Download Clinical and diagnostic imaging of bisphosphonate

Dentomaxillofacial Radiology (2006) 35, 236–243
q 2006 The British Institute of Radiology
http://dmfr.birjournals.org
RESEARCH
Clinical and diagnostic imaging of bisphosphonate-associated
osteonecrosis of the jaws
S Chiandussi*,1, M Biasotto1, F Dore2, F Cavalli3, MA Cova4 and R Di Lenarda1
1
Department of Dental Sciences, University of Trieste, Trieste, Italy; 2Department of Nuclear Medicine, Ospedale Maggiore, Trieste,
Italy; 3Department of Radiodiagnostic Imaging, Ospedale Maggiore, Trieste, Italy; 4Department of Radiology, Ospedale di Cattinara,
Trieste, Italy
Objectives: It is important to recognize osteonecrosis of the jaws in patients treated with
bisphosphonates because an early diagnosis can make a significant difference to the outcome of the
disease. The aim of this study is to describe the radiological features of bisphosphonate
osteonecrosis (BON) in order to aid its prompt recognition.
Methods: A conventional radiograph, a computed tomograph (CT), a magnetic resonance image
(MRI) and a 99Tcm-MDP 3-phase bone scan were carried out for 11 patients with BON. The main
imaging findings of osteonecrosis are described.
Results: Conventional radiography and CT displayed osteolytic lesions with the involvement of
cortical bone. MRI demonstrated the characteristic features of osteonecrosis and the oedema of soft
tissues. Both CT and MRI were very useful in defining the extent of the lesions. 99Tcm-MDP threephase bone scan was the most sensitive tool to detect the osteonecrosis at an early stage.
Conclusions: 99Tcm-MDP three-phase bone scans who could be used as a screening test to detect
subclinical osteonecrosis in patients who have received bisphosphonates. CT scans and MRI are
useful in defining the features and extent of osteolytic lesions.
Dentomaxillofacial Radiology (2006) 35, 236–243. doi: 10.1259/dmfr/27458726
Keywords: osteonecrosis; bisphosphonates; jaws; imaging
Introduction
Bisphosphonates act through the inhibition of bone
resorption and are used in conjunction with antineoplastic
chemotherapy for treatment of hypercalcaemia associated
with malignancy, lytic bone metastasis and multiple
myeloma.1 Several cases describing a correlation between
osteonecrosis of the jaws and intravenous administration of
bisphosphonates have been recently reported in the
literature.2 – 14
The clinical examination of the patient needs to be
accompanied by a careful evaluation of the imaging
features of bone lesions to better understand their extent
and features. Digital panoramic radiography, computed
tomography (CT) scans, magnetic resonance imaging
(MRI) and 99Tcm-MDP three-phase bone scans are
diagnostic tools that add value to the clinical findings by
revealing different aspects of bone involvement. To the
best of our knowledge there is no report in the literature
*Correspondence to: Silvia Chiandussi, Clinica Stomatologica, Via Stuparich 1,
34100 Trieste, Italy; E-mail: [email protected]
Received 28 October 2005; revised 21 February 2006; accepted 13 March 2006
that describes the imaging manifestations of bisphosphonates-associated osteonecrosis of the jaws.
The aim of this study is to assess the imaging
investigations that better describe the nature, size and
features of the bone lesions in a series of 11 patients who
attended our clinic with a diagnosis of bisphosphonates
osteonecrosis (BON).
Materials and methods
From January to August 2005, ten oncology patients were
referred to the Dental Institute, University of Trieste to
investigate non-specific facial swelling accompanied by
bone exposure, pain and occasional fever. All patients had
previously been diagnosed with extraoral malignant
disease. Seven of them had bone metastases (five
secondary to breast cancer and two secondary to carcinoma
of the lung) and three patients had multiple myeloma with
generalized bone lesions. All patients had been treated with
intravenous zoledronic acid and were therefore at risk of
Bisphosphonate osteonecrosis
S Chiandussi et al
having developed bisphosphonates osteonecrosis. The
diagnosis of BON was confirmed through the histological
evaluation of the exposed bone. We documented the
patient’s symptoms, the localization of the necrosis, the
presence of fistulae or suppuration and the association with
previous extractions or traumas as possible triggering
factor for the onset of the lesions. Another patient attended
our Clinic for a prosthodontic rehabilitation. Her medical
history was positive for a multiple myeloma, for which she
was on treatment with zoledronic acid. She had a dental
extraction 3 months earlier without apparent complications. Despite the fact that at the time of the examination
she reported no oral symptoms or discomfort, she was
considered at risk for developing either BON or bone
metastases. The diagnosis of osteonecrosis was confirmed
on the basis of the radiological investigations described
below.
