Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench.
ABSTRACT Osteonecrosis of the jaw (ONJ) has received significant attention as a potential side effect of bisphosphonate treatment. The limited understanding of the underlying pathophysiology of the condition emphasizes the need to transition ONJ research from the bedside to the bench, supplementing ongoing clinical research with animal/basic science studies. The goal of this review is to briefly highlight the most commonly proposed mechanisms for ONJ and then summarize our laboratory's recent efforts to begin transitioning ONJ research to an animal model. Remodeling suppression, disrupted angiogenesis and infection have all been proposed to connect bisphosphonates to ONJ, although most supportive data for each of these are either indirect or nonexistent. Our laboratory has begun studying the dog as a potential model of ONJ. We have shown regions of necrotic bone matrix within the mandible of dogs treated with oral or intravenous bisphosphonate. We hypothesize these regions are the result of remodeling suppression, and if combined with additional factors such as dental intervention or infection, would result in manifestation of exposed oral lesions, the clinical definition of ONJ. Although these findings suggest the dog may be a viable animal model to study ONJ, many questions remain unanswered. No matter what animal model is found to mimic the clinical presentation of ONJ, once established it will allow significant progress toward understanding the specific role of bisphosphonates in the pathophysiology of ONJ and if/how the entity of ONJ can best be treated and prevented.
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ABSTRACT: Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-κB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc–treated and OPG-Fc–treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ. © 2014 American Society for Bone and Mineral Research.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2013; · 6.04 Impact Factor
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ABSTRACT: Background Bisphosphonates are powerful drugs used for the management of osteoporosis and metastatic bone disease to avoid skeletal-related complications. Side effects are rare but potentially serious such as the bisphosphonate-related osteonecrosis of the jaws (BRONJ). BRONJ impairs the quality of life and can even lead to pathologic fractures of the mandible. Management of BRONJ is difficult per se. If complicated with pathologic mandibular fractures in advanced stages, the treatment options are controversially discussed. This review delineates the epidemiology and pathogenesis of BRONJ to put the various modalities for the treatment of pathologic mandible fractures into perspective. Methods Various case reports and case series in the literature were reviewed. Cases were reviewed of patients suffering from pathologic fracture due to bisphosphonate-related osteonecrosis of the jaw treated in the Department of Oral and Maxillofacial Surgery (Ludwig-Maximilians-University of Munich) from 2003 to 2010. Of 140 patients suffering from BRONJ, four were identified with pathologic fracture of the mandible. Results Management of pathologic mandibular fractures in patients suffering from BRONJ is an unsolved issue. At present there is a paucity of information to establish reliable therapy guidelines. The published strategies range from conservative treatment to major bone resections with or without internal or external fixation and with or without autogenous reconstruction. There is no evidence for the superiority of a single therapeutic mode, however. Conclusion Further understanding of BRONJ is mandatory to establish a sound rationale for the treatment of associated mandibular fractures.Craniomaxillofacial Trauma and Reconstruction 09/2013; 6(3):147-154.
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ABSTRACT: Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a feared side effect which is hard to treat and often affects patient s quality of life in an extensive manner. Adalimumab (Humira(R)), a fully human recombinant antibody specific for tumor necrosis factor- alpha, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease. In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009. This patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-alpha antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.BMC Gastroenterology 01/2014; 14(1):6. · 2.11 Impact Factor
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Cells Tissues Organs 2009;189:289–294
Bisphosphonates and Osteonecrosis
of the Jaw: Moving from the Bedside
to the Bench
Matthew R. Allen
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Ind. , USA
model is found to mimic the clinical presentation of ONJ,
once established it will allow significant progress toward un-
derstanding the specific role of bisphosphonates in the
pathophysiology of ONJ and if/how the entity of ONJ can
best be treated and prevented.
