Skeletal complications of bisphosphonate use: what the
radiologist should know
A E HAWORTH, MB ChB, FRCR and J WEBB, DMRD, FRCR
Department of Radiology, University Hospital Aintree, Liverpool, UK
ABSTRACT. Bisphosphonates are widely used for prevention of fractures in patients at
risk, mainly in the presence of osteoporosis and bone metastases. A number of adverse
effects of prolonged bisphosphonate treatment have emerged. We would like to
highlight the skeletal complications from which a radiologist may be the first
healthcare professional to recognise the association with bisphosphonate therapy. We
illustrate these complications (namely osteonecrosis of the jaw and less well-known
atypical femoral shaft fractures), presenting radiological findings in our patients.
Recommendations for safer use of bisphosphonates are included in the conclusion of
Received 27 August 2011
Revised 11 January 2012
Accepted 8 February 2012
’ 2012 The British Institute of
Bisphosphonates are non-metabolic synthetic analo-
gues of pyrophosphate and have a significant effect on
bone turnover, inhibiting osseous resorption by suppres-
sing osteoclast activity [1, 2]. This results in bone
microarchitecture modifications. As they are metaboli-
cally inactive, they bind to bone, creating a reservoir that
remains even after discontinuation of treatment .
Studies have shown antifracture efficacy to persist for
1–2 years following discontinuation of aledronate, and
between 3 and 5 years following risedronate use .
Bisphosphonates are the treatment of choice in condi-
tions characterised by an increase in bone resorption. In
the UK they are used in the treatment of lytic metastases
arising from breast cancer, osteoporosis, hypercalcaemia
secondary to malignancy, Paget’s disease of bone and
multiple myeloma . Less well-known indications
include osteogenesis imperfecta and juvenile idiopathic
arthritis. Worldwide, their indications are extending to
include lytic metastases from other solid tumours .
Two forms of the drug are used: intravenous (iv) and
oral. In 2009–10 alone over 1 million people in the UK
were prescribed bisphosphonates and over 6.5 million
prescriptions were issued . In the USA, an estimated
30 million prescriptions for bisphosphonates are written
every year . There is abundant evidence in the
literature extolling the benefits of bisphosphonate use,
and indeed these are multiple and often provide sig-
nificantincreases inqualityof lifefor patients.Thenumber
of patients needed to be treated with bisphosphonates for
3 years to prevent 1 vertebral and 1 hip fracture are 14
and 91, respectively . There are, however, several
potential side-effects relating to their use. These include
gastrointestinal discomfort, influenza-like illness (due to
acute phase reaction), renal complications (rare even in
high-dose iv treatment) and a theoretical link to accelera-
tion of coronary artery disease.
More importantly for a radiologist, there is increasing
evidence to suggest a separate subset of complications
affecting the skeleton. Although they are well described in
metabolic and orthopaedic journals, they are less well
known to the radiological community. These are compli-
cations that might be expected from the mechanism of
action of bisphosphonates, and, in view of their rising
usage, are likely to be seen with increasing frequency.
In this article we describe the skeletal complications of
bisphosphonate use and the radiographic findings of each.
Bisphosphonate-related osteonecrosis of the
(BRONJ) is a painful destructive process, which is
distinguishable from other impaired healing conditions
by the following features:
N current or previous treatment with a bisphosphonate;
N exposed bone in the maxillofacial region that has
persisted for more than 8 weeks; and
N no history of radiation therapy to the jaws .
Causes, predisposing factors and histopathological
The exact underlying aetiology of BRONJ is unknown.
It tends to affect the mandible rather than the maxilla,
although both jaws can be affected simultaneously. The
maxilla is thought to be relatively spared because of its
Address correspondence to: Dr Jolanta Webb, Department of
Radiology, University Hospital Aintree, Lower Lane, Liverpool L9
7AL, UK. E-mail: firstname.lastname@example.org
The British Journal of Radiology, 85 (2012), 1333–1342
The British Journal of Radiology, October 20121333
The suggested mechanism is via the inhibition of bone
turnover. Bisphosphonates are thought to incorporate at
sites of high osseous turnover (e.g. the mandible, where
marked suppression of bone metabolism results in accu-
mulation of physiological microdamage, occurring as a
result of mastication).
