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Review Article

Clinical impact of bisphosphonates in root canal therapy

Mothanna K. AlRahabi, MSc, PhD, Hani M. Ghabbani, ABE, Dip.FRCD(C).

ABSTRACT B isphosphonates (BPs) are an essential medication in


the treatment of osteoporosis, and are also used in
the treatment of certain cancers.1 In 1995, the United
‫البايفوسفونيت نظير الهيكلة املستقرة من بيروفسفات التي تقمع‬ States approved the first BP, fosamax or alendronate
‫فهي‬. ‫نشاط األوستيوكالست مما أدى إلى انخفاض ارتشاف العظم‬ sodium, produced by Merck & Co for use in the
treatment of osteoporosis.2 Further developments led
‫ يعتبر نخر عظم الفك تأثير‬.‫أدوية أساسية في عالج هشاشة العظام‬ to the introduction of new generations of BPs, which
‫ حيث أنه تختلف نسبة انتشار‬.‫سلبي من عالج البايفوسفونيت‬ are characterized by their long-acting effects that
‫ ومن املمكن‬28% ‫ إلى‬0% ‫تنخر عظم الفك من البايفوسفونيت من‬ improve patient compliance.2 Currently, BPs are an
‫ ميكن تأخير عالج‬.)‫أن يسببها قلع االسنان والرضح (صدمة نفسية‬ essential component in the treatment of osteoporosis.1
‫ وبالتالي يقلل من‬.‫قناة اجلذر أو حتى القضاء على احلاجة لقلع السن‬ Bisphosphonate is broadly described worldwide.2 In the
European Union countries, approximately 5% of the
‫ ونقترح قد يكون‬.‫خطر تنخر عظم الفك املرتبط بالبايفوسفونيت‬ population aged 50 years or older has osteoporosis, and
. ‫أفضل عالج لألسنان من مرض لبي أو محيط الذروة‬ receives treatment with BPs frequently.3 As with any
other medication, BPs have side effects; osteonecrosis
Bisphosphonates are stable structural analogs of of the jaw (BRONJ) related to BP use has important
pyrophosphate, which suppress the activity of medical and dental implications.4
osteoclasts, leading to decreased bone resorption. The purpose of this review is to provide an overview
They are essential medications in the treatment of of BPs, highlight their implications in endodontic
osteoporosis. Osteonecrosis of the jaw is a serious adverse treatment, and provide guidelines to promote oral care
effect of bisphosphonate therapy. The prevalence of in all patients receiving BP therapy during root canal
bisphosphonate-related osteonecrosis of the jaw varies treatment, to prevent BRONJ.
from 0% to 28%, and it can be triggered by dental Bisphosphonate properties and effects.
extraction and trauma. Root canal therapy can delay, Bisphosphonates are stable structural analogs of
or even eliminate, the need for tooth extraction, and pyrophosphate, which are deposited on the bone
surface in the first few minutes or hours after
therefore, may reduce the risk of bisphosphonate-related
uptake, with unbound BP swiftly removed renally.1,4
osteonecrosis of the jaw. We suggest that this might be
Bisphosphonates suppress the activity of osteoclasts,
the best treatment for teeth with pulpal and/or periapical
which leads to decreased bone resorption.5 The effects
disease. of BPs vary according to the generation they belong to
(first, second, or third generation). The first generation
Saudi Med J 2018; Vol. 39 (3): 232-238 (non-nitrogen containing) BPs induce apoptosis by the
doi: 10.15537/smj.2018.3.20923 formation of a toxic analog of adenosine triphosphate,
whereas the second and third generations (nitrogen-
From the College of Dentistry, Taibah University, Madinah containing BPs) inhibit osteoclast function by targeting
Al Munawwarah, Kingdom of Saudi Arabia. the enzyme farnesyl diphosphate synthase, which is
necessary for post-translational modification of small
Address correspondence and reprint request to: Dr. Mothanna
Guanosine Triphosphate(GTP)-binding proteins.1 Both
AlRahabi, Associate Professor, College of Dentistry, Taibah
University, Madinah Al Munawwarah, Kingdom of Saudi Arabia.
the potency and strength of binding to hydroxyapatite
E-mail: mrahabi@taibahu.edu.sa differ greatly between individual compounds.6
ORCID ID: orcid.org/0000-0002-3405-9524 Table 1 shows the types of BPs, their modes of action,
and examples of commercially available BPs.

