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C OPYRIGHT Ó 2013 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

Exhibit Selection
Atypical Femoral Fractures: What Do We
Know About Them?
AAOS Exhibit Selection
Aasis Unnanuntana, MD, Anas Saleh, MD, Kofi A. Mensah, MD, PhD, John P. Kleimeyer, BA, and Joseph M. Lane, MD

Investigation performed at Siriraj Hospital, Mahidol University, Bangkok, Thailand, and the Hospital for Special Surgery, New York, NY

B
isphosphonates are the most commonly prescribed type
of medication for the treatment of osteoporosis. Studies
have shown that bisphosphonates reduce the inci-
dence of vertebral and nonvertebral fractures when used to
treat postmenopausal osteoporosis1-4. The indications for
use of bisphosphonates also extend to other metabolic bone
diseases such as glucocorticoid-induced osteoporosis, Paget
disease, hypercalcemia due to a variety of causes, and skeletal
metastases5-7. Treatment with bisphosphonates, however, is
not without adverse effects. Because bisphosphonates act by
inhibiting osteoclast function and inducing osteoclast apo-
ptosis8,9, there is a substantial concern regarding the potential
side effects related to severe suppression of the bone turnover
rate.
Several case reports and case series have indicated an as-
sociation between a unique fracture type, so-called ‘‘atypical
femoral fractures,’’ and prolonged bisphosphonate use10-14.
These fractures differ from typical osteoporotic femoral frac-
tures in many respects, including the mechanism of injury,
location, and fracture configuration. Although the American
Society for Bone and Mineral Research (ASBMR) published a
task force report on atypical femoral fractures in 201015, little
information about this type of fracture is known. The present
report will critically review current evidence on the charac-
teristics, epidemiology, pathogenesis, and treatment outcomes
of atypical femoral fractures to identify gaps in knowledge
calling for future research and to provide guidance for ortho-
paedic surgeons.
Characteristics of Atypical Femoral Fractures
M any case reports and case reviews have described several
common radiographic features of atypical femoral frac-
tures associated with bisphosphonate use, including a transverse,
noncomminuted fracture at the subtrochanteric or femoral shaft
region with a medial cortical spike at the fracture area (Fig. 1).
Other features include prodromal pain and generalized thick-
ening of the femoral cortices on radiographs13,14,16,17. Because of
the lack of clear criteria to define atypical femoral fractures, the
ASBMR task force established major and minor features for both
complete and incomplete atypical fractures of the femur15 (Table
I). All of the major features should be present to designate a
fracture as atypical and distinguish it from more common os-
teoporotic hip fractures (Fig. 2). The minor features have also
been described in association with atypical femoral fractures, but
they are not required for diagnosis.
Although the ASBMR criteria are useful for defining atyp-
ical femoral fractures and allowing consistent diagnosis across
studies, some features remain controversial. For instance, gener-
alized cortical thickening (one of the minor radiographic features)
is believed to result from an impaired ability of bone to remodel
because of prolonged bisphosphonate use, leading to an accu-
mulation of microdamage and compromised bone strength17-19.
However, a recent study by our group found that prolonged
alendronate treatment (‡5 years) did not cause thickened femoral
cortices20. This result suggested that femoral cortices in patients
who have undergone long-term bisphosphonate treatment may
have already been thick prior to the initiation of bisphosphonate

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of
any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of
this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No
author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what
is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the
article.

J Bone Joint Surg Am. 2013;95:e8(1-13) d http://dx.doi.org/10.2106/JBJS.L.00568

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15
TABLE I Major and Minor Features for Diagnosing Atypical Femoral Fractures *

Major Features Minor Features

No history of trauma, or associated with low-energy trauma†
Fracture located anywhere from distal to the lesser trochanter to proximal to
the supracondylar area
Transverse or short oblique fracture configuration
Noncomminuted fracture
Medial spike in complete fractures; incomplete fractures involve only the
lateral cortex
Localized periosteal thickening of the lateral cortex
Generalized thickening of the femoral cortices
Prodromal symptoms
May be associated with bilateral fractures or symptoms
Evidence of delayed fracture-healing
Comorbid conditions or the use of some medications‡

*All major features, accompanied by none or some of the minor features, are required to diagnose atypical femoral fractures. †Low-energy trauma
is defined as a fall from a standing height or less. ‡Examples of comorbid conditions and medications are rheumatoid arthritis, rickets and
osteomalacia, renal osteodystrophy, and the use of bisphosphonates, glucocorticoids, or proton pump inhibitors.

