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International Endodontic Journal / Volume 46, Issue 5

/ p. 391-398

Review !Free Access

Bisphosphonates and their clinical

implications in endodontic therapy

A.-T. Moinzadeh ", H. Shemesh, N. A. M. Neirynck, 

C. Aubert, P. R. Wesselink

First published: 01 October 2012

https://doi.org/10.1111/iej.12018
Citations: 25

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 e"ect of these drugs
has been described as bisphosphonate-
related osteonecrosis of the jaw (BRONJ).
As this condition is debilitating and di#cult
to treat, all e"orts 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 with 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 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 indication
for the use of BPs is 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).

Rare systemic adverse events linked to the

use of BPs include renal (acute renal
insu#ciency, deterioration of chronic renal
insu#ciency), 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 taking BPs was
dental extraction. This was con$rmed by
several studies which identi$ed 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, Ho" et al. 2008, Filleul
et al. 2010).

In 2003, the $rst cases of osteonecrosis of the

jaw in patients medicated with BPs were
reported (Marx 2003), and later, 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.
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 $ndings, nonsurgical

endodontic treatment should be favoured to
dental extractions in patients at higher risk of
BRONJ whenever possible.

The $rst 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
Bisphosphonates (BPs) and their
mechanism of action
Bisphosphonates (BPs) are structural
analogues of pyrophosphate (P-O-P), with a
carbon (P-C-P) replacing the central oxygen
($g. 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 a#nity of BPs for hydroxyapatite
(HAP) whereas the di"erence in R2 side chain
determines the antiresorptive properties and
plays to a lesser extent a role in HAP a#nity.
Based on the structure of the R2–side chain,
BPs can be divided into 2 classes, the
nonnitrogen 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.

Figure 1

Open in !gure viewer #PowerPoint

Caption $

As BPs bind to HAP, it was $rst 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 whether
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

a"ect osteoclast function through inhibition
of di"erentiation and maturation, loss of
function and apoptosis. This eventually
results in a decrease in bone resorption and
an increase in mineralization (Fleisch 1998).

Bisphosphonate-related
osteonecrosis of the jaw (BRONJ)
De!nition

The American Association of Oral &

Maxillofacial Surgeons (2007) provided a
position paper which de$nes 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 a"ected 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,
in%ammation, 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
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
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 e"ects of
BPs aggravate the osteomyelitis and result in
the osteonecrosis as described earlier.

Other contributing factors in the pathogenesis

are local in%ammation, antiangiogenic e"ects
of BPs, an interplay between bone and
overlying mucosa, direct toxic e"ects 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 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 it is radiographically visible, 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 a"ected areas and identi$ed
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 di"erential diagnosis with other
conditions such as nonodontogenic pain or
periapical in%ammation.

Several classi$cations have attempted to

de$ne BRONJ (Kalmar 2012), amongst which
the $ve stages classi$cation adopted by the
American Association of Maxillofacial
Surgeons (AAOMS) and authored by Ruggiero
et al. (2009) (Table 1).

Table 1. Five stage classi$cation for the

diagnosis of bisphosphonate-related
osteonecrosis of the jaw (BRONJ) as proposed
by the American Association of Maxillofacial
Surgeons (AAOMS) (Ruggiero et al. 2009)

Stages Description

At risk The patient has been treated with BP's

category (either oral or intravenous (i.v.)), and there

is no apparent necrotic bone

Stage 0 Presence of nonspeci$c clinical $ndings 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 $stula, oral antra/oral nasal

communication or osteolysis extending to

the inferior border of the mandible or the

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 describing i.v.
administration at oncologic dosage and nine
with oral administration at osteoporotic
dosage. The 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. Additionally, in a
retrospective study with 4019 patients treated
with i.v. BPs, only patients who received
signi$cantly higher doses of BPs for a longer
period of time related to their underlying
condition developed BRONJ (Ho" 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.

Con%icting results are reported regarding the

role of oral health and dental procedures. The
study by Ho" et al. (2008) recognized poor
oral health as a signi$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 Ho" 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, Ho"
et al. 2008, Filleul et al. 2010) and di"erent
guidelines concerning the cessation of BPs
administration prior to invasive dental
surgery have been proposed by several
scienti$c 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
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
scienti$c 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:

1. Several studies (Kyrgidis 2009 Kyrgidis

2010 Kyrgidis & Andreadis 2009) 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 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 tissues 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),
Actinomyces species seem to be
ubiquitous once infection has been
identi$ed (Hellstein & Marek 2005). It
has also been demonstrated that the
microbiota of periapical lesions
refractory to endodontic treatment is
often composed of Actinomyces species
(Sunde et al. 2002). In a case series by
Sedghizadeh et al. (2008), micro-
organisms that are consistent with
pathologic conditions such as periapical,
pulpal, periodontal and mucosal (fungal)
disease were identi$ed by scanning
electron microscopy, organized in
bio$lm 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 coverage is indicated during
nonsurgical endodontic 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 a"ect the bone remodelling process,

they could therefore in%uence the dynamics
of the healing process of periapical lesions of
endodontic origin. Retrospectively, no
di"erence could be found on the healing
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 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 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 con$ned 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 triggering factors is
dental extraction. A position paper of the
American Association of Endodontics (2006)
discussed some of the endodontic
implications of BRONJ. Endodontic therapy
has not been identi$ed as a signi$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.

The low incidence of BRONJ makes it di#cult

to conduct clinical trials with high level of
evidence 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
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
concomitantly present systemic issues
(such as chronic kidney 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 osteonecrosis in general, the use of
anaesthetic agents with vasoconstrictors
should be avoided because BPs already
exert an antiangiogenic action (Tarasso" &
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 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 min (Peters et al. 2002).

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.

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

over$lling and overextension of the $lling
material are recommended because these
may impair the endodontic treatment
e"ectiveness (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 nonexistent, 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
patients with cancer treated with
chemotherapy are immunosupressed and at
risk of 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 may be advocated, because the
adverse e"ects of the recommended
antibiotics, once allergies have been ruled
out, are minimal. As Actinomyces species are
common in BRONJ loci, amoxicillin would
appear as the $rst choice (Smith et al. 2005).
Whenever there is allergy or severe
intolerance to amoxicillin, clindamycin is an
appropriate alternative (Smith et al. 2005). If
several teeth in the same patient need to be
treated, all treatments should be scheduled
during a single visit if possible, to take place
during a single antibiotic coverage period. The
bene$t 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 %are-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 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