Clinic of Hospital Dentistry, School of Dentistry, University of Athens, Athens, Greece

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1 Dental extractions as risk factor of bisphosphonates related jaw osteonecrosis Dental extractions as the major local risk factor of bisphosphonates related jaw osteonecrosis in cancer patients receiving intravenous bisphosphonates therapy. A systematic review Vardas E 1, Coward T 2, Papadopoulou E 1, Nicolatou-Galitis O 1 1 Clinic of Hospital Dentistry, School of Dentistry, University of Athens, Athens, Greece 2 Department of Prosthetic Dentistry, King s College London Dental Institute at King s Hospital, London, UK Abstract Background: Dental extractions have been reported to be strongly associated with the development of bisphosphonaterelated osteonecrosis of the jaw (BRONJ). Objectives: To assess dental extractions as the major risk factor for BRONJ in cancer patients receiving intravenous (IV) bisphosphonates (BPs). Method: The literature was electronically searched using MEDLINE/PubMed, Science Direct and Cochrane library from 2003 to July These were complemented using manual search, to identify all articles, containing data relating to the incidence of new cases of BRONJ, associated to dental extractions or other local risk factors in cancer patients receiving IV BPs. The selected papers that fulfilled the predefined inclusion criteria were classified according to the Oxford Centre for Evidence-based Medicine and were evaluated for quality assessment using quality assessment tools according to each study design. Results: The searches yielded 794 titles. A total of 34 published studies provided accurate data for this cohort of patients. All 34 papers fulfilled the inclusion criteria. In 24 papers, dental extraction and other local risk factors were presented as the trigger event for the development of BRONJ. A PICO process was performed. Factors that significantly correlate with BRONJ were: dental extraction (high correlation, rho=0.931, p<0.0001), periodontal disease (moderate correlation, rho=0.437, p<0.029) and dental prosthesis (moderate correlation, rho=0.410, p<0.042). In 10 papers dental extraction, the only local risk factor for BRONJ moderate correlation, (rho=0.692, p<0.027) was found. Conclusion: This review presented the current evidence from the literature, suggesting that dental extraction was the local risk factor most significantly correlated with BRONJ in cancer patients receiving IV PBs therapy. This conclusion was based on a limited number of studies and therefore further studies are required. Key words: Bisphosphonates, osteonecrosis, dental extraction, jaw, cancer. Introduction Osteonecrosis of the Jaw (ONJ) is a rare, but potentially serious complication, which has been described among cancer patients treated with various regimens. However, since 2003, there have been numerous reports that associate ONJ with intravenous bisphosphonate therapy [1]. A clinical staging system was developed by Ruggiero et al. and subsequently updated in the 2009 AAOMS guidelines (Table 1) [2]. he risk factors that may potentiate the development of BRONJ can be divided into three main groups: i) bisphosphonate administration, ii) systemic risk factors and iii) local risk factors [3]. Dentoalveolar surgery and mouth diseases during BPs treatment represent the most important local risk factors for the development of BRONJ. he majority of ONJ cases reported, occurred ater so called triggering events (dental *Corresponding author: Emmanouil Vardas, 42, Perikleous Street, Cholargos, , Athens, Greece, Tel.: , Fax: , mbardas@gmail.com 26 extractions, implants or pressure sores) although jaw osteonecrosis may also develop spontaneously [3]. Several studies have reported dental extraction as a potential risk factor for the development of BRONJ. he incidence of BRONJ associated with dental extractions varies between 36.7% and 73% of reported cases [4]. he scope of this study was: to identify all studies reporting dental extraction and other local risk factors (dental implants, periodontal disease, dental prosthesis, etc.) as the trigger event for the development of BRONJ in cancer patients receiving IV bisphosphonates and to investigate if the dental extraction is the major local risk factor correlate with BRONJ development to this cohort of patients. Methods Search strategy and study selection he literature and electronic databases were searched for articles to be included in the review. Searches were carried out using MEDLINE/PubMed data, Science Direct data and the Cochrane