The thin mucosa and periosteum covering the jaws are
easily breached by infection (oral flora) or local trauma
(dental procedures) and the presence of either micro-
trauma, infection or iatrogenic damage can increase
demand for osseous repair beyond the capacity of the
newly hypodynamic bone, resulting in local osteonecro-
sis. Commonly, oral flora such as Actinomyces israelii are
found colonising biopsy specimens of BRONJ; however,
while some lesions have responded to antibiotic therapy
it is unclear whether the organisms are causative or
Generally there is no classic histopathological appear-
ance for BRONJ. Specimens from exposed bone often
show non-vital bone with rough margins and empty
lacunae, consistent with necrosis. Unexposed bone speci-
mens contain hypervascular fibrotic tissue with inflam-
matory infiltrates filling the trabecular space, which is
often seen in chronic osteomyelitis. Fungal contamination
is common in exposed specimens .
Incidence and prevalence
The estimated risk of BRONJ in patients receiving anti-
resorptive therapy is rare. The occurrence in oral bisphos-
phonate use is estimatedto be between 1 in 10 000and1 in
100 000 patient years, with more frequent occurrences in
females and age groups older than 60 years [13, 14].
The majority of reported cases of BRONJ (approxi-
mately 95%) are associated with iv bisphosphonate
therapy in the management of metastatic bone disease
(often with doses up to 12 times greater than those used
in oral treatment regimes for osteoporosis) [14, 15].
Woo et al , in a systematic review of 368 published
cases of BRONJ, suggested a prevalence of between 6%
and 10% for patients on iv therapy for metastatic bone
disease . There is also evidence to suggest an
association between subtypes of bisphosphonates and
risk. Pamidronate (containing an aminoterminal group)
was less commonly associated with osteonecrosis of the
jaw than zoledronate (containing a nitrogen side-chain)
. In addition, the chemotherapeutic agents and
steroids taken by many of the patients receiving bisphos-
phonate treatment will almost certainly contribute to
impaired wound healing, and so exacerbate osteonecro-
Thediagnosis of BRONJisoftenclinical,with a relatively
consistent symptomatology. However, it is frequently de-
tected late as the patient becomes symptomatic only after
osteonecrosis is well established. It usually presents with
pain and/or a non-healing extraction socket. This leads to
exposed, non-vital bone with subsequent sequestrum
formation and associated swelling or purulent discharge.
Sometimes it can be recognised solely by the exposed bone
As BRONJ occurs most commonly in oncology
patients receiving iv bisphosphonate therapy for bone
Figure 1. (a) Female patient diagnosed with metastatic breast
cancer. Increasing pain following left lower premolar extrac-
tions 5 years after commencing on intravenous pamidronate.
Photograph of exposed bone at presentation post extraction.
(b) Two orthopantomograms1 yearapartshowing lytic process
developing at the site of tooth extraction (arrows).
A E Haworth and J Webb
1334The British Journal of Radiology, October 2012
metastases it is important to differentiate this from
neoplastic invasion, osteomyelitis and radiotherapy-
induced osteonecrosis. This is an important distinction
as similar radiographic appearances can be seen follow-
ing radiotherapy (therefore a history of previous head
and neck irradiation needs to be excluded before a
diagnosis of BRONJ can be made). As unnecessary bone
biopsy causes local osseous damage (and can exacerbate
osteonecrosis) it is to be avoided if possible. In general,
most institutions use the presence of 8 weeks of exposed
bone in a bisphosphonate-treated patient without a
history of radiotherapy as diagnostic of BRONJ [3, 14].
The radiographic appearances are non-specific at both
anatomical and functional imaging. The bone changes
may be mixed, predominantly sclerotic or predomin-
The early imaging findings in BRONJ seem to be focal
medullary sclerosis with poor corticomedullary differ-
entiation and involvement of the inferior alveolar canal,
which is clinically associated with tooth loosening. De-
layed socket healing following tooth extraction should
Figure 2. Male patient on high-
dose intravenous pamidronate for
hypercalcaemia of prostatic malig-
nancy. The orthopantomogram
shows subtle lysis and sclerosis in
the left lower premolar region post
Figure 3. Male patient (same patient as in Figure 2). T1
weighted axial image showing abnormal low signal change
in the left and central mandible with subtle low signal
(oedema) in the adjacent soft tissue (arrow).
