Bone 66 (2014) 105–110

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The fracture sites of atypical femoral fractures are associated with the weight-bearing lower limb alignment Yoshitomo Saita a, Muneaki Ishijima a,⁎, Atsuhiko Mogami b, Mitsuaki Kubota a, Tomonori Baba c, Takefumi Kaketa a, Masashi Nagao d, Yuko Sakamoto d, Kensuke Sakai d, Rui Kato e, Nana Nagura b, Kei Miyagawa f, Tomoki Wada b, Lizu Liu a, Osamu Obayashi b, Katsuo Shitoto c, Masahiko Nozawa d, Hajime Kajihara e, Hogaku Gen f, Kazuo Kaneko a a

Department of Orthopaedics, Juntendo University Faculty of Medicine, Tokyo, Japan Department of Orthopaedic Surgery, Juntendo Shizuoka Hospital, Shizuoka, Japan c Department of Orthopaedic Surgery, Juntendo Urayasu Hospital, Chiba, Japan d Department of Orthopaedic Surgery, Juntendo Nerima Hospital, Tokyo, Japan e Department of Orthopaedic Surgery, Koto Hospital, Tokyo, Japan f Department of Orthopaedic Surgery, Chiba Central Medical Center, Chiba, Japan b

a r t i c l e

i n f o

Article history: Received 1 April 2014 Revised 23 May 2014 Accepted 7 June 2014 Available online 14 June 2014 Edited by: David Fyhrie Keywords: Atypical femoral fracture (AFF) Osteoporosis Lower limb alignment Femorotibial angle (FTA) Bisphosphonate

a b s t r a c t Purpose: Atypical femoral fractures (AFFs) are stress-related fractures that are speculated to associate with longterm treatment with bisphosphonates for osteoporosis. A history of AFF is a high risk factor for the development of a subsequent AFF in the same location of the contralateral femur, suggesting that a patient's individual anatomical factor(s) are related to the fracture site of AFFs. In this study, we investigated the radiographs of fourteen AFFs (four bilateral fractures among ten patients) treated at six hospitals associated with our university between 2005 and 2010. The fracture site and standing femorotibial angle (FTA), which reflects the mechanical axis of the lower limb, were measured on weight-bearing lower limb radiographs. The fracture site and FTA of patients with typical femoral fractures (TFF) were compared to those of patients with AFFs. The correlations were examined using Spearman's rank correlation coefficients. The fracture locations in the femora were almost the same in the patients with bilateral AFFs. There was a positive correlation between the fracture site and the standing FTA in the patients with AFFs (r = 0.82, 95% confidence interval; 0.49 to 0.94), indicating that the larger the standing FTA (varus alignment), the more distal the site of the fracture in the femur. The FTA of the patients with atypical diaphyseal femoral fracture were significantly larger compared to that of those with not only atypical subtrochanteric fractures but also TFFs. In conclusion, the fracture sites of AFFs are associated with the standing lower limb alignment, while those of TFFs are not. © 2014 Published by Elsevier Inc.

Introduction Atypical femoral fractures (AFFs) are becoming an issue due to their relationship with long-term administration of bisphosphonates (BPs) [1–5]. Although this type of fracture can occur anywhere in the femoral bone from just beneath the lessor trochanter to the femoral shaft [6,7], it remains unclear how the fracture site of an AFF is determined [8–11].

Abbreviations: AFF, atypical femoral fracture; TFFs, typical femoral fractures; BPs, bisphosphonates; FTA, femorotibial angle; FN, neck fracture; IT, intertrochanteric femoral fracture; ST, subtrochanteric fracture; D, diaphyseal fracture; SLE, systemic lupus erythematosus; PM/DM, polymyositis and dermatomyositis. ⁎ Corresponding author at: Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 1138421, Japan. E-mail address: [email protected] (M. Ishijima).

http://dx.doi.org/10.1016/j.bone.2014.06.008 8756-3282/© 2014 Published by Elsevier Inc.

