Received Date : 02-Aug-2012 Accepted Date : 20-Sep-2012 Article type : Review

Accepted Article

Bisphosphonates and their clinical implications in endodontic therapy

A.T. Moinzadeh1, H. Shemesh1, N.A.M. Neirynck2, C. Aubert3, P.R. Wesselink1

Department of Endodontology, Academic Center for Dentistry Amsterdam (ACTA),

Amsterdam, the Netherlands, 2Department of Internal Medicine, Ghent University Hospital, Gent, Belgium, 3Department of Head and Neck Surgery, CHU Charleroi, Montigny le Tilleul, Belgium

Running title: Bisphosphonates and endodontic treatment

Keywords: Bisphosphonate, BRONJ, ONJ, endodontic treatment, root canal, osteonecrosis.

Corresponding author A.T. Moinzadeh Department of Endodontology, Academisch Centrum Tandheelkunde Amsterdam (ACTA), Gustav Mahlerlaan 3004, 1081 LA Amsterdam, the Netherlands, e-mail: a.moinzadeh@acta.nl tel: +31(0)205980363 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/iej.12018 2012 International Endodontic Journal

Abstract This review gives an overview of the factors that may play a role in the development of osteonecrosis of the jaw in patients treated with bisphosphonates (BPs) and undergoing nonsurgical endodontic treatment as well as some recommendations for its prevention. BPs are a widely prescribed group of drugs for diverse bone diseases. The occasional but devastating adverse effect of these drugs has been described as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Since this condition is debilitating and difficult to treat, all efforts should be made to prevent its occurence in patients at risk. The main triggering event is considered to be dental extraction. Even though nonsurgical endodontic treatment appears to be a relatively safe procedure, care remains essential. After an overview of this class of drugs, the clinical presentation, epidemiology and pathogenesis of BRONJ, as well as the possible risk factors associated to its development after nonsurgical endodontic treatment will be described. Finally, several strategies will be proposed for the prevention of BRONJ during nonsurgical endodontic treatment.

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Introduction Bisphosphonates (BPs) are non-metabolized analogues of pyrophosphates that are often prescribed to treat patients with bone disorders, such as osteoporosis (Gates et al. 2009), and Pagets disease. Other indications for the use of BPs are the control of symptoms and signs (pain, fractures, hypercalcemia) due to bone invasion in multiple myeloma or bone metastasis in other malignancies (Zysset et al. 1992, Mhaskar et al. 2012). Between 2005 and 2009 more than 150 million prescriptions for BPs were dispensed worldwide for the treatment of osteoporosis (Whitaker et al. 2012).

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Rare systemic adverse events linked to the use of BPs include: renal (acute renal insufficiency, deterioration of chronic renal insufficiency), gastrointestinal (gastrointestinal intolerance, anorexia), and bone and joint pain (Kuhl et al. 2012). BP-related osteonecrosis of the jaw (BRONJ) is also one of the complications associated with the administration of these drugs (Marx et al. 2005). A positive correlation exists between the duration and cumulative dosage of BP treatment and the incidence of BRONJ (Kuhl et al. 2012). According to several observational studies, dental procedures are one of the risk factors for the development ofBRONJ. Mavrokokki et al. (2007) found that the main trigger of BRONJ in patients taking BPs was dental extraction. This was confirmed by several studies which identified dental extractions or invasive surgical procedures as being one of the risk factors for the development of BRONJ (Marx et al. 2005, Pazianas et al. 2007, Hoff et al. 2008, Filleul et al. 2010). In 2003 the first cases of osteonecrosis of the jaw in patients medicated with BPs were reported (Marx 2003) and in 2005, Marx et al. (2005) mentioned a possible association between root canal treatment and the development of BRONJ in a case series. In a total of 119 patients presenting with BRONJ, the most common dental comorbidity was considered to be clinically and radiographically apparent marginal periodontitis, which was present in 84% of the patients. Previous root canal treatments with supposed evidence of failure (presence of an apical radiolucency or an inadequate root lling) counted for 10.9 % of the cases. Among the inciting events leading to BRONJ, dental extraction counted for 37.8 % of the cases as compared to 0.8% for endodontic surgery. As a result of these findings, nonsurgical endodontic treatment should be favored to dental extractions in patients at higher risk for BRONJ whenever possible.

