Introduction
Medication-related osteonecrosis of the jaw (MRONJ)
is described as an exposed bone or bone that can be
probed with an intraoral or extra-oral fistula in the
maxillofacial region that has persisted for more than
8 weeks in a patient with a history of antiresorptive
or antiangiogenic therapy and who has not received
radiation therapy to the jaw or suffered an apparent
metastatic disease of the jaw.[] Symptoms of MRONJ
include dull bone pain, odontalgia, and neurosensory
dysfunction such as paresthesia, loosening of teeth,
periapical or periodontal fistula, and purulent drainage
unexplained from an odontogenic or periodontal
cause.[] MRONJ is more common in patients receiving
bisphosphonates, but also occurs in patients treated
with denosumab or some antiangiogenic.
MRONJ is particularly important for cancer patients,
as high-dose antiresorptive therapy is the mainstay
of treatment for metastasized solid tumors and primary
bone tumors. Level 1 evidence studies have shown
that the overall incidence of tumor patients developing
MRONJ under zoledronate therapy is approximately
1%. It has been reported with denosumab at a rate of
0.9?1.7% among cancer patients.[,] Benign diseases
have a lower risk of developing MRONJ, and the risk
of MRONJ in patients treated with bisphosphonates
or denosumab has been reported to be only approximately
0.017?0.21%.[] There have also been reports
of MRONJ in patients receiving sunitinib, and the risk
may be higher when associated with bisphosphonates.
[] Despite these rather low incidences, the treatment
of MRONJ has become more complex in recent years.
The pathophysiology of MRONJ is uncertain and
multifactorial due to inhibition of osteoclasts, decreased
vascularity, inflammation and infection, and
impaired wound healing.[] Although the role of
trauma is not fully defined, tooth extraction is considered
the most common triggering event in the development
of MRONJ. Other identified risk factors
include length of antiresorptive drug administration,
concomitant use of antiangiogenic and antiresorptive
drugs, concomitant corticosteroid therapy, diabetes,
use of dentures, and poor oral hygiene.[8,9] A very restrictive
approach to tooth extraction is recommended
because of the up to 33-fold increased risk for MRONJ
after extraction.[] Dentists and oral and maxillofacial
surgeons feel endangered when aiming to avoid
MRONJ after tooth extraction and other dentoalveolar
surgical procedures. Most recommendations aim to
control local infection during perioperative antibiotic prophylaxis and plastic wound closure. However, data
on the treatment outcomes of patients treated according
to these recommendations are scarce.[] As far
as we know, there is no study in Türkiye investigating
the risk of MRONJ in patients receiving antiresorptive
and/or antiangiogenic drug therapy. Therefore, the
aim of this study was to investigate the clinical course
after tooth extraction and other dento-alveolar procedures
in patients under antiresorptive/antiangiogenic
therapy and to decide whether these surgical procedures
can be performed safely and predictably while
following treatment recommendations.
Methods
Study Design and Sample
A retrospective longitudinal cohort study of the risk
of post-operative MRONJ development was conducted
in patients who applied to Afyonkarahisar Health
Sciences University, Faculty of Dentistry, oral, and
maxillofacial surgery clinic and used antiresorptive
and antiangiogenic drugs between January 1, 2019,
and December 31, 2020. The study was approved
by the Afyonkarahisar Health Sciences University,
Clinical Research Ethics Committee (2020/13-505)
and was conducted in accordance with the Helsinki
Declaration principles. Written and verbal informed
consent was obtained from all patients. Patients using
antiresorptive and antiangiogenic drugs and undergoing
tooth extraction or similar oral surgery were
included in the study. Patients who were treated in an
external center and presented with the diagnosis of
direct mronj were excluded from the study. All surgical
procedures were performed by a single surgeon in
accordance with the recommendations of the American
Association of Oral and Maxillofacial Surgeons
(AAOMS) guideline. All patients were consulted with
the physician who prescribed the antiresorptive/antiangiogenic
drug before the surgical procedure (Fig.
