Osteoporos Int DOI 10.1007/s00198-017-4063-7

ORIGINAL ARTICLE

A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? T. Hasegawa 1 & A. Kawakita 2 & N. Ueda 3 & R. Funahara 1 & A. Tachibana 4 & M. Kobayashi 5 & E. Kondou 6 & D. Takeda 7 & Y. Kojima 8 & S. Sato 9 & S. Yanamoto 2 & H. Komatsubara 7 & M. Umeda 2 & T. Kirita 3 & H. Kurita 6 & Y. Shibuya 9 & T. Komori 1 & Japanese Study Group of Cooperative Dentistry with Medicine (JCDM)

Received: 13 December 2016 / Accepted: 18 April 2017 # International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Abstract Summary Root amputation, extraction of a single tooth, bone loss or severe tooth mobility, and an unclosed wound were significantly associated with increased risk of developing medication-related osteonecrosis of the jaw (MRONJ). We recommend a minimally traumatic extraction technique, re-

* T. Hasegawa [email protected]

1

Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

2

Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

3

Department of Oral and Maxillofacial Surgery, Nara Medical University, Nara, Japan

4

Department of Oral and Maxillofacial Surgery, Kakogawa Central City Hospital, Kakogawa, Japan

5

Department of Oral and Maxillofacial Surgery, Shin-Suma General Hospital, Kobe, Japan

6

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Japan

7

Department of Oral and Maxillofacial Surgery, Kobe Central Hospital, Kobe, Japan

8

Department of Dentistry and Oral Surgery, Kansai Medical University, Hirakata, Japan

9

Department of Oral Maxillofacial Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

moval of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. Introduction Osteonecrosis of the jaws can occur following tooth extraction in patients receiving bisphosphonate drugs. Various strategies for minimizing the risk of MRONJ have been advanced, but no studies have comprehensively analyzed the efficacy of factors such as primary wound closure, demographics, and drug holidays in reducing its incidence. The purpose of this study was to retrospectively investigate the relationships between these various risk factors after tooth extraction in patients receiving oral bisphosphonate therapy. Methods Risk factors for MRONJ after tooth extraction were evaluated using univariate and multivariate analysis. All patients were investigated with regard to demographics; type and duration of oral bisphosphonate use; whether they underwent a discontinuation of oral bisphosphonates before tooth extraction (drug holiday), and the duration of such discontinuation; and whether any additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. Results We found that root amputation (OR = 6.64), extraction of a single tooth (OR = 3.70), bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were significantly associated with increased risk of developing MRONJ. Conclusions We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. We find no evidence supporting the efficacy of a pre-extraction short-term drug holiday from oral bisphosphonates in reducing the risk of MRONJ.

Osteoporos Int

Keywords Antibiotics administration . BRONJ . Discontinuation . Primary closure . Surgical procedure