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The first part of this review describes the biochemical mechanism of action of BPs molecules and discusses the pathosis of BRONJ. The second part will describe the endodontic clinical implications for patients medicated with systemic BPs.

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Review Mechanism of action of BPs and BRONJ BPs and their mechanism of action BPs are structural analogs of pyrophosphate (P-O-P), with a carbon (P-C-P) replacing the central oxygen (fig. 1). Molecules of BPs all have two side chains from the central carbon, R1 and R2, which vary in structure depending on the product. The structure of the R1 side chain changes the affinity of BPs for hydroxyapatite (HAP) whereas the difference in R2 side chain determines the antiresorptive properties, and plays to a lesser extent a role in HAP affinity. Based on the structure of the R2 side chain, BPs can be divided into 2 classes, the non-nitrogen containing, and the nitrogen containing which inhibits osteoclast activity to a greater extent (Russell 2006). Examples of non-nitrogen containing BPs are etidronate and clodronate, and examples of nitrogen containing BPs are pamidronate and zolendronate. Since BPs bind to HAP, it was first hypothesized that BPs work by preventing the dissolution of HAP (Fleisch et al. 1966) and this theory even led to a dental study, using BPs as an intracanal medication to investigate if they may delay the progressive replacement of dentine by bone in cases of late reimplantation (Thong et al. 2009). However, it is now accepted that BPs mainly affect osteoclast function through inhibition of differentiation and maturation, loss of function and apoptosis. This eventually results in a decrease of bone resorption and an increase of mineralization (Fleisch 1998).

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BRONJ Definition The American Association of Oral and Maxillofacial Surgeons (2007) provided a position paper which defines BRONJ as : the persistence of exposed bone in the oral cavity, despite adequate treatment for 8 weeks, without local evidence of malignancy and no prior radiotherapy to the affected region in patients having been administrated BPs.

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Pathophysiology The pathophysiologic mechanism of BRONJ remains unclear and current hypotheses are mainly based on histopathological observations showing bone necrosis, inflammation, the presence of bacterial aggregates and/or areas of thickening of trabecular bone (Favia et al. 2009, Lesclous et al. 2009, Paparella et al. 2012). A widely accepted hypothesis considers BPs toxicity and the resulting decrease in bone remodeling as the initial and main event in the development of BRONJ (Sarin et al. 2008, Cheng et al. 2009, Tubiana-Hulin et al. 2009). Jaws are characterized by high bone turnover and are highly vascularized, which result in high local concentrations of BPs. Their action hampers normal bone turnover, resulting in acellular bone, which can get secondarily infected, due to (micro) trauma of the oral mucosa. Naik & Russo (2009) stressed the importance of infection, often caused by Actinomyces, in the initiation of BRONJ. The adverse effects of BPs aggravate the osteomyelitis and result in the osteonecrosis as described above. Other contributing factors in the pathogenesis are local inflammation, anti-angiogenic effects of BPs, an interplay between bone and overlying mucosa, direct toxic effects of BPs to oral epithelium and oral trauma (Sarin et al. 2008, Naik & Russo 2009, Tubiana-Hulin et al. 2009, Landesberg et al. 2011).

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Multiple risk factors for the development of BRONJ such as the dose of BPs, the duration of treatment, smoking, alcohol use, diabetes, chemotherapeutic, corticosteroid use and dental procedures, (especially dental extraction as mentioned above) have been described (Sarin et al. 2008, Allen & Burr 2009, Tubiana-Hulin et al. 2009, Landesberg et al. 2011).

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Clinical presentation Although one third of the lesions are painless, once established, BRONJ is often debilitating to the patient and refractory to treatment (Edwards et al. 2008). Some patients will present with persistent jaw pain, gingival swelling and a sinus tract (Fedele et al. 2010). When radiographically visible, BRONJ would appear as a radiolucency (Chiandussi et al. 2006) and could therefore be misdiagnosed as an empty socket or periapical lesion. Estilo et al. (2008) described tooth mobility and numbness of affected areas and identified Actinomyces species in all histological samples. Recently a non-exposed variant of BRONJ, which can even be undetected by computed tomography has been described (Fedele et al. 2010, Patel et al. 2012). Such clinical situation could easily mislead the clinician while establishing a differential diagnosis with other conditions such as non-odontogenic pain or periapical inflammation. Several classifications have attempted to define BRONJ (Kalmar 2012), among which the 5 stages classification adopted by the American Association of Maxillofacial Surgeons (AAOMS) and authored by Ruggiero et al. (2009) (Table 1).

