Pulp and periapical disease as a risk factor for osteonecrosis of the jaw: a national cohort-based study in Korea.

INTRODUCTION

Bisphosphonates (BPs), which are analogs of pyrophosphate, are inhibitors of osteoclast-mediated bone resorption that are used to treat metabolic and pathologic bone diseases such as osteoporosis, Paget’s disease, and metastatic malignant disease [ 1 ]. Despite being beneficial in the treatment of cancer and metabolic bone disease, the use of BPs can result in osteonecrosis of the jaw (ONJ) [ 2 , 3 ]. Even though ONJ is uncommon, its severe consequences can have a negative impact on patients’ quality of life [ 4 ]. Inhibition of angiogenesis, suppression of bone turnover, infection/inflammation, soft tissue toxicity, and immune-related mechanisms are among the possible pathophysiological aspects of ONJ that have received attention from researchers [ 5 ].

Dental procedures can cause ONJ, with tooth extraction inducing almost 50% of ONJ cases [ 6 , 7 , 8 , 9 ]. Therefore, most studies on ONJ have concentrated on tooth extraction, while ignoring the implications of other dental risks. Pathologic disorders are affected by delayed local wound healing or infection, which may have an impact on ONJ [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Dental caries and pulp and periapical disease, which are prevalent infectious dental illnesses, can lead to jaw bone inflammation and local catabolic consequences [ 17 ]. Inflammation plays an important role in the pathophysiology of ONJ related to osteoimmunology and is a key risk factor for ONJ [ 18 , 19 ]. Pulp and periapical disease may lead to tooth extraction or periodontitis, which are considered risk factors for ONJ. Therefore, pulp and periapical disease-induced inflammation may have a direct or indirect impact on the development of ONJ. However, its role in ONJ remains to be clarified.

Root canal treatment is performed to disinfect the pulp, resolve pulpal inflammation and periapical disease, and prevent further microbial invasion of periapical tissue. According to Vahtsevanos et al., [ 20 ] root canal treatment does not increase the risk of ONJ; nonetheless, the relationship between root canal treatment and ONJ remains unclear.

Previous research has shown associations among BP use, ONJ, and pulp and periapical disease [ 18 , 19 ]. However, those investigations using ONJ animal models were unable to establish a relationship between pulp and periapical disease and ONJ. Using a nationally representative cohort database in Korea, this study aimed to confirm the association between ONJ and pulp and periapical disease in patients receiving BPs.

MATERIALS AND METHODS

Data source

The National Health Insurance Service (NHIS) is the sole insurance provider in Korea; it is managed and supported by the Korean government, and it covers almost 97% of the Korean population. Health screening of the entire population is conducted by the NHIS every year or every other year depending on the age and occupation of those covered by insurance, and the results are released to the public [ 21 ]. We conducted a longitudinal cohort study using the general health screening database of the NHIS. The cohort comprised random samples representing approximately 510,000 individuals (aged 40–79 years), equivalent to 10% of the total population who were offered health examinations [ 21 ]. Data were extracted by sampling high-demand information from the national health insurance database. We used the health examination cohort database to analyze the medication use and examination results. Data from January 1, 2002 to December 31, 2015 were extracted.

Ethical approval of studies and informed consent

This study was approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB No. X-2004/606-905) and conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived because this retrospective study used anonymized data.

Study population

We extracted diagnosis codes from the NHIS database using Korean Standard Classification of Diseases and Causes of Death-7 (KCD-7) codes, a modified version of the 10th edition of the International Classification of Diseases and Related Health Problems. The treatment codes were based on the treatment and surgery fee codes in Korea.

Women who fulfilled the following inclusion criteria were included in the study: i) aged >50 years, ii) taking BPs for at least a year, and iii) medication adherence of >0% during the year (or a medication possession ratio >80%). Both oral and injectable methods were covered. Alendronate, ibandronate, risedronate, pamidronate, and zoledronate were the BPs examined. The index date was set as January 1, 2009.