232 www.smj.org.sa Saudi Med J 2018; Vol. 39 (3) OPEN ACCESS


Impact of Bisphosphonates in root canal therapy ... AlRahabi & Ghabbani

Table 1 - Types and mode of action of bisphosphonates (BPs).

Generation Type Examples Mode of action


First generation Non-nitrogen Etidronate (Didronel® Norwich Pharmaceuticals, Formation of an ATP derivative that diminishes
containing Inc. North Norwich osteoclast function
BPs and encourages osteoclastic, programmed cell
Clodronate (Bonefos® Bayer PLC, UK) death by apoptosis.

Tiludronate (Skelid® Sanofi-Aventis Australia Pty Ltd)


Second Alkyl-amino non-nitrogen Pamidronate (Aredia®, Novartis International AG, Prevents sterol formation by the
generation containing BPs Basel, Switzerland) isoprenoid pathway through
Alendronate (Fosamax®, Merck & Co., Inc. prohibiting its farnesyl pyrophosphate
Kenilworth, New Jersey, USA)  synthase enzyme
Ibandronate (Boniva®Roche and
GlaxoSmithKline Brentford, London,UK)

Olpadronate (Olpadronate Sodium®,


PharmaChem USA)
Third generation Heterocyclic nitrogen Risedronate (Actonel®, Sanofi S.A. Gentilly, France) Prevents farnesyl pyrophosphate synthase
containing BPs Zoledronate (Reclast® Novartis Pharma AG, FPPS enzyme and stabilizes
Switzerland) conformational changes.
ATP - adenosine triphosphate, NBPs - nitrogen containing bisphosphonates,
FPPS - farnesyl pyrophosphate synthase enzyme

Side effects of bisphosphonates. As with any other exposed area of the bone in the upper or lower jaw, in
drug, BPs have their own side effects. Oral BPs can the maxillofacial region, which does not recover within
cause nausea, epigastric pain, esophagitis, and gastric 8 weeks after diagnosis in a patient taking a BP, who
ulcer.7,8 Myalgia, arthralgia, low-grade fever, headache, has not received radiation therapy in the maxillofacial
and bone pain due to a temporary acute-phase response region.22
could occur during the first 24 to 72 hours following The occurrence of BRONJ has been correlated with
intravenous (IV) administration of BPs.9 Some reports 2 hypotheses: firstly, BPs tend to be highly concentrated
mention an association between atrial fibrillation and in the jaw because of high vascularity, causing an anti-
the use of BPs.7,10,11 There is no definitive evidence of angiogenic effect, and secondly, its cytotoxic effect on
the increased risk of esophageal cancer or gastric cancer osteoclasts and periodontal ligament cells suppresses
in male and female patients taking BPs.12 A case series bone turnover.23,24
study that extracted data from 2 main primary care The prevalence of BRONJ varies from 0% to 28%,
centers in the United Kingdom showed that there was with a higher incidence associated with the use of IV
no relationship between BPs and esophageal cancer, but nitrogen-containing BP.25 The type of BP, frequency
that using alendronate for a short duration might increase of use, and therapy duration are all factors that have
the possibility of gastric cancer.13 Bisphosphonates may effects on BRONJ. Moreover, oral BP use is associated
rarely cause uveitis, scleritis, and orbital inflammatory with not more than a 4% incidence of BRONJ.26
disease.14-16 Atypical proximal femoral fractures could Dental extractions and trauma trigger 64% of BRONJ
occur with long-term use of BP.17,18 cases;27 periodontitis accompanies 84% of BRONJ
Bisphosphonate-related osteonecrosis of the jaw cases.28 The differential diagnoses of BRONJ include
(BRONJ). Bisphosphonate-related osteonecrosis of the sinusitis, alveolar osteitis, periapical pathosis, gingivitis/
jaw is one of the serious adverse effects of BP therapy.19,20 periodontitis, and some types of cemento-osseous
The first cases of BRONJ related to BPs were reported dysplasias with secondary resorption.29 The exposed
over a decade ago.21 The American Society for Bone necrotic bone may continue to be asymptomatic for a
and Mineral Research (ASBMR) defines BRONJ as an long duration.27 Inflammation of tissues surrounding
these lesions will cause signs and symptoms such as
tooth mobility, soft tissue swelling, erythema, ulcers
in the mucosa and soft tissues,25,30 paresthesia, or even
Disclosure. Authors have no conflict of interests, and the numbness of the associated branch of the trigeminal
work was not supported or funded by any drug company. nerve.31 Signs and symptoms may appear before
osteonecrosis becomes clinically noticeable.25,32

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Impact of Bisphosphonates in root canal therapy ... AlRahabi & Ghabbani

