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doi:10.1111/iej.

12018

Review
Bisphosphonates and their clinical implications in
endodontic therapy

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


1
Department of Endodontology, Academic Center of Dentistry Amsterdam (ACTA), University of Amsterdam and VU
University, Amsterdam, The Netherlands; 2Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium; and
3
Department of Head and Neck Surgery, CHU Charleroi, Charleroi, Belgium

Abstract efforts should be made to prevent its occurence in


patients at risk. The main triggering event is consid-
Moinzadeh A-T, Shemesh H, Neirynck NAM, Aubert
ered to be dental extraction. Even though nonsurgical
C, Wesselink PR. Bisphosphonates and their clinical
endodontic treatment appears to be a relatively safe
implications in endodontic therapy. International Endodontic
procedure, care remains essential. After an overview
Journal, 46, 391–398, 2013.
of this class of drugs, the clinical presentation, epide-
This review gives an overview of the factors that may miology and pathogenesis of BRONJ, as well as the
play a role in the development of osteonecrosis of the possible risk factors associated with its development
jaw in patients treated with bisphosphonates (BPs) after nonsurgical endodontic treatment will be
and undergoing nonsurgical endodontic treatment as described. Finally, several strategies will be proposed
well as some recommendations for its prevention. BPs for the prevention of BRONJ during nonsurgical end-
are a widely prescribed group of drugs for diverse odontic treatment.
bone diseases. The occasional but devastating adverse
Keywords: bisphosphonate, BRONJ, endodontic
effect of these drugs has been described as bisphosph-
treatment, ONJ, osteonecrosis, root canal.
onate-related osteonecrosis of the jaw (BRONJ). As
this condition is debilitating and difficult to treat, all Received 2 August 2012; accepted 20 September 2012

Between 2005 and 2009, more than 150 million pre-


Introduction
scriptions for BPs were dispensed worldwide for the
Bisphosphonates (BPs) are nonmetabolized analogues treatment of osteoporosis (Whitaker et al. 2012).
of pyrophosphates that are often prescribed to treat Rare systemic adverse events linked to the use of
patients with bone disorders, such as osteoporosis BPs include renal (acute renal insufficiency, deteriora-
(Gates et al. 2009), and Paget’s disease. Another indi- tion of chronic renal insufficiency), gastrointestinal
cation for the use of BPs is the control of symptoms and (gastrointestinal intolerance, anorexia), and bone and
signs (pain, fractures, hypercalcemia) due to bone inva- joint pain (Kühl et al. 2012). BP-related osteonecrosis
sion in multiple myeloma or bone metastasis in other of the jaw (BRONJ) is also one of the complications
malignancies (Zysset et al. 1992, Mhaskar et al. 2012). 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 (Kühl et al.
Correspondence: Amir-Teymour Moinzadeh, Department of 2012). According to several observational studies,
Endodontology, Academisch Centrum Tandheelkunde
Amsterdam (ACTA), University of Amsterdam and VU
dental procedures are one of the risk factors for the
University, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, development of BRONJ. Mavrokokki et al. (2007)
The Netherlands (e-mail: a.moinzadeh@acta.nl). found that the main trigger of BRONJ in patients

© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd International Endodontic Journal, 46, 391–398, 2013 391
Bisphosphonates and endodontic treatment Moinzadeh et al.

