J Clin Periodontol 2015; 42: 190195 doi: 10.1111/jcpe.

12322

Dramatic osteonecrosis of the Alberto Fernandez Ayora1, Francine

Herion1, Eric Rompen1, Jean Yves
le Magremanne3
Reginster2, Miche

jaw associated with oral and France Lambert4,5

1
Department of Periodontology and Oral
Surgery, Faculty of Medicine, University of

bisphosphonates, periodontitis, Liege, Liege, Belgium; 2Department of Public

Health, Epidemiology and Health Economics,
Faculty of Medicine, University of Liege,

and dental implant removal Liege, Belgium; 3Oral and Maxillofacial

Surgery, Faculty of Medicine and Dentistry,
 Catholique de Louvain, Louvain,
Universite
Belgium; 4Department of Periodontology and
Oral Surgery, CHU of Liege, Lie
ge, Belgium;
5
Dental Biomaterials Research Unit (DBRU),
Fernandez Ayora A, Herion F, Rompen E, Reginster JY, Magremanne M, Lambert
Faculty of Medicine, University of Liege,
F. Dramatic osteonecrosis of the jaw associated with oral bisphosphonates,
Liege, Belgium
periodontitis and dental implant removal. J Clin Periodontol 2015; 42: 190195.
doi: 10.1111/jcpe.12322.

Abstract
Introduction: Osteoporosis affects millions of elderly patients, and anti-resorptive
drugs (ARD) such as bisphosphonates (BP) represent the first-line therapy.
Despite the benefits related to the use of these medications, osteonecrosis of the
jaw is a significant complication in a subset of patients receiving these drugs.
Case presentation: This report documents a case of dramatic bisphosphonate-
related osteonecrosis associated with periodontitis and dental implant removal in
an osteoporotic patient treated with per os bisphosphonates for an uninterrupted
period of 15 years.
Key words: alendronate; implant; medication
Conclusion: The aim of this report was to discuss the administration period of related osteonecrosis of the jaw;
BP in the treatment of osteoporosis, the decision-making and clinical manage- osteonecrosis; osteoporosis; periodontitis
ment of severe MRONJ and the indications for dental implant placement in these
specific patients. Accepted for publication 14 October 2014

Bisphosphonates (BPs) have been
used since 1968 for the treatment of
bone diseases such as bone metasta-
ses, multiple myeloma, Pagets
disease and calcium metabolism dis-
orders (osteoporosis) (Fleisch 1998).
After being deposited on the bone
surface, BPs are internalized by oste-
oclasts and induce the apoptosis of
Conflict of interest and source of
funding statement
No external funding, apart from the
support of the authors institution,
was available for this case report. The
authors declare that they have no con-
flicts of interest in this case report.
190
osteoclasts, resulting in the disrup-
tion of bone turnover and the heal-
ing process (Fleisch 1998,
Magopoulos et al. 2007). Because of
their confirmed effectiveness in
reducing osteoporosis-related bone
fractures, oral BPs such as ibandro-
nate (Bonviva, Hoffmann, La
Roche, Basel, Switzerland), alendro-
nate (Fosamax, Merck Sharp &
Dhome, White House Station, NJ,
USA) and risedronate (Actonel,
Sanofi-Aventis, Paris, France) and
intravenous BP, such as zoledronate
(Aclasta, Novartis, Basel, Switzer-
land), are considered first-line ther-
apy in the treatment of osteoporosis
and are widely prescribed anti-
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
resorptive agents (Black et al. 1996,
Reginster et al. 2000, Kanis et al.
2013).
Despite the benefits of these
drugs, bisphosphonate-related osteo-
necrosis of the jaw (BRONJ), a
severe side effect of bisphosphonate
therapy, was first described in the lit-
erature in 2003 (Marx 2003). Since
this initial identification, many cases
have been reported, typically when
massive doses of BP were adminis-
tered intravenously, usually for on-
cologic reasons (Dimitrakopoulos
et al. 2006). Recently, similar cases
of osteonecrosis of the jaw have
been reported in patients treated
with denosumab (DMab), a human