The patterns in the radiological findings of AFFs, such as cortical thickening, beaking and flaring of the lateral cortex of the femoral shafts, clearly indicate that this type of fracture is caused by tensile failures of the lateral cortex of the femoral shaft [6,12]. In addition to these radiological features, bilateral fractures are one of the clinical characteristics of patients with AFFs [6,10,13] and occur in the same anatomical location in most cases of bilateral AFFs [10], suggesting that individual factor(s) determine the fracture sites of AFFs. These clinical features indicate that AFFs develop due to fatigue failure mechanisms and are related to altered bone tissue properties as a result of accumulation of microdamage as well as altered adaptations to mechanical forces, that may be related to BP treatment and/or other conditions that cause bone fragility. We hypothesized that the fracture site of AFFs is associated with the weight-bearing alignment of the lower limb. In this study, we analyzed the standing alignment of the lower limb in patients with AFFs and typical femoral fractures (TFFs) and found an

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association between the fracture site and the weight-bearing alignment of the lower limb in patients with AFFs. Methods Objectives and definition of AFFs A flow chart of this study is shown in Fig. 1. We retrospectively reviewed the patient admission records of the orthopedic wards of six hospitals associated with our university in Japan between 2005 and 2010 [14]. We reviewed the radiographs of all patients with hip fractures (n = 2238, femoral neck fractures, intertrochanteric fractures, and subtrochanteric fractures) and diaphyseal femoral fractures treated at these hospitals. These six hospitals consisted of four universityassociated hospitals and two university-associated municipal hospitals. Subtrochanteric femoral fracture was defined as a fracture located within 5 cm distal to the lesser trochanter [15]. We defined an AFF as a fracture with all major features, in accordance with the previously described definition of AFF [6]. All the patients with AFF in this study also fulfilled the revised AFF definition [7]. Between 2005 and 2010, fourteen AFFs were observed. Four patients had AFFs on both sides; therefore, a total of 10 patients were observed during this period. With regard to TFFs, one-hundred forty-two patients with TFFs were treated in the university hospital, one of the six hospitals included in this study, during this period. Forty-four [twenty-eight were either femoral neck or intertrochanteric fracture (FN and IT, respectively), six were subtrochanteric fracture (ST), and the remaining ten were diaphyseal fracture (D)] among 142 patients with TFFs were undertaken radiographs of their lower limb for the purpose of following the fracture healing and/or checking lower limb alignment. Two TFFs who had high-energy fractures were excluded. For the definition of collagen disease, the diagnosis of rheumatoid arthritis, systemic lupus erythematosus (SLE), and polymyositis and dermatomyositis (PM/DM) was made by the rheumatologists who managed the patients based on the American College of Rheumatology defined criteria for SLE [16] and Peter–Bohan's criteria for PM/DM [17,18]. Among the patients with AFFs, five patients were diagnosed with collagen disease (three patients with SLE and two patients with PM/DM) and had long-term use of glucocorticoids (22.3 years on average).

Measurement of the fracture site in the femur using radiograph To measure the site of the AFFs in the femur, we measured both the femoral full length [A] and the length from the proximal end of the femur to the location of the lateral cortex of the AFF [B]. The femoral full length was measured from the top of the femoral head to the distal end of the medial femoral condyle, as previously described [19]. The ratio of [B]/[A] was used as a measure of the fracture site in the femur (Fig. 2). Weight-bearing radiographs and measurement of the femorotibial angle (FTA) To examine the weight-bearing alignment of the lower limb, standing radiographs of the lower limbs were obtained in the patients with AFFs. The standing femorotibial angle (FTA) was measured in the anteroposterior view, as previously described [20,21]. The FTA is the lateral angle of the intersection between the femoral axis and the tibial axis on an anteroposterior radiograph (Fig. 3) [22]. In patients with normal findings, the large joints of the lower limb are aligned on a straight line that represents the mechanical longitudinal axis of the leg, the Mikulicz line (Fig. 3) [23]. This line stretches from the hip joint (the center of the head of the femur) through the knee joint (the intercondylar eminence of the tibia) and down to the center of the ankle (the ankle mortise, the fork-like grip between the medial and lateral malleoli). In the tibial shaft, the mechanical and anatomical axes coincide; however, the femoral shaft diverges 2–6°, resulting in an FTA of 174–178° in a leg with a normal axial alignment [24]. One of fourteen AFFs was excluded from the FTA analysis because FTA was apparently altered after internal fixation thereby decreasing confidence of radiological measures after surgery. Therefore, thirteen AFFs were included in FTA analysis. The 95% confidence interval (CI) of the mean value and the 95% prediction interval of the standing FTA in Japanese populations (n = 5860, 40 years or older) were from 175.1° to 178.0° and 168.6° to 184.6°, respectively [25]. The intra-observer reproducibility (YS) of the FTA was measured at separate times for fourteen patients [interclass correlation coefficient (ICC): 0.97 (95% CI: 0.86–0.99)]. The inter-observer reproducibility was measured by two observers (YS and MI) who conducted 14 examinations [ICC: 0.98 (95% CI: 0.88–0.99)].