Figure 4. Male patient (same patient as in Figure 2). Short-
tau inversion–recovery image at the same level as Figure 3
shows high signal in the adjacent soft tissue (oedema) but
variable signal in the mandible (arrow).
Review article: Skeletal complications of bisphosphonate use
The British Journal of Radiology, October 20121335
also raise the possibility of osteonecrosis of the jaw
(Figures 1b and 2).
Sequestrum formation, fractures and periosteal reac-
tion are all associated with late disease [3, 13, 17–19].
When the maxilla is involved there may be mucosal
thickening in the adjacent sinus with fluid levels or
Radiographs may appear normal if lesions are ,1cm in
diameter and as such multidetector CT (MDCT) is often
required with multiplanar reformats to fully assess the
extent of disease involvement. More recently cone-beam
CT (CBCT) with three-dimensional reformats has been
described as a possible way of improving detection of
early BRONJ . A facial bone trauma protocol (slice
thickness 1.25mm, interval 0.75mm, 120 kV and 350–440
mAs) with multiplanar reconstructions is usually suffi-
cient in most circumstances.
MRIcharacteristics are variable, depending on thestage
of disease. Typically osteonecrosis of the jaw displays
low signal intensity on T1weighted (T1W) sequences,
with a more variable pattern on T2weighted (T2W), short-
tau inversion–recovery (STIR) and on T1W sequences
post-iv gadolinium. The MRI changes in early disease are
not well described in the literature, owing in part to the
lack of MRI in early disease. Bisdas et al  describe
variable T2W signal generally but they noted focal low
T1W and intermediate/high T2W signal in the region of
the open wound consistent with oedema.
Late-stage disease typically appears similar to the ex-
pected histological findings, with unexposed bone
displaying high signal on T2W and STIR sequences com-
patible with a chronic osteomyelitic pattern, and exposed
bone displaying low T2W/STIR intensity compatible with
necrosis. These signal characteristics can be localised to
the cortex or extend into the marrow, inferior alveolar
canal, adjacent soft tissues and/or the maxillary sinus.
Soft tissue involvement is often seen in late-stage disease
with high T2W signal (oedema) and soft tissue enhance-
ment (often extending to the mylohyoid ridge, buccinator
muscle and masticator space). This can present as focal,
mass-like thickening of the involved muscles, mimicking
neoplastic invasion, which can complicate management
. Cervical adenopathy, in particular of the subman-
dibular and jugulodigastric chains, is also a common
finding on MRI, again complicating matters in oncology
patients (Figures 3–6) .
In general the MRI findings are non-specific, relating
to oedema/inflammation and necrosis. However, when
put in clinical context they can accurately evaluate
the extent of disease and surrounding soft tissue
Figure 5. Male patient (same patient as in Figure 2). Post-
gadolinium axial T1 weighted image showing areas of
abnormal enhancement in the affected mandible and
surrounding tissue (arrow).
Figure 6. Female patient taking
aledronic acid (75mg per os per
week) for osteoporosis (6 years).
Admission radiographs following
trivial trauma show a transverse
right femoral fracture (asterisk) with
a medial unicortical beak (arrows).
There is subtle thickening of the
lateral cortex in the region of the
fracture. She had experienced pro-
dromal pain, but a pelvic radiograph
3 weeks earlier did not include the
upper femoral diaphysis.
A E Haworth and J Webb
1336The British Journal of Radiology, October 2012
involvement, to help in the planning of surgical
debridement of intractable cases.