monoclonal antibody of the receptor
activator of nuclear factor kappa-B
ligand (RANKL), used intravenously
for the management of postmeno-
pausal osteoporosis. The more recent
designation of these secondary
effects is Medication-Related Osteo-
Necrosis of the Jaw (MRONJ)
(Neuprez et al. 2014). The associated
main risk factor of MRONJ is
dento-alveolar trauma, periodontal
disease or tooth extraction (2006,
Bamias et al. 2005). Subsets of eden-
tulous and dentate patients have
developed MRONJ spontaneously
(Kanis et al. 2013).
These complications are extre-
mely difficult to control and, despite
innovative surgical protocols that
have been newly described; the rec-
ommended standard of care remains
a conservative non-surgical approach
to limit osteomyelitis dissemination.
The incidence of BRONJ varies
from 0% to 27,5% with high dose
IV administration of BPs (specially
for the treatment of multiple mye-
loma and metastases) (Campisi et al.
2014), but the reported occurrence
remains insignificant (0.004%) when
BPs are administered per os for the
management of osteoporosis or Pa-
gets disease of the bone (Mariotti
2008).
This report documents a case of
dramatic bisphosphonate-related
osteonecrosis of the jaw associated
with periodontitis and dental
implant removal in an osteoporotic
patient treated with per os BP for an
uninterrupted period of 15 years.
The specificity and the management
of this case are discussed.
Case Report
An 82-year-old female was referred
to the Department of Periodontol-
ogy and Oral Surgery, Faculty of
Medicine, University of Liege in
March 2011 with chief complaints of
pain on chewing and gingival swell-
ing in the left lower molar area for
three months. Six months earlier, the
patient underwent implant removal
in the lower left mandible performed
by her general dentist who diagnosed
a peri-implantitis (Figs 1 and 2). The
implant was placed 5 years earlier,
and according to the dentist, the
removal procedure was uneventful.
Two months after the explantation,
the site failed to heal properly and
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Medication-Related Osteonecrosis of the jaws
Fig. 1. First panoramic radiograph in 2005 shortly after implant placement at the
lower jaw.
Fig. 2. Periapical radiograph in 2011
before the implant was removed.
was infected. The general dentist
performed curettage of the granula-
tion tissues and the extraction of the
first left lower molar (Fig. 3). After
several weeks, the patient was
referred to a specialized centre, the
Department of Periodontology and
Oral Surgery of the University of
Liege, Belgium. The intra-oral exam-
ination showed necrotic bone expo-
sure with swelling and pus discharge
through a fistula and a fibrotic, bur-
geoning, and neoplastic-like soft
tissue lesion. A hard and soft tissues
biopsy was performed for the differ-
ential diagnosis. The biopsy excluded
malignancy and demonstrated
sequestrum infiltrated with chronic
inflammatory cells. The radiographic
exams showed an increased bone
marrow density with bone sequestra-
tion on the panoramic X-ray
(Fig. 4), and the CT images demon-
strated cortical bone destruction in
the left lower edentulous area includ-
ing the upper component of the
ramus. Based on these clinical, histo-
pathological and radiographic exam-
inations, the patient was diagnosed
with a grade 2 MRONJ. The medi-
cal history revealed hypothyroidism,
191
neurodegeneration and weekly
administration of oral risedronate
(35 mg Actonel) for 15 years for the
treatment of osteoporosis. No fur-
ther medication was involved. The
serum C-terminal cross-linked telo-
peptide of type I collagen (CTX)
level was measured at 313 pg/ml.
The cessation of bisphosphonate
therapy was immediately recom-
mended. According to the AAOMS
position paper, the standard of
care for a grade 2 MRONJ is a con-
servative approach to contain the
infection process. The remaining
granulated tissue and the necrotic
bone were debrided, and the wound
was irrigated monthly with a solu-
tion of doxycycline (100 mg/ml). At
each wound irrigation, small necrotic
bone fragments were expelled
through multiple fistulas (Fig. 4).
Doxycycline resistance was detected
in the antibiogram, and the doxycy-
cline irrigations were replaced by a
metronidazole solution (500 mg/
20 ml). For each acute infection epi-
sode, a broad-spectrum course of
antibiotics was prescribed. The initial
antibiotic therapy of choice was a
combination of amoxicillin and cla-
vulanic acid TID 875 mg and metro-
nidazole BID 500 mg. Because
penicillin resistance was identified
some months later, the combination
of cefadroxil 500 mg and metronida-
zole 500 mg was given. In a few
months, the severity and the rapidity
of the progression of the osteonecro-
sis were unexpected. The patient was
referred to the Maxillofacial Depart-
ment but the option of undergoing a
hemimandibulectomy and jaw recon-
struction was rejected. Extensive sur-
gery was not recommended because
of the age of the patient and general
anaesthesia related risks. However,
192 Fern
andez Ayora et al.

