection were observed in 244 (6.5%), 440 (11.8%), 329 (8.8%), 907 (24.3%), 231 (6.2%), and 205 (5.5%) teeth, respectively ( Table 3 ). A total of 2402 teeth (64.3%) had at least one of the aforementioned dental symptoms.

MRONJ developed in 68 teeth. In univariate analysis, being male ( P = 0.021), old age ( P = 0.002), a smoking habit ( P < 0.001), diabetes ( P = 0.003), higher serum creatinine levels ( P = 0.043), fewer teeth ( P < 0.001), apical lesions ( P < 0.001), enlargement of the periodontal space ( P < 0.001), thickening of the lamina dura ( P = 0.005), alveolar bone resorption of >1/3 ( P < 0.001), periapical osteosclerosis ( P < 0.001), and local infection symptoms ( P < 0.001) were significant factors for developing MRONJ. Patients with one or more of the aforementioned dental findings showed a significantly higher risk of developing MRONJ ( P < 0.001). Multivariate analysis showed that fewer teeth ( P < 0.001), apical lesions ( P < 0.001), periapical osteosclerosis ( P < 0.001), local infection symptoms ( P = 0.002), and one or more dental findings ( P < 0.001) were significantly correlated with the development of MRONJ ( Table 4 ) ( Fig. 3 ).

Jaw-by-jaw analysis

A total of 329 jaws were included. Apical lesions, enlargement of the periodontal space, thickening of the lamina dura, alveolar bone resorption of >1/3, periapical osteosclerosis, and local infection were observed in 127 (38.6%), 166 (50.5%), 119 (36.2%), 196 (59.6%), 113 (34.3%), and 26 (7.9%) jaws, respectively ( Table 5 ). In total, 262 (79.6%) teeth exhibited one or more of the aforementioned symptoms.

MRONJ developed in 33 jaws. In the univariate analysis, old age ( P = 0.019), fewer teeth ( P = 0.009), apical lesions ( P = 0.004), periapical osteosclerosis ( P = 0.017), and local infection symptoms ( P < 0.001) were significant risk factors for the development of MRONJ. The number of radiographic abnormalities ( P = 0.003) and total number of radiographic abnormalities/number of remaining teeth ( P < 0.001) were also significantly correlated with the development of MRONJ. Furthermore, those who had one or more of the above-mentioned radiographic abnormalities showed a significantly higher risk of developing MRONJ ( P = 0.012). Multivariate analysis showed that old age ( P = 0.028), local infection symptoms ( P = 0.001), and the number of radiographic abnormalities per tooth ( P = 0.003) were significantly correlated with the development of MRONJ ( Table 6 ).

In the jaw-by-jaw ROC analysis, the incidence of MRONJ was significantly higher when the number of radiographic abnormalities per tooth was greater than 1.1 (AUC = 0.632) ( Fig. 4 ). The 5-year cumulative MRONJ incidence rate was 13.3% in jaws with less than 1.1 radiographic abnormalities per tooth, and 35.7% in those with 1.1 or more radiographic abnormalities per tooth ( Fig. 5 ).

Discussion

In the present study, cancer patients receiving high-dose ARAs had a significantly higher risk of developing subsequent MRONJ if they had teeth with apical lesions, periapical osteosclerosis, or local infection symptoms.

Patients receiving ARAs are at increased risk of developing MRONJ. Various risk factors of MRONJ have been reported. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 Local factors related to the occurrence of MRONJ include dentoalveolar surgery, anatomical factors (mandible), denture use, and concomitant inflammatory oral diseases, such as periodontal disease or periapical pathology (AAOMS2022). 13 Among these, dentoalveolar surgery, including tooth extraction, is considered the most important local risk factor, and it is recommended that ARAs be withdrawn for several months prior to tooth extraction in these patients, or that tooth extraction be avoided as much as possible at the outset. Conversely, there are reports of persistent local infection in teeth that require extraction, and that it is the local infection in the tooth to be extracted that is at risk for MRONJ, not the surgical invasion of the bone itself. 14 , 15 , 16 We previously reported that patients with cancer who received high-dose ARAs and whose teeth were the source of infection had a significantly higher incidence of MRONJ if they avoided tooth extraction after adjusting for background factors using propensity score matching, 16 and stated that teeth with apical lesions >3 mm, periodontal pockets deeper than 4 mm, and local infection symptoms should be extracted. However, this study included 92 patients with teeth that showed abnormal radiographic findings, while in the present study, factors associated with the development of MRONJ in a larger number of patients, including those without abnormal radiographic findings, were examined.

