Odontology DOI 10.1007/s10266-015-0207-4
ORIGINAL ARTICLE
Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients Akira Matsuo1 • Hayato Hamada2 • Hidetoshi Takahashi2 • Ayako Okamoto2 Hiroshi Kaise3 • Daichi Chikazu2
•
Received: 25 January 2015 / Accepted: 30 March 2015 Ó The Society of The Nippon Dental University 2015
Abstract It remains unclear whether dental implants are a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We retrospectively evaluated the status of dental implants in patients given intravenous bisphosphonates (BPs) in a breast cancer cohort to elucidate the risk for BRONJ at the implant site. We established a BRONJ oral monitoring program for 247 breast cancer patients given intravenous BP in our institution. The 3-year cumulative incidence rate was determined. The systemic and local risk factors of 44 patients who completed comprehensive oral examinations were evaluated by logistic regression analysis. The 3-year cumulative incidence rate of the 247 patients was 0.074 % (8/ 247, 95 % CI 0.0081–0.014). In the 44 orally examined patients, 6 (13.6 %: 6/44) had dental implants. Of these 6 patients, 1 developed BRONJ at the implant site. There were no significant differences in the age, total BP treatment period, number of residual teeth, time of regular oral monitoring, oral hygiene level, or dental implant insertion. Although a case of ONJ was identified, dental implants which were inserted before intravenous BP administration were not a risk factor for the development of ONJ in breast cancer patients.
& Akira Matsuo [email protected] 1
Department of Oral and Maxillofacial Surgery, Ibaraki Medical Center, Tokyo Medical University, 3-20-1 Chuo, Amimachi, Inashikigun, Ibaraki 300-3095, Japan
2
Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
3
Department of Breast Oncology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Keywords Bisphosphonates Osteonecrosis Jaw Implant Risk factor
Introduction Bisphosphonates (BPs) are widely used to prevent skeletalrelated events in patients with various diseases, particularly osteoporosis [1] and solid cancers with bone metastasis [2]. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been widely recognized as a severe adverse reaction to BPs owing to its unresponsiveness to treatment [3–6]. Both dental implants and BPs are currently very common treatments in adult patients. There is, however, an increasing concern regarding the consequences of placing dental implants in patients taking BPs, most of which are related to the effects of the administered BPs on oral implant therapy [7]. In particular, type IV intravenous BPs (zoledronate and pamidronate) are the strongest BP group, and the frequency of BRONJ is reportedly higher after intravenous BP than after oral BP [7]. Therefore, many reports on BRONJ have indicated that oral BP is not a contraindication for implant therapy; however, some studies do not recommend dental implant insertion in patients who receive intravenous BP [3–6]. Moreover, a recent systematic review showed that the history of oral and intravenous BP use is not an absolute contraindication for dental implant placement [8]. Over the past few years, treatments of bone metabolic disease have greatly changed with the development of new drugs for severe BP complications, mainly BRONJ [3–6], and atypical subtrochanteric and diaphyseal femoral fracture [9]. AAOMS changed the name of the disease from BRONJ to medication-related osteonecrosis of the jaw (MRONJ) [3]. For patients with benign lesions, particularly
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osteoporosis, it is possible to select other drugs to prevent the development of BRONJ, for example, selective Estrogen Receptor Modulator (SERM) which does not increase the risk for ONJ [10], or parathyroid hormone (PTH) which was reported to improve BRONJ in several studies [11, 12]. However, for patients with malignancy, ONJ has been reported in both denosumab-administered and BP-administered patients [13]. PTH administration in cancer patients is contraindicated because of their carcinogenesis [14], and SERM is usually used only for osteoporosis [15]. Therefore, the potential risk for osteonecrosis is inevitable in cancer patients. In previous studies, BRONJ was induced at the implant site in both orally and intravenously administered BP patients [16–18]. In contrast, other studies that evaluated the incidence of BRONJ in a case series of oral BP administration after dental implant insertion showed no development of BRONJ [19, 20]. However, a recent case–control study of middleaged women has shown an increasing risk of dental implant failure associated with oral BP [21]. Information regarding the frequency or natural history of BRONJ at the implant site in association with intravenous BP has remained scarce. Therefore, it is not clear whether dental implants are actual risk factors for the development of osteonecrosis as well as the natural history of implants in patients intravenously administered with BPs because no cohort-based studies of intravenous BP have been performed. In our institution, an oral monitoring program of BRONJ incidence for all breast cancer patients who received intravenous BP treatment has been put in place. This serves as a collaborative program among breast oncologists and oral and maxillofacial surgeons, in which several risk factors for BRONJ using this cohort in a single center have been evaluated [22]. In this study, we retrospectively evaluated the status of dental implants in breast cancer patients who received intravenous BPs using the same cohort that we previously investigated, and clarified the natural history of implants in patients administered with intravenous BPs in a single cohort of breast cancer patients.