TFFs: 142

AFFs: 14

TFFs with FTA: 44 (FN/IT: 28, ST: 6, D: 10) Excluded one patient whose lower limb alignment was altered after internal fixation

Excluded FN/IT fractures

TFFs with FTA: 16 (ST: 6, D: 10) Excluded 2 diaphyseal femoral fractures with high energy trauma

AFFs with FTA : 13 (subtrochanteric: 7 and diaphyseal: 6)

TFFs with FTA : 14 (subtrochanteric: 6 and diaphyseal: 8)

Multiple comparison Fig. 1. Methodological flow chart for the comparison of lower limb alignment between patients with AFFs and those with TFFs.

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Statistical analysis Spearman's correlation coefficient was used to examine the correlation between the fracture site in the femur and the standing FTA. The analysis of variance (ANOVA) test was used for the comparison of FTA and the post hoc analysis was performed with Tukey's test, if ANOVA was significant. A p value of less than 0.05 was considered to be statistically significant. The analysis was performed using the SPSS ver.17 statistical software package (SPSS Inc., Chicago, IL).

B

Results Bilateral fracture in the patients with AFFs

A

Four patients fractured the femora bilaterally and one patient suffered from an additional AFF on the contralateral side in 2011, resulting in a total of five (50%) of 10 patients having AFFs in the femora bilaterally. Although the fracture sites in the femur differed in the individual patients with AFFs, the five patients with bilateral AFFs had fractures in almost the same location in the femora (Table 1, Fig. 4). Association between the fracture site of the AFFs and the weight-bearing lower limb alignment

Fig. 2. Measurement of the fracture site in the femur on a radiograph. In order to measure the site of the AFFs in the femur, we measured both the femoral full length [A] and the length from the proximal end of the femur to the location of lateral cortex of the AFF [B]. The femoral full length was measured from the top of the femoral head to the distal end of the medial femoral condyle, as previously described [19]. The ratio of [B]/[A] was used as the fracture site in the femur.

Normal alignment

A

B

FTA

Interestingly, as the bilateral AFFs occurred almost symmetrically on the right and left legs, we hypothesized that the AFF fracture site in the femur is determined by the patient's individual factor(s) of the lower limb and analyzed the fracture site in the patients with AFFs on standing radiographs of the lower limbs. The average fracture site in the femur was 39.5% (SD, 15.8%). The fracture sites of the patients with bilateral AFFs were almost the same on the femora (Fig. 4). Since we next hypothesized that AFFs would develop at the location of the maximal tensile force loading, we analyzed the standing mechanical axis of the lower limb of the patients with AFFs and TFFs, which is represented by the standing FTA (Fig. 3), and examined the correlation between

Valgus alignment

C

D

Varum alignment

E

F

FTA FTA

Fig. 3. The FTA and mechanical axis of the lower limb. The femorotibial angle (FTA) is the lateral angle between the axis of the femoral shaft and that of the tibial shaft (A, C and E). The mechanical axis is indicated by dotted lines in panels B, D and F. A and B: normal alignment, C and D: valgus alignment, E and F: varus alignment. In patients with a normal alignment, the mechanical axis passes through the center of knee joint (B). In patients with a valgus alignment, the FTA becomes smaller (C) and the mechanical axis passes through the lateral side of the knee joint (D). In patients with a varus alignment, the FTA becomes larger (E) and the mechanical axis passes through the medial side of the knee joint (F). The amount of mechanical force passed to the lateral cortex of the femur changes depending on the alignment of the lower limb.

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Table 1 Characteristics and clinical data of the patients with AFFs. Case

1 2 3 4 5 6 7 8 9 10

Age

60 67 49 78 80 89 41 69 57 70

Gender

F F F F F F F F F F

Race

Asian Asian Asian Asian Asian Asian Asian Asian Asian Asian

Fracture side Left Right Bilateral Right Bilateral Left Left Bilateral Bilateral Bilateral⁎

Table 2 The characteristics of patients with TFFs and AFFs.