treatment. Another recent study by Feldstein et al. found that
individuals with atypical femoral fractures who exhibited only the
major radiographic features tended to be older and thinner than
those who exhibited both major and minor criteria. In addition,
the incidence of atypical femoral fractures exhibiting only the
major radiographic features appeared relatively constant over the
study period (cumulative incidence, 5.9 per 100,000 person-years)
while the proportion of atypical femoral fractures with both major
and minor features increased over time21. Thus, it may be more
accurate to diagnose atypical femoral fractures only in patients
who exhibit both major and minor features. Nevertheless, that
study and ours support the need for a more precise measure to
define atypical femoral fractures. As the pathogenesis and clinical
presentation of such fractures become better elucidated, future
refinement of the current ASBMR criteria for atypical femoral
fractures will be necessary.
Epidemiology
O ver twenty-five case reports and series related to atypical
femoral fractures, as well as a number of controlled studies
and several larger studies using national registries and Phase-III
trial data, have been published15,22,23. In this section we will
consider the incidence of atypical femoral fractures; their rela-
tionship to bisphosphonate use is discussed later in this article.

Fig. 1
Radiographs of patients diagnosed with atypical femoral fractures. The radiographic features of an atypical femoral fracture include a common location in
the subtrochanteric (Fig. 1-A) or femoral shaft region (Fig. 1-B), transverse or short oblique fracture configurations, absence of comminution, a medial spike
(asterisks), localized periosteal thickening of the lateral cortex (black arrowheads), and generalized thickening of the femoral cortices (white arrows).
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All current evidence indicates that atypical femoral

fractures represent a rare subset of subtrochanteric and femoral TABLE II Prevalence of Factors Shown To Be Associated with
15,22,29
Atypical Femoral Fractures
shaft fractures. The average incidence of subtrochanteric and
femoral shaft fractures, ranging from twenty to thirty per Associated Factor Prevalence* (%)
100,000 person-years in the United States24,25, represents the
upper bound for an estimate of the incidence of atypical fem- Asian descent 32.6 to 50.0
oral fractures. In a Finnish registry, femoral shaft fractures had Bilateral fractures 28 to 44.2
an incidence of 2.5 to 9.9 per 100,000 person-years, but 75% oc- Prodromal pain 63.6 to 70
curred with high-energy trauma26 and the majority were com- Concomitant glucocorticoids 34
minuted and had a spiral configuration26,27. Thus, the actual Concomitant proton pump inhibitors 39
incidence of atypical femoral fractures is expected to be con- Delayed fracture-healing 26 to 38.8
siderably less than the total incidence of subtrochanteric and
femoral shaft fractures. In the osteoporotic population, sub- *According to previously published studies.
trochanteric and femoral shaft fractures account for 3% and
5% of femoral fractures, respectively24,28.
Atypical femoral fractures have been associated with vari- thickness was comparable between patients with and without
ous factors, including Asian descent, bilateral fractures, prodro- atypical fractures, and they also found an association between
mal pain, the use of glucocorticoids and proton pump inhibitors, atypical femoral fractures and a history of glucocorticoids use30.
and delayed fracture-healing (Table II). Other factors that have Incidence estimates made on the basis of reviews of radio-
been reported to be associated with such fractures include the graphs have ranged from 0.9 to seventy-eight atypical femoral
presence of rheumatoid arthritis or diabetes mellitus as well as fractures per 100,000 person-years15,21,30-32. The ASBMR task force
vitamin-D3 deficiencies15. However, Lo et al. showed that women reported an incidence of two per 100,000 cases per year after two
with atypical femoral fractures were less likely to have diabetes years of bisphosphonate use, increasing to seventy-eight per
and chronic kidney disease29. Giusti et al. found that cortical 100,000 cases per year after eight years of use (n = 15,000)15. A

Fig. 2
Radiographs and a table comparing common clinical and radiographic features of an atypical femoral fracture (Fig. 2-A), an osteoporotic femoral fracture
(Fig. 2-B), and a high-energy fracture of the femur (Fig. 2-C).
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TABLE III Bradford-Hill Criteria for Determining a Causal Relationship Between Bisphosphonate Use and Atypical Femoral Fracture