For every patient, a digital panoramic radiograph was
taken as routine diagnostic investigation. The panoramic
X-ray was taken using a Kodak 8000C Digital Panoramic
& Cephalometric System (Eastman Kodak Company,
Rochester, NY) at 73 kV and 12 mA for 13.9 s, and the
image was observed with a Trophy Windows 6.0 software
(Trophy Radiologie, Croissy Beaubourg, France). In all
radiographs an osteolytic lesion was noticed and, to better
detect the characteristics of the lytic region, a CT scan and
an MRI were performed. CT images were obtained using a
Toshiba Aquilion 16 (Toshiba Italia, Milan, Italy) at
120 kV and 200 mA with a slice thickness of 0.5 mm. A
three-dimensional reconstruction of the CT images was
obtained using the Osirix Medical Imaging Software,
MacOs X 10.3 (http://homepage.mac.com/rossetantoine/
osirix/Index2.html).
Patients were imaged with MRI using a 1.5 T Super
Conductive Magnet (Philips Gyroscan Intera, Best, The
Netherlands). The following imaging sequences were
obtained with 5 mm thickness in coronal, axial and sagittal
planes: turbo spin echo (TSE) T1 weighted spin echo
(repetition time (TR) ¼ 598, echo time (TE) ¼ 15), TSE T2
weighted turbo spin echo (TR ¼ 4670, TE ¼ 100), T-short
tau inversion recovery (STIR) (TR ¼ 2024, TE ¼ 15) and
spectral presaturation with inversion recovery (SPIR)
(TR ¼ 513, TE ¼ 12). The images were acquired before
and after intravenous administration of gadolinium-containing contrast agent (gadopentate dimeglumine, Magnevist; Schering, Berlin, Germany). Both normal fat intensity
areas surrounded by low intensity band and diffuse low
intensity areas were defined as osteonecrosis.
Our patients were all having regular technetium-99mmethylene diphosphonate (99Tcm-MDP) three-phase bone
scans in planar and SPECT technique with gamma
camera collimators centred in maxillary and mandibular
regions. Moreover, they were undergoing whole-body
bone scan to monitor the neoplastic bone involvement.
Therefore, we used the data obtained from the existing
imaging to determine the bone metabolic activity of the
necrotic lesions of the jaws. The bone scan was
performed after intravenous injection of technetium99 m labelled methylene diphosphonate (740 MBq)
(Osteosol; Amersham Health, Little Chalfont, UK).
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The 99Tcm-MDP three-phase dynamic procedure allowed
examination of perfusion, immediate soft-tissue blood
pool and, after 2 – 4 h, bone uptake.
Bone scan was performed using a high-resolution
low-energy parallel-hole collimator and a large-field-ofview dual-detector g-camera with a mounted CT
scanner (Infinia-Hawkeye; General Electric Healthcare,
Hayes, UK). SPECT and CT images of the same area
were obtained over a 3608 arc, using 120 frames at 20 s
per frame and 38 angles. The images were acquired into
a 128 £ 128 matrix and reconstructed using a twodimensional ordered-subset expectation maximization
iterative technique (10 subsets and 2 iterations), both
with and without CT-based attenuation correction and a
Hanning
three-dimensional
post-filter
(cut-off
frequency ¼ 0.85 cycles cm21). The CT part was
acquired at 2.5 mA and 140 kV, with a slice step of
10 mm and a slice time of 14 s. The SPECT acquisition
took approximately 25 min, whereas the CT acquisition
took approximately 10 min.
