M u s c u l o s k e l e t a l I m a g i n g C l i n i c a l Pe r s p e c t i ve

Chan et al.
Femoral Fractures and Alendronate Therapy

Musculoskeletal Imaging
Clinical Perspective

Subtrochanteric Femoral
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Fractures in Patients Receiving

Long-Term Alendronate Therapy:
Imaging Features
Sarah Shock Chan1 OBJECTIVE. A paradoxical association between long-term alendronate therapy and low-
Zehava Sadka Rosenberg1 energy subtrochanteric femoral fractures has been recently recognized. A retrospective re-
Keith Chan2 view of 34 such femoral fractures was performed.
Craig Capeci2 CONCLUSION. Subtrochanteric femoral fractures associated with long-term alen-
dronate therapy present with minimal trauma, may be chronic, and when incomplete may be
Chan SS, Rosenberg ZS, Chan K, Capeci C missed. The characteristic imaging features include initial involvement and focal thickening
of the lateral cortex, transverse orientation, medial beak, and superior displacement and varus
angulation at the fracture site.

A
lendronate sodium (alendronate)
is a bisphosphonate that has been
extensively and successfully used
for the treatment of osteoporosis
[13]. The mechanism of action involves the
induction of osteoclast apoptosis, thereby re-
ducing bone resorption [4]. Recently, several
studies have reported an increased prevalence
of low-energy subtrochanteric femoral frac-
tures in patients receiving long-term alen-
dronate therapy [513]. Studies have also re-
ported an association between the use of
bisphosphonates and osteonecrosis of the jaw
[14, 15]. The pathogenesis of these complica-
tions is not fully understood but may be relat-
ed to osteoclast inhibition and the resulting
suppression of bone turnover and bone re-
modeling, leading to atypical skeletal fragility
Keywords: alendronate, fracture, trauma
[1620]. The significance of recognizing this
type of fracture is paramount. In our experi-
DOI:10.2214/AJR.09.3588 ence, the number of these types of fractures
continues to increase and the clinical implica-
Received September 6, 2009; accepted after revision
tions and importance of fractures reported in
November 17, 2009.
women receiving long-term bisphosphonates
1
Department of Radiology, New York University Hospital cannot be understated. This study focuses on
for Joint Diseases, 301 E 17th St., 6th Fl., New York, NY the imaging findings in a series of patients re-
10009. Address correspondence to S. S. Chan ceiving long-term alendronate therapy who
(sarahshockchan@gmail.com).
experienced proximal femoral fractures.
2
Department of Orthopedics, New York University
Hospital for Joint Diseases, New York, NY. Materials and Methods
Institutional review board approval was ob-
AJR 2010; 194:15811586 tained, and informed consent was waived for this
0361803X/10/19461581
retrospective HIPAA-compliant study.
A retrospective review of the imaging findings
American Roentgen Ray Society in 34 proximal femoral fractures in 22 patients
receiving long-term alendronate therapy was per-
formed. The fractures occurred in 22 patients, 12
of whom suffered bilateral fractures. Twenty of
these patients were seen at our orthopedic depart-
ment, and two patients were referred for imaging
during a 4-year period. All patients were women
(age range, 5081 years; mean age, 64 years).
The patients had received alendronate therapy for
a minimum of 4 years and up to 14 years (mean,
6 years). All patients reported no or minor trau-
ma. The imaging studies included radiography
(n = 34), bone scintigraphy (n = 4), CT (n = 4),
and MRI (n = 5). For the complete fractures, the
bone scintigraphy and the cross-sectional studies
were performed to exclude underlying pathologic
processes, in view of the lack of significant
trauma; for the incomplete fractures, the studies
were performed to further assess the cause for
hip pain. For one patient with incomplete frac-
ture, MRI was performed to exclude an osteoid
osteoma, suspected on radiographs; for the other
patients, MRI was performed to evaluate the cause
of continued pain.
Two musculoskeletal radiologists, one with 20
years and one with 1 year of musculoskeletal radi-
ology experience, reviewed the studies in consen-
sus. The following fracture characteristics were
recorded: complete or incomplete fracture, dis-
tance from lesser trochanter, fracture orientation,
alignment, presence of associated lateral cortical
thickening, and time to complete healing. When
additional imaging techniques were used, the re-
viewers also reviewed those studies in consensus,
with knowledge of the radiographic findings. In the
case of CT scans, the same fracture characteristics