Support for a
Criterion Definition Causal Relationship

Strength of the association The risk of disease in exposed individuals is larger than that expected Demonstrated
by chance alone
Consistency Different studies under different conditions have similar results Not demonstrated
Specificity The disease is associated specifically with the exposure in question Not demonstrated
Temporality Exposure precedes the disease Demonstrated
Dose-response relationship Increasing exposure results in increased risk of disease Uncertain for dose,
demonstrated for time
Plausibility Credible scientific mechanisms can explain the association Demonstrated
Coherence The association is consistent with the natural history of the disease Demonstrated
Analogy Analogous examples exist as a precedent Demonstrated
Experimental evidence An intervention changing the exposure has an effect on the disease Uncertain
consistent with the presumed association

review of radiographs by Girgis and Seibel indicated an incidence
of 2.3 to sixteen atypical femoral fractures per 100,000 person-
years, with a higher incidence in patients who were sixty-five
years or older (n = 174,448)31. As described above, a review of
radiographs by Feldstein et al. found that fractures characterized
by the presence of only the ASBMR major criteria occurred at a
rate of 5.9 per 100,000 person-years (n = 5034), and the
number of such atypical fractures was stable over the study
period despite an increase in the use of bisphosphonates21. A
review of radiographs of 906 femoral fractures by Giusti et al.
found ten atypical fractures that also met some of the minor
criteria, accounting for 1.1% of all of the femoral fractures and
10.4% of the subtrochanteric and femoral shaft fractures30. A
review of radiographs by Schilcher et al. found an incidence
of fifty-five atypical fractures per 100,000 person-years among
bisphosphonate users compared with 0.9 per 100,000 person-
years among those with no bisphosphonate use (age-adjusted
relative risk = 47.3; 95% confidence interval [CI], 25.6 to 87.3)
(n = 12,777)32.
Discordant results have also been published. In a matched
control analysis within a cross-sectional study of 11,944 patients,
the hazard ratio (HR) for subtrochanteric fractures in alendronate-
exposed patients (HR = 1.46; 95% CI, 0.91 to 2.35) was similar to
the hazard ratio for proximal femoral fractures (HR = 1.45; 95%
CI, 1.21 to 1.74)33. A similar study using Danish national health
care data on 39,567 alendronate users and 158,268 untreated
controls, however, found subtrochanteric and diaphyseal fracture
rates of thirteen per 10,000 person-years in untreated women and
thirty-one per 10,000 person-years in women receiving alendro-
nate (HR = 1.88; 95% CI, 1.62 to 2.17)34. A post hoc analysis of
data from three randomized trials of bisphosphonates for post-
menopausal osteoporosis identified twelve subtrochanteric or
diaphyseal femoral fractures in ten of the 14,195 study par-
ticipants35, yielding a rate of twenty-three per 100,000 person-
years. The relative hazard for subtrochanteric or diaphyseal
fracture in the intervention group compared with the control
subjects was not significant in any trial, indicating no associ-
ation between bisphosphonate use and subtrochanteric or di-
aphyseal fracture even among women who were treated for as
long as ten years35. These studies, however, were limited by the
unavailability of radiographs for review, leaving the atypical
nature of fractures unconfirmed, and most patients had an ex-
posure of less than four years. The statistical power of the study
was also low, with a reduced chance of detecting rare events such
as atypical fractures.
Atypical femoral fractures, although rare, are important
to consider in patients who present with thigh pain. Case re-
ports provided the first evidence of such fractures but had
limitations of historical bias, varying definitions of the fracture
type, and inability to directly compare the risk of these fractures
according to bisphosphonate use. In addition, administra-
tive data and register-based studies do not capture all atypical
fractures, as they rely on identification by diagnostic codes that
may misclassify fracture location, and they do not assess the
radiographic hallmarks of atypia15. In various studies, 2.3% to
34% of atypical femoral fractures were misidentified on the
basis of International Classification of Diseases, Ninth Revision
(ICD-9) codes21,24,30.
The Causal Relationship Between Bisphosphonates
and Atypical Femoral Fractures
A n association between bisphosphonate use and the occur-
rence of atypical femoral fractures has been suggested10. Ac-
cording to a task force report from the ASBMR, this relationship
has not yet been shown to be causal15. Pharmacoepidemiologic
