Brazilian Journal of Otorhinolaryngology 2022;88(5):683---690

Brazilian Journal of

OTORHINOLARYNGOLOGY
www.bjorl.org

ORIGINAL ARTICLE

Risk factors for medication-related osteonecrosis of

the jaw and salivary IL-6 IN cancer patients
Aristilia Pricila Tahara Kemp a,b , Vitor Hugo Candido Ferreira a ,
Rafael Zancan Mobile a , Thais Bianca Brandão b , Laurindo Moacir Sassi c ,
Amanda Zarpellon d , Paulo Henrique Braz-Silva d,e , Juliana Lucena Schussel a,∗

a
Universidade Federal do Paraná, Programa de Pós-Graduação em Odontologia, Departamento de Estomatologia, Curitiba, PR,
Brazil
b
Instituto do Câncer do Estado de São Paulo, Serviço de Odontologia, São Paulo, SP, Brazil
c
Hospital Erasto Gaerner, Departamento de Cirurgia Bucomaxilofacial, Curitiba, PR, Brazil
d
Universidade de São Paulo, Faculdade de Odontologia, Divisão de Patologia Geral, Departamento de Estomatologia, São Paulo,
SP, Brazil
e
Universidade de São Paulo, Instituto de Medicina Tropical de São Paulo, Laboratório de Virologia, São Paulo, SP, Brazil

Received 22 June 2020; accepted 14 September 2020

Available online 25 October 2020

KEYWORDS
Abstract
Bisphosphonates;
Introduction: Medication-related osteonecrosis of the jaws is a severe complication of the use
Osteonecrosis of the
of antiresorptive and antiangiogenic therapy, with limited treatment options and great impact
jaw;
on patient’s quality pf life.
Biomarkers in saliva;
Objective: The aim of this study was to assess the risk factors associated with medication-
Interleukin-6
related osteonecrosis of the jaws in oncologic patients undergoing bisphosphonate treatment.
In addition, salivary levels of interleukin-6, IL-6, were measured to investigate their association
with severity and risk of medication-related osteonecrosis of the jaws.
Methods: Case-control study with 74 patients with bone metastases from solid tumors and
multiple myeloma was included. Patients were divided into three groups: 1) those undergoing
bisphosphonate treatment with medication-related osteonecrosis of the jaws; 2) those under-
going bisphosphonate without medication-related osteonecrosis of the jaws; and 3) those with
bisphosphonate pretreatment. The demographic and medical data of the patients were col-
lected to assess risk. The clinical evaluation was performed to diagnose medication-related
osteonecrosis of the jaws and unstimulated saliva was collected for quantification of IL-6.

∗ Corresponding author.
E-mail: [email protected] (J.L. Schussel).
Peer Review under the responsibility of Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial.

https://doi.org/10.1016/j.bjorl.2020.09.010
1808-8694/© 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A.P. Kemp, V.H. Ferreira, R.Z. Mobile et al.

Results: As result, it was observed that patients diagnosed with medication-related osteonecro-
sis of the jaws were submitted to higher number of bisphosphonate doses (p = 0.001) and
monthly infusion protocol (p = 0.044; OR = 7.75). Patients who did not have routine followup
with specialized dentists during therapy with bisphosphonate and smoking were associated
with medication-related osteonecrosis of the jaws (p = 0.019; OR = 8.25 and p = 0.031; OR = 9.37
respectively). Group 1 had a higher frequency of treatment with chemotherapy and corticos-
teroids concomitant with bisphosphonate, and surgical dental procedures (p = 0.129). Salivary
IL-6 levels showed no statistically significant difference between the groups (p = 0.571) or asso-
ciation with medication-related osteonecrosis of the jaws severity (p = 0.923).
Conclusion: A higher number of bisphosphonate cycles, monthly infusion protocol, no dental
follow-up for oral health maintenance and smoking were associated with medication-related
osteonecrosis of the jaws. Specialized dental follow up during bisphosphonate treatment has
been shown to be an important factor in preventing this complication.
© 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by
Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction and hypothyroidism9 with MRONJ. Evaluation of local factors