2 Review 01/04 library. hese searches were conducted using a combination of key words and were limited to articles published between 2003 to July Restriction was also made to only those written in the English language Papers were selected if the combination of words appeared anywhere in the paper and the electronic search was followed by manual searches on the articles reference lists to identify relevant studies. A preliminary review conducted in line with the studies resulted in the database search to identify efective papers for the review. he following types of papers were excluded: abstracts, animal studies, experimental studies, report of a case, letters to editor, editorials, and commentaries according to the inclusion and exclusion criteria listed below. Multiple published reports from the same study identiied contributed not more than once to the project. Duplicates were removed and papers were excluded ater evaluating full article and for not meeting the inclusion criteria. All data retrieved from the efective papers were registered and summarized. he selected papers were then classiied according to the Oxford Centre for Evidence-based Medicine and evaluated for quality assessment using quality assessment tools according to studies design (prospective, retrospective, etc.) Inclusion Criteria Retrospective studies, reviews, prospective clinical trials, case series were all eligible for inclusion in this review. Tooth extraction performed in cancer patients who received IV BPs. Incidents of new BRONJ cases ater the extraction reported in the study. Studies that their abstract and full text access were available. No history of radiation therapy Exclusion criteria Case reports, commentaries, letters to the editor and abstracts presented at congresses. Clinical studies on non-cancer patients or patients received oral BPs. Databases search he initial search was conducted on the 12th of July 2013 MEDLINE/PubMed (advanced search) from 2003 to July Table I BRONJ clinical staging system according to AAOMS guidelines. ONJ stage At risk Stage 0 Stage 1 Stage 2 Stage 3 Description No apparent exposed/necrotic bone in patients who have been treated with either oral or IV bisphosphonates No clinical evidence of necrotic bone, but nonspecific clinical findings and symptoms (Figure 1) Exposed and necrotic bone in asymptomatic patients without evidence of infection (Figure 2) Exposed and necrotic bone associated with infection as evidenced by pain and erythema in region of exposed bone with or without purulent drainage (Figure 3) Exposed and necrotic bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extraoral fistula, oral antral/ oral nasal communication, or osteolysis extending to the inferior border of the mandible or the sinus floor (Figure 4) he MEDLINE/PubMed data search included the terms tooth extractions AND BRONJ that identiied 50 articles, BRONJ AND cancer patients yielded 76 articles tooth extractions AND BRONJ AND iv Bisphosphonates produced 6 articles and BRONJ AND cancer patients AND iv bisphosphonates AND tooth extractions found 2 articles. he next search was performed in Science Direct database. Search terms included tooth extractions AND BRONJ that yielded 196 articles, BRONJ AND cancer patients identiied 276 articles, tooth extractions AND BRONJ AND iv Bisphosphonates Figure 1. Osteonecrosis of the jaw stage 0 five months following dental extractions. Multiple fistulas are seen on the maxillary alveolar ridge. Figure 2. Osteonecrosis of the jaw stage I. Exposed necrotic bone is observed on the maxilla with no clinical signs of infection. 27

