The n e w e ng l a n d j o u r na l
original article
From the Department of Experimental
and Clinical Medicine, Faculty of Health
Science, Linköping University, Linköping
(J.S., P.A.); and the Department of Surgi-
cal Sciences, Section of Orthopedics,
and Uppsala Clinical Research Center,
Uppsala University, Uppsala (K.M.) —
both in Sweden. Address reprint requests
to Dr. Aspenberg at the Department of
Experimental and Clinical Medicine, Fac-
ulty of Health Sciences, Linköping Uni-
versity, SE-581 85 Linköping, Sweden, or
at per.aspenberg@liu.se.
Drs. Schilcher and Michaëlsson contrib-
uted equally to this article.
This article (10.1056/NEJMoa1010650) was
last updated on August 9, 2012, at NEJM
.org.
N Engl J Med 2011;364:1728-37.
Copyright © 2011 Massachusetts Medical Society.
1728
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of m e dic i n e
Bisphosphonate Use and Atypical Fractures
of the Femoral Shaft
Jörg Schilcher, M.D., Karl Michaëlsson, M.D., Ph.D.,
and Per Aspenberg, M.D., Ph.D.
A bs t r ac t
Background
Studies show conflicting results regarding the possible excess risk of atypical frac-
tures of the femoral shaft associated with bisphosphonate use.
Methods
In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur
in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochan-
teric or shaft fracture and identified 59 patients with atypical fractures. Data on
medications and coexisting conditions were obtained from national registries. The
relative and absolute risk of atypical fractures associated with bisphosphonate use
was estimated by means of a nationwide cohort analysis. The 59 case patients were
also compared with 263 control patients who had ordinary subtrochanteric or shaft
fractures.
Results
The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval
[CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per
10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10%
of the controls had received bisphosphonates, corresponding to a multivariable-
adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of co-
existing conditions and of concurrent use of other drugs with known effects on bone.
The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI,
1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the
last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38).
Conclusions
These population-based nationwide analyses may be reassuring for patients who
receive bisphosphonates. Although there was a high prevalence of current bisphos-
phonate use among patients with atypical fractures, the absolute risk was small.
(Funded by the Swedish Research Council.)
n engl j med 364;18 nejm.org may 5, 2011
The New England Journal of Medicine
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 Bisphosphonate Use and Atypical Fr actures
B
isphosphonates reduce the overall
risk of fracture among patients with osteo-
porosis, with a long-lasting beneficial ef-
fect.1 However, since bisphosphonates reduce bone
remodeling, they might “freeze” the skeleton, al-
lowing accumulation of microcracks over time,
leading to fatigue fractures (also called stress frac-
tures).2 Fatigue fractures are well known in me-
chanical engineering, and they occur with age and
overload in many materials. They result from the
slow propagation of cracks, resulting in a peculiar
appearance. In bone, their appearance is charac-
terized by a straight fracture line running perpen-
dicularly to tractional forces. Such fractures are
not uncommon in athletes, and if they are not
displaced, they heal slowly with minor external
bone formation, often appearing as cortical thick-
ening.
Stress fractures in compact bone occur at sites
with high tensional stress, such as the lateral
cortex of the proximal femoral shaft; this site
corresponds to the locations of reported bisphos-
phonate-associated atypical fractures.2-11 In pub-
lished case reports that classified femoral frac-
tures as stress fractures or nonstress fractures
according to their radiographic appearance, among
patients admitted to tertiary centers, such stress
fractures (commonly called atypical femoral frac-
tures, the term used here) were more common
in patients who received bisphosphonates than
in those who did not.3,7 A large proportion of
patients who were receiving bisphosphonate treat-
ment and who had atypical fractures did, how-
ever, also receive other medications, especially
systemic glucocorticoids and proton-pump inhibi-
tors. This finding has prompted the suggestion
that these two types of drugs, in addition to be-
ing markers of coexisting conditions, are impor-
tant contributors to the risk of the development
of atypical femoral fractures.9,10
In contrast, an association between atypical
fractures and bisphosphonate use was not shown
in nationwide cohort analyses based on registry
identification of “atypical” femoral fractures or
in randomized trials in which the classification
of fractures was based on radiologic reports.12-14
It might be that either the case series were bi-
ased or the registry studies and the randomized
studies did not identify a sufficient number of
atypical fractures accurately. We reviewed radio-
graphs of all femoral subtrochanteric and shaft
fractures that occurred in 2008 in the entire popu-
n engl j med 364;18
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
lation of Sweden. Individual linkage of these frac-
ture cases to national registries allowed both a
nationwide cohort analysis and a population-based
case-control study to elucidate the relation be-
tween atypical femoral fractures and bisphospho-
nate use.
Me thods
Study Population
In 2008, according to the National Swedish Pa-
tient Register, 12,777 women 55 years of age or
older sustained a fracture of the femur (Fig. 1).
Of these women, 1271 had a femoral subtro-
chanteric or shaft fracture (International Classifi-
cation of Diseases, 10th Revision [ICD-10] diagnosis
code S722 or S723 with external-cause code W
[i.e., excluding any type of transportation acci-
dent]). Digitized radiographs from 1234 patients
were obtained from the involved hospitals. The
remaining 37 case patients were excluded be-
cause of an insufficient quality of the radiographs
(30 patients) or because the radiographs were
not available (7 patients). The study was approved
by the regional ethics committee, and patients
were enrolled without consent being obtained.
The 1234 radiographs were reviewed and clas-
sified according to the pattern of fractures, as
described below. After the fractures were classi-
fied, data on drug use and inpatient and outpa-
tient care were obtained from registries of the
Swedish National Board of Health and Welfare.
The Swedish Prescribed Drug Register contains
data on all prescriptions dispensed to the entire
Swedish population (approximately 9 million in-
habitants) from July 2005 onward. The Swedish
National Patient Register contains discharge di-
agnoses for hospitalizations in Sweden, with com-
plete coverage since 1987.15 This registry also
contains data on outpatient visits since 2001. Com-
plete linkage between the registries is possible
through the use of the personal identification
number provided to all Swedish citizens.
Classification of Fractures
Patients who were identified in the National Swed-
ish Patient Register as having subtrochanteric or
shaft fractures were categorized into four major
groups. The first group included 47 patients with
typical stress fractures that were transverse on
the lateral side without intermediate fragments,
together with thickening of the lateral cortex at
nejm.org may 5, 2011 1729
 The n e w e ng l a n d j o u r na l of m e dic i n e