showed the association of surgical dental procedures such as
Bisphosphonates (BP) are antiresorptive agents indicated extraction and MRONJ.14
for the treatment of skeletal complications associated with There are few studies that analyzed the association of
multiple myeloma and bone metastases from solid tumors, in salivary and plasma interleukin with the inflammatory pro-
addition to the treatment of osteoporosis and osteopenia.1,2 cess at the onset of MRONJ.20,21 Higher values in the salivary
Despite its clinical benefit, one of its side effects is and blood levels of Interleukin-6 (IL-6) were observed in the
medication- related osteonecrosis of the jaw (MRONJ), group of MRONJ patients when compared to the group of
which is a serious complication, with a direct impact on patients treated with bisphosphonates, but without MRONJ,
patients’ quality of life and oncologic treatment.2,3 as well as to the control group, without the use of BP
Medication- related osteonecrosis of the jaw is defined (p < 0.01), suggesting that L-6 could be used as a contributing
as the presence of exposed bone or bone that can be marker in the diagnosis of MRONJ.20 Overproduction of IL-6
probed through an intra- or extra-oral fistula in the max- was related to autoimmune and inflammatory diseases.22,23
illofacial region with persistence of more than 8 weeks, The aim of this study was to investigate the association of
absence of radiotherapy or metastatic disease in the jaws of risk factors for MRONJ in cancer patients undergoing treat-
patients in current or previous treatment with antiresorptive ment with BP. Additionally, to evaluate salivary levels of IL-6
or antiangiogenics.4 Symptoms may include pain, swelling, among patients ongoing or without BP and its association
erythema and tooth loss associated with infections.5 with MRONJ.
The incidence of intravenous BP in cancer patients ranges
from 1.2% to 9.9%. The highest frequency is associated with Methods
multiple myeloma and lowest in breast cancer patients.2
The pathophysiology of MRONJ has not been fully According to the Declaration of Helsinki for Human Studies,
elucidated.4,6 It is believed that its occurrence caused by 1964, a case control study was conducted after approval by
BP begin with pH reduction after oral infection or dental the Research Ethics Committee of the Institute of Cancer
surgery that cause release and cause activation of toxic BP of São Paulo --- Hospital 1 (Protocol no 2,981,115) and Erasto
levels.2 BPs have anti-osteoclastic action, causing an inhi- Gaertner Cancer Center --- Hospital 2 (Protocol no 3,280,348)
bition of bone resorption and consequently a suppression with the inclusion of seventy-four patients who signed the
of bone remodeling and also antiangiogenic action, causing Informed Consent Form (ICF).
ischemia.2,5 Some theories, still under investigation, point Patients with a diagnosis of breast cancer and other
out the effect of BP on MRONJ with inhibition of the immune metastatic tumors for bone (prostate, kidney, lung, ovar-
system, susceptibility to infections and soft tissue toxicity ian and uterus) and multiple myeloma were included in the
by BP.2 study.
The etiology of MRONJ is multifactorial2 as a result of the The patients were selected by convenience and divided
association of metabolic, local and genetic factors.7 into 3 groups according to clinical signs and oncological
Several studies have assessed risk factors for MRONJ.2,8---19 treatment. Group 1 was composed of 8 patients diagnosed
In the evaluation of the factors related to cancer treat- with MRONJ on BP treatment, Group 2 with 60 patients on BP
ment, MRONJ was associated with the type of BP,11,13,16 treatment, but without bone exposure and Group 3 with 6
number of infusions,9,16 concomitance with corticosteroids13 patients prior to BP treatment. Patients included in Groups 1
and chemotherapy14 Some studies have shown an associa- and 2 were treated with zoledronic acid 4 mg at least 3 doses
tion between smoking9,19 and comorbidities such as diabetes alone or after treatment with pamidronate 90 mg, with the

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 Brazilian Journal of Otorhinolaryngology 2022;88(5):683---690

vals of 60 s.24 Saliva contaminated with blood was discarded.