1). Drug holiday was applied to the patients who were
allowed by the relevant physician. Antibiotic treatment
was given to all patients after the surgical procedure.
Before the surgical procedure, periodontal
treatment of the patients was performed when necessary.
After the surgical procedure, the patients were
followed up clinically and radiologically for a minimum
of 6 months in terms of MRONJ findings.
Fig. 1. Distribution of consulted clinics (%).
Outcome Variable
The primary outcome variable in patients was whether
they developed MRONJ. Factors that may cause osteo necrosis in patients were analyzed as secondary variables.
These variables were categorized into four groups.
1. General-systemic factors associated with the patient
(Age, gender, oral hygiene status, smoking
status, systemic diseases, and comorbid diseases associated
with MRONJ)
2. Drug-related factors (type of drug, for which disease
it is used, route of administration, frequency of
use, and duration of use).
3. Local anatomical factors associated with the patient
(presence of oral torus/exostosis, use of removable
prosthesis, presence of periodontal disease and
periapical lesion, and jaw to be operated).
4. Factors related to the surgical procedure (type of
surgical procedure, drug holiday status, pre-operative
and post-operative antibiotic treatment status,
periodontal treatment before the procedure, number
of teeth extracted, need for surgical extraction,
and socket closure).
Statistical analysis of the data was performed using
version 20 of the SPSS statistical program (SPSS
Inc, Chicago, IL, USA). Mean and standard deviation
values were given in the descriptive statistics of continuous
data, and number and percentage values were
given in nominal data. The normal distribution of data
was evaluated using the Kolmogorov-Smirnov test.
Continuous data that were found to fit normal distribution
were analyzed by student's t-test. When comparing
categorical variables, Chi-square test was employed.
P=0.05 was considered significant.
Results
General-systemic Factors Related to the Patient
Data on the socio-demographic characteristics and
general health status of the patients are presented in Table 1. Most of the participants in the study were
women. (The male/female ratio was about 1/4). Most
of the patients were over 50 years old. The minimum
age of the patients was 19 and the maximum age was
82 (Mean age 59.23±14.89). Three quarters of the
participants were illiterate or primary school graduates.
Half of the participants brushed less than one
tooth a day, while 40.78% were smokers. In addition,
69.73% of the participants had a comorbid disease related
to MRONJ (Table 1).
Table 1 Patient-related demographic and general systemic
factors
Drug-Related Factors
Drug-related factors that may cause MRONJ in patients
are presented in Table 2. Half of the patients were using Alendronic acid, followed by zolendronic acid
and ibandronic acid equally with 18.4%. While 6.6%
of the patients were using denosumab, 5.3% were using
an antiangiogenic drug. While 78.9% of the patients
were being treated for osteoporosis, the others were
being treated for bone metastases of internal organ tumors.
About 65.8% of the patients were taking the drug
orally, 28.9% IV and 5.3% subcutaneously. The majority
of the patients were taking medication on a weekly
and monthly basis. While the duration of drug use in
71.05% of the patients was less than 4 years, the duration
of use of 28.94% was more than 4 years (Table 2).
Table 2 Antiresorptive/antiangiogenic drug-related factors
Local-Anatomical Factors Related to the Patient
Only 10.5% of patients had a bone exostosis/torus that
could cause trauma. In addition, 42.1% of the patients
were using a removable prosthesis, which could pose a
risk of trauma. About 90.79% of the patients had periodontal
disease such as gingivitis or periodontitis. In
28.95% of the patients, there was a periapical lesion in the teeth associated with the surgical site. While the
surgical procedure was in the mandible in 39.5% of the
patients, it involved both jaws in 18.4% (Table 3).
Table 3 Local-anatomical and surgical procedure related
factors
Oral Surgical Treatment Related Factors
In the study, tooth extraction was performed in 66
patients, cyst enucleation was performed in 6 patients,
and preprosthetic surgical procedures such
as epulis/fibroma excision and alveoplasty were performed
in four patients. In 77.63% of the patients,
with the permission of the physician who prescribed
the drug, the drug was suspended for a while (average
3 months) before the procedure (drug holiday).