studies involving the monitoring of, detection of, evaluation of,
and response to adverse drug events have used the Bradford-Hill
criteria. These criteria provide a better perspective on the lines
of evidence in a given drug-disease association, thus helping to
determine whether an apparent association between a medicine
and an effect is likely to represent a causal relationship36 (Table III).
The first criterion, the strength of the association, refers to
the extent to which the risk of the disease is greater than that
resulting from chance alone37,38. Bisphosphonates substantially
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Flowchart illustrating the potential pathogenesis by which long-term bisphosphonate treatment may increase the risk of atypical femoral fractures.
increase the risk of atypical femoral fracture (with estimates of the
odds ratio ranging from 2.29 to 139.33)13,21,32,39. Almost 40% of
patients who sustained a subtrochanteric or femoral shaft frac-
ture had used bisphosphonates for a significantly longer period of
time than subjects who sustained an intertrochanteric or femoral
neck fracture (odds ratio = 4.44, p = 0.002)14. Despite these
results, reanalysis of the data in three major randomized con-
trolled trials showed no statistically significant increase in the risk
of subtrochanteric femoral fracture in patients treated with bis-
phosphonates for as long as ten years35. Given the mixture of
results and the different methodologies used in these studies, it
is difficult to demonstrate consistency of this association. Fur-
thermore, not all fractures located in the femoral subtrochanteric
or diaphyseal region of patients taking bisphosphonates are
atypical. Only 17% to 29% of subtrochanteric or diaphyseal
fractures can be classified as atypical fractures15. Additionally,
some atypical femoral fractures occur in patients who have
not taken bisphosphonates34,40. Therefore, there is a lack of spec-
ificity for associating bisphosphonate use with atypical femoral
fractures.
Studies have shown an increased risk of atypical femoral
fractures in patients taking bisphosphonates for five or more
years, suggesting a dose-response relationship13,14,39. Despite this,
an analysis of patients with skeletal malignant involvement who
received a minimum of twenty-four doses of intravenous bis-
phosphonates revealed no difference in the dosage or the du-
ration of therapy between those who sustained atypical femoral
fractures and those who did not41. The authors of the study cite
the lack of long-term follow-up as a limitation of their study
and their ability to draw conclusions about the long-term effects
of bisphosphonate usage41. Thus, there is no dose-response re-
lationship on the basis of higher bisphosphonate dosage; how-
ever, there appears to be a dose-response relationship on the
basis of the cumulative dose over time, which can be explained
by the fact that bisphosphonates bind to bone for many years42.
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The cause-effect relationship between bisphosphonate use
and atypical femoral fractures is plausible given the hypothesized
pathologic mechanisms involving bisphosphonate-induced mi-
crodamage accumulation, decreased spatial variation in the bone
mineral density distribution, and decreased bone heterogene-
ity43-46. In addition, the potential for a causal relationship be-
tween bisphosphonate use and the risk of atypical femoral
fractures is supported by analogous examples of drug-enhanced
fracture risk, including effects in patients taking corticosteroids,
antiepileptic drugs, and antidepressants47,48. Nevertheless, there is
a dearth of experimental evidence that supports the causation of
atypical femoral fractures in patients on bisphosphonate ther-
apy, and many of the studies are observational. On the basis of
the currently available data, a mechanistic cause-and-effect re-
lationship between bisphosphonate usage and atypical femoral
fractures has not been established.
Pathogenesis
V arious pathogenic mechanisms that could explain the re-
lationship between prolonged bisphosphonate therapy and
atypical femoral fractures have been the subject of extensive re-
search. Prolonged bisphosphonate treatment may be responsible
for deleterious effects on bone quality by inhibiting bone remod-
eling at the cellular level. Although increased bone remodeling
predisposes to bone fragility, overly suppressed bone remodeling
can also lead to microdamage accumulation and impaired stress-
fracture-healing, a reduction in matrix heterogeneity, and an in-
crease in advanced glycation end-products (Fig. 3).
Microdamage Accumulation and Impaired
Stress-Fracture-Healing
Bisphosphonates reduce the risk of fractures by suppressing