Introduction Bisphosphonates (BPs) are inhibitors of bone resorption and are widely used for various bone diseases and complications associated with bone. Oral BPs have also been used to treat osteoporosis and osteopenia [1, 2]. Since Marx et al. first reported BP-related osteonecrosis of the jaw (BRONJ), it has been known as a complication of invasive procedures performed during BP therapy [3]. However, the exact etiopathology remains unknown. BPs mainly inhibit function and induce apoptosis in osteoclasts, resulting in a reduction in bone resorption [4]. BPs also inhibit other cell types such as osteogenic cells, endothelial cells, human fibroblasts, and macrophages [5–8], and reduce the viability of oral keratinocytes, with associated impairment in mucosal wound healing [9]. A large review by Filleul et al. concluded that tooth extraction was the main trigger factor in 67% of BRONJ cases [10]. Furthermore, a medication-related osteonecrosis of the jaw (MRONJ) position paper of the American Association of Oral and Maxillofacial Surgeons (AAOMS) concurred that tooth extraction was a common predisposing event, with 52– 61% of patients reporting tooth extraction as the precipitating event [11]. MRONJ after tooth extraction is believed to have an overall incidence rate of 0.09–0.34% [12], and a recent estimate of the risk of MRONJ in patients exposed to oral BPs after tooth extraction was 0.5% [13]. In patients requiring extractions, the concept of a drug holiday from oral BPs or denosumab has been controversial. Damm and Jones proposed several alternatives to a drug holiday from oral BPs before invasive dental treatment [14]. They noted that the level of free BP within the serum would be extremely low within 2 months of the last administration of oral BPs and that a drug holiday of 2 months before an invasive dental procedure should be adequate. Accordingly, the committee of the AAOMS recommended a modified drug holiday strategy for osteoporotic patients with extended exposure histories (>4 years) for oral BPs, although this recommendation was not supported by any firm evidence [11]. In contrast, an advisory committee from the American Dental Association (ADA) Council on Scientific Affairs and an international consensus paper did not recommend a drug holiday from oral BPs and denosumab before invasive dental procedures in osteoporosis patients [15, 16]. Additional oral surgery during tooth extraction (e.g., removal of bone edges and mucosal coverage of the wound) has also been controversial. Some investigators noted that primary intention closure of the wound in oral BP-treated patients was of little benefit [17–19], but several other studies

reported lower rates of MRONJ where primary closure was performed to minimize bone exposure [20–22]. In summary, no studies have comprehensively analyzed the influence of surgical procedure-related factors such as primary closure of the wound, demographic factors, and drug holidays on MRONJ incidence. We hypothesize that surgical procedure-related factors, such as primary closure of the wound and drug holidays, influence the occurrence of MRONJ. In this study, we investigated the multivariate relationships between these various MRONJ risk factors, including the use of a drug holiday.

Methods This was a nonrandomized, multicenter retrospective cohort study. This multicenter validation study included pooled individual patient data from nine institutions belonging to the Japanese Study Group of Co-operative Dentistry with Medicine (JCDM). Between January 2008 and December 2015, tooth extractions were performed at the following institutes: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine; Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences; Department of Oral and Maxillofacial Surgery, Nara Medical University; Department of Oral and Maxillofacial Surgery, Kakogawa Central City Hospital; Department of Oral and Maxillofacial Surgery, Shin-Suma General Hospital; Department of Dentistry and Oral Surgery, Shinshu University School of Medicine; Department of Oral and Maxillofacial Surgery, Kobe Central Hospital; Department of Dentistry and Oral Surgery, Kansai Medical University; and Nagoya City University Graduate School of Medical Sciences. A total of 2458 dental extractions performed on 1175 patients (161 males and 1014 females) receiving oral bisphosphonate therapy were investigated in this study. The mean age of the patients was 70.7 ± 11.7 years (range 23–102 years). This study was approved by the institutional review board of Kobe University Graduate School of Medicine (authorization number 1900) and by the Institutional Review Boards of the respective hospitals. Before surgery, each patient was informed about MRONJ and other extraction-associated risks, and gave their consent for treatment. The definition of MRONJ was taken from the AAOMS position paper [11]. MRONJ can be diagnosed by the following three characteristics: (1) current or previous treatment with antiresorptive or antiangiogenic agents; (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks; and (3) no history of radiation therapy to the jaws or obvious metastatic disease of the jaw. In this study, patients receiving intravenous BPs, denosumab, or antiangiogenic agents were excluded. None of the patients

