DOI:10.2214/AJR.07.3045
AJR 2008; 190:949-955
© American Roentgen Ray Society
MRI of Mandibular Osteonecrosis Secondary to Bisphosphonates
Luis García-Ferrer1,
Jose V. Bagán2,
Vicente Martínez-Sanjuan3,
Sergio Hernandez-Bazan2,
Raquel García3,
Yolanda Jiménez-Soriano2 and
Vicente Hervas1
1 Department of Radiology, Consorcio Hospital General, Universitario de
Valencia, Valencia, Spain.
2 Department of Stomatology, Consorcio Hospital General, Universitario de
Valencia, Valencia, Spain.
3 CT and MR ERESA Unit, Consorcio Hospital General, Universitario de Valencia,
Avida. Tres Cruces s/n, Valencia, Valencia, Spain 46014.
Received August 20, 2007;
accepted after revision October 27, 2007.
Address correspondence to V. Martínez-Sanjuan
(marsan{at}comv.es).
Abstract
OBJECTIVE. Bisphosphonates are a group of drugs used in the
treatment of oncology patients with bone metastases. However, in the past few
years, osteonecrosis of the jaw has been reported as a serious complication of
such treatment. The objective of this study was to examine the use of MRI in
the assessment of bone lesions caused by this disease.
MATERIALS AND METHODS. Fourteen patients were studied who had been
treated with IV bisphosphonates and had developed focal lesions of
osteonecrosis of the jaw. These patients were referred by the stomatology
department of Hospital General Universitario de Valencia. We evaluated both
the morphology and the behavior of the lesions in T1, STIR, and after the
administration of gadolinium.
RESULTS. Twenty-six focal lesions were detected clinically and 36
were detected radiologically. All the clinically detected focal lesions were
visible on MRI. There were 15 focal lesions detected radiologically that were
not detected on clinical examination. In all patients, it was possible to
assess bone involvement and involvement of the bone marrow, soft tissues,
sinuses, and mandibular canal as well as the presence of adenopathy.
CONCLUSION. MRI is an effective tool in the assessment of
osteonecrosis of the jaw. The significance of focal lesions detectable on
radiologic examination but without clinical correlation and their progression
over time remains to be determined.
Keywords: bisphosphonates • jaw • MRI • osteonecrosis
Introduction
Bisphosphonates are synthetic com pounds with a structure similar to
inorganic pyrophosphate, obtained by substituting an oxygen molecule for a
carbon molecule between two phosphates (P-C-P). With a great capacity for
binding to the bone matrix, this structure makes them more resistant to
hydrolysis in an acid medium and to the action of pyrophosphatase and
therefore more difficult to metabolize
[1]. These drugs are used in
the treatment of lytic bone metastases, multiple myeloma, hypercalcemia of
malignant origin, osteoporosis, and diseases such as Paget's disease,
providing a significant improvement in the symptoms as a result of reducing
pain, bone demineralization, and bone fractures, either pathologic or due to
insufficiency. Given the prevalence of these diseases, bisphosphonates are one
of the most prescribed drug groups in the world
[1,
2].
Although the drugs are well tolerated with a low incidence of adverse
effects, in the past few years, a new problem has surfaced associated with the
bisphosphonates, which have nitrogen in their structure (pamidronate,
zoledronic acid, and alendronate): osteonecrosis of the jaw (ONJ). This
adverse effect was first described in 2003 by Marx
[3], Migliorati
[4], and Pogrel
[5], with further reports
appearing later [1,
6–17].
In September 2004, in view of the growing number of publications, the
manufacturer and the U.S. Food and Drug Administration (FDA) accepted
osteonecrosis as a possible side effect of the use of Zometa (zoledronic acid,
Novartis) and Aredia (pamidronate, Novartis)
[18].
Until 2006, except for a description of the CT images in one case
[7], there had been no studies
describing the assessment of bisphosphonate-associated osteonecrosis by MRI. A
series of 11 patients has recently been published
[19] with scintigraphy, CT,
and MRI studies, but few details are provided about the characteristics on
MRI. The aim of this article is to contribute a new series of cases with this
disease and its study following a specific MRI protocol.
Materials and Methods
The patients attended the CT and MRI unit of the Consorcio Hospital General
Universitario de Valencia. They were referred by the stomatology department
with the clinical and histopathologic diagnosis of ONJ. All signed informed
consent for the MRI.