Copyright © 2008 S. Karger AG, Basel
Since first brought to light in 2003 [Marx, 2003; Meh-
rotra et al., 2003], osteonecrosis of the jaw (ONJ) has re-
ceived significant attention as a potential side effect of
bisphosphonate treatment. PubMed currently lists over
300 citations pertaining to bisphosphonates and ONJ, all
of which are case studies, reviews, editorials and position
statements. Although these publications have been in-
valuable for documenting, summarizing and clarifying
the prevalence, risk factors and management strategies
for ONJ, they have provided limited data on the underly-
ing pathophysiology of the condition. This emphasizes
the need to transition ONJ research from the bedside to
Animal models ? Bisphosphonate ? Osteonecrosis of the jaw ?
Mandible ? Remodeling suppression ? Review
Osteonecrosis of the jaw (ONJ) has received significant
attention as a potential side effect of bisphosphonate treat-
ment. The limited understanding of the underlying patho-
physiology of the condition emphasizes the need to transi-
tion ONJ research from the bedside to the bench, supple-
menting ongoing clinical research with animal/basic science
studies. The goal of this review is to briefly highlight the
most commonly proposed mechanisms for ONJ and then
summarize our laboratory’s recent efforts to begin transi-
tioning ONJ research to an animal model. Remodeling sup-
pression, disrupted angiogenesis and infection have all been
proposed to connect bisphosphonates to ONJ, although
most supportive data for each of these are either indirect or
nonexistent. Our laboratory has begun studying the dog as
a potential model of ONJ. We have shown regions of necrot-
ic bone matrix within the mandible of dogs treated with oral
or intravenous bisphosphonate. We hypothesize these re-
gions are the result of remodeling suppression, and if com-
bined with additional factors such as dental intervention or
infection, would result in manifestation of exposed oral le-
sions, the clinical definition of ONJ. Although these findings
suggest the dog may be a viable animal model to study ONJ,
many questions remain unanswered. No matter what animal
Published online: August 13, 2008
Dr. Matthew R. Allen
Department of Anatomy and Cell Biology, MS 5035
Indiana University School of Medicine
635 Barnhill Dr., Indianapolis, IN 46202 (USA)
Tel. +1 317 274 1283, Fax +1 317 278 2040, E-Mail email@example.com
© 2008 S. Karger AG, Basel
Accessible online at:
Abbreviation used in this paper
ONJ osteonecrosis of the jaw
Cells Tissues Organs 2009;189:289–294
the bench, supplementing ongoing clinical research with
animal/basic science studies. It is these animal/basic sci-
ence studies that in all likelihood will provide the neces-
sary advances toward understanding the true causes of
ONJ and the most viable prevention/treatment strate-
While a definitive cause/effect relationship between
bisphosphonate treatment and ONJ has yet to be docu-
mented, compelling evidence exists in the literature [Zer-
vas et al., 2006]. Working under the assumption of a di-
rect connection, determining the underlying mecha-
nism(s) connecting bisphosphonate treatment to ONJ
becomes the top priority. The literature contains an ex-
haustive list of proposed mechanisms for ONJ, most of
which have limited, or no, supportive data. The 3 most
commonly proposed mechanisms include remodeling
suppression, disrupted angiogenesis and infection; these
are briefly reviewed below.