The maxillary and mandibular areas of abnormal uptake
were recorded.
Retrospective analysis of the imaging investigations
was carried out by an experienced radiologist (panoramic
radiograph, CT scan, MRI) and Nuclear Medicine
physician. The CT scan, MRI and scintigraphy were
reviewed without benefit of clinical and radiological
information. The interpretation of the image in accordance
with the clinical findings, the possibility of distinguishing
between BON and bone metastases and the presence of
clear margins were assessed by the examiners.
An informed consent was not necessary as our study
was based on the assessment of data already available from
routine investigations.
Results
Among the patients with bone metastases (six females and
one male), the mean age was 72 years (range 61 – 84 years).
The four patients with multiple myeloma were equally
distributed in terms of gender (two females and two male)
and had a mean age of 71.5 years, with a range between
57 years and 82 years.
Seven patients had BON in the mandible, while three
subjects showed maxillary involvement. One patient had
lesions affecting both upper and lower jaws.
In ten subjects, the osteonecrosis was associated with
severe pain, swelling and exposed bone, but only one
patient developed cutaneous fistula with suppuration.
In four cases the necrosis was triggered by previous
dental extractions, and in one subject the BON was
diagnosed following a perimplantitis. Another patient
developed the osteonecrosis after pre-prosthodontic surgery and, in one case, the BON followed a bone biopsy. For
the remaining subjects it was not possible to associate the
onset of the necrosis with any procedure.
Table 1 summarizes the clinical features of BON in our
series of patients.
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Bisphosphonate osteonecrosis
S Chiandussi et al
238
Table 1
Clinical features of our series of patients
Patients Age (years) Gender Reason for taking Zometa
1
84
F
2
69
F
3
4
57
71
M
F
5
6
71
71
F
F
7
61
F
8
9
10
76
82
70
F
M
F
11
78
M
Bone metastases secondary
breast cancer
Bone metastases secondary
breast cancer
Multiple myeloma
Bone metastases secondary
breast cancer
Multiple myeloma
Bone metastases secondary
breast cancer
Bone metastases secondary
lung cancer
Multiple myeloma
Multiple myeloma
Bone metastases secondary
breast cancer
Bone metastases secondary
lung cancer
Site of necrosis
Pain Bone sequestrum Fever Possible associated factor
to Mandible
Yes
Yes
Yes
Not known
to Maxilla
Yes
Yes
Yes
Not known
Maxilla and mandible Yes
to Mandible
Yes
Yes
Yes
Yes
Yes
Not known
Perimplantitis
Mandible
to Mandible
Yes
Yes
Yes
Yes
Yes
Yes
Dental extraction
Dental extraction
to Maxilla
Yes
Yes
Yes
Not known
Mandible
Mandible
to Mandible
No
Yes
Yes
No
Yes
Yes
No
Yes
No
Dental extraction
Biopsy
Dental extraction
to Maxilla
Yes
Yes
No
Pre-prosthodontic surgery
Panoramic radiography
In all symptomatic patients, areas of bone destruction were
present in correspondence with the regions of clinical
involvement. The radiolucent areas were patchy, with
occasional evidence of radiopaque sequestra of necrotic
bone and little evidence of healing. The border between the
necrotic and normal bone was not sharply defined and
subperiosteal new bone formation was not usually evident
(Figures 1 and 2). The radiographic imaging of the
asymptomatic patient showed a radiolucent lesion corresponding to an empty socket.
The 99Tcm-MDP three-phase bone scan aroused the
suspicion of an area of increased activity in the mandible of
the asymptomatic patient. The presence of increased uptake
was confirmed through the SPECT (Figures 8 and 9).
Discussion
Bisphosphonates are non-metabolic synthetic analogues of
pyrophosphate synthase. They bind to osteoclasts, particularly in areas where bone resorption and formation is
taking place, causing reduction in the recruitment, life span
CT scan
Imaging evaluation of CT scan disclosed abnormalities in
all symptomatic patients. The images showed a moderate
irregularity of the cortical margins and, in all symptomatic
patients, destruction of cortical bone was noticed. Both
clear areas of osteolysis and osteosclerosis were noticed
(Figures 3 and 4). The CT scan did not add significant data
to the panoramic radiograph of the asymptomatic subject.
