Radiographic patterns of multiple myeloma in the jawbones of patients treated with intravenous bisphosphonates

Abstract

Background:
The purpose of this study was to evaluate whether intravenous (IV) bisphosphonate (BP) therapy can change the radiographic patterns of multiple myeloma (MM) in the jawbones.

Methods:
The authors evaluated panoramic radiographs obtained from 188 patients with MM for the presence of solitary osteolytic lesions, multiple osteolytic lesions, diffuse osteoporosis, diffuse sclerosis, lamina dura abnormalities, nonhealing alveolar sockets, and bone sequestration. The authors compared results obtained from patients treated with IV BPs with those obtained from patients who had never been exposed to BPs.

Results:
Multiple osteolytic lesions (P = .001), diffuse osteoporosis (P = .001), and diffuse sclerosis (P = .0036) occurred more often in the mandible in both groups. Solitary osteolytic lesions occurred less frequently in the BP group (P = .0078). Lamina dura abnormalities (P = .0006) and nonhealing alveolar sockets (P = .0021) were associated with BP treatment.

Conclusions:
IV BP therapy changes the radiographic patterns of MM in the jawbones.

Practical implications:
The effect of BPs in the maxillofacial area is a matter of concern for health practitioners because this type of medication causes several alterations of the jawbones in patients with cancer.

Full text

Original Contributions
Radiographic patterns of multiple myeloma
in the jawbones of patients treated with
intravenous bisphosphonates
Karina Morais Faria, DDS, MSc, PhD; Ana Carolina Prado Ribeiro, DDS, MSc, PhD;
Thais Bianca Brandão, DDS, MSc; Wagner Gomes Silva, DDS, MSc;
Marcio Ajudarte Lopes, DDS, MSc, PhD; Juliana Pereira, MD, MSc, PhD;
Marcelo Corrêa Alves, MSc, PhD; Luiz Alcino Gueiros, DDS, MSc, PhD;
Werner Harumiti Shintaku, DDS, MSc; Cesar Augusto Migliorati, DDS, MSc, PhD;
Alan Roger Santos-Silva, DDS, MSc, PhD
ABSTRACT
Background. The purpose of this study was to evaluate whether intravenous (IV) bisphosphonate
(BP) therapy can change the radiographic patterns of multiple myeloma (MM) in the jawbones.
Methods. The authors evaluated panoramic radiographs obtained from 188 patients with MM for
the presence of solitary osteolytic lesions, multiple osteolytic lesions, diffuse osteoporosis, diffuse
sclerosis, lamina dura abnormalities, nonhealing alveolar sockets, and bone sequestration. The
authors compared results obtained from patients treated with IV BPs with those obtained from
patients who had never been exposed to BPs.
Results. Multiple osteolytic lesions (P¼.001), diffuse osteoporosis (P¼.001), and diffuse sclerosis
(P¼.0036) occurred more often in the mandible in both groups. Solitary osteolytic lesions
occurred less frequently in the BP group (P¼.0078). Lamina dura abnormalities (P¼.0006) and
nonhealing alveolar sockets (P¼.0021) were associated with BP treatment.
Conclusions. IV BP therapy changes the radiographic patterns of MM in the jawbones.
Practical Implications. The effect of BPs in the maxillofacial area is a matter of concern for health
practitioners because this type of medication causes several alterations of the jawbones in patients
with cancer.
Key Words. Multiple myeloma; bisphosphonate; panoramic radiography.
JADA 2018:149(5):382-391
https://doi.org/10.1016/j.adaj.2017.12.028
Multiple myeloma (MM), 1 of the most frequent hematologic malignancies worldwide, is a
malignant monoclonal plasma cell disorder of the bone marrow, which produces me-
diators that stimulate osteoclasts and lead to the formation of generalized osteolytic bone
lesions. Common locations of such lesions include the skull, axial skeleton, and pelvis; conse-
quently, patients with MM are at increased risk of developing pathologic bone fractures.
1-4
Diag-
nosis of MM is supported by the detection of paraproteins in the serum and urine, as well as by the
histopathologic evidence of excessive amounts of monoclonal plasma cells in the bone marrow.
5
In
addition, the detection of maxillofacial manifestations of MM, such as soft-tissue amyloid deposits,
external dental root resorption, and, most importantly, several bone changes, including poorly
marginated osteolytic jaw lesions (reported in more than 30% of patients with MM), may be
important diagnostic features.
6-8
Patients with MM are living longer because of advances in therapy, such as agents that include
immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and antiresorptive drugs,
including bisphosphonates (BPs).
7,9-11
BPs inhibit the progression of osteoclastic activity in patients
with MM and have been used to reduce the occurrence of bone fractures and pain.
12
In addition to
inducing osteoclast apoptosis, BPs also increase bone mineral density when associated with anti-
myeloma agents.
3,13
Copyright ª2018
American Dental
Association. All rights
reserved.
382 JADA 149(5) nhttp://jada.ada.org nMay 2018