Fracture height (R/L)

Type of BPs (duration, year) 23.9%

33.6% 23.5% 56.2% 45.8% 60.2% 29.3% 55.6% 21.5% 55.1%

29.1% 51.0%

56.7% 20.5% 53.4%

Alendronate (3.0) Alendronate (3.5) Alendronate (3.5) Risedronate (3.0) Risedronate (6.0) None Alendronate (5.5) Alendronate (5.0) Alendronate (5.0) Alendronate (10.0)

⁎ The patient in case 10 suffered from an AFF in the contralateral (right) side in 2011.

fracture site and FTA. The characteristics of the subjects with TFF were shown in Table 2. There was no correlation between the fracture site and FTA in the patients with typical subtrochanteric and diaphyseal fractures (Fig. 5). On the other hand, there was a positive correlation between the fracture sites of the AFFs and the standing FTA (r = 0.82, 95% CI; 0.49 to 0.94, Fig. 5). Larger FTA in the patients with atypical diaphyseal femoral fractures To further examine the effect of lower limb alignment for AFFs, the patients with AFFs were divided into subgroups depending on the fracture site [subtrochanteric fractures (n = 7) and diaphyseal fractures (n = 6)] and the FTA of these patients was compared with that of those with TFFs. Mean FTA of the TFF patients with hip fracture, subtrochanteric femoral fracture, and diaphyseal femoral fracture was within the 95%CI for FTA in Japanese populations aged 40 years or older [25] (Fig. 6). No significant differences in FTA were observed between the subgroups of the patients with TFFs (Fig. 6). In contrast, the mean value of FTA in the patients with AFFs was out of the 95%CI of FTA in Japanese populations; that in those with atypical subtrochanteric femoral fracture (172.8°) was smaller, while that in those with atypical diaphyseal femoral fracture (183.3°) was larger than the 95%CI of FTA in Japanese populations (Fig. 6). The FTA of the patients with atypical diaphyseal femoral fractures was significantly larger than that of those with typical hip and femoral fractures and atypical subtrochanteric femoral fractures (Fig. 6). One of the patients with atypical diaphyseal femoral fracture without using bisphosphonate (case 6 in Table 1) showed a severe varus lower limb alignment, which

A

C

Fracture type (n)

TFFs (14)

AFFs (10)

p

Age (years) Gender (male/female)

74.9 2/12 (16.7%/83.3%) 22.8 4 (28.6%) 2 (14.3%) 2 (14.3%) −2.53 9.51

66.0 0/10 (0.0%/100.0%) 21.8 9 (90.0%) 6 (60.0%) 5 (50.0%) −2.85 9.35

0.14

BMI (kg/m2) Medications

Bisphosphonate Glucocorticoid Comorbid condition Collagen disease BMD (T-score of DEXA) Corrected serum calcium level (mg/dl)

0.57 b0.01⁎ 0.03⁎ 0.08 0.77 0.58

TFFs; typical femoral fractures, AFFs; atypical femoral fractures, BMI; body mass index, BMD; bone mineral density, DEXA; dual-energy X-ray absorptiometry. ⁎ p b 0.05.

was out of 95% prediction interval of standing FTA (FTA: 193.4°, case 6 in Supplemental Fig. 1). Discussion In this study, we demonstrated that the fracture sites of AFFs are associated with the weight-bearing lower limb alignment, while those of TFFs are not. The patients with larger FTAs (varus alignment) exhibited fractures at the diaphyseal lesions of the femora (the mid to distal part of the femur), while the patients with smaller FTAs (valgus alignment) tended to exhibit fractures at the subtrochanteric lesions (the proximal part of the femur). To our knowledge, no previous reports have revealed a relationship between the weight-bearing lower limb alignment and the fracture sites of AFFs. Several risk factors for developing AFFs have been reported [26]. In our previous study, we also retrospectively investigated the radiographs of all 2238 hip and femoral shaft fractures and examined the incidence of AFFs and characteristics of the patients with AFFs in Japan [14]. Similar to the recent study [26], the patients with AFFs were significantly younger than those with TFFs in our case–control study [14], although no age differences were observed between patients with TFFs and those with AFFs in the present (Table 2). On the other hand, no significant differences of the serum calcium levels and BMI were observed between patients with AFFs and those with TFFs in our study, in contrast to the recent study [26]. No significant differences of the lumber BMD and bone turnover markers were also observed between the patients with AFFs and those with TFFs in our study (Table 2) [14].

