To systematize the clinico-radiological symptoms and course of bisphosphonate-related osteonecrosis of jaw bone and toevaluate the diagnostic potential of various radiological techniques to detect mild osteonecrosis in each stage of the disease.
The sample consisted of 22 patients previously diagnosed with extraoral malignant disease. Diagnosis was based on a clinical examination in conjunction to digital panoramic radiography and cone beam computed tomography (CBCT). Two dentomaxillofacial radiologists reviewed all images.
Twenty
patients showed mandibular involvement clinically, while two others had
a maxillary involvement. Four stages of the disease were proposed based
on the clinico-radiological findings. Subclinical cortical and
The present study showed that bisphosphonate-related osteonecrosis of jaw bone occurs in four distinct clinico-radiological stages. For mild cases, panoramic image diagnosis was much less obvious, whereas cone beam computed tomography was able to fully characterise the bony lesions and describe their extent and involvement of neighbouring structures in all cases. Thus cone beam computed tomography might better contribute to the prevention of bisphosphonate-related osteonecrosis of jaw bone as well to the disease management.
The relationship between intravenous bisphosphonate administration and jaw bone
osteonecrosis was first reported in 2003 [1]. It is defined as an area of exposed
bone in the maxillofacial region for more than eight weeks in a patient who was
receiving a bisphosphonate and had not had radiation therapy to the craniofacial
region [
Bisphosphonates are non-metabolic synthetic analogues of pyrophosphate which
have potent inhibitory effects on bone resorption [
Though there is abundant evidence in the literature of the benefit of bisphosphonates
therapy, growing evidence from several recently published reports show that patients
treated with bisphosphonates have a potential risk of develop necrosis of the jaw
bone [
The diagnosis of BRONJ is currently based on the patients' medical history of bisphosphonate treatment and clinical evaluation (pain, bone exposure, purulent secretion or swelling). The initial appearance of the disease is variable and thus, it often comes to the attention of the clinician late, when BRONJ has become symptomatic.
The role of imaging in the diagnosis of BRONJ and the imaging findings has previously
been described in the literature [
Recently, several cone beam computed tomography (CBCT) systems have become available,
which are specifically designed to image hard tissues in the maxillofacial region
[
This results in new diagnostic possibilities with increased diagnostic image
quality. With the available CBCT systems, high-contrast structures can be visualized
at very low radiation doses, sometimes as low as two panoramic radiographs [
The purpose of the present study was to systematize the clinico-radiological symptoms and course of bisphosphonate-related osteonecrosis of jaw bone and to create guidelines for the most optimal radiological examination methods in each stage of the disease.
A series of 22 subjects (17 males and 5 females, age range 54 - 87 years, mean age 69.2 years) with a diagnosis of osteonecrosis development in the jaw bone(s) were consecutively recruited from the patient sample visiting the Department of Paediatric and Special Dental Care, School of Dentistry, Oral Pathology and Maxillofacial Surgery, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium between October 2007 and March 2008. They all had undergone a biophosphonate treatment based on a previous diagnosis of extraoral malignant disease. All patients gave their informed consent to participate in the study, in accordance with the ethical regulations of the University Hospitals, Catholic University of Leuven.
Nine patients had multiple myeloma, 6 prostate cancer, 3 breast cancer and 4 renal cell cancer. All patients had been treated with either individual intravenous doses of zoledronate or pamidronate and were therefore at risk for developing BRONJ. The diagnosis of BRONJ was confirmed through the clinical evaluation of the exposed bone to the oral cavity in addition to the negative history of radiotherapy to the head and neck.
The presenting symptoms: the localization of the necrosis, the presence of suppuration and the association with previous extractions or traumas as possible triggering factor for the onset of the lesions were documented in all patients.
As part of a routine clinical examination, a digital panoramic radiograph was taken using a Cranex Tome® (Soredex, Tuusula, Finland) and the CBCT of the jaws was obtained using a SCANORA 3D® CBCT unit (Soredex, Tuusula, Finland). The CBCT device uses complementary metal-oxide semiconductor (CMOS) flat panel/CsI detector and is operated at 85 kV and 13 mA, with a full jaw scan with a 75 x 145 mm field of view for a single 360° rotation.
Primary reconstruction of the data provided 1.0 mm axial, coronal, and sagittal slices (300 - 500 slices) as well as the three-dimensional volumetric surface renderings. The data set had a voxel size of 0.25 x 0.25 x 0.25 mm and consisted of contiguous slices with respect to the Z-axis. These were reconstructed secondarily to provide a curved planar two-dimensional multiplanar reconstruction (MPR) 20 mm thick along the arch of the mandible that provides a simulated "panoramic" equivalent. Panoramic reconstruction at narrower defined "focal trough" limits (such as 5 – 10 mm) better depicted the degree of involvement and extent of margins in a projection that was still cross-sectional imaging at 1 mm thick slices, and in 1 mm slice increments also provided orthogonal views to the panoramic curved planar view. Previous radiographs of the patients were also retrieved and correlated with the present ones for possible changes.