Table 2 - Clinical signs and symptoms of Bisphosphonate-related Endodontic clinical implications of bisphosphonates.
osteonecrosis of the jaw (BRONJ).
Pulpal necrosis is the result of microorganism invasion
Traditional signs of Possible clinical signs and symptoms into the root canal system, leading to infiltration and
BRONJ associated with Bisphosphonate-related inflammation through the apical foramen, into the
osteonecrosis of the jaw BRONJ
periapical tissues, causing an increase in osteoclastic
Exposed necrotic Pain in the tooth or bone purulence
mandibular bone Swelling activity and bone resorption.34,35
Fistula and sinus in the affected jaw The activated inflammatory cells secrete multiple
Teeth mobility
Trismus
proteins, including cytokines (namely, interleukin 6 or
Non-healing extraction sockets TNF-a) and degrading proteins (namely, collagenase
Ulcers in soft tissue or proteinases) that interfere with healing.36 Bacterial
Gross deformation in lower jaw
Bone resorption endotoxins will activate the complement system, all
these factors provoke the differentiation of macrophages
into osteoclasts.37
Table 2 shows the clinical signs and symptoms The BPs target osteoclast-mediated bone resorption,
of Bisphosphonate-related osteonecrosis of the jaw and ultimately inhibit bone remodeling. This process
(BRONJ). Most cases of BRONJ undergo conservative can interfere with healing of periapical lesions following
treatment; the treatment regimen includes improving root canal treatment.38 The periapical lesions can be
and maintaining oral hygiene, removing dental and considered as predisposing factors that may aggravate the
periodontal disease, mouthwashes with local antibiotics, development of BRONJ, following tooth extraction.39
and systemic antibiotics.29 In unresponsive cases, A recent animal study evaluated the role of periapical
lesions in exacerbation of BP-related osteonecrosis of the
surgical management should be considered; ostectomy
jaw (BRONJ) following tooth extraction. This revealed
of the affected bone should be continued until normal the increasing occurrence of BP-related osteonecrosis
bone is observed.29 following the extraction of teeth with periapical lesions,
Table 3 shows BRONJ staging systems and suggested and pointed out that periapical lesions should be
treatments, according to the American Association of controlled before tooth extraction, to minimize the risk
Oral and Maxillofacial Surgeons.33 of BRONJ.39

Table 3 - Bisphosphonate-related osteonecrosis of the jaw staging systems according to the American Association of Oral and Maxillofacial Surgeons and
suggested treatments.21

Stage Specification Treatment


At-risk category No evidence of exposed or necrotic bone in These patients do not require treatment.21 However, patients should
patients treated with bisphosphonates be educated regarding the risk of developing Bisphosphonate-related
osteonecrosis of the jaw (BRONJ), including, quickly reporting each sign and
symptom. Perform local risk factor management and periodic clinical and
radiological check‑ups.
Stage 0 Non-specific clinical findings and symptoms Perform medical treatment (antiseptic, analgesic, antibiotic, and
such as mandibular pain or osteosclerosis, but antiphlogistic therapy) and management of local risk factors.21 Low‑level laser
no clinical evidence of exposed bone. therapy is a possible choice for the treatment of osteonecrosis by aiding the
reparative process, improving the osteoblastic index, and stimulating growth
of the lymphatic system and blood capillaries.65 A careful follow‑up for
evolution to a higher stage is necessary.
Stage 1 Exposed/necrotic bone in asymptomatic patients If exposed/necrotic bone or fistulae are present, rinse them with antiseptic
with no proof of infection fluids and cover them with an adhesive paste 3 times a day. In the absence
of a healing development, after 8 weeks, a surgical debridement approach is
possible.66
Stage 2 Exposed/necrotic bone associated with proof of Conservative surgical debridement after 2 weeks of medical therapy,
infection such as pain and erythema in the area to minimize inflammation., removing all the affected bone.67 Administer
of the exposed bone, with or without antibiotic and antiphlogistic treatments. Follow‑up examinations are
pus drainage necessary.
Stage 3 Exposed/necrotic bone with pain, infection. Perform marginal or segmental osteotomies for severe cases.67,68 Perform
This stage is associated with one or more of the invasive surgery only if it could improve the patient’s quality of life. In other
following: pathologic fracture, extraoral fistula, cases, or if the patient rejects surgery, perform a conservative approach to
or osteolysis extending to the inferior control symptoms and prevent osteonecrosis progression.67
border or sinus floor.

