J. Maxillofac. Oral Surg.

https://doi.org/10.1007/s12663-019-01211-2

REVIEW ARTICLE

Bisphosphonate-Induced Osteonecrosis of the Jaws (BIONJ)

Madhumati Singh1 • Giriraj Sandeep Gonegandla1

Received: 13 August 2018 / Accepted: 13 March 2019

 The Association of Oral and Maxillofacial Surgeons of India 2019

Abstract and Paget’s disease [5]. Various bisphosphonates used for

Introduction The risk of osteonecrosis of the jaw is greater this purpose are alendronate, pamidronate, zoledronate,
for patients receiving intravenous bisphosphonates for ibandronate, etc. Although bisphosphonates have been used
cancer than for patients receiving oral bisphosphonates for clinically for more than three decades, there have been no
osteoporosis or Paget’s disease. documented long-term complications of their effects on the
Materials and Methods This article provides a review of the jaws until recently, where there is now growing evidence of
treatment of Bisphosphonate induced osteonecrosis of jaws. the influence of bisphosphonates on osteonecrosis of the
Conclusion Bisphonates associated jaw necrosis and its jaws [1, 5].
relation to dentisitry and maxillofacial surgery has become
common now a days. Proper diagnosis and treatment may Terminology Evolution
help the patients health getting worsen.
Bisphosphonate-related osteonecrosis of the jaws (BRONJ)
Keywords Bisphosphonate-related osteonecrosis
was the term given by American Association of Oral and
BIONJ
Bisphosphonates in maxillofacial surgery
Maxillofacial Surgeons [6]. Bisphosphonate-associated
Bisphosphonate-induced osteonecrosis osteonecrosis of the jaws (BAONJ) was the term coined by
American Dental Association [7]. Both terms are inaccu-
rate because they do not explain the underlying mechanism
Introduction of the condition.
Osteochemonecrosis is also stated in the literature [8].
Bisphosphonate-induced osteonecrosis of the jaws (BIONJ) Avascular necrosis has also been used by few researchers.
refers to a condition characterized by exposure of bone in A more recent term in this list is bisphosphonate-induced
mandible or maxilla persisting for more than 8 weeks in osteonecrosis of the jaws (BIONJ) which was widely
patient who has taken or is currently taking bisphosphonate accepted till 2014 [1].
and who has no radiation therapy to the jaws. Bisphos- AAOMS in 2014 finally gave a terminology which is
phonate-induced osteonecrosis of the jaws (BIONJ) was ‘‘medication-related osteonecrosis of the jaw’’ (MRONJ).
first described by Marx and Stern in 2002 [1–4]. This condition is also caused by drugs such as RANK
Bisphosphonates are used in the treatment of metastatic ligand inhibitor (denosumab) which is antiresorptive and
bone diseases, osteoporosis, hypercalcemia of malignancy other antiangiogenic medications [9].

& Giriraj Sandeep Gonegandla Mechanism of Action

sandeepkashyapg@gmail.com
1 Bisphosphonates are powerful inhibitors of osteoclastic
RajaRajeswari Dental College and Hospital, Ramohalli
Cross, Mysore Road, (p.o), Kumbalgodu, Bengaluru 560074, activity. They are analogues of inorganic pyrophosphates
India with low intestinal absorption, are excreted through the

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kidneys without metabolic alteration and have a high If more bisphosphonate accumulates as the demand of
affinity for hydroxyapatite crystals [10, 11]. Because they remodeling continues or trauma such as tooth extraction
are incorporated into the skeleton without being degraded, occurs, the alveolar bone can no longer respond with new
they are remarkably persistent drugs; the estimated half-life bone from osteoclastic bone resorption followed by new
of alendronate is up to 12 years [12]. bone formation and it becomes necrotic. The overlying
The non-aminobisphosphonates are metabolized by bone is subsequently deprived of its blood supply from
osteoclasts to inactive non-hydrolyzable adenosine underlying bone and breaks down, leading to clinically
triphosphate analogues that are directly cytotoxic to the cell exposed bone [18] (Fig. 2).
and induce apoptosis [10, 11]. The newer aminobisphos-
phonates have two actions [13]: induction of another ade-
nosine triphosphate analogue that induces apoptosis and Revised Staging for BIONJ
inhibition of farnesyl diphosphate synthase, which is part
of the mevalonate pathway of cholesterol synthesis. Such • Stage 1: One quadrant or less of exposed bone without
inhibition results in dysregulation of intracellular transport, osteolysis beyond the alveolus or sinus involvement
cytoskeletal organization and cell proliferation, leading to • Stage 2: Two quadrant or more of exposed bone without
inhibition of osteoclast function (Fig. 1). In addition, evidence of osteolysis beyond the alveolus or sinus
aminobisphosphonates reduce recruitment of osteoclasts involvement
and induce osteoblasts to produce an osteoclast-inhibiting • Stage 3: Any presentation with osteolysis beyond
factor [14, 15]. alveolus or pathologic fracture or cutaneous fistula or
sinus involvement [19].
Why Only in the Jaws?