The risk of MRONJ development

has been described to be significantly
higher in patients treated with high
doses of BP intravenously for onco-
logic reasons. The prevalence varies
from 0% to 27.5% (Mariotti 2008).
For patients taking BPs via the oral
route, typically for the treatment of
osteoporosis, the estimated preva-
lence is approximately 0.00007
0.04% (Mariotti 2008). According to
some authors, this difference is due
Fig. 3. Panoramic radiograph when the patient was seen for the first time in the to the low lipid solubility of orally
Department of Periodontology and Oral Surgery, University of Liege, Belgium. administered BP, which results in the
The large osseous crater on left lower edentulous area is the radiological sign of the intestinal absorption of only 0.63%
BRONJ (July 2011). of the drug. The American Dental
Association (ADA) (2006) and the
AAOMS (Ruggiero et al. 2009) have
confirmed that this risk is dose/time
dependent. BPs are retained in the
skeleton for more than 10 years, and
their administration over a long time
period might result in high-dose
accumulation in the jawbones,
increasing the risk of BRONJ even
through the oral route of administra-
tion (Ott 2011).
Some studies have reported that
the weekly consumption of per os BP
for 3 years (156 week doses) is
Fig. 4. Panoramic radiograph shows the progression of the BRONJ and lost of the
required for the development of
teeth in the left lower jaw and the evolution to a grade 3 BRONJ (April 2012).
MRONJ, and the risk might increase
with each additional year of BP use
(Black et al. 2012). The serum CTx
test (C-terminal telopeptide of type I
collagen, or ITCP), a marker of bone
turnover that assesses the elimination
of specific fragments produced by
type I collagen hydrolysis, can be
used as a parameter to assess the risk
of developing MRONJ (Marx et al.
2007). However its role as a predic-
tive marker of MRONJ remains con-
troversial (Otto et al. 2011),
incidentally, in this particular case
the measured values represented a
minimal risk value. In this case
Fig. 5. Panoramic radiograph shows progress of the osteonecrosis and lost of the spon- report, the patient did not show any
taneous exfoliation of the teeth in the left lower jaw (January 2013). risk factors, such as tobacco use, che-
motherapy, or corticoid intake, but
she took BP orally weekly for
the conservative approach did not physically and psychologically. At 15 years and this long and uninter-
provide relief of the symptoms or this level, treatment options are lim- rupted exposure to the molecule
prevent BRONJ evolution. All the ited and a palliative approach is car- might have contributed to the sever-
mandibular teeth (13 in total) were ried out. ity of the complications after implant
lost due to the progressive necrosis removal. This long-term therapy is
of the periodontal tissues and questionable because the majority of
Discussion
spontaneous exfoliation (Fig. 5). In the data about the safety and efficacy
2 years, the osteonecrosis has dis- The present case report describes a of bisphosphonate drugs to treat
seminated to the entire jaw and the dramatic and rapidly progressing osteoporosis is focused on BP intake
left mandible condyle (Figs 6 and 7). grade 2 BRONJ diagnosed in a for less than 5 years (Ott 2011). The
The patient has lost hearing on the patient treated with per os bisphosph- evidence of fracture risk reduction in
left side and is extremely affected onate. BPs given for osteoporosis is derived
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Fig. 6. The BRONJ has disseminated to the entire jaw and the left mandible condyle.
Fractures are visible under the left condyle and on the left horizontal part of the man-
dible (March 2013).
Fig. 7. Exposed necrotic bone of the alveolar process bilaterally in the mandible.
from the Fracture Intervention Trial
Research Group (FIT) and the
Health Outcomes and Reduced Inci-
dence with Zoledronic Acid Once
