Learning objectives
- •
Recognize the symptoms and presentation of atypical femoral shaft fractures (AFF).
- •
Understand the pathophysiology of AFF and the role of antiresorptive medication.
The case study
Reason for seeking medical help
- •
GL, 66 years old, is complaining of pain in her left upper thigh that started insidiously about 8 weeks ago. Initially it was only a discomfort, but it gradually becomes worse. She now rates it as “7” on a scale of 1–10, with 10 being the worst possible pain. It is constant, occasionally throbbing, and often precipitated by exertion, especially walking or standing on the left leg.
- •
She had to stop jogging about 3 weeks ago because of the pain in her left hip. The pain is partly relieved by rest and local heat. It is not worse at night when she is in bed. It does not wake her up but is starting to interfere with her daily activities.
Past medical and surgical history
- •
Osteoporosis, diagnosed about 12 years ago: lowest T-score in the lumbar vertebrae was −3.0. She was prescribed alendronate. She still takes the tablets exactly as directed. She has not experienced adverse effects.
- •
Status postnatural menopause at age 43, no hormonal replacement therapy.
Lifestyle
- •
Daily dietary calcium intake estimated to be about 1200 mg.
- •
No excessive caffeine, sodium, or alcohol intake.
- •
No cigarette smoking.
- •
Physically active lifestyle; also, she jogs for about an hour every weekday.
Medication(s)
- •
Alendronate tablets, 70 mg once a week, 12 years, good adherence.
- •
Cholecalciferol 400 units daily.
Family history
- •
Mother and older sister sustained fragility hip fractures.
Clinical examination
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Weight 153 pounds, steady, height 65″, used to be 66″.
- •
Some limitation in range of movement of the left hip.
- •
Pain in left upper thigh worse on standing up on left leg.
- •
Tenderness along the upper third of left femoral shaft.
- •
No evidence of localizing neurological lesions.
- •
No significant arthritic changes.
- •
No edema of the lower limbs.
- •
No evidence of peripheral arterial or venous insufficiency.
Laboratory results
- •
Comprehensive metabolic profile: no abnormality detected.
- •
Serum 25-hydroxy-vitamin D: 46 ng/mL.
DXA and radiological results
- •
T-scores: left femoral neck −2.4, left total hip −2.1, lumbar vertebrae −2.5.
- •
Compared to the baseline DXA scans, there has been an increase in the BMD: 6% in the total hip and 11% in the lumbar vertebrae. These changes exceed the least significant change of the center where the DXA scans were done.
- •
Vertebral fracture assessment: no evidence of vertebral compression fracture.
Multiple choice questions
- 1.
GL’s clinical presentation is compatible with:
- A.
Osteoarthritis left hip.
- B.
Paget’s disease of bone.
- C.
Atypical femur fracture (AFF) left proximal femur.
- D.
Any of the above.
- E.
None of the above.
Correct answer: C
Comments:
The presentation is suggestive of an atypical femoral shaft fracture (AFF). About 70% of patients who sustain an AFF complain of pain and tenderness in the thigh or groin, at the site of the fracture. The pain, sometimes throbbing, is worsened by movement and standing up on the affected leg.
Atypical femoral fractures (AFF) are stress fractures. However, unlike typical stress fractures which start in the medial cortex, and then spread out, AFF usually originate in the lateral cortex and spread medially, hence their name “atypical.” The process starts by an accumulation of microscopic cracks that are usually resorbed by osteoclasts and replaced with new healthy bone laid by the osteoblasts, a process known as “targeted remodeling.”
Antiresorptives, especially if administered over prolonged periods, may lead to the development of AFF. Bisphosphonates interfere with the removal of these microscopic cracks which then accumulate, enlarge, fuse, cause the bone to weaken. This in turn results in a fracture: a fracture that has the potential to increase in size to become a full transverse fracture, an atypical fracture. The osteoclasts are normally steered by a receptor-activator of nuclear factor kappa-B ligand (RANKL) to areas of the bone where microcracks are present in order to start the clearing process.
Denosumab is an antibody to RANK-L and blocks the formation of osteoclasts. As a result of its long-term administration, however, the microcracks may not be resorbed, may accumulate, and may lead to a full fracture.
