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?
Atypical fracture of the proximal left femoral shaft.
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.
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
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
- Borrelli J, Lane J, Bukata S, Egol KA, Takemoto R, et al. Atypical femur fractures. J Orthop Trauma. 2014;28:S36-S42. ↩
- Reid IR. Bisphosphonates. Skeletal Radiol. 2007;36:711-714. ↩
- Egol KA, Park JH, Prensky C, Rosenberg ZS, Peck V, et al. Surgical treatment improves clinical and functional outcomes for patients who sustain incomplete bisphosphonate-related femur fractures. J Orthop Trauma. 2013;27(6):331–335. ↩
- Unnanuntana A, Saleh A, Mensah KA, Kleimeyer JP, Lane JM. Atypical femoral fractures: what do we know about them? J Bone Joint Surg. 2013;95:e8(1-13). ↩
- Zheng N, Tang N, Qin L. Atypical femoral fractures and current management. J Orthop Transl. 2016;7:7-22. ↩
- Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, et al; American Society for Bone and Mineral Research. 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 Nov;25(11):2267-2294. ↩
- Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29:1-23. ↩
- Vieira RL, Rosenberg ZS, Allison MB, Im SA, Babb, et al. Frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy. AJR. 2012;198:1144-1151. ↩
- Feldman F. Atypical diaphyseal femoral fractures—new aspects. Skeletal Radiol. 2012;41:75-81. ↩
- Hagen JE, Miller AN, Ott SM, Gardner M, Morshed S, et al. Association of atypical femoral fractures with bisphosphonate use by patients with varus hip geometry. J Bone Joint Surg Am. 2104;96(22):1905-1909. ↩
- Taormina DP, Marcano AI, Karia R, Egol KA, Tejwani NC. Symptomatic atypical femoral fractures are related to underlying hip geometry. Bone. 2014;63:1-6. ↩
- Saita Y, Ishijima M, Mogami A, Kubota M, Baba T, et al. The fracture sites of atypical femoral fractures are associated with the weight-bearing lower limb alignment. Bone. 2014;66:105-110. ↩
- Yoo H, Cho Y, Park Y, Ha S. Lateral femoral bowing and the location of atypical femoral fractures. Hip Pelvis. 2017;29(2):127-132. ↩
- Ang BF, Koh JS, Ng AC, Howe TS. Bilateral ulna fractures associated with bisphosphonate therapy. Osteoporos Int. 2013;24(4):1523-1525. ↩
- Tan SH, Saseender S, Tan BH, Pawasker A, Kumar VP. Ulnar fractures with bisphosphonate therapy: a systematic review of published reports. Osteoporos Int. 2015;26(2):421-429. ↩
- Bissonnette L, April PM, Dumais R, Boire G, Roux S. Atypical fracture of the tibial diaphysis associated with bisphosphonate therapy: a case report. Bone. 2103;56(2):406-409. ↩
- Breglia MD, Carter JD. Atypical insufficiency fracture of the tibia associated with long-term bisphosphonate therapy. J Clin Rheumatol. 2010;16(2):76-78. ↩
- Murray J, Audet M, Bedard M, Michou L. Bilateral distal fibula fractures in a woman on long-term bisphosphonate therapy. Osteoporos Int. 2016;27(2):833-836. ↩
- Hegazy A, Kenawey M, Sochett E, Tile L, Cheung A, et al. Unusual femur stress fractures in children with osteogenesis imperfecta and intramedullary rods on long-term intravenous pamidronate therapy. J Pediatr Orthop. 2016;36(7):757-761. ↩
- Schilcher J. Aspenberg P. Atypical fracture of the femur in a patient using denosumab—a case report. Acta Orthop. 2014;85(1):6-7. ↩
- Villiers J, Clark D, Jeswani T, Webster S, Hepburn A. An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis treated with denosumab. Case Rep Rheumatol. 2013;2013:249872. ↩
- Dell R, Greene D, Tran D. Stopping bisphosphonate treatment decreases the risk of having a second atypical femur fracture. Read at the Annual Meeting of the American Academy of Orthopaedic Surgeons; 2012 Feb 7-11; San Francisco, CA. Paper 190. ↩
- Favinger JL, Hippe D, Ha AS. Long-term radiographic follow-up of bisphosphonate-associated atypical femur fractures. Skeletal Radiol. 2016;45:627-633. ↩
- Patel RN, Ashraf A, Sundaram M. Atypical fractures following bisphosphonate therapy. Semin Musculoskelet Radiol. 2016;20(04):376-381. ↩
- Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011 May 5;364(18):1728-37. ↩
- Banffy MB, Vrahas MS, Ready JE, Abraham JA. Nonoperative versus prophy- lactic treatment of bisphosphonate-associated femoral stress fractures. Clin Orthop Relat Res. 2011 Jul;469(7):2028-2034. ↩
- Gemdintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 2013;28(8):1729-1737. ↩