Dixon et al. studied bone remodeling at various sites and

Initiation of BIONJ
found that alveolar crest remodels at ten times the rate of
tibia and five times the rate of mandible at inferior border.
Robert Marx studied osteonecrosis on the patient with
Hence, alveolar bone of the jaws has greater uptake of
intravenous bisphosphonates and observed that 25% of
bisphosphonates and drug accumulates in higher concen-
BIONJ developed spontaneously and 75% of cases were
tration. This study also demonstrated that alveolar bone
precipitated by some type of invasive dental procedure
depends more on osteoclastic remodeling and renewal than
performed to resolve dental comorbidity. The most com-
any other bone in adult skeleton [16].
mon factor in those cases was surgical dental trauma or
During normal occlusion, compression forces get con-
inflammatory condition of periodontium [18].
centrated at root apex and crest of furcation, while tension
forces are directed on lamina dura throughout the rest of
periodontal ligament fibers. So lamina dura remodels in
Incidence
response to these forces. However, if patient has absorbed
and accumulated sufficient quantity of bisphosphonates,
BIONJ is most commonly found in mandible with total
lamina dura cannot remodel and instead becomes
incidence rate of 68% and less frequent in maxilla, around
hypermineralized.
28%. Both the jaws are involved 4% of the times [18].

Fig. 1 Mechanism of action of bisphosphonates Fig. 2 Clinical picture of BIONJ. Image Credits: Mayo Clinic

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Prevention of BIONJ and acceptance of the presence of some exposed bone are
the mainstays of therapy.
As 75% of BIONJ cases are triggered by surgical trauma, This approach is reported to be successful related to
uncontrolled occlusal trauma or active dental inflammatory normal function in a pain-free state in 87% of patients [20].
disease, the most effective strategy to prevent BIONJ The article ‘‘Management of Medication-Related
would be to avoid the need for any invasive dental surgery Osteonecrosis of the Jaw’’ published in Oral Maxillofacial
after bisphosphonate therapy has been initiated [17]. Surgery Clinics of North America 2015 by Bradford and
Medical oncologists are well advised to refer all the Felice states various treatment approaches to patients with
patients in whom bisphosphonate therapy is indicated to an MRONJ once the diagnosis has been made.
experienced dentist or Oral and Maxillofacial Surgeon for Medical Management [17]
consultation.
• Antimicrobials.
Bisphosphonate therapy should be postponed for
Topical antimicrobials.
2–3 months if feasible providing adequate time for dental
Oral antimicrobials.
team to remove all concerning initiators of osteonecrosis of
Intravenous antimicrobials.
jaws and achieve optimum dental health. All the non-
• Pentoxifylline and vitamin E therapy.
restorable and periodontally unsalvageable teeth should be
• Teriparatide.
removed first to give maximum time for wound healing.
• Hyperbaric oxygen therapy.
Next, priority should be given to caries control, tooth
restoration, root canal treatment and periodontal care Topical Antimicrobials
including periodontal surgery. Subsequently prosthetic
• Chlorhexidine gluconate 0.12% is a topical bactericidal
procedures of fixed or removable dentures can be followed.
and bacteriostatic agent that has been shown to be
These patients are not candidates of dental implants
effective in the treatment of patients with MRONJ.
because it depends on bone remodeling for maintenance of
• There is evidence that the oral flora, and more
osseointegration. Thus, there are higher chances of
specifically biofilms, contributes to the disease process
osteonecrosis taking place.
which is disrupted by the use of topical antimicrobials.
Prophylactic antibiotic coverage should be considered
• Chlorhexidine is recommended for management of
for invasive dental procedure because cancer patients carry
stage 1 disease as a singular therapy.
high risk of infection. Penicillin can be given during the
• For more advanced stages, it can be advised in addition
procedure, and penicillin VK 500 mg, four times daily, can
to medical and surgical therapies.
be followed for 5 days. For patients allergic to penicillin,
azithromycin 500 mg should be given 1–2 h prior to pro- Oral Antimicrobials
cedure, followed by once daily for 5 days [18, 20–23].
• Antimicrobials are a mainstay in the management of
MRONJ.
• Antimicrobial therapy is based on clinical observation
Management of BIONJ and scientific literature, suggesting that pathogenic
bacteria may contribute to MRONJ.
Proper medical history should be elicited which includes:
• Most of the infections are polymicrobial.
drug name, indication, route, dose, frequency of adminis-
• Common colonizers of MRONJ lesions are Actinobac-
tration and any concomitant medication. In dental history,
teria, Fusobacteria and Bacteroides.
it is recommended to check for exposed bone (especially in
• These organisms are susceptible to penicillin; therefore,
posterior lingual cortex), mobility of teeth, constant deep
penicillin remains the first antibiotic choice.
pain, intermittent swelling and gingival recession. Any
• Alternatives to penicillin are clindamycin, fluoro-
inflammatory of tooth or periodontium has to be noted.
quinolones and/or metronidazole.
Robert Marx has stressed in his paper that this type of
• Prescribe a 2-week course for patients with persistent
osteonecrosis is a dead bone due to toxic effects of bis-
stage 1 disease and up to a 4–6-week course for more
phosphonates. So it is likely to be permanent and any
severe cases.
attempts of bone debridement short of resection have been
counterproductive and produced additional exposed bone, Intravenous Antimicrobials
worsening of symptoms and increased risk of pathologic
• Intravenous antimicrobials may be of benefit in patients
fracture [18]. The exposed bone itself cannot be painful as
with pathogenic organisms resistant to oral agents.
it is deinnervated, unless secondarily infected. Therefore,
• IV antimicrobials may provide greater tissue
prevention and/or control of secondary infection and pain
penetration.