D

E

B

Fig. 4. Symmetrical fracture sites in the femora in the patients with bilateral atypical femoral fractures (AFFs). Radiographs of bilateral atypical subtrochanteric femoral fractures (A and C) and bilateral atypical diaphyseal fractures (B, D, and E) are shown. Panels C, D and E are images of weight-bearing full length radiographs of the patients with bilateral AFFs. The closed arrowheads indicate the fracture sites. The fracture sites were symmetrical in the femora in the patients with bilateral AFFs.

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*

A

***

80 60 40 20 0 160

170

180

**

200

r = -0.05 (95%CI: -0.58 - 0.51) p = 0.82

Femorotibial angle (degree)

Fracture height (%)

100

190

190

180

170

200 160

Hip (FN and IT)

Femorotibial angle (degree)

TFFs

B 100

Fracture height (%)

ST

80

D

ST

D AFFs

Fig. 6. Comparison of FTA in patients with TFFs and AFFs. The mean, standard deviation, and data plots of femorotibial angle (FTA) in the patients with femoral fractures [typical femoral fractures (TFFs) and atypical femoral fracture (AFFs)] were shown. Gray zone between dotted lines indicates the 95% confidence interval of the mean value of the standing FTA in the 5860 Japanese populations aged 40 years or older (175.1 to 178.0°) [25]. Gray zone between dashed line indicates the 95% prediction interval of standing FTA (168.6° to 184.6°) [25]. *p b 0.05, **p b 0.01, FN; femoral neck fractures, IT; intertrochanteric fractures, ST; subtrochanteric fractures, D; femoral diaphyseal fractures.

r = 0.82 (95%CI: 0.49 - 0.94) p < 0.001

60 40 20 0 160

170

180

190

200

Femorotibial angle (degree) Fig. 5. Association between the fracture site and the lower limb alignment in patients with AFFs. Relationships between the standing femorotibial angle (FTA, as shown in Fig. 2) and the fracture site (the proportion of the fracture site per the full length of the femur, as shown in Fig. 1) in patients with typical subtrochanteric and diaphyseal femoral fractures (typical femoral fractures) (A) and atypical subtrochanteric and diaphyseal femoral fractures (atypical femoral fractures) (B). Solid lines; approximate line, dotted curves; 95% prediction intervals, n.s.; not significant.

Cortical stress reactions, a characteristic radiological findings of AFFs [6,7], were primarily observed in the lateral cortex in this study, suggesting that AFFs may be caused by tensile failure of the femur and occur at sites of high tensile stress loading. Schematic diagrams of tensile stress loading on the lateral cortex of the femur in varus and valgus lower limb alignment are shown in Supplemental Fig. 2. Therefore, mechanical alterations due to the lateral bowing of the femur and/or genu varum alignment may increase the bending force on the lateral cortex of the femur. The progression of such age-related changes in the femur, which are frequently observed in Asian populations, shifts the area of maximal tensile stress to a more distal site in the femoral shaft (Fig. 3). Indeed, in our study, the patients with atypical diaphyseal femoral fractures (77.2 years) were significantly older than those with atypical subtrochanteric fractures (54.8 years) (p b 0.01). On the other hand, the presence of a genu valgus alignment, which is frequently observed in Asian patients with collagen diseases [27], shifted the maximal loading site to a more proximal location in the femoral cortex (Fig. 3). Giusti et al. reported that, compared to patients with a femoral shaft fracture, those with a subtrochanteric femoral fracture had a higher number of chronic diseases and were more frequently of Asian origin [28]. In our study, all the patients with atypical subtrochanteric fracture suffered from collagen diseases (case 1, 2, 3, 7, and 9) and the FTA of these patients was low (172.8° on average) compared with that of the