The National Cancer Institute states that a thorough oral examination for patients with cancer
should include radiographic assessment.
14
In this context, clinicians routinely use panoramic
radiography to image the hard tissues of the maxillofacial region, and it is a modality readily
accessible to most oral health care specialists. Panoramic radiographs are well established as an
optimum radiographic examination regimenforpatientswithadiagnosisofMM.
15
Digital
panoramic radiography is a contemporary advancement in dental imaging, and the dental pro-
fession has adopted it widely because of its ability to provide images with higher quality than plain
radiographs. It also is considered a readily accessible, rapid, and inexpensive technique based on a
relatively low level of radiation exposure.
16-18
Furthermore, panoramic radiography is considered
a screening tool for the identification of BP-related bone changes in patients with MM and in
other cancer populations exposed to intravenous (IV) BPs; investigators have described various
radiographic findings for jawbones from panoramic radiographs, including sclerosis, cortical sur-
face irregularities, persistent extraction sockets, bone sequestration, and lytic or radiolucent
changes.
16,17,19-21
However, the frequency and consistency of these findings in patients with MM
and the relationship between the radiographic jawbone alterations and IV BP therapy remain
unclear.
Radiographic features of incipient (stage 0) medication-related osteonecrosis of the jaw
(MRONJ) are not specific and may overlap with MM radiographic patterns.
19,21,22
In this sense,
Hutchinson and colleagues
20
stated that there is a need to understand the radiographic features
associated with BP exposure better and to determine whether sclerotic areas, disorganized medullary
trabeculation, osteosclerosis of the alveolar margins and lamina dura, persisting alveolar socket after
extractions, and small bone sequestrationsdsome of which are similar to the radiographic patterns
of MM in the jawbonesdare specificfindings indicative of the risk of developing MRONJ or
whether they are related to underlying medical conditions and physiological changes in bone ar-
chitecture induced by cancer progression. Therefore, our objective in this study was to determine
the extent to which radiographic features of the jawbones in patients with MM are affected by the
use of IV BPs.
METHODS
Our study was a collaboration among the University of Campinas, Piracicaba Dental School, São
Paulo, Brazil; the Dental Oncology Service of the Instituto do Câncer do Estado de São Paulo, São
Paulo, Brazil; and the University of Tennessee Health Science Center (UTHSC) College of
Dentistry in Memphis, Tennessee. This was a cross-sectional retrospective study performed with
patients treated at the Dental Oncology and Hematology Services of Instituto do Câncer do Estado
de São Paulo from April 2010 through June 2014.
The University of Campinas Ethics Committee (118/2014) and the UTHSC Institutional
Review Board (516827) approved the research protocol. To be included in the study, patients had
to have a confirmed diagnosis of MM manifesting with bone disease after complete clinical workup,
according to International Myeloma Working Group criteria
23
; a digital panoramic radiograph
obtained after a minimum of 3 IV BP cycles; and a complete medical record. Exclusion criteria were
the presence of non-MM neoplastic bone disease, long-term osteoporosis, and previous use of BPs.
We used the Durie-Salmon
24,25
default staging system for the clinical staging of MM. We divided
patients into 2 groups; group 1 was composed of 88 patients with MM who received IV BPs as part
of the institutional treatment protocol for MM, and group 2 (control) was composed of 100 patients
with MM who had never been exposed to BPs.
We obtained all radiographs by using a dental radiography machine (PaX-400, VATECH
Global), with 68 peak kilovolts, 8 milliamperes, and an exposure time of 14 seconds. We coded
the radiographs to protect patients’health information. A radiologist (W.H.S.) certified by the
American Board of Oral and Maxillofacial Radiology and an oral medicine practitioner
(C.A.M.) certified by the American Board of Oral Medicine independently evaluated the
radiographs at UTHSC. Images were displayed on a 24-inch liquid-crystal display, flat-panel
monitor (UltraSharp 2408WFP, Dell) with a screen resolution of 1,920 1,200 pixels in a
room with reduced light. The evaluators were blinded to clinical data. To avoid interexaminer
variability in interpretation of the panoramic images, the evaluators performed all assessments in
the same viewing room with optimal lighting viewing conditions, and no adjustment to the
display system was allowed.
ABBREVIATION KEY
BP: Bisphosphonate.
IV: Intravenous.
MM: Multiple myeloma.
MRONJ: Medication-related
osteonecrosis of the
jaw.
UTHSC: University of
Tennessee Health
Science Center.
JADA 149(5) nhttp://jada.ada.org nMay 2018 383