3 Dental extractions as risk factor of bisphosphonates related jaw osteonecrosis produced 78 articles and BRONJ AND cancer patients AND iv bisphosphonates AND tooth extractions found 72 articles. he search conducted in Cochrane library revealed two protocols in regard to BRONJ and were excluded from the study. Manual searches on the articles reference lists produced 18 articles. Summary of the search strategy First electronic search in MEDLINE/PubMed database found 134 articles he second electronic search in Science Direct found 622 articles 28 Table II Level and quality of evidence of the 34 selected papers included in the review. No Study Publication Study Level Quality year type of of evidence evidence 1 Thumbigere-Math 2012 retrospective 2b 26 et al. [10] 2 Jadu et al. [11] 2007 retrospective 2b 21 3 Badros et al. [12] 2006 retrospective 2b 22 4 Martins et al. [13] 2012 retrospective 2b 25 5 Regev et al. [14] 2008 case series Boonyapakorn 2008 prospective 1b 13 et al. [15] 7 Vescovi et al. [16] 2013 case series Andriani et al. [17] 2012 retrospective 2b 22 9 Scoletta et al. [18] 2011 prospective 1b Vahtsevanos 2009 retrospective 2b 22 et al. [19] 11 Mozzati et al. [20] 2012 case series Ferlito et al. [21] 2011 case series Mozzati et al. [22] 2012 case-control 3b 5 14 Lodi et al. [23] 2010 case series Scoletta et al. [24] 2013 prospective 1b Bagan et al. [25] 2012 retrospective 2b Nomura et al. [26] 2013 case series Fortuna et al. [27] 2012 prospective 1b Rugani et al. [28] 2013 prospective 1b Graziani et al. [29] 2006 case series Nicolatou-Galitis 2011 prospective 1b 15 et al. [30] 22 Bianchi et al. [31] 2007 prospective 1b Farias et al. [32] 2013 case series Fehm et al. [33] 2009 retrospective 2b Hoefert et al. [34] 2011 prospective 1b Yamazaki et al. [35] 2012 retrospective 2b Jabbour et al. [36] 2012 case series Bamias et al. [37] 2005 prospective 1b Kato et al. [4] 2013 retrospective 2b Bedogni et al. [38] 2011 prospective 1b Heufelder et al. [39] 2012 prospective 1b Curi et al. [40] 2011 case series O Ryan et al. [41] 2009 retrospective 2b Walter et al. [42] 2008 prospective 1b 13 he third electronic search in Cochrane library found 2 articles (Cochrane protocols) Hand searching references produced 36 articles Duplicated papers + not related articles to our subject + Inclusion and Exclusion criteria + quality assessment Final numbers of studies included: 34 articles Statistical analysis In order to compare the impact of each local risk factor on BRONJ onset, Spearman s rho correlation coeicient was calculated, due to the inaccurate distribution of the data in Tables 3 and 5 (SPSS IBM,v21). he level of statistical signiicance was set at 0.05 value. Results he primary search from three databases and manual searches revealed 794 papers altogether. A preliminary search was conducted, duplicated although not full text papers were discarded. Of the 426 papers retrieved ater preliminary search, 61 papers were reviews, 41 were report of cases, 22 were case series, 52 were retrospective, 38 articles were prospective studies, 49 were animal studies - experimental studies hypotheses - protocols, 54 papers were poster or oral presentations abstracts presented in meetings, 28 were letters to editor, editorial, news and announcements and 81 articles were not concerned primarily with tooth extractions in cancer patients. Among the 426, only the 34 studies provided accurate data for this cohort of patients and fulilled the inclusion criteria. Dental extraction was the only reported local risk factor for BRONJ development in 10 studies. Also, dental extraction and other local risk factors were reported as trigger events in 24 articles. hese studies were 11 retrospective, 12 prospective studies, 10 case series, and a case control study. All studies were classiied according to the Oxford Centre for Evidencebased Medicine. Prospective studies could be categorized as having 1b level of evidence, retrospective studies as 2b, control study as 3b and case series as 4 [5]. he quality of the evidence of the 34 studies was also evaluated. Four diferent quality assessment tools were used according to each study design (case series - case control prospective - retrospective). he highest quality of evidence was the maximum score of 18 for case series studies, 8 for case control study, 18 for prospective studies and 38 for retrospective studies. he score of 0 indicated the weakest quality of evidence (Table 2) [6-9]. he studies where dental extraction was the only local risk factor were listed in Table 3. In these 10 studies, we identiied 27 new cases of BRONJ in 550 cancer patients. To assess the dental extraction as a major local risk factor relating to the others contributor local factors (dental prosthesis, dental implants, etc.) a PICO process (Table 4) was performed in 24 studies (PICO is an acronym for patient problem or population [P], intervention [I], comparison [C] and outcomes [O]).

