Does dental and oral health influence the development and course of bisphosphonate-related osteonecrosis of the jaws (BRONJ)?
The main causes for the occurrence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) are the application of aminobisphosphonates and the extraction of teeth. However, the question which factors in dental and oral health are relevant has not been answered completely.
Materials and methods
In a retrospective study, 50 patients who were treated with BRONJ between 2000 and 2009 were analyzed. As underlying diseases, they suffered from breast cancer (n = 24), multiple myeloma (n = 16), prostate cancer (n = 5), osteoporosis (n = 4), and kidney cancer (n = 1). The data were collected from the patient charts of the treating dentists, oral and maxillofacial surgeons, general practitioners, and oncologists. The time of occurrence of BRONJ after treatment onset with bisphosphonates (BP) was examined with Kaplan–Meier estimator and logrank test (level of significance 0.05).
At the time of BP treatment, onset the decayed, missing, and filled teeth (DMFT) index was 20.5 ± 4.2. Patients with a DMFT value less than 20 showed a significantly longer BRONJ-free time interval after BP treatment onset with 39.7 ± 1.1 months compared to patients with a DMFT value higher than 20, in whom BRONJ appeared after 14.4 ± 2.8 months (p < 0.001). However, the DMFT value had no influence on the success rate of BRONJ treatment.
As a pre-existing oral disease, 60 % of the patients (n = 30) had marginal periodontitis; 38 % (n = 19), apical periodontitis; and 22 % (n = 11), a pressure lesion from their dentures.
In patients with marginal periodontitis, BRONJ occurred after 26.3 months (range 20.9–31.3) and in patients without marginal periodontitis, after 27.4 months (range 14.6–40.1) (p = 0.58). Only 20 % of the patients with marginal periodontitis received adequate treatment. Without parodontal treatment, BRONJ occurred 15 months earlier compared to patients with parodontal treatment (p = 0.12). The state of the periodontium did not influence the healing rate of BRONJ (p > 0.999).
The present study highlights the great benefit of good dental and oral health in the prevention of BRONJ; but it also shows that after the appearance of BRONJ, these factors do no longer seem to play a relevant role in the disease course.
KeywordsBisphosphonate-related osteonecrosis of the jaws BRONJ Oral health Dental health Marginal periodontitis
Since the first description of bisphosphonate-related osteonecrosis of the jaws (BRONJ) by Marx, multiple studies were published . The causality between bisphosphonates (BP) application and the occurrence of BRONJ has been established, although its pathophysiology is still not clearly understood. Multiple different biological or cellular pathways may lead to this side effect of BPs . Nevertheless, in practice often a dental invasive intervention secondary to a pathologic condition precedes BRONJ. The exact dental condition of the extracted teeth or the general dental health of the affected patients is not addressed in detail in the literature. The aim of the present study was therefore to examine the influence of these factors on the occurrence of BRONJ and the treatment success rate.
Patients and methods
The present retrospective study was granted exemption by the author's institution and is in accord with local IRB standards.
In a retrospective study, 50 patients with BRONJ according to the definition of the American Association of Oral and Maxillofacial Surgeons (AAOMS) were included . They were all treated at the Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Germany between 2000 and 2009. Data were collected retrospectively from the patient charts of the treating dentists, oral and maxillofacial surgeons, general practitioners, and oncologists. Follow-up time after surgical treatment of BRONJ ranged from 3 to 45 months.
As a single medication, 29 patients received zoledronate; 5, pamidronate; 2, clodronate; 1, alendronate; and 1, risedronate. All other patients had two or more different bisphosphonates during their treatment. The sites of BRONJ manifestation were the mandible in 31 cases, the maxilla in 9 cases, and both jaws in 10 cases. BRONJ was treated surgically in 39 patients with sequestrotomy and local flap coverage of the exposed bone and conservatively in 11 patients.
The presence of a normal distribution was tested with the Shapiro–Wilk or Kolmogorov–Smirnov test. As there was a normal distribution, the t test was applied. The times of occurrence (i.e., survival time and occurrence of BRONJ) were examined with the Kaplan–Meier estimator and logrank test. Frequencies were displayed in contingency tables and were tested with chi-square test or Fisher's exact test in low frequencies. The level of significance was set at 0.05.
BRONJ-preceding events included tooth extraction (n = 34) and denture pressure lesions or spontaneous mucosal lesions (n = 12). The nature of the preceding event did not influence the duration until occurrence of BRONJ (tooth extraction 29.7 ± 17 months, pressure lesion/spontaneous 25.3 ± 11.9 months).
Oral hygiene was considered as good in 34 %, as moderate in 36 %, and insufficient in 22 % of the cases by the regularly attended dentists. The status of oral hygiene was unknown to the treating dentists in 8 % of the patients.
In the group with surgical treatment, the healing process was uneventful after 3–4 weeks in 41 % of the patients. At the last follow-up appointment (14.2 ± 12.4 months (range 3–45 months)), this result dropped to 17.1 %. Although not significantly, the success rate of the surgical treatment of BRONJ was influenced by the way of administration of BPs and the BP treatment time. Patients treated with i.v. BP showed a success rate of 15.2 %; patients treated with oral BP showed a success rate of 66.7 % (p = 0.09). Patients treated shorter than 24 months showed a complete healing from BRONJ in 24 % of the cases, with a treatment time longer than 24 months only in 9.1 % of the cases (p = 0.4).