Osteoporos Int

were receiving intramuscular agents. All patients were investigated with regard to demographics; medical background; type and duration of oral BP use; whether or not they underwent a discontinuation of oral BP before tooth extraction (drug holiday), and the duration of such discontinuation; the presence of any additional surgical procedures such as incision, bone removal, intentional relaxation (relieving) incision, removal of bone edges, root amputation, or suturing; whether antibiotics were administered before extraction; bone loss around the tooth; and the duration of follow-up and primary wound healing with no evident sign of infection. The reason for tooth extraction, the number of extracted teeth, and the site of tooth extraction were also investigated. Alveolar bone loss was measured at the mesial and distal surfaces of the tooth between the apex of the root and the cervical margin using orthopantomography. Bone loss around a tooth was defined as follows: (average length) / (distance between root apex and cervical margin) × 100 = >50%. Details of these characteristics and the demographics of patients are listed in Table 1. The data were introduced into a multiple logistic regression model, where patients were divided according to the number of teeth extracted (single vs. multiple); the state of wound (open vs. closed); the duration of oral BP administration (≥4 years vs. <4 years); and the use of a drug holiday before tooth extraction (≥2 months vs. <2 months). This study investigated the incidence of BRONJ as the primary outcome. Possible development of MRONJ was noted and (if present) classified into different stages (0–3) according to the criteria defined in the AAOMS position paper [11]. Stage 0 is characterized by no clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms. Stage 1 features exposed and necrotic bone or fistulas that probe to bone in patients who are asymptomatic and have no evidence of infection. Stage 2 features exposed and necrotic bone or fistulas that probe to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage. Stage 3 is characterized by exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and more than one of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e., inferior border and ramus of the mandible, maxillary sinus, and zygoma in the maxilla) resulting in pathologic fracture, extraoral fistula, oral antral or oral nasal communication, or osteolysis extending to inferior border of the mandible or the sinus floor [11]. The treatment methods were divided into three categories: (1) nonsurgical treatment, including use of an antiseptic mouth rinse, systemic antibiotics, or the debridement of separated necrotic bone; (2) conservative surgical treatment, including the removal of necrotic bone only; and (3) extensive surgical treatment, including removal of necrotic and surrounding bone (i.e., marginal mandibulectomy or partial maxillectomy).

Table 1

Characteristics and demographics of patients receiving oral BP

Variables

Number (%)

Sample size

1175 (100.0)

Sex Male Female Age (years) Range (years) Mean ± SD Smoking history Smoker Nonsmoker Unknown

161 (13.7) 1014 (86.3) 23–102 70.7 ± 11.7 50 (2.3) 836 (71.2) 289 (24.6)

Type of oral bisphosphonate Alendronate Risedronate

695 (59.1) 304 (25.9)

Minodronate Others

106 (9.0) 8 (0.7)

Alendronate/risedronate

27 (2.3)

Alendronate/minodronate Alendronate/others Risedronate/minodronate Minodronate/others

19 (1.6) 1 (0.1) 3 (0.3) 1 (0.1)

Unknown Duration of oral BP administration (months) Range Mean ± SD Disease history (overlapping distribution)

11 (0.9) 1–246 38.5 ± 37.7

Osteoporosis Rheumatism Diabetes mellitus Cancer Renal insufficiency including dialysis

943 (80.3) 110 (9.4) 102 (8.7) 61 (5.2) 6 (0.5)

Others

321 (27.3)

Statistical analysis SPSS 22.0 (SPSS, Chicago, IL) and Ekuseru-Toukei 2012 (Social Survey Research Information Co., Ltd., Tokyo, Japan) were used for the statistical analyses. The association of each variable with the MRONJ was analyzed by the Mann-Whitney U nonparametric test for ordinal variables and the Fisher’s exact test or the chi-squared test for categorical variables. Probabilities of less than 0.05 were accepted as significant. All of the variables associated with the MRONJ were introduced into a multiple logistic regression model. Forward stepwise algorithms were used, with the rejection of those variables that did not fit the model significantly. Odds ratio (OR) and 95% confidence intervals (CIs) were also calculated.

