Atypical Femur Fractures

Clinical History:

A 62 year-old female with a history of arthritis has had vague left thigh pain for several months. An MRI was performed to evaluate the musculature and femur.  Coronal, sagittal, and axial fat-suppressed T2-weighted images and an axial T1-weighted image of the left thigh are provided (Figure 1).

What are the findings? What is your diagnosis?

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Figure 1

Findings

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Figure 2:

Coronal (2a), sagittal (2b), and axial (2c) fat-suppressed T2-weighted images reveal focal periosteal and endosteal cortical thickening, adjacent endosteal edema, and a transverse intracortical fracture line (arrows) involving the lateral proximal femoral shaft cortex. Minimal adjacent periosteal edema is present on the coronal view. The axial T1-weighted image (2d) demonstrates smooth lateral cortical periosteal and endosteal thickening (arrow). A corresponding AP radiograph (2e) reveals similar periosteal and endosteal cortical thickening with intracortical transverse fracture lucency (arrow).

Diagnosis

Atypical fracture of the proximal left femoral shaft.

Introduction

Atypical femur fractures (AFFs) are the result of an uncommon stress reaction developing in the lateral cortex of the femoral shaft.  There is a strong association between bisphosphonate usage and the development of AFFs, increasing in incidence with longer durations of bisphosphonate usage.  It is important to detect AFFs as patients may have minimal or no pain prior to fracture completion.

Pathogenesis and incidence  

Antiresorptive agents are a diverse class of medications used to treat bone loss of various etiologies.  These agents include estrogen, bisphosphonates, estrogen receptor modulators, and denosumab, an inhibitor of osteoclast maturation.

Bisphosphonates are far and away the most commonly prescribed antiresorptive agent.  They are used to treat osteoporosis of any etiology, bone loss and hypercalcemia associated with metastases and multiple myeloma, Paget disease, and certain genetic disorders (e.g. McCune-Albright syndrome).  Bisphosphonates significantly decrease the incidence of fractures in patients with osteoporosis; for example, they decrease the incidence of hip fractures 20-50%.¹

Bisphosphonates are osteoclast inhibitors and cause osteoclast apoptosis.  By decreasing bone resorption and shifting the balance towards bone formation, they increase bone mass.  Alendronate and risedronate, the two most commonly used bisphosphonates for the treatment of osteoporosis, reduce bone resorption 50 to 90%, increasing bone mineral density in the spine 5-10% after 3 years.²

However, longstanding bisphosphonate suppression of normal remodeling causes bone to become excessively mineralized and more brittle and homogeneous, increasing the initiation of intracortical microcracks.^3,4,5

Microdamage accumulates and normal stress-related microcracks are not repaired effectively.^5,6 Callus and the formation of woven bone is not affected.⁷ Prolonged insufficient attempts to repair physiologic microcracks related to bisphosphonates can result in a frank intracortical fracture.

Bisphosphonates as a class have all been associated with AFFs.  There is a dose-duration relationship — the longer the treatment the higher the risk.  AFFs are more frequently seen after more than 3 years of use (median of 7 years).^4,6,7  Estimated incidence in studies using radiograph correlation range from 0.9 to 78 AFFs per 100,000 person-years.⁴  Bisphosphonates increase the risk of AFFs with odds ratios ranging from 2.29 to 139.33.⁴  However, the absolute risk is very low, ranging from 3.2 to 50 cases per 100,000 person-years.⁷

While usually seen in more chronic treatment, AFFs have been seen in patients taking bisphosphonates less than 3 years.⁷  And, it is important to note, AFFs have occurred in patients who have never taken bisphosphonates; every case series has had patients who have had an AFF without a history of bisphosphonate use.⁷  No definite increased incidence has been seen with more potent osteoclast inhibitors such as zoledronic acid or ibandronate, or with increased dosages.⁸

The lateral femoral shaft is a site of high tensile stress, greatest in the subtrochanteric femur where AFFs are most frequently seen.^4,7,9  Although unproven, this high tensile stress is presumably why these fractures are seen in the lateral cortex of the femur.  It is felt that the geometry of the femur may play a role in the development of AFFs.⁷  Studies have found an increased risk of an AFF in patients with an increased femoral neck-shaft angle.^10,11 Similar fracture location in cases of bilateral AFFs suggests a relationship between the axis of the lower extremity and the risk of AFF development.⁷ It has been found that the location of AFFs is related to femoral bowing or the weight-bearing axis of the lower extremity; the greater the bowing or larger the weight-bearing femorotibial angle the more likely the AFF is located in the diaphysis (as opposed to the subtrochanteric region).^12,13