Antibiotics were prescribed to prevent infection in
82.89% of the patients before the surgical procedure,
and periodontal treatment was performed in 39.47%
of the patients. Except for simple surgical procedures
such as tooth extraction, in approximately 20% of the
patients, flap removal was performed like surgical extraction.
While the socket was left open in 54.16%
of the patients who underwent tooth extraction, suturing
was applied in 30.55% and complete closure
was applied in 15.27%. After the surgical procedure,
antibiotics were prescribed to all patients according
to their condition (Table 3).
In the study, patients were followed up for a minimum
of 6 months in terms of postoperative wound healing. No
mucosal healing problem or osteonecrosis was observed
in any of the patients in the post-operative period.
Discussion
In recent years, due to the increasing prevalence of
antiresorptive drugs such as denosumab, other than
bisphosphonates, tooth extraction and other dentoalveolar
surgical procedures are becoming more
important for dentists and maxillofacial surgeons
in patients taking antiresorptive/antiangiogenic
drugs. Tooth extraction and dentoalveolar surgical
procedures are considered risk factors for the
onset of MRONJ.[] Some guidelines even recommend
avoiding extractions and dentoalveolar surgery
whenever possible under bisphosphonate intake.[]
MRONJ is a growing problem, as prescription levels
of MRONJ-related drugs have risen notably in recent
years and are expected to increase further. In this
study, patients using antiresorptive/antiangiogenic
drugs were comprehensively evaluated for the development
of MRONJ and risk factors.
Age and gender are reported to be variable risk
factors for MRONJ. The high prevalence of MRON
in women is likely due to the underlying disease for
which the agents were prescribed (e.g., osteoporosis
and breast cancer).[] Consistent with the literature
in this study, 78.9% of the patients were women and it was approximately 4 times more than men. The
mean age of the patients was 60 years and it was
observed that these patients were quite advanced
(81.6% over 50 years old). Comorbid conditions associated
with MRONJ risk include anemia (hemoglobin
<10 g/dL) and diabetes. Corticosteroids have
been linked to a higher risk of MRONJ.] The kind
of cancer is also cited as a risk factor.[] Tobacco
usage has been cited as a risk factor for MRONJ in a
variety of studies.[] In the present study, 70% of patients
had a comorbid disease such as diabetes, anemia
and cancer. Corticosteroid intake was present
in 10.52% of the patients. In addition, 40% of them
were smokers. It is observed that the education level
of the patients in the study is quite low. Almost all of
the patients were not informed about MRONJ by the
physician who prescribed the drug, and they did not
know that the drug could cause osteonecrosis of the
jaws as a side effect.
Potent nitrogen bisphosphonates may persist for
years because they bind to the hydroxylapatite of
bone.[] Therefore, most patients who initially use
bisphosphonates switch to Denosumab. The risk is
around 1% among cancer patients who have had intravenous
(iv) zoledronate.[] The risk of MRONJ is 100
times higher in cancer than in osteoporotic patients
taking the same drug.[] All patients in the study, except
for osteoporosis, were under cancer treatment.
Most of them were using antiresorbtive drugs such
as IV bisphosphonate (28.9%) or denosumab (6.6%)
for bone metastases of solid tumors such as lung,
breast, and colon cancer. In this study, four patients
were using antiangiogenic drugs for visceral tumors.
It has been reported that especially in patients using
bisphosphonates, when the duration of treatment exceeds
3 years, patients are faced with an increased risk
of osteonecrosis. In this study, the duration of drug use
in 43.8% of the patients was over 3 years.
Dentoalveolar surgery is thought an important
factor in the occur of MRONJ.[,] About 66.7%
of the lesions occur in the mandible. This might be
due to variations in anatomical structure between the
maxillary and mandibular bones.[] In this study,
the most common procedure was tooth extraction.