The onset of ONJ could be affected by underlying disorders or some other contributing elements, and the frequency of ONJ is expected to be significantly higher in patients who have cancer or other bone diseases that require BP therapy. Therefore, patients taking high doses of BPs for cancer treatment were not included. Additionally, patients who died prior to the index date were not included in the study.

Definitions of ONJ, pulp and periapical disease, and dental caries

ONJ was diagnosed using a combination of KCD-7 and therapy codes. First, we divided ONJ into established ONJ and potential ONJ. Established ONJ was defined as individuals with 1 of the following criteria: osteonecrosis due to drugs, multiple sites (M87.1); inflammatory conditions of jaws (K10.2) as a diagnosis; 1 of the treatments was also registered; or both diagnoses were registered after the index date ( Supplementary Table 1 ).

Potential ONJ is a broad concept encompassing all aspects of suspected ONJ, such as diagnosis and treatment. The following diagnosis and treatment codes were considered as potential ONJ: osteonecrosis due to drugs, multiple sites (M87.1, 87.3, 87.8, and 87.9); inflammatory conditions of jaws (K10.2, 10.3 10.8); acute hematogenous osteomyelitis, multiple sites (M86); and disorders of teeth and supporting structures, unspecified (K08.9) ( Supplementary Table 2 ).

Pulp and periapical disease and dental caries were defined as the presence of the diagnosis code after the index date ( Supplementary Table 3 ). Root canal treatment was defined as the existence of a root canal treatment code recorded after the diagnosis of pulp and periapical disease, dental caries, or ONJ ( Supplementary Table 4 ).

Data collection

Patient variables such as the baseline year, age, income level, and disability were included. The National Statistical Office uses the income quintile to classify all families in Korea into 10 levels, with each level reflecting a 10% division based on the quarterly income level. The first quintile has the lowest income levels. The income increases as the quintile rises. There were 5 stages in the analysis. Disability was categorized as present or absent ( Table 1 ). The prevalence of diseases was defined according to the presence of hypertension (I10, I15), diabetes (E10, E118, E119, E13, E149), hyperlipidemia (E78), myocardial infarction (I21, I22), stroke (I60–63), or anemia (D46, D50-53, D55-64, D74) ( Table 1 ).

Statistical analyses

Baseline characteristics are presented as numbers (%) for categorical variables and as mean ± standard deviations. We conducted the χ 2 test (median with interquartile range) for continuous variables, as well as the t -test or analysis of variance. Moreover, we adjusted the 14 years of cohort data for baseline year, age, comorbidities, income disability, type of BP administered, and cumulative proportion of days to analyze the hazard ratio (HR) of ONJ based on the prevalence of pulp and periapical disease and dental caries. Cox proportional-hazards models were used to evaluate the associations between independent variables and the occurrence of ONJ events. In addition, we calculated HRs and 95% confidence intervals (CIs) to evaluate these associations. Statistical significance was defined as a 2-tailed P -value <0.05. All statistical analyses were conducted using the R programming language (version 3.3.3; The R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

After excluding patients with cancer or ONJ and those who died before the index date, this study 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 dental caries, respectively.

Among patients with and without pulp and periapical disease, established ONJ was diagnosed in 26 (0.62%) and 69 (0.30%), while potential ONJ was diagnosed in 62 (1.47%) and 158 (0.69%) patients, respectively. Moreover, established ONJ was present in 15 (0.44%) and 80 (0.34%) patients with and without dental caries, and potential ONJ was present in 30 (0.88%) and 190 (0.80%) patients, respectively. The significance of the difference varied depending on the diagnostic criteria. Nonetheless, pulp and periapical disease was associated with the development of both established and potential ONJ. Contrarily, the proportion of patients with established and potential ONJ was higher in the dental caries group, but no significant difference was noted ( Table 1 ).

The presence of pulp and periapical disease significantly increased the risk of ONJ development compared with the absence of this disease (HR, 2.21; 95% CI, 1.40–3.48 and HR, 2.22; 95% CI, 1.65–2.98 for established and potential ONJ, respectively). However, the presence of dental caries was not significant (HR, 1.52; 95% CI, 0.87–2.64 and HR, 1.22; 95% CI, 0.83–1.79 for established and potential ONJ, respectively) ( Table 2 ). We analyzed the HR of root canal treatment for ONJ development among patients with pulp and periapical disease and dental caries and did not find statistically significant results ( Table 3 ).