It seems reasonable that while the lateral femur is a site of high tensile stress, other sites of stress would be susceptible to fractures similar to AFFs.  As expected, fractures similar in appearance to AFFs have been seen in patients taking bisphosphonates in the ulna in patients using walking aids ^14,15, in the tibia ^16,17, and in the fibula.¹⁸ Also, fractures with similarities to AFFs have been seen in the femurs of children with osteogenesis imperfecta with preexisting intramedullary rods on bisphosphonate therapy.¹⁹  Additionally, there have been case reports of patients taking denosumab, an inhibitor of the receptor activator of nuclear factor kappa-B ligand (RANKL) and atypical fractures of the femoral shaft similar to those associated with bisphosphonates.^20,21

Clinical and Imaging Features

AFFs may or may not be symptomatic.  They are present for an unknown time duration. It is not known if they can be present for years prior to presentation due to pain or fracture completion.⁸  Patients may present with vague dull or aching thigh, hip, or groin pain of variable duration, most commonly thigh pain. Symptoms may be attributed to hip osteoarthritis or muscle strain.  However, it is not uncommon for patients to have no symptoms and present only after fracture completion occurs.  By definition, the completed fractures occur with no or minimal trauma (e.g. tripping, fall from standing height or less).⁷

AFFs always occur in the lateral cortex, unlike typical stress fractures and pseudofractures/Looser zones of osteomalacia.  They can occur anywhere along the shaft, from the subtrochanteric region to just proximal to the supracondylar flare.  Most commonly they occur in the proximal third of the femoral shaft.^6,8

As AFFs often occur in the subtrochanteric femur, the lateral cortex of the imaged proximal femur (or femurs) on MRI and radiographs should be particularly scrutinized in older females, the largest cohort of bisphosphonate users.  This area should also be scrutinized in older males and patients of any age with known metastatic cancer, multiple myeloma, or Paget disease as they are more likely to be taking bisphosphonates.

On radiographs, MRI, or CT, focal, smooth, diffuse (periosteal and endosteal) lateral cortical thickening, with or without an intracortical fracture, is far and away the most common finding (Figures 4 and 5). However, only isolated periosteal or endosteal cortical thickening may be seen (Figure 6).  Much less frequently an intracortical fracture may be seen in the absence of cortical thickening (Figures 3 and 7).

On MRI, there is often slightly increased intracortical signal, particularly on fluid-sensitive sequences.  There may be only very mild periosteal and endosteal edema about the cortical thickening.  A transverse intracortical fracture line may be seen amidst the cortical thickening. The fracture line may or may not extend into the medullary canal.

On bone scan, AFFs manifest as a small round or ovoid area of increased radiotracer accumulation in the lateral femoral shaft cortex.  They may be incidentally identified on scans performed for other reasons (e.g. evaluating for bone metastases) (Figure 5).

Completed AFFs have a distinct appearance.  They are either simple or minimally comminuted, transverse or slightly oblique, have cortical thickening at their lateral margin, and a cortical “spike” at the medial margin (Figure 8). They differ from a typical osteoporotic femur fracture which commonly have a long oblique or spiral configuration and usually involve the femoral neck and intertrochanteric region.⁴  They differ from femur fractures due to high-energy trauma which are typically comminuted and displaced.

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Figure 3:

Coronal (3a) and sagittal (3b) fat-suppressed proton density-weighted images in a 72 year-old male taking alendronate reveal a low-signal intracortical fracture line (arrow) surrounded by mild endosteal and periosteal edema (arrowheads). The intracortical fracture (arrow) is particularly well seen in 3b. The intracortical fracture is often best seen on sagittal images. The axial fat-suppressed proton density-weighted image (3c) in the same location shows minimal endosteal and periosteal edema (arrowheads). Note that no focal endosteal or periosteal cortical thickening is present, an atypical finding for AFFs.