While a single tooth was extracted in half of the patients,
more than three teeth were extracted in 11.2%
of the patients. Both jaws were undergone to similar
dentoalveolar surgery. About 42% of the patients were
using removable prostheses and 10% of patients had
bone exostosis that could cause trauma. In patients
receiving bisphosphonates, mucosal healing is imperfect and trauma caused by prostheses can lead to
bone infection. A two-fold increased risk of MRONJ
was reported in prosthetic wearers in 1621 patients
treated with bisphosphonates.[] Another research
reported that 27.5% of 80 MRONJ patients had denture
pressure ulcers.[]
The timing of discontinuation of antiresorptive
agents is still for discussion, but it has been reported
that early discontinuation of bisphosphonates in
MRONJ treatment is associated with faster resolution
of symptom.[] According to the AAOMS, discontinuation
of antiresorptive therapy may be considered
until bone exposure is resolved.[] In this study,
77.63% of the patients had a "drug holiday" before the
surgical procedure. Dental care before the initiation
of antiresorptive drugs and following guidelines emphasizing
the need for active dental care in these patients
have been shown to reduce the risk of MRONJ.
[,] Biofilm formation on exposed bone may require
long-term antibiotic therapy or even surgical
treatment.[] Hence, when necessary, periodontal
treatment of the patients was performed before the
procedure. Pre-operative antibiotic therapy was administered
to most patients. All surgical procedures
were performed atraumatically. Antibiotics, analgesic/
anti-inflammatory, and mouthwash were prescribed
to all patients after the surgical procedure.
Treating individuals with MRONJ is still a difficult
task, and it has been a contentious subject since
the occurrence of the disease.[] The best method is
to prevent MRONJ by evaluating risk factors and taking
measures to minimize the risk of osteonecrosis in
patients under antiresorptive therapy. In a cohort of
patients with a low-risk profile, namely, osteoporotic
patients receiving only oral bisphosphonates, Mozzati
et al.[] reported that they had a 100% success rate
in atraumatic tooth extraction combined with antibiotic
prophylaxis in subgroups with (n=334 patients)
and without (n=366 patients) plastic wound closure. A
recent study reported an high success rate (uneventful
recovery at 96.8% and 209/216 extraction sites) in
high-risk patients with underlying malignant disease
receiving intravenous bisphosphonate therapy.[]
Heufelder et al.[] reported a 97% rate for complete
mucosal healing (n rate 114/117 extraction sites), taking
very similar preventive measures in a comparable
patient cohort. In this study, wound healing was uneventful
in all patients in the post-operative period and
no complications were observed. Moreover, some of
these patients were at high risk and underwent multiple
surgical procedures.
Study Limitations
The retrospective design and sample size of the study
are the limitations of the study. The minimum follow-up
period was judged to be 6 months, which was a shorterthan-
desired length, but this constraint was compensated
by a mean follow-up period of 10 months. The study's
strength is that therapy and clinical follow-up were conducted
by a single surgeon using the same treatment
protocol. The study comprehensively revealed possible
risk factors in patients taking antiresorptive/antiangiogenic
drugs and showed that the risk of MRONJ can be
reduced or completely eliminated after surgical procedures
performed in accordance with AAOMS principles.
Conclusion
The results of this study show that although the patient
cohort contained at-risk patients with underlying malignant
disease who received intravenous bisphosphonate
or denosumab therapy, the emergence of osteonecrotic
lesions was prevented when the procedures were
performed in accordance with international guidelines
such as AAOMS. We recommend a minimally traumatic
method involving removal of the bone margins and closure
of the mucosal wound as standard procedures in patients
receiving antiresorptive and antiangiogenic drug
therapy. In these patients, periodontal treatment and oral
hygiene education before the surgical procedure, antibiotic
treatment before and after the procedure are effective
methods in controlling the infection. In addition, we
think that taking a break from the antiresorptive drug for
a while by consulting the physician who prescribed the
drug may reduce the risk of MRONJ. Clinical guidelines
recommend that patients be in optimal oral health possible
at which they start MRONJ-related medications. It
should be noted that preventing MRONJ as much as possible
is a much better option than treating it.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the
Afyonkarahisar Health Sciences University Clinical Research
Ethics Committee (no: 2020/13?505, date: 06/11/2020).
Financial Support: None declared.
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