Mysterious Femur Fracture in an Aged Man

Background
A 69-year-old man with a history of osteopenia and HIV infection presents for follow-up. He had
been seen in the emergency department about 8 months ago after several days of dull thigh pain
followed by a sudden, intense pain after making a twisting motion when walking. He was
diagnosed with a midshaft femoral fracture. He has had no previous bone fractures.
He has long-standing HIV infection and is taking antiretroviral medications. He is also on
supplemental calcium, vitamin D, and 8 years of alendronate therapy as part of a clinical HIV
study. He has no known history of cancer. The patient does not have any known allergies and the
family medical history is unremarkable.
Physical Examination and Workup
Upon physical examination, his vital signs are normal. His height is about the same length as his
arm span. The patient's physical appearance is remarkable for HIV-treatment–induced
lipodystrophy and a Cushingoid habitus (Figure 1).

Figure 1.

The sclera and tympanic membranes are clear. Gonadal examination demonstrates bilaterally
descended and normal-sized testicles. Upon laboratory investigations, the complete blood cell
count, urinalysis, complete metabolic panel, vitamin D level, thyroid-stimulating hormone level,
and testosterone level are normal. Urinary free cortisol and an overnight dexamethasone
suppression test for Cushing syndrome are also normal. He has an undetectable HIV viral load
and a normal CD4 count. He has normal plasma and urine calcium, serum phosphorus, alkaline
phosphate, and parathyroid hormone levels.

The patient had been enrolled in an HIV alendronate study 7 years prior to injury. Bone mineral
density (BMD) testing at that time showed osteopenia. The patient was then started on
alendronate therapy. Repeat BMD testing 4 years before the injury showed normal density scores
at both his hip and spine. Now, 8 months after his injury, his BMD is still normal although it is
decreased from his levels 4 years previously (Table 1).
Table 1. Bone Mineral Density*
Time before or after fracture Spine (L1- Spine (L1- Femoral Neck Femoral Neck
L4) L4) T-Score Z-score
T-Score Z-score
-7 years -1.08 -0.92 -1.23 -0.68
-4 years 0.1 0.4 -0.6 0.1
+8 months -0.6 -0.1 -0.3 -0.1
*Densities reported in g/cm2

Discussion
In this case, the patient, who was in relatively stable medical health, experienced an atypical
midshaft femoral fracture (Figures 1 and 2).
Figure 1. Figure2.

This fracture met all major and several of the minor criteria for an atypical femur fracture (Table
2). The specific criteria this fracture met include a midshaft location, lack of trauma, short
oblique configuration, noncomminuted, presence of a medial spike (also referred to as unicortical
beak), increased diaphyseal cortical thickness, prodromal leg pain near the area of the fracture,
and a 7-year history of alendronate use. Given the patient's history and study results, alendronate
seemed the most likely cause.

Table 2. Atypical Femoral Fracture: Major and Minor Features*[1]

Major  Located anywhere along the femur from just distal to the lesser
Features† trochanter to just proximal to the supracondylar flare
 Associated with no trauma or minimal trauma, as in a fall from a
standing height or less
 Transverse or short oblique configuration
 Noncomminuted
 Complete fractures extend through both cortices and may be associated
with a medial spike; incomplete fractures involve only the lateral cortex
Minor  Localized periosteal reaction of the lateral cortex‡
Features  Generalized increase in cortical thickness of the diaphysis
 Prodromal symptoms such as dull or aching pain in the groin or thigh
 Bilateral fractures and symptoms
 Delayed healing
 Comorbid conditions (eg, vitamin D deficiency, RA, hypophosphatasia)
 Use of pharmaceutical agents (eg, BPs, GCs, proton pump inhibitors)
BPs = bisphosphonates; GCs = glucocorticosteroid; RA = rheumatoid arthritis
*
Specifically excluded are fractures of the femoral neck, intertrochanteric fractures with
spiral subtrochanteric extension, pathologic fractures associated with primary or metastatic
bone tumors, and periprosthetic fractures.
†
All major features are required to satisfy the case definition of atypical femoral fracture.
None of the minor features are required but have been sometimes associated with these
fractures.
‡
Often referred to in the literature as "beaking" or "flaring"

All the other features listed can cause atypical fractures but were less likely in this patient. This
patient had no evidence of malignancy. He had none of the laboratory data associated with
osteomalacia or primary hyperparathyroidism (ie, normal plasma and urine calcium, serum
phosphorus, alkaline phosphate, vitamin D, and parathyroid hormone), nor did he have the
physical stigmata and repeated bone fracture history of pycnodysostosis or osteogenesis
imperfecta.

