Underestimated Risk Factor of Osteonecrosis of the Jaw, Pulp and Periapical Disease: A National Cohort-Based Study in Korea


 Background: Osteonecrosis of the jaw (ONJ) is one of the complication of bisphosphonate (BP). Despite being a major risk factor for ONJ, tooth extraction cannot explain all cases of ONJ. However, disease that induce inflammation in the jawbone, such as pulp and periapical disease is underestimated, and studies suggesting relationship are arising. This necessitates the determination of the relationship between ONJ and inflammatory disease, which would contribute to the understanding and treatment of ONJ.Methods: We analyzed the relationship between ONJ and pulp and periapical disease, and caries in women aged over 50 years who were administered BP for over 1 year from 2010 to 2015, based on a nationwide cohort study. ONJ, pulp and periapical disease, and caries were defined according to the Korean Standard Classification of Diseases and Causes of Death-7 and claims data. ONJ was operationally defined into definite ONJ and possible ONJ because of the ambiguity of population-based ONJ diagnosis.Results: Pulp and periapical disease significantly increased ONJ development [hazard ratio 2.21 (95% CI 1.40-3.48) and 2.22 (95% CI 1.65-2.98) in definite ONJ and possible ONJ, respectively]. Additionally, the risk of ONJ development increased when caries addition to pulp and periapical disease [hazard ratio 2.28 (95% 1.50-3.47) and 2.05 (95% 1.55-2.70) in definite ONJ and possible ONJ, respectively]. Nonetheless, those in the caries were not significant. Root canal treatment in most cases did not increase ONJ development significantly, but the pulp and periapical disease or caries significantly increased possible ONJ development [hazard ratio 2.17 (95% CI 1.04-4.52)].Conclusions: It is necessary to focus on pulp and periapical disease resulting in inflammation as a major risk factor for ONJ. Future studies should determine the role of low-grade inflammation for ONJ on other ONJ-inducing drugs as anti-resorptive agents.

Conclusions: It is necessary to focus on pulp and periapical disease resulting in in ammation as a major risk factor for ONJ. Future studies should determine the role of low-grade in ammation for ONJ on other ONJ-inducing drugs as anti-resorptive agents.
Background Bisphosphonate (BP), an analog of pyrophosphate, is used as an inhibitor of osteoclast-mediated bone resorption for the treatment of metabolic and pathologic bone disease including osteoporosis, Paget's disease, and metastatic malignant disease [1]. Despite being bene cial for cancer and metabolic bone disease treatment, BP use results in osteonecrosis of the jaw (ONJ) [2,3]. While the incidence of the condition is rare, serious complications can affect the quality of life [4]. There are various hypotheses, including the suppression of bone turnover, infection/in ammation, angiogenesis inhibition, soft tissue toxicity, and immune-related theory because the pathophysiology of ONJ is still controversial [5].
ONJ occurs most frequently following dental interventions, particularly tooth extraction accounting for half of ONJ [6][7][8][9]. Therefore, most studies on ONJ have focused on tooth extraction, overlooking the effects of other dental risks. Local wound healing or infection affects pathologic conditions, which would have a possible impact on ONJ [10][11][12][13]. Pulp and periapical disease, and caries, the two common infectious dental diseases, can cause chronic in ammation in the jawbone. This in turn induces catabolic effects within the jawbone and is considered one of the risk factors for ONJ [14,15]. In ammation is a major risk factor for ONJ as one of important role of ONJ pathophysiology relating to osteoimmunology.
Pulp and periapical disease is another risk factor for tooth extraction, which is considered one of the risk factors for ONJ. However, its role in ONJ has not yet been elucidated. Thus, in ammation caused by pulp and periapical disease would exert a direct or indirect effect on ONJ development.
Root canal treatment is used to disinfect the pulp, resolve in ammation in the pulp and periapical disease, and protect further microbial invasion to periapical tissue. While Vahtsevanos et al. reported that root canal treatment does not increase the risk of ONJ, the relationship between root canal treatment and ONJ has not been identi ed [16].
Some studies have demonstrated that pulp and periapical disease is related to BP and ONJ. These studies were based on animal models of ONJ and are not su cient to explain the causal relationship between pulp and periapical disease and ONJ. We aimed to verify the relationship between ONJ and pulp and periapical disease in patients administered BP with a nationally representative cohort database in Korea.