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• However, there have been no satisfactory trials demon- • Additionally, HBO reverses impaired leukocyte func-
strating greater efficacy of intravenous agents compared tion, thus resulting in improved wound healing and
with oral medications. bone turnover.
• IV should be employed as last chance when all the oral • The clinical utility of HBO for management of MRONJ
agents have been used. remains unclear, and for this reason, it is not commonly
• Long-term (6-week) intravenous antimicrobials should advised for the patients with MRONJ.
be administered.
Surgical Management
Pentoxifylline and Vitamin E
• Patients with stage 0 and stage 1 disease generally do
• The combination of pentoxifylline and vitamin E has not warrant surgical intervention, but benefit from
been used successfully in the treatment of jaw osteo- medical management,
radionecrosis and MRONJ. • A wide spectrum of disease is often seen with stage 2
• The specific mechanism of action in MRONJ remains MRONJ, ranging from focal minimally symptomatic
unclear. exposed bone to severely painful widespread bone
• Pentoxifylline (Trental), a xanthine derivative with an necrosis.
excellent safety profile, is used primarily for the • Maxilla/mandible resection is advised in the cases of
treatment of vascular diseases. stage III MRONJ.
• Vitamin E decreases tissue inflammation and fibrosis • It is thus difficult to recommend a single surgical
and is a scavenger of free radicals capable of cellular treatment approach in these patients.
injury. • Debridement and marginal and segmental resection are
• Numerous reports supporting the role of both inflam- terms commonly seen in the literature describing the
mation and decreased vascularity as contributors to surgical treatment of MRONJ.
MRONJ make the use of this relatively well-tolerated • Debridement and marginal resection both refer to
drug combination a rational choice. removal of necrotic bone, primarily in the alveolus,
• The recommended dose: with the goal of maintaining an intact inferior border of
• Pentoxifylline 400 mg sustained release twice daily the mandible.
• 1000 IU vitamin E daily for 36 months. • Segmental resection, on the other hand, refers to en bloc
• These medications to be maintained perioperatively in removal of involved bone, including the inferior border
patients who require the surgical treatment of MRONJ. of the mandible, with a resulting continuity defect.
• Intraoperative fluorescence-guided debridement has
Teriparatide
been suggested to assist in differentiating necrotic from
• Teriparatide (Forteo) is a subcutaneously administered viable bone.
drug used primarily in the treatment of osteoporosis. • Tetracycline is incorporated into sites of bone remod-
• This is the only available drug that can stimulate new eling and thus will only be seen in viable bone.
bone formation. • The technique involves preoperative administration of
• The drug is composed of 34 amino acids of the doxycycline (100 mg twice a day for 10 days before
N-terminal chain of parathyroid hormone and retains surgery).
the anabolic effects of endogenous parathyroid hor- • A fluorescent light source is applied to the affected
mone, including promotion of bone remodeling. region during debridement and areas of necrotic bone
• Teriparatide is thought to stimulate effectively osteo- are seen to fluoresce as a pale bluish-white color
blast function and proliferation, increase osseous cell whereas viable bone appears brightly fluorescent.
signaling and activate osteoclasts.
For the Surgical Management of MRONJ, the Fol-
• Recommended dosage: 20 mcg SC daily for up to
lowing Principles Should Be Applied:
2 years.
• Appropriate preoperative imaging to assess the extent
Hyperbaric Oxygen Therapy
of disease.
• HBO therapy has been used for management of • Removal of all necrotic bone and any involved teeth to
osteoradionecrosis of the jaw for many years and more achieve disease-free bony margins.
recently has been applied to the treatment of MRONJ. • Removal of any sharp bony edges and spicules.
• HBO provides greater oxygen to tissues with impaired • Achievement of a layered tension-free primary wound
vascularization. closure whenever possible.
• Culture-directed postoperative antibiotic therapy until
mucosal healing is seen.