1,521,131 Women 55 yr or older in 2008 were eligible

for the study, bisphosphonate use, 5%

12,777 Had fractures of the femur,

bisphosphonate use, 11%

6254 Had femoral- 4664 Had trochan- 1351 Had subtrochanteric or shaft 435 Had distal 73 Had other type
neck fractures teric fractures fractures from any cause, fractures of fractures
bisphosphonate use, 17%

1271 Had fractures because of falls and were

included in blinded radiographic classification

37 Were excluded because radiographs were

not available or were of bad quality
912 Had fractures that were not relevant for
comparison with stress fractures
625 Had trochanteric or condylar fractures
238 Had fractures associated with implants
16 Had pathologic fractures
24 Had femoral-neck fractures
9 Did not have femoral fractures

59 Had atypical fractures, 263 Had control fractures,

bisphosphonate use, 78% bisphosphonate use, 10%

Figure 1. Identification of Stress (Atypical) Fractures in the Study Population.

the fracture site. The fracture did not involve the
trochanteric or the condylar area. The femur did
not have implants, and the fracture was not patho-
logic. The second group included 12 patients with
suspected stress fractures. These fractures were
the same as those described in the first group,
but without clear thickening of the lateral cortex
or with a separate intermediate fracture fragment.
The third group included 263 control patients
with fractures that did not appear to be stress
fractures but were relevant for comparison with
stress fractures. None of the shaft fractures were
transverse on the lateral side, and there was no
trochanteric or condylar engagement, except for
minor trochanteric fracture extensions. There were
no implants or pathologic fractures. The fourth
group included 912 patients with fractures that
were not relevant for comparison with stress frac-
tures. Of these fractures, 625 were associated with
major involvement of a trochanter or distal con-
dyle, 238 were associated with implants, and 16
were pathologic. This last group also included 24
femoral-neck fractures and 9 fractures that were
not femoral.
During the revision of this article, a consen-
sus document was published in which stress frac-
tures without cortical thickening were defined as
“atypical.”16 We therefore analyzed the first two
groups together (Fig. 1).
After completion of our analysis, we reviewed
all the routine radiologic reports. These reports
mentioned a transverse fracture in 23 of the 59
case patients and a fatigue (also called stress or
insufficiency) fracture or an atypical fracture pat-
tern in only 1 case patient. The remainder men-
tioned only the location of fractures.