Materials and methods Patients There were 274 breast cancer patients who visited and received intravenous BPs in our institution between 2002 and 2009. Our monitoring program was initiated from November 2005. Therefore, 27 patients who had died before the monitoring time were excluded from the study. The remaining 247 eligible patients were given 4 mg of zoledronic acid, 45 mg of pamidronate or 10 mg of
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ibandronic acid intravenously every 4 weeks. They were managed in our monitoring program until 2009. All eligible patients were Japanese, and no patients had metastasis or had received previous irradiation to the jaw bone. All patients gave their informed consent and the Ethics Committee of Tokyo Medical University approved the research study protocol (No. 1570). Details of the 247 patients of this cohort and our oral monitoring program were described previously [22]. In brief, with regard to our oral monitoring program, breast oncologists initially informed patients about BRONJ, conducted a medical interview regarding their oral and maxillofacial conditions, and if possible, performed oral examination, including dentition assessment. Patients were referred to the Department of Oral and Maxillofacial Surgery when they met the following criteria: (1) an intraoral or jaw bone problem was suspected and (2) if they agree to participate in the present study. Comprehensive intraoral examinations were then performed by a qualified oral and maxillofacial surgeon (A.M.). Subsequently, further detailed examinations were performed for suspected BRONJ patients, followed by the administration of suitable treatments. Routine follow-up was continued for all patients as long as possible. For nonparticipants, breast oncologists continued the medical interview in their routine medical examination for as long as possible. Clinical evaluations Cumulative hazard was evaluated from the clinical data of the eligible 247 patients between 2002 and June 2010 before starting denosumab administration in our hospital, which were retrospectively extracted from the patient files. Risk evaluation was performed using the clinical data of 44 oral monitoring cases. A case–control study of the systemic and local risk factors of the 44 patients who visited the Department of Oral and Maxillofacial Surgery from our single cohort was performed. The patients were divided into 2 groups: 6 patients with a dental implant and 38 without a dental implant. BRONJ diagnosis was based on the American Association of Oral and Maxillofacial Surgeons (AAOMS) criteria [3]. Age, BP treatment period, and types of BP were designated as systemic risk factors. The types of BP used were classified into 2 groups: zoledronic acid only (zoledronate group); pamidronate or ibandronic acid followed by zoledronic acid (zoledronate and other BP groups). The number of remaining teeth, oral hygiene level, and the dental implants were considered as local risk factors. Oral hygiene was classified into 3 categories (i.e., good, fair, and poor) based on the consensus of 1 dentist and 1 dental hygienist.
Odontology
Statistical analysis The time to BRONJ development was determined using the Kaplan–Meier method. The proportion of the 247 eligible patients without BRONJ was calculated, and the 3-year cumulative hazard was estimated. All continuous variables were presented as mean ± standard deviation. These variables were compared between the 2 groups with and without dental implants. The unpaired t test was used for analysis of the continuous variables, and the Chi-squared test was used for the categorical variables. Age, BP treatment period, types of BP, number of remaining teeth, oral hygiene level, and dental implant insertion were selected as independent variables, and each subject was evaluated for BRONJ by logistic regression analysis. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) v16.0 (SPSS, Chicago, IL). A P value of \0.05 was considered to indicate a statistically significant difference.
Results Clinical course of BRONJ in breast cancer patients The average age of the 247 eligible patients (246 women and 1 man) was 58.7 years (range, 31-92). The average BP treatment period was 19.2 months (range 1–79). By June 2010, 166 patients were still alive, but 81 patients (32.8 %) already died. A total of 44 patients (17.8 %) visited the oral surgery department for comprehensive oral examination. On the final evaluation of these 247 patients, a total of 8 [crude incidence rate (CIR): 3.2 %] patients received a
Fig. 2 Cumulative hazard of BRONJ. This figure shows the proportion of patients free of BRONJ. The 3-year cumulative hazard of BRONJ was 0.74 % (95 % CI 0.0081–0.014). Up arrow a case of BRONJ at the implant site (necrotic bone was exposed after 18 months of BP administration)
diagnosis of BRONJ. In the 44 patients who underwent comprehensive oral examination, 6 (13.6 %) had dental implant insertion. All patients had implant inserted before BP administration. BRONJ developed at the implant site in 1 of the 6 patients and at a distant site from the dental implants in 2 patients (Fig. 1). The 3-year cumulative hazard of BRONJ in this cohort was 0.074 % (95 % CI 0.0081–0.014: 8/247). BRONJ at the implant site occurred after 18 months (Fig. 2). Risk factors for BRONJ The average age of the 44 patients was 56.9 ± 9.7 years. The BP treatment period was 27.0 ± 19.9 months. The total protein (TP) level was 7.3 ± 2.4 g/dl, the number of remaining teeth was 22.2 ± 7.4, and the period between BP start and the first visit at the oral surgery department was 14 ± 14 months. Zoledronate was administered alone in 23 patients, whereas zoledronate and other BPs were given in 21 patients. Regarding the performance status, stage 0 consisted of 25 patients and stages 1–4 consisted of 19 patients. There were 11 patients with good, 26 with fair, and 7 with poor oral hygiene. There were no cases of extraction after BP medication, and 10 cases had dental infection disease. There were no significant differences in all variables between the patients with and without dental implants (Table 1). Logistic regression analysis showed that all the variables were not significant risk factors for BRONJ, including the dental implants (Table 2). Clinical status of patients with dental implants (Table 3)
Fig. 1 Clinical course of eligible patients. Asterisks a case of BRONJ at the implant site. Double asterisks the crude incidence rate of BRONJ was 3.2 % (8/247)
Of the 6 patients with dental implants, the average followup period of the oral status was 24 (range 8–50) months. In
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Odontology Table 1 Characteristics of breast cancer patients who received intravenous bisphosphonate with and without dental implants Risk factors
(Unit)
With dental implant (n = 6)
Without dental implant (n = 38)
P value
Age
Years
56.5
(48 \ 62)
57
(42 \ 86)
0.88
Total protein
g/dl
6.8
(6.4 \ 7.1)
7.4
(5.1 \ 7.8)
0.59
BP treatment period
Months
26.6
(1 \ 66)
30.4
(7 \ 66)
0.92
BP types
Zoledronate only
5
18
Zoledronate and others
1
20
Residual tooth
Number
18.7
Oral hygiene
Good
2
9
Fair
3
23
Poor Yes
1 3 (1a)
6 5
No
3
33
Systemic factors
0.18
Local factors
BRONJ
(0 \ 27)
22.9
(1 \ 28)
0.37 0.88
0.12
BP Bisphosphonate a
BRONJ at the implant site
Table 2 Logistic regression analysis of risk factors for BRONJ in breast cancer patients who received intravenous bisphosphonate SE
P value
Odds ratio
95 % CI
Age
0.54
0.687
1.02
0.92–1.14
BP treatment period BP types
0.29 1.3
0.5 0.84
1.02 0.77
0.96–1.08 0.06–9.78
Remaining tooth
0.6
0.9
0.9
0.80–1.0
Oral hygiene
0.98
0.05
6.7
0.98–45.60
Implants
1.31
0.08
0.1
0.08–1.34
these 6 patients, 4 died. All the patients were administrated with only zoledronate. BRONJ developed at the implant site in 1 patient after 18 months of BP administration. BP was stopped and her bone exposure was cured by marginal resection, including all dental implants (Fig. 3). BP administration was continued for residual cases, with accompanying change in the BP administration interval. BRONJ developed at a site distant from the implant areas in 2 patients. Although a regular follow-up was not achieved in most patients, implantitis or bone resorption at the implant site was not observed during the follow-up period even if the adjacent tooth was deflexed (Fig. 4).