Osteoporos Int

Results Post-extraction MRONJ was diagnosed in 41 teeth (1.7%) in 35 patients. In two patients, MRONJ occurred in two adjacent teeth. In three patients, MRONJ occurred in different sites (three sites in one patient and two sites in two patients). MRONJ was diagnosed in 36 teeth (87.8%) at 8 weeks (following extraction). The average duration until diagnosis was 9.5 ± 4.2 weeks. Of these, 6 (14.6%) were at stage 0; 16 (39.0%) at stage 1; 13 (31.7%) at stage 2; and 6 (14.6%) at stage 3. The treatment methods used were conservative treatment (20 teeth; 48.8%), conservative surgical treatment (13 teeth; 31.7%), and extensive surgical treatment (8 teeth; 19.5%). The healing rate was 75.0% for conservative treatment and 100.0% for conservative surgical treatment and extensive surgical treatment. Patients who developed MRONJ were significantly older than those who did not (p = 0.039) (Table 2). No significant differences in MRONJ incidence were observed relating to sex or smoking history (Table 2). The duration of oral BP administration in patients with MRONJ was significantly longer than in those who did not (p < 0.001) (Table 2), but there was no significant difference between patients treated for 3 years and those treated for 4 years with oral BPs. Similarly, there were no significant differences in MRONJ incidence when comparing patient comorbidities, other drug-induced risk factors, or the use of a drug holiday before tooth extraction. Extraction of a tooth in the mandibular region or in any molar region was found to be a significant predictor of MRONJ (Table 2), as was extraction of single teeth (p = 0.008) (Table 2). Procedure-related factors such as incision and bone removal were not significant risk factors for MRONJ (Table 2), but root amputation and an open wound were significantly associated with its development (Table 2). Notably, no patients developed MRONJ after receiving complete wound closure with relaxation (relieving) incisions and/or removal of bone edges. Applying a logistic regression model and forward stepwise algorithms, we found that the performance of root amputation (OR = 6.64), the extraction of a single tooth (OR = 3.70), the presence of bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were each significantly associated with MRONJ (Table 3).

Discussion Since Marx et al. first reported BRONJ, this condition has been known as a complication in patients receiving tooth extractions during BP therapy [3], despite the general systemic benefits of these drugs. Tooth extraction has been indicated as the main trigger for MRONJ [3, 10, 11], so several attempts have been made to develop preventative methods that minimize the incidence of MRONJ [23–26]. Many experts

recommended that necessary dental treatment including tooth extraction should be completed before commencing BP therapy and that tooth extraction during therapy should be avoided where possible [23–26]. However, excessive delay in extracting an inflamed tooth increases the risk of MRONJ, so tooth extraction cannot be avoided completely, despite tooth extraction itself being the main risk factor in MRONJ [27]. The incidence of MRONJ after tooth extraction in patients exposed to oral BPs is relatively low, at 0.09–0.5% [12, 13, 28]. Nevertheless, several publications have reported a small number of cases related to oral BPs. Therefore, it is challenging to properly assess the risk factors for MRONJ in patients receiving oral BPs. The most controversial procedural factors around tooth extraction in osteoporosis patients receiving oral BPs are the necessity of taking a drug holiday and the procedure for wound closure. There have been no studies comprehensively analyzing surgical procedure-related factors such as primary wound closure, demographic factors, and drug holidays. To correct this deficit, we performed a multivariate analysis of these risk factors for MRONJ after tooth extraction. BPs retained in the bone have a terminal half-life of many years [29], so discontinuation of BP therapy for a few months (a drug holiday) will have little effect on the BP already incorporated into the bone [30]. However, other effects of these drugs, such as their antiangiogenic activity and inhibition of the proliferation and migration of epithelial cells, may be minimized, which may help in the healing of the overlying mucosa [31]. Previously, we investigated whether a 3-month drug holiday affected the degree of wound healing after tooth extraction in patients receiving oral BP therapy, and recorded a single case of stage 1 BRONJ in the Bno drug holiday^ group. Despite there being no significant difference between these groups, we could not conclusively dismiss the effectiveness of a drug holiday [32]. Similarly, the AAOMS committee recommended a modified drug holiday strategy for osteoporotic patients with a history of extended exposure (>4 years) to oral BPs, even in the absence of convincing evidence that this was necessary. Conversely, neither an advisory committee from the ADA Council on Scientific Affairs nor an international consensus paper recommended any drug holiday from oral BPs before invasive dental procedures in osteoporosis patients [15, 16]. Curtis et al. demonstrated that the rate of hip fracture was increased by BP discontinuation of 2 years or more in women compliant with their BP therapy [33]. In this study, we found no significant difference between the incidence of MRONJ with and without a drug holiday before tooth extraction, suggesting that this strategy might not be able to reduce the risk of MRONJ. However, this does not invalidate the use of a drug holiday from denosumab: the short halflife of denosumab may make a drug holiday more relevant to MRONJ than to BRONJ [34]. If there is no urgent need for tooth extraction, and if BP therapy can be postponed for a