Bisphosphonate-induced remodeling suppression is
by far the most often cited causative factor underlying the
pathophysiology of ONJ despite the fact that there are no
published data in humans showing the effects of bisphos-
phonates on jaw remodeling. Through their direct ac-
tions on osteoclasts, bisphosphonates significantly re-
duce bone remodeling [Rodan and Fleisch, 1996], the
mechanism responsible for slowing bone loss in osteopo-
rosis patients and lessening complications associated
with skeletal metastases in cancer patients. Both human
[Chavassieux et al., 1997; Eriksen et al., 2002; Recker et
al., 2006] and animal studies [Balena et al., 1993; Smith
et al., 2003; Allen et al., 2006] show that bisphosphonate
doses used for osteoporosis treatment significantly sup-
press tissue-level bone remodeling (measured using fluo-
rochrome-labeled bone histomorphometry). There are
no data, in either humans or animals, describing the tis-
sue-level remodeling effects of bisphosphonates when ad-
ministered at doses used for cancer treatment. Such data
are vital, because although measures of systemic remod-
eling suppression are similar between these 2 bisphos-
phonate dosing regimens [Chesnut et al., 1995; Berenson
et al., 2001], different levels of remodeling suppression
certainly could occur at the tissue level [Smith et al., 2003;
Odvina et al., 2005]. This could help explain the greater
incidence of ONJ in patients treated with bisphospho-
nates for cancer compared to those treated for osteopo-
It is important to note that the effects of bisphospho-
nates on tissue-level remodeling suppression are site spe-
cific with those sites that normally undergo higher rates
of remodeling experiencing more marked suppression. In
ovariectomized nonhuman primates, trabecular bone of
the vertebrae remodels twice as fast as trabecular bone in
the iliac crest and distal radius [Smith et al., 2003]. Treat-
ment of these animals with ibandronate (10 ? g/kg month-
ly, intravenously) suppresses trabecular remodeling by
75% in the vertebra, yet only by 20% in the iliac crest and
distal radius [Smith et al., 2003]. Similar results were doc-
umented for cortical sites which differ in their normal
remodeling rates; those with higher rates were more af-
fected by bisphosphonates. These data have important
implications for the jaw, which has been shown to have
intracortical remodeling rates in humans that are 10–20
times higher than within the cortex of the iliac crest [Ga-
retto et al., 1995; Han et al., 1997]. Remodeling rates in
the jaw cortex can be even higher in the presence of infec-
tion or following dental intervention. With high remod-
eling rates that are unparalleled elsewhere in the skeleton,
the jaw may be uniquely susceptible to remodeling sup-
pression with bisphosphonates. Data from beagle dogs
are consistent with this theory; etidronate, at doses 16
times higher than those used clinically, reduced alveolar
bone intracortical remodeling from more than 40 to ap-
proximately 5% per year, while suppression at the rib (a
cortical bone site with relatively rapid turnover) was re-
duced from 15 to 5% per year [Garetto and Tricker, 1998;
Mashiba et al., 2001].
It is important to note that despite frequent use of the
term avascular necrosis to describe ONJ in bisphospho-
nate-treated patients, there is no evidence that the ne-
crotic regions have reduced vasculature or blood supply.
Antiangiogenic effects of bisphosphonates have been
documented by various groups, using both in vitro and
in vivo experimental models. Wood et al.  have
shown that zoledronic acid significantly suppresses new
vessel sprouting in culture and angiogenesis when tissue
chambers are implanted subcutaneously in mice. These
findings are supported by others showing reductions in
tissue revascularization of rats and lower vessel densities
in humans that had been treated with bisphosphonates
[Fournier et al., 2002]. There are no data describing ef-
fects of bisphosphonates on angiogenesis in bone or bone
marrow, the tissues of interest with respect to ONJ. Given
Ostonecrosis of the Jaw: From Bedside to
Cells Tissues Organs 2009;189:289–294
the reductions in remodeling with bisphosphonates, sup-
pression of angiogenesis within the bone matrix is ex-
pected as new remodeling units (and their associated ves-
sels) would be initiated at a much slower rate. Reduced
angiogenesis in this context would be considered second-
ary to the effects of remodeling suppression. Antiangio-
genic effects of bisphosphonates could have a direct influ-
ence on soft tissue mucosa, vasculature of the bone mar-
row or in the wound-healing response that follows dental
intervention, none of which have been studied. Some in-
sight into wound healing may be gleaned from the frac-
ture-healing literature, which shows that bisphospho-
nates allow normal callus formation [Peter et al., 1996; Li
et al., 1999; Cao et al., 2002]. This suggests that early stag-
es of wound healing (such as revascularization) are not
adversely affected by bisphosphonates. However, these
same studies show impairment of callus remodeling. De-
layed remodeling, if also shown to occur in the oral cav-
ity following tooth extraction, would be consistent with
the ONJ literature.
The universal presence of Actinomyces in a case series
of samples from ONJ patients strongly suggests a role of
infection in ONJ [Hansen et al., 2006]. The oral cavity is
home to hundreds of microorganisms, the risk of infec-
tion is increased following dental procedures and cancer
patients are routinely treated with immunosuppressive
agents. These factors may all come together to provide the
perfect environment for chronic infection (osteomyelitis).