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• Restraint from wearing any oral prosthetic devices until thickness flap. Healing was stimulated by filling the ex-
complete mucosal healing is seen. traction site with autologous plasma rich in growth factors
(PRGF system). Local and systemic infection control was
Treatment protocol advised by Marx [18, 20] depending
obtained with dental hygiene and antibiotic therapy. This
on the stage of disease:
protocol was successful in 202 extractions performed in 63
Stage 0 (subclinical): patients.
• Eliminate inflammatory pathologies.
• Withheld therapy for 2–3 months if possible.
Conclusion
• Remove unrestorable tooth.
• Perform procedures for restorations, root canal and
BIONJ can appear spontaneously, but more commonly it is
periodontal care.
associated with local trauma, predominantly dental
• Undertake procedures of fixed or removable partial
extraction [18, 20, 22]. Currently, there is no way of pre-
dentures.
dicting which individuals taking bisphosphonates are at
• Leave impacted tooth undisturbed unless they have
greatest risk of developing BRONJ. Equally, there are no
oral communication.
prognostic indicators predictive of outcomes. The only
• Prophylactic antibiotics for invasive dental
persistent finding is a correlation between duration of
procedures.
therapy and occurrence of BRONJ
Stages 1 and 2: Prevention is superior to treatment, and as such, the
Asymptomatic exposed bone can be maintained by establishment of meticulous oral hygiene and preemptive
0.12% chlorhexidine rinse three times daily. If accom- surgical treatment prior to commencement of bisphospho-
panied by pain due to infection, antibiotic regimen can nate therapy is recommended. During therapy, strict review
be prescribed. There are three types of regimen given: and maintenance of oral hygiene practices should occur in
order to prevent pathology necessitating surgical manage-
ment. Patients treated with these drugs need to be aware of
Regimen A—penicillin VK 500 mg, four times a day
complications that can arise in the jaws, especially related
can be ongoing.
to trauma. It should be stressed upon those taking bispho-
Regimen B—penicillin VK 500 mg, four times a day
sphonates, especially the intravenous forms, the need to
till pain and infection are controlled.
avoid invasive dental management [22].
Regimen C—levofloxacin 500 mg/azithromycin
The most conservative approach to controlling pain and
500 mg once daily for the patients allergic to
infection is followed. Bone debridement can be tempting,
penicillin.
but it is counterproductive and produces additional exposed
Stage 3: bone and worsening of symptoms. So it is better avoided
Stage 3 osteonecrosis can be palliated with Regimen A, [18, 20].
B or C to allow for function. Patients who do not respond
to this or have painful pathologic fracture are the
candidates for alveolar resection or continuity resec-
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