First, the factors associated with each tooth were examined. Apical lesions, periapical osteosclerosis, thickening of the lamina dura, alveolar bone resorption of >1/3, and enlargement of the periodontal space are reactive changes in the bone around the teeth, and ARAs may affect these bone responses, making it difficult to distinguish them from changes due to local infection. 17 , 18 Therefore, it is important to diagnose these changes using bone imaging before administering ARAs. In our current study, the risk of developing MRONJ was significantly higher in the presence of apical lesions, periapical osteosclerosis, one or more of the above dental findings, and local infection symptoms before ARA administration. Therefore, treatment of endodontic disease and occlusal trauma should be performed as much as possible prior to the administration, without priority. Ueda et al. also reviewed 679 patients scheduled to receive ARAs. They reported that root apex lesions were a risk factor for developing MRONJ and that teeth should be extracted before ARA administration. 19 However, it is difficult to treat some dental diseases before administration. If everything is to be treated within a short period, tooth extraction may be an option; however, there is no evidence that tooth extraction prevents the development of MRONJ, and some reports suggest that tooth extraction at sites of chronic inflammation may actually predispose patients to MRONJ. 20 In addition, if multiple tooth extractions are necessary, the invasiveness of the procedure may be significant and reduce the quality of life. While dental treatment should be performed on a small number of teeth if there is time to do so, treatment methods for patients who need treatment for multiple teeth should be considered in the future.

Next, we examined the risk of developing MRONJ on a jaw-by-jaw basis. Old age, local inflammatory symptoms, and number of abnormal dental findings per tooth were significant factors in the development of MRONJ. Old age was the only significant systemic factor. Local infection symptoms are also important factors in any analysis, and anti-inflammatory treatment prior to ARA administration is essential.

ROC analysis showed a tendency for MRONJ to develop with a higher number of imaging events per tooth, although the AUC was not sufficient, and 1.1 events per tooth was the cutoff value. In other words, if there are more imaging events per tooth, the jaw is at a higher risk of developing MRONJ and patients with more imaging events per tooth should be considered high-risk. In addition, a high number of imaging events is likely to indicate that the patient is not receiving adequate dental care. Therefore, it may be difficult to obtain cooperation for dental treatment before ARA administration. In a prospective study of 253 patients with bone metastases from prostate cancer, Mücke et al. reported a 2.59-fold higher risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ) in the group that did not receive dental intervention every 3 months during treatment with zoledronic acid than in the group that did. 21 Therefore, it is important to increase the motivation for oral management in patients with a high number of imaging events per tooth.

In the patient-by-patient analysis, diabetes and the number of remaining teeth were significant factors in the development of MRONJ. Considering the jaw-by-jaw analysis, it is important to note that advanced age and diabetes are systemic factors in. In addition, it is important to provide guidance on oral hygiene, because a small number of remaining teeth may indicate poor oral hygiene.

This study had some limitations. First, because of the retrospective, single-center nature of the study, there may have been some bias in the registered patients, and it is unclear whether the results obtained can be generalized. Second, most patients with dental diseases did not undergo any subsequent dental intervention; therefore, it was not possible to determine whether dental treatment reduced the risk of developing MRONJ. However, this study clarified the relationship between dental disease and the onset of MRONJ using a large number of teeth and provided valuable data for the establishment of future MRONJ prevention methods.

Patients with diabetes, fewer teeth, dental diseases, such as apical disease, thickening of the lamina dura, alveolar bone resorption of more than 1/3, periapical osteosclerosis, and local infection symptoms are more likely to develop MRONJ. Therefore, it is important to improve the oral environment prior to ARA administration.

Declaration of competing interest

The authors declare no conflict of interest. This research received no external funding.

Acknowledgments

None.

References

1. Yarom N., Shapiro C.L., Peterson D.E., et al. Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO clinical practice guideline. J Clin Oncol. 2019;37:2270–2290. doi: 10.1200/JCO.19.01186.

2. Vandone A.M., Donadio M., Mozzati M., et al. Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol. 2012;23:193–200. doi: 10.1093/annonc/mdr039.

3. Troeltzsch M., Cagna D., Stähler P., et al. Clinical features of peri-implant medication-related osteonecrosis of the jaw: is there an association to peri-implantitis? J Cranio-Maxillo-Fac Surg. 2016;44:1945–1951. doi: 10.1016/j.jcms.2016.09.018.

4. McGowan K., McGowan T., Ivanovski S. Risk factors for medication-related osteonecrosis of the jaws: a systematic review. Oral Dis. 2018;24:527–536. doi: 10.1111/odi.12708.