The age-adjusted incidence of AFF increases with the increased exposure to antiresorptive agents. It is estimated to be 1.8 per 100,000 person-years in patients who have been on bisphosphonates for less than 2 years increasing to 118 per 100,000 person-years with more than 8 years exposure. AFF has also been seen in patients who have not been on bisphosphonates or other antiresorptive medications.
The diagnostic features of AFF as developed by the American Society for Bone and Mineral Research (ASBMR) include a fracture located anywhere along the femoral shaft: from just distal to the lesser trochanter to just proximal to the supracondylar flare.
In addition: 4 of the 5 following “ Major features ” should be present:
- 1.
The fracture is preceded by only minimal or no trauma.
- 2.
The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur.
- 3.
Complete fractures extend through both cortices and may be associated with a medial spike.
- 4.
Incomplete fractures involve only the lateral cortex.
- 5.
The fracture is noncomminuted or minimally comminuted.
- 6.
Localized periosteal or endosteal thickening of the lateral cortex at the fracture site: “beaking” or “flaring”.
- A.
Minor features
Although often associated with AFF, none of the minor features are required to diagnose AFF. They include generalized increase in cortical thickness of the femoral diaphysis, unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh, bilateral incomplete or complete femoral diaphysis fractures, and delayed fracture healing.
Criteria that have been removed with the 2014 ASBMR revision include:
Exclusion criteria
Exclusion criteria: fracture of the femoral head and neck, intertrochanteric fracture with spiral subtrochanteric extension, periprosthetic femoral fractures, and pathological fractures such as those associated with Paget’s disease and fibrous dysplasia.
Comorbid conditions which have been removed from the ASBMR 2014 revision include vitamin D deficiency, rheumatoid arthritis, hypoparathyroidism, and hypophosphatasia. Pharmaceutical agents which may lead to atypical femoral fractures such as bisphosphonates, as well as glucocorticoids, hypoparathyroidism, and proton pump inhibitors.
- •
Of interest:
- ○
Very occasionally, AFF are seen in patients who have not been on antiresorptive therapy.
- ○
Severe suppression of bone turnover is not seen in most patients sustaining AFF.
- ○
The geometry of the proximal femur may predispose to the development of AFF, specifically, bowed femurs and varus femoral neck/shaft angle. Particularly vulnerable to AFF are patients with an increased femur bowing angle (>5.25 degrees) or a decreased femur neck/shaft angle (<125 degrees). The increased risk of AFF is such that it has been recommended to evaluate these 2 angles before prescribing bisphosphonates and to refrain from such a prescription if both angles are outside the “safe” zone.
- ○
It has also been recommended that if bisphosphonates cannot be avoided that they be given for shorter periods with timely “drug holidays” and that the angles of the 2 femurs be evaluated by X-rays at 6-monthly intervals and to be prepared to switch to another medication.
- ○
Complete AFF needing surgical repair: intramedullary rods or other orthopedic hardware.
- ○
Although osteoarthritis is associated with hip pain, it is not associated with localized pain and tenderness in the femoral shaft. The range of movement of the affected joint is also often diminished or limited by pain. Other joints are also usually affected particularly the knees and hands.
- ○
Pain associated with Paget’s disease of bone is usually worse at night when the patient lies in a warm bed, as this increases the blood flow through the already congested bone. AFF have also been seen in patients with Paget’s disease of bone.
- ○
- 2.
At this stage, the following imaging studies are indicated:
- A.
Plain X-ray, MRI, or CT scan left femur.
- B.
Plain X-ray, MRI, or CT scan of both femurs.
- C.
Technetium bone scan.
- D.
A or C.
- E.
B or C.
Correct answer: B
Comment:
Anatomical visualization of the underlying pathology is necessary to develop an appropriate management strategy. Bilateral imaging studies are indicated because 50%–60% of patients who sustained an atypical femoral shaft fracture have, at almost the exact position on the contralateral femur, evidence of cortical thickening with or without an insufficiency fracture. Although the diagnosis is usually quite obvious on X-rays, it is sometimes missed in early cases. In case of doubt an MRI is more sensitive. The technetium scan shows a localized increased blood flow but will not identify the underlying pathology. Insufficiency fractures may not be visualized on a plain X-ray, but localized cortical swelling may be seen.
- A.
- 3.
Given the radiological appearances, the following is/are recommended:
- A.
Discontinue alendronate.