O’Ryan et al  reported an increase in uptake on
bone scintigraphy in nearly 66% of patients who
subsequently developed clinically overt BRONJ. Rarely,
single photon emission CT (SPECT) can help to
differentiate between the increased uptake of reactive
bone and the decreased uptake of a sequestrum, further
increasing diagnostic confidence; however, this is highly
dependent on the lesion size . Limited information on
the use of fludeoxyglucose (FDG) positron emission
tomography (PET) is available. It appears to be sensitive
(but not specific) in the assessment of osteonecrosis of
the jaw, with the increased uptake of FDG possibly
relating to the healing response, surrounding inflam-
mation or superadded infection (Table 1) .
The severity of BRONJ has been graded by the American
Association of Oral and Maxillofacial Surgeons, and
management has been tailored to each grade . Before
commencing with iv bisphosphonates, preventative mea-
sures are undertaken in patients at risk of developing
BRONJ, consisting of oral examination, removal of non-
viable teeth, completion of any invasive dental treatment
and achievement of optimal orodental health. No such
measures are necessary prior to commencing oral bispho-
sphonates. Patients who develop symptoms are given
antimicrobial oral rinses, systemic antibiotics and have
necessary surgical treatment, with removal of necrotic
bone fragments without exposing non-affected bone.
Following resection or fracture, reconstructive surgery
may be undertaken. Hyperbaric oxygen, ozone and laser
therapy have all been tried, with variable results.
Case reports of successful use of recombinant human
parathyroid hormone, teriparatide, have been published,
but no randomised trials are yet available ; in the light
of opposing cellular and tissue effects of bisphosphonates
and teriparatide such a trial would be of interest.
Discontinuation of bisphosphonate therapy is of no
benefit in the short term, but may improve the outcome
in the long term.
Low-impact atypical femoral fractures
Atypical femoral fractures are seen predominantly in
the proximal third of the shaft just distal to the lesser
trochanter; however, they can occur throughout the
diaphysis down to the supracondylar region. By defini-
tion they occur as a result of minimal or no trauma,
usually said to equate to a fall from a standing height or
less (whereas 75% of femoral fractures occur as a result
of high-impact trauma, and are spiral in nature in more
Table 1. Imaging findings in osteonecrosis of the jaw
RadiographicOsteolysis, sclerosis, periosteal reaction, narrowing of the marrow space with sclerosis,
fractures, inferior alveolar canal involvement
Usually decreased signal
Variable; usually intermediate or increased in early disease (oedema), increased or decreased
in late disease (oedema vs sclerosis)
Variable; usually increased signal in early disease (oedema), increased or decreased as
disease progresses (oedema vs sclerosis)
Variable; usually correlates with decreased T1W signal area, but spares low T2W signal
Occasionally decreased uptake in early disease; increase in uptake in late disease,
occasionally with central scar (dependent on lesion size)
T1W post gadolinium
99mTc MDP bone scintigraphy
MDP, methylenediphosphonate; STIR, short-tauinversion–recovery; T1W,T1weighted; T2W,T2weighted;99mTc,technetium-99m.
Table 2. Major and minor criteria in diagnosing atypical femoral fractures
Major criteriaLocated anywhere along the femur from just distal to the lesser trochanter to just proximal to the
Associated with no trauma or minimal trauma (fall from a standing height or less)
Transverse or ,30u uoblique configuration
Complete fractures extend through both cortices and may be associated with a medial spike
Incomplete fractures involve only the lateral cortex
Localised periosteal reaction of the lateral cortex
Generalised increase in cortical thickness of the diaphysis
Prodromal symptoms such as dull or aching pain in the groin or thigh
Bilateral fractures and symptoms
Comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia)
Use of pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors)
Review article: Skeletal complications of bisphosphonate use
The British Journal of Radiology, October 20121337
than 50%). Characteristically, patients report prodromal
symptoms of deep thigh or groin pain. The fracture may
be complete or incomplete. Complete fractures are us-
ually transverse with a characteristic medial unicortical
‘‘beak’’. They may also have a slight oblique (,30u u)
orientation [26, 27]. For the diagnosis of an atypical
fracture a number of exclusion criteria must be met:
The fracture must not be:
N femoral neck, intertrochanteric or spiral diaphyseal
N associated with a local primary bone tumour
N associated with metastatic bone disease
Both subtypes (complete/incomplete) are commonly
associated with a periosteal stress reaction. This is often
seen as thickening of the lateral cortex at the fracture site.