4 Review 01/04 Table III Studies providing data for new BRONJ related to dental extractions. Study Study design Cancer population Number of patients Percentage with new BRONJ cases % Kato et al. [4] Retrospective 20 (11 BC, 5 MM, 3 PC 1 NHL) 4 4/20 (20%) Yamazaki et al. [35] Retrospective 27 (13BC, 11MM, 3 OMC) 4 4/27 (14.81%) Heufelder et al. [39] Prospective 47 (18MM, 10BC, 10PC, 9 OMC) 3 3/47 (6.38%) Vescovi et al. [16] Case series 91 (No specific data) 5 5/91 (5.5%) Scoletta et al. [18] Prospective 57 (30BC, 20MM, 5PC, 1L, 1LC) 1 1/57 (1.75%) Scoletta et al. [24] Prospective 60 (32BC, 21MM, 4PC, 1LC, 1, OMC, 1RPC) 5 5/60 (8.33%) Ferlito et al. [21] Prospective 43 (28MM, 8BC, 5PC, 2LC) 0 0/43 (0%) Mozzati et al. [22] Case-control 176 (60PC, 57MM, 51BC, 5LC, 3 OMC) 5 5/176 (2.84%) Lodi et al. [23] Prospective 21 (11MM, 8BC, 2 OMC) 0 0/21 (0%) Regev et al. [14] Prospective 8 (6BC, 2MM) 0 0/8 (0%) Abbreviations: BC, breast cancer; MM, multiple myeloma; PC, prostate cancer; LC, lung cancer; RPC, rhinopharyngeal cancer; NHL, Non Hodgkin lymphoma; OMC, Other malignant conditions he correlation of the local risk factors to the new cases of BRONJ reported in the 24 studies was shown in Table 5, as well as local risk factors and number of new BRONJ cases. According to Spearman s test, the factors found to be signiicantly correlated to BRONJ cases are: dental extraction (high correlation, rho=0.931, p<0.0001), periodontal disease (moderate correlation, rho=0.437, p<0.029) and dental prosthesis (moderate correlation, rho=0.410, p<0.042). In relation to the studies presented in Table 3 (in which dental extraction was the only local risk factor for BRONJ), dental extraction was found to be signiicantly correlated to BRONJ (moderate correlation, rho=0.692, p<0.027). In conclusion, statistical analysis conirmed that dental extraction is the major among the other local risk factors reported to have contributed to BRONJ development at this patient s cohort. Discussion A total of 34 articles were included in the study. Also, no randomized controlled trials papers were identiied in the literature with regard to this topic. To our knowledge, this review is the irst to evaluate the incidence and risk ratio of new BRONJ cases correlated with dental extraction and other local risk factors. Although the fact that the development of BRONJ in cancer patients may be strongly linked to dentoalveolar surgery, information relating to the incidence of this condition when dental extraction preceded is limited. Several studies have reported tooth extraction as a potential risk factor for the development of BRONJ. Kyrgidis et al. [43] and Hof et al. [44] found the increased risk of BRONJ for cancer patients receiving IV bisphosphonates ater routine dental extractions ranging from 16-fold to 53-fold. he incidence of BRONJ associated with dental extractions reported in the literature varies between 36.7% and 73% [4]. In this literature review, the incidence ranged between 38% and 87.5% with mean incidence of 62.53%. his percentage depicted the new BRONJ cases in the 24 studies, where all the local risk factors were reported. Nevertheless, the statistical analysis showed signiicant association between the incidence of BRONJ ater dental extraction (high correlation). Figure 3. Osteonecrosis of the jaw stage II. Exposed necrotic bone, erythema and inflammatory swelling of the soft tissues is seen. Figure 4. Osteonecrosis of the jaw stage III. Exposed necrotic bone with purulence, which was extended to the inferior border of the mandible. 29