Discussion Although several reports have recommended the non-insertion of dental implants in patients administered with intravenous BP [3–6], this recommendation was not always followed. In fact, other studies have reported that many patients given intravenous BP had dental implant insertion
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and eventually developed BRONJ at the implant site [16– 18]. Moreover, ‘‘Blue rose’’ cases, in which dental implants were inserted after administering intravenous BP, were precisely investigated in some studies [16, 18]. Holzinger et al. [23] reported that the insertion of dental implants during or after BP treatment accelerated the development of BRONJ, but this occurred less frequently when the implant had been inserted before BP therapy had been started. Therefore, it is important to clarify the status and the natural history of BRONJ at the implant site in patients administered with intravenous BP. However, the patients in those previous studies had various primary diseases and administration routes (intravenous or oral). To the best of our knowledge, the present study is the first to evaluate the status of dental implants in patients given intravenous BP and who had a single primary disease in a single cohort. Notably, more than 13.6 % of the patients who underwent oral examination had inserted dental implants. We speculated that the reason for the higher frequency of dental implants in the subject patients administered with BP was a missing tooth occurring mainly after the middle age [22]. Improvement of oral hygiene has been shown to reduce the frequency of BRONJ [24, 25], and the cumulative incidence in the present study was low. However, BRONJ may also develop at a relatively early time at the implant site. Therefore, when dentists examine the oral status of BP-administered patients, the dentition must be carefully checked by X-ray examination whether dental implants were inserted or not. Many systemic and local factors have been considered to be risk factors for BRONJ [26]. Dental implants have also been evaluated whether they are potential risk factors for BRONJ [5, 7]. Our previous study using the same
No change – Yes (42) Follow-up
b
Classification of BRONJ according to AAOMS a
There was no period of treatment interruption of more than 6 months during the follow-up period
Continue BP Crown No 5 47–46 – 48 6
66
61 5
35–37
Remove Cure No (8) Marginal Resection Stop until resection Bridge Implantitis 3 46–44 (2)
62 4
18
52 3
7
–
Infection
46–44
No change – No (10) Follow-up Continue BP Broken 2 mm on 1 fixture 2 36, -37
No change No change No (50) Follow-up Continue BP Crown No 3
56 2
53
–
60
4
17 (1)
Spontaneous
46, -45, 36
No change – No (15) Follow-up Change the BP interval Full bridge 3 mm on 1 fixture 4 46–36
No change Natural healing No (20) Follow-up Continue BP Crown No 2 47, 37 Spontaneous 48 (1)
Bone resorption Number
1
8
BRONJ Bone metastasis Site
Restoration
Treatment Implant Cause
BRONJ site (classa) BP period (months) Age (years) Case
Table 3 Clinical status of dental implants of breast cancer patients who received intravenous bisphosphonate
Oral a jaw bone
Regular follow-up (period)b
Prognosis
Implant
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present cohort showed that the correlations of BRONJ with all systemic factors were significantly low. Such correlation was, however, significantly high with many local factors, particularly oral hygiene and dental infectious disease [22]. However, our present results using the same cohort showed that it was not possible to determine conclusively whether dental implants were a significant risk factor for BRONJ. Another important point when discussing the risks for BRONJ in intravenously administered BP patients is that the dose schedule of intravenous BP for cancer patients was usually monthly [2]. Recently, some studies have shown that dental implants have been successfully inserted in patients who received intravenous BP [26–28]; however, in these previous studies, intravenous BP was administered every half of the year for osteoporosis patients. Specifically, a study involving a large number of cases involving half a year dose schedule for osteoporosis patients showed no determined BRONJ patients for 3 years, although there were 3 suspected patients [29]. The risk for BRONJ increased according to the BP administration time and accumulation quantity [30], and that the systemic conditions between cancer and osteoporosis patients were greatly different. The risks for BRONJ induced by intravenous BP should therefore be carefully evaluated separately by month and by half a year schedule, as both primary disease and cumulative dose were completely different between the 2 usages. In the present study, we discussed dental implants that have already been inserted in cancer patients who received intravenous BP, because all implants were inserted before BP administration and there were no cases of insertion of new dental implants. In these patients, the risk for BRONJ without any regard for surgery-related complications can be evaluated. However, dental inflammation was reported to be a risk factor for BRONJ [3], and the development of infection also represented a significant risk for the onset of peri-implantitis and implant loss [31]. Therefore, BP-administered patients with a dental implant have 2 risk factors, implantitis and BRONJ. Improvement of oral hygiene has been shown to reduce the frequency of BRONJ [24, 25], and anti-infective preventive measures improved the risk of implantitis [31]. Kwon et al. [16] reported that histologically en bloc sequestration of bone with the dental implant might be one of the characteristic features of implant-related BRONJ, which is different from peri-implantitis-induced bone destruction. Several studies including the present case confirmed this feature, in which even the dental implants have already been affected by BRONJ [16, 18, 32]. Interestingly, the present study showed that although BRONJ developed in other areas, implantitis or bone resorption was not observed at the implant sites during the follow-up period in 2 patients. These findings implied that the dental implants have shown
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Fig. 3 A case of BRONJ at the implant site. Case 5 was a 61-yearold woman in whom a fixture was inserted in 2006. Bone resorption was not observed until February 2008. Administration of zoledronic acid was started from July 2008. Her breast oncologist noted her oral problem, and stopped BP on February 2009. a At the first visit of the patient, diffuse swelling and redness of the gum were observed at the implant area, but no bone exposure was seen. b Sclerotic and osteolytic changes around the dental implants were seen on X-ray
examination (stage 0). c After 4 months of conservative treatment, the symptoms were reduced but not cured, and necrotic bone was observed (arrow, Stage 2). d The necrotic bone was not completely sequestrated. e Marginal resection was performed, and the dental implants were observed to be tightly adhered to the necrotic bone at surgery. f After surgery, the wound was completely closed and no postoperative symptom developed
more resistibility against BRONJ than the native tooth. It could be speculated that even if the dental implant was already affected by the implantitis or BRONJ, this would be difficult to detect earlier because the dental implant was tightly attached to the surrounding bone without mobility or bone resorption. Notably, the survival time in breast or prostatic cancer patients after metastasis is relatively long [33]; however, 32.8 % of the subject patients died during the follow-up period and there were few patients in whom we were able to continue regular oral monitoring in our cohort [22]. The same tendency was shown in another study of intravenous BP treatment in breast cancer patients [34]. Moreover, we previously reported that the activities of daily living (ADL) of these patients were gradually decreased during the follow-up period [22]. The ADL of these patients decreased not only with BP administration but also with routine chemotherapy, which is the standard