osteoclast-mediated bone resorption, thereby interrupting the
normally coupled resorption-formation process of bone re-
modeling. Since bone remodeling is essential for continuous
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TABLE IV Key Recommendations for Management of Patients with Atypical Femoral Fractures
Stop bisphosphonates
Consider an anabolic agent such as teriparatide
Calcium and vitamin-D supplementation
Identify any underlying metabolic bone diseases by laboratory investigations such as serum calcium, phosphate, 25-hydroxyvitamin D,
intact parathyroid hormone, thyroid-stimulating hormone, bone turnover markers, and 24-hour urine calcium
Intramedullary nailing is the preferred method of fixation
Assess the contralateral femur, especially in patients who have a history of thigh pain
bone renewal and repair of microdamage, severe suppression of
bone remodeling can lead to microdamage accumulation49,50. It
should be noted, however, that microdamage accumulation
alone does not explain the decline in bone toughness, as minimal
association between changes in microdamage accumulation and
bone toughness was found in preclinical studies51,52.
Studies on stress fractures induced in the rat ulna showed
that bisphosphonates impair stress-fracture-healing by reduc-
ing the volume of bone resorbed and replaced during the re-
modeling process53,54. Several clinical reports also showed that a
periosteal stress reaction and a transverse radiolucent line in-
dicative of stress fracture usually preceded the complete atyp-
ical fracture in patients taking bisphosphonates, indicating a
possible role for bisphosphonates in impaired stress-fracture-
healing55-57 (Fig. 4).
Reduced Heterogeneity of Organic Matrix
and Mineral Properties
Bone maintains its compositional heterogeneity through the
continuing process of bone remodeling. Heterogeneity of bone
A T Y P I C A L F E M O R A L F R A C T U R E S : W H AT D O W E
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matrix and mineral density is preferable to homogeneity. Com-
putational models of trabecular and cortical bone showed that
a heterogeneous tissue distribution reduces local stress and en-
hances energy dissipation58,59, whereas a homogeneous distri-
bution is associated with greater propensity for crack formation
and propagation, thereby increasing the risk of fracture60. By
inhibiting the process of bone remodeling, bisphosphonates lead
to a less heterogeneous structure with narrowed distributions
of mineral and collagen properties45,61,62. Boskey et al. found that
treatment with alendronate for three years increased tissue min-
eral content and decreased the spatial heterogeneity of mineral
properties of iliac crest tissue in healthy postmenopausal women
without fractures61. In addition, Donnelly et al. used Fourier
transform infrared (FTIR) imaging to compare the mineral and
collagen properties of corticocancellous bone biopsies from
forty patients diagnosed with proximal femoral fractures62. The
authors found that FTIR-measured parameters in the twenty
bisphosphonate-treated patients were similar to those in the
twenty patients who had not received bisphosphonate treat-
ment. However, the distributions of collagen maturity and crystal
Fig. 4
Figs. 4-A and 4-B Radiographs of a fifty-eight-year-
old postmenopausal Thai woman with an atypical
femoral fracture. Fig. 4-A An anteroposterior ra-
diograph of the proximal aspect of the femur re-
vealed an ellipsoidal thickening in the left
subtrochanteric region (arrow), compatible with a
chronic stress reaction of the lateral femoral
cortex. Fig. 4-B A complete fracture developed
from the stress reaction, creating a beak in the
cortex on one side (arrowhead). (Reproduced
from: Unnanuntana A, Kleimeyer JP. Osteoporo-
sis: risk factors, evaluation and management.
In: Peña AR, Perez VO, editors. Osteoporosis: risk
factors, symptoms and management.
Hauppauge, New York: Nova Science Publishers;
2012. This material is reproduced with permis-
sion of Nova Science Publishers, Inc.)
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Fig. 5
Fourier transform infrared (FTIR) images and associated pixel histograms with Gaussian fits of collagen maturity (Fig. 5-A) and crystallinity (Fig. 5-B) in
cortical bone treated (1BIS) and untreated (2BIS) with bisphosphonate. The mean and the full width at half maximum (FWHM) values of the Gaussian curve
are indicated on each histogram. (Reproduced from: Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DG, Lane JM,
Boskey AL. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and
subtrochanteric fractures. J Bone Miner Res. 2012;27(3):672-8. Copyright 2012 by the American Society for Bone and Mineral Research. This material is
reproduced with permission of John Wiley & Sons, Inc.)