5 Dental extractions as risk factor of bisphosphonates related jaw osteonecrosis Table IV PICO (Population, Intervention, Control, Outcome). Studies Population Intervention Comparison Outcome (cancer patients) (trigger event: (trigger event: other (BRONJ cases) dental extraction) local risk factors ) Andriani et al. [17] 55 (BRONJ) 43 patients Dental implant 3 patients (5.4%) 43/55 (78.4%) Periodontal disease 5 patients (9%) Dental prothesis 3 patients (5.4%) No trigger 1 patient (1.8%) Badros et al. [12] 90 (22 BRONJ) 10 patients Periodontal disease 2 patients (9.1%) 10/22 (45.45%) Non dental procedures 10 patients (45.45%) Bagan et al. [25] 102 (BRONJ) 65 patients Dental Prosthesis 8 patients (7.8%) 65/102 (63.7%) Dental Implants 4 patients (4%) Unknown 25 (24.5%) Boonyapakorn et al. [15] 80 (22 BRONJ) 17 patients Spontaneously 5 patients (23%) 17/22 (77%) Fortuna et al. [27] 26 (BRONJ) 20 patients Periodontal disease patients 4 (15.38%) 20/26 (76.92%) Dental prosthesis 1 patient (3.84%) Dental implants 1 patient (3.84%) Graziani et al. [29] 14 (BRONJ) 9 patients Spontaneously 5 patients (35.6%) 9/14 (64%) Jadu et al. [11] 655 (24 BRONJ) 9 patients Scaling 2 patients (8%) 9/24 (38%) Spontaneous 7 patients (29%) Not specific data 6 patients (25%) Martins et al. [13] 22 (BRONJ) 12 patients Dental prosthesis 6 patients (27.3%) 12/22 (55%) Spontaneous lesions in 2 patients (9%) Periodontal disease 1 patient (5%) Torus mandibularis in 1 patient (5%) Mozzati et al. [22] 32 (BRONJ) 17 patients Dental prosthesis 7 patients (21.9%) 17/32 (53.1%) Periodontal disease 8 patients (25%) Nicolatou-Galitis et al. [30] 162 (65 BRONJ) 48 patients Dental prosthesis 7 patients (10.7%) 48/65 (73.85%) Orthodontic treatment 1 patient (1.6%) Periodontal disease 1 patient (1.6%) Not identified 8 patients (12.3%) Nomura et al. [26] 8 (BRONJ) 4 patients Dental prosthesis 2 patients (25%) 4/8 (50%) Dental implants 1 patient (12.5%) Unknown 1 patient (12.5%) Rugani et al. [28] 48 (10 BRONJ) 5 patients Dental implants 1 patient (10%) 5/10 (50%) Unknown 4 patients (40%) Thumbigere-Math et al. [10] 576 (18 BRONJ) 10 patients Spontaneously 7 patients (41%) 10/18 (59%) Missing data 1 patient (5.5%) Vahtsevanos et al. [19] 1,621 (80 BRONJ) 46 patients Dental prosthesis 24 patients (30%) 46/80 (57.5%) Other 10 patients (12.5%) Bianchi et al. [31] 32 (BRONJ) 21 patients Spontaneously 10 patients (31.3%) 21/32 (65.63%) Dental implants 1 patient (3.1%) Farias et al. [32] 5 (BRONJ) 3 patients Spontaneously 2 patients (40%) 3/5 (60%) Fehm et al. [33] 10 (BRONJ) 6 patients Dental prosthesis 3 patients (30%) 6/10 (60%) Periodontal disease 1 patient (10%) Hoefert et al. [34] 46 (BRONJ) 30 patients Pressure sore 9 patients (19.5%) 30/46 (65.2%) Spontaneously 1 patient (2.2%) Abscess 1 patient (2.2%) Dental implants 1 patient (2.2%) Unknown 4 patients (8.7%) Jabbour et al. [36] 10 (BRONJ) 5 patients Tooth came out on its own 1 patient (10%) 5/10 (50%) Dental prosthesis 2 patients (20%) Spontaneously 1 patient (10%) Unknown 1 patient (10%) 30

6 Review 01/04 Table IV PICO (Population, Intervention, Control, Outcome). Studies Population Intervention Comparison Outcome (cancer patients) (trigger event: (trigger event: other (BRONJ cases) dental extraction) local risk factors ) Bamias et al. [37] 17 (BRONJ) 13 patients Dental prosthesis 2 patients (11.75%) 13/17 (76.5%) Unknown 2 patients (11.75%) Bedogni et al. [38] 30 (BRONJ) 21 patients Spontaneously 2 patients (6.5%) 21/30 (70%) Dental prosthesis 5 patients (16.5%) Dental implants 1 patient (3.5%) Periodontal disease 1 patient (3.5%) Curi et al. [40] 25 (BRONJ) 14 patients Dental implants 2 patients (8%) 14/25 (56%) Dental prosthesis 7 patients (28%) Spontaneously 2 patients (8%) O Ryan et al. [41] 59 (BRONJ) 29 patients Spontaneously 16 patients (27.1%) 29/59 (49.15%) Periodontal disease 6 patients (10.2%) Trauma 5 patients (8.5%) Other 2 patients (6.90%) Not recorded 1 patient (1.85%) Walter et al. [42] 8 (BRONJ) 7 patients Dental prosthesis 1 patient (12.5%) 7/8 (87.5%) P: Population = cancer patients receiving IV BPs, I: Intervention = dental extraction, C: Comparison = other local risk factors*, O: Outcome = new cases of BRONJ *Reported in the study In the studies, dental extraction was