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 Bisphosphonate Use and Atypical Fr actures

Before the retrieval of registry information, was treated as a continuous variable and in cate-
72 of the 1234 fractures (including 22 atypical gories (<1.0 year, 1.0 to 1.9 years, or ≥2.0 years
fractures) were randomly selected for reclassifi- since the end of treatment). The use or nonuse of
cation by one of the authors who was not in- systemic glucocorticoids, estrogen-replacement
formed about the previous categorization or the ther­apy, selective estrogen-receptor modulators,
number of atypical fractures in the sample. There antiepileptic drugs, antidepressants, or proton-
was complete agreement between the two clas- pump inhibitors was categorized into separate
sifications. marker variables. Diseases that were diagnosed
before the fractures occurred were identified from
Statistical Analysis the Swedish National Patient Register (as ICD-10
Cohort Study codes) and defined as present or not present.
All 1.5 million women who were 55 years of age From these registry data, the Charlson comorbid-
or older and who were residents of Sweden in ity index score was calculated.18 Odds ratios with
2008 according to data from Statistics Sweden 95% confidence intervals were calculated by means
were included as a reference population in a co- of unconditional logistic regression and used as
hort analysis. Of these women, 83,311 received measures of association for the relative risk of
bisphosphonates and 59 had atypical fractures. atypical fracture with bisphosphonate use. Age-
Age was divided into 5-year strata, and the age of adjusted odds ratios (with age as a continuous
patients who were older than 90 years of age was variable) and odds ratios additionally adjusted ac-
an additional category. Age-stratified incidence cording to use or nonuse of glucocorticoids and
proportions of atypical fractures were calculated the Charlson comorbidity index score (a continu-
for women who received bisphosphonates and for ous variable) were determined. Odds ratios changed
women with no reported use of bisphosphonates; little after adjustment for the use of estrogen ther-
these calculations were used to estimate both the apy, antiepileptic agents, antidepressants, or pro-
age-adjusted relative risk and the absolute risk of ton-pump inhibitors. We also performed strati-
atypical fracture (with 95% confidence intervals17) fied analyses according to the use or nonuse of
in the total population. The duration of bisphos- glucocorticoids, the use or nonuse of proton-pump
phonate use and the time since the last use were inhibitors, or age, with a test for homogeneity
considered in three categories (<1.0 year, 1.0 to between strata.17
1.9 years, and ≥2.0 years). In addition, similar
nationwide cohort analyses were performed, al- R e sult s
beit with only registry identification of catego-
ries of femoral fractures according to ICD-10 Cohort Study
codes, as described by Abrahamsen et al.12 Of all 12,777 women with a fracture of the femur,
we identified 59 with atypical fractures (Fig. 1).
Case–Control Study The incidence proportion of atypical fracture
The case patients with atypical fractures were com- among users and nonusers of bisphosphonates
pared with the 263 control patients who had frac- in the entire Swedish population is shown in
tures in a similar location. To reduce the risk of Table 1. The age-adjusted relative risk of atypical
selection bias, these control patients were select- fracture with any use of bisphosphonates was
ed because they were representative of the popu- 47.3 (95% confidence interval [CI], 25.6 to 87.3).
lation of patients with underlying vulnerability to The difference in the risk of atypical fracture be-
fractures. All drug exposures were analyzed in re- tween users and nonusers of bisphosphonates was
lation to the date of fracture. Bisphosphonate use 5 cases (95% CI, 4 to 7) per 10,000 patient-years,
before the fracture was categorized according to corresponding to an average number needed to
the type of bisphosphonate. The total duration of harm (i.e., the number of bisphosphonate users
bisphosphonate use was estimated according to needed for one case of fracture to occur) of 2000
defined daily doses from July 2005 to the date of per year of use. The risk was higher with a longer
the fracture, excluding periods of nonuse. The duration of use. Most bisphosphonate users with
duration of use was analyzed both as a continu- atypical fractures had a history of recent use.
ous variable and in categories (<1.0 year, 1 to 1.9 Bisphosphonate users also had a higher rela-
years, and ≥2.0 years). The time since the last use tive risk of registry-identified fractures of the

n engl j med 364;18 nejm.org may 5, 2011 1731

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Risk of Atypical Femoral Fracture Associated with Bisphosphonate Use during the 3 Years (2005–2008)
Preceding the Fracture.*