The evaluators included all anatomic structures in the maxillomandibular complex in the digital
panoramic radiographic evaluation. The evaluators evaluated maxillary and mandibular images
separately, according to the radiographic patterns for MM in the craniofacial bones described by
Witt and colleagues
22
:
nsolitary bone lesion (radiolucent round image similar to bone cysts);
nmultiple osteolytic lesions (multiple radiolucent round images without marginal sclerosis);
ndiffuse osteoporosis (generalized decreased bone density marked by decreased cortical thickness
and loss of trabecular bone);
ndiffuse sclerosis (generalized increased bone density).
We further evaluated maxillary and mandibular images separately for the possible presence of 3
bone alterations, which investigators have recognized as frequent radiographic findings in patients
with cancer who are undergoing IV BP therapy
17,19-21
:
nlamina dura abnormalities (sclerosis or thickening);
nnonhealing alveolar sockets (decreased bone density in the dental socket extending from the
alveolar cortical to the central portion of the dental socket and from the apical area to the
cervical area);
nbone sequestration (a portion of bone that has been separated from its surroundings by
resorption).
We classified the data obtained as a binary response model. Statistical analysis included a c
2
test
or Fisher exact test, and we determined the odds ratio (OR) for statistically significant variables. For
statistical analysis, we evaluated events of both the maxilla and the mandible together so that we
included 376 bones in 188 patients. We assessed interexaminer agreements by using a Cohen ktest
to analyze the reliability of the examiners, and we considered agreement fair when kwas from 0.20
through 0.40, moderate when kwas from 0.41 through 0.60, and substantial when kwas from 0.61
through 0.80.
24
We determined the effects of the test model by using software (SAS Software
Version 9.3, SAS Institute).
RESULTS
We included 188 patients in the study, divided into 2 groups according to the use of BPs (Table 1).
Table 2 presents the distribution of IV BP protocols according to the duration of treatment.
Among all 188 patients enrolled in this study, 188 (100%) had MM bone disease. Overall, we
observed a variety of radiographic findings for MM in the mandible and maxilla in both groups
(Table 3). Interexaminer kwas 0.7916 and was considered appropriate for this study. We observed
multiple osteolytic lesions (P¼.001), diffuse osteoporosis (P¼.001), and diffuse sclerosis
(P¼.0036) more often in the mandible than in the maxilla in both groups studied. We observed
solitary bone lesions, multiple osteolytic lesions, diffuse osteoporosis (mottled bone appearance),
and diffuse sclerosis in both groups (Figures 1 and 2).
IV BP therapy was associated with 3 radiographic patterns. Solitary osteolytic lesions occurred less
frequently in the BP group (P¼.0078; OR ¼0.1994; 95% confidence interval [CI], 0.057 to
0.696). Lamina dura abnormalities (Figure 3) and nonhealing alveolar sockets (Figure 4) were
associated with BP treatment (P¼.0006; OR ¼2.447; 95% CI, 1.47 to 4.08 and P¼.0021; OR ¼
20.23; 95% CI, 1.158 to 3.533, respectively).
In all cases, osteolytic lesions had a “punched-out”appearance. We detected no case of bone
sequestration or MRONJ in this study population.
DISCUSSION
In this study, we evaluated the pattern of radiographic alterations in the maxilla and mandible in
patients with MM who were exposed to BP treatment. This study seems to be 1 of the largest case
series in which investigators evaluate maxillary and mandibular radiographic patterns in MM. The
underlying medical diagnosis in our study was homogeneous and based on a large cohort of patients
with advanced MM, minimizing any disease- or treatment-specific confounding factors. Our data
demonstrate for the first time, to our knowledge, that, regardless of IV BP therapy, radiographic
patterns of MM in the jawbones include solitary bone lesions, multiple osteolytic lesions, diffuse
osteoporosis, diffuse sclerosis, and lamina dura abnormalities. However, BP therapy affects radio-
graphic patterns of MM in the jawbones by decreasing the presence of solitary osteolytic lesions,
increasing lamina dura abnormalities, and causing nonhealing alveolar sockets. The data obtained
384 JADA 149(5) nhttp://jada.ada.org nMay 2018