DISCUSSION

Even though tooth extraction is a significant risk factor for ONJ, the chronic inflammation induced by pulp and periapical disease, which can lead to tooth extraction, has received less attention in ONJ. BPs depress osteoclast activity, causing decreased bone remodeling. As a result, periapical radiolucent lesions in the alveolar bone are concealed in individuals using BPs. Furthermore, the morbidity of pulp and periapical disease is frequently overlooked in patients taking BPs. Therefore, research on the relationship between pulp and periapical disease and ONJ is sparse. Nevertheless, the few studies conducted on this issue—including the one by Cheong et al. [ 18 ]—have reported that the uptake of BPs increases in patients with pulp and periapical disease. Kang et al. [ 19 ] demonstrated that pulp and periapical disease with BP administration caused ONJ in mice. Those studies have limitations because they were based on ONJ animal models, but they nonetheless suggested an association between pulp and periapical disease and ONJ. We found that patients with pulp and periapical disease who received BPs for more than 1 year showed increased morbidity due to established and potential ONJ. We hypothesized that pulp and periapical disease increases the inflammation in the alveolar bone close to the root is induced. According to research using animal models, this inflammation results in an overabundance of BPs, subsequently leading to the development of ONJ [ 18 , 19 ].

In addition, lesions that produce inflammation, including periodontitis and pulp and periapical disease, increase the susceptibility of sites to ONJ development, although tooth extraction is undoubtedly also a risk factor for ONJ. Difficulties in analyzing or studying ONJ have led to a focus on consequent interventions. To understand the causes of ONJ and the approach to treatment, it is vital to understand how inflammation affects ONJ. Because the jaw bone changes more frequently than other peripheral bones, an increased concentration of BPs is noted in that location [ 15 ]. According to Gong et al., [ 22 ] the bone-marrow stroma of the jaw bone is more vulnerable to BPs than that of the iliac and tibial bones. Moreover, Lim et al. [ 23 ] reported that the osseous healing mechanism differs based on the site. These traits would be very important in ONJ. Therefore, it would be beneficial to comprehend the association between osteoimmunology and inflammation to treat ONJ.

We focused on the progression of dental caries, even though the development of pulp and periapical disease may be attributable to different factors, including the periapical status and pathosis [ 24 , 25 , 26 ]. Despite being a pulp-limited disease, dental caries causes pulp and periapical disease that results in chronic inflammation of the jaw bone. Inflammation is a definitive risk factor for the development of ONJ. The morbidity of ONJ in patients with dental caries was also investigated, and we found that, contrastingly, dental caries did not substantially increase the risk of ONJ. Therefore, we contend that ONJ cannot be caused by tooth pulp tissue inflammation alone.

Furthermore, untreated pulp and periapical disease can cause inflammation to extend to the adjacent periodontal tissue. This can lead to retrograde periodontitis with subsequent bone destruction, which is another risk factor for ONJ, and can exacerbate the severity of periodontal disease [ 27 , 28 ]. Retrograde peri-implantitis can also arise from untreated pulp and periapical disease [ 29 , 30 , 31 ]. For these reasons, it is necessary to treat pulp and periapical disease.

We also examined the effect of endodontic treatment for pulp and periapical disease on the risk of ONJ. Similar to the findings of Vahtsevanos et al., [ 20 ] we found that root canal therapy did not affect the risk of ONJ in cases of BP treatment. Therefore, BP deposition in pulp and periapical disease is unaffected by endodontic treatment. However, as the analysis only covered a very small number of events, this finding is difficult to interpret conclusively. Furthermore, root canal therapy may have been used to treat pulpal lesions alone or prior to the emergence of an osteolytic lesion. Our research indicates that preventive root canal therapy would be required before BP use. Additionally, a BP drug holiday would be necessary for those who need root canal therapy while taking a BP. This finding supports studies, including articles and reviews published by the American Association of Oral and Maxillofacial Surgeons, which recommend that patients be administered an anti-resorptive drug to treat or control dental disease prior to starting therapy. Moreover, individuals should continue practicing good oral hygiene even after receiving medication to lower the probability of developing ONJ [ 32 , 33 , 34 , 35 , 36 ].

