This study aimed to evaluate the incidence of MRONJ and associated antiresorptive drugs in the Finnish population. The incidence of MRONJ was 0.8% during the follow-up period (2013/2015 to 2020). The risk of developing MRONJ among denosumab users was six times higher and three times higher among combination therapy (bisphosphonates followed by denosumab) users compared to only bisphosphonates users. Additionally, the patients diagnosed with cancer had more than ten folds risk of developing MRONJ compared to those diagnosed with osteoporosis. Likewise, simultaneous use of corticosteroids and VEGF inhibitors in addition to AR drug increased the risk of developing MRONJ by more than three and one and half times, respectively.
To our knowledge, this is the first population-based cohort study among the antiresorptive drug users in Finland. Another strength of the present study was large sample (n=58367) that were followed up for a period of 5 to 7 years. Merging of the observations in steps in Kaplan-Meier survival analyses can be considered as limitation of the present study. However, in order to maintain the anonymity of the patient as required by the secondary use of social and health data act in Finland16, it was necessary.
In the present study, a cumulative incidence of MRONJ was 0.8% among antiresorptive drugs users during the study period. This figure seems to be higher than an earlier case-report study conducted in four Nordic countries (Denmark, Finland, Norway, and Sweden) during the period of 2003-20108. However, Krüger and colleagues (2013) studied the incidence of bisphosphonate-related osteonecrosis of jaw (BRONJ). In contrast, patients who were prescribed with any antiresorptive drugs (bisphosphonates, denosumab, or combination therapy) were studied here and incidence of BRONJ is relatively low compared to the study by Krüger and colleagues (2013). The incidence of BRONJ in the present study corroborates with a registry-based study from Hungary17. Furthermore, when patients are stratified by the diagnosis, incidence of MRONJ was similar to a South Korean study conducted in osteoporotic patient as well as Swedish study conducted in breast cancer patient with malignancy12,18.
Notably, the risk of developing MRONJ was higher among denosumab users as well as among bisphosphonate combined with denosumab users compared to bisphosphonate only users. There is robust evidence related to higher risk of denosumab users compared to bisphosphonate users1,7,9,11,12. The possible pathophysiology could be due to the effect of tissue’s TRAP (tartrate-resistant acid phosphatase) level, which indicates the number of osteoclasts in the tissue as explained by Williams and colleagues19. Denosumab therapy reduces the TRAP level close to zero whereas TRAP level is high during bisphosphonate therapy and so is the number of osteoclasts. If the development of MRONJ is largely related to inhibiting the direct activity of osteoclasts, then one could assume that denosumab is a more likely drug to induce the development of MRONJ lesions19. In addition, denosumab and bisphosphonates have not necessarily been compared equally, as it has been observed that bisphosphonate-induced ONJ lesions develop slower than those of denosumab. Unlike bisphosphonates, denosumab does not accumulate in the bones and it has a circulatory half-life of 26 days, compared to bisphosphonates half-life of 10 years20,21. Hereby, denosumab is not necessarily any more likely to cause MRONJ than bisphosphonates, but the onset of the disease and thus the diagnosis is probably made earlier in patients with denosumab medication22. Longer follow-up period even up to 10 to 15 years would be needed to exclude these questions more definitely.
Use of corticosteroids and VEGF inhibitors increased the risk of developing MRONJ in the present study. These findings are similar to a recent position paper by the American Association of Oral and Maxillofacial Surgeons4. Furthermore, authors reported that when corticosteroids and antiresorptive are used together the risk multiplies. However, Hallmer and colleagues (2020) reported that use of corticosteroids decreases the risk of MRONJ. It can be presumed that the VEGF inhibitor medication affects bone remodeling by inhibiting vascular endothelial growth factors (VEGFs) thereby inhibiting the growth of new blood vessels, bone regeneration and differentiation of osteoblasts23. Simultaneous antiresorptive use, which by virtue, inhibits osteoclast activity and cell apoptosis is thought to accumulate the development process of MRONJ4,24. Corticosteroids on the other hand are theorized to induce osteocyte apoptosis, which results in similar consequences as VEGF inhibition25,26. While corticosteroids are commonly prescribed in cancer patients, the incidence should be studied between corticosteroid-medicated cancer patients and non-corticosteroid-medicated cancer patients to deduce the definite differences in risk of corticosteroid use.
Patients diagnosed with any type of cancer had a higher risk of developing MRONJ in the current study. This may be related to higher doses and administration route of ARs, but it is also to be noted that cancer patients are immunocompromised and thereby in higher risk of developing MRONJ. Furthermore, chemotherapy induces xerostomia, which exposes to increased risk of caries and tooth extractions. In a Brazilian prospective cohort study, prevalence of xerostomia was 48 % in breast cancer patients27 and in another American cross-sectional study 39% of the oropharyngeal cancer patients reported severe symptoms of xerostomia28. Poor oral hygiene has also been linked to a lower survival in head and neck cancers, which might similarly play a role in overall occurrence rate of MRONJ29. It is well known that poor oral hygiene is one of the leading causes for dental caries, periodontitis and if left untreated leads to periapical periodontitis and fistulas. Additionally, it has recently been suggested that MRONJ lesion requires inflammatory stimulus to occur, and the trauma caused by tooth extraction itself would play a smaller role than previously assumed30. Oral cavity offers ideal conditions for infections in terms of potent microbes (for example Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis), plaque and oral traumas. Low pH levels, which are present in infection sites, are shown to induce osteonecrosis development by releasing bisphosphonate from bone tissue. Besides, bone regeneration becomes disturbed by reduced osteoclast activity due to antiresorptive therapy increasing risk for MRONJ30. The presence of inflammatory conditions is naturally higher in poor oral conditions, which suggests that poor oral hygiene increases the risk of MRONJ.
Female had lower risk of MRONJ compared to male. This might be related to a higher risk of developing MRONJ due to prostate cancer than to breast cancer. Hata et al., 2022 studied the difference in MRONJ incidence between different cancer diagnosis patients. Prostate cancer was similarly found to be a risk factor in MRONJ development. Although, in their study other types of cancers and especially lung cancer diagnosis balanced the differences in cumulative incidence between genders as male-dominated lung cancer patients rarely developed MRONJ31. It can be speculated that the difference is more likely to be found in dental hygiene practices, comorbidities, and other qualitative habits of living. For instance, Finnish men brush teeth less frequently, have more plaque on tooth surfaces, use more often prosthesis and drink and smoke more often than females32. Therefore, future studies should incorporate oral health-related factors and comorbidities among MRONJ patients.
Given the risk of bisphosphonate being low, evasion of denosumab treatment should be seriously considered if bisphosphonate treatment is a respectable alternative. Additionally, health care practitioners should be encouraged for a comprehensive proactive dental treatment for each patient before the initiation of antiresorptive medications.
In conclusion, denosumab or sequential use of both denosumab and bisphosphonate, any type of cancer diagnosis, and simultaneous corticosteroid and/or VEGF treatment were the most noteworthy risk factors for MRONJ in our study. Therefore, choice of antiresorptive drugs must be cautiously considered before its use.