perfection were narrowed by 28% and 17%, respectively, in the Management

bisphosphonate-treated patients compared with those without
a history of bisphosphonate therapy (Fig. 5).
Increased Advanced Glycation End-Products
Collagen in the extracellular bone matrix contains both enzy-
matic and nonenzymatic crosslinks63. Enzymatic crosslinks, me-
diated by the actions of lysyl and prolyl hydroxylases, have a
substantial impact on bone mechanical properties and are es-
sential to stabilize the bone matrix. Nonenzymatic crosslinks
are formed through the interaction of collagen and sugars in a
series of glycation and oxidation reactions, leading to the for-
mation of advanced glycation end-products64,65. Bisphosphonate
treatment increased advanced glycation end-products in the ribs
of dogs66, and such an increase has been associated in animals
with deleterious effects on bone mechanical properties, in-
cluding a lower threshold of energy to fracture 67.
The bulk of evidence on the pathogenesis of these atypical
fractures stems from animal models, with few studies of human
bone. Furthermore, multiple biomechanical considerations and
patient risk factors may play a role in the pathogenesis of these
fractures. The subtrochanteric region of the femur is subjected
to the greatest tensile loading68. It is possible that Asian pop-
ulations have a higher risk of developing these fractures because
of their greater femoral bowing29,69. Patients with atypical frac-
tures may also have a preexisting defect in bone quality that is
exacerbated by bisphosphonate use. Therefore, an atypical
femoral fracture should be considered pathologic, and fur-
ther work-up is warranted to identify an underlying skeletal
abnormality.
T he management of atypical femoral fractures requires a
specific protocol that includes both medical and surgical
treatment. Because we are aware of no prospective controlled
studies evaluating treatment protocols in patients with atypical
femoral fractures, the guidelines proposed in this article are
based on the recommendations outlined by the ASBMR task
force and several recently published case series.
Management of Patients with Atypical Femoral Fractures
Management of patients with atypical femoral fractures in-
cludes fracture fixation and initiation of medical management
(Table IV). Once a patient is diagnosed with an atypical femoral
fracture, bisphosphonates must be discontinued. In a large ob-
servational study including a total of 126 patients with atypical
femoral fractures, the incidence of bilateral atypical femoral
fractures was 41.2% in patients who continued bisphospho-
nates for three or more years after the index atypical femoral
fracture compared with 19.3% in patients who continued bis-
phosphonates for less than three years after the index atypical
femoral fracture70. The risk of a contralateral atypical femoral
fracture decreased by approximately 53% (p = 0.042) if bis-
phosphonates were discontinued after the index atypical fem-
oral fracture70.
In addition, all patients should receive daily calcium and
vitamin-D supplementation. Recommendations for optimal
treatment include a daily calcium intake of 1000 to 1200 mg/
day71. Although current recommendations from the Institute of
Medicine state that 400 to 800 IU/day of vitamin D3 is adequate71,
many experts and studies have shown these recommendations
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Fig. 6
Figs. 6-A, 6-B, and 6-C Radiographs of a sixty-five-year-old woman with a history of alendronate treatment for five years. Fig. 6-A An atypical femoral fracture
on the right side was diagnosed. Fig. 6-B There were no signs of fracture-healing at seven months after the initial fixation with a cephalomedullary nail, and a
diagnosis of nonunion was made (arrow). Fig. 6-C Revision of the internal fixation was performed with a fibular strut allograft and plate fixation. The patient
also received teriparatide along with calcium and vitamin-D supplementation. A postoperative radiograph at one year after the revision surgery revealed a
healed fracture (arrow).