However, there may also be a more diffuse thickening
throughout the affected region [28–32].
A task force commissioned by the American Society for
atypical femoral fractures . All of the major criteria need
to be met for an atypical femoral fracture. The minor criteria
are associated findings from their meta-analysis of the
literature (Table 2).
Causes, predisposing factors and histopathological
Bisphosphonates have a number of effects on bone, as
discussed above. The exact aetiology responsible for
atypical fractures, however, remains unclear, and no
definite causal link has been established. The effects of
bisphosphonates on several components of bone are,
however, pointing towards their role in atypical femoral
The organic matrix of bone is the critical determinant
of its strength. Bisphosphonates are associated with both
positive and negative alterations on the formation of
bone matrix by changes in both collagen maturity and
cross-links. The bone matrix contains both enzymatic
and non-enzymatic collagen cross-links, which add to
the structural integrity of the matrix . In the short
term, bisphosphonates were shown to decrease turnover
of enzymatic collagen cross-links, which leads to in-
creased strength. In the longer term, however, they
increased non-enzymatic collagen cross-links, reducing
bone strength [34, 35].
Bone density distribution
This is a marker of the heterogeneity of the bone
matrix. In general the density distribution varies only
slightly within cancellous bone in the adult population,
corresponding to a mechanical and biological optimum
state for stability . A slight change in this hetero-
geneity, to a more homogeneous distribution, leaves the
bone more susceptible to ‘‘cracks’’ and less able to slow
the process of microdamage. In reducing bone turnover
with bisphosphonates the overall mineralisation is in-
creased, but there seems to be an associated reduction in
the heterogeneity of the matrix [36, 37]. This leaves the
bone more susceptible to injury. There is evidence
emerging to suggest that this is transient and the
distribution returns to a normal state after 5–10 years
of treatment .
Bone remodelling is a critical mechanism in which
bones strengthen and repair themselves in response to
stress. Excessive remodelling reduces bone mass and
strength by distorting the micro-architecture. Bisphos-
phonate therapy aims to suppress remodelling to avoid
this; however, by reducing remodelling, the ability to
repair the microtrauma that occurs on a daily basis is
inadvertently reduced, leading to accumulation of da-
mage . This accumulation occurs naturally with
ageing (particularly in those over 70 years of age), but
occurs more rapidly with bisphosphonate use .
Incidence and prevalence
The most up-to-date work, published in 2011 by Park-
Wyllie et al , showed that when compared with
transient bisphosphonate use, treatment for 5 years or
longer was associated with an increased risk of atypical
femoral shaft fracture (adjusted odds ratio, 2.74; 95%
confidence interval, 1.25–6.02). This was, however,
weighed up against the reduced risk of typical osteo-
porotic fractures among women with more than 5 years
of bisphosphonate therapy (adjusted odds ratio, 0.76;
95% confidence interval, 0.63–0.93).
The typical scenario is prodromal pain in the affected
limb(s) over several weeks to months prior to presenta-
tion with an atypical fracture. This often occurs following
normal activity with no significant trauma.
The radiological findings are now well described. The
fractures are transverse (or ,30u uoblique) diaphyseal
fractures occurring in a region of underlying cortical
thickening. The thickening is often seen on the acute
radiographs; however, it is also usually present prior to
injury on images acquired because of the persistent pain.
The fracture itself has a characteristic medial unicor-
tical beak, with no features to suggest an underlying lytic
If these are available prior to the diagnosis of atypical
femoral fracture, the findings are variable, with possible
thickening of the cortex. However, many radiographs
will be normal and CT often will not assist in diagnosis.
Post fracture, the medial unicortical beak is characteristic
and CT (performed for surgical planning as the fracture
would be obvious on radiographs) will only help in
further assessing the fracture anatomy.
The appearances tend to be similar to those seen in
stress fractures. The typical periosteal callus seen prior to
A E Haworth and J Webb
1338The British Journal of Radiology, October 2012
occult stress fracture is evidence of an attempt at repair.