5. AlRowis R., Aldawood A., AlOtaibi M., et al. Medication-related osteonecrosis of the jaw (MRONJ): a review of pathophysiology, risk factors, preventive measures and treatment strategies. Saudi Dent J. 2022;34:202–210. doi: 10.1016/j.sdentj.2022.01.003.

6. Kim H.Y. Review and update of the risk factors and prevention of antiresorptive-related osteonecrosis of the jaw. Endocrinol Metab. 2021;36:917–927. doi: 10.3803/EnM.2021.1170.

7. Hallmer 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;126:477–485. doi: 10.1016/j.oooo.2018.08.015.

8. Ishimaru M., Ono S., Morita K., Matsui H., Hagiwara Y., Yasunaga H. Prevalence, incidence rate, and risk factors of medication-related osteonecrosis and cancer: a nationwide population-based study in Japan. J Oral Maxillofac Surg. 2022;80:714–727. doi: 10.1016/j.joms.2021.12.007.

9. Yang G., Singh S., Chen Y., et al. Pharmacogenomics of osteonecrosis of the jaw. Bone. 2019;124:75–82. doi: 10.1016/j.bone.2019.04.010.

10. Yang G., Collins J.M., Rafiee R., et al. SIRT1 Gene SNP rs932658 is associated with medication-related osteonecrosis of the jaw. J Bone Miner Res. 2021;36:347–356. doi: 10.1002/jbmr.4185.

11. Park S., Kanayama K., Kaur K., et al. Osteonecrosis of the jaw developed in mice: disease variants regulated by γδT cells in oral mucosal barrier immunity. J Biol Chem. 2015;290:17349–17366. doi: 10.1074/jbc.M115.652305.

12. Soundia A., Hadaya D., Esfandi N., et al. Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone. 2016;90:133–141. doi: 10.1016/j.bone.2016.06.011.

13. Ruggiero S.L., Dodson T.B., Aghaloo T., Carlson E.R., Ward B.B., Kademani D. Reply: American association of oral and maxillofacial surgeons' position paper on medication-related osteonecrosis of the jaws-2022 update. J Oral Maxillofac Surg. 2022;80:920–943. doi: 10.1016/j.joms.2022.02.008.

14. Otto S., Tröltzsch M., Jambrovic V., et al. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Cranio-Maxillo-Fac Surg. 2015;43:847–854. doi: 10.1016/j.jcms.2015.03.039.

15. Soutome S., Hayashida S., Funahara M., et al. Factors affecting development of medication-related osteonecrosis of the jaw in cancer patients receiving high-dose bisphosphonate or denosumab therapy: is tooth extraction a risk factor? PLoS One. 2018;13 doi: 10.1371/journal.pone.0201343.

16. Soutome S., Otsuru M., Hayashida S., et al. Relationship between tooth extraction and development of medication-related osteonecrosis of the jaw in cancer patients. Sci Rep. 2021;11 doi: 10.1038/s41598-021-96480-8.

17. Suei Y. Radiographic findings of bisphosphonate-related osteomyelitis of the jaw: investigation of the diagnostic points by comparison with radiation osteomyelitis, suppurative osteomyelitis, and diffuse sclerosing osteomyelitis. Oral Radiol. 2013;29:121–134.

18. Klingelhöffer C., Klingelhöffer M., Müller S., Ettl T., Wahlmann U. Can dental panoramic radiographic findings serve as indicators for the development of medication-related osteonecrosis of the jaw? Dentomaxillofacial Radiol. 2016;45 doi: 10.1259/dmfr.20160065.

19. Ueda N., Nakashima C., Aoki K., et al. Does inflammatory dental disease affect the development of medication-related osteonecrosis of the jaw in patients using high dose bone-modifying agents? Clin Oral Invest. 2021;25:3087–3093. doi: 10.1007/s00784-020-03632-7.

20. Moreno-Rabié C., Gaêta-Araujo H., Ferreira-Leite A., et al. Local radiographic risk factors for MRONJ in osteoporotic patients undergoing tooth extraction. Oral Dis. 2023 doi: 10.1111/odi.14496. (in press)

21. Mücke T., Deppe H., Hein J., et al. Prevention of bisphosphonate-related osteonecrosis of the jaws in patients with prostate cancer treated with zoledronic acid – a prospective study over 6 years. J Cranio-Maxillo-Fac Surg. 2016;44:1689–1693. doi: 10.1016/j.jcms.2016.07.026.