to be insufficient72-74. The minimum adult intake of vitamin D3
should be 1000 to 2000 IU/day75. Recombinant parathyroid
hormone (teriparatide) should also be considered, especially as
there is evidence to suggest that teriparatide improves bone
turnover and microarchitecture in patients on long-term alendro-
nate treatment76,77. Furthermore, teriparatide enhances and ac-
celerates fracture-healing by increasing callus formation and
mechanical strength78-82. Additional clinical trials also showed
that teriparatide shortened the time to healing in patients with
osteoporotic fractures83,84. Therefore, teriparatide may be bene-
ficial to enhance fracture-healing in patients with atypical fem-
oral fractures.
Although there are no randomized controlled trials com-
paring a plate-and-screw construct and intramedullary nail fix-
ation for the treatment of atypical femoral fractures, most
orthopaedic surgeons recommend an intramedullary full-length
reconstruction nail as the preferred method of treatment. A
fracture treated by intramedullary nailing heals by endo-
chondral repair, whereas a plate-and-screw construct generally
precludes the endochondral repair process and is not recom-
mended for these fractures. The outcome of surgical treatment
in patients with bisphosphonate-related atypical femoral frac-
tures is poor (Fig. 6). Weil et al. showed that seven (44%) of six-
teen fractures treated with intramedullary nail fixation required
secondary operative procedures85. Although some studies sug-
gested a potential negative effect of bisphosphonates on the
fracture-healing process, current evidence shows conflicting re-
sults17,57,86,87. Visekruna et al. reported on three patients with
atypical subtrochanteric fractures, one of whom had no radio-
graphic evidence of union at twenty-two months17. Conversely,
Ha et al. reported that ten atypical femoral fractures all healed,
with osseous union after internal fixation during the follow-up
period of twelve to sixty months57. These differing results may
be due to differences in preoperative status and in the medi-
cation type or dose used in these patients.
We recommend careful surveillance of patients with atyp-
ical femoral fractures because 28% to 44.2% of patients with
atypical femoral fractures have bilateral involvement15,22,29. Ra-
diographs of the contralateral femur must be evaluated for
evidence of a stress fracture. Technetium bone scintigraphy or
magnetic resonance imaging (MRI) should be considered if a
stress fracture is suspected (Fig. 7).