The saliva samples were immediately refrigerated and cen-
trifuged at 3000 g for 10 min and stored at −80 ◦ C until
analysis.
The ELISA assay for human IL-6 was used for quantifi-
cation of salivary IL-6 (Elabscience, Texas, USA), through
colorimetric detection with a range between values of 7.81
and 500 pg/mL. Briefly, 100 u L of saliva were used into each
well containing pre-coated human IL-6 specific antibody,
incubation at 37 ◦ C for 90 min. Biotinylated detection anti-
body specific for human IL-6 was then added and incubated
at 37 ◦ C for 1 h, followed by 3 washes. Avidin-Horseradish
Peroxidase (HRP) was incubated at 37 ◦ C for 1 h and washed
5 times. Finally, the substrate reagent was added, incu-
Figure 1 Image showing a MRONJ Stage 2, that occurred after bated at 37 ◦ C for 15 min with the addition of stop solution.
exodontia and was included in the study. Measurement of optical density (OD) at wavelength 450 nm
by spectrophotometry was evaluated and the calculation of
human IL-6 concentration of the samples was performed by
last dose being used after up to 6 months from the salivary comparing the OD of the samples with the pre-established
collection. The interval between infusion cycles varied from standard curve. Reactions were made in duplicate, accord-
monthly to quarterly. ing to the manufacturer’s guidelines and compared among
Patients with a history of radiotherapy or tumors (includ- the 3 study groups.
ing metastases) involving the head and neck region were The Statistical Package for the Social Sciences software
excluded from the study. In addition, patients undergoing (version 13, spss INC) was used for data analysis. A descrip-
prior surgical MRONJ treatment or diagnosis of autoimmune tive analysis of the data with frequency evaluation was
and inflammatory diseases such as rheumatoid arthritis, performed. The Mann-Whitney test and the Kruskal---Wallis
juvenile idiopathic arthritis syndrome and Castleman’s dis- test were used to analyze the quantitative variables. The
ease were also excluded from the sample. Kolmogorov-Smirnov test (n > 50) was used to analyze the
The MRONJ stages were classified as Stage 0: absence of data distribution normality. Fisher’s test was used for the
clinical evidence of necrotic bone, presence of non-specific nominal categorical variables. Odds ratio was calculated to
clinical findings with radiographic changes and symptoma- assess the chance of occurrence of a 95% Confidence Inter-
tology; Stage 1: exposed and necrotic bone or fistula, val event (95% CI). The Spearman correlation coefficient
asymptomatic or absence of infection; Stage 2: presence was used for assessing the association of IL-6 levels with
of exposed and necrotic bone or fistula, infection evidenced MRONJ severity. A p-value of less than 0.05 was considered
by pain and erythema in the exposed bone region with or statistically significant.
without purulent drainage; Stage 3: exposed and necrotic
bone or fistula, infection and pain, exposed with necrotic
bone extending below the alveolar bone region resulting
in pathological fracture, extraoral fistula, buccal- sinus
communication or osteolysis extending to lower mandibular Results
border or floor sinus.4 Panoramic radiographic images were
evaluated so that the correct diagnosis could be made, as Of the 74 patients evaluated, 78.4% were women. The mean
well as the MRONJ classification. Fig. 1 shows example of age in Groups 1, 2 and 3 were respectively 63.88, 56.27 and
MRONJ diagnosed after tooth extraction and classified as 51.33 years (p = 0.134). The oncologic diagnoses were breast
Stage 2. cancer (n = 45), multiple myeloma (n = 20) and other solid
Demographic information (gender, age, oncologi- tumors such as ovarian cancer, uterine cancer, kidney can-
cal/hematological diagnosis) and cancer treatment (type cer, and lung cancer (n = 9). The demographic data of the
and number of BP infusions, chemotherapy and corticos- participants were shown in Table 1.
teroid treatment concomitant with BP treatment) were The median for salivary levels of IL-6 for Group 1 was
collected from medical records. 22.34 pg/mL (minimum 13.86 and maximum of 198.88);
Patients were evaluated regarding the performance of Group 2, 21.87 pg/mL (minimum of 10.45 and maximum
dental procedures during oncologic treatment such as of 75.91); and Group 3, 25.27 pg/mL (minimum 19.28 and
infection outbreaks removal like periodontics, dentistry, maximum of 88.72). There was no statistically significant
endodontics and invasive dental procedures like extractions. difference for the groups (p = 0.571). These results are
Dental followup with specialized dentist care during BP shown in Table 2.
treatment and smoking were also evaluated. There was no association between salivary IL-6 levels and
According to the technique described by Navazesh in MRONJ stages (rs = −0.41 and p = 0.923).
1993, the patients were instructed not to smoke, drink or The patients with MRONJ received a greater number of
eat at least 1 h before the dental appointment for the collec- infusions of zoledronic acid 4 mg compared to patients with-
tion of the non-stimulated saliva. The patient was instructed out MRONJ using BP (p = 0.001). Among the patients who
to expectorate all saliva accumulated in the mouth within developed MRONJ, 7 patients (87.5%) were treated to at
a 15 mL Falcon tube for 5 min without swallowing at inter- least 10 infusions.

