Hindawi Publishing Corporation

International Journal of Dentistry

Volume 2014, Article ID 471035, 9 pages
http://dx.doi.org/10.1155/2014/471035

Review Article
Bisphosphonate Associated Osteonecrosis of the Jaw:
An Update on Pathophysiology, Risk Factors, and Treatment

Lars Rasmusson1 and Jahan Abtahi2

1
Department Oral and Maxillofacial Surgery, The Sahlgrenska Academy, University of Gothenburg,
P.O. Box 450, 405 30 Gothenburg, Sweden
2
Maxillofacial Unit, Linköping University Hospital, 581 85 Linköping, Sweden

Correspondence should be addressed to Lars Rasmusson; lars.rasmusson@gu.se

Received 6 May 2014; Accepted 18 July 2014; Published 1 September 2014

Academic Editor: Giuliano Ascani

Copyright © 2014 L. Rasmusson and J. Abtahi. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Osteonecrosis of the jaw in patients treated with bisphosphonates is a relatively rare but well known complication at maxillofacial
units around the world. It has been speculated that the medication, especially long-term i.v. bisphosphonate treatment, could cause
sterile necrosis of the jaws. The aim of this narrative review of the literature was to elaborate on the pathological mechanisms behind
the condition and also to gather an update on incidence, risk factors, and treatment of bisphosphonate associated osteonecrosis
of the jaw. In total, ninety-one articles were reviewed. All were published in internationally recognized journals with referee
systems. We can conclude that necrotic lesions in the jaw seem to be following upon exposure of bone, for example, after tooth
extractions, while other interventions like implant placement do not increase the risk of osteonecrosis. Since exposure to the
bacterial environment in the oral cavity seems essential for the development of necrotic lesions, we believe that the condition
is in fact chronic osteomyelitis and should be treated accordingly.

1. Introduction aims to elaborate on the pathogenic mechanisms behind

bisphosphate associated necrosis of the jaw and incidence,
The first report describing osteonecrosis of the jaw (ONJ) in prevention, and treatment of the condition.
patients receiving bisphosphonates came 2003 [1]. Since then
this condition, sometimes called BRONJ (bisphosphonate- 2. Methods
related osteonecrosis of the jaw), has shown increasing
interest by dentists and oral-maxillofacial surgeons. It is The present paper is authored as a narrative review contribu-
defined as an area of exposed bone in the maxillofacial tion. Data synthesis and analysis: the articles were picked and
region that does not heal within 8 weeks in a patient who sorted according to their corresponding key area of focus.
is currently receiving bisphosphonate medication and has
not had radiation to the head-neck region. The diagnosis 3. Results
is usually made clinically. It is believed mainly to be asso-
ciated with high dose intravenous bisphosphonate therapy, Ninety-one studies were included, consisting of 9 reviews, 79
but sometimes the condition occurs also in patients with original papers, 2 letters and 1 thesis.
low-dose osteoporotic treatment. The current perception
among dentists and oral-maxillofacial surgeons seems to be 4. Discussion
that low-dose bisphosphonate treatment for osteoporosis is
linked to an increased incidence of ONJ, while on the other 4.1. Structure and Bioactivity of Bisphosphonates. Bispho-
hand endocrinologists may suggest increased prescribing to sphonates (BPs) are antiresorptive drugs that act specifi-
decrease the incidence of osteoporotic fractures. This review cally on osteoclasts, thereby maintaining bone density and
2 International Journal of Dentistry