Fig. 7
Figs. 7-A and 7-B Imaging studies showing stress
fractures of the femur. Fig. 7-A Technetium bone
scintigraphy revealed increased tracer uptake
in the femoral shaft on both sides. Fig. 7-B
Magnetic resonance imaging showed an in-
creased intensity around the subtrochanteric
region of the left femur. An ellipsoidal cortical
thickening was also noted at this region (arrow).
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Fig. 8
A proposed guideline for management of patients with atypical femoral fractures.
If the patient has an incomplete fracture with no or
minimal pain, a period of conservative therapy may be con-
sidered. This includes partial weight-bearing with use of a
cane, crutches, or walker; avoidance of strenuous activity; and
the use of teriparatide. The failure rate of this conservative
treatment, however, is high56,57. Banffy et al. reviewed patients
with nondisplaced stress fractures that were initially treated
nonoperatively. Five of six patients had progression of the
lesion to complete fracture at a mean of ten months56. Thus,
close monitoring is necessary in this particular group of pa-
tients. Prophylactic intramedullary nail fixation should be con-
sidered when there is moderate to severe pain in the affected
limb, persistent or worsening pain after a period of conservative
A T Y P I C A L F E M O R A L F R A C T U R E S : W H AT D O W E
KNOW ABOUT THEM?
treatment, or progression of the fracture line observed on serial
radiographs57 (Fig. 8).
Management of Patients with Prolonged
Bisphosphonate Therapy
Once administered, bisphosphonates accumulate in the bone
and continue to be released for months or years after treatment
is discontinued. Data from the Fracture Intervention Trial Long-
term Extension (FLEX) study showed that the fracture risk in
postmenopausal women who discontinued alendronate after
five years of treatment was not higher than in those who con-
tinued alendronate for a total of ten years, despite a moderate
decline in bone mineral density at both the spine and femoral
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d d
Fig. 9
A proposed guideline for management of patients on prolonged bisphosphonate treatment.
neck and a rise in bone markers in the former1. For risedronate,
the extension of the Vertebral Efficacy with Risedronate Therapy
(VERT)-North America study showed that one year after dis-
continuation of a three-year protocol of risedronate treatment,
bone mineral density decreased (but remained higher than
baseline and higher than in the former placebo subjects) and
bone turnover markers increased (to levels no different from
those in the former placebo subjects). Despite these changes,
the incidence of new morphometric vertebral fractures was
46% lower in the former risedronate group compared with
the former placebo group88. This information supports the
hypothesis that there is continued release of bisphosphonate
from bone resulting in statistically significant and clinically
important fracture prevention following discontinuation of
bisphosphonates. Thus, there may be some lingering effects
on bone even after bisphosphonates are discontinued.
Because of a concern regarding oversuppression of bone
turnover with prolonged bisphosphonate therapy, it is recom-
mended that osteoporosis treatment with bisphosphonates be
stopped after a period of five years to provide patients a so-called
‘‘drug holiday.’’ The duration of bisphosphonate treatment and
the length of the drug holiday are based on fracture risk and the
pharmacokinetics of the bisphosphonate used89. The four bis-
phosphonates commonly used in clinical practice (alendronate,
risedronate, ibandronate, and zoledronate) have different bind-
ing affinities and different antiresorptive potencies, depending on
their side chains. The order of binding affinity to bone, from
highest to lowest, is zoledronate, alendronate, ibandronate, and
risedronate90, whereas the order of potency for inhibiting the
enzyme farnesyl pyrophosphate synthase, from highest to lowest,
is zoledronate, risedronate, ibandronate, and alendronate91. Be-
cause of the differences in binding affinity and antiresorptive
A T Y P I C A L F E M O R A L F R A C T U R E S : W H AT D O W E
KNOW ABOUT THEM?
potency, each bisphosphonate has a unique profile of the speed of
onset and offset of its effect, as well as a unique degree of bone
turnover suppression. Park-Wyllie et al. performed a nested case-
control study to explore the association between bisphosphonate
use and femoral fractures, and they reported that bisphosphonate
treatment of more than five years was associated with an in-
creased risk of atypical subtrochanteric or femoral shaft fractures
(adjusted odds ratio = 2.74; 95% CI, 1.25 to 6.02)39. Therefore, it
may be appropriate to consider a drug holiday in patients with a
cumulative duration of bisphosphonate treatment of more than
five years.
By stratifying patients on the basis of the fracture risk, a
logistic approach to providing management guidelines for pa-
tients with prolonged bisphosphonate use can be established
(Fig. 9). Although there are no clear criteria to define the risk of
fracture, fracture risk can be estimated with use of the World
Health Organization’s fracture risk assessment tool (FRAX)
as well as bone turnover markers92. For patients at low risk of
fracture, bisphosphonates can be discontinued and the patients
placed on a drug holiday. Patients should nevertheless take daily
calcium and vitamin-D supplements. For those at high risk
of fracture, it may be beneficial to continue bisphosphonate
treatment beyond five years. Alternatively, other medications
such as denosumab or teriparatide may be provided during the
holiday from bisphosphonates. For patients at moderate risk of
fracture, the management plan can be further divided on the
basis of the bone turnover state (low and high-turnover states).
Patients who are at moderate risk of fracture and in a low-
turnover state can be managed in a fashion that is similar to
those at low risk of fracture. However, patients who are at
moderate risk but in a high-turnover state should be managed
as if they have high risk of fracture (Fig. 9). In general, the drug
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holiday should be continued until there is substantial loss of
bone mineral density, marked increase in bone turnover
markers, or the occurrence of a new fracture89.
Given that the incidence of atypical femoral fractures is
low and the actual incidence of abnormal radiographic features
in the entire patient population taking bisphosphonates is not
known, it may not be appropriate to screen all patients with a
history of prolonged bisphosphonate treatment by means of ra-
diographs of the femur. Nevertheless, the development of groin
or thigh pain in a patient on long-term bisphosphonate treat-
ment should raise the index of suspicion of an atypical femoral
fracture, particularly if the patient has a history of rheumatoid
arthritis, diabetes, or exposure to glucocorticoid therapy11,12.
Further work-up with serial radiography, bone scintigraphy,
and MRI should be considered in this setting to facilitate the
early diagnosis of bone fragility.
Summary
T he causal relationship between prolonged bisphosphonate
use and the occurrence of atypical femoral fractures has
not yet been established. If a patient sustains an atypical femoral
fracture, bisphosphonates must be stopped and an anabolic
agent should be employed. These patients should also have daily
calcium and vitamin-D supplementation. As fractures treated
by intramedullary nailing heal by endochondral repair, such
nailing is a preferred method of fixation for atypical femoral
fractures. Atypical femoral fractures are relatively rare events,
and the balance between patient efficacy and safety still favors
bisphosphonate therapy for the treatment of osteoporosis. Bis-
phosphonates appear to have lingering efficacy against fractures
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Aasis Unnanuntana, MD
Department of Orthopaedic Surgery,
Siriraj Hospital, Mahidol University,
2 Prannok Road, Bangkoknoi District,
Bangkok 10700, Thailand.
E-mail address: uaasis@gmail.com
Anas Saleh, MD
Kofi A. Mensah, MD, PhD
Joseph M. Lane, MD
Department of Orthopaedic Surgery,
Hospital for Special Surgery,
523 East 72nd Street,
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