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
Moinzadeh A-T, Shemesh H, Neirynck NAM, Aubert
C, Wesselink PR. Bisphosphonates and their clinical
implications in endodontic therapy. International Endodontic
Journal, 46, 391–398, 2013.
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 bisphosph-
onate-related osteonecrosis of the jaw (BRONJ). As
this condition is debilitating and difficult to treat, all
Introduction
Bisphosphonates (BPs) are nonmetabolized analogues
of pyrophosphates that are often prescribed to treat
patients with bone disorders, such as osteoporosis
(Gates et al. 2009), and Paget’s disease. Another indi-
cation for the use of BPs is the control of symptoms and
signs (pain, fractures, hypercalcemia) due to bone inva-
sion in multiple myeloma or bone metastasis in other
malignancies (Zysset et al. 1992, Mhaskar et al. 2012).
Correspondence: Amir-Teymour Moinzadeh, Department of
Endodontology, Academisch Centrum Tandheelkunde
Amsterdam (ACTA), University of Amsterdam and VU
University, Gustav Mahlerlaan 3004, 1081 LA Amsterdam,
The Netherlands (e-mail: a.moinzadeh@acta.nl).
© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd
efforts should be made to prevent its occurence in
patients at risk. The main triggering event is consid-
ered 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, epide-
miology and pathogenesis of BRONJ, as well as the
possible risk factors associated with its development
after nonsurgical endodontic treatment will be
described. Finally, several strategies will be proposed
for the prevention of BRONJ during nonsurgical end-
odontic treatment.
Keywords: bisphosphonate, BRONJ, endodontic
treatment, ONJ, osteonecrosis, root canal.
Received 2 August 2012; accepted 20 September 2012
Between 2005 and 2009, more than 150 million pre-
scriptions for BPs were dispensed worldwide for the
treatment of osteoporosis (Whitaker et al. 2012).
Rare systemic adverse events linked to the use of
BPs include renal (acute renal insufficiency, deteriora-
tion of chronic renal insufficiency), gastrointestinal
(gastrointestinal intolerance, anorexia), and bone and
joint pain (Kühl 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 (Kühl et al.
2012). According to several observational studies,
dental procedures are one of the risk factors for the
development of BRONJ. Mavrokokki et al. (2007)
found that the main trigger of BRONJ in patients
International Endodontic Journal, 46, 391–398, 2013 391
 Bisphosphonates and endodontic treatment Moinzadeh et al.
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 later, Marx et al. (2005) mentioned a possi-
ble 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 com-
mon 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. Amongst
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 endodon-
tic treatment should be favoured to dental extractions
in patients at higher risk of BRONJ whenever possible.
The first part of this review describes the biochemi-
cal mechanism of action of BPs molecules and dis-
cusses 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
Bisphosphonates (BPs) and their mechanism of action
Bisphosphonates (BPs) are structural analogues of
pyrophosphate (P-O-P), with a carbon (P-C-P) replac-
ing 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 prod-
uct. The structure of the R1 side chain changes the
Figure 1 Chemical structure of the bisphosphonate mole-
cule.
392 International Endodontic Journal, 46, 391–398, 2013
affinity of BPs for hydroxyapatite (HAP) whereas the
difference in R2 side chain determines the antiresorp-
tive 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 nonnitro-
gen containing and the nitrogen containing, which
inhibits osteoclast activity to a greater extent (Russell
2006). Examples of nonnitrogen containing BPs are
etidronate and clodronate, and examples of nitrogen
containing BPs are pamidronate and zoledronate.
As BPs bind to HAP, it was first hypothesized that
BPs work by preventing the dissolution of HAP (Fle-
isch et al. 1966), and this theory even led to a dental
study, using BPs as an intracanal medication to
investigate whether they may delay the progressive
replacement of dentine by bone in cases of late reim-
plantation (Thong et al. 2009).
However, it is now accepted that BPs mainly affect
osteoclast function through inhibition of differentia-
tion and maturation, loss of function and apoptosis.
This eventually results in a decrease in bone resorp-
tion and an increase in mineralization (Fleisch 1998).
Bisphosphonate-related osteonecrosis of the jaw
(BRONJ)
Definition. The American Association of Oral & Maxil-
lofacial 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 show-
ing bone necrosis, inflammation, the presence of bac-
terial 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 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
bone, which can get secondarily infected, due to
(micro) trauma of the oral mucosa.
© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd

Naik & Russo (2009) stressed the importance of
infection, often caused by Actinomyces, in the initia-
tion of BRONJ. The adverse effects of BPs aggravate
the osteomyelitis and result in the osteonecrosis as
described earlier.
Other contributing factors in the pathogenesis are
local inflammation, antiangiogenic 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).
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).
Clinical presentation. Although one-third of the lesions
are painless, once established, BRONJ is often debilitat-
ing 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 it is radiographically visi-
ble, BRONJ appears 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 nonexposed 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 whilst establishing a differential
diagnosis with other conditions such as nonodonto-
genic pain or periapical inflammation.
Several classifications have attempted to define
BRONJ (Kalmar 2012), amongst which the five 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
(Kühl et al. 2012). They reviewed 47 studies describ-
ing i.v. administration at oncologic dosage and nine
with oral administration at osteoporotic dosage. The
© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd
Moinzadeh et al. Bisphosphonates and endodontic treatment
mean incidence of BRONJ was 7% (mean duration of
the studies 5–75 months) and 0.12% (mean duration
of the studies 24 to >60 months), respectively. Addi-
tionally, in a retrospective study with 4019 patients
treated with i.v. BPs, only patients who received sig-
nificantly 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 in 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 signifi-
cant 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
Table 1 Five stage classification for the diagnosis of bis-
phosphonate-related osteonecrosis of the jaw (BRONJ) as
proposed by the American Association of Maxillofacial
Surgeons (AAOMS) (Ruggiero et al. 2009)
Stages Description
At risk category The patient has been treated with BP’s
(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.