The factors indicating oral and dental health, however, did not seem to influence the treatment outcome at all. In patients with successful surgical treatment, oral hygiene was estimated as being good in 28.6 %, moderate in 15.4 %, and insufficient in 11.1 % of the cases (p = 0.476). The DMFT index was 21.4 ± 3.8 in patients with uneventful healing after surgical treatment and 19.7 ± 4.1 in patients with a failure (p = 0.325). A pre-existent marginal periodontitis, as the most frequent dental disease, did also not play any role in the treatment outcome (success rate 15.4 % with marginal periodontitis vs. 14.3 % without marginal periodontitis, p > 0.999).
In the current literature, there is a common agreement that the proven and major risk factors for the development of BRONJ are the application of aminobisphosphonates and the surgical dental procedure under an ongoing or previous BP treatment [4, 5, 6, 7, 8]. In addition, patients who receive highly potent i.v. aminobisphosphonates (i.e., zoledronate) are more likely to develop BRONJ than patients treated with less-potent BPs. For example, Durie et al. showed that from 211 patients under zoledronate, 10 % developed BRONJ and from 413 patients under pamidronate, only 4 %. Furthermore, Melo et al. found that patients suffered from BRONJ after a median of 17 months under zoledronate and after a median of 30.5 months under pamidronate [6, 9]. The results of our study are similar. Patients treated with zoledronate developed significantly earlier BRONJ than others. The majority of our patients also underwent tooth extraction prior to the occurrence of BRONJ. This finding is also in accordance with the results of other groups.
However, the question whether other underlying and pre-existent dental pathologies may predispose patients for the development of BRONJ is only partially addressed in the literature.
In 2005, the Fourth German Oral Health Survey conducted by the Institute of German Dentists found a mean of 22.1 DMFT index in senior persons (aged 64–70 years) . With 20.5 DMFT index, our study group had even better dental status. The negative influence of a poor dental status is demonstrated by the 2.8-fold earlier manifestation of BRONJ in patients with more than 20 DMFT index. The most frequent dental pathology found in our patients was marginal periodontitis. Although Marx et al. described a predisposition of these patients for BRONJ, we could not show any negative influence . But there seemed to be a tendency for patients, who received parodontal treatment under BP therapy, to develop BRONJ later than patients without treatment. The hypothesis that dental pathologies predispose for BRONJ is underlined by the findings of Hoff et al., who described a 7-fold higher risk for patients with parodontal or apical abscess formation in their history . As a consequence, Woo et al. emphasized the necessity to eliminate all potential infectious foci prior to the onset of BP treatment in order to prevent later dental procedures . Moreover, the studies of Ripamonti et al. and Kyrgidis et al. demonstrated the great benefit of preventive dental measures with a reduction of the BRONJ incidence by 75 % and 73 %, respectively, compared to patients without preventive measures [14, 15].
The success rate for surgical therapy of BRONJ is estimated between 27.5 % and 91.6 % in the literature [16, 17, 18]. However, Carlson and Basile describe that their 91.6 % patients who are treated successfully “healed in an acceptable fashion”, which is not further defined. Our results show a markedly lower success rate. This may be due to a longer follow-up—which is highlighted by the decrease of healed lesions between 3 to 4 weeks postoperatively and the last follow-up—and a meticulous physical examination. Even a tiny nonproductive fistula was regarded as a failure. In addition, patients with stage 1 disease according to the AAOMS were not treated surgically in our study, which accounts for a negative selection [3, 19]. Ruggiero et al. describe the difficulty to define vital bone with normal perfusion at the resection margins, because the complete bone is exposed to the pharmacological influence of BPs . This may also explain the wide range of success rates reported in the literature.
To the best of our knowledge, there is no study that investigated the influence of oral health and hygiene on the healing process after surgical resection of BRONJ. Surprisingly, these factors did not influence the success rate of surgical therapy of BRONJ in our examination.
The major steps towards a reduction of the rate of BRONJ are not only preventive dental measures prior and during BP therapy, but also the different schedules or limited administration of BPs . In the present study, we could demonstrate the importance of a healthy dental and oral status and the performance of parodontal treatment during BP treatment in order to delay the onset of BRONJ. However, the course of the manifestation of BRONJ is not influenced by these factors.
Conflict of interest
The authors declare that they have no conflict of interest.
- 8.Hoff A, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836PubMedCrossRefGoogle Scholar
- 10.Micheelis W, Hoffmann T, John M, Kerschbaum T, Potthoff P, Reich E, Reis U, Reiter F, Schiffner U, Schroeder E (2005) Vierte Deutsche Mundgesundheitsstudie (DMS IV). Neue Ergebnisse zu oralen Erkrankungsprävalenzen, Risikogruppen und zum zahnärztlichen Versorgungsgrad in Deutschland. Deutscher Zahnärzteverlag DÄV 31:22–25Google Scholar
- 12.Hoff A, Toth BB, Altundag K, Guarneri V, Adamus A, Nooka AK, Sayegh GG, Johnson MM, Gagel RF, Hortobagyi GN (2006) Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy. ASCO Annual Meeting Proceedings (post meeting edition). J Clin Oncol 24:8528Google Scholar
- 14.Ripamonti C, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E (2008) Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20:137–145PubMedCrossRefGoogle Scholar
- 19.AAOMS, 2007, American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 369–376Google Scholar