population-based cohort study in Japan (177.6° on average in women) [25]. In addition, in the patients with collagen disease, the joint motion of hip abduction is decreased and the hip abductor moment is low in the patients with collagen disease in comparison to healthy controls [29]. These biomechanical factors of lower limb would be one of the reasons why the patients with atypical subtrochanteric femoral fractures frequently occur in the patients with multiple chronic diseases especially in the patients with collagen diseases in Japan. Sasaki et al. reported that low-energy diaphyseal femoral fractures were observed in Japanese patients with lateral and anterior bowing of the femur [30]. Similarly, one elderly patient with a severe varus alignment of the lower limb who had not been taking BPs in the present study exhibited a fracture at distal part of the femoral shaft (Supplemental Fig. 1). As lower limb alignment is changed by knee osteoarthritis (OA), this change may affect the fracture location for AFFs. In the current study, two of six patients (33.3%) with atypical subtrochanteric fractures showed lateral knee OA, and two of eight (25%) with atypical diaphyseal femoral fractures showed medial knee OA, while three of fourteen in patients with TFFs (21.4%) showed medial knee OA. Lower limb alignment is also affected by osteomalacia, which is mainly caused by vitamin D deficiency, and induces the genu varus lower limb alignment and bowing of the femur. As some but not all of the patients were examined for serum levels of calcium, phosphate and alkaliphosphatase, no doubtful cases of osteomalacia were observed among them. However, as serum levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) were not measured, and histological analysis was not conducted, we cannot exclude the possibility that the undermineralized bone matrix caused by vitamin D deficiency/insufficiency might have contributed to fractures and FTA. In addition, other diseases, such as vertebral fractures and lumber spondylosis, may also affect the lower limb alignments. Although the number of patients was small, no differences of the prevalence for the vertebral fracture were observed between in patients with AFFs [2/5 (40%)] and those with AFFs [5/9 (55.5%)]. In terms of the lumber scoliosis, there was only one patient who showed radiographic lumbar scoliosis in each groups (TFFs and AFFs) in the present study. These observations suggest that abnormal mechanical properties of the femoral shaft due to the malalignment of lower limb are one of the risk factors for the development of AFFs. Therefore, AFFs may

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occur when a patient has multiple risk factors associated with AFFs, and the summation of these factors overcomes the AFF threshold, leading to stress-related fractures [31]. Consequently, the anatomical features of the lower limb, as well as altered bone tissue properties [31,32], are associated with the development of AFFs. The current study is associated with several limitations. First, this investigation was a retrospective study; therefore, the design may have introduced certain bias into the results. Interpretation of the is limited due to the small number of AFF patients. Second, it has not been clarified whether patients with abnormal alignment have a higher risk of AFFs. In order to clarify this hypothesis, prospective cohort studies including investigations of the lower limb alignment as well as the occurrence of AFFs in adequate populations are required. Third, as mentioned above, the presence of osteomalacia may also contribute to the findings of the current study. However, as the measurement of serum levels of 25(OH)D in the patients with osteoporosis is not permitted under the regulation of the health insurance system to which almost all the citizens are affiliated in Japan [33]. Fourth, FTA was measured using post-operative radiographs. We cannot exclude the possibility that the operation may alter FTA. Accordingly, one patient with AFFs was excluded due to the apparent alteration of FTA following the operation (Fig. 1). In conclusion, the fracture sites of AFFs were associated with the standing alignment of the lower limb. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.bone.2014.06.008. Conflict of interest All authors state that they have no conflict of interest. Acknowledgments We thank all orthopedic surgeons working in Juntendo University Hospital, Juntendo Urayasu Hospital, Juntendo Shizuoka Hospital, Juntendo Nerima Hospital, Koto Hospital and Chiba Central Medical Center for providing the clinical data and treatment courses of patients. We express our deep appreciation for Dr. Yoshihiko Yamada for his checking the manuscript. We also express our deep appreciation for Dr. Joe Matsuoka for his helpful comments and suggestions regarding the statistical analysis. This work was not funded by any research and training grants. The authors declare no competing interests. References [1] Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 2010;362:1761–71. [2] Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med 2010;362:1848–9. [3] Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358:1304–6. [4] Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011;364:1728–37. [5] Stevenson JC. Bisphosphonates and atypical femoral shaft fractures. N Engl J Med 2011;365:377. [6] Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010;25:2267–94.

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The fracture sites of atypical femoral fractures are associated with the weight-bearing lower limb alignment.

Atypical femoral fractures (AFFs) are stress-related fractures that are speculated to associate with long-term treatment with bisphosphonates for oste...
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