MRI
In all cases, it was possible to identify the involvement of
the cancellous bone, which produced low signal intensity
on T1 weighted images and a mild hyperintensity on T2
weighted and T-STIR images. A mild and irregular
enhancement of the lytic areas was noticed after injection
of the contrast agent. Where the bone sequestrum was
evident, it presented as a well-defined dark area (Figure 5).
In patients with evident swelling, an area of oedema of
soft tissues was clearly visible on T-STIR images as high
signal intensity.
Scintigraphy
In all cases, the bone scan was judged positive for the
presence of bone lesions and showed abnormal localized
activity in the jaws in comparison with the surrounding
regions. In three cases, a central or adjacent spot of
decreased uptake was observed within the area of uptake of
the radionuclide (Figures 6 and 7).
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Figure 1 Panoramic radiograph that shows wide areas of bilateral bone
destruction in a patient with multiple myeloma. On the left side, the patient
experienced swelling with bone exposure. The histological examination of
the exposed bone revealed the presence of avascular osteonecrosis
Figure 2
bone
Osteolysis of the right mandible with damage to the cortical
Bisphosphonate osteonecrosis
S Chiandussi et al
Figure 5
Figure 3 Computed tomography of a mandibular bone defect due to
osteonecrosis
and activity of osteoclasts and modulation of the
osteoclast – osteoblast interrelation.1,15,16 They also show
potent antiangiogenetic properties due to their ability to
significantly decrease circulating levels of vascular
endothelial growth factor in breast cancer patients with
bone metastases.17
In our series of patients, the initial symptoms corresponded to the typical presentation already described in
the literature: the patients were complaining of a painful
“non-healing” extraction socket or exposed bone with
progression to sequestrum formation associated with
localized swelling. In accordance with the literature, in
our series of patients the osteonecrosis was preceded by
traumas or surgical procedures of the involved bone.2 – 13 To
the best of our knowledge, this correlation is not based on
scientific evidence and it can not be excluded that a surgical
procedure merely exposes some bone which was already
necrotic.
Figure 4
Figure 3
Three-dimensional reconstruction of the bone defect shown in
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MRI showing bone sequestrum in the right maxilla
The diagnosis of BON is generally established in a late
stage of the disease since patients usually present to the
attention of the clinician when the osteonecrosis is already
symptomatic. It is essential that the medical and dental
professions are able to recognize subclinical signs of this
condition early, as a timely diagnosis can make a significant
Figure 6 99Tcm-MDP three-phase bone scan showing increased uptake
of the radionuclide in correspondence with an osteonecrotic area
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Bisphosphonate osteonecrosis
S Chiandussi et al
240
Figure 7
SPECT-CT image of the same patient shown in Figure 6
difference to the outcome of the disease. BON may remain
asymptomatic for many weeks or months and is usually
recognized exclusively by exposed bone in the oral cavity.
These lesions typically become symptomatic following a
secondary infection or trauma to adjacent and/or opposing
healthy soft tissues from irregular surfaces of the exposed
bone.18 Radiological and nuclear medicine imaging can be
of crucial value in helping the recognition and definition of
bone lesions in patients on therapy with bisphosphonates.
Nuclear medicine scans of the jaws are usually available
for patients receiving bisphosphonates since they undergo
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regular bone scans as routine investigations for metastatic
diseases. 99Tcm-MDP uptake is associated with both
osteoblastic metabolism and blood flow, and is much
more sensitive than radiography in detecting early and
subclinical osteonecrosis. During the early stages of BON,
areas of reduced uptake are consistent with the decreased
level of vascularity of the bone. However, as the disease
progresses, the scintigraphy is able to show areas of
radionuclide uptake representative of osteoblastic hyperactivity in a subchondral distribution. Among our patients,
in three cases the centre of the osteonecrosis showed a
Bisphosphonate osteonecrosis
S Chiandussi et al
Figure 8
99
241
Tcm-MDP three-phase bone scan of the asymptomatic patient
significant decrease of radionuclide activity or even
complete lack of activity. This feature can be interpreted
as a sign of decreased metabolism in the necrotic focus due
to the absence of blood supply. Limitations of the use of
scintigraphy in such patients include low resolution and a
difficulty in differentiating between inflammation and
metastasis during the late stages of the disease. However,
increased uptake of technetium-99 in the scintigraphy of
the jaws of patients who receive bisphosphonates should
always be considered as an indicator of probable BON. A
bone scan is therefore recommended as a screening
technique for all patients taking bisphosphonates.