taking BPs was dental extraction. This was confirmed affinity of BPs for hydroxyapatite (HAP) whereas the
by several studies which identified dental extractions difference in R2 side chain determines the antiresorp-
or invasive surgical procedures as being one of the tive properties and plays to a lesser extent a role in
risk factors for the development of BRONJ (Marx et al. HAP affinity. Based on the structure of the R2–side
2005, Pazianas et al. 2007, Hoff et al. 2008, Filleul chain, BPs can be divided into 2 classes, the nonnitro-
et al. 2010). gen containing and the nitrogen containing, which
In 2003, the first cases of osteonecrosis of the jaw in inhibits osteoclast activity to a greater extent (Russell
patients medicated with BPs were reported (Marx 2006). Examples of nonnitrogen containing BPs are
2003), and later, Marx et al. (2005) mentioned a possi- etidronate and clodronate, and examples of nitrogen
ble association between root canal treatment and the containing BPs are pamidronate and zoledronate.
development of BRONJ in a case series. In a total of As BPs bind to HAP, it was first hypothesized that
119 patients presenting with BRONJ, the most com- BPs work by preventing the dissolution of HAP (Fle-
mon dental comorbidity was considered to be clinically isch et al. 1966), and this theory even led to a dental
and radiographically apparent marginal periodontitis, study, using BPs as an intracanal medication to
which was present in 84% of the patients. Previous investigate whether they may delay the progressive
root canal treatments with supposed evidence of failure replacement of dentine by bone in cases of late reim-
(presence of an apical radiolucency or an inadequate plantation (Thong et al. 2009).
root filling) counted for 10.9% of the cases. Amongst However, it is now accepted that BPs mainly affect
the inciting events leading to BRONJ, dental extraction osteoclast function through inhibition of differentia-
counted for 37.8% of the cases as compared to 0.8% for tion and maturation, loss of function and apoptosis.
endodontic surgery. This eventually results in a decrease in bone resorp-
As a result of these findings, nonsurgical endodon- tion and an increase in mineralization (Fleisch 1998).
tic treatment should be favoured to dental extractions
in patients at higher risk of BRONJ whenever possible. Bisphosphonate-related osteonecrosis of the jaw
The first part of this review describes the biochemi- (BRONJ)
cal mechanism of action of BPs molecules and dis-
cusses the pathosis of BRONJ. The second part will Definition. The American Association of Oral & Maxil-
describe the endodontic clinical implications for lofacial Surgeons (2007) provided a position paper
patients medicated with systemic BPs. which defines BRONJ as: ‘the persistence of exposed
bone in the oral cavity, despite adequate treatment
for 8 weeks, without local evidence of malignancy
Review
and no prior radiotherapy to the affected region in
patients having been administrated BPs’.
Mechanism of action of BPs and BRONJ
Bisphosphonates (BPs) and their mechanism of action Pathophysiology. The pathophysiologic mechanism of
Bisphosphonates (BPs) are structural analogues of BRONJ remains unclear, and current hypotheses are
pyrophosphate (P-O-P), with a carbon (P-C-P) replac- mainly based on histopathological observations show-
ing the central oxygen (fig. 1). Molecules of BPs all ing bone necrosis, inflammation, the presence of bac-
have two side chains from the central carbon, R1 and terial aggregates and/or areas of thickening of
R2, which vary in structure depending on the prod- trabecular bone (Favia et al. 2009, Lesclous et al.
uct. The structure of the R1 side chain changes the 2009, Paparella et al. 2012).
A widely accepted hypothesis considers BPs toxicity
and the resulting decrease in bone remodelling 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 ham-
pers normal bone turnover, resulting in acellular
Figure 1 Chemical structure of the bisphosphonate mole- bone, which can get secondarily infected, due to
cule. (micro) trauma of the oral mucosa.

392 International Endodontic Journal, 46, 391–398, 2013 © 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd
Moinzadeh et al. Bisphosphonates and endodontic treatment

