Incidence of antiresorptive agent-related osteonecrosis of the jaw: A multicenter retrospective epidemiological study in Hyogo Prefecture, Japan.

Introduction

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ), first reported in 2003, 1 dramatically impairs patients’ quality of life. Similarly, denosumab (Dmab), an anti-receptor activator of NF-κB ligand antibody, causes osteonecrosis of the jaw (DRONJ). DRONJ is clinically indistinguishable from BRONJ and occurs at almost the same rate, 2 albeit with a different histopathological profile. 3 Antiresorptive agent (ARA)-related osteonecrosis of the jaw (ARONJ), which includes BRONJ and DRONJ, is a rare, intractable disease that reduces oral-health related quality of life. Other medications, such as anti-vascular endothelial growth factors and multi-kinase inhibitors, also cause osteonecrosis of the jaw. The American Association of Oral and Maxillofacial Surgeons (AAOMS) defined these cases as medication-related osteonecrosis of the jaw (MRONJ) in 2014. 4

In Japan, a 2017 position paper presented the pathophysiology and management of ARONJ. 5 A national survey reported a clear increasing trend in the number of patients with ARONJ in Japan. 6 A survey by the Japanese Association of Oral and Maxillofacial Surgeons (JAOMS) in 2019 reported approximately 7000 cases of BRONJ nationwide. 7 However, the interpretation of the criteria for BRONJ varied across the individual centers. Therefore, the reported number of BRONJ cases may include cases of DRONJ, which is an emerging category. Thus, the survey, in fact, reports ARONJ cases. It does not provide details such as BRONJ-to-DRONJ ratio, stage classification, drug dosage, and duration. Furthermore, the dose of the causative drug administered was not disclosed. 7 Urade et al. reported that BRONJ low-dose BP accounted for less than 40% of patients in a nationwide survey between 2006 and 2008 8 and almost 50% in a survey between 2011 and 2013, 9 but no recent data are available. Although the number of patients with ARONJ is assessed in the annual disease survey by JAOMS, the causative drugs, as well as the proportion of BRONJ and DRONJ cases, remain unknown. Clinically, the number of patients with DRONJ among ARONJ cases is clearly increasing, 6 but the details of patients with DRONJ have been unclear. Therefore, this study aimed to classify the disease survey data of patients in Hyogo Prefecture, harboring 1/20 of the total population, between January 2018 and December 2020 into BRONJ and DRONJ for evaluation, and further investigate the disease occurrence caused by both high and low doses of BP and Dmab.

Materials and methods

Ethical considerations

This study was approved by the Kobe City Medical Center General Hospital (ethic committee number: zn220217) and was carried out in accordance with the 7th revision of the 2013 Declaration of Helsinki. Informed consent was obtained in the form of an opt-out option on the website.

Cooperative research facilities and researchers

This study was conducted at several institutions of the Hyogo Hospital Dental Association (HHDA), Hyogo, Japan ( Table 1 ). These institutions included university hospitals and major municipal or private hospitals with an oral and maxillofacial surgery department.

Subjects and study design

We designed a retrospective multi-center cohort study and enrolled subjects who visited the HHDA institutions and were diagnosed with BRONJ or DRONJ between January 2018 and December 2020. The inclusion criteria comprised diagnosis with ARONJ (stage ≥1) according to the AAOMS criteria. 10 The exclusion criteria were as follows: (1) no history of antiresorptive therapy, (2) missing information (e.g., medical records, medication history), (3) stage 0 cases (stage 0 exhibits no bone exposure or jaw fistula, and it is possible that odontogenic infection symptoms may be misdiagnosed as osteonecrosis of the jaw, leading to overdiagnosis; 6 moreover, previous studies in Japan have excluded stage 0 cases 8 , 9 ). The patients who received switch therapy (i.e., BP to Dmab or Dmab to BP) were assigned to either the BRONJ or DRONJ group according to their attending physician's comprehensive judgment based on the percentage of treatment duration with ARA and other factors. In this study, treatment with ARA for bone metastases of malignant tumors and multiple myeloma was defined as high dose, while that for cancer treatment-induced bone loss and osteoporosis, regardless of the administration route, was defined as low dose. 11

Statistical analysis

All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University), which is based on R (The R Foundation for Statistical Computing) and R commander. 12 Categorical data were presented as number of subjects (% subjects) and were compared using the chi-square test. Statistical significance was set at P < 0.05 unless otherwise indicated.

Results

Eligible patients

Of the 1031 patients who were diagnosed with MRONJ, three cases with insufficient information and seven cases that appeared to have angiogenesis inhibitor-derived etiology were considered unsuitable for analysis. Ultimately, 1021 cases of ARONJ were included in this study ( Table 2 ).