Yearly Extension trial (HORIZON).
These studies suggested that the dis-
continuation of per os alendronate
for up to 5 years and of IV zoledro-
nate for up to 3 years does not
appear to significantly increase the
fracture risk. Some recent studies
reported that the incidence of other
secondary complications of BP, such
as atypical subtrochanteric and dia-
physeal femoral fractures, decreases
after the discontinuation of oral BP
therapy, and a prolonged therapy
might influence the occurrence of
MRONJ (Shane et al. 2014). The
available data suggest that bis-
phosphonates might be safely discon-
tinued in some patients without
compromising therapeutic gains,
but no adequate clinical trials
have delineated how long the drug
benefits are maintained after drug
cessation. To optimize the efficacy of
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Medication-Related Osteonecrosis of the jaws
bisphosphonates in reducing the frac-
ture risk, decisions to continue treat-
ment must be based on the individual
assessment of the risks and benefits
and on patient preference (Whitaker
et al. 2012). Patients at mild risk are
recommended to stop the treatment
after 5 years and to remain off ther-
apy as long as the bone mineral den-
sity is stable. Higher risk patients
should be treated for 10 years and
have a holiday of 12 years after
5 years of taking BPs; eventually
non-anti-resorptive drug treatment
could be provided during the BP
interruption (Whitaker et al. 2012).
According to these guidelines, the
present patient likely received exces-
sive doses of ARD, especially because
the risk of fracture was mild.
The management AAOMS (2007)
recommendations for a stage 2
MRONJ is the non-surgical debride-
ment of necrotic bone combined
with mouth rinses, BP interruption,
pain control, and antibiotic therapy
in cases of acute infection (Ruggiero
193
et al. 2004, Magopoulos et al. 2007).
The monthly irrigation of the wound
was performed with a low dose of
doxycycline (100 mg/ml) for its abil-
ity to join the calcium ions of bone
hydroxyapatite (Grevstad & Boe
1995, Holmes et al. 2004), its anti-
metalloprotease activity preventing
the destruction of the extracellular
matrix and its contribution on fibro-
blast and epithelial cells adhesion
potentially influencing soft tissue
healing (Rompen et al. 1993, Almazin
et al. 2009).
In this case, such measures did not
achieve resolution of the clinical find-
ings. The multiple antibiotic resis-
tances likely contributed to the
acceleration of the dissemination of
the necrosis. The maxillofacial team
according to age and physical status
of the patient and the risk of the gen-
eral anaesthesia did not consider any
kind of large surgical resection and
mandibular reconstruction. Accord-
ing to the literature (Engroff & Kim
2007, Ferrari et al. 2008, Seth et al.
2010, Sacco et al. 2011), radical surgi-
cal treatment must be considered
when the MRONJ seems to involve a
large area of the jaw, if the disease is
not resolved by conservative therapy
and if the donor site of the patient is
well perfused and exempt of bone
metastases. In the light of these state-
ments, and considering the absence of
cancer morbidities (bisphosphonates
were prescribed for osteoporosis rea-
sons), and the poor medical status of
the patient, a segmental mandibulec-
tomy without reconstruction might
have been the treatment option of
choice when the MRONJ was still
limited at the left horizontal branch
of the mandible. In this case, if the
mucosal defect was important, recon-
struction with a pedicled pectoralis
major flap could have been proposed,
with or without a titanium plate.
Nevertheless, given the highly pro-
gressive MRONJ, the success of the
surgical resective treatment would
not have been ensured. At this more
advanced stage of the MRONJ
involving the chin and vertical branch
of the mandible, other surgical
modalities such as mandibulectomy
reconstruction with a vascularized
flap might be considered (Mucke