Callus formation has been seen on the lateral aspect of
the femur prior to atypical femoral fractures, although
there is often a more generalised cortical thickening. The
evidence for this is again unclear as there is genetic
variance in cortical thickness, and there is no evidence to
suggest that the processes thought to be responsible for
atypical fractures cause enhanced endosteal formation or
MRI of a complete atypical femoral fracture will show a
fracture line of low signal intensity on all sequences,
traversing an area of bone marrow oedema, represented
by diffusely decreased signal intensity on T1W sequences
and increased signal intensity on T2W and STIRsequences
. A single coronal T1W or STIR sequence may be suf-
ficient and there is no need for iv contrast administration
. However, the role of MRI is more important in
making the diagnosis before the complete fracture occurs
and in this respect it is the most sensitive modality. The
findings at this stage are essentially the same as in in-
sufficiency or stress fracture, but characteristically they
occur along the lateral aspect of the femur, starting with
some periosteal high signal and normal marrow on
STIR, progressing through an increasing amount of
periosteal changes and marrow oedema . Cortical
thickening may be evident. Doubt may occur as to the
nature of the bone oedema, and distinction from a
pathological fracture or neoplastic lesion may be needed,
aided by the linear nature of the marrow oedema  and
absence of any well-defined T1W lesion, endosteal
scalloping or soft tissue mass .
MRI also has an important role in the assessment of the
contralateral femur in patients with atypical femoral
fracture. Irrespective of whether the contralateral side is
symptomatic, following a normal or inconclusive radio-
graph, MRI should be performed to look for signs of
bone oedema .
Figure 7. Female patient (same patient as in Figure 6).
Technetium-99m methylene diphosphonate bone scintigram
shows uptake in the region of the acute fracture (localised to
the cortices). No evidence of metastatic bone disease.
Degenerative changes only. Ant, anterior; Post, posterior.
Figure 8. Female patient (same patient as in Figure 6).
Radiograph taken for intermittent left thigh pain approxi-
mately 1 year after previous admission. There is focal
thickening of the lateral cortex in the upper femoral
Review article: Skeletal complications of bisphosphonate use
The British Journal of Radiology, October 20121339
MRI has a role in guiding the treatment of incomplete
atypical femoral fractures in asymptomatic patients. A
trial of conservative treatment with reduced activity and
limitation of weight bearing is deemed successful if MRI
shows resolution of bone oedema .
Nuclear medicine studies, most frequently techne-
tium-99m-labelled methylene diphosphonate bone scin-
tigrams, may be performed before or soon after fracture
in an attempt to identify a pathological process. The
fracture itself will display high uptake (as all fractures
will); however, barring the single ‘‘hot spot’’, most
patients will have a normal study. Pre-fracture studies
have been described showing mild uptake in the region of
the thickened cortex (Figures 7–9).
Once a fracture has occurred, the immediate concern is
for stabilisation and surgical fixation (preferentially with
an intramedullary nail). Many of these are suspected to
be pathological fractures at presentation, but investiga-
tion is unremarkable. Patients often re-present with a
contralateral fracture, at which point the diagnosis may
become more obvious.
At present it is unclear how to manage patients
suspected to be developing an atypical fracture from
clinical and radiographic signs. In patients at low risk of
osteoporotic fracture (clinically assessed using a tool
such as the World Health Organization—Fracture Risk
and Assessment Tool) , bisphosphonates should be
discontinued . Das et al  recently published a
report outlining one management approach, including
investigations (bone mineral density, radiographs of
both femurs, serum biochemistry markers) and treat-
ment options (prophylactic surgical fixation, post-opera-
tive cessationof bisphosphonates,
of recombinant parathyroid hormone and serial fracture
risk assessment). They also suggested radiological follow-
upofthe contralateralfemur,whichisa commonthemein
all of the available literature .
The Food and Drug Administration in the USA has
reviewed the literature on two occasions, most recently in
2010 . In asymptomatic patients the evidence is
insufficient to warrant withdrawal of therapy in those
who benefit from the effects of bisphosphonates. This was
echoed by the Medicines and Healthcare products
Regulatory Agency in 2009  and in the American
College of Rheumatology hotline report from 2010 .