considered as the only local risk factor for the development of BRONJ. his incidence ranged between 0% and 20% with mean incidence of 5.36% which was also found to be signiicantly correlated with BRONJ (moderate correlation). Moreover, a very interesting issue is the inding of the less strong statistical correlation presented (from high to moderate correlation) in cases where the only local risk is the dental extraction. Non-exposed bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a newly reported complication arising from bisphosphonate therapy, that presents with it atypical symptoms and no apparent mucosal fenestration or exposure of necrotic bone [45]. If BRONJ already exists, it could be the cause of pain and infection, leading to the extraction of the involved tooth [46]. herefore, the extraction itself would not be the inciting event of osteonecrosis but the outcome. An explanation of the previous indings could be that many published studies may have not considered the nonexposed variant of BRONJ [46]. his is due to the fact that when these studies were planned and during the time of data collection, this variant had not been introduced into the clinical staging system [47]. Osteonecrotic lesions may be asymptomatic for a period of time, which may lead to misdiagnosis of asymptomatic stage I cases in patients who needed tooth extractions and did not have a regular dental follow-up [47]. Few studies in the literature reported that oncology patients underwent dental assessment or were referred for a dental examination by their oncologist before initiation of IV BPs Table V Local risk factors and number of new BRONJ cases. Local risk factor as BRONJ (new cases and trigger event percentage) Dental extraction 464/742 (62.53%) Dental implants 15/742 (2.02%) Periodontal disease 29/742 (3.91%) Dental prosthesis 78/742 (10.51%) Spontaneously 61/742 (8.22%) Missing data, unknown 66/742 (8.90%) Other* 29/742 (3.91%) Total number of cases 742 *bone exostosis, abscess, orthodontic treatment, periapical infection, root canal treatment etc. therapy. In the oldest reports, it remains unknown how many patients were informed about the risk of developing ONJ ater dental extraction. Also there was not reported if the extractions were performed by a specialist or if preventive protocols for BRONJ development were implemented. We can assume that the number of extraction leading to the development of BRONJ may be lower in recent studies, since it is well known that dental and oral health inluence the development and course of BRONJ. Fusco et al. [48] reported the decreasing number of BRONJ cases observed in cancer and myeloma patients with the implement of preventive dental measures including a pretherapy dental assessment. Woo et al. [49] emphasized the necessity to eliminate all potential infectious foci prior to the onset of BP treatment 31

7 Dental extractions as risk factor of bisphosphonates related jaw osteonecrosis in order to prevent later dental procedures. Moreover, the studies of Dimopoulos et al. [50], Ripamonti et al. [51] and Kyrgidis et al. [52] demonstrated the beneit of preventive dental measures with a reduction of the BRONJ incidence by 75% and 73%, respectively, compared to patients without preventive measures. In most of the 10 articles, in which moderate correlation was found, the authors implemented preventive measures (oral hygiene, antibiotic prophylaxis, other intervention) for the prevention of BRONJ. Conclusions Dental extraction is associated with an increased risk of BRONJ in cancer patients receiving IV PBs medication at present, which represent a moderate to high local risk factor. Further prospective studies are therefore needed to evaluate the efectiveness of interventions implemented for BRONJ prevention. However, evidence-based guidelines are still lacking. 32 References 1. 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