in our study contribute to the growing body of knowledge regarding maxillofacial findings in pa-
tients receiving IV BPs.
MM is a cytogenetically heterogeneous clonal plasma cell proliferative disorder,
23
counted as one
of the most frequent hematologic malignancies worldwide, with an incidence rate of 6 per 100,000
people per year in the United States and Europe. The incidence of MM is 2 to 3 times higher in
African Americans, making it the most common hematologic malignancy in this ethnic group.
26
The international incidence of MM has been increasing by 0.7% each year for the past 10 years,
accounting for 10% of all hematologic malignancies.
1,12
In addition, the number of deaths is 3.4 per
100,000 people per year.
1
MM is slightly more prevalent in male than in female patients, and the
mean age at diagnosis is 66 years, with only 2% of patients receiving the diagnosis when younger
Table 1. Patient characteristics.
CHARACTERISTIC CONTROL GROUP BISPHOSPHONATE GROUP
Sex, No. (%)
Men 52 (52.0) 53 (60.2)
Women 48 (48.0) 35 (39.8)
Age, y, Mean (Interquartile Range) 64.9 (31-90) 63.5 (33-86)
Stage, No. (%)*
IA 0 (0) 0 (0)
IIA 10 (10.0) 6 (6.8)
IIIA 70 (70.0) 63 (71.6)
IB 0 (0) 0 (0)
IIB 0 (0) 0 (0)
IIIB 20 (20.0) 19 (21.6)
Bisphosphonate, No. (%)
Pamidronate
†
0 (0) 64 (72.7)
Zoledronate
‡
0 (0) 7 (8.0)
Pamidronate
†
and zoledronate
‡
0 (0) 17 (19.3)
Medical Condition, No. (%)
Hypertension 45 (45.0) 36 (41.0)
Diabetes mellitus 18 (18.0) 10 (11.3)
Heart disease 12 (12.0) 15 (17.0)
Depression 2 (2.0) 3 (3.4)
Renal insufficiency 2 (2.0) 8 (9.0)
Hyperparathyroidism 5 (5.0) 2 (2.3)
Hypothyroidism 2 (2.0) 2 (2.3)
Hepatitis 2 (2.0) 0 (0)
No medical complication 12 (12.0) 12 (13.7)
* According to the Durie-Salmon staging system. †Intravenous pamidronate 90 milligrams every 28 days (mean of 9 cycles, ranging
from 3 to 25). ‡Intravenous zoledronate 4 mg every 28 days (mean of 5 cycles, ranging from 3 to 11).
Table 2. Distribution of 88 patients with multiple myeloma treated with intravenous bisphosphonates, according to
duration of treatment.*
DURATION,
MO.
PAMIDRONATE
90 MILLIGRAMS, NO. (%)
ZOLEDRONATE 4 MG,
NO. (%)
PAMIDRONATE 90 MG AND
ZOLEDRONATE 4 MG, NO. (%)
0-12 50 (56.8) 6 (6.8) 9 (10.2)
12-24 13 (14.8) 1 (1.1) 5 (5.7)
24-36 1 (1.1) 0 (0) 3 (3.4)
* The percentages do not total 100% because of rounding.
JADA 149(5) nhttp://jada.ada.org nMay 2018 385