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Figure 4:

69 year-old female with left femur pain after slip and fall approximately 9 weeks ago. She has taken alendronate for “many years.” Coronal fat-suppressed T2-weighted images of the left femur (4b more anterior than 4a) show focal periosteal and endosteal cortical thickening with adjacent mild edema (arrows). The intracortical fracture line is better seen in 4b. Note the slightly more distal milder lateral periosteal cortical thickening, consistent with another site of atypical stress reaction (short arrow). It is not uncommon to see adjacent sites of milder cortical thickening in patients with an AFF. AP pelvis radiograph (4c) obtained at the time of the fall demonstrates the left proximal femoral AFF (arrow) as well as slightly more distal milder periosteal cortical thickening (short arrow), also visible on 4b. Note the two sites of mild periosteal lateral cortical thickening of the proximal right femoral shaft (arrowheads). Patients with an AFF may have clinically silent atypical stress reactions or a fracture of the contralateral femur. It is thus imperative to image the entire contralateral femur at the time of index diagnosis of an AFF.

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Figure 5:

An 81 year-old female with remote bilateral total knee arthroplasty performed for osteoarthritis presented with a three-month history of right knee pain. She had a 10-year history of bisphosphonate use (ibandronate for four years preceded by alendronate). A three-phase bone scan was performed to evaluate for right knee component loosening and/or infection. Delayed bone scan projections of the knees (5a) reveals a small ovoid focus of increased radiotracer accumulation in the lateral cortex of the mid right femoral shaft (ovals). This is a typical appearance of an AFF on bone scan. No abnormal radiotracer accumulation in the right knee is present. Blood flow and pool phases (not shown) were normal in the lateral right mid femoral shaft. An MRI was then performed. Axial and coronal fat-suppressed T2-weighted images (5b and 5c) reveal periosteal and endosteal cortical thickening, which is slightly increased in signal, with an intracortical low signal fracture line in the lateral mid femoral shaft (arrows) at the site of the previously seen increased radiotracer accumulation. Note the prominent adjacent endosteal edema, mild anterior periosteal edema in 5b, and mild lateral periosteal edema in 5c. Corresponding axial and coronal T1-weighted images (5d and 5e) reveal smooth periosteal and endosteal thickening and adjacent prominent heterogeneously low intramedullary signal adjacent to the endosteum (arrows), corresponding to the endosteal edema. Subsequent AP coned-down radiograph (5f) shows smooth cortical thickening without visible intracortical fracture lucency (arrow). This case demonstrates how MRI can reveal an intracortical fracture that is not seen on radiographs. Also note the milder smooth slightly more proximal periosteal lateral cortical thickening (arrowhead in 5f)). Less extensive cortical thickening(s) adjacent to AFFs are not uncommon.

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Figure 6:

AP pelvis radiograph (6a) of a woman on bisphosphonate therapy reveals focal endosteal sclerosis in the subtrochanteric right femur (arrow) with minimal adjacent convex periosteal cortical thickening. Subsequent delayed whole body bone scan reveals characteristic ovoid radiotracer accumulation in the same location (arrow in 6b). Infrequently, AFFs present with only isolated or predominantly endosteal cortical thickening.

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Figure 7:

AFFs may be very subtle and may be a “corner-of-the-film” finding. Scrutiny of the lateral cortex of the imaged proximal femoral shaft(s) should be made on all hip and pelvis radiographs and MRIs, particularly in older women, far and away the largest bisphosphonate users. Relatively underpenetrated AP pelvis radiograph (7a) shows a subtle intracortical fracture lucency of the proximal right femoral shaft (arrow) without cortical thickening, which is seen to much better advantage after manually altering contrast on the PACS workstation (arrow in 7b). Evaluation of the contralateral femur must be made when an AFF is seen. In this case, a subtle intracortical fracture is seen in the magnified and contrast-altered contralateral femoral shaft near the edge of the radiograph (arrow in 7c).

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Figure 8:

AP radiograph of the proximal left femur shows the characteristic findings of a completed AFF. An oblique, non-comminuted, moderately displaced fracture is present with associated lateral cortical thickening (straight arrow) and a bone “spike” at the medial margin of the fracture (arrowhead).

