Bisphosphonates and Their Clinical Implications in Endodontic Therapy

8/13/2019 Bisphosphonates and Their Clinical Implications in Endodontic Therapy

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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

Received Date : 02-Aug-2012

Accepted Date : 20-Sep-2012

Article type : Review

Bisphosphonates and their clinical implications in endodontictherapy

A.T. Moinzadeh1, H. Shemesh

1, N.A.M. Neirynck

2, C. Aubert

3, P.R. Wesselink

1

1Department 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: [email protected]

tel: +31(0)205980363


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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.

Introduction

Bisphosphonates (BPs) are non-metabolized analogues of pyrophosphates that are often

prescribed to treat patients with bone disorders, such as osteoporosis (Gateset 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 (Whitakeret 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 (Kuhlet al.2012). BP-related osteonecrosis of

the jaw (BRONJ) is also one of the complications associated with the administration of these

drugs (Marxet al.2005). A positive correlation exists between the duration and cumulative

dosage of BP treatment and the incidence of BRONJ (Kuhlet 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 (Marxet al.2005, Pazianaset al.2007, Hoffet al.2008, Filleulet

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 filling) 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.

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-nitrogencontaining, and the nitrogencontaining 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 (Thonget 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.

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, Lesclouset al.2009, Paparellaet 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,

Chenget al.2009, Tubiana-Hulinet 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 (Sarinet al.2008, Naik & Russo 2009, Tubiana-Hulinet al.2009,

Landesberget 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-Hulinet al.2009, Landesberget al.2011).

Clinical presentation

Although one third of the lesions are painless, once established, BRONJ is often debilitating

to the patient and refractory to treatment (Edwardset 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 (Hoffet al.2008). Furthermore, according to a retrospective study on 4835 patients

treated with i.v.BPs (Estiloet 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),in84% 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 (Marxet al.2005, Hoffet 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 (Edwardset al.2008). Indeed, nonsurgical


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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) pointedout 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 secondaryevent in BRONJ pathophysiology (Marxet 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 case-

series 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 (Ferrazet 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 (Hsiaoet 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.

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 includepatients 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.) (Bamiaset al.2005, Ruggieroet al.2009).

- A one minute mouth-rinse with chlorhexidine prior to the start of the treatment wouldlower the bacterial load of the oral cavity (Cousidoet 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 ofanaesthetic agents with vasoconstrictors should be avoided since BPs already exert an

anti-angiogenic action (Tarassoff & Csermak 2003, Soltauet al.2008).

- Working under aseptic conditions is mandatory. This includes steps such as theremoval 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 (Peterset al.2002).


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- Particular care should be given to avoid any damage to the gingival tissues during theplacement of a rubber dam clamp (Kyrgidis 2009). An alternative may be the use of

wedges to stabilize the rubber dam instead of using clamps.

- Patency of the apical foramen should be avoided. This could only elevate thebacteremia (Debelianet al.1995) inherent to any dental procedure without improving

the outcome of the treatment (Wuet al.2000).

- Techniques which lower the risk of overfilling and overextension of the fillingmaterial are recommended since these may impair the endodontic treatment

effectiveness (Liang et al. 2011) and exert irritation and cytotoxicity to the

surrounding tissues (Scelzaet 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 (Smithet 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 (Saadet 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.

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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Table 1: 5 stage classification for the diagnosis of BRONJ as proposed by the AAOMS

(Ruggiero et al.2009)

Stage Description

At risk

category

The patient has been treated with BPs (either oral or intravenous (i.v.)) and there

is no apparent necrotic bone

Stage 0 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.


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Figure 1: Chemical structure of the bisphosphonate molecule

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Bisphosphonates and Their Clinical Implications in Endodontic Therapy