Naik & Russo (2009) stressed the importance of mean incidence of BRONJ was 7% (mean duration of
infection, often caused by Actinomyces, in the initia- the studies 5–75 months) and 0.12% (mean duration
tion of BRONJ. The adverse effects of BPs aggravate of the studies 24 to >60 months), respectively. Addi-
the osteomyelitis and result in the osteonecrosis as tionally, in a retrospective study with 4019 patients
described earlier. treated with i.v. BPs, only patients who received sig-
Other contributing factors in the pathogenesis are nificantly higher doses of BPs for a longer period of
local inflammation, antiangiogenic effects of BPs, an time related to their underlying condition developed
interplay between bone and overlying mucosa, direct BRONJ (Hoff et al. 2008). Furthermore, according to
toxic effects of BPs to oral epithelium and oral trauma a retrospective study on 4835 patients treated with
(Sarin et al. 2008, Naik & Russo 2009, Tubiana- i.v. BPs (Estilo et al. 2008), the interruption or
Hulin et al. 2009, Landesberg et al. 2011). decrease in BP therapy did not seem to modify the
Multiple risk factors for the development of BRONJ course of BRONJ.
such as the dose of BPs, the duration of treatment, Conflicting results are reported regarding the role of
smoking, alcohol use, diabetes, chemotherapeutic, oral health and dental procedures. The study by Hoff
corticosteroid use and dental procedures (especially et al. (2008) recognized poor oral health as a signifi-
dental extraction as mentioned above) have been cant risk factor for developing BRONJ whereas the
described (Sarin et al. 2008, Allen & Burr 2009, study by Estilo et al. (2008) did not, although 51.4%
Tubiana-Hulin et al. 2009, Landesberg et al. 2011). of the patients in that study had a nonhealing dental
surgical procedure in the BRONJ site. In a cohort
Clinical presentation. Although one-third of the lesions study of 1621 patients, dental extraction and the use
are painless, once established, BRONJ is often debilitat- of dentures but not nonsurgical endodontic treatment
ing to the patient and refractory to treatment or periodontitis were associated with an increased
(Edwards et al. 2008). Some patients will present with probability of developing BRONJ (Vahtsevanos et al.
persistent jaw pain, gingival swelling and a sinus tract 2009). On the contrary, periodontal disease was a
(Fedele et al. 2010). When it is radiographically visi- comorbidity in the studies by Marx et al. (2005) and
ble, BRONJ appears as a radiolucency (Chiandussi
et al. 2006) and could therefore be misdiagnosed as
Table 1 Five stage classification for the diagnosis of bis-
an empty socket or periapical lesion. Estilo et al.
phosphonate-related osteonecrosis of the jaw (BRONJ) as
(2008) described tooth mobility and numbness of proposed by the American Association of Maxillofacial
affected areas and identified Actinomyces species in all Surgeons (AAOMS) (Ruggiero et al. 2009)
histological samples. Recently, a nonexposed variant
Stages Description
of BRONJ, which can even be undetected by computed
tomography, has been described (Fedele et al. 2010, At risk category The patient has been treated with BP’s
Patel et al. 2012). Such clinical situation could easily (either oral or intravenous (i.v.)), and there
is no apparent necrotic bone
mislead the clinician whilst establishing a differential
Stage 0 Presence of nonspecific clinical findings and
diagnosis with other conditions such as nonodonto- symptoms and no clinical evidence of
genic pain or periapical inflammation. bone necrosis
Several classifications have attempted to define Stage 1 Presence of exposed and necrotic bone in
BRONJ (Kalmar 2012), amongst which the five stages asymptomatic patients and no evidence of
infection
classification adopted by the American Association of
Stage 2 Presence of exposed necrotic bone
Maxillofacial Surgeons (AAOMS) and authored by associated with infection (pain and
Ruggiero et al. (2009) (Table 1). erythema, with or without purulent
drainage)
Stage 3 Presence of exposed necrotic bone, pain,
Endodontic clinical implications of BPs infection and one of the following clinical
administration manifestations:
exposed and necrotic bone extending
BPs can be administered orally or intravenously (i.v.), beyond the region of alveolar bone,
the latter being the most at risk of developing BRONJ resulting in pathologic fracture, extraoral
(Kühl et al. 2012). They reviewed 47 studies describ- fistula, oral antra/oral nasal communication
or osteolysis extending to the inferior
ing i.v. administration at oncologic dosage and nine
border of the mandible or the sinus floor.
with oral administration at osteoporotic dosage. The

© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd International Endodontic Journal, 46, 391–398, 2013 393
Bisphosphonates and endodontic treatment Moinzadeh et al.