AJR:194, June 2010 1581

 Chan et al.

described for radiographs were evaluated. When an

MR study was performed (incomplete fractures
only), the presence of cortical thickening, endosteal
or periosteal edema, as well as a fracture line was
noted. Finally, when a bone scan was obtained,
the degree and pattern of uptake were noted.
A complete fracture was defined as a fracture
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that extended through the entire femoral cortex.

An incomplete fracture was defined as partial in-
volvement of the femoral cortex. In cases of in-
complete fractures, the location of the fracture
along the femoral shaft (medial or lateral) was
documented. In cases of complete fractures, the
displacement pattern of the distal fracture frag-
ment and the presence of a medial beak were not-
ed. A medial beak was defined as a spiked appear-
ance of the medial femoral cortex at the fracture
site. The distance from the lesser trochanter was
determined by measuring the distance from the
inferior edge of the lesser trochanter to the level Fig. 174-year-old woman who sustained fracture Fig. 263-year-old woman who sustained complete
of the most superior portion of the fracture site. after fall from chair. Image shows most commonly fracture after fall from standing. Anteroposterior
seen complete fracture pattern. Anteroposterior radiograph of left hip shows typical complete fracture
Fracture orientation referred to the direction of radiograph shows transverse fracture orientation, characteristics with prominent skirt-like thickening
the major fracture component (transverse, verti- skirt-like focal lateral cortical thickening (short at opposing lateral cortices (arrows).
cal, or oblique). The presence of associated cor- arrow), medial beak (long arrow), superior
displacement of distal fracture fragment, and
tical thickening was noted when there was a con- varus angulation at fracture site.
spicuous difference in the thickness of the femoral
cortex in the region of the fracture. Also, evolu- three of the 20 complete fractures, no medial nearly complete fracture over the course of 2
tion of healing and time to complete healing, de- beak was present (Fig. 3b). years (Fig. 6).
fined as complete or almost complete resolution In 14 (41%) of 34 cases, the fractures were For one patient with complete fracture,
of the fracture line, were determined on follow-up incomplete. For all 14 incomplete fractures, bone scintigraphy studies showed increased
radiographs for 21 (62%) of 34 fractures. radiographs showed focal thickening at the uptake at the fracture site in all three phases,
lateral aspect of the femoral cortex (indica- as would be expected in the setting of acute
Results tive of chronicity), with (n = 10) (Fig. 4) or fracture. No additional sites of uptake were
All of the patients reported either no trau- without (n = 4) (Fig. 5) a visible transverse detected to indicate metastatic disease. Bone
ma history or a history of minor trauma, such cortical fracture line. One incomplete frac- scintigraphy of three incomplete fractures
as a fall from a standing height. In one pa- ture was followed up, and it progressed to a showed increased uptake along the lateral
tient with bilateral fractures (one side com-
plete and the other side incomplete), the in-
complete side was relatively asymptomatic.
All fractures were transverse and were lo-
cated 0.518.3 cm away from the lesser tro-
chanter (mean, 4.8 cm). Most of the fractures
(27 [79%] of 34) occurred 5 cm distal to
the lesser trochanter.
Twenty (59%) of the 34 fractures were
complete, and 17 (85%) of those factures
had a medial beak with superior displace-
ment and varus angulation of the distal frac-
ture fragment (Fig. 1). In all 20 patients with
complete fractures, the presence of a skirt
of focal buttressing and thickening at the op- A B
posing lateral cortices could be seen (Fig. 2),
Fig. 3Radiographs from two different patients showing atypical fracture patterns.
suggesting chronicity as well as indicating A, 66-year-old woman who sustained bilateral complete fractures after fall from standing. Anteroposterior
that the fractures originate laterally. radiograph shows that fractures occurring more distally along shaft without varus angulation at either fracture
In three of the 20 complete fractures, the site. Minimal lateral cortical thickening is seen (arrows).
fracture occurred much more distal to the B, 76-year-old woman who sustained complete femoral fracture after stepping off curb. Anteroposterior
radiograph shows that, although fracture is in typical location with usual superior displacement and varus
lesser trochanter and there was no varus an- angulation pattern, there is no medial beak on distal fracture fragment (arrow). Skirt-like focal thickening of
gulation at the fracture sites (Fig. 3a). In opposing lateral cortices is noted (arrowheads).