Management and Treatment

If an AFF is seen on radiographs without a definite intracortical fracture lucency, MRI, CT, or bone scan should be performed.  Fractures may be better seen on MRI or CT due to their multiplanar capabilities.  MRI can assess for adjacent hyperemia, manifesting as edema.  Bone scan can similarly show hyperemia and an active healing response indicative of ongoing fracture repair, manifesting as increased radiotracer accumulation.

When an AFF is detected, bisphosphonate therapy should be discontinued as there is a significant increased incidence of developing a contralateral AFF with continuation of the drug.²² This is despite their having a long (years for clinically used dosages) residence time in bone.^4,23,24

A study by Schilcher et al. found the risk of an AFF decreased 70% per year after bisphosphonate discontinuation.²⁵ Additionally, all should have calcium and Vitamin D supplementation.⁴  Teriparatide, a PTH analog, should be considered, although there is no clear evidence of its efficacy.⁷

Long-length intramedullary nail femur fixation is recommended to prevent fracture completion if the patient has pain.⁶  Plate-screw constructs are not recommended as they preclude endochondral fracture healing and have a high failure rate.^4,7  If the patient has minimal pain, a 2-3 month trial of conservative treatment including protected weight-bearing may be undertaken; if symptoms or radiographic findings worsen or are unchanged, then fracture fixation is recommended.⁶ If the patient has no pain, protected weight bearing can be continued (6).  Some have argued that all AFFs should be treated operatively as the failure rate is high (i.e. fracture completion occurs).^3,26

When an AFF is detected, imaging of the contralateral femur is necessary to evaluate for a “silent” AFF.  A simultaneous AFF of the contralateral femur may be seen. The true incidence of synchronous AFFs is unknown⁶, although studies have found the incidence to be 22.5%-42%.^1,4  There is an increased incidence of the development of an AFF in the contralateral femur at some time after the index AFF; Feldman states more than 50% will have a contralateral AFF, either at the same time or subsequent to the index case.⁹

If conservative management is chosen, the optimal imaging modality and timing of following AFFs to evaluate for healing is unclear.  In a radiographic study which included 31 AFFs at baseline in women with a history of bisphosphonate use, some of which had had fracture fixation, Favinger et al. found the median time to fracture healing took 56 weeks and only 45% had fracture healing by 6 months. Of 47 femurs that had cortical thickening with or without an intracortical fracture lucency, a decrease in cortical thickening was seen in only 22% by 6 months.²³  In another study of 22 AFFs treated non-operatively, only 18% demonstrated radiographic healing at an average of 11 months (range 6-24 months).³  Thus, AFF fracture healing is slow. It is expected that manifestations of healing on MRI would be a decrease in adjacent marrow and soft tissue edema, decrease in cortical thickening, and, obviously, a decrease in length or conspicuity of the fracture line, although the author is aware of no study following AFFs with MRI.  The Task Force of the American Society for Bone and Mineral Research recommends that reduced activity should continue until no marrow edema is seen on MRI.⁷

Conclusion

AFFs are an uncommon unusual fracture that have a strong association with bisphosphonates.  They have the characteristics of an insufficiency fracture, occurring with normal stresses on abnormal bone.  They only occur in the lateral cortex of the femoral shaft, typically in the proximal third.  There is often associated vague prodromal thigh pain, though this is definitely not universal as some patients are completely asymptomatic.

MRI, radiographs, and bone scan may detect AFFs incidentally.  While they usually manifest as localized periosteal and endosteal cortical thickening, cortical thickening may be absent.  Adjacent reactive edema on MRI may be minimal.  Scrutiny of the imaged proximal femur on hip and pelvis studies should be made, particularly in older females who are most likely to be bisphosphonate users as well as older males and in those with a history of metastatic disease, multiple myeloma, or Paget disease.

AFFs are important to diagnose as the vast majority will eventually proceed to completion without intervention.  When an AFF is detected, it is imperative to begin protected weight bearing and discontinue bisphosphonate use.  The majority of patients will undergo prophylactic intramedullary rod fixation to prevent fracture completion.  At the time of AFF diagnosis, it is also important to recommend imaging the contralateral femur as synchronous AFFs are not uncommon.

Although the incidence of AFFs is very low relative to the entire population of bisphosphonate users, it is expected that the number of cases will increase given the increased prevalence of osteoporosis.²⁷

References