The idea of a ‘‘drug holiday’’ every 5 years of treat-
ment has been postulated in those at intermediate risk of
osteoporotic fracture [32, 46–47]. The National Osteo-
porosis Foundation published a clinical update in 2008
suggesting that for most patients such an approach did
not increase the risk of osteoporotic fracture and ‘‘may be
advantageous’’, although it was clinically reasonable to
continue bisphosphonate therapy in those at high risk of
Bisphosphonates are a crucial weapon in the clinician’s
armoury. Their proven benefits have, over the years,
prevented many vertebral, hip and other osteoporotic
fractures, and improved quality of life. For instance, it
has been estimated that for each atypical femoral fracture
caused, at least 30 vertebral and 5 hip fractures will be
prevented . However, the described complications
are significant, need to be expected and are likely to
become more frequently seen as prescription numbers
BRONJ is a well-known skeletal phenomenon asso-
ciated with bisphosphonate therapy in certain high-risk
groups, namely patients receiving high doses of iv
bisphosphonates. Problems tend to arise as a result of
dental work, which overloads the capacity for bone
repair, either prior to or during bisphosphonate therapy.
Figure 9. Female patient (same
patient as in Figure 6). Readmitted
following sudden onset of left thigh
pain following minor trauma approxi-
mately 6 months after radiograph
shown in Figure 8. (a) Transverse
diaphyseal fracture through the upper
left femur with medial unicortical
beaking (straight arrow) and cortical
thickening (wavy arrow). (b) Post-
operative films demonstrate the lat-
A E Haworth and J Webb
1340The British Journal of Radiology, October 2012
While this is often detected clinically, radiographic
correlation is used to assess evolution and, hopefully,
resolution. When bone is not directly exposed it is a
challenge to detect, and it is essential that we, as
radiologists, be alert to the possibility of osteonecrosis
of the jaw and look for the subtle signs.
Whether there is a causal relationship between bisphos-
phonate therapy and atypical fractures is widely debated,
but as yet unresolved, as summarised in the recent
position paper produced jointly by the European Society
onClinicalandEconomic Aspects of Osteoporosisand the
Osteoarthritis and International Osteoporosis Foun-
dation . The interesting (and concerning) issue has
been that the link is not with high-dose iv bisphosphonate
therapy in patients with underlying malignancy (as in
BRONJ), but in the general osteoporotic population who
are on long-term oral bisphosphonate (alendronic acid)
therapy. This encompasses a much larger cohort, and yet
although this is a relatively well-known phenomenon
within endocrine and ortho-geriatric circles, it appears to
have largely bypassed the radiological community.
The typical imaging findings are quite characteristic
once a fracture has occurred. During the prodromal
phase, many radiographs will be normal; however, a
percentage will display a subtle area of cortical thicken-
ing, and this could potentially be an area in which we as
radiologists can raise awareness in the correct clinical
Clinical radiologists, although not directly managing
patients, have the responsibility to ensure that appro-
priate questions are raised when imaging findings sug-
gest complications of bisphosphonate therapy. We need
to be alert to the potentially devastating skeletal com-
plications associated with mandibular osteonecrosis
(without history of radiotherapy), or when a low-impact
horizontal/short oblique non-comminuted fracture or
lateral cortical thickening occur in the femoral diaphysis,
especially in a patient with a preceding history of deep
thigh or groin pain. Bilateral atypical femoral fractures,
either simultaneous or sequential, should definitely
trigger suspicion of bisphosphonate therapy complica-
tion. In unilateral atypical femoral fractures, imaging of
the contralateral femur should be initiated. At present
there is lack of awareness and under-reporting of the
often subtle skeletal complications of bisphosphonate
therapy among radiologists.
Thanks to Dr Mashood Siddiqi, consultant physician
with special interest in metabolic bone disease, and Dr
Huw Lewis Jones, consultant radiologist, (both
University Hospital Aintree, UK) for their editorial
advice, and to Prof Simon N Rogers, consultant in
maxillofacial surgery (University Hospital Aintree, UK)
for his contribution in images and access to his patients’
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1342The British Journal of Radiology, October 2012