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 A.P. Kemp, V.H. Ferreira, R.Z. Mobile et al.

Table 1 Demographic distribution between Groups 1, 2 and 3.

Group Total

1 2 3
Gender n (%)
Female 5 (62.5) 48 (80.0) 5 (83.3) 58
Male 3 (37.5) 12 (20.0) 1 (16.7) 16
Mean age (standard deviation) 63.8 (13.1) 56.2 (11.9) 51.3 (10.8)
Diagnosis, n (%)
Breast cancer 5 (62.5) 36 (60.0) 4 (66.6) 45
Multiple myeloma 2 (25.0) 17 (28.3) 1 (16.7) 20
Others 1 (12.5) 7 (11.7) 1 (16.7) 9
Group 1, patients with bisphosphonates and medication related osteonecrosis of the jaw; Group 2, patients with bisphosphonates and
without medication related osteonecrosis of the jaw; Group 3, patients without bisphosphonates.

Table 2 Salivary levels of IL-6 (pg/mL) between groups 1, 2 and 3.

Group p-Value

1 2 3
Median IL-6 22.34 21.87 25.27 0.571a
Minimum---Maximum (15.78---198.88) (10.45---275.91) (19.28---88.72)
Group 1, Patients with bisphosphonates and medication related osteonecrosis of the jaw; Group 2, Patients with bisphosphonates and
without medication related osteonecrosis of the jaw; Group 3, Patients without bisphosphonates.
a Kruskal---Wallis test. Statistical significance: p < 0.05.

Regarding the monthly or quarterly intervals of BP infu- presented simultaneous bone exposure in the mandible and
sion, the monthly interval was associated with MRONJ posterior maxilla.
(p = 0.044). Smoking was a factor associated with MRONJ (p = 0.031).
In the evaluation of cancer therapies concomitant with The odds ratio for smoking was 9.37.
the use of BP in Group 1, chemotherapy treatment was Table 3 presents data on dental followup during treat-
present in 6 (75.0%) of 8 patients with MRONJ (p = 1.000) and ment with BP, tooth extraction and smoking in Groups 1 and
corticosteroid treatment was present in 7 (87.5%) of the 8 2.
patients with MRONJ (p = 0.427). Fig. 1 illustrates the case of patient number 6, with
Table 3 presents the data of the oncological treatment as MRONJ Stage 2, after exodontia of 38 tooth during antire-
the type and number of BP infusions, interval between infu- sorptive therapy.
sions, concomitant chemotherapy and corticosteroids use Table 4 summarizes the demographic data, BP treatment
with BP (Groups 1 and 2). and clinical data from 8 patients in Group 1.
Patients without a dental check-up routine with
procedures for eliminating infection outbreaks (caries Discussion
lesions, periodontal disease, endodontics and exodon-
tia) or prosthetic traumas had association with MRONJ
The incidence of MRONJ among cancer patients on intra-
(p = 0.019).
venous BP may vary from 1.2% to 9.9%.2 This incidence is
Of the dental risk factors for MRONJ, 26 patients (38,2%)
higher among patients with multiple myeloma compared to
out of 68 trans- BP patients were submitted to exodontias
patients with breast or prostate cancer.5,9,16 Our study, in
(Hospital 1). There was no significant difference between
turn, presented the frequency of 10.8% in the sample of
the Groups 1 and 2 to exodontias (p = 0.129). However, of
patients studied, a figure higher than that reported in the lit-
the 8 patients who developed MRONJ, 6 patients (75.0%)
erature, probably due the fact that the study was conducted
had occurrence after surgical dental procedures and 2 cases
at the two cancer treatment centers with a specialized Ser-
occurred spontaneously (25.0%). Of the 6 patients who
vice of Maxillofacial Surgery, which makes them a reference
developed MRONJ after surgical procedures, in 5 cases the
center for the treatment of MRONJ.
procedures were performed in external services and referral
Most of MRONJ cases were diagnosed with breast can-
for MRONJ treatment for Hospital 1 (1 patient) and Hospital
cer, while 1 had prostate cancer and 2 patients had multiple
2 (4 patients). Only 1 patient with MRONJ (Stage 1) occurred
myeloma (MM). Our sample had a higher number of breast
after extraction at Hospital 1.
cancer, the most frequent in our region, and BP infusion pro-
The maxilla was the site of MRONJ’s greatest involve-
tocols, such as dose and periodicity for solid tumors with
ment. Four patients (50.0%) developed MRONJ in the
osseous metastases and for MM do not differ in the sample
maxilla, 3 patients (37.5%) in the mandible, while 1 (12.5%)
of patients studied.