Endodontic clinical implications of BPs administration. BPs can be administered orally or intravenously (i.v.), the latter being the most at risk of developing BRONJ (Khl et al. 2012). They reviewed 47 studies describing i.v. administration at oncologic dosage and 9 with oral administration at osteoporotic dosage. The

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mean incidence of BRONJ was 7% (mean duration of the studies 5 to 75 months) and 0.12% (mean duration of the studies 24 to > 60 months) respectively. Additionally, in a retrospective study with 4019 patients treated with i.v. BPs, only patients who received significantly higher doses of BPs for a longer period of time related to their underlying condition, developed BRONJ (Hoff et al. 2008). Furthermore, according to a retrospective study on 4835 patients treated with i.v. BPs (Estilo et al. 2008), the interruption or decrease of BP therapy did not seem to modify the course of BRONJ. Conflicting results are reported regarding the role of oral health and dental procedures. The study by Hoff et al. (2008) recognized poor oral health as a significant risk factor for developing BRONJ whereas the study by Estilo et al. (2008) did not, although 51,4% of the patients in that study had a nonhealing dental surgical procedure in the BRONJ site. In a cohort study of 1621 patients, dental extraction and the use of dentures but not nonsurgical endodontic treatment or periodontitis were associated with an increased probability of developing BRONJ (Vahtsevanos et al. 2009). On the contrary, periodontal disease was a comorbidity in the studies by Marx et al. (2005) and Hoff et al. (2008), in 84% and 41% of the cases of BRONJ respectively. Overall, surgical invasive procedures such as dental extraction seem to be the main precipitating factor associated with the development of BRONJ (Marx et al. 2005, Hoff et al. 2008, Filleul et al. 2010), and different guidelines concerning the cessation of BPs administration prior to invasive dental surgery have been proposed by several scientific societies but without consensus (Borromeo et al. 2011). The best prevention to invasive dental surgery may therefore be abstention and on account of this, any surgical endodontic procedure should also be avoided. Nonsurgical endodontic treatment has been recommended as an alternative to extraction in order to minimize the risk of developing BRONJ (Edwards et al. 2008). Indeed, nonsurgical

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2012 International Endodontic Journal

endodontic treatment aims to control and prevent the spread of infection to the periapical tissues. Nevertheless, there is no scientific evidence concerning the risk/safety ratio of endodontic therapy in patients taking BPs. Two steps during nonsurgical endodontic treatment may be able to trigger the pathophysiological process of BRONJ: Several studies (Kyrgidis 2009 Kyrgidis & Andreadis 2009 Kyrgidis 2010) pointed out the possible role of soft tissue damage in the initiation of BRONJ and insist on the fact that one should try to be as cautious and atraumatic as possible when placing a rubber dam clamp. This was emphasized by Gallego et al. (2011) who questioned the role played by the rubber dam clamp as trigger of BRONJ. Nase & Suzuki (2006) reported a case where gingival correction without bone involvement prior to nonsurgical endodontic treatment led to BRONJ in a patient medicated with oral BPs for 5 years. It therefore appears prudent to avoid any damage to the gingival tissues during tooth isolation and caries excavation. Even though there is no clear evidence whether infection is a primary or secondary event in BRONJ pathophysiology (Marx et al. 2005), Actinomyces species seem to be ubiquitous once infection has been identified (Hellstein & Marek 2005). It has also been demonstrated that the microbiota of periapical lesions refractory to endodontic treatment is often composed of Actinomyces species (Sunde et al. 2002). In a caseseries by Sedghizadeh et al. (2008), micro-organisms that are consistent with pathologic conditions such as periapical, pulpal, periodontal and mucosal (fungal) disease were identified by scanning electron microscopy, organized in biofilm in osteonecrosis sites. Furthermore, even when following guidelines, extrusion of debris beyond the apical foramen remains unavoidable during nonsurgical endodontic treatment (Ferraz et al. 2001). This raises the question whether antibiotic prophylactic

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coverage during nonsurgical endodontic treatment of a necrotic tooth with patients currently or formerly treated with BPs is indicated. This question has not yet been answered in the relevant literature. Since BPs affect the bone remodeling process, they could therefore influence the dynamics of the healing process of periapical lesions of endodontic origin. Retrospectively, no difference could be found between patients medicated or not with oral BPs for more than 1 year [2-12 years] on the healing pattern of apical periodontitis (Hsiao et al. 2009). However, the number of patients included in this study was small and no information was provided concerning comorbidities. It should also be mentioned that the evaluation of healing in this study was done by means of conventional radiography. It is a well-established fact that 2-dimensional radiography fails to accurately assess the periapical status when lesions are confined to the cancellous bone (Bender & Seltzer 2003, Liang et al. 2011). One can therefore speculate wheter some of the cases of BRONJ with unknown etiology were not be related to lesions of endodontic origin which went undetected by conventional radiography.