than 40 years.
27,28
In this study, most of the patients were elderly men with MM in an advanced
stage at the time of diagnosis. The time of radiographic follow-up was variable because of the high
death rate caused by the advanced stage of the disease.
A major complication of MM is the development of bone disease characterized by osteolytic
lesions, fractures, and bone pain. Bone disease in patients with MM is associated with an advanced
stage and can have devastating clinical effects by increasing morbidity.
1,6
Skeletal radiographic
Table 3. Radiographic features of 188 patients with multiple myeloma.
RADIOGRAPHIC FEATURE MANDIBLE, NO. (%) MAXILLA, NO. (%)
BP*Group Control Group BP Group Control Group
Solitary Bone Lesion 0 (0) 2 (2.0) 3 (3.4) 14 (14.0)
Multiple Osteolytic Lesions 76 (86.3) 86 (86.0) 17 (19.3) 11 (11.0)
Diffuse Osteoporosis 69 (78.4) 73 (73.0) 35 (39.8) 37 (37.0)
Diffuse Sclerosis 57 (64.8) 55 (55.0) 38 (43.2) 51 (51.0)
Lamina Dura Abnormalities 39 (44.3)
(NE
†
¼15)
25 (25.0)
(NE ¼23)
23 (26.1)
(NE ¼33)
13 (13.0)
(NE ¼40)
Nonhealing Alveolar Sockets
‡
8 (9.0) 0 (0) 0 (0) 0 (0)
Bone Sequestration 0 (0) 0 (0) 0 (0) 0 (0)
* BP: Bisphosphonate. †NE: Not evaluable, edentulous. ‡Four weeks after tooth extraction.
Figure 1. Digital panoramic radiographs obtained in patients with multiple myeloma. A. Radiologic evaluation of a
patient in the bisphosphonate group showing generalized presence of multiple osteolytic lesions (*) with a “punched-
out”appearance in the maxillomandibular complex and showing zygomatic arch and cervical spine involvement. The
mandible has sclerosis of the lamina dura (arrows), and the maxilla and mandible reveal diffuse osteoporosis (arrow-
heads) with mottled bone appearance. B. Radiologic evaluation of a patient in the control group with the maxilla and
mandible demonstrating multiple osteolytic lesions (*) with a punched-out appearance. The mandible reveals diffuse
sclerosis (arrows), and the maxilla reveals diffuse osteoporosis (arrowheads) with mottled bone appearance.
386 JADA 149(5) nhttp://jada.ada.org nMay 2018

surveys have an important role in the Durie-Salmon
25,29
clinical staging criteria for MM diagnosis,
in which the presence of 2 clearly defined lytic lesions indicates high tumor burden and stage III
disease.
1
Bone disease in MM commonly shows numerous punched-out areas of radiolucency on
radiographs, being most commonly observed in the pelvis, spine, ribs, and skull.
30,31
The detection
of osteolytic lesions has a pivotal role in decision-making protocols and treatment protocols because
Figure 2. Digital panoramic radiographs obtained in patients with multiple myeloma. A. Radiologic evaluation of a
patient in the bisphosphonate group shows diffuse osteoporosis (arrows) in the mandible, as well as osteolytic lesions
(arrowheads). B. Radiologic evaluation of a patient in the control group reveals diffuse osteoporosis (arrows) in the
maxilla and multiple osteolytic lesions (arrowheads) in the mandible.
Figure 3. Lamina dura abnormalities in a patient with multiple myeloma. Radiologic evaluation of a patient in the
bisphosphonate group. The mandible manifests thickening of the alveolar crest and sclerosis of the alveolar margin in
the area of the anterior teeth (arrows).
JADA 149(5) nhttp://jada.ada.org nMay 2018 387

the International Myeloma Working Group recommends the use of BP therapy in patients with
active MM and at least 1 osteolytic lesion.
3,23
We based our study on the premise that the
radiographic identification of jawbone lesions frequently leads to the diagnosis of MM and also
founded it on the ability of IV BPs to cause bone changes that can alter typical osteolytic lesions.
Despite the ongoing development of new antiresorptive drugs, BPs remain the standard of care for
MM.
23
Because of BPs’beneficial effects in the management of MM, the International Myeloma
Working Group states that BPs must be prescribed to all patients receiving MM therapy, whether
bone lesions are evident or not, which highlights the importance of knowing radiographic MM
patterns in patients receiving IV BP treatment.
23
In addition, routine dental radiographic exami-
nations are recommended for the detection of MRONJ in patients with MM. This situation
highlights the importance of knowing whether the radiographic patterns of MM are affected in any
way in patients treated with IV BPs, especially because of possible overlapping features between MM
radiographic patterns and early MRONJ.
21
This scenario may be a challenge to the early diagnosis
and management of these conditions, making panoramic radiography fundamental for the clinical
assessment and tracking of the progression of these 2 conditions.
16,19
Our study, therefore, con-
tributes to the understanding of digital radiographic findings in patients with MM and their rela-
tionship with the use of IV BP therapy.
Second-generation BPs (pamidronate and zoledronate) play a fundamental role in minimizing
bone complications in MM.
3
Pamidronate and zoledronate have higher bioavailability and lower
elimination during resorption and bone remodeling than do oral BPs.
32
In a 2015 study, Jarnbring
and colleagues
33
concluded that zoledronate is a more potent inducer of jawbone changes than is
pamidronate in patients with MM. In our study, patients received both drugs, and some of the
patients had taken both pamidronate and zoledronate in combination. However, we could not study
Figure 4. Radiographic findings in nonhealing alveolar sockets associated with intravenous bisphosphonate therapy.
A. Panoramic radiograph obtained in a patient who had received intravenous bisphosphonate before tooth extraction
(arrow). B. Follow-up panoramic radiograph obtained in the same patient shows nonhealing alveolar socket (arrow) 12
months after tooth extraction.
388 JADA 149(5) nhttp://jada.ada.org nMay 2018