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 Brazilian Journal of Otorhinolaryngology 2022;88(5):683---690

Table 3 Assessment of systemic and local risk factors for MRONJ between groups 1 and 2.
Group p-Value OR 95% IC

1 2
BP type, n (%)
Zoledronic acid 7 (87.5) 53 (88.3) 1.000a 0.92 0.099---8.673
Pamidronate and zoledronic acid 1 (12.5) 7 (11.8)
Number of cycles zoledronic acid
Median (Minimum---Maximum) 16.0 (10---32) 7.0 (3---38) 0.001b
Number of cycles Pamidronate
Median (Minimum---Maximum) 0.00 (0---25) 0.00 (0---18) 0.852b
Infusion interval, n (%)
Monthly 6 (75.0) 19 (31.7) 0.044a 7.75 1.194---35.092
Quartely 2 (25.0) 41 (68.2)
Chemotherapy, n (%)
Yes 6 (75.0) 43 (70.0) 1.000a 1.18 0.155---4.597
No 2 (25.0) 17 (28.3)
Steroids, n (%)
Yes 7 (87.5) 42 (70.0) 0.427a 3.20 0.038---2.910
No 1 (12.5) 18 (30.0)
Check-up and procedures trans BP, n (%)
No 6 (75.0) 18 (30.0) 0.019a 8.25 1.288---38.046
Yes 2 (25.0) 42 (70.0)
Exodontia, n (%)
Yes 6 (75.0) 25 (41.7) 0.129a 4.80 0.044---1.278
No 2 (25.0) 35 (58.3)
Smoking, n (%)
Yes (ex-smoking < 5 years) 3 (37.5) 4 (6.7) 0.031a 9.37 1.453---48.549
No (ex-smoking > 5 years) 5 (62.5) 56 (93.3)
Group 1, patients with bisphosphonates and medication related osteonecrosis of the jaw; Group 2, patients with bisphosphonates and
without medication related osteonecrosis of the jaw.
a Fischer’s exact test.
b Mann---Whitney Test. Statistical significance: p < 0.05.

Table 4 Demographic, clinical and cancer treatment characteristics of Group 1.

Patient Diagnosis Type of BP Number of MRONJ Stage Location Factor MRONJ Painful
o
(N /age/ infusions (AAOMS 2014) trigger symptoms
gender)
1/65/F Breast AZ 13 2 Anterior Mx Implant Yes
2/77/F Breast AZ 22 1 Posterior Mx Exodontia No
3/58/F Breast AZ 33 0 Posterior Md Spontaneous No
4/47/F Breast AZ 10 2 Posterior Mx Exodontia Yes
5/64/M MM AZ 13 2 Anterior Mx Exodontia Yes
6/88/M Prostate AZ 11 2 Posterior Md Exodontia Yes
7/58/F Breast AZ 33 1 Posterior Md Spontaneous No
8/54/F MM AZ 19 2 Posterior Mx Exodontia Yes
P 25 Posterior Md
P, bisphosphonate; AZ, zolendronic acid; P, pamidronate; F, female; M, male; MM, multiple myeloma; MRONJ, medication related
osteonecrosis of the jaw; Md, mandibula; Mx, maxilla.