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Recommendations It is well-established that patients treated with BPs are at higher risk of developing osteonecrosis of the jaw (Mavrokokki et al. 2007). One of the main triggering factors is dental extraction. A position paper of the American Association of Endodontists (2006) discussed some of the endodontic implications of BRONJ. Endodontic therapy has not been identified as a significant risk factor in promoting BRONJ and is therefore considered as the favored alternative to extraction when possible (Marx et al. 2005). However, as soft tissue damage during tooth isolation might occur as well as extrusion of microorganisms during root canal instrumentation, care is recommended. Since there is scarce evidence on the consequences of nonsurgical endodontic treatment on patients treated with BPs, the informed

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consent of the patient and communication with the treating physician are of utmost importance. The low incidence of BRONJ makes it difficult to conduct clinical trials with high level of evidence in order to allow the establishment of evidence-based guidelines for nonsurgical endodontic treatment in patients treated with BPs. Even though the occurrence of BRONJ is considered to be a rare event, its consequences for the patient are catastrophic. Therefore, until more evidence is available, it is necessary to be cautious while performing nonsurgical endodontic treatment on patients medicated with BPs and at risk of developing BRONJ. The following recommendations are suggested by inductive reasoning and based on the literature: Some groups are particularly at risk and deserve particular care. These include patients treated with i.v. BPs as well as patients taking BPs orally for more than 3 years and who concomitantly present systemic issues (such as chronic kidney disease, diabetes, corticosteroid therapy etc.) (Bamias et al. 2005, Ruggiero et al. 2009). A one minute mouth-rinse with chlorhexidine prior to the start of the treatment would lower the bacterial load of the oral cavity (Cousido et al. 2010) and aim at decreasing the bacteremia caused by any soft tissues trauma. As impaired vascularization is a risk factor for osteonecrosis in general, the use of anaesthetic agents with vasoconstrictors should be avoided since BPs already exert an anti-angiogenic action (Tarassoff & Csermak 2003, Soltau et al. 2008). Working under aseptic conditions is mandatory. This includes steps such as the removal of caries and leaking restorations, the cleaning of the tooth as well as the placement of a rubber dam prior to the start of the intra-canal procedures. The proper adaptation of the dam should be checked. Disinfection of the tooth and of the dam should thereafter be performed by rubbing a disinfecting solution such as 80% ethanol for 2 minutes (Peters et al. 2002).

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2012 International Endodontic Journal

Particular care should be given to avoid any damage to the gingival tissues during the placement of a rubber dam clamp (Kyrgidis 2009). An alternative may be the use of wedges to stabilize the rubber dam instead of using clamps.

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Patency of the apical foramen should be avoided. This could only elevate the bacteremia (Debelian et al. 1995) inherent to any dental procedure without improving the outcome of the treatment (Wu et al. 2000).

Techniques which lower the risk of overfilling and overextension of the filling material are recommended since these may impair the endodontic treatment effectiveness (Liang et al. 2011) and exert irritation and cytotoxicity to the surrounding tissues (Scelza et al. 2012).

The evidence concerning the administration of a prophylactic dose of antibiotics in patients treated with BPs prior to nonsurgical endodontic treatment is non-existent and there is actually no consensus on this topic. It is important to balance the risk of developing BRONJ against the risk of adverse events from antibiotic prophylaxis. There should be concerns about the risks associated with the careless use of antibiotics in regards to adverse events such as allergic reactions caused by antibiotics or the induction of antibiotic resistance. However the risk of antibiotic resistance is considered to be low after a single dose of prophylactic antibiotics (Woodman et al. 1985). Another point is that cancer patients treated with chemotherapy are immunosupressed and at risk for neutropenia and subsequent related serious infections. Therefore it may be expected that such patients would be more prone to infectious complications following procedures such as nonsurgical endodontic treatment in infected canals. In cases of necrotic (infected) pulps in patients treated with i.v. BPs, or medicated with oral BPs for more than 3 years with concomitant risk factors, an antibiotic single-dose prophylaxis