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Impact of Bisphosphonates in root canal therapy ... AlRahabi & Ghabbani

Patients undergoing BP therapy are at a higher risk intentional replanted teeth.48,49 The low concentrations
of developing BRONJ.40 Extraction of the affected of alendronate could inhibit the receptor activator of
teeth may trigger BRONJ. Dental extraction could nuclear factor kappa-ß ligand (RANKL) of generated
be delayed or even avoided by performing root canal osteoclasts without cytotoxic influences.49 The clinical
therapy in the affected teeth.41 Non-surgical root canal importance of these in vitro findings are not known;
treatment, as an alternative to extraction, will decrease further studies must be conducted to prove its clinical
the risk of BRONJ incidence.38 The purpose of root capability as a therapeutic procedure for avulsion teeth.
canal therapy is to eliminate infection and prevent it Open apex teeth with pulpal necrosis provides a
from infiltrating into the periapical tissues.38 In a study, great challenge to dental practitioners; however, recent
it was found that the healing rate of periapical lesions years have witnessed a new concept for management
following root canal treatment in patients taking oral of these cases which is called “revascularization.”50 This
BPs for long time was 73.5%; and was not significantly concept, based on disinfecting the root canal system
difference than the healing rate of periapical lesions and inducing intracanal bleeding through the apical
after root canal treatment in patients who did not use
foramen creates a suitable atmosphere for endogenous
oral BPs (81.6%).38
mesenchymal stem cells (MSCs) to differentiate to
The major limitation of the study was the small
size of the sample. The evidence-quality of that study several type of odontogenic cells and complete root
was moderate. Therefore, this subject requires further maturity.50 The root canal revascularization procedures
research to explain the relationship between endodontic include induction of intracanal bleeding through the
treatment and the effects on patients undergoing BP apical foramen by over instrumentation, and this may
therapy.42 A recent study evaluated the effect of IV trigger BRONJ. Therefore, the treatments of choice in
zolendronate on the clinical and radiographic success these cases are apexification or apexogenesis.
of non-surgical root canal treatment. The results of Clinical recommendations. The following
this study revealed a strong relationship between the recommendations could reduce the risk of BRONJ
duration of BP treatment and the success of root canal during endodontic treatment.51
treatment, where the success rate increased in patients 1. Informed consent and communication with
with shorter BP treatment durations (less than 1 the patient’s treating physician are the first and most
year).43 Also, the major limitation of the study was a essential steps before any procedure.
small sample size, and observation period was only 12 2. A chlorhexidine mouthwash rinse for one minute,
months. Further studies are needed on this subject. Most before starting treatment, reduces the number of
patients reported to have BRONJ have had a history of microorganisms in the oral cavity,52 and minimizes the
chemotherapy or dexamethasone use.44 The other risk possibility of bacteremia that may be present due to soft
factors of BRONJ are intraoral trauma, alcohol/tobacco tissue trauma.
use, and preexisting periodontal disease.44 3. Avoid using anesthetic agents with
Root canal therapy can trigger the process of BRONJ vasoconstrictors53 to reduce the risk of inadequate
through soft tissue damage, especially during application vascularization, as BPs already have anti-angiogenic
of a rubber dam and apical extrusion of debris during effects.54
cleaning and shaping of the root canal system.45 Patel
4. Minimize trauma, particularly to the soft tissues,
and Saberi46 described case series of external cervical
during rubber dam clamp application.45
resorption in patients taking BPs, where there was no
other possible cause of resorption. Amino-containing 5. Perform the work in a strictly aseptic environment.
BPs could cause an acute-phase response and release Disinfect the tooth and the rubber dam by rubbing
of proinflammatory cytokines, which appears to be them with a suitable disinfecting solution for 2
associated with the release of tumor necrosis factor- minutes.51 Tincture of iodine (5%) has proved to be one
alpha (TNF-α), Interleukin-1 (IL-1), and IL6;46 this of the few reliable agents for disinfecting rubber dam
may initiate external cervical resorption in teeth.46 In and tooth surfaces during the preparation of an aseptic
rats, the local application of BPs causes an increasing endodontic workfield.55
of IL-1 and TNF- α activity which lead to increasing 6. Avoid patency of the apical foramen, which
of odontoclast numbers.47 Animal studies revealed can increase the possibility of bacteremia from
that the superficial application of zoledronate and extruded debris.51 Electronic apex locators are used to
alendronate decreased replacement root resorption in determine the apical constriction. Therefore, it may be

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Impact of Bisphosphonates in root canal therapy ... AlRahabi & Ghabbani

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