- B.
Initiate therapy with an osteoanabolic medication such as teriparatide or abaloparatide.
- C.
Consider prophylactic placement of orthopedic software.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The radiological appearances are compatible with an insufficiency fracture. If left untreated it may lead to a complete AFF. Alendronate should be discontinued as it may reduce the rate of bone resorption and possibly interfere with the normal healing process of insufficiency fractures. These patients should be closely monitored and may benefit from raloxifene, estrogen, tibolone, calcitonin, or a short course of bisphosphonates.
There are several reports of teriparatide being useful in the management of insufficiency fractures. Orthopedic hardware could also be inserted prophylactically.
Patients should be investigated for secondary causes of osteoporosis including hypovitaminosis D and metabolic bone diseases such as hypophosphatasia.
- A.
- 4.
Femoral shaft fractures:
- A.
Are also known as subtrochanteric fractures.
- B.
Represent about 10% of all femoral fractures.
- C.
Have a bimodal age distribution.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Femoral shaft fractures, also known as subtrochanteric fractures, represent about 10% of all femoral fractures and have a bimodal age distribution, with an increased prevalence among young and older subjects. About 75% are secondary to severe trauma, the remaining 25% are fragility fractures: atraumatic, low trauma, or low impact injuries and occur mostly in patients with osteoporosis. They share common features with classical osteoporotic fractures: a steep increase in old age, more common in women than men, and occurring spontaneously or after low trauma that would not be expected to lead to a fracture.
In patients treated with antiresorptives there are three separate types of femoral shaft fractures: First, the “typical” fragility femoral shaft fractures due to mechanically weak osteoporotic bone. Second, the “atypical” femoral fragility shaft fractures which are the result of insufficiency fractures that have not healed, have spread across the femur shaft, and are possibly due to antiresorptive medication. Both types of fractures may occur spontaneously, in the absence of trauma or as a result of trauma that ordinarily would not be expected to induce a fracture.
- A.
- 5.
Prognosis of fragility femoral shaft fractures:
- A.
About 15% mortality at 12 months.
- B.
About 50% of patients do not achieve their prefracture functional level.
- C.
About 70% of patients need alternative accommodation.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The prognosis of fragility femoral shaft fractures is similar to that of fragility hip fractures. Hence the need to be alert to this potential complication of antiresorptive therapy. There is evidence that whereas the rate of hip and intertrochanteric fractures has significantly declined since the advent of bisphosphonates, the rate of subtrochanteric fractures has increased during this period, suggesting that it may be, at least partly, due to the antiresorptive medication.
- A.
- 6.
Mechanisms leading to AFF in patients on bisphosphonates:
- A.
Antiangiogenesis effect of bisphosphonates and impaired healing.
- B.
Accumulation of microfractures and microarchitectural deterioration.
- C.
Increased bone brittleness.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comments:
Data from experimental animals show that by suppressing bone turnover bisphosphonates may interfere with the healing process of bone microdamage, thus leading to microdamage accumulation, stress fractures, and eventually complete fractures. Bisphosphonates also increase advanced glycation end products which are associated with more brittle bone and have an antiangiogenic effect.
- A.
- 7.
Match the following:
- (a)
Atypical femoral shaft fractures.
- (b)
Osteoporotic femoral shaft fractures.
- (c)
Both.
- (d)
Neither.
- A.
Usually comminuted.
- B.
Transverse fracture line on the lateral cortex.
- C.
Medial spike is often identified.
- D.
Lateral cortical thickening.
- E.
Short oblique configuration.
- A.
Correct answers: A (b); B (a); C (a); D (a); E (a)
Comment:
Atypical femoral shaft fractures originate as insufficiency or stress fractures and extend perpendicularly through the femur shaft. Unlike traumatic or osteoporotic fractures, they are noncomminuted and are transverse or have a short oblique configuration. As they approach the medial cortex, they may have a medial spike. Cortical thickening is often seen and represents an attempt to increase the mechanical strength of the bone in the presence of an insufficiency fracture that is unable to heal. The cortical thickening could be either localized (beaking or flaring) or generalized.
Insufficiency fractures tend to originate in the lateral cortex which is subject to higher levels of tensile stress.