demonstrated that, in rats, alendronate binds to serum

Pyrophosphate Bisphosphonate
albumin and this binding seems to be dependent on serum
calcium-levels and pH. Plasma protein binding in human has
R1 been found to be less with alendronate showing an unbound
HO OH HO OH fraction 22% compared to 4% in rats [13].
Intravenous administration of a single dose of alen-
O P O P O O P C P O dronate leads on the other hand to rapid accumulation of this
drug in bone tissue, approximately 30% in 5 min and 60% in
HO OH HO OH 1 hour [14]. The half-life in plasma is 1-2 hour and this rapid
R2
elimination is due to bone uptake and renal clearance. Once
incorporated into the bone, bisphosphonates are liberated
Figure 1: Chemical structure of pyrophosphate and bisphospho- again only when the bone in which it was deposited is
nate. R1 and R2 signify the side chains of bisphosphonate. resorbed. Therefore the rate of the bone turnover influences
the half-life of this drug [15].
The distribution of BPs in bone is determined by blood
strength [2]. The drug is used for many indications including flow and favours deposition at sites of the skeleton undergo-
prevention and treatment of primary and secondary osteo- ing active resorption [14].
porosis, hypercalcaemia, multiple myeloma, and osteolysis Neither orally nor intravenously administrated BPs are
due to bone metastases and Paget’s disease [3, 4] metabolized in humans [16].
BPs act on both osteoblast and osteoclasts. It has been
shown in vitro that BPs promote proliferation and differentia-
tion of human osteoblast-like cells [5] and inhibit osteoclasts.
The BPs are synthetic analogs with a P–C–P bond instead 4.2. Mechanism of Action. During bone resorption, bispho-
of the P–O–P bond of inorganic pyrophosphates, which are sphonates impair the ability of the osteoclasts to form the
used as a bone-specific radionuclide in technetium 99 m ruffled border, to adhere to the bony surface and to produce
methylene diphosphonate (Tc 99 m MDP) bone scans. Unlike the protons necessary for continued bone resorption [17–19].
pyrophosphates, bisphosphonates are resistant to breakdown Following cellular uptake, a characteristic morphological
by enzymatic hydrolysis, which explains their accumulation feature of bisphosphonate-treated osteoclasts is the lack of
in the bone matrix and their extremely long half-life [6]. a ruffled border, leading to reduced adhesion to the bony
The P–C–P structure (Figure 1) allows a great number of surface. Bisphosphonates also promote osteoclast apopto-
possible variations, especially by changing the two lateral sis by decreasing osteoclast progenitor development and
chains (R1 and R2) in the carbon atom. The two phosphate recruitment [20]. Nevertheless, following exposure to certain
groups are essential for binding to the bone mineral such as bisphosphonates, inhibition of the osteoclast proton pumping
hydroxyapatite and together with the R1 side chain they act H-ATPase phosphatases and lysosomal enzymes could also
as a “bone hook.” A hydroxyl (OH) group or amino group at contribute to the loss of resorptive capacity of osteoclasts
the R1 position increases the affinity for calcium and thus for [21, 22].
bone mineral [7, 8] Figure 1. Clodronates are the first generation, nonnitrogen-con-
The structure and three-dimensional conformation of the taining bisphosphonates which entered osteoclasts, incorpo-
R2 side chain determine the antiresorptive potency and the rated into nonhydrolyzable analogues of adenosine triphos-
enhanced binding to hydroxyapatite [7, 9]. phate (ATP) and converted into methylene-containing
It is known that bisphosphonates containing a basic (AppCp type) analogues of ATP. Accumulation of these
primary nitrogen atom in an alkyl chain such as alendronate toxic by-products interferes with mitochondrial function and
are 10–100 times more potent at inhibiting bone resorption ultimately leads to apoptosis of osteoclasts [23, 24].
than earlier generation BPs like clodronate which lack this In contrast, nitrogen-containing bisphosphonates (such
feature. Compounds that contain tertiary nitrogen such as zoledronate and pamidronate) act by inhibiting farnesyl
as ibandronate and olpadronate are even more potent at pyrophosphate (FPP) synthase and geranylgeranyl pyrophos-
inhibiting bone resorption. Risedronate and zoledronate are phate (GGPP) synthase, two key enzymes in the mevalonate
among the most potent BPs, containing a nitrogen atom pathway. As a consequence, the disruption of the mevalonate
within a heterocyclic ring [10]. pathway by nitrogen-containing bisphosphonates results
The gastrointestinal uptake of orally administrated BPs in impaired protein prenylation and activation av small
is low with a bioavailability of 0.3–0.7% [11, 12]. The poor GTPases such as Ras, Rho, Rac, and Cdc42. The small
absorption of BPs can probably be attributed to their very GTPases are important signalling proteins regulating osteo-
poor lipophilicity which prevents transcellular transport clast morphology, cytoskeleton arrangement, membrane ruf-
across epithelial barriers. Consequently BPs must be ab- fling, and trafficking and cell survival [10, 25].
sorbed by the paracellular route, which means passage though It has been suggested that another target of BPs could be
the pores of tight junctions between the epithelial cells. the osteoblast, which in turn influence the osteoclasts. It has
Bisphosphonates are completely ionized in blood at been shown experimentally that BPs inhibit the expression
physiological pH (7.4). Therefore, plasma protein binding of receptor activator of NF-kappa B ligand (RANK-L) in rat
is high, expectedly as ion binding. Lin and coworkers [13] osteoblast cells and increase the expression of osteoprotegerin
International Journal of Dentistry 3