therapeutic strategy for patients with bone metastatic cancer [35]. Therefore, dental implants that were inserted before BP administration were not a risk factor for the development of ONJ in breast cancer patients; however, it is difficult to achieve good oral hygiene measure because of the short life time and low ADL of the patients. At this point, it is best to determine the optimal treatment option for cancer patients with BRONJ at the implant site. Conservative treatment has been the usual recommended therapy for patients with BRONJ [3–6]. However, the high success rate of surgical treatments has recently been reported [36–39]. Lazarovici et al. [18] have reported that the complete response rate for BRONJ treatment was similar between patients in whom the dental implants were removed and patients in whom the dental implants were not removed. When selecting the surgical procedure, en bloc resection including the dental implant is needed
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Fig. 4 BRONJ occurrence at a site distant from the implant areas. Case 3 was a 53-year-old woman. a Her first oral monitoring was performed 3 months after BP administration and bone exposure was not observed. b The patient did not visit the oral surgery department until bone exposure on her left palatal area at 39 months after first
oral examination. c Since then, the BRONJ was not cured, causing tooth defluxion next to the dental implant (arrow). No clinical symptoms or bone resorption was, however, observed at the implant site until the final evaluation at 50 months after first oral examination
because the dental implant is tightly connected to the surrounding bone [16]. In the present study, we selected surgical treatment for a patient with BRONJ because conservative treatment was not effective, the lesion area was relatively obvious, and the patient’s ADL was normal. On the other hand, conservative treatment would be a first choice for the patients with low ADL because dental implants could be used functionally without being mobile, even if it may be difficult to cure the BRONJ. It is therefore important to consider not only the local status but also the systemic conditions when designing the treatment strategies for BRONJ, particularly with regard to surgical procedures. This study has several limitations. First, not all patients received a comprehensive oral examination. We would expect a slightly higher incidence of BRONJ in a prospective study in which every patient receives a comprehensive oral examination as asymptomatic BRONJ cases are now frequently reported [40]. Second, the number of patients examined was small. Age and drug duration are frequently recognized as risk factors for ONJ development, and third, however, the treatment period and age in this study were not significantly associated with ONJ development because of the small population size examined. Although this presents difficulty in drawing a statistically clear conclusion, this study calls our attention to the need for careful monitoring of patients with dental implants treated with BP for BRONJ development. To the best of our knowledge, there has been no study to evaluate cancer
patients administered with intravenous BP based on a single cohort. Our next step is to perform a large-scale study involving a larger number of patients and multiple drugs using a multicenter prospective cohort. In conclusion, although a case of ONJ was identified, dental implants that were inserted before BP administration were not a risk factor for the development of ONJ in breast cancer patients. Acknowledgments The authors are grateful to Dr. Edward Barroga, Associate Professor and Senior Medical Editor of the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the manuscript. Conflict of interest All authors declare that they have no conflict of interest associated with this study. All patients gave their informed consent and the Ethics Committee of Tokyo Medical University approved the research study protocol.
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undergoing bisphosphonate treatment. Clin Oral Implants Res. 2014;25:632–40. Jacobsen C, Metzler P, Roossle M, Obwegeser J, Zemann W, Gratz KW. Osteopathology induced by bisphosphonates and dental implants: clinical observations. Clin Oral Invest. 2013;17:167–75. Lazarovici TS, Yahalom R, Taicher S, Schwartz-Arad D, Peleg O, Yarom N. Bisphosphonate-related osteonecrosis of the jaw associated with dental implants. J Oral Maxillofac Surg. 2010;68:790–6. Fugazzotto PA, Lightfoot WS, Jaffin R, Kumar A. Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates. Postoperative healing, early follow-up, and the incidence of complications in two private practices. J Periodontol. 2007;78:1664–9. Grant B-T, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates. A review of 115 cases. J Oral Maxillofac Surg. 2008;66:223–30. Yip JK, Borrell LN, Cho S-C, Francisco H, Tarnow DP. Association between oral bisphosphonate use and dental implant failure among middle-aged women. J Clin Periodontol. 2012;39:408–14. Matsuo A, Hamada H, Kaise H, Chikazu D, Yamada K, Kohno N. Characteristics of the early stages of intravenous bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer. Acta Odontol Scand. 2014;72:656–63. Holzinger D, Seemann R, Matoni N, Ewers R, Millesi W, Wutzl A. Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2014;72:e1–8. Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, Bamias A. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009;20:117–20. Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E. 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. 2009;20:137–45. Vescovi P, Campisi G, Fusco V, Mergoni G, Manfredi M, Merigo E, Solazzo L, Gabriele M, Gaeta GM, Favia G, Peluso F, Colella G. Surgery-triggered and non surgery-triggered bisphosphonaterelated osteonecrosis of the jaws (BRONJ): a retrospective analysis of 567 cases in an Italian multicenter study. Oral Oncol. 2011;47:191–4. Mattheos N, Caldwell P, Petcu EB, Ivanovski S, Reher P. Dental implant placement with bone augmentation in a patient who received intravenous bisphosphonate treatment for osteoporosis. J Can Dent Assoc. 2013;79:d2. Siebert T, Jurkovic R, Statelova D, Strecha J. Immediate implant placement in and a patient with osteoporosis undergoing patient using bisphosphonate therapy: 1-year preliminary prospective study. J Oral Implantol. 2013;39:510–20. Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol. 2010;21:2188–94. Hoff AO, 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. Frequency and risk factors associated with osteonecrosis of the Jaw in cancer patients
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treated with intravenous bisphosphonate. J Bone Miner Res. 2008;23:826–36. Salvi GE, Zitzmann NU. The effects of anti-infective preventive measures on the occurrence of biologic implant complications and implant loss: a systematic review. Int J Oral Maxillofac Implants. 2014;29(Suppl):292–307. Marx RE. Oral and intravenous bisphosphonate-induced osteonecrosis of the Jaws. History, etiology, prevention, and treatment. Illinois: Quintessence Publishing Co.; 2007. p. 128–32. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(Suppl):1588–94. Van den Wyngaert T, Claeys T, Huizing M, Vermorken JB, Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol. 2009;20:331–6. National Comprehensive Cancer Network: Practice guidelines in oncology v. 2. 2007. (http://www.Nccn.org/professionals/physi cian-gls/PDF/breast.pdf). Accessed 2 Aug 2014.
36. Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, Nocini PF, Blandamura S. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol. 2009;47:420–4. 37. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67(Suppl 1):85–95. 38. Williamson RA. Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg. 2010;39:251–5. 39. Abu-Id MH, Warnke PH, Gottschalk J, Springer I, Wiltfang J, Acil Y, Russo PA, Kreusch T. ‘‘Bisphossy jaws’’—high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Cranio Maxillofac Surg. 2008;36:95–103. 40. Hess LM, Jeter JM, Benham-Hutchins M, Alberts DS. Factors associated with osteonecrosis of the jaw among bisphosphonate users. Am J Med. 2008;121:475–83.
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ORIGINAL ARTICLE
Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients Akira Matsuo1 • Hayato Hamada2 • Hidetoshi Takahashi2 • Ayako Okamoto2 Hiroshi Kaise3 • Daichi Chikazu2
•
Received: 25 January 2015 / Accepted: 30 March 2015 Ó The Society of The Nippon Dental University 2015
Abstract It remains unclear whether dental implants are a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We retrospectively evaluated the status of dental implants in patients given intravenous bisphosphonates (BPs) in a breast cancer cohort to elucidate the risk for BRONJ at the implant site. We established a BRONJ oral monitoring program for 247 breast cancer patients given intravenous BP in our institution. The 3-year cumulative incidence rate was determined. The systemic and local risk factors of 44 patients who completed comprehensive oral examinations were evaluated by logistic regression analysis. The 3-year cumulative incidence rate of the 247 patients was 0.074 % (8/ 247, 95 % CI 0.0081–0.014). In the 44 orally examined patients, 6 (13.6 %: 6/44) had dental implants. Of these 6 patients, 1 developed BRONJ at the implant site. There were no significant differences in the age, total BP treatment period, number of residual teeth, time of regular oral monitoring, oral hygiene level, or dental implant insertion. Although a case of ONJ was identified, dental implants which were inserted before intravenous BP administration were not a risk factor for the development of ONJ in breast cancer patients.
& Akira Matsuo [email protected] 1
Department of Oral and Maxillofacial Surgery, Ibaraki Medical Center, Tokyo Medical University, 3-20-1 Chuo, Amimachi, Inashikigun, Ibaraki 300-3095, Japan
2
Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
3
Department of Breast Oncology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Keywords Bisphosphonates Osteonecrosis Jaw Implant Risk factor
Introduction Bisphosphonates (BPs) are widely used to prevent skeletalrelated events in patients with various diseases, particularly osteoporosis [1] and solid cancers with bone metastasis [2]. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been widely recognized as a severe adverse reaction to BPs owing to its unresponsiveness to treatment [3–6]. Both dental implants and BPs are currently very common treatments in adult patients. There is, however, an increasing concern regarding the consequences of placing dental implants in patients taking BPs, most of which are related to the effects of the administered BPs on oral implant therapy [7]. In particular, type IV intravenous BPs (zoledronate and pamidronate) are the strongest BP group, and the frequency of BRONJ is reportedly higher after intravenous BP than after oral BP [7]. Therefore, many reports on BRONJ have indicated that oral BP is not a contraindication for implant therapy; however, some studies do not recommend dental implant insertion in patients who receive intravenous BP [3–6]. Moreover, a recent systematic review showed that the history of oral and intravenous BP use is not an absolute contraindication for dental implant placement [8]. Over the past few years, treatments of bone metabolic disease have greatly changed with the development of new drugs for severe BP complications, mainly BRONJ [3–6], and atypical subtrochanteric and diaphyseal femoral fracture [9]. AAOMS changed the name of the disease from BRONJ to medication-related osteonecrosis of the jaw (MRONJ) [3]. For patients with benign lesions, particularly
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osteoporosis, it is possible to select other drugs to prevent the development of BRONJ, for example, selective Estrogen Receptor Modulator (SERM) which does not increase the risk for ONJ [10], or parathyroid hormone (PTH) which was reported to improve BRONJ in several studies [11, 12]. However, for patients with malignancy, ONJ has been reported in both denosumab-administered and BP-administered patients [13]. PTH administration in cancer patients is contraindicated because of their carcinogenesis [14], and SERM is usually used only for osteoporosis [15]. Therefore, the potential risk for osteonecrosis is inevitable in cancer patients. In previous studies, BRONJ was induced at the implant site in both orally and intravenously administered BP patients [16–18]. In contrast, other studies that evaluated the incidence of BRONJ in a case series of oral BP administration after dental implant insertion showed no development of BRONJ [19, 20]. However, a recent case–control study of middleaged women has shown an increasing risk of dental implant failure associated with oral BP [21]. Information regarding the frequency or natural history of BRONJ at the implant site in association with intravenous BP has remained scarce. Therefore, it is not clear whether dental implants are actual risk factors for the development of osteonecrosis as well as the natural history of implants in patients intravenously administered with BPs because no cohort-based studies of intravenous BP have been performed. In our institution, an oral monitoring program of BRONJ incidence for all breast cancer patients who received intravenous BP treatment has been put in place. This serves as a collaborative program among breast oncologists and oral and maxillofacial surgeons, in which several risk factors for BRONJ using this cohort in a single center have been evaluated [22]. In this study, we retrospectively evaluated the status of dental implants in breast cancer patients who received intravenous BPs using the same cohort that we previously investigated, and clarified the natural history of implants in patients administered with intravenous BPs in a single cohort of breast cancer patients.