Age-Adjusted Age-Adjusted
No. of Relative Risk Absolute Risk
Variable Women Cases of Atypical Fracture (95% CI) (95% CI)
No. of Atypical
Fracture Cases Crude Incidence
no./10,000 patient-yr
Bisphosphonate use
Never 1, 437,820 13 0.09 1.0 (reference)
Ever 83,311 46 5.5 47.3 (25.6–87.3) 0.0005 (0.0004–0.0007)
Duration of use
<1.0 yr 15,672 3 1.9 18.4 (5.3–64.3) 0.0002 (0.0000–0.0004)
1.0–1.9 yr 21,406 4 1.9 17.0 (5.7–50.7) 0.0002 (0.0000–0.0004)
≥2.0 yr 46,233 39 8.4 67.0 (35.8–125.8) 0.0008 (0.0006–0.0011)
Time since last use
<1.0 yr 83,311 42 5.0 42.9 (22.9–80.4) 0.0005 (0.0004–0.0007)
1.0–1.9 yr 70,036 1 0.1 3.5 (1.0–11.9) <0.0001 (0.0000–0.0000)
≥2.0 yr 75,583 3 0.4 3.2 (1.0–10.1) <0.0001 (0.0000–0.0001)

* CI denotes confidence interval.

hip (relative risk, 1.32; 95% CI, 1.25 to 1.40), the
subtrochanteric region alone (relative risk, 1.80;
95% CI, 1.50 to 2.17), and the femoral shaft (rela-
tive risk, 3.83; 95% CI, 3.08 to 4.78) as compared
with persons who did not receive bisphosphonates
(Table 2). After exclusion of irrelevant fractures
and atypical fractures in the subtrochanteric and
shaft regions by our review of radiographs, the
relative risk of other types of fractures (i.e., in
the controls in our case–control study) was 1.27
(95% CI, 0.85 to 1.90) — an estimate similar to
that for hip fractures (Table 2).
Case–Control Study
The characteristics of the study participants are
listed in Table 3. Case patients with atypical frac-
tures were younger than control patients. Case
patients were also less frequent users of antide-
pressants and were less likely to have sustained a
previous osteoporotic or hip fracture, even after
adjustment for the age difference. A greater pro-
portion of the bisphosphonate users (both cases
and controls) had received systemic glucocorti-
coids and had a diagnosis of osteoporosis or in-
flammatory joint disease.
Of the case patients, 78% had received bisphos-
phonates (81% of the women with stress fractures
and 67% of the women with suspected stress
fractures), as compared with 10% of the controls
(Table 4). This finding corresponds to a multi-
variable-adjusted odds ratio of 33.3 (95% CI, 14.3
to 77.8), with a similar estimate for women who
had received alendronate and risedronate. No
atypical fractures were associated with etidronate,
but few women received this bisphosphonate. At
the time of the latest prescription, bisphospho-
nates were predominantly taken once a week (in
83% of the women) or daily. None of the patients
received injections.
The risk of an atypical fracture was higher
with an increasing duration of bisphosphonate
use, with an odds ratio of 1.3 (95% CI, 1.1 to 1.6)
per 100 prescribed daily doses. This risk was ap-
proximately 10 times as high as a normal level of
risk within the first 2 years of use and 50 times as
high thereafter (Table 4). The data did not suggest
that the risk continued to increase with a longer
duration of treatment. In Sweden, patients renew
their prescriptions every 3 months. Therefore, in
an additional analysis, we excluded women who
received prescriptions for bisphosphonates dur-
ing the first 3 months after the initiation of the
Swedish Prescribed Drug Register in order to spe-
cifically evaluate the association in women who
had drug exposure for 2.0 to 2.9 years. Of these
women, 14 of 17 were case patients with atypi-
cal fractures, corresponding to a multivariable-­
adjusted odds ratio of 61.7 (95% CI, 14.0 to 272.6).