The MRI studies were performed with a 1.5-T superconducting MRI magnet
(Somatom Sonata, Siemens Medical Solutions) using the 8-channel head antenna.
The examination was performed according to the following protocols.
Three-plane locator (FLASH): axial T1-weighted (TR/TE, 639/17; number of
excitations [NEX], 4; matrix, 320 x 320; field of view, 240 mm; slice
thickness, 5 mm), axial STIR (6,230/93; inversion time, 130 milliseconds; NEX,
4; field of view, 240 mm; matrix, 256 x 240; slice thickness, 5 mm),
axial T1-weighted turbo FLASH fat-saturated (263/4.76; flip angle, 70°;
NEX, 3; field of view, 200 mm; matrix, 320 x 320; slice thickness, 5
mm), and oblique sagittal of each side T1-weighted (400/17; NEX, 5; field of
view, 140 mm; matrix, 256 x 256; slice thickness, 3 mm). STIR: sagittal
of the diseased side—that is, of the side in which the T1 images show
low-signal lesions and if bilateral, of both sides (2,500/99; inversion time,
130 milliseconds; NEX, 4; matrix, 256 x 256; field of view, 140 mm;
slice thickness, 3 mm), axial diffusion-weighted imaging (DWI) (3,000/83; NEX,
3; field of view, 230 mm; matrix, 128 x 128; b = 0, 500, and 1,000
s/mm2; slice thickness, 5 mm), and axial perfusion (42/2.47; flip
angle, 70°; field of view, 280 mm; fat satur ation; NEX, 1; matrix, 192
x 192; slice thickness, 5 mm; repeated 20 times).
After this acquisition, the axial sequence T1-weighted turboFLASH
fat-saturated, the axial sequence T1-weighted, and the oblique sagittal of the
affected side or sides were all repeated. The scanning duration was about 45
minutes. The contrast material was injected with a power injector
(Mississippi, Ulrich), at a rate of 3 mL/s at a dose of 0.1 mmol/kg of body
weight, followed by 60 mL of normal saline. The most objective way to check
the contrast enhancement is to compare images of the same series before and
after con trast administration.
The images were assessed by two radiologists with head and neck experience
who were unaware of the clinical location of the lesions. All the cases were
later reviewed with the dental surgeons and assessed with the findings from
the dental views.
In our studies, we assessed the presence of areas of change in signal in
the bone, primarily in the mandible and the upper maxilla. This signal change
shows up as hypointense areas in the T1-weighted sequences before injecting
the contrast material and with high-intensity signal in the STIR sequences.
These areas were measured, particularly the larger ones, and the independent
focal areas found in each subregion were counted. We categorized four
quadrants for both clinical and radiologic assessment: upper maxilla, right
side (quadrant 1); upper maxilla, left side (quadrant 2); mandible, left side
(quadrant 3); and mandible, right side (quadrant 4).
We assessed involvement of the cortical bone, the bone marrow, and
extension to the soft tissues adjacent to the cortical bone. In the upper
maxilla, extension to the maxillary sinus or nasal fossa was also assessed.
Involvement of the mandibular canal and the mental foramen was assessed in the
mandible.
We evaluated the enhancement of the paramagnetic contrast material by the
inflammatory component of the lesions, with enhance ment being observed in the
areas of inflammatory tissue in which previous gadolinium injections showed
low signal intensity in T1-weighted images. Another element we looked for was
the presence of nodal involvement indicating the chain in which we identified
adenopathy (sub mandi bular, sub mandibular angle, and
jugular–digastric).
Results
Our study contained 14 patients (Table
1), five men (35.7%) and nine women (64.3%), average age 58.43
± 11.02 (± SD) years. The indication for treatment with
bisphosphonates was breast cancer bone metastases in seven patients (50%),
multiple myeloma in six (42.9%), and prostate cancer bone metastases in one
(7.1%). Eight patients (57.1%) re ceived zoledronic acid, two (14.3%) received
pamidronate, and four (28.6%) received pamidronate plus zoledronic acid. The
average time during which they received the treatment with bisphosphonates was
32.36 ± 14.7 months. The trigger factor was a tooth extraction in seven
patients (50%), prosthesis implant in three patients (21.4%), and unknown in
four (28.6%).