Materials and methods Patients There were 274 breast cancer patients who visited and received intravenous BPs in our institution between 2002 and 2009. Our monitoring program was initiated from November 2005. Therefore, 27 patients who had died before the monitoring time were excluded from the study. The remaining 247 eligible patients were given 4 mg of zoledronic acid, 45 mg of pamidronate or 10 mg of
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ibandronic acid intravenously every 4 weeks. They were managed in our monitoring program until 2009. All eligible patients were Japanese, and no patients had metastasis or had received previous irradiation to the jaw bone. All patients gave their informed consent and the Ethics Committee of Tokyo Medical University approved the research study protocol (No. 1570). Details of the 247 patients of this cohort and our oral monitoring program were described previously [22]. In brief, with regard to our oral monitoring program, breast oncologists initially informed patients about BRONJ, conducted a medical interview regarding their oral and maxillofacial conditions, and if possible, performed oral examination, including dentition assessment. Patients were referred to the Department of Oral and Maxillofacial Surgery when they met the following criteria: (1) an intraoral or jaw bone problem was suspected and (2) if they agree to participate in the present study. Comprehensive intraoral examinations were then performed by a qualified oral and maxillofacial surgeon (A.M.). Subsequently, further detailed examinations were performed for suspected BRONJ patients, followed by the administration of suitable treatments. Routine follow-up was continued for all patients as long as possible. For nonparticipants, breast oncologists continued the medical interview in their routine medical examination for as long as possible. Clinical evaluations Cumulative hazard was evaluated from the clinical data of the eligible 247 patients between 2002 and June 2010 before starting denosumab administration in our hospital, which were retrospectively extracted from the patient files. Risk evaluation was performed using the clinical data of 44 oral monitoring cases. A case–control study of the systemic and local risk factors of the 44 patients who visited the Department of Oral and Maxillofacial Surgery from our single cohort was performed. The patients were divided into 2 groups: 6 patients with a dental implant and 38 without a dental implant. BRONJ diagnosis was based on the American Association of Oral and Maxillofacial Surgeons (AAOMS) criteria [3]. Age, BP treatment period, and types of BP were designated as systemic risk factors. The types of BP used were classified into 2 groups: zoledronic acid only (zoledronate group); pamidronate or ibandronic acid followed by zoledronic acid (zoledronate and other BP groups). The number of remaining teeth, oral hygiene level, and the dental implants were considered as local risk factors. Oral hygiene was classified into 3 categories (i.e., good, fair, and poor) based on the consensus of 1 dentist and 1 dental hygienist.
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Statistical analysis The time to BRONJ development was determined using the Kaplan–Meier method. The proportion of the 247 eligible patients without BRONJ was calculated, and the 3-year cumulative hazard was estimated. All continuous variables were presented as mean ± standard deviation. These variables were compared between the 2 groups with and without dental implants. The unpaired t test was used for analysis of the continuous variables, and the Chi-squared test was used for the categorical variables. Age, BP treatment period, types of BP, number of remaining teeth, oral hygiene level, and dental implant insertion were selected as independent variables, and each subject was evaluated for BRONJ by logistic regression analysis. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) v16.0 (SPSS, Chicago, IL). A P value of \0.05 was considered to indicate a statistically significant difference.
Results Clinical course of BRONJ in breast cancer patients The average age of the 247 eligible patients (246 women and 1 man) was 58.7 years (range, 31-92). The average BP treatment period was 19.2 months (range 1–79). By June 2010, 166 patients were still alive, but 81 patients (32.8 %) already died. A total of 44 patients (17.8 %) visited the oral surgery department for comprehensive oral examination. On the final evaluation of these 247 patients, a total of 8 [crude incidence rate (CIR): 3.2 %] patients received a
Fig. 2 Cumulative hazard of BRONJ. This figure shows the proportion of patients free of BRONJ. The 3-year cumulative hazard of BRONJ was 0.74 % (95 % CI 0.0081–0.014). Up arrow a case of BRONJ at the implant site (necrotic bone was exposed after 18 months of BP administration)
diagnosis of BRONJ. In the 44 patients who underwent comprehensive oral examination, 6 (13.6 %) had dental implant insertion. All patients had implant inserted before BP administration. BRONJ developed at the implant site in 1 of the 6 patients and at a distant site from the dental implants in 2 patients (Fig. 1). The 3-year cumulative hazard of BRONJ in this cohort was 0.074 % (95 % CI 0.0081–0.014: 8/247). BRONJ at the implant site occurred after 18 months (Fig. 2). Risk factors for BRONJ The average age of the 44 patients was 56.9 ± 9.7 years. The BP treatment period was 27.0 ± 19.9 months. The total protein (TP) level was 7.3 ± 2.4 g/dl, the number of remaining teeth was 22.2 ± 7.4, and the period between BP start and the first visit at the oral surgery department was 14 ± 14 months. Zoledronate was administered alone in 23 patients, whereas zoledronate and other BPs were given in 21 patients. Regarding the performance status, stage 0 consisted of 25 patients and stages 1–4 consisted of 19 patients. There were 11 patients with good, 26 with fair, and 7 with poor oral hygiene. There were no cases of extraction after BP medication, and 10 cases had dental infection disease. There were no significant differences in all variables between the patients with and without dental implants (Table 1). Logistic regression analysis showed that all the variables were not significant risk factors for BRONJ, including the dental implants (Table 2). Clinical status of patients with dental implants (Table 3)
Fig. 1 Clinical course of eligible patients. Asterisks a case of BRONJ at the implant site. Double asterisks the crude incidence rate of BRONJ was 3.2 % (8/247)
Of the 6 patients with dental implants, the average followup period of the oral status was 24 (range 8–50) months. In
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Odontology Table 1 Characteristics of breast cancer patients who received intravenous bisphosphonate with and without dental implants Risk factors
(Unit)
With dental implant (n = 6)