How, or if, this contributes to ONJ is unclear; however,
most evidence suggests the necrotic tissue becomes in-
fected as opposed to the infected tissue becoming necrot-
ic [Yarom et al., 2007]. Conflicting reports exist with re-
spect to effects of bisphosphonates on immune cells.
Bisphosphonates have been shown to inhibit T lympho-
cyte activation and proliferation as well as to suppress
monocytes production of various pro-inflammatory cy-
tokines (IL-1 ? , IL-6 and TNF- ? ), which in turn affect an-
tigen-presenting cells [Milhaud et al., 1983; Sansoni et al.,
1995]. However, data also exist showing enhanced pro-
duction of pro-inflammatory cytokines by lymphocytes
(specifically ? / ? T cells) in response to bisphosphonates.
This latter effect has been deemed responsible for the
acute-phase reaction associated with intravenous bisphos-
phonate treatment [Hewitt et al., 2005; Coxon et al., 2006].
These limited data suggest that bisphosphonates do exert
direct effects on cells of the immune system.
From the Bedside to the Bench: Working toward an
Animal Model of ONJ
There are numerous limitations to studying ONJ in
humans, emphasizing the need to transition toward ani-
mal/basic science studies. For nearly a decade, our labo-
ratory has been studying the effects of bisphosphonates
on tissue-level properties using a dog model. The dog of-
fers numerous advantages as an animal model for study-
ing skeletal physiology. The bone turnover rate of beagles
is similar to humans, albeit with a slightly shorter remod-
eling period [Eriksen et al., 1994; Boyce et al., 1995]. Like
humans, dogs also undergo intracortical remodeling (re-
modeling within cortical bone) which is essential in stud-
ies where cortical bone physiology is of interest. Rodents,
under normal conditions, do not undergo appreciable
amounts of intracortical bone remodeling. With the goal
of understanding the effects of bisphosphonates on vari-
ous tissue-level bone properties, our laboratory recently
undertook a study in which female beagles were treated
with clinically relevant doses of daily oral alendronate for
1 or 3 years [Allen et al., 2006; Allen and Burr, 2007]. Al-
though the original aims of the study did not involve the
craniofacial bones, mandibles from these animals were
harvested and are now being analyzed to determine what
effects bisphosphonates may have on the jaws of these
animals [Allen and Burr, 2008].
Using dynamic histomorphometry, the level of intra-
cortical bone remodeling in the mandible of untreated
dogs in this experiment was found to be more than 10
times higher than within the tibial cortex of the same
animals. Specifically, it was the alveolar portion of the
mandible that had the highest rate of intracortical turn-
over, being more than 8 times higher than in the nonal-
veolar portions of the mandible. These results are similar
to those previously shown in untreated dogs [Garetto and
Tricker, 1998; Huja et al., 2006]. Treatment for 3 years
with clinically relevant doses of alendronate significantly
suppressed (–75%) the level of intracortical remodeling in
the alveolar bone compared to vehicle-treated animals.
These data support previous reports in dogs treated with
etidronate [Garetto and Tricker, 1998], while extending
the results to encompass clinically relevant dosing regi-
mens. There was no significant effect of 3 years of alen-
dronate on the remodeling rate of nonalveolar bone in the
mandible. Interestingly, the most prominent suppression
of remodeling in the alveolar bone is consistent with the
anatomical location of the jaw bone most often associated
with ONJ in humans.
Cells Tissues Organs 2009;189:289–294
None of these dogs treated for 1 or 3 years with oral
alendronate developed exposed lesions in the oral cavity.
To determine if necrosis existed within the bone matrix
of the mandible, segments were stained en bloc with basic
fuchsin, a stain that passively diffuses into and fills all
void spaces within the bone (Haversian canals, canalicu-
li, microdamage). This technique allows histological as-
sessment of necrotic matrix regions as those regions
which have lost patent canalicular/osteocyte networks
are void of stain [Frost, 1960; Enlow, 1962, 1966]. We
found significant amounts of necrotic bone matrix in ap-
proximately 25% of the bisphosphonate-treated animals
that had been treated for 1 or 3 years ( fig. 1 ) [Allen and
Burr, 2008]. No such regions existed in any of the vehicle-
treated animals. These regions averaged approximately
1 mm 2 in size and were predominantly found in the al-
veolar portion of the mandible [Allen and Burr, 2008].