Several studies have shown time of exposure to BP as time of exposure MRONJ risk, since the patients included in
a risk factor for the development of MRONJ8,9,14,16 and the study had interval protocols between BP infusions rang-
have also shown an association between the number of ing monthly and quarterly. In our study, we evaluated the
BP infusions and MRONJ development.9,16 In studies eval- number of infusions and the group of patients with MRONJ
uating BP exposure time, infusion protocols ranged from who received a higher number of 4 mg zoledronic acid infu-
3 to 4 weeks, and were associated with the development sions compared to the group of patients without MRONJ
of MRONJ. In our study, it was not feasible to assess the (p = 0.001). Our results are in agreement with the studies

687
 A.P. Kemp, V.H. Ferreira, R.Z. Mobile et al.

that reported an association of the number of infusions with shown in 26 cases of trans BP extractions performed at Hos-
MRONJ.8,9,16 pital 1, and just 1 case of MRONJ (Stage 1). Hospital 1
Some studies have shown that the risk for MRONJ was performed a minimally traumatic surgical protocol, primary
significantly higher in patients taking zoledronic acid com- closure of the surgical area, pre- and postoperative antibi-
pared with pamidronate alone or after pamidronate.9,16,25 otic therapy with amoxicillin 500 mg or clindamycin 600
This fact explains that the potency of zoledronic acid is 100 mg for patients allergic to penicillin and periodic followup
times greater than pamidronate.5 Our study showed that with these patients. These measures may decrease the risk
MRONJ was associated with a higher number of zoledronic for MRONJ and thus justify the absence of association of
acid cycles (p = 0.001) as described in the literature. extraction with MRONJ in this study.
Regarding the BP infusion interval, there is evidence that MRONJ lesions appear more commonly in the mandible
quarterly infusions may decrease the risk for MRONJ com- than in the maxilla, in the 2:1 ratio. However, it may develop
pared to monthly infusions. A study has shown that risk in both arches.6 The reason for MRONJ predilection in the
for MRONJ decreases 8-fold in quarterly infusions compared mandible when compared to the maxilla may be due to the
with monthly infusions (p = 0.049).25 Another study showed high mandibular bone remodeling suppressed by antiresorp-
that the quarterly regimen was not inferior to the monthly tive agents14 and also structurally by the thick bone cortical
regimen for effectiveness of cancer treatment and 2 cases of and medullary cavity.6
MRONJ were associated with the monthly infusion group.26 Some studies have shown that the mandible is the most
Our study showed association of MRONJ with monthly infu- affected site for MRONJ and, most of the time, associ-
sion interval (p = 0.044), in agreement with the literature. ated with exodontia2,7,8,10,12,14,16,27 In our study, however, the
Patients with monthly BP infusion interval have 7.75 times region of greatest involvement with MRONJ was the maxilla,
more chance for MRONJ compared to those with quarterly contrary to what is reported in previous reports. This fact
infusion. can be explained because 4 of the 8 cases were associated
The association of BP use concomitant with chemother- with surgical dental procedures exclusively in the maxilla. In
apeutic has been previously reported.14 However, the study the cases of MRONJ of spontaneous cause, the mandible was
did not classify the types of chemotherapy used according to affected, consistent with that reported in the literature.
the type of cancer diagnosis to assess the risk for MRONJ.14 Pre-BP dental therapy with the institution of preven-
In our study, 6 patients (75.0%) of the 8 MRONJ patients had tive measures of dental care in routine visits to the dental
chemotherapy treatment concomitant with BP treatment. surgeon3,27,29,30 has had a direct implication in reducing
However, we have to consider the diversity of chemotherapy the incidence of MRONJ.2,8,18 Thus, invasive dental treat-
regimens used due to the different tumor diagnoses in the ment, such as extractions, should be performed prior to
sample, which compromises the evaluation of concomitant BP therapy, in order to reduce the need for these proce-
chemotherapy with BP in the development of MRONJ. dures trans BP.8,10,12,29 During BP therapy, however, clinical