The radiographs and CBCT images were evaluated by two dentomaxillofacial radiologists under standardized viewing conditions (40 cm viewing distance, diagnostic screen, dimmed room). Calibration was done beforehand to reduce the intra- and inter-examiner variability regarding the following variables: imaging characteristics of the alveolar and basal bone (lytic/erosive, sclerotic, and mixed), presence of sequestrum, cortical discontinuity, periosteal response, involvement of vital structures (e.g. the mandibular canal and maxillary antrum) and soft tissues involvement. Four stages of the disease progression were proposed based on the clinico-radiologic findings.
Demographic data are presented in
Patients data
S/Na | Age
| Genderb | Underlying
| Localisation | Initiating event | Signs and symptoms | Bisphosphonate |
---|---|---|---|---|---|---|---|
1 | 66 | M | Prostate carcinoma | Left body of mandible | Tooth extraction | Non healing extraction socket | Zoledronate |
2 | 71 | M | Prostate carcinoma | Right body of mandible | Spontaneous | Pain, exposed bone | Zoledronate |
3 | 74 | M | Multiple myeloma | Left body of mandible | Pain from bone | Pain, exposed bone | Zoledronate |
4 | 54 | M | Renal cell carcinoma | Left body of mandible | Tooth extraction | Non healing extraction socket | Zoledronate |
5 | 75 | M | Multiple myloma | Left body of mandible | Spontaneous | Mobile tooth | Zoledronate |
6 | 55 | M | Prostate carcinoma | Left body and anterior of mandible | Tooth extraction | Non healing extraction socket |
Zoledronate |
7 | 82 | M | Prostate carcinoma | Left maxilla left body of mandible | Tooth extraction | Exposed bone, oro-antral fistula, |
Zoledronate |
8 | 69 | M | Renal cell carcinoma | Right body of mandible | Spontaneous | Ulceration | Zoledronate |
9 | 71 | M | Renal cell carcinoma | Right body of mandible | Spontaneous | Ulceration | Zoledronate |
10 | 70 | F | Multiple myeloma | Cortical plate and
|
No clinical manifestation | None | Zoledronate |
11 | 74 | M | Multiple myeloma | Anterior and left body of mandible | Tooth extraction | Non healing extraction socket | Zoledronate |
12 | 73 | M | Multiple myeloma | Right and left body of mandible | Tooth extraction | Non healing extraction socket | Zoledronate |
13 | 71 | M | Prostate carcinoma | Right and left body of mandible | Spontaneous | Intra oral discharging sinus | Zoledronate |
14 | 59 | M | Multiple myeloma | Right body of mandible | Tooth extraction | Non healing extraction socket | Zoledronate |
15 | 57 | F | Renal cell carcinoma | Left body of mandible | Tooth extraction | Bone exposure | Zoledronate |
16 | 56 | M | Multiple myeloma | Left body of mandible | Spontaneous | Bone exposure | Zoledronate |
17 | 69 | F | Breast cancer | Right body of mandible | Spontaneous | Bone exposure | Zoledronate |
18 | 87 | F | Breast cancer | Left body of mandible | Extraction of mobile tooth #37 | Painful and mobile tooth #37 | Zoledronate |
19 | 87 | M | Prostate carcinoma | Left body of mandible | Pain from tooth #36 | Non healing extraction socket | Zoledronate |
20 | 62 | F | Breast cancer | Right and left maxilla | Spontaneous | Bone exposure | Zoledronate |
21 | 68 | M | Multiple myeloma | Left body of mandible | Pain from bone | Pain, exposed bone | Zoledronate |
22 | 72 | M | Multiple myeloma | Left body of mandible | Pain from bone | Pain, exposed bone | Zoledronate |
aS/N = serial numbers.
bM = male; F = female.
The staging of the disorder was done based on the clinico-radiological findings (
Summary of the clinical and radiologic findings, classified according to different stages and manifestations of the disease
Stage | N | Clinical presentation | Radiological findings | Optimal radiological
|
---|---|---|---|---|
I | 2 | None | Generalised thickening of cortical plate and
|
Periapical/CBCT |
II | 2 | Discomfort, denuded bone
|
Thickening of cortical plate | CBCT |
III | 14 | Pain, denuded bone involving alveolar bone | Mixed sclerotic and lytic bone destructioninvolving alveolar bone
|
Panoramic/CBCT |
IV | 4 | Denuded bone involving alveolar bone,
|
Mixed sclerotic and lytic bone destruction involving alveolar
|
Panoramic/CBCT |
The least changes at first presentation were observed in patients with radiological
evidence of osteosclerosis involving the cortical bone, alveolar margin and lamina
dura but with clinically intact mucosa and no oral symptoms or discomfort (stage
I). This radiological finding was only detected using the periapical radiographs
and CBCT (
Periapical radiographs of a 71 years
old woman (patient number 10), showing generalized osseous sclerosis of uniform
thickness involving the cortical plate and
A = Axial images of the mandible obtained with Scanora 3D® CBCT unit showing thickening of cortical plate and focal region of medullary bone density on the left body of mandible, the overlying mucosa is clinically intact.