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 Table 2. Risk of Fracture Associated with the Use of Bisphosphonates.*

Age-Adjusted Age-Adjusted
Bisphosphonate Users Nonusers of Bisphosphonates Relative Risk Absolute Risk
Variable (N = 83,311) (N = 1,437,820) (95% CI) (95% CI)
No. of No. of
Fracture Crude Fracture Crude
Cases Incidence Cases Incidence
no./10,000 no./10,000
patient-yr patient-yr
Diagnosis from registry data
Any hip fracture, ICD-10 code S720, S721, or S722 1255 151 10,585 74 1.32 (1.25–1.40) 0.0036 (0.0028–0.0045)

n engl j med 364;18

Femoral-neck fracture, ICD-10 code S720 599 72 5,655 39 1.19 (1.09–1.29) 0.0011 (0.0005–0.0017)
Trochanteric fracture, ICD-10 code S721 528 63 4,136 29 1.41 (1.29–1.54) 0.0018 (0.0013–0.0024)
Subtrochanteric fracture, ICD-10 code S722 128 15 794 5.5 1.80 (1.50–2.17) 0.0007 (0.0004–0.0009)

nejm.org
Femoral-shaft fracture, ICD-10 code S723 105 13 324 2.3 3.83 (3.08–4.78) 0.0009 (0.0009–0.0012)
Subtrochanteric or femoral-shaft fracture 233 28 1,118 7.8 2.34 (2.03–2.70) 0.0016 (0.0012–0.0019)
After radiographic classification

may 5, 2011

The New England Journal of Medicine

Subtrochanteric or femoral-shaft fracture, with atypical 26 3 237 1.6 1.27 (0.85–1.90) 0.0001 (0.0000–0.0002)
fractures excluded
Bisphosphonate Use and Atypical Fr actures

Subtrochanteric or femoral-shaft fracture, with atypical 72 8.6 250 1.7 3.39 (2.61–4.39) 0.0006 (0.0004–0.0008)
fractures included
Atypical fracture 46 5.5 13 0.09 47.3 (25.6–87.3) 0.0005 (0.0004–0.0007)

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

* ICD-10 denotes International Classification of Diseases, 10th Revision.

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1733
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Characteristics of the Case Patients and Controls.*

Variable Case Patients (N = 59) Controls (N = 263)

Bisphosphonate Nonusers of Bisphosphonate Nonusers of
Users Bisphosphonates Users Bisphosphonates
(N = 46) (N = 13) (N = 26) (N = 237)
Age─— yr 75.1± 9.5 76.2±11.9 80.0±8.0 83.7± 9.4
Drug use — no. (%)
Glucocorticoid 17 (37) 2 (15) 11 (42) 26 (11)
Estrogen 12 (26) 3 (23) 5 (19) 42 (18)
Selective estrogen-receptor modulator 0 0 0 0
Antidepressants 6 (13) 3 (23) 11 (42) 79 (33)
Antiepileptic agents 4 (9) 1 (8) 2 (8) 19 (8)
Proton-pump inhibitors 18 (39) 5 (38) 11 (42) 61 (26)
Previous diagnoses — no. (%)
Any fracture 18 (39) 4 (31) 13 (50) 104 (44)
Osteoporotic fracture 7 (15) 3 (23) 11 (42) 85 (36)
Hip fracture 3 (7) 2 (15) 5 (19) 57 (24)
Musculoskeletal disease 22 (48) 4 (31) 13 (50) 52 (22)
Inflammatory joint disease 3 (7) 0 3 (12) 1 (<1)
Osteoporosis 3 (7) 0 3 (12) 2 (1)
Cardiovascular disease 15 (33) 3 (23) 15 (58) 116 (49)
Ischemic heart disease 8 (17) 1 (8) 8 (31) 33 (14)
Stroke 2 (4) 0 0 24 (10)
Endocrine disorder 2 (4) 1 (8) 5 (19) 56 (24)
Diabetes mellitus 1 (2) 0 4 (15) 25 (11)
Cancer 7 (15) 1 (8) 3 (12) 28 (12)
Neurologic disorder 3 (7) 0 3 (12) 40 (17)
Psychiatric disorder 2 (4) 0 4 (15) 38 (16)
Kidney or urinary disease 8 (17) 2 (15) 5 (19) 72 (30)
Gastrointestinal disease 9 (20) 4 (31) 8 (31) 61 (26)
Respiratory disease 4 (9) 1 (8) 6 (23) 37 (16)

* Plus–minus values are means ±SD.