Signs and symptoms that may occur before the develop-

ment of clinically detectable osteonecrosis include pain, tooth
mobility, mucosal swelling, erythema, and ulceration. The
incidence of ONJ in bone malignancy cases, mainly treated
with high dose intravenous bisphosphonates, is about 1–12%
[48, 49].
Wang and coworkers [50] found that the incidence of ONJ
was at least 3.8% in patients with multiple myeloma, 2.5% in
breast cancer patients, and 2.9% in prostate cancer patients.
In osteoporosis, bisphosphonate associated osteonecrosis of
the jaw is rare and the incidence may not be greater than
the natural background incidence. Epidemiological studies
Figure 2: Exposed necrotic bone after tooth extractions in a patient have indicated an estimated incidence of less than 1 cases per
treated with i.v. zoledronic acid. 100 000 person-years of exposure to oral bisphosphonates.

4.5. Pathogenesis. The etiology of ONJ remains uncertain.

(OPG) in human osteoblastic cells, suggesting that the antire- Initially, when the condition was called bisphosphonate-
sorptive effect of BPs is mediated by influence of osteoblasts related osteonecrosis of the jaw (BRONJ) [48] its similarities
on RANK-L signalling [26, 27]. with radiation-induced osteonecrosis led to the assumption
that the condition started with sterile necrosis of the jaw
4.3. Systemic and Local Delivery of Bisphosphonates. Several bone. Therefore, the term osteonecrosis was used otherwise
experimental studies showed that systemic bisphosphonates reserved for sterile bone death usually because of impaired
reduced alveolar bone loss [28–30]. In animal models, several blood supply. At that time, it was speculated that BPs could
investigators have shown that surface-immobilized bispho- cause osteonecrosis through effects on blood vessels in bone,
sphonates improve mechanical fixation of metal screws in possibly by inhibition of vascular endothelial growth [51].
terms of an increased bone-to-implant contact and pullout Later, it has been suggested that the condition does
force [31–35]. Single systemic infusion of zoledronate has not begin as a form of classical osteonecrosis but in fact
shown promising results on initial fixation of cementless osteomyelitis from the start [52, 53].
orthopaedic implants [36, 37]. Bacterial contamination with Actinomyces and Staphylo-
Local application of BPs during total joint surgery has coccus may play a role in maintaining osteomyelitic wounds
been shown to reduce migration of metal prostheses as and because maxillofacial bone tissue containing BPs will
measured by radiostereometry [38]. resorb slowly, it is conceivable that contaminated bone cannot
In a recent series of randomized controlled trials, local be removed fast enough to prevent the development of
treatment of periodontitis with a gel containing a very high chronic osteomyelitis. This view is supported by the fact
concentration of alendronate was successful in regenerating that similar lesions appear after treatment with anti-RANK-
a large part of lost bone, whereas placebo had little effect [39– L antibodies that reduces osteoclast recruitment [54]. Thus, it
41]. appears that reduced resorptive activity is a key factor behind
In the randomized study of 16 patients, a thin bisphos- the impaired healing capacity of these lesions [55].
phonate-eluting fibrinogen coating improved the fixation of We suggest that the term BRONJ should be avoided and
dental implants in human bone Abtahi et al. [42]. The efficacy replaced by the term bisphosphonate associated osteomyelitis
of the topical administration of bisphosphonates in implant of the jaw, BAOJ, which better reflects the conditions aetiol-
therapy has been investigated by Zuffetti et al. [43]. By the 5- ogy.
year follow-up, no implant failure had been recorded in test Antibiotics can prevent the development of ONJ-like
group. lesions in a rat model [56]. One hundred twenty animals
underwent tooth extraction and received combination of
dexamethasone and pamidronate during different time peri-
4.4. Osteonecrosis of the Jaw (ONJ). Historically, osteonecro- ods. Animals which received the same treatment except for
sis of the jaw (ONJ) was first reported by occupational the addition of penicillin showed four times less ONJ-like
exposure to white phosphorus which was called “phossy jaw” lesions than the other group. There is no clinical study on
[44, 45]. ONJ has also seen in osteopetrosis, a rare inherited the use of antibiotics associated with ONJ. However, in the
disease with impairment of bone resorption and remodeling clinical situation antibiotics has its use since the condition is
[46]. More recently, ONJ is defined as a complication of considered osteomyelitis of the jaw.
head and neck radiotherapy [47]. The definition of ONJ The antiangiogenic role of bisphosphonate is still unclear
is nonhealing exposed jawbone for more than 8 weeks in and ONJ proceeds despite the use of antibiotics in some
patients receiving BPs and without any local radiation ther- cases. One explanation could be the fact that bacterial
apy. Clinically, the disease presents as exposed alveolar bone contamination maintains chronic osteomyelitis of the jaws.
that becomes evident following a surgical procedure such as Another explanation is perhaps the reduced microcirculation
tooth removal or periodontal therapy [48, 49] Figure 2. of the gingiva causing the soft tissue unable to heal.
4 International Journal of Dentistry