The management of BON also remains extremely
difficult, and at the moment there are no scientific data to
support a universally accepted treatment protocol. Surgical
debridements are not completely effective in eradicating
the necrotic areas, as it is extremely difficult to obtain
surgical margins with good quality vital bone. Even though
bleeding is able to distinguish between necrotic and vital
tissues, no intraoperative technique can help the clinician
in determining whether the surgical margins consist of
really healthy bone. This is why it is important to identify
the clinical image that better defines the border between the
lesion and surrounding good quality tissues.
Conventional radiographs are widely used in the
evaluation of osteonecrosis and it is therefore recommended to take a panoramic radiograph as first routine
radiological investigation. In our series of patients, ten out
of 11 subjects presented to our Clinic during a late stage of
their condition. In all cases, the panoramic radiographs
were able to demonstrate clear signs of osteolytic lesions,
but the margins between necrotic areas and healthy bone
Dentomaxillofacial Radiology
Bisphosphonate osteonecrosis
S Chiandussi et al
242
Figure 9
SPECT-CT image of the same patient shown in Figure 7
were not always well-defined. On the basis of conventional
radiography, the ability to distinguish between metastatic
lesions and osteonecrosis is good, mainly when radiopaque
sequestra are present or when osteolysis is combined with
Dentomaxillofacial Radiology
osteosclerosis. However, an osteonecrosis presenting as an
osteolytic lesion can occasionally be difficult to distinguish
from malignancy. The specificity of panoramic radiography is therefore high, but early lesions are often missed.
Bisphosphonate osteonecrosis
S Chiandussi et al
Another inconvenience of this technique is the limit of
showing a two-dimensional image of three-dimensional
structures, preventing the clinician from understanding the
real extent of the lesion. This disadvantage is overcome by
both CT and MRI as they show axial, sagittal and coronal
sections, allowing a three-dimensional reconstruction of
the osteolysis. CT and MRI are also very helpful in
differentiating osteonecrosis from other causes of osteolysis. CT is useful in providing detailed information about
both cortical and trabecular bone. On the other hand, MRI
is not able to show destruction of the cortical bone, but is
useful in detecting the involvement of soft tissues. The
contrast agent in MRI can differentiate between the bone
sequestrum, where there is no enhancement, and areas of
hyperaemia where the contrast medium reaches high
concentrations. As to diagnostic imaging, it has to be
underlined that although panoramic radiography, and
especially CT and MRI, have a good specificity in
distinguishing osteonecrosis from other pathologies,
these techniques are not able to distinguish bisphosphonate-induced osteonecrosis of the jaws from other
known causes of exposed bone in the jaws such as
243
osteoradionecrosis, osteonecrosis of the jaws related to
osteomyelitis, or steroid-induced osteonecrosis, which is
rarely found in the jaws.
In this study, the small number of patients available
for assessment is a limitation and it may reflect the rate
of reported occurrence, which is actually low. However,
awareness of imaging features of this condition is very
important in establishing the correct diagnosis and could
help in the recognition of osteonecrotic lesions of the
jaws in patients being treated with bisphosphonates.
In conclusion, conventional radiography that shows a
lesion with the characteristic imaging features of osteonecrosis in patients receiving bisphosphonates should alert
the clinician to the diagnosis of BON. A CT scan is
extremely useful in defining the features and extent of the
lesions and, in selected cases, an MRI can add value to the
radiological findings by showing the soft tissue involvement. Scintigraphy is a very sensitive investigation and
therefore could be used as a screening test to detect
subclinical osteonecrosis in patients receiving
bisphosphonates.
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