Most atypical fractures associated with bisphos-
phonate use occurred within 1 year after the last
prescription. There was a 70% reduction in risk
for every year since the last use (multivariable-
adjusted odds ratio, 0.28; 95% CI, 0.21 to 0.38).
The risk reduction was similar if the bisphospho-
nates had been prescribed for less than 2 years
(odds ratio, 0.45; 95% CI, 0.26 to 0.76) or for
2 years or more (odds ratio, 0.26; 95% CI, 0.19
to 0.35).
The association between the risk of atypical
fracture and bisphosphonate use was not increased
among users of glucocorticoids or proton-pump
inhibitors as compared with nonusers (see the
Table in the Supplementary Appendix, available
with the full text of this article at NEJM.org).
The increase in risk associated with bisphospho-
nate use was similar for women younger than 85
years and those 85 years of age or older.
Discussion
These population-based nationwide analyses
should be reassuring for bisphosphonate users.
Although there was a high prevalence of current
bisphosphonate use among patients with atypi-

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 Bisphosphonate Use and Atypical Fr actures

Table 4. Odds Ratios for Atypical Femoral Fractures Associated with Bisphosphonate Use.*

Case
Patients Controls
Variable (N = 59) (N = 218) Odds Ratio (95% CI)
Age-Adjusted Multivariable-Adjusted†
Bisphosphonate use
Never 13 195 1.0 (reference) 1.0 (reference)
Ever 46 23 24.6 (11.3–55.5) 33.2 (13.6–80.9)
Type of bisphosphonate
Alendronate 38 16 31.2 (13.5–72.0) 36.8 (14.6–92.7)
Risedronate 6 4 15.5 (3.6–65.9) 32.4 (5.5–192.0)
Etidronate 0 4 NA NA
Ibandronate 2 0 NA NA
Risk of fracture per 100 defined daily doses NA NA 1.4 (1.2–1.6) 1.3 (1.1–1.6)
Duration of use
<1.0 yr 3 6 6.0 (1.2–29.4) 9.9 (1.7–55.8)
1.0–1.9 yr 4 6 5.3 (1.2–23.6) 7.7 (1.6–36.2)
≥2.0 yr 39 11 47.7 (19.1–119.1) 52.0 (19.7–137.4)
Time since last use
<1.0 yr 42 15 37.0 (15.8–86.9) 42.8 (16.8–108.9)
1.0–1.9 yr 1 3 2.8 (0.2–31.4) 5.7 (0.5–69.3)
≥2.0 yr 3 5 5.7 (1.1–30.0) 9.4 (1.7–52.6)
Risk of fracture per yr since last use NA NA 0.31 (0.23–0.41) 0.29 (0.22–0.40)

* NA not applicable.
† Variables were adjusted for age (as a continuous variable), use or nonuse of a glucocorticoid, and Charlson index score (as a
continuous variable).