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may be advocated, since the adverse effects of the recommended antibiotics, once allergies have been ruled out, are minimal. Since Actinomyces species are common in BRONJ loci, amoxicillin would appear as the first choice (Smith et al. 2005). Whenever there is allergy or severe intolerance to amoxicilline, clindamycin is an appropriate alternative (Smith et al. 2005). If several teeth in the same patient need to be treated, all treatments should be scheduled during a single visit if possible, in order to take place during a single antibiotic coverage period. The benefit of antibiotic prophylaxis for patients at risk of BRONJ is not proven and therefore no dosage recommendations can be suggested. Proper communication with the patient and the treating physician is therefore essential. In case of flare-up in a patient at risk of BRONJ and according to the observed symptoms, antibiotic coverage in addition to the required dental treatment may be a safe choice. Finally, it should be mentioned that recently osteonecrosis of the jaw has also been observed in patients medicated with a new antiresorptive class of drugs, Denosumab, a monoclonal antibody against RANKL (Saad et al. 2012). It therefore appears important to establish and adopt working protocols for patients undergoing nonsurgical endodontic treatment and who are medicated with drugs which may induce osteonecrosis of the jaws.

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Conclusion BPs are a commonly and widely prescribed group of drugs used for the treatment of various bone pathologies. Nonsurgical endodontic treatment is a safe alternative to dental extraction which is the main trigger to BRONJ. However, caution is mandatory during nonsurgical endodontic treatment in these patients. More studies are needed in order to obtain further insight on the safety of nonsurgical endodontic treatment in patients at risk of BRONJ.

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Acknowledgment The authors would like to thank Prof. Roeland De Moor for the stimulating initiative.

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Nase JB, Suzuki JB (2006) Osteonecrosis of the jaw and oral bisphosphonate treatment. Journal of the American Dental Association 137, 1115-9. Paparella ML, Brandizzi D, Santini-Araujo E, Cabrini RL (2012) Histopathological features of osteonecrosis of the jaw associated with bisphosphonates. Histopathology 60, 514-6. Patel S, Choyee S, Uyanne J, Nguyen A et al. (2012) Non-exposed bisphosphonate-related osteonecrosis of the jaw: a critical assessmen of current definition, staging and treatment guidelines. Oral Diseases doi: 10.1111/j.1601-0825.2012.01911.x [Epub] Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P (2007) A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clinical Therapeutics 29, 1548-58. Peters LB, van Winkelhoff AJ, Buijs JF, Wesselink PR (2002) Effects of instrumentation, irrigation and dressing with calcium hydroxide on infection in pulpless teeth with periapical bone lesions. International Endodontic Journal 35, 13-21. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. Journal of Oral and Maxillofacial Surgery 67, 2-12. Russell RG (2006) Bisphosphonates: from bench to bedside. Annals of the New York Academy of Sciences 1068, 367-401. Saad F, Brown JE, Van Poznak C et al. (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Annals of Oncology 23, 1341-7. Sarin J, DeRossi SS, Akintoye SO (2008) Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosis. Oral Diseases 14, 277-85.

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Accepted Article

2012 International Endodontic Journal

Table 1: 5 stage classification for the diagnosis of BRONJ as proposed by the AAOMS (Ruggiero et al. 2009) Stage At risk category Stage 0 Description The patient has been treated with BPs (either oral or intravenous (i.v.)) and there is no apparent necrotic bone Presence of nonspecific clinical findings and symptoms and no clinical evidence of bone necrosis Stage 1 Presence of exposed and necrotic bone in asymptomatic patients and no evidence of infection Stage 2 Presence of exposed necrotic bone associated with infection (pain and erythema, with or without purulent drainage) Stage 3 Presence of exposed necrotic bone, pain, infection, and one of the following clinical manifestations: exposed and necrotic bone extending beyond the region of alveolar bone, resulting in pathologic fracture, extraoral fistula, oral antra/oral nasal communication or osteolysis extending to the inferior border of the mandible or the sinus floor.

Accepted Article

2012 International Endodontic Journal

Figure 1: Chemical structure of the bisphosphonate molecule

Accepted Article
2012 International Endodontic Journal