Data source
Health screening for the entire population is conducted by the National Health Insurance Service (NHIS) every year or every alternate year, depending on the age and occupation of people covered in the insurance and released to the public [17]. We conducted a longitudinal cohort study based on the general health screening database of the NHIS. The sampling research database was extracted by sampling highdemand information from the national health insurance data. We used the health examination cohort The inclusion criteria were women (i) aged over 50 years, (ii) who were administered BP for more than 1 year, and (iii) demonstrated compliance ≥ 0% during the year (or those with a medication possession ratio ≥ 80%). Both the oral and injectable routes were covered. Thus, the analysis eventually included BP, namely alendronate, ibandronate, residronate, pamidronate, and zoledronate.
However, the underlying condition or some contributing factor would have effects on the onset of ONJ, and the estimated ONJ frequency is quite higher in cases of cancer or other bone diseases that need to use BP. Therefore, the case of using BP above the dose for osteoporosis treatment, and the case of cancer were excluded.
In addition, we excluded cases where ONJ occurred within 1 year of the use of BP. This can be attributed to our di culty in determining the result of BP use. Deaths before the index date were also excluded from the analysis.
De nition of ONJ, pulp and periapical disease, and caries We combined the KCD-7 code and treatment code to diagnose ONJ. First, we categorized ONJ into two parts as follows: de nite ONJ and possible ONJ. The condition was de ned as de nite ONJ if it included one of the following: Osteonecrosis due to drugs, multiple site (M87.1), In ammatory conditions of jaws (K10.2) as a diagnosis, and one of the treatment were registered together, or both diagnoses were registered after the index date (Supplementary Table 1).
Possible ONJ is a broader concept that covered the diagnosis and treatment used in cases of suspected ONJ. It included Osteonecrosis due to drugs, multiple sites (M87.  Table 2).
Pulp and periapical disease, and caries were de ned as the diagnosis code in registration, following the index date (Supplementary Table 3).
Root canal treatment was de ned as the root canal treatment code on record between pulp and periapical disease, or caries diagnosis and ONJ diagnosis (Supplementary Table 4).

Confounding variables
We included patient demographics on the baseline year, age, income level, and disability. The income quintile refers to an index in which the National Statistical O ce divides Korea's total households into ten levels by 10%, according to the quarterly income level. The income level in the rst quintile is the lowest.

Statistical analyses
Baseline characteristics were reported using numbers (%) for categorical variables and means ± standard deviation. We conducted the χ 2 test, median with interquartile range for continuous variables, and t-test or analysis of variance. Moreover, we adjusted the cohort data of 14 years, baseline year, age, comorbidities, income disability, the type of BP administered, and cumulative proportion of days to analyze the hazard ratio (HR) of ONJ, according to the prevalence of pulp and periapical disease, caries, or pulp and periapical disease or caries. Cox proportional hazards models were used to evaluate the associations between the independent variables and the occurrence of ONJ events. In addition, we calculated the HRs and 95% con dence intervals (CIs) to evaluate the associations between the independent variables and the occurrence of ONJ events. Statistical signi cance was de ned as two-tailed p-values <0.05. Statistical analysis was conducted using R programming (version 3.3.3; The R Foundation for Statistical Computing, Vienna, Austria).

Results
Excluding patients with cancer diagnosis, death, and ONJ diagnosis before the index date, we eventually included 27,168 patients ( Figure 1). Among them, 4,205 (15.48%) and 3,413 (12.56) patients were diagnosed with pulp and periapical disease and caries, respectively. Moreover, 6,260 (23.04%) patients were diagnosed with either pulp and periapical disease or caries.
De nite ONJ accounted for 26 (0.62%) cases and 69 (0.30%) cases of the pulp and periapical disease groups and the non-pulp and periapical disease groups, respectively. Possible ONJ accounted for 62 (1.47%) and 158 (0.69%) of the pulp and periapical disease groups and non-pulp and periapical disease groups, respectively. Moreover, de nite ONJ accounted for 36 (0.58%) cases and 59 (0.28%) cases in the pulp and periapical disease or caries group and non-pulp and periapical disease or caries group, respectively. Possible ONJ accounted for 80 (1.28%) cases and 140 (0.67%) cases in the pulp and periapical disease or caries group and non-pulp and periapical disease or caries group, respectively. The statistical difference varied depending on the diagnostic criteria. However, the pulp and periapical disease and the pulp and periapical disease or caries increased both de nite and possible ONJ development (Table 1). On the other hand, the proportion of patients with ONJ was higher in the caries group in de nite and possible ONJ, but there was no signi cant difference (Supplementary Table 5 We analyzed the HR of ONJ in case of root canal treatment among patients in the pulp and periapical disease and caries groups. While only possible ONJ in the pulp and periapical disease or caries group signi cantly increased risk of possible ONJ development [2.17 (95% CI 1.04-4.52)], others were not signi cant (Table 3).