cal fractures, the magnitude of the absolute risk
was small. With a correct indication, the benefits
of fracture prevention with bisphosphonate use
will greatly outweigh the risk of atypical femoral
fracture (i.e., the numbers needed to treat14 will
be lower than the numbers needed to harm).
The risk appeared to be unrelated to the use
of systemic glucocorticoids and other drugs with
effects on bone and was independent of coexist-
ing conditions and age. Previous nationwide pop-
ulation-based studies and randomized trials have
shown only modest site-specific increases in the
risk of femoral fractures with bisphosphonate
use.12-14 The use of registry classification alone
enabled us to confirm these results.12,13 The in-
creased risks of femur fracture, irrespective of
fracture location, that were associated with bis­
phosphonate use are probably the consequence
of osteoporosis.12 The relative risk with bisphos-
phonate use among our controls who had radio-
logically defined fractures of the femoral shaft
was similar to the risk of hip fractures, indicat-
ing a similar and somewhat increased base risk
of femur fracture in this fracture-prone subpopu-
lation. Earlier studies relied on registry data or
hospital records, whereas the present investiga-
tion used reclassification of fractures according
to radiographs. The specific radiographic classifi-
cation is important, since our analysis shows that
the rare atypical femoral fracture will be over-
shadowed by other types of fractures in registry
studies, impeding the detection of their associa-
tion with bisphosphonates.
Our results appear to contrast with those of a
recent reanalysis of three randomized trials14 in
which 10 patients with fractures that were located
at the femoral shaft or subtrochanteric areas were
identified from radiologists’ reports. No relation
to bisphosphonates was shown.14 The specific
type of fracture was not reported, and our data
suggest that in most cases, routine radiologic
assessment does not detect the atypical fracture

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 The n e w e ng l a n d j o u r na l of m e dic i n e

pattern. If identified, the atypical fractures in
these 10 women would probably have been few,
and the results are therefore not incongruent with
our data.
In our study, the women who sustained atypi-
cal fractures did not appear to be especially frail.
They had a lower frequency of previous osteopo-
rotic fractures than the controls. It is possible that
for the women with bisphosphonate-associated
atypical fractures, the drug had not been pre-
scribed for a proper indication. However, more
than one third of all patients receiving bisphos-
phonates in this study were receiving systemic
glucocorticoids, which is a correct indication for
prophylactic use of bisphosphonates.
We19 and other investigators3 have previously
presented data similar to the current results. The
present study adds to the previous literature with
a larger number of cases, estimates of relative and
absolute risk, and strictly population-based com-
parisons both with patients with other types of
fractures and with the general population. We
also conducted analyses of the type of bisphos-
phonate, the duration of treatment, and how
recently the drug was used, and in the analyses
we considered the concomitant use of other drugs
and coexisting conditions. It has been proposed
that glucocorticoids and proton-pump inhibitors
are likely to contribute to the risk of atypical
fractures,3,9 but our data suggest that this is not
the case.
The risk of atypical fractures decreased more
rapidly after drug withdrawal than would be ex-
pected, given the prolonged presence of the drug
in the bone. This observation and the increased
risk during the first year of treatment are diffi-
cult to reconcile with the etiologic hypothesis that
these fractures are a consequence of increased age
of the cortical bone because of reduced remodel-
ing. Thus, the pathogenic role of bisphosphonates
probably involves faster processes. Bisphospho-
nates accumulate on fracture surfaces immediately
after dosing. Ongoing treatment thus makes these
surfaces highly resistant to resorption, whereas
previous treatment does not. It is therefore con-
ceivable that ongoing bisphosphonate treatment
blocks targeted remodeling of cracks, which can
grow and cause a stress fracture. This explanation,
which implies that the long-lasting protective ef-
fect after bisphosphonate withdrawal1 is not as-
sociated with a similarly lasting risk of atypical
fracture, argues in favor of intermittent use.16
Our study has several limitations. First, the
observational design precludes definite causal in-
terpretation of the results. Nonetheless, our study
design precluded any bias associated with differ-
ential recall of bisphosphonate use and covariate
information. Second, drug use before 2005 was
not measured. We were therefore unable to esti-
mate the risk pattern with a longer duration of
use. Third, results adjusted for coexisting condi-
tions and the use of other drugs were based on the
case-control analysis only. Fourth, the study was
performed in women and in a Northern European
country, limiting the generalizability to men and
other ethnic groups. Finally, no data were avail-
able to evaluate whether the risk of atypical frac-
ture was dependent on bone density.
We conclude that the absolute risk of atypical
fracture associated with bisphosphonates for the
individual patient with a high risk of osteoporotic
fractures is small as compared with the benefi-
cial effects of the drug.
Dr. Aspenberg reports receiving consulting fees from Eli Lilly
and Amgen and grant support to his institution, Linköping Uni-
versity, from Eli Lilly and Amgen, as well as holding stock in
AddBIO, a company trying to commercialize a method for
bisphosphonate coating of implants to be inserted in bone, and
holding a patent for this method. No other potential conflict of
interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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