Antiresorptive agent types and doses

Of the 1021 patients with confirmed ARONJ, 664 (65.0%) and 357 (35.0%) had received BP and Dmab, respectively. Notably, 471 (46.1%) and 550 (54.8%) patients had received high and low doses of the causative drug, respectively. Among these, about 60% and 15% patients received high and low doses of Dmab, respectively, resulting in DRONJ ( Table 3 ).

ARONJ stages

Most patients in the present study were classified as ARONJ stage ≥2, with one-fourth of the cases being classified as stage 1. A comparison of past reports and this study revealed that the proportion of stage 1 and 3 cases of the total increased over each study ( Table 4 ).

Relationship between treatment duration of ARA and stage

We investigated the relationship between treatment duration of ARA and stage progression in 978 patients, excluding 43 patients for whom the treatment duration was unclear. Interestingly, ARONJ was caused by high-dose ARA in about 60% of patients with shorter treatment duration (<5 years). In contrast, with increasing treatment duration of ARA (≥5 years), the proportion of ARONJ cases due to low-dose ARA increased ( Table 5 ).

Number of patients with ARONJ

According to our results and the JAOMS survey, we calculated the number of patients with ARONJ per 10,000 person-years ( Table 6 ). As data for each year from 2011 to 2013 were not available, 9 , 14 we divided the findings by the three years and calculated the number of persons per year.

Switch therapy

The characteristics of patients who received switch therapy are presented in Table 7 . Treatment shift from BP to Dmab was observed in 74 cases, Dmab to BP in 4 cases, and BP/Dmab to teriparatide in 11 cases. The proportion of patients with stage 3 ARONJ who received switch therapy was lower than that of those who did not receive switch therapy.

Discussion

A recent nationwide population-based study in Japan reported the prevalence of MRONJ in patients with osteoporosis and cancer to be 0.06% and 1.47%, resectively. 15 The JAOMS documents the current status of ARONJ outbreaks that are found to be rapidly increasing in clinical practice, and a similar trend is observed worldwide. 7 Although the majority of MRONJ cases are expected to be ARONJ, their details have been largely unknown until now. One difference from the AAOMS position paper 4 was that the cut-off for treatment duration of ARA was set at four years. Similarly, previous studies reported a median duration of ARA use for MRONJ as 3.0–4.4 years. 16 , 17 Considering the possibility of underestimation, we set a cut-off of 5 years in the present study. The cutoff period of treatment duration of ARA for both the high and low doses was set at 5 years. However, the details of patients with ARONJ who had high-dose ARA may have been underestimated because some patients died early from malignant lung cancer tumors. The appropriate cutoff should be determined in the future. Among the patients for whom the treatment duration of ARA was recorded, patients with ARONJ with longer treatment durations (≥5 years) accounted for more than 60% of cases, and the treatment duration may have affected the onset of ARONJ.

The findings of this study suggest a few important points. First, the proportion of BRONJ and DRONJ cases among the ARONJ cases must be identified. BP binds to the bone for a long time, from 1 to 10 years. 18 In contrast, Dmab does not bind to the bone, and its effects on bone remodeling mostly diminish within 6 months. Unnecessary drug discontinuation may be harmful to the patient. Although drug discontinuation remains a controversial topic, Dmab discontinuation reportedly increases the risk of rebound-associated fractures. 19 Moreover, DRONJ is reportedly more easily resolved than BRONJ. 20 Therefore, we believe that determining the exact causative agent of ARONJ will contribute to more appropriate treatment and prevention strategies. In the past, the majority of ARONJ cases were thought to be caused by BP. However, the number of Dmab prescriptions has increases as only one injection every 6 months is required for osteoporosis; moreover, it is easy to use for bone metastases of malignant tumors in patients with impaired renal function and is superior to BP in delaying skeletal-related events in patients with bone metastases. 21 , 22 , 23 A population-based study showed that 12.1% of the patients with osteoporosis and 47.6% of the patients with cancer-bearing disease received Dmab. 15 In fact, our results showed that DRONJ accounted for 14.5% and 58.8% of cases at low and high doses, respectively. Our study could not account for background factors as in previous reports. 23 Therefore, our results present a limited consideration that the higher incidence of osteonecrosis of the jaw is due to high-dose Dmab rather than BP.