Discussion
While tooth extraction is a major risk factor for ONJ, chronic in ammation that is caused by pulp and periapical disease and results in tooth extraction have been disregarded in ONJ. BP induces the depression of osteoclast activity, which results in a decrease in bone modeling. Thus, the periapical radiolucent lesion in the alveolar bone of patients taking BP is masked. Furthermore, the morbidity of pulp and periapical disease in patients taking BP is supposedly underestimated. This results in a lack of interest and study of the relationship between pulp and periapical disease and ONJ. However, few studies, such as the one conducted by Cheong et al., have mentioned uptake of BP increases at the pulp and periapical disease site [14]. Kang et al. demonstrated that pulp and periapical disease and BP results in ONJ in mice [15], these studies are limited because they are based on animal models of ONJ that imply a correlation between pulp and periapical disease and ONJ. However, we con rmed an increase in the morbidity of de nite ONJ and possible ONJ in patients with pulp and periapical disease, who were administered BP for over 1 year. We hypothesized that pulp and periapical disease induces in ammation in the alveolar bone near the root. This in ammation causes the over-accumulation of BP and results in ONJ development, as mentioned in the animal model studies.
In addition, while tooth extraction is a de nite risk factor for ONJ, lesions that cause in ammation, such as periodontitis and pulp and periapical disease, increase the susceptibility of sites to developing ONJ. Di culties in analyzing or studying ONJ have led to a focus on consequent intervention. However, it is necessary to discover the effects of in ammation on ONJ to identify the mechanism of ONJ, and to overcome it. The jaw bone has a higher turnover rate than peripheral bones, and leads to high BP accumulation [18]. Gong mentioned that jaw bone site-speci c bone marrow stromal cell is more susceptible to BP than the iliac and tibial bone [19]. Moreover, the osseous healing mechanism is different site-dependently, as mentioned by Lim [20]. These different characteristics would play an important part of ONJ. Hence, it would be helpful to understand the relationship between osteoimmunology and in ammation to treat ONJ.
While pulp and periapical disease may result from various reasons, most cases arise from the advancement of caries. Despite being a pulp-limited disease, caries causes pulp and periapical disease that results in chronic in ammation of the jaw bone. In ammation is a de nite risk factor for the development of ONJ. We further identi ed the morbidity of ONJ in patients with caries. However, caries did not signi cantly increase the risk of ONJ. We suggest that caries is insu cient to cause in ammation to induce ONJ. In other words, in ammation within the dental pulp tissue is not correlated with ONJ. Our ndings support the position paper guidelines that recommend performing caries treatment before or during BP use.
Furthermore, we explored the impact of root canal treatment for pulp and periapical disease on the risk of ONJ. Root canal treatment did not supposedly in uence the risk of ONJ with BP, similar to the results of Vahtsevanos [16]. Therefore, root canal treatment does not exert any effect on BP accumulation in pulp and periapical disease. However, this nding was insigni cant, and the number of events included in analysis was extremely low to analyze. And, root canal treatment may be performed in case of pulp only lesion or before the development of an osteolytic lesion. Our ndings suggested preemptive root canal treatment would be necessary, prior to BP use. Moreover, a BP drug holiday would be required for the patient requiring root canal treatment during BP use. This support studies, including the American Association of Oral and Maxillofacial Surgeons articles and reviews recommend patients who would be administered an anti-resorptive agent, to treat or control the dental disease with screening dental health before commencing the treatment. Moreover, they should maintain good oral hygiene even after treatment to reduce the risk of ONJ [21][22][23].
This study proposed that pulp and periapical disease is the risk for ONJ. BP is generally used for bone diseases, such as Paget's disease, multiple myeloma, and cancer that have the possibility of bone metastasis, such as breast cancer, besides osteoporosis. Despite excluding the aforementioned diseases in this study, patients should undergo routine dental check-ups to identify caries and pulp and periapical disease, before or during BP use. In addition to anti-resorptive agents, such as BP, agents inducing medication-related ONJ, including anti-angiogenic agents, are other concerns [24,25]. This necessitates con rmation of the relationship between anti-angiogenic agents and periapical agents on ONJ in future.
The rst limitation of this study was the inclusion of a small number of events, owing to its restriction to the NHIS cohort database including only women aged over 50 years. Second, it was di cult to assert a grade and stage ONJ because the condition was not con rmed by medical records or a direct oral examination of ONJ. Therefore, further studies are required to determine the correlation between pulp and periapical disease and ONJ.

Conclusions
Considering nationally representative databases, the risk of ONJ would increase signi cantly with pulp and periapical disease. Pulp and periapical disease should be considered as risk factors for ONJ. Furthermore, future studies should clarify the effect of low-grade in ammation on ONJ development.

Abbreviations
Osteonecrosis of the jaw (ONJ), bisphosphonate (BP), Korean Standard Classi cation of Diseases and Causes of Death-7 (KCD-7), hazard ratios (HRs), con dence intervals (CIs), National Health Insurance Service (NHIS), skeletal-related events (SREs) Declarations None Ethics approval and consent to participate The study was performed in accordance with the guidelines of the Helsinki Declaration (2013), protecting the participants' anonymity, privacy and maintaining public con dence.

Consent for publication
Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.