Osteoporos Int Table 2 Characteristics and incidence rates of MRONJ

Variables

MRONJ

P value

Present (%)

Absent (%)

Sample size

41 (1.7)

2417 (98.3)

Stage 0

6 (14.6)

–

Stage 1 Stage 2

16 (39.0) 13 (31.7)

– –

6 (14.6)

–

5 (12.2) 36 (87.8)

359 (14.9) 2058 (85.1)

Stage 3 Sex Male Female Age Range (years)

0.825a

51–93

23–102

Mean ± SD Smoking history

74.8 ± 8.9

70.9 ± 11.7

0.039b

Yes No Unknown The duration of oral BP administration

1 (2.4) 30 (73.2) 10 (24.4)

102 (4.2) 1750 (72.4) 565 (23.4)

1.000a

1–204 45.0 ± 40.6 18 (43.9) 12 (29.3)

1–246 38.4 ± 36.6 976 (40.4) 1150 (47.6)

11 (26.8) 12 (29.3) 18 (43.9) 11 (26.8)

291 (12.0) 653 (27.0) 1473 (60.9) 291 (12.0)

33 (80.5) 8 (19.5)

1897 (78.5) 520 (21.5)

0.850a

3 (7.3) 38 (92.7)

164 (6.8) 2253 (93.2)

0.756a

3 (7.3) 38 (92.7)

226 (9.4) 2191 (90.6)

1.000a

9 (22.0) 32 (78.0)

354 (14.6) 2063 (85.6)

0.185a

0 (0) 41 (100.0)

28 (1.2) 2388 (98.8)

1.000a

17 (41.5) 24 (58.5)

893 (36.9) 1524 (63.1)

0.625a

3 (7.3) 38 (92.7)

194 (8.0) 2223 (92.0)

1.000a

Range (months) Mean ± SD More than 3 years Less than 3 years Unknown More than 4 years Less than 4 years Unknown Comorbidity (overlapping distribution) Osteoporosis Yes No Cancer Yes No Rheumatism Yes No Diabetes mellitus Yes No Renal insufficiency including dialysis Yes No Drug-induced risk factor (overlapping distribution) Steroid therapy Yes No Immunosuppressive therapy Yes No

< 0.001b 0.142a

0.319a

Osteoporos Int Table 2 (continued) Variables

MRONJ

P value

Present (%)

Absent (%)

25 (61.0) 16 (39.0)

1874 (72.0) 543 (27.9)

0 (0)

1 (0.0)

27 (65.9) 14 (34.1)

1791 (74.1) 625 (25.9)

0 (0)

1 (0.0)

Periapical periodontitis (per) Per + radicular cyst

14 (34.1) 1 (2.4)

537 (22.2) 41 (1.7)

P4 periodontitis

11 (26.8)

660 (27.3)

C4 caries Pericoronitis Root fracture

12 (29.3) 2 (4.9) 1 (2.4)