For some authors, MRONJ is associated with the conco- and radiographic dental monitoring of these patients is also
mitant treatment of corticosteroids with antiresorptive important.8 Otto et al. 2012, showed that only 7 (10.6%) of
agents.6,18,27 The immunosuppressive effect of corticos- 66 patients with MRONJ were referred to the dentist before
teroids may be related to delayed healing, alteration of BP treatment.2 Water et al. 2008, reported that 6 out of 8
the oral microbiota and higher risk for infection and devel- MRONJ patients (75.0%) had routine dental appointments.15
opment of MRONJ.18 Study has shown an increased risk of The sample of this study originated from services with dif-
MRONJ as corticosteroid use, but did not classify the risk ferent care protocols, while Hospital 1 is characterized as
according to clinical indication and corticosteroid dose.13 In a clinical dentistry service performing procedures such as
our study, MRONJ patients presented an 87.5% frequency of dentistry, endodontics, periodontics and extractions; also
corticosteroids use compared with 12.5% of patients without radiographic/clinical followup occurred up to 1 year after
corticosteroids with MRONJ (p = 0.427). As previously men- last BP infusion, Hospital 2 is characterized by an oral
tioned for the chemotherapeutic treatment, the different maxillofacial surgery service that provides guidance and
protocols and periodicity of corticosteroids in the concomi- prevention, but with limitations in performing clinical pro-
tant treatment with BP may make it unfeasible to use this cedures, referring patients when necessary. The importance
data to predict the risk for MRONJ. of trans-BP dental monitoring is highlighted as a result of
Regarding the dental factors that trigger MRONJ, we our study, since 6 patients (75.0%) with MRONJ did not
can mention trauma, spontaneous cause,28 presence of have trans BP dental checkup with dental procedures (den-
pre-existing dental diseases, such as periodontitis and sur- tistry, endodontics, periodontics and extractions) and only 2
gical dental procedures.8 However, tooth extraction is the patients (25.5%) had routine appointments for dental proce-
local factor predominantly associated with MRONJ.18 Several dures. This result is a statistical difference between Groups
studies have shown the association of MRONJ with den- 1 and 2 (p = 0.019). Our results showed that patients who did
tal extraction.9,15,16,25 Conscious of what has been exposed, not eliminate foci of infection before or during BP therapy
it is thought that non-surgical dental procedures can pre- showed a higher risk for MRONJ, according to Otto et al.
vent MRONJ8 In our study, of the 8 patients who developed 2012.2 It is believed that patients undergoing trans-BP den-
MRONJ, 6 cases of MRONJ occurred after surgical proce- tal checkups have hygiene orientation, procedures such as
dures and 2 cases were spontaneous (p = 0.129). In 5 cases removal of infection outbreaks and preventive procedures
of MRONJ, the surgical procedures were performed in exter- and these measures will have a direct impact on the devel-
nal services and referral for MRONJ treatment in hospitals opment of MRONJ.
1 (1 case) and 2 (4 cases). This result shows the importance Other studies have reported smoking as a risk fac-
of performing dental extraction by skilled professionals, as tor for MRONJ9,19 The result of our study showed that

688
 Brazilian Journal of Otorhinolaryngology 2022;88(5):683---690

smokers are 9.37 times more likely to develop MRONJ Conflicts of interest
than those without the habit (p = 0.031). Smoking promotes
delayed bone healing and worsening of the periodontal The authors declare no conflicts of interest.
condition.31,32 Among the deleterious effects of toxins found
in tobacco smoke are vasoconstriction and platelet aggre-
gation induced by nicotine and reduced oxygen transport
Acknowlegments
capacity by hemoglobin.31 Increased vasoconstriction may
lead to ischemia that is associated with MRONJ pathophysi- CAPES - Coordination of Higher Education Improvement.
ology.
In bone metabolism, IL-6 induces osteoclast differentia- References
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baum S, et al. Bisphosphonate-related osteonecrosis of the jaws
in the production of RANKL, inhibiting bone turnover and
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