Again, the predominant localization of these necrotic re-
gions to alveolar bone is consistent with the anatomical
location of the jaw which undergoes the greatest amount
of remodeling suppression (from these dog studies) and
has the highest incidence of ONJ (from human studies).
Fig. 1. Photomicrographs of devitalized bone matrix in the man-
dible of bisphosphonate-treated dogs. a Matrix necrosis, assessed
using en bloc basic fuchsin staining, can be observed in the man-
dible of a dog treated daily for 1 year with oral alendronate, by
the complete absence of fuchsin stain (red) in a localized region.
b A region from the mandible of a vehicle-treated animal shows
staining of viable tissue. c Focal loss of viable osteocytes, assessed
using lactate dehydrogenase histochemistry which labels viable
osteocytes blue, can be observed in the alveolar bone of an animal
treated for 3 months with intravenous zoledronate. d A region
from a vehicle-treated animal shows the majority of osteocytes are
viable (stained blue). Scale bars = 200 ? m.
Ostonecrosis of the Jaw: From Bedside to
Cells Tissues Organs 2009;189:289–294
Our laboratory is currently undertaking a follow-up
study aimed at investigating whether intravenous zole-
dronate, at dosing regimens consistent with those used in
cancer patients, differentially produces nonviable tissue
in the mandible compared to oral alendronate. Prelimi-
nary observations of tissue from animals treated for 3
months show focal regions of nonviable osteocytes (as-
sessed using lactate dehydrogenase histochemistry) in
the alveolar bone of zoledronate-treated animals ( fig. 1 ).
Similar regions were not evident in the alveolar bone of
animals treated with vehicle or alendronate in the small
subset of animals examined to date (5 animals per group).
Ongoing analyses will quantify osteocyte viability, ma-
trix necrosis (using basic fuchsin staining) and bone re-
modeling following both 3 and 6 months of these treat-
We hypothesize that the accumulation of nonviable
osteocytes and matrix necrosis observed in these dogs is
the result of suppressed intracortical remodeling and that
they are part of the underlying pathophysiology of ONJ.
Loss of osteocyte viability is a normal process [Jilka et al.,
2007] and when a collection of cells becomes nonviable,
the tissue is targeted for remodeling [Verborgt et al.,
2002]. By suppressing turnover, regions of nonviable os-
teocytes are inevitably removed at a slower rate. This pro-
duces localized tissue necrosis, containing regions of
nonviable osteocytes or, if allowed sufficient time, re-
gions where the osteocytes and their canaliculi fill with
mineral [Frost, 1960; Remaggi et al., 1996]. Presence of
matrix necrosis in the alveolar bone of a tooth that un-
dergoes dental extraction (or some other invasive dental
procedure) is likely to contribute to a disrupted healing/
remodeling response. The addition of infection to such a
region would contribute, but would not be necessary, to
further compromise healing and eventually result in sig-
nificant devitalization of the region.
While these results are intriguing and suggest the dog
may be a viable animal model to study ONJ, many ques-
tions remain unanswered. Specifically, it will be impor-
tant to determine if focal matrix necrosis is part of the
ONJ pathophysiology. Documenting a connection be-
tween matrix necrosis and exposed oral lesions, for in-
stance with an additional intervention such as dental ex-
traction, would establish whether this can be used as a
model system to study ONJ. Once established, this or any
other animal model would pave the way for a series of
studies to help determine the specific role of remodeling
suppression, angiogenesis and infection in the patho-
physiology of ONJ and if/how the entity of ONJ can be
treated and prevented.
The author would like to thank Dr. David Burr for his intel-
lectual contributions to many of the concepts addressed herein.
The animal studies and analyses discussed in this work were sup-
ported by funds from the National Institutes of Health, the Na-
tional Osteoporosis Foundation, Eli Lilly Research Laboratories
and Amgen. Merck kindly provided alendronate for the 1- and 3-
year animal experiments.
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