873 (36.1) 99 (4.1) 180 (7.5)

Per + root fracture C4 caries + root fracture Periapical periodontitis

0 (0) 0 (0)

2 (0.1) 2 (0.1)

15 (36.6) 26 (63.4)

580 (24.0) 1837 (76.0)

0.067a

11 (26.8) 30 (73.2)

661 (27.3) 1756 (72.7)

1.000a

2 (4.9) 39 (95.1)

99 (4.1) 2318 (95.9)

0.685a

27 (65.8) 14 (34.2)

1191 (49.3) 1226 (50.7)

0.040a

36 (87.8) 5 (12.2)

1555 (64.3) 1226 (35.7)

0.001a

18 (43.9) 23 (56.1)

1447 (59.9) 970 (40.1)

0.053a

15 (36.6) 26 (63.4)

869 (36.0) 1548 (64.0)

1.000a

20 (48.8) 21 (51.2)

680 (28.1) 1737 (71.5)

0.008a

4 (9.8) 37 (90.2) 0 (0)

362 (15.0) 2030 (84.0) 25 (1.0)

0.507a

Drug holiday before tooth extraction 3 months Yes No Unknown 2 months Yes No Unknown Reason of tooth extraction

Yes No P4 periodontitis Yes No Pericoronitis Yes No Jawbone Mandibular Maxillary Site of tooth extraction Molar region Anterior region Bone volume around tooth Adequate alveolar bone volume Bone loss or sever tooth mobility (grade 3) Preoperative antibiotics administration Yes No Number of teeth extracted Single Multiple Additional surgical procedure Incision Yes No Unknown

0.118a

0.280a

Osteoporos Int Table 2 (continued) Variables

MRONJ

Bone removal Yes No Unknown Root amputation Yes No Unknown Wound state after extraction Open Closed with suture Completely closed with relaxation incision or removal of bone edge Unknown a

Mann-Whitney U test

c

Chi-squared test

Table 3 Results of multivariate logistic regression analysis of the risk factors for MRONJ P value Odds ratio 95% CI Lower Upper Root amputation Extraction of single tooth Bone loss or severe tooth mobility Open wound CI confidence interval

Present (%)

Absent (%)

5 (12.2) 36 (87.8)

174 (7.2) 2216 (91.7)

0 (0)

27 (1.1)

5 (12.2) 36 (87.8)

113 (4.7) 2278 (94.2)

0 (0)

26 (1.1)

23 (56.1) 18 (43.9)

832 (34.4) 1452 (60.1)

0 (0)

105 (4.3)

0 (0)

28 (1.2)

0.210a

0.046a

0.012c

Fisher’s exact test

b

longer duration, a long-term drug holiday may be a strategy to minimize the risk of MRONJ in the osteoporotic patient [35]. Theoretically, tooth extraction should always be performed with an atraumatic extraction technique and minimal bone damage [15, 19]. In this multivariate analysis study, we found that traumatic extraction (including root amputation) was found to be a significant risk factor in the development of MRONJ (OR = 6.64). However, this result was affected by the extraction of wisdom teeth, where root amputation was more common. Additional surgical procedures such as the removal of bone edges and mucosal coverage of the wound also have unclear significance to MRONJ. Malden et al. suggested that sharp wall margins and/or inter-radicular bony regions should be selectively reduced without separating the periosteum from the bone but that primary wound closure was not imperative [19]. Mozzati et al. described two different