1582 AJR:194, June 2010

 Femoral Fractures and Alendronate Therapy
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Fig. 456-year-old woman who reported chronic
left hip and leg pain. Image reveals incomplete
fracture. Anteroposterior radiograph shows cortical
thickening along lateral cortical shaft of femur,
which is indicative of chronicity, and transversely
orientated fracture line (arrow).
A B
Fig. 656-year-old woman with chronic left leg pain.
A and B, Images show progression of incomplete fracture involving lateral femoral cortex, with increased
amount of cortical thickening and enlargement of fracture lucency. Radiograph in A was obtained almost 2
years before radiograph in B. (B is reprinted with permission from The Journal of Bone and Joint Surgery [13])
AJR:194, June 2010 1583
Fig. 562-year-old woman who had right leg pain
for 6 months. Anteroposterior radiograph shows
incomplete fracture with only lateral cortical
thickening (arrow) without visible fracture line.
cortex, corresponding to the site of cortical
thickening (Fig. 7).
Three of the four CT studies were per-
formed for patients with complete fractures
(Fig. 8) and revealed the typical transverse
fracture pattern, skirt-like focal cortical thick-
ening with a medial beak and fragment dis-
placement, and no evidence for underlying
lesion. The MRI studies for the incomplete
fractures showed focal lateral cortical thick-
ening and endosteal edema compatible with
an incomplete fracture (Fig. 9). None of the
studies revealed an underlying process. For
one patient with a complete fracture (Figs.
10a and 10b), a stress fracture involving the
lateral cortex was diagnosed according to an
MRI performed elsewhere, 1 month before
the complete fracture developed (Fig. 10c).
All (100%) of the complete fractures and
seven (50%) of the 14 incomplete fractures
were treated with cephalomedullary nail fix-
ation. Follow-up for 21 (62%) of 34 fractures
revealed complete healing in 38 months
(mean, 5 months). The remaining five com-
plete and eight incomplete fractures were ei-
ther lost to follow-up or occurred so recently
that assessment of healing could not be com-
pleted before this article was written.
Discussion
Alendronate was the first oral bisphos-
phonate available in the United States for
the treatment of osteoporosis. It has been
proven in randomized controlled studies to
significantly reduce the risk of osteoporotic
fractures and to increase bone mineral den-
sity [13]. Thus, the paradoxical association
of low-energy subtrochanteric femoral frac-
tures associated with long-term (defined in
this series as 4 years) alendronate thera-
py is an unexpected and only recently recog-
nized phenomenon.
Alendendronate induces osteoclast apop-
tosis, thereby inhibiting osteoclast-mediat-
ed bone resorption. Although osteoclast in-
hibition will increase bone mineral density,
in the long term, it can lead to abnormal
bone remodeling and repair, allowing bone
microdamage and atypical skeletal fragil-
ity [1620]. This process will increase the
fracture risk in some patients. Cheung et
al. [10] described the findings on bone bi-
opsy for a patient who sustained a low-en-
ergy alendronate-related femoral fracture.
The histologic specimen depicted depressed
bone formation and marked reduction in os-
teoid thickness and volume. Although 40%
of the trabecular surface was covered with
 Chan et al.