B = Two-dimensional multiplanar reconstruction image showing the vertical dimension of the region of osteosclecrosis and the relationship with mandibular canal.
In stage II, ulceration was located in the posterior/lingual mandible in the area of the mylohyoid ridge, the exposed bone surface was smooth and patients presented with discomfort as the tongue constantly rub on the ulceration. Thickening of the cortical plate in the affected region was the only radiological findings on CBCT.
Panoramic radiographs did not yield obvious evidence of the disease status in
stage I and II of the disease (
Increases in sclerotic manifestations correlated with a more sever expression
of BRONJ in stage III and IV lesions were detected on both imaging modality, yet
much more pathologic characteristics and the entire lesion extent could be visualized
on CBCT (
A = coronal, B = sagital, C = axial and D = three-dimensional images of the mandible obtained with Scanora 3D® CBCT unit showing region of extensive necrosis in a 71 years old patient. Centrally, a well demarcated bony sequestrum is evident, involving the upper border of the mandibular canal.
A = coronal, B = sagital, C = axial and D = three-dimensional images of the mandible obtained with Scanora 3D® CBCT unit with region of extensive necrosis and pathological fracture of the mandible.
A = Panoramic radiograph of an 87 years old woman (patient number 18) with breast cancer treated with zoledronate who presented with a painful tooth #37.
B = Panoramic radiograph after 7 months, showing non healing extraction site in the left posterior mandible, absence of bone remodeling and sclerotic bone changes of the body of the mandible.
C = Panoramic radiograph after 9 months demonstrates a nonhealing extraction site in the left posterior mandible with progressive sclerosis of the left body and angle of the mandible with encroachment on the left mandibular canal.
D = Panoramic radiograph after 19 months with intervening curettage, demonstrates progression of sclerosis to pathologic fracture of the mandible.
A major limitation of this study is the small sample size; however the data presented
was representative of the various clinico-pathologic manifestation of BRONJ. Bisphosphonate-associated
necrosis of jaw bone remains a challenge with respect to diagnosis and management.
This presents a growing concern for oral health care workers since the disorder
appears almost exclusively in the jaws [
The pathogenesis of BRONJ remains unclear however, many theories have been proposed
by various authors [
The most common clinical finding in this series is an area of ulcerated mucosa
with exposed devitalized bone. In all patients with exposed necrotic bone, the observed
area of ulceration was smaller with wider area of underlying bone necrosis as previously
reported by Bedogni et al. [
Avoiding invasive procedures and institution of preventive measures at this bone pre-exposure stage may delay the clinical progress and possibly provide an environment conducive to resolution of the condition.
Patients with stage II of the disease had an area of ulceration at the posterior/lingual
mandible in the area of the mylohyoid ridge with no apparent radiological changes
on the panoramic view but presents as cortical thickening on the CBCT. This region
had earlier been reported as one of most common site of BRONJ [
Diagnosis at these vital stages may give room for prompt implementation of the
preventive measure recommended for BRONJ in the literature [
Panoramic radiograph may not be useful in the diagnosis of this early lesssion
because of its limited resolution, two-dimensional nature with anatomic overlap
and tomographic effect which may not allow visualization of the true extent of the
bone defects. The present finding correlate well with those earlier described by
Arce et al. [
Patients with a more advanced stage of the disease presented with bone exposure
to the oral cavity at previous tooth extraction sites [
In most severe cases, Stage IV the CBCT and the panoramic radiograph now revealed
larger areas of osseous sclerosis involving the entire cross-sectional area of the
jaw in all cases, with sclerotic changes encroached on the mandibular canal and
the maxillary antrum. Devitalized bone with radiodense appearance and radiolucent
rim (
In all the patients, necrosis involved the alveolar margin and the cortical plate,
in line with the findings reported by Phal et al. [
CBCT imaging allowed high resolution hard tissue diagnosis, and when offering a field of view, covering both jaws, affected areas could be easily compared to non-affected areas while asymptomatic area can also be detected.
Furthermore, the CBCT data could also be considered valuable for volumetry which
helps to determine the extent of the disease. As such it can serve as a guide towards
management planning. Indeed, cross-sectional slices allowed identification of the
true extent of affected marrow and thus facilitated transfer from the
The observed radiological characteristics suggests a distinct pattern of occurrence
and progress of BRONJ, starting from the
While routine jaw imaging for patients receiving bisphosphonate therapy may not be justified, it is essential that oral health care providers rule out such early bone changes, when a patient at risk presents with a need for jaw bone imaging. This may allow for early diagnosis, better treatment and prevention of new potential case as this can make a significant difference in the outcome of the disease.
The present study showed that bisphosphonate-related osteonecrosis of jaw bone occur in four distinct clinico-radiological stages. For mild cases, panoramic image diagnosis was much less obvious. Whereas cone beam computed tomography was able to fully characterise the bony lesions and describe their extent and involvement of neighbouring structures in all cases. Thus cone beam computed tomography might better contribute to the prevention of bisphosphonate-related osteonecrosis of jaw bone as well to disease management.
The authors report no conflicts of interest related to this study.