In total, 36 focal lesions were detected radiologically, whereas only 26
were confirmed clinically. All the clinically detected focal lesions were
visible in the MRI study (Table
2), but not all those detected by MRI were visible in the clinical
examination, even after the dental surgeon knew where to look.
On evaluation of the degree of bone involvement
(Table 3), 14 patients (100%)
had cortical lesions, 13 (92.9%) also had bone marrow involvement (Figs.
1A and
1B), eight (57.1%) patients had
soft-tissue involvement (Figs.
2A and
2B), three (21.4%) also had
maxillary sinus lesions (Figs.
3A and
3B), and in nine (64.3%)
patients, there was occupation of the mandibular canal (Figs.
4A and
4B). All the patients studied
had submandibular adenopathy, 71.4% of them also in the submandibular angle
and jugular–digastric chain (Figs.
1A,
1B,
3A, and
3B).
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Fig. 1A —55-year-old man with prostate cancer. T1-weighted image shows
hypointense area in right mandible (white arrow) that corresponds to
focal lesion of osteonecrosis and associated adenopathy (black
arrow).
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Fig. 2A —62-year-old woman with breast cancer. Axial T1-weighted image
shows mass of soft tissue (large arrow) that affects masseter muscle
and internal pterygoid with extension reaching cheek. Small arrow indicates
break of cortical bone in retromolar trigone area.
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Fig. 3A —70-year-old woman with breast cancer. Oblique sagittal
T1-weighted image shows occupation of right maxillary sinus caused by
hypointense lesion in upper right maxilla (white arrow), causing
lysis of floor of maxillary sinus. Associated submaxillary adenopathy
(black arrow) is seen.
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The mandibular osteonecrosis lesion was identified as delimited focal
lesions with reduction of the signal in enhanced sequences on T1-weighted
(100%) imaging. The STIR study showed an increase in the lesion signal (Figs.
5A,
5B,
5C, and
5D) in nine patients (64.3%),
whereas in four (28.6%), there was virtually no bright signal from the lesion
and in one case the lesion showed no signal. In these last four patients,
after the IV administration of paramagnetic contrast material, there was a
significantly lower enhancement (Figs.
6A,
6B, and
6C) than in the lesions that
showed increased signal in STIR sequences
(Table 4).
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Fig. 5A —62-year-old woman with breast cancer. Typical behavior of
osteonecrotic lesion on T1 (A), STIR (B), and contrast-enhanced
T1 (C) sequences. Hypointense lesion with bright signal in STIR and
contrast enhancement in quadrants 1 and 2 are seen. Arrows show focal lesions
of osteonecrosis in quadrant 1 (black arrows) and quadrant 2
(white arrows).
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Fig. 5B —62-year-old woman with breast cancer. Typical behavior of
osteonecrotic lesion on T1 (A), STIR (B), and contrast-enhanced
T1 (C) sequences. Hypointense lesion with bright signal in STIR and
contrast enhancement in quadrants 1 and 2 are seen. Arrows show focal lesions
of osteonecrosis in quadrant 1 (black arrows) and quadrant 2
(white arrows).
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Fig. 5C —62-year-old woman with breast cancer. Typical behavior of
osteonecrotic lesion on T1 (A), STIR (B), and contrast-enhanced
T1 (C) sequences. Hypointense lesion with bright signal in STIR and
contrast enhancement in quadrants 1 and 2 are seen. Arrows show focal lesions
of osteonecrosis in quadrant 1 (black arrows) and quadrant 2
(white arrows).
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Fig. 6A —59-year-old woman with multiple myeloma. T1 (A), STIR
(B), and contrast-enhanced T1 (C) sequences show atypical
behavior of osteonecrotic lesion (arrows). There is hypointense
lesion with little brightness on STIR (B) and with no contrast
enhancement (C).
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Fig. 6B —59-year-old woman with multiple myeloma. T1 (A), STIR
(B), and contrast-enhanced T1 (C) sequences show atypical
behavior of osteonecrotic lesion (arrows). There is hypointense
lesion with little brightness on STIR (B) and with no contrast
enhancement (C).