osteoid, the osteoid was very thin [10]. A re-

cent study on skeletal fragility related to bis-
phosphonate therapy by Visekruna et al. [16]
speculates that some patients have physio-
logically vulnerable osteoclasts, with less
tolerance for bisphosphonate effects, thereby
increasing the fracture risk.
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The characteristic imaging features for

our patients included transverse orientation
of the proximal femoral fracture line, me-
dial beak, superior displacement of the dis-
tal fragment, and varus angulation at the
fracture site. In addition, the fractures were
0.518.3 cm away from the lesser trochant-
er (mean, 4.8 cm). A skirt of lateral cortical
thickening and buttressing was also noted in
all cases of incomplete fractures, indicating
chronicity and a lateral origin of the fracture.
In cases of incomplete fractures, the only
finding that may be evident on radiographs is
subtle focal cortical thickening of the lateral
femoral cortex, although in some cases (10 of A B
14 fractures in our series), a faint transverse- Fig. 776-year-old woman with pain.
ly oriented fracture line can be appreciated. A, Anteroposterior radiograph shows lateral cortical thickening (circle) and subtle transverse lucency (arrow).
Our observations corroborated the findings B, Delayed image of right femur from Tc99-MDP bone scan shows increased radiotracer uptake along lateral
cortical shaft corresponding to radiographic findings (arrow).
reported in four prior series published in the
orthopedic literature [57, 13].
Proximal femoral fractures are typically
seen in the setting of major trauma, such as
motor vehicle accidents, and tend to be spi-
ral or oblique. Conversely, subtrochanteric
femoral fractures associated with long-term
alendronate therapy present with minimal or
no history of trauma and, when incomplete,
may be missed clinically or radiographically.
When fractures are incomplete, their typical
transverse orientation and their origin along
the lateral femoral cortex resemble stress or
insufficiency fractures. Other stress fractures
with a transverse orientation are commonly
recognized as being related to either insuffi-
ciency or fatigue, such as those within the sa-
crum, fibula, distal tibia, tarsal navicular, and
metatarsals [21, 22]. In contrast to the alen-
dronate-associated fractures seen in our se-
ries, most of these fractures are recognized
before progression to a displaced fracture and
present as areas of sclerosis with associated
callus formation. Some of these fractures are
also noted to occur in characteristic locations
within certain bones, such as the medial fem-
oral neck, anterior tibial shaft, or dorsal as- Fig. 874-year-old woman who suffered fracture Fig. 962-year-old woman who had right leg
after fall from chair. Image shows typical complete pain for 1 year. Patient had incomplete fracture.
pect of the tarsal navicular bone [22]. fracture pattern. CT was performed to exclude Radiographs (unavailable) were initially interpreted
Because of the minimal trauma reported pathologic fracture. Coronal CT image shows focal as negative; however, on rereview, cortical
by patients with alendronate-associated fem- lateral cortical thickening (short arrow) transverse thickening was suggested, and fat-suppressed
oral fractures, underlying pathologic pro- fracture orientation, medial beak (long arrow), MRI was performed to exclude osteoid osteoma.
superior displacement of distal fracture fragment, T2-weighted MR image shows endosteal edema
cesses, such as a bone tumor or metastasis, and varus angulation at fracture site. No underlying (arrow) and lateral cortical thickening compatible
are often suspected clinically. In our study, lesion is identified. with chronic incomplete fracture.

1584 AJR:194, June 2010

 Femoral Fractures and Alendronate Therapy
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A B C
Fig. 1066-year-old woman with leg pain.
A and B, Coronal T2-weighted (a) and T1-weighted (b) fat-suppressed MR images of right femur from outside institution show intramedullary edema and lateral cortical
thickening. Diagnosis of stress fracture was made.
C, Anteroposterior radiograph of right femur obtained at our institution 1 month later shows development of complete fracture.