Hoff et al. (2008), in 84% and 41% of the cases of (fungal) disease were identified by scanning elec-
BRONJ, respectively. tron microscopy, organized in biofilm in osteone-
Overall, surgical invasive procedures such as dental crosis sites. Furthermore, even when following
extraction seem to be the main precipitating factor guidelines, extrusion of debris beyond the apical
associated with the development of BRONJ (Marx foramen remains unavoidable during nonsurgical
et al. 2005, Hoff et al. 2008, Filleul et al. 2010) and endodontic treatment (Ferraz et al. 2001). This
different guidelines concerning the cessation of BPs raises the question whether antibiotic prophylac-
administration prior to invasive dental surgery have tic coverage is indicated during nonsurgical end-
been proposed by several scientific societies but odontic treatment for a necrotic tooth with
without consensus (Borromeo et al. 2011). The best patients currently or formerly treated with BPs.
prevention to invasive dental surgery may therefore This question has not yet been answered in the
be abstention, and on account of this, any surgical relevant literature.
endodontic procedure should also be avoided. As BPs affect the bone remodelling process, they
Nonsurgical endodontic treatment has been recom- could therefore influence the dynamics of the healing
mended as an alternative to extraction to minimize process of periapical lesions of endodontic origin. Ret-
the risk of developing BRONJ (Edwards et al. 2008). rospectively, no difference could be found on the heal-
Indeed, nonsurgical endodontic treatment aims to ing pattern of apical periodontitis between patients
control and prevent the spread of infection to the medicated or not with oral BPs for more than 1 year
periapical tissues. Nevertheless, there is no scientific [2–12 years] (Hsiao et al. 2009). However, the num-
evidence concerning the risk/safety ratio of endodon- ber of patients included in this study was small, and
tic therapy in patients taking BPs. no information was provided concerning comorbidi-
Two steps during nonsurgical endodontic treatment ties. It should also be mentioned that the evaluation
may be able to trigger the pathophysiological process of healing in this study was carried out by means of
of BRONJ: conventional radiography. It is a well-established fact
1. Several studies (Kyrgidis 2009 Kyrgidis 2010 that two-dimensional radiography fails to accurately
Kyrgidis & Andreadis 2009) pointed out the pos- assess the periapical status when lesions are confined
sible role of soft tissue damage in the initiation of to the cancellous bone (Bender & Seltzer 2003, Liang
BRONJ and insist on the fact that one should try et al. 2011). One can therefore speculate whether
to be as cautious and atraumatic as possible some of the cases of BRONJ with unknown aetiology
when placing a rubber dam clamp. This was were not be related to lesions of endodontic origin,
emphasized by Gallego et al. (2011) who ques- which went undetected by conventional radiography.
tioned the role played by the rubber dam clamp
as a trigger of BRONJ. Nase & Suzuki (2006)
Recommendations
reported a case where gingival correction without
bone involvement prior to nonsurgical endodontic It is well established that patients treated with BPs
treatment led to BRONJ in a patient medicated are at higher risk of developing osteonecrosis of the
with oral BPs for 5 years. It therefore appears jaw (Mavrokokki et al. 2007). One of the main trigger-
prudent to avoid any damage to the gingival tis- ing factors is dental extraction. A position paper of
sues during tooth isolation and caries excavation. the American Association of Endodontics (2006) dis-
2. Even though there is no clear evidence whether cussed some of the endodontic implications of BRONJ.
infection is a primary or secondary event in Endodontic therapy has not been identified as a signifi-
BRONJ pathophysiology (Marx et al. 2005), Acti- cant risk factor for promoting BRONJ and is therefore
nomyces species seem to be ubiquitous once infec- considered as the favoured alternative to extraction
tion has been identified (Hellstein & Marek 2005). when possible (Marx et al. 2005). However, as soft
It has also been demonstrated that the microbiota tissue damage during tooth isolation might occur as
of periapical lesions refractory to endodontic well as extrusion of micro-organisms during root canal
treatment is often composed of Actinomyces spe- instrumentation, care is recommended. As there is
cies (Sunde et al. 2002). In a case series by scarce evidence on the consequences of nonsurgical
Sedghizadeh et al. (2008), micro-organisms that endodontic treatment on patients treated with BPs, the
are consistent with pathologic conditions such informed consent of the patient and communication
as periapical, pulpal, periodontal and mucosal with the treating physician are of utmost importance.

394 International Endodontic Journal, 46, 391–398, 2013 © 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd
Moinzadeh et al. Bisphosphonates and endodontic treatment