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Fig. 6C —59-year-old woman with multiple myeloma. T1 (A), STIR
(B), and contrast-enhanced T1 (C) sequences show atypical
behavior of osteonecrotic lesion (arrows). There is hypointense
lesion with little brightness on STIR (B) and with no contrast
enhancement (C).
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Discussion
Bisphosphonate-associated osteonecrosis is a new disease that is becoming
increasingly more common. A search on MEDLINE with the terms
"osteonecrosis," "jaw," and
"bisphosphonates" comes up with 127 articles, two having been
published in 2003, seven in 2004, 50 in 2005, and 118 in 2006. Various texts
discuss the help of imaging in the diagnosis of this disease, but only one
mentions the use of MRI for classification
[19]. This article
characterizes the lesions of 11 patients by orthopantomography, CT, MRI, and
scintigraphy, arriving at the conclusion that the first examination to be
performed should be orthopantomography; that CT is very useful for the ability
to see and characterize the extension of the lesions and in detecting cortical
involvement; that MRI should be reserved for those patients who have
soft-tissue extension; and that scintigraphy is highly sensitive and can be a
useful screening tool for this disease.
In MRI, the osteonecrosis appeared hypointense on T1-weighted images.
However, in our series, there was different behavior in STIR and after the
administration of gadolinium. The lesions showing very little bright ness in
STIR had little or no contrast enhancement, all suggestive of nonviable bone.
These findings have also been described by Chiandussi et al.
[19], being classed as areas
of bone sequestrum. Nevertheless, after review of the orthopantomograms, we
found no radiologic data compatible with this diagnosis.
DWI and perfusion-weighted imaging (PWI) were acquired in our study. In
DWI, the artifacts from echo-planar imaging acquisition were present in all
the patients, and image quality was not good enough to provide correct
anatomic definition. The perfusion-weighted images were acquired with
T1-weighted fat saturation (turboFLASH), and they provide correct dynamic
information about the enhancement of the lesions. This enhancement was
maintained in the later sequences after gadolinium injection. For this reason,
we considered PWI unnecessary in this pathology.
In addition to the behavior of the lesion according to the sequence, we are
able to add more information evaluating the involvement of cortical bone, bone
marrow, adjacent soft tissues, paranasal sinuses and the mandibular canal, and
locoregional adenopathy as well as supply information on the number and
location of focal lesions. The treatment for ONJ is controversial and depends
to a great extent on the experience of the unit in treating this disease. In
our center, débridement of the necrotic bone is performed only on the
exposed lesions, leaving them to be treated conservatively in cases that have
not exteriorized. Although the surgical technique involves extracting bone
until healthy edges are reached on the basis of bleeding from the wound
borders, the information we provide about the extension of the lesion, parts
affected, and the size are of great assistance when it comes to planning the
procedure.
In patients treated with bisphosphonates, the development of ONJ is
generally preceded by a tooth extraction, although in up to 20% there is no
identifiable trigger factor. This means that taking a biopsy of a focal lesion
with characteristics on MRI of osteonecrosis but with no clinical signs has
obvious ethical connotations because of the risk of triggering the disease
process. In our series, there were 15 quadrants with radiologically detected
lesions compatible with bisphosphonate-associated osteonecrosis but without
clinical correlation. The bisphosphonates are distributed over all the bones
and follow the same pattern over the jaws. We believe that these focal lesions
are affected areas of the mandible on which a factor (as yet unknown)
triggering the process of infection and opening up the focal lesion has not
yet acted. Chiandussi et al.
[19] described the case of an
asymptomatic patient with signs of hyperperfusion on the scintigram but with
no findings on either the orthopantomogram or CT (the MRI evaluation of this
patient is omitted). This case, even taking into account the omission of the
MRI as a negative aspect of the test, supports the existence of silent focal
lesions of bisphosphonate-associated osteonecrosis.
We believe that there is a need for prospective studies of patients to
confirm these data. In conclusion, we believe that MRI is a very useful
imaging technique for the assessment of patients with
bisphosphonate-associated osteonecrosis, providing information about the
number and extension of the focal lesions and anatomic involvement. Because it
could be used as a technique for early detection in patients susceptible to
this disease, the lesions diagnosed would not be as advanced as they were in
our study, which means probably a better prognosis due to early treatment and
less necessity of surgery.
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Abstract
Introduction