the effects of pamidronate and zoledronate separately because only a few patients had received
isolated zoledronate. The number of cycles of BP therapy was decided based on International
Myeloma Working Group recommendations for the treatment of MM-related bone disease.
This study included patients who had received a minimum of 3 IV BP cycles (and had a digital
panoramic radiograph obtained after at least 3 months of IV BP therapy), according to previously
published data suggesting that the risk of developing MRONJ begins after a medication period of up
to 90 days.
34
Similar to all previous reports on BP-related radiographic changes, there was a wide
range of exposure to IV BP therapy,
16
and owing to our study’s limitation, we can make no con-
clusions about when or how radiographic jawbone alterations may develop. Given the range of
cancer types (diagnoses) and variable stages previously published, the cohort of patients with
advanced MM in our study seems to be representative of reported series of BP-induced radiographic
jawbone abnormalities from academic medical centers.
8,16,17,19,32,34,35
Investigators have reported a wide spectrum of radiographic findings, including sclerotic areas,
disorganized medullary trabeculation, dense osteosclerosis in the alveolar margins, lamina dura
abnormalities, bone sequestrations, areas of mottled bone similar to diffuse osteoporosis, and
MRONJ, in patients with cancer, including patients with MM exposed to IV BP ther-
apy.
8,16,17,19,32,34,35
To our knowledge, this study seems to be the first in which investigators
evaluate whether IV BP therapy changes MM manifestation in jawbones.
Diffuse osteoporosis with generalized involvement is a type of bone manifestation in patients with
MM.
22
However, when Witt and colleagues
22
performed a radiographic evaluation in 77 patients
with MM, none of the patients had diffuse osteoporosis. In our study, a large number of patients had
diffuse osteoporosis, mostly affecting the mandible. Osteoporosis also may occur in patients with
smoldering, asymptomatic, or indolent myeloma.
36
We enrolled a large number of elderly patients
with advanced disease, which may account for the presence of this manifestation. In some cases,
mandibular involvement affected the entire bone. Oral BPs have a well-established role in the
treatment of osteoporosis for reducing osteoporotic fracture risk,
5,36,37
but none of the patients
enrolled in our study were taking oral BPs at the time MM was diagnosed.
A review of the literature revealed that primary osteosclerosis in myeloma is a rare entity, with an
estimated incidence of only 3%.
38
Beyond osteolytic lesions, Ghosh and colleagues
39
reported that
osteosclerosis in patients with MM also constitutes a component of the disease; sclerotic lesions may
be mixed and, as in other types of myelomatous deposit, the axial skeleton primarily is involved,
although osteosclerosis in skull lesions occurs. We observed changes in trabecular pattern with
diffuse sclerosis in both groups.
In the BP group, we noted a clinically significant increased thickness of the lamina dura asso-
ciated with thickening of the alveolar crest with osteosclerosis of the alveolar margin. Investigators
previously have observed such sclerotic changes in the jaws of patients with MRONJ treated with
BPs; this finding was statistically significant compared with findings in patients in the control
group.
40
Osteosclerosis is a specific radiographic finding that clinicians have to identify and consider
with other oral and medical information because investigators have described it as an indicator of
the risk of developing MRONJ in patients exposed to IV BP therapy.
41
Tooth extractions are the main risk factor for MRONJ.
20,35,42
Thus, prevention of MRONJ is an
important clinical consideration in patients with MM who are receiving BP therapy.
20,43
Groetz and
Al-Nawas
44
reviewed radiographic features in a series of cases of osteonecrosis of the jaw and
concluded that nonhealing alveolar sockets might be an early radiographic sign of preclinical
MRONJ. In addition, Migliorati and colleagues
42
proposed that postextraction healing is delayed in
patients taking BPs. In our study, nonhealing alveolar sockets were associated with BP treatment,
but we observed no cases of MRONJ.
In this study, we presented some issues that clinicians should consider. Although the study results
demonstrated the effect of BP treatment on jawbone lesions in MM, the lack of baseline panoramic
radiographs limits the comprehensiveness of these findings. Also, we did not evaluate the patients
clinically, so clinical diagnosis of stage 0 MRONJ was limited. Radiographic data for the BP group
before BP therapy was not available for most of the patients, making it impossible to determine
when the jawbone lesions had started. A larger number of carefully documented MM cases will be
required to determine whether there is correlation among MM stage, BP duration, and patterns of
jawbone alterations. Likewise, further studies will be necessary to demonstrate how these bone
alterations change in the context of MM treatment, clinical improvement, or disease progression.
JADA 149(5) nhttp://jada.ada.org nMay 2018 389