Corticosteroids and chemotherapeutics have been sug- person-years of exposure [66]. Similar findings have been
gested as factors that can predispose to ONJ or increase reported by German investigators, as determined by cases
the risk of developing ONJ; the duration of BP therapy also captured by a German Central Registry [73, 74]. By using
appears to be related to the likelihood of developing necrosis postmarketing surveillance method Abtahi et al. identified
with longer treatment regimens associated with a greater risk one case of ONJ among 952 patients, who had received
[55]. The time to develop osteonecrosis after i.v. zoledronate chronic oral bisphosphonate therapy [75]. Moreover, these
treatment was in mean 1.8 years, after i.v pamidronate 2.8 findings contrast to those from an Australian study, which
years and after oral BP therapy, like alendronate, the mean identified ONJ cases by nationwide maxillofacial surgeon
time was 4.6 years [57]. survey [70].
Numerous studies have explored the toxic effect of BPs The trigger for developing necrotic bone in BP treated
on a variety of epithelial cells [58–62]. There is clear doc- patients seems to be dental extractions. A review of 114 cases
umentation of bisphosphonate toxicity to gastrointestinal of BP associated ONJ in Australia showed that 73% of the
epithelia [63]. It has been suggested that high concentrations cases occurred after dental extractions. The frequency of ONJ
of bisphosphonate in the oral cavity (bone tissue) disrupt the in BP treated osteoporotic patients was 0.01%–0.04% and if
oral mucosa [64]. Failure of healing of the soft tissue may dental extraction occurred 0.09%–0.34%. In patients on BPs
cause secondary infection of the underlying bone. However, for bone malignancies, the incidence was 0.33%–1.15% and
this theory has not yet been accepted by investigators. after dental extractions 6.7%–9.1% [70].
Recently, in a rat model of ONJ, following tooth extraction
a high dose of alendronate (200 𝜇g/kg) did not cause ONJ-
4.8. Risk Factors. There are general and local risk factors for
like lesions [65]. When calculated as dose per body weight
development of ONJ.
per day, the rat dose was 100 times higher than the human
General risk factors include malignancies, chemotherapy,
dose.
glucocorticoid treatment, and high dose or long-term bispho-
sphonate treatment [48, 66].
4.6. Clinical Characteristics. Blood supply to the cortical Local risk factors include anatomical features where pro-
bone is derived from the periosteum and exposed bone truding cortical bone with thin mucosal coverage like tori
surface is indicating necrosis in the underlying bone layers. and exostoses implies greater risk for necrosis as well as
The condition can then progress into a more severe bony periodontal disease, any surgical intervention which breaks
lesion with nerve disturbances, mobile teeth, fistulas, and the mucosal lining, especially tooth extractions [48, 67]. In
in the end fracture [66]. Pain is common and these signs an experimental study by Abtahi and coworkers [75], it was
and symptoms are often evident in patients with jaw bone shown that immediate soft tissue coverage after tooth extrac-
osteomyelitis that are not on BP treatment. Radiographs may tion prevented ONJ completely whilst all noncovered sites
show sclerotic bone, sclerotic lamina dura around individual developed ONJ in osteoporotic rats treated with alendronate,
teeth, and widened periodontal ligaments but there are no Figure 3.
report published indicating specific features for BP associated The use of bisphosphonates is associated with the devel-
osteomyelitis [67]. opment of ONJ in some patients. Length of exposure seems
to be the most important risk factor for this complication
with an estimated range from 1.6 to 4.7 years, depending on
4.7. Incidence. The incidence of BP associated osteomyelitis
BPs type [55]. Subsequent to ONJ development the minimum
can be divided into 2 groups: the high dose i.v treated cancer
duration of use was reported to be 6 months [76, 77]. Barasch
patients and osteoporotic patients. In a systematic review,
and coworkers showed that the risk for development of
Kahn et al. found that, for the first group, the cumulative
ONJ begins within 2 years of treatment, for both cancer
incidence varied from 1% to 12% after 36 months of treat-
and noncancer patients, showing that even the less potent
ment [66]. However, most of the reported cases have been
bisphosphonates are linked to ONJ after a relatively brief
related to intravenous use of bisphosphonates (zoledronic
treatment period [76]. Furthermore, for noncancer patients
and pamidronic acid) to control metastatic bone disease or
this risk seems to increase substantially after 5 years. This
multiple myeloma. The incidence of ONJ in these studies
highlights the importance of drug holiday after 5 years
ranges from 4 to 10% [1, 68, 69] and the mean time of onset
of treatment. In a prospective study by Bamias et al. the
varies from 1 to 3 years [55, 70, 71].
incidence of ONJ was studied among patients treated with
Osteoporosis is a common and costly condition that
bisphosphonates for bone metastases. The incidence of ONJ
impaired quality of life [71]. It is estimated that 10 mil-
increased with time to exposure from 1.5% among patients
lion individuals (aged >50 years) in the United States
treated for 4 to 12 months to 7.7% for treatment for 37 to 48
have osteoporosis, by 2010 [72]. Few studies have reported
months [77].
the prevalence of ONJ in persons receiving exclusive oral
bisphosphonate therapy. No cases of ONJ were reported
by Felsenberg et al. among clinical trials involving almost 4.9. Bisphosphonates and Oral Implant Therapy. In a sys-
17000 patients [73]. The authors estimated the worldwide tematic review from 2009, Madrid and Sanz [78] included
reporting rate of ONJ to be <3/100,000 years of exposure studies where patients had been on BP treatment for 1–
[72]. In osteoporosis patients, by systemic review Kahn et al. 4 years before implant placement. None of the patients
estimated incidence of ONJ to be <1 case per 100,000 developed osteonecrosis up to 36 months postoperatively
International Journal of Dentistry 5