Without dental implant (n = 38)
P value
Age
Years
56.5
(48 \ 62)
57
(42 \ 86)
0.88
Total protein
g/dl
6.8
(6.4 \ 7.1)
7.4
(5.1 \ 7.8)
0.59
BP treatment period
Months
26.6
(1 \ 66)
30.4
(7 \ 66)
0.92
BP types
Zoledronate only
5
18
Zoledronate and others
1
20
Residual tooth
Number
18.7
Oral hygiene
Good
2
9
Fair
3
23
Poor Yes
1 3 (1a)
6 5
No
3
33
Systemic factors
0.18
Local factors
BRONJ
(0 \ 27)
22.9
(1 \ 28)
0.37 0.88
0.12
BP Bisphosphonate a
BRONJ at the implant site
Table 2 Logistic regression analysis of risk factors for BRONJ in breast cancer patients who received intravenous bisphosphonate SE
P value
Odds ratio
95 % CI
Age
0.54
0.687
1.02
0.92–1.14
BP treatment period BP types
0.29 1.3
0.5 0.84
1.02 0.77
0.96–1.08 0.06–9.78
Remaining tooth
0.6
0.9
0.9
0.80–1.0
Oral hygiene
0.98
0.05
6.7
0.98–45.60
Implants
1.31
0.08
0.1
0.08–1.34
these 6 patients, 4 died. All the patients were administrated with only zoledronate. BRONJ developed at the implant site in 1 patient after 18 months of BP administration. BP was stopped and her bone exposure was cured by marginal resection, including all dental implants (Fig. 3). BP administration was continued for residual cases, with accompanying change in the BP administration interval. BRONJ developed at a site distant from the implant areas in 2 patients. Although a regular follow-up was not achieved in most patients, implantitis or bone resorption at the implant site was not observed during the follow-up period even if the adjacent tooth was deflexed (Fig. 4).
Discussion Although several reports have recommended the non-insertion of dental implants in patients administered with intravenous BP [3–6], this recommendation was not always followed. In fact, other studies have reported that many patients given intravenous BP had dental implant insertion
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and eventually developed BRONJ at the implant site [16– 18]. Moreover, ‘‘Blue rose’’ cases, in which dental implants were inserted after administering intravenous BP, were precisely investigated in some studies [16, 18]. Holzinger et al. [23] reported that the insertion of dental implants during or after BP treatment accelerated the development of BRONJ, but this occurred less frequently when the implant had been inserted before BP therapy had been started. Therefore, it is important to clarify the status and the natural history of BRONJ at the implant site in patients administered with intravenous BP. However, the patients in those previous studies had various primary diseases and administration routes (intravenous or oral). To the best of our knowledge, the present study is the first to evaluate the status of dental implants in patients given intravenous BP and who had a single primary disease in a single cohort. Notably, more than 13.6 % of the patients who underwent oral examination had inserted dental implants. We speculated that the reason for the higher frequency of dental implants in the subject patients administered with BP was a missing tooth occurring mainly after the middle age [22]. Improvement of oral hygiene has been shown to reduce the frequency of BRONJ [24, 25], and the cumulative incidence in the present study was low. However, BRONJ may also develop at a relatively early time at the implant site. Therefore, when dentists examine the oral status of BP-administered patients, the dentition must be carefully checked by X-ray examination whether dental implants were inserted or not. Many systemic and local factors have been considered to be risk factors for BRONJ [26]. Dental implants have also been evaluated whether they are potential risk factors for BRONJ [5, 7]. Our previous study using the same
No change – Yes (42) Follow-up
b
Classification of BRONJ according to AAOMS a
There was no period of treatment interruption of more than 6 months during the follow-up period
Continue BP Crown No 5 47–46 – 48 6
66
61 5
35–37
Remove Cure No (8) Marginal Resection Stop until resection Bridge Implantitis 3 46–44 (2)
62 4
18
52 3
7
–
Infection
46–44
No change – No (10) Follow-up Continue BP Broken 2 mm on 1 fixture 2 36, -37
No change No change No (50) Follow-up Continue BP Crown No 3
56 2
53
–
60
4
17 (1)
Spontaneous
46, -45, 36
No change – No (15) Follow-up Change the BP interval Full bridge 3 mm on 1 fixture 4 46–36
No change Natural healing No (20) Follow-up Continue BP Crown No 2 47, 37 Spontaneous 48 (1)
Bone resorption Number
1
8
BRONJ Bone metastasis Site
Restoration
Treatment Implant Cause
BRONJ site (classa) BP period (months) Age (years) Case
Table 3 Clinical status of dental implants of breast cancer patients who received intravenous bisphosphonate
Oral a jaw bone
Regular follow-up (period)b
Prognosis
Implant
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present cohort showed that the correlations of BRONJ with all systemic factors were significantly low. Such correlation was, however, significantly high with many local factors, particularly oral hygiene and dental infectious disease [22]. However, our present results using the same cohort showed that it was not possible to determine conclusively whether dental implants were a significant risk factor for BRONJ. Another important point when discussing the risks for BRONJ in intravenously administered BP patients is that the dose schedule of intravenous BP for cancer patients was usually monthly [2]. Recently, some studies have shown that dental implants have been successfully inserted in patients who received intravenous BP [26–28]; however, in these previous studies, intravenous BP was administered every half of the year for osteoporosis patients. Specifically, a study involving a large number of cases involving half a year dose schedule for osteoporosis patients showed no determined BRONJ patients for 3 years, although there were 3 suspected patients [29]. The risk for BRONJ increased according to the BP administration time and accumulation quantity [30], and that the systemic conditions between cancer and osteoporosis patients were greatly different. The risks for BRONJ induced by intravenous BP should therefore be carefully evaluated separately by month and by half a year schedule, as both primary disease and cumulative dose were completely different between the 2 usages. In the present study, we discussed dental implants that have already been inserted in cancer patients who received intravenous BP, because all implants were inserted before BP administration and there were no cases of insertion of new dental implants. In these patients, the risk for BRONJ without any regard for surgery-related complications can be evaluated. However, dental inflammation was reported to be a risk factor for BRONJ [3], and the development of infection also represented a significant risk for the onset of peri-implantitis and implant loss [31]. Therefore, BP-administered patients with a dental implant have 2 risk factors, implantitis and BRONJ. Improvement of oral hygiene has been shown to reduce the frequency of BRONJ [24, 25], and anti-infective preventive measures improved the risk of implantitis [31]. Kwon et al. [16] reported that histologically en bloc sequestration of bone with the dental implant might be one of the characteristic features of implant-related BRONJ, which is different from peri-implantitis-induced bone destruction. Several studies including the present case confirmed this feature, in which even the dental implants have already been affected by BRONJ [16, 18, 32]. Interestingly, the present study showed that although BRONJ developed in other areas, implantitis or bone resorption was not observed at the implant sites during the follow-up period in 2 patients. These findings implied that the dental implants have shown