The low incidence of BRONJ makes it difficult to odontic treatment effectiveness (Liang et al. 2011)
conduct clinical trials with high level of evidence to and exert irritation and cytotoxicity to the sur-
allow the establishment of evidence-based guidelines rounding tissues (Scelza et al. 2012).
for nonsurgical endodontic treatment in patients trea- The evidence concerning the administration of a
ted with BPs. Even though the occurrence of BRONJ is prophylactic dose of antibiotics in patients treated
considered to be a rare event, its consequences for the with BPs prior to nonsurgical endodontic treatment is
patient are catastrophic. Therefore, until more evi- nonexistent, and there is actually no consensus on
dence is available, it is necessary to be cautious whilst this topic. It is important to balance the risk of devel-
performing nonsurgical endodontic treatment on oping BRONJ against the risk of adverse events from
patients medicated with BPs and at risk of developing antibiotic prophylaxis. There should be concerns
BRONJ. The following recommendations are suggested about the risks associated with the careless use of
by inductive reasoning and based on the literature: antibiotics in regards to adverse events such as aller-
• Some groups are particularly at risk and deserve gic reactions caused by antibiotics or the induction of
particular care. These include patients treated with antibiotic resistance. However, the risk of antibiotic
i.v. BPs as well as patients who have been taking resistance is considered to be low after a single dose
BPs orally for more than 3 years and who concom- of prophylactic antibiotics (Woodman et al. 1985).
itantly present systemic issues (such as chronic kid- Another point is that patients with cancer treated
ney disease, diabetes, corticosteroid therapy). with chemotherapy are immunosupressed and at risk
(Bamias et al. 2005, Ruggiero et al. 2009). of neutropenia and subsequent related serious infec-
• A one minute mouth rinse with chlorhexidine tions. Therefore, it may be expected that such patients
prior to the start of the treatment would lower the would be more prone to infectious complications fol-
bacterial load of the oral cavity (Cousido et al. lowing procedures such as nonsurgical endodontic
2010) and aim at decreasing the bacteremia treatment in infected canals.
caused by any soft tissue trauma. In cases of necrotic (infected) pulps in patients trea-
• As impaired vascularization is a risk factor for osteo- ted with i.v. BPs, or medicated with oral BPs for more
necrosis in general, the use of anaesthetic agents than 3 years with concomitant risk factors, an antibi-
with vasoconstrictors should be avoided because otic single-dose prophylaxis may be advocated,
BPs already exert an antiangiogenic action (Tarassoff because the adverse effects of the recommended anti-
& Csermak 2003, Soltau et al. 2008). biotics, once allergies have been ruled out, are mini-
• Working under aseptic conditions is mandatory. mal. As Actinomyces species are common in BRONJ
This includes steps such as the removal of caries loci, amoxicillin would appear as the first choice
and leaking restorations, the cleaning of the tooth (Smith et al. 2005). Whenever there is allergy or
and the placement of a rubber dam prior to the severe intolerance to amoxicillin, clindamycin is an
start of the intracanal procedures. The proper adap- appropriate alternative (Smith et al. 2005). If several
tation of the dam should be checked. Disinfection teeth in the same patient need to be treated, all treat-
of the tooth and of the dam should thereafter be ments should be scheduled during a single visit if pos-
performed by rubbing a disinfecting solution such sible, to take place during a single antibiotic coverage
as 80% ethanol for 2 min (Peters et al. 2002). period. The benefit of antibiotic prophylaxis for
• Particular care should be given to avoid any dam- patients at risk of BRONJ is not proven, and therefore,
age to the gingival tissues during the placement of no dosage recommendations can be suggested. Proper
a rubber dam clamp (Kyrgidis 2009). An alterna- communication with the patient and the treating
tive may be the use of wedges to stabilize the rub- physician is therefore essential. In case of flare-up in
ber dam instead of using clamps. a patient at risk of BRONJ and according to the
• Patency of the apical foramen should be avoided. observed symptoms, antibiotic coverage in addition to
This could only elevate the bacteremia (Debelian the required dental treatment may be a safe choice.
et al. 1995) inherent to any dental procedure Finally, it should be mentioned that osteonecrosis
without improving the outcome of the treatment of the jaw has also been recently observed in patients
(Wu et al. 2000). medicated with a new antiresorptive class of drugs,
• Techniques which lower the risk of overfilling denosumab, a monoclonal antibody against RANKL
and overextension of the filling material are (Saad et al. 2012). It therefore appears important to
recommended because these may impair the end- establish and adopt working protocols for patients

© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd International Endodontic Journal, 46, 391–398, 2013 395
Bisphosphonates and endodontic treatment Moinzadeh et al.

undergoing nonsurgical endodontic treatment and bisphosphonate-associated osteonecrosis of the jaws. Dento-
who are medicated with drugs which may induce maxillofacial Radiology 35, 236–43.
osteonecrosis of the jaws. Cousido MC, Tomas Carmona I, Garcia-Caballero L, Limeres
J, Alvarez M, Diz P (2010) In vivo substantivity of 0.12%
and 0.2% chlorhexidine mouthrinses on salivary bacteria.
Conclusion Clinical Oral Investigations 14, 397–402.
Debelian GJ, Olsen I, Tronstad L (1995) Bacteremia in con-
BPs are a commonly and widely prescribed group of junction with endodontic therapy. Endodontics and Dental
drugs used for the treatment of various bone patholo- Traumatology 11, 142–9.
gies. Nonsurgical endodontic treatment is a safe alter- Edwards BJ, Gounder M, McKoy JM et al. (2008) Pharmaco-
native to dental extraction which is the main trigger vigilance and reporting oversight in US FDA fast-track
to BRONJ. However, caution is mandatory during process: bisphosphonates and osteonecrosis of the jaw.
nonsurgical endodontic treatment in these patients. Lancet Oncology 9, 1166–72.
More studies are needed to obtain further insight into Estilo CL, Van Poznak CH, Wiliams T et al. (2008) Osteone-
the safety of nonsurgical endodontic treatment in crosis of the maxilla and mandible in patients with
patients at risk of BRONJ. advanced cancer treated with bisphosphonate therapy. The
Oncologist 13, 911–20.
Favia G, Pilolli GP, Maiorano E (2009) Histologic and histo-
Acknowledgement morphometric features of bisphosphonate-related osteone-
crosis of the jaws: an analysis of 31 cases with confocal
The authors would like to thank Prof. Roeland De laser scanning microscopy. Bone 45, 406–13.
Moor for the stimulating initiative. Fedele S, Porter SR, D’Aiuto F et al. (2010) Nonexposed vari-
ant of bisphosphonate-associated osteonecrosis of the jaw:
a case series. American Journal of Medicine 123, 1060–4.
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