(a) (b)

(c)

Figure 3: Histological sections showing the region of the second molar 14 days after extraction in male Sprague-Dawley rat. (a) Control rat
with no treatment, (b) BP treated with coverage, and (c) BP treated without coverage. Note necrotic tissue.

and the implant survival rate ranged from 95 to 100%. This were followed for a mean period of 337 days. Surgical
may indicate that exposed/noncovered bone is necessary for treatment improved the stage distribution from 19% stage I,
bacterial invasion and an osteomyelitic process. 56% stage II, and 25% stage III to 59% intact mucosa, 19%
Furthermore, in a study from 2010, Koka and coworkers stage I and 13% stage II and 8% stage III. The improvement
found high implant survival rates for both bisphosphonate in the stage of disease achieved by surgery was statistically
users and nonusers in postmenopausal women [79]. significant. However, the choice between surgery and con-
servative therapy is a difficult issue and must be made on an
4.10. Treatment. The optimal treatment strategy for ONJ is individual basis.
still to be established. Cessation of BP treatment will not Recently there have been discussions regarding the appli-
be sufficient. A multidisciplinary team approach for evalu- cability of “drug holidays” to minimize long-term bisphos-
ation and management of the conditions is recommended phonate exposure and avoid potential adverse events such as
including a dentist, an oral-maxillofacial surgeon, and an ONJ. However, given the long half-life of bisphosphonates in
oncologist. In early stages, surgical debridement and coverage bone (measured in years) whether or not temporary cessation
has been successful [80]. Hyperbaric oxygen (HBO) is an of treatment with these agents would reduce associated risks
effective adjunctive therapy in situations in which normal is not known. These questions require further study.
wound healing is impaired and the effects of HBO therapy Antibiotics: Samples should be taken for culture and
have been discussed by several investigators [81, 82]. The sensitivity testing before starting ab treatment. Traditionally,
authors showed that patients with ONJ, adjunctive HBO2 the antibiotics of choice to treat osteomyelitis will include
therapy had remission or improvement in over 62.5% of Flucloxacillin or Clindamycin.
patients. Laser therapy at low intensity has been reported for Prevention is a cornerstone to reduce the incidence of
treatment of ONJ by improving reparative process, increasing ONJ and before starting BP therapy, the patient should be
osteoblastic index, and stimulating lymphatic and blood referred for thorough dental evaluation to identify and treat
capillaries growth [83–85]. any potential source of infection. Start of BP therapy should
Segmental osteotomies are recommended only for severe be delayed by 4–6 weeks to allow appropriate bone healing
cases [86–89], due to relatively high levels of morbidity and [90].
impaired quality of life for the patients [90]. The treatment of bisphosphonate-related osteonecrosis of
In a study by Holzinger et al. [91], 108 patients with the jaw is generally difficult. For this reason, prevention plays
bisphosphonate therapy underwent surgery and 88 patients a predominant role in the management of this condition.
6 International Journal of Dentistry

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