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Fig. 3 A case of BRONJ at the implant site. Case 5 was a 61-yearold woman in whom a fixture was inserted in 2006. Bone resorption was not observed until February 2008. Administration of zoledronic acid was started from July 2008. Her breast oncologist noted her oral problem, and stopped BP on February 2009. a At the first visit of the patient, diffuse swelling and redness of the gum were observed at the implant area, but no bone exposure was seen. b Sclerotic and osteolytic changes around the dental implants were seen on X-ray
examination (stage 0). c After 4 months of conservative treatment, the symptoms were reduced but not cured, and necrotic bone was observed (arrow, Stage 2). d The necrotic bone was not completely sequestrated. e Marginal resection was performed, and the dental implants were observed to be tightly adhered to the necrotic bone at surgery. f After surgery, the wound was completely closed and no postoperative symptom developed
more resistibility against BRONJ than the native tooth. It could be speculated that even if the dental implant was already affected by the implantitis or BRONJ, this would be difficult to detect earlier because the dental implant was tightly attached to the surrounding bone without mobility or bone resorption. Notably, the survival time in breast or prostatic cancer patients after metastasis is relatively long [33]; however, 32.8 % of the subject patients died during the follow-up period and there were few patients in whom we were able to continue regular oral monitoring in our cohort [22]. The same tendency was shown in another study of intravenous BP treatment in breast cancer patients [34]. Moreover, we previously reported that the activities of daily living (ADL) of these patients were gradually decreased during the follow-up period [22]. The ADL of these patients decreased not only with BP administration but also with routine chemotherapy, which is the standard
therapeutic strategy for patients with bone metastatic cancer [35]. Therefore, dental implants that were inserted before BP administration were not a risk factor for the development of ONJ in breast cancer patients; however, it is difficult to achieve good oral hygiene measure because of the short life time and low ADL of the patients. At this point, it is best to determine the optimal treatment option for cancer patients with BRONJ at the implant site. Conservative treatment has been the usual recommended therapy for patients with BRONJ [3–6]. However, the high success rate of surgical treatments has recently been reported [36–39]. Lazarovici et al. [18] have reported that the complete response rate for BRONJ treatment was similar between patients in whom the dental implants were removed and patients in whom the dental implants were not removed. When selecting the surgical procedure, en bloc resection including the dental implant is needed
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Fig. 4 BRONJ occurrence at a site distant from the implant areas. Case 3 was a 53-year-old woman. a Her first oral monitoring was performed 3 months after BP administration and bone exposure was not observed. b The patient did not visit the oral surgery department until bone exposure on her left palatal area at 39 months after first
oral examination. c Since then, the BRONJ was not cured, causing tooth defluxion next to the dental implant (arrow). No clinical symptoms or bone resorption was, however, observed at the implant site until the final evaluation at 50 months after first oral examination
because the dental implant is tightly connected to the surrounding bone [16]. In the present study, we selected surgical treatment for a patient with BRONJ because conservative treatment was not effective, the lesion area was relatively obvious, and the patient’s ADL was normal. On the other hand, conservative treatment would be a first choice for the patients with low ADL because dental implants could be used functionally without being mobile, even if it may be difficult to cure the BRONJ. It is therefore important to consider not only the local status but also the systemic conditions when designing the treatment strategies for BRONJ, particularly with regard to surgical procedures. This study has several limitations. First, not all patients received a comprehensive oral examination. We would expect a slightly higher incidence of BRONJ in a prospective study in which every patient receives a comprehensive oral examination as asymptomatic BRONJ cases are now frequently reported [40]. Second, the number of patients examined was small. Age and drug duration are frequently recognized as risk factors for ONJ development, and third, however, the treatment period and age in this study were not significantly associated with ONJ development because of the small population size examined. Although this presents difficulty in drawing a statistically clear conclusion, this study calls our attention to the need for careful monitoring of patients with dental implants treated with BP for BRONJ development. To the best of our knowledge, there has been no study to evaluate cancer
patients administered with intravenous BP based on a single cohort. Our next step is to perform a large-scale study involving a larger number of patients and multiple drugs using a multicenter prospective cohort. In conclusion, although a case of ONJ was identified, dental implants that were inserted before BP administration were not a risk factor for the development of ONJ in breast cancer patients. Acknowledgments The authors are grateful to Dr. Edward Barroga, Associate Professor and Senior Medical Editor of the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the manuscript. Conflict of interest All authors declare that they have no conflict of interest associated with this study. All patients gave their informed consent and the Ethics Committee of Tokyo Medical University approved the research study protocol.
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