Second, to the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, the causative drug, and the doses by disease stage associated with cases. In previous surveys, most cases (60%–70%) were detected and diagnosed at advanced stages such as stage 2 of the disease. 9 In the present study, the percentage of stage 2 cases was 52.4%, and stage 1 and 3 cases accounted for 25.7% and 21.8%, respectively, which is greater than previously reported. Moreover, according to the JAOMS survey, 6 most of the cases were stage ≥2, and the percentage of stage 1 cases tended to increase with each statistic; a similar trend was observed in the present study. This positive result may be attributed to increased awareness and early detection of the disease. We propose two hypotheses to explain the increase in the number of stage 3 cases. First, there is a deep-rooted perception that surgical procedures, such as tooth extraction, are contraindicated, and many cases were referred after conservative progress was made without excluding the cause of odontogenic inflammation, resulting in the development of severe stages of ARONJ. Second, stage 3 cases were more likely to be Dmab-derived, regardless of low/high-dose, as seen in the present study. It is possible that the change in prescription resulted in more severe stages of ARONJ in patients. Many reports have stated that tooth extraction itself is not necessarily a risk factor for MRONJ, but only exposes necrotic bone, as in MRONJ. 24 , 25 Since MRONJ can develop as a chronic inflammation without invasive dental treatment, it is important to explain it to the patients and extract the infected teeth as soon as possible. Thus, it is necessary to educate clinicians to perform tooth extraction without hesitation. Furthermore, stage 3 cases in previous reports accounted for less than 20% of cases regardless of the ARA dose. However, in the present study, stage 3 cases accounted for as high as 30% in patients administered low-dose Dmab. As low-dose Dmab is just as likely to cause stage 3 ARONJ as high-dose BP, low-dose Dmab may have a higher risk of progression to stage 3 than BP ( Table 3 ). Interestingly, when analyzing these data by treatment duration of ARA, we found that stage 3 BRONJ rates were significantly higher in patients treated for >5 years at both low ( P < 0.01) and high ( P = 0.01) doses. However, a significant difference was not observed in DRONJ cases ( P > 0.05) (Supple. 1). Further, patients who received high-dose Dmab were more likely to develop ARONJ than high-dose BP recipients. However, high doses of Dmab are not necessarily associated with a high incidence of ARONJ, especially as some patients received switch therapy. 26

The number of patients with ARONJ is increasing worldwide. 7 , 10 Approximately 1/20 of the Japanese population resides in Hyogo Prefecture, and we believe that we can estimate patient demographics for the nation based on the survey in this region. The most recent JAOMS survey estimates that there are approximately 6000 to 7000 new patients with ARONJ per year. 7 Supporting this estimate, 1021 patients were registered over a 3-year period in the present survey. The number of patients with ARONJ reported in 2011–2013 did not significantly differ between Hyogo Prefecture and Japan as a whole. Thereafter, a steady increase in this number has been observed in both Hyogo Prefecture and Japan as a whole ( Table 6 ). Although national survey data from 2020 onward are scarce, this increasing trend is expected to continue. Based on the results of this survey, we hypothesize that approximately 30% of ARONJ cases may be DRONJ. Verification by a nationwide survey is desired for confirmation.

A unique finding of the present study is that the ARA dose varied according to the duration of treatment ( Table 5 ). Recently, the AAOMS stated that the cumulative dose of drugs is not related to severity, which is in contrast with its previous stand. 10 This study revealed that, as expected, high-dose ARONJ cases were more common in durations <5 years. However, the number of low-dose ARONJ cases were 253 and 264 for durations <5 and >5 years, respectively, with the majority of cases developing after 5 years. In addition, we observed a higher incidence of stage 3 cases when the duration of treatment was more than 5 years. This finding suggests that the occurrence of severe disease may be more likely beyond a certain threshold, irrespective of low or high doses, and that cumulative dose may be related to disease severity and onset. Nevertheless, our results allow only a limited discussion of cumulative dosage, and further investigations are desirable.

The reports on the association between switch therapy and risk of disease onset are controversial, with some studies reporting an increased risk and others claiming that it remains the same. 27 , 28 Although our study does not address the risk of disease onset, we analyzed the relationship between disease severity and switch therapy ( Table 7 ). A comparison between switch therapy and BP/Dmab treatment alone revealed no significant difference in the number of Stage 3 ARONJ cases ( P = 0.49). Thus, switch therapy may contribute to the onset, but not the severity of the disease.

A limitation of our study was that it was a retrospective observational study with missing information. Our study did not investigate primary diseases, past patient history, chemotherapy type, and smoking history. These are risk factors for ARONJ onset that should have been considered.

In conclusion, our survey revealed the following important findings: Low-dose ARONJ accounted for more than half of the total cases. DRONJ accounted for 58% of the high-dose and 35% of low-dose cases. Stage 3 cases accounted for 20.1% and 19.6% of high-dose and low-dose BRONJ cases, respectively, and 24.5% and 30.0% of high-dose and low-dose DRONJ cases, respectively. Considering the increasing number of patients with ARONJ, further studies to develop strategic treatment and preventive measures are desirable. We intend to conduct additional surveys of eligible patients to gain further insights in the future.

Declaration of competing interest

Hiromitsu Kishimoto received compensation from Asahi Kasei Pharma Corporation.

Acknowledgements

We would like to thank Editage ( www.editage.com ) for the English language editing.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jds.2022.10.030 .

Supplementary data

The following is the Supplementary data to this article:

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Associated Data

Supplementary Materials

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