The results of this study indicate that pulp and periapical disease is a risk factor for ONJ. In addition to osteoporosis, BPs are typically used to treat bone conditions such as Paget’s disease, multiple myeloma, and tumors (e.g., breast cancer) that may metastasize to the bones. Despite excluding the aforementioned diseases in this study, the results indicate that patients should undergo routine dental examinations to detect dental caries and pulp and periapical disease, either before or while using BPs.

Other drugs that cause ONJ, such anti-angiogenic agents, are another issue [ 37 , 38 ]. The relationship between anti-angiogenic drugs and periapical disease in ONJ needs to be further investigated.

The study has some limitations. First, the study covered a small number of cases because it was limited to the NHIS cohort database, which only included women aged >50 years. Second, it was challenging to assess the grade and stage of ONJ because the disease was not verified by medical records or direct oral examinations. Third, the analysis would have been more accurate if it had accounted for periodontitis and tooth extraction. Due to the specific characteristics of the data set, whether the cases of pulp and periapical illness included in this study were induced by dental caries was also unknown. In addition, it is difficult to be sure whether pulp and periapical disease had been diagnosed, and whether the diagnosis and treatment codes were assigned accurately. Moreover, caution in interpreting the results for specific conditions is needed, especially for reversible pulpitis and pulp degeneration. Reversible pulpitis can return to a normal state if the cause is removed, and pulp degeneration results from the aging process. Therefore, further research is needed to establish the relationship between pulp and periapical disease and ONJ.

In conclusion, our research on a nationally representative database showed that pulp and periapical disease substantially increased the risk of ONJ. Consequently, pulp and periapical disease needs to be considered as a risk factor for ONJ. Future research should explain how low-grade inflammation affects the development of ONJ.

Footnotes

Funding: This work was supported by Seoul National University Bundang Hospital (grant numbers 02-2018-042 and 06-2020-020) and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant number 2020R1A2C4001842).

Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Availability of Data: All data used in this study are publicly available upon request from the National Health Insurance Service of Korea ( https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do ).

Author Contributions: Conceptualization: Hyeong-Jin Baek, Hyo-Jung Lee, Jin-Woo Kim. Data Curation: Hyeong-Jin Baek, Hyejin Lee, Jae-Ryun Lee, Jung-Hyun Park, Keun-Suh Kim, Min-Jeong Kwoen, Tae-Yeon Lee. Formal Analysis: Hyeong-Jin Baek, Hyejin Lee, Jae-Ryun Lee. Investigation: Hyejin Lee, Jae-Ryun Lee, Jung-Hyun Park. Methodology: Hyeong-Jin Baek, Hyejin Lee, Jung-Hyun Park, Keun-Suh Kim, Tae-Yeon Lee. Software: Jae-Ryun Lee. Validation: Hyo-Jung Lee, Jin-Woo Kim. Project Administration: Hyo-Jung Lee, Jin-Woo Kim. Writing - original draft: Hyeong-Jin Baek. Writing - review & editing: Hyejin Lee, Jae-Ryun Lee, Jung-Hyun Park, Keun-Suh Kim, Min-Jeong Kwoen, Tae-Yeon Lee, Hyo-Jung Lee, Jin-Woo Kim.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Treatment codes related to established osteonecrosis of the jaw

Supplementary Table 2

Treatment codes related to potential osteonecrosis of the jaw

Supplementary Table 3

Diagnosis codes for pulp and periapical disease and dental caries

Supplementary Table 4

Treatment codes for root canal treatment

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Associated Data

Supplementary Materials

Supplementary Table 1

Treatment codes related to established osteonecrosis of the jaw

Supplementary Table 2

Treatment codes related to potential osteonecrosis of the jaw

Supplementary Table 3

Diagnosis codes for pulp and periapical disease and dental caries

Supplementary Table 4

Treatment codes for root canal treatment