et al. 2009, Nocini et al. 2009). In
any case, it is a clinical decision that
depends on many factors as the risk
of the surgery, the maxillofacial team
194 Fern
andez Ayora et al.
experience, the patient, age, family or
economic costs.
Alveolar bone surgery represents
one of the main risk factors for the
development of MRONJ (Badros
et al. 2006). Madrid and Sanz
(Madrid & Sanz 2009) reviewed one
prospective and three retrospective
studies and reported that there were
no cases of MRONJ after implant
placements in 217 patients who took
oral BPs for less than 5 years. They
concluded that oral BP administra-
tion did not affect the short-term
implant success rate from 14 years.
More recently, some studies showed
that ligatures-induced periodontitis
in rats can initiate MRONJ develop-
ment. The physiopathological bone
remodelling related to periodontitis
would not occur because of the lack
of osteoclast activity and the peri-
odonthopathogens would directly
colonize the necrotic bone (Kang
et al. 2013). In this case, the origin
of the MRONJ process is question-
able. It is difficult to determine
whether the periodontitis on teeth
36/peri-implantitis or implant
removal or a combination of both
triggered the MRONJ. In the peri-
apical radiograph performed before
implant removal (Fig. 2) displays
radiolucency and an open bifurca-
tion on tooth 36 and peri-implant
bone resorption. The open furcation
was already visible in the panoramic
x-ray 5 years earlier and it can be
assumed that the implant was placed
in a patient while the periodontal
disease was not controlled. Consider-
ing that the initial steps of therapy
provided to this patient are retro-
spective, the clear identification of
the initial cause of this dramatic
osteonecrosis remains uncertain.
Finally, the importance of a com-
prehensive oral examination and pre-
ventive treatment before the initiation
of treatment with an inhibitor of
osteoclastic resorption should be con-
sidered to decrease MRONJ develop-
ment as suggested by some authors
for before IV administration of BPs
(Dimopoulos et al. 2009, Ripamonti
et al. 2009, AAOMS, 2014).
Conclusions
This report serves to alert den-
tists and ARD prescribers about
the potential complication of
bone necrosis in patients receiv-
ing this type of therapy. As the
ageing population grows, the
number of patients with osteopo-
rosis increases, and the number
of patients taking BPs for the
treatment of osteoporosis is
increasing. Prescribers of these
drugs should be aware that
potential consequences could
occur at any time during treat-
ment.
Not all bisphosphonates are the
same, so recommendations for
the discontinuation of bisphosph-
onates need to be drug-specific,
although recommendations about
monitoring after drug discontinu-
ation and reinitiating anti-frac-
ture therapy await further
studies.
Despite the low risk of MRONJ
in oral BPs users, role of active
periodontitis and the fate of den-
tal implants in these patients
remain uncertain. Patients at risk
should be given a full explana-
tion of the potential risks of
implant failure and BRONJ
development.
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Clinical Relevance
Scientific rationale for the study:
Unusual clinical complications and
clinically relevant observations are
important to report especially for
the emphasis of rare but dramatic
drug side effects.
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Medication-Related Osteonecrosis of the jaws
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195
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Address:
France Lambert
Department of Periodontology and Oral
Surgery
CHU de Li ege, Domaine du Sart Tilman Bat
B-35
B-4000 Liege, Belgium
E-mail: france.lambert@chu.ulg.ac.be
receiving per os bisphosphonate,
these complications can occur.
Comprehensive oral examination
and preventive treatment before the
initiation of anti-resorptive drugs
treatment might be of interest.