seven cases required additional cross-sec-
tional studies (CT or MRI) to arrive at the
correct diagnosis or to exclude a pathologic
fracture. Also, four patients underwent bone
scanning, in one case to exclude metastatic
disease (in the setting of a complete fracture)
and in three cases to confirm the presence of
an incomplete fracture.
Unlike a few reports in the literature [16],
our patients had a fairly typical healing
course not significantly different from that of
other patients with traumatic proximal femo-
ral fractures, with all but one of the fixated
fractures healing within 6 months. However,
in one case of incomplete fracture that was
monitored for 2 years before fixation, the
fracture did not heal with time and protected
weightbearing.
Given the relatively new phenomenon of
proximal femoral fractures associated with
alendronate therapy, no globally accepted
treatment has been established, but in our
experience and in other case reports [8, 12],
these fractures are typically treated with in-
tramedullary nail fixation, as would conven-
tional subtrochanteric traumatic fractures.
At our institution, the orthopedic surgeons
generally recommend prophylactic operative
treatment of incomplete fractures, to avoid
progression to complete fractures. In addi-
tion, given the high number of patients who
suffer bilateral factures, radiographs of the
contralateral femur are recommended for pa-
tients receiving long-term alendronate ther-
apy who present with a subtrochanteric or
diaphyseal femur fracture. If a contralater-
al stress fracture is found, prophylactic fixa-
tion of the femur should also be considered
[13]. Furthermore, our clinical colleagues at
our institution think that alendronate therapy
should be discontinued, at least temporarily,
in patients with proximal femoral fractures
that are characteristic of those associated
with alendronate. Therefore, familiarity with
the characteristic clinical and imaging fea-
tures of these fractures, whether complete or
incomplete, is crucial for appropriate clinical
management. In patients receiving long-term
alendronate therapy who present with hip or
femoral pain, imaging, primarily with radi-
ography and perhaps with MR, should cer-
tainly be performed.
The association of proximal femoral frac-
tures with long-term alendronate therapy re-
quires future extensive study. At present, there
is no consensus on the appropriate duration of
alendronate therapy in osteoporotic patients
and, more specifically, in patients with associ-
ated proximal femoral fractures. Also, it is
unknown whether the association with low-
energy subtrochanteric fractures holds true
for all classes of bisphosphonates or is limited
solely to alendronate therapy, because most
studies to date have focused on alendronate.
Two case reports have been published that de-
scribe similar fractures in patients receiving
zoledronic acid (Zometa, Novartis) and rise-
dronate sodium (Actonel, Procter & Gamble
Pharmaceuticals) [23, 24]. The question wheth-
er IV infusion is a more potent form of bisphos
phonate, which may lead to an increased prev-
alence of fractures as compared with the oral

AJR:194, June 2010 1585


bisphosphonates, is also unknown. This is the
case with osteonecrosis of the jaw. Further-
more, it is unclear which category of patients
is more susceptible to the development of
proximal femoral fractures and what clinical
markers may herald the onset of these frac-
tures. Regardless, the association of alen-
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dronate with femoral fractures indicates that
greater caution is required in the administra-
tion and monitoring of bisphosphonate thera-
py. Familiarity with the characteristic clinical
and imaging features of these fractures,
whether complete or incomplete, is also cru-
cial for appropriate clinical management.
The major limitations of our study are its
retrospective nature and small sample size.
Also, we had limited access to the clinical in-
formation on the patients. It would have been
useful to correlate our findings with metabol-
ic indexes, such as serum calcium level, phos-
phorus and alkaline phosphatase levels, bone
mineral density, and parathyroid hormone
levels. Also, the use of other drugs that may
influence bone stock, such as hormone re-
placement therapy or steroids, was not known.
Future prospective studies may be useful to
assess the prevalence of these fractures in pa-
tients receiving alendronate therapy.
In conclusion, subtrochanteric femoral
fractures associated with alendronate thera-
py have typical clinical and radiographic pat-
terns. In complete fractures, these include mi-
nor or no trauma, initial involvement of the
lateral proximal femoral cortex, transverse
orientation, medial beak, skirt-like focal
thickening at the opposing lateral cortical sur-
faces, superior displacement of the distal frag-
ment, and varus angulation at the fracture site.
Incomplete fractures show focal lateral corti-
cal thickening with or without an incomplete
transverse fracture line. Familiarity with these
features will expedite detection and treatment
and alert the clinician to reconsider the risks
and benefits of alendronate therapy.
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