Variable

P value

0.001 0.001 0.005 0.026

6.638 3.699 3.601 2.512

2.08 1.65 1.48 1.12

21.19 8.29 8.79 5.66

surgical protocols: a delicate surgery and closure by primary intention and an atraumatic avulsion and closure by secondary intention [18]. Both protocols were effective, with no incidence of MRONJ. Furthermore, Migliorati et al. suggested that antibiotic prophylaxis and plastic wound closure were not necessary in lower risk patients (those receiving oral BPs for osteoporosis for less than 3 years) [36]. Conversely, Hellstein et al. recommended primary tissue closure wherever possible [15]. Several studies reported lower rates of MRONJ when primary closure was performed to minimize bone exposure [20–22]. Some investigators demonstrated a high success rate (∼97.0%) in tooth extractions carried out according to a protocol of prolonged perioperative antibiotic prophylaxis, atraumatic extraction, post-operative smoothing of sharp bony edges, and thorough mucosal wound closure [37]. In the current study, failure to close the wound was found to be a significant risk factor in MRONJ (OR = 2.51) in multivariate analysis, as was extraction of a single tooth (OR = 3.70). The difficulty in achieving primary closure when anteroposterior adjacent teeth are present may be relevant to this finding. Notably, there was no incidence of MRONJ when the wound was completely closed with a relaxation incision and/or sharp bone edges were removed. Therefore, we recommended post-extraction removal of bone edges and mucosal wound closure. Theoretically, teeth with severe bone loss (e.g., where the epithelium lies between the alveolar bone and the tooth root) may have a lower risk of developing MRONJ. However, in our multivariate analysis, bone loss and/or severe tooth

Osteoporos Int

mobility were found to be significant risk factors for MRONJ (OR = 3.60). This discrepancy may arise from our definition of bone loss as being more than half of the overall root length. Periapical periodontitis and C4 caries with bone loss of more than half of the root were classified as Bbone loss.^ Therefore, local infection and inflammation associated with bone loss may be more relevant as risk factors than the bone loss itself. Some investigators have demonstrated that the presence of local infection was a risk factor in in vitro and in vivo studies [38, 39]. Localized infection—and the acidic environment this creates—might promote MRONJ by neutralizing BPs as they are released from surrounding tissues and preventing them from inhibiting the activity of various cells including osteoclasts [40–42]. Osteomyelitic and/or osteonecrotic changes in the bony architecture at the time of tooth extraction might also be vitally important in the pathogenesis of ONJ [22, 38]. We aim to investigate this further in future work. Nevertheless, the results of this study suggest that tooth extraction should not necessarily be postponed in patients receiving oral BPs when the intent is to control a local infection that cannot be cured by conservative measures. Katsarelis et al. proposed that infection could be the factor initiating the development of MRONJ, rather than low bone turnover [43]. Macrophages are crucial in the development of local infection and the defense against invading microorganisms [43, 44]. The macrophages exposing BPs induce apoptosis and lose their ability to activate and respond to infection [43, 44]. Several reports demonstrated that prophylactic administration of antibiotics prevented local infection and significantly reduced the risk of MRONJ [18, 22]. Some investigators also speculated that complete wound closure and removal of bone edges at the surgical extraction site produced better results because they both reduced bacterial contamination of the jaw bone [22, 45]. We agree with their supposition. Therefore, prophylactic antibiotics may still be necessary before tooth extraction in patients receiving oral BPs, despite our finding that the preoperative administration of antibiotics did not significantly reduce the risk of MRONJ. Further prospective studies are necessary to provide definitive scientific evidence for these recommendations. In conclusion, we have successfully demonstrated multivariate relationships among the various risk factors for MRONJ after tooth extraction in patients receiving oral BPs. The performance of root amputation, the extraction of a single tooth, the presence of bone loss or severe tooth mobility, and an unclosed wound were all significantly associated with the development of MRONJ. Therefore, we recommend a minimally traumatic extraction technique, removal of bone edges and mucosal wound closure. The effectiveness of a short-term drug holiday was not confirmed as it has no significant impact on MRONJ incidence.

Acknowledgements We received no individual, institutional, or departmental funding from external sources. Compliance with ethical standards This study was approved by the institutional review board of Kobe University Graduate School of Medicine (authorization number 1900) and by the Institutional Review Boards of the respective hospitals. Conflicts of interest None.

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