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
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 recom-
mended as an alternative to extraction to minimize
the risk of developing BRONJ (Edwards et al. 2008).
Indeed, nonsurgical 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 endodon-
tic therapy in patients taking BPs.
Two steps during nonsurgical endodontic treatment
may be able to trigger the pathophysiological process
of BRONJ:
1. Several studies (Kyrgidis 2009 Kyrgidis 2010
Kyrgidis & Andreadis 2009) pointed out the pos-
sible 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 ques-
tioned the role played by the rubber dam clamp
as a 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 tis-
sues during tooth isolation and caries excavation.
2. Even though there is no clear evidence whether
infection is a primary or secondary event in
BRONJ pathophysiology (Marx et al. 2005), Acti-
nomyces species seem to be ubiquitous once infec-
tion 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 spe-
cies (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
394 International Endodontic Journal, 46, 391–398, 2013
(fungal) disease were identified by scanning elec-
tron microscopy, organized in biofilm in osteone-
crosis 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 prophylac-
tic coverage is indicated during nonsurgical end-
odontic treatment for a necrotic tooth with
patients currently or formerly treated with BPs.
This question has not yet been answered in the
relevant literature.
As BPs affect the bone remodelling process, they
could therefore influence the dynamics of the healing
process of periapical lesions of endodontic origin. Ret-
rospectively, no difference could be found on the heal-
ing pattern of apical periodontitis between patients
medicated or not with oral BPs for more than 1 year
[2–12 years] (Hsiao et al. 2009). However, the num-
ber of patients included in this study was small, and
no information was provided concerning comorbidi-
ties. It should also be mentioned that the evaluation
of healing in this study was carried out by means of
conventional radiography. It is a well-established fact
that two-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 whether
some of the cases of BRONJ with unknown aetiology
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 trigger-
ing factors is dental extraction. A position paper of
the American Association of Endodontics (2006) dis-
cussed some of the endodontic implications of BRONJ.
Endodontic therapy has not been identified as a signifi-
cant risk factor for promoting BRONJ and is therefore
considered as the favoured alternative to extraction
when possible (Marx et al. 2005). However, as soft
tissue damage during tooth isolation might occur as
well as extrusion of micro-organisms during root canal
instrumentation, care is recommended. As there is
scarce evidence on the consequences of nonsurgical
endodontic treatment on patients treated with BPs, the
informed consent of the patient and communication
with the treating physician are of utmost importance.
© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd

The low incidence of BRONJ makes it difficult to
conduct clinical trials with high level of evidence to
allow the establishment of evidence-based guidelines
for nonsurgical endodontic treatment in patients trea-
ted 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 evi-
dence is available, it is necessary to be cautious whilst
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 who have been taking
BPs orally for more than 3 years and who concom-
itantly present systemic issues (such as chronic kid-
ney disease, diabetes, corticosteroid therapy).
(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 tissue trauma.
• As impaired vascularization is a risk factor for osteo-
necrosis in general, the use of anaesthetic agents
with vasoconstrictors should be avoided because
BPs already exert an antiangiogenic 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
and the placement of a rubber dam prior to the
start of the intracanal procedures. The proper adap-
tation 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 min (Peters et al. 2002).
• Particular care should be given to avoid any dam-
age to the gingival tissues during the placement of
a rubber dam clamp (Kyrgidis 2009). An alterna-
tive may be the use of wedges to stabilize the rub-
ber dam instead of using clamps.
• 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 because these may impair the end-
© 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd
Moinzadeh et al. Bisphosphonates and endodontic treatment
odontic treatment effectiveness (Liang et al. 2011)
and exert irritation and cytotoxicity to the sur-
rounding 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
nonexistent, and there is actually no consensus on
this topic. It is important to balance the risk of devel-
oping 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 aller-
gic 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 patients with cancer treated
with chemotherapy are immunosupressed and at risk
of neutropenia and subsequent related serious infec-
tions. Therefore, it may be expected that such patients
would be more prone to infectious complications fol-
lowing procedures such as nonsurgical endodontic
treatment in infected canals.
In cases of necrotic (infected) pulps in patients trea-
ted with i.v. BPs, or medicated with oral BPs for more
than 3 years with concomitant risk factors, an antibi-
otic single-dose prophylaxis may be advocated,
because the adverse effects of the recommended anti-
biotics, once allergies have been ruled out, are mini-
mal. As 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 amoxicillin, clindamycin is an
appropriate alternative (Smith et al. 2005). If several
teeth in the same patient need to be treated, all treat-
ments should be scheduled during a single visit if pos-
sible, 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 osteonecrosis
of the jaw has also been recently 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
International Endodontic Journal, 46, 391–398, 2013 395
 Bisphosphonates and endodontic treatment Moinzadeh et al.
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 patholo-
gies. Nonsurgical endodontic treatment is a safe alter-
native 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 to obtain further insight into
the safety of nonsurgical endodontic treatment in
patients at risk of BRONJ.
Acknowledgement
The authors would like to thank Prof. Roeland De
Moor for the stimulating initiative.
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