Insufficiency fractures are due to an abnormally “weak bone” and a “normal or usual” load that should not ordinarily lead to a fracture. Stress fractures, on the other hand, are due to an abnormal load on a relatively healthy bone, as often occurs when a person who for years has led a sedentary lifestyle abruptly decides to go hiking, puts on a heavy load on his shoulders and back, and walks for a long distance. That person is likely to develop a stress fracture.
- (a)
- 8.
Fracture healing:
- A.
Complete fractures heal through callus formation.
- B.
Stress fractures heal through a process of bone remodeling.
- C.
Antiresorptives may interfere with the healing process of stress fractures.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Complete fractures heal through the formation of a soft callus which is gradually invaded by chondrocytes which subsequently ossify and undergo remodeling. Stress and insufficiency fractures heal through a process of bone remodeling: activated osteoclasts remove damaged bone, followed by osteoblasts depositing new healthy bone. Therefore, by interfering with the activity of osteoclasts, antiresorptive agents may interfere with the healing process of these stress and insufficiency fractures and may lead to a complete “atypical” fracture. It must be noted nevertheless that when bisphosphonates are administered to bisphosphonate naïve patients 2 weeks after a hip fracture, they do not interfere with fracture healing.
- A.
- 9.
The following medications have been associated with an increased risk of atypical femoral fractures:
- A.
Bisphosphonates.
- B.
Teriparatide.
- C.
Denosumab.
- D.
A and C.
- E.
A, B, and C.
Correct answer: D
Comment:
Several studies have documented an increased rate of subtrochanteric fractures in patients on bisphosphonates, or denosumab, especially in patients who have been on these medications for more than 3 years. Studies have also shown that longer treatment periods are associated with higher risks. A study on 87,820 women between the ages of 45 and 84 years shows that the risk of AFF is higher if they took bisphosphonates for 3 or more years compared to those who were on bisphosphonates for less than 3 years. Discontinuation of bisphosphonates is associated with a rapid decrease in the risk of AFF.
In patients on bisphosphonates, although the relative risk of an atypical femoral shaft fracture is increased, the absolute risk is very low: it is estimated to range from 3.2 to 50 cases per 100,000 person-years, and to increase to more than 100 per 100,000 person-years among patients on long-term bisphosphonate therapy. This increased risk, however, must be weighed against the bisphosphonate-induced decrease in hip and intertrochanteric fracture.
A recent study based on 196,129 women has shown that after 3 years of bisphosphonate therapy 149 hip fractures were prevented and only two bisphosphonate-associated AFF occurred. The authors also noted that the discontinuation of bisphosphonates was associated with a rapid decrease in the risk of AFF.
- A.
- 10.
The following increases the risk of atypical femoral shaft fractures:
- A.
Glucocorticoids.
- B.
Hypovitaminosis D.
- C.
Rheumatoid arthritis.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Glucocorticoids, antiresorptives (bisphosphonates and denosumab, calcitonin and raloxifene), omeprazole, and a number of medications increase the risk of subtrochanteric fractures. Active rheumatoid arthritis, a serum 25-hydroxy-vitamin D level below 16 ng/mL, prior low-energy fractures, and hypophosphatasia also increase the risk.
- A.
Case summary
Analysis of data
The clinical presentation of an atypical femoral shaft fracture incudes ill-defined pain, tender points, and leg shortening.
Diagnosis
Atypical femoral fracture.
GL has been diagnosed with osteoporosis about 12 years ago and was prescribed alendronate. She adhered well to the medication and now presents with an insufficiency fracture in her left femur. Secondary causes of osteoporosis have been excluded. She is not vitamin D deficient. Her T-score is lower than −2.5.
Management recommendations
Treatment recommendation(s)
- •
Given the insufficiency fracture, which could be the precursor of a complete AFF, the bisphosphonate should be discontinued, and an osteoanabolic agent, teriparatide or abaloparatide, may be considered, especially as her lowest T-score is less than −2.5. Similarly, these patients may benefit from romosozumab which has both osteoanabolic and antiresorptive effects on the skeleton.
- •
Prophylactic femoral rod insertion, possibly bilateral.
- •
Follow-up clinic, 4–6 weeks to ensure she is adhering to teriparatide or abaloparatide therapy. If romosozumab is prescribed the follow-up visit could be postponed for about 2 months. This visit also will ensure the patient has adopted a healthy lifestyle and is getting a well-balanced diet.
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