CONCLUSIONS
In conclusion, digital panoramic radiography was able to help detect myriad jawbone alterations in
patients with MM, such as solitary and multiple MM bone lesions, diffuse osteoporosis, diffuse
sclerosis, lamina dura abnormalities, and nonhealing alveolar sockets, some of which were affected
by IV BP therapy. These data support the need to understand the radiographic features associated
with BP exposure better in patients with MM and to determine whether a larger number of carefully
documented MM cases will be required to determine correlation among MM stage, BP duration,
and patterns of jawbone alterations. Likewise, further studies will be necessary to demonstrate how
these bone alterations change in the context of MM treatment, clinical improvement, or disease
progression. Osteoporosis, osteosclerosis, and lamina dura abnormalities are specificfindings
indicative of the risk of developing MRONJ. n
Dr. Faria is a dentist, Dental Oncology Service, Instituto do Câncer do
Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo,
São Paulo, Brazil.
Dr. Ribeiro is a dentist, Dental Oncology Service, Instituto do Câncer do
Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo,
Av. Dr. Arnaldo, 251, Cerqueira César, São Paulo, Brazil, 01246-000,
e-mail ana.prado@hc.fm.usp.br. Address correspondence to Dr. Ribeiro.
Dr. Brandão is a dentist coordinator, Dental Oncology Service, Instituto
do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade
de São Paulo, São Paulo, Brazil.
Dr. Silva is a PhD student, Oral Diagnosis Department, Semiology Area,
Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo,
Brazil, and a dentist, Dental Oncology Service, Instituto do Câncer do
Estado de São Paulo, Faculdade de Medicina da Universidade de São
Paulo, São Paulo, Brazil.
Dr. Lopes is a professor, Oral Diagnosis Department, Semiology Area,
Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo,
Brazil.
Dr. Pereira is a medical doctor coordinator, Hematology Service, Instituto
do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade
de São Paulo, São Paulo, Brazil.
Dr. Alves is a systems analyst, Technical Section of Informatics at Luiz de
Queiroz College of Agriculture, University of São Paulo, Piracicaba, São
Paulo, Brazil.
Dr. Gueiros is a professor, Department of Clinic and Preventive Dentistry,
Federal University of Pernambuco, Recife, Pernambuco, Brazil.
Dr. Shintaku is a professor, Department of Diagnostic Sciences and Oral
Medicine, University of Tennessee Health Science Center College of
Dentistry, Memphis, TN.
Dr. Migliorati is a professor, Department of Diagnostic Sciences and Oral
Medicine, University of Tennessee Health Science Center College of
Dentistry, Memphis, TN.
Dr. Santos-Silva is a professor, Oral Diagnosis Department, Semiology
Area, Piracicaba Dental School, University of Campinas, Piracicaba, São
Paulo, Brazil.
Disclosure. Dr. Migliorati is a consultant for Amgen. None of the other
authors reported any disclosures.
This work was supported by grants 99999.010709/2014-02 and AUXPE/
PROEX 758/2012 from Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior, Brasília, Brazil, and grants 13/00429-7, 13/18402-8, and
12/06138-1 from Fundação de Amparo à Pesquisa do Estado de São Paulo,
São Paulo, Brazil.
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