This patient had been taking alendronate as part of an HIV bone-protection study. Alendronate
(and possibly other bisphosphonates) have been linked to atypical femoral fractures. In fact, 94%
of 310 cases of atypical femur fracture studied by an American Society for Bone and Mineral
Research Atypical Femoral Fracture Task Force were associated with bisphosphonate usage
(mostly alendronate). The task force stopped short of declaring these medications to be the cause
of the fractures because similar fractures have been documented in patients who are not on
bisphosphonate therapy. However, this report led to the US Food and Drug Administration
(FDA) adding a warning about atypical fractures to bisphosphonate package labeling. Both the
task force and the FDA believe that this is a drug class (bisphosphonates) association and that the
association with alendronate is the strongest because it has the largest usage and longest approval
time.
The cause of this fracture may be related to alendronate's mechanism of action. Alendronate
inhibits the osteoclast mevalonate pathway, resulting in decreased bone resorption and increased
apoptosis. Reducing bone resorption is the mechanism by which this drug reduces osteoporotic
fractures. Because osteoblastic bone formation follows osteoclastic bone resorption, overall bone
turnover and bone remodeling decreases. Bone remodeling, however, is the primary repair
mechanism for microdamage occurring in the bone. Increased evidence of microdamage has
been demonstrated in bone biopsies from both animal and human subjects treated with long-term
alendronate (5 years). Accumulation of this microdamage can reduce bone strength, thereby
increasing the risk for fracture, especially in areas of high mechanical stresses (eg, femur).
Most atypical femoral fractures show a common radiographic pattern. Conventional x-rays in the
anteroposterior and lateral projections will show a transverse or oblique fracture. Diffuse cortical
thickening can be present, particularly laterally, wherein the fracture often initiates. When
cortical thickening is focal and substantial, an appearance of "beaking" or "flaring" adjacent to
the transverse fracture line may be noted. As the fracture evolves and propagates medially,
ultimately displacing and becoming a complete fracture, an oblique component may be observed
as a prominent medial "spike." Discrete linear lateral cortical translucencies may be observed in
the prefracture-displacement phase, often with adjacent focal cortical thickening from periosteal
new-bone apposition.
Atypical fractures are often preceded by prodromal symptoms of aching, deep thigh or groin
pain, and normal x-rays (as they were in this case). Radionuclide bone scintigraphy may be used
to document the presence of an evolving stress or atypical fracture. In these cases, the
scintigraphic appearance is that of increased uptake in a broad diffuse zone and a centrally
located focal region of more intense uptake, usually in the lateral cortex. Like bone scintigraphy,
MRI may detect an evolving stress or insufficiency fracture. These MRI findings manifest as
diffuse decreased signal on T1-weighted images and diffuse increased signal on T2-weighted
images related to the associated inflammation and hyperemia.
The evolving fracture line in the lateral cortex may be seen. Spiral CT imaging occasionally
detects subtle reactive periosteal new-bone formation and the small discrete radiolucency of an
evolving fracture. Although more costly, MRI and CT scanning have superior sensitivity and
specificity for detecting the early stages of stress or atypical fractures. Even the lower-resolution
images of dual x-ray absorptiometry may occasionally detect the hypertrophic new-bone
formation of an evolving proximal subtrochanteric femoral shaft fracture and aid in the
differentiation of proximal thigh pain in this condition.
The rarity of atypical femoral fractures makes them difficult to study, and there is controversy
regarding causality with bisphosphonates. These fractures may share the same epidemiology
with osteoporosis and may be a marker for otherwise ill health.[5,6] A large nationwide cohort
study by Vestergaard and colleagues also suggested that an increased risk for femoral shaft and
subtrochanteric fractures seen with the use of bisphosphonate agents may be a confounding
effect of a patient's underlying disease. The investigators noted there was an increased risk for
such fractures both before and after the administration of these drugs.

This patient, however, was relatively young and in good health compared with other reports of
patients with atypical femoral fracture. Despite this, alendronate may not have been his only risk
factor. An additional risk may relate to the presence of HIV-associated lipodystrophy syndrome.
Evidence supports the possibility that this syndrome is caused by tissue hypercortisolism
resulting in a Cushing's appearance, even though blood and urine cortisol levels are normal. The
tissue hypercortisolism is the result of increased production of a tissue enzyme (11 beta-
hydroxysteroid dehydrogenase) that converts cortisone (inactive) to cortisol (active).[8]
Pharmacologic hypercortisolism is known to increase the risk for atypical femoral fracture
fivefold, and this patient's lipodystrophy syndrome may confer a risk similar to that of using
exogenous glucocorticoids.[9,10] Therefore, the additive risk of alendronate usage and tissue
lipodystrophy-associated hypercortisolism may explain the occurrence of this fracture in an
otherwise relatively healthy middle-aged man.
Despite the possible association between bisphosphonates and these atypical fractures, atypical
femoral fractures are still relatively rare compared with hip fractures, and the benefits of
osteoporotic fracture protection still outweigh this risk. For example, the occurrence of hip
fractures in women is approximately 100/10,000 patient-years, but atypical femoral fractures
occur in only about 1/10,000 patient-years. If, for instance, alendronate prevents 50% of these
hip fractures, the benefit of preventing 50 of these osteoporotic hip fractures offsets the risk of 1
atypical femoral fracture. The short-term benefits of hip-fracture protection begin well before the
long-term risk of an atypical femoral fracture. In a study of 102 cases of atypical femoral
fractures, 97 patients had taken a bisphosphonate, and the risk for fracture increased with the
duration of use (2/100,000 patients/year after 2 years, and 78/100,000 patients/year after 8 years
of use). Therefore, shorter durations of alendronate therapy may be useful to maximize the
benefits and reduce the risks. Thus, further data are required to determine the optimal duration of
alendronate therapy.
Given the state of our imperfect knowledge of this problem, following the recommendations of
experts is reasonable. In patients without an osteoporotic fracture, the recommendations are as
follows:
Limit the use of alendronate (and other bisphosphonates) to 5 years or when bone markers show
that bone remodeling has stopped (continue calcium and vitamin D).
Restart bisphosphonate therapy if bone loss resumes, but do so at the lowest possible dose.
Bisphosphonate-treated patients with thigh pain may need to be evaluated for a prodromal stress
fracture (eg, x-ray, MRI, and/or bone scanning).
When an atypical fracture occurs, stop the alendronate and treat with an anabolic agent (eg,
teriparatide) to prevent a contralateral fracture.
In patients with an osteoporotic fracture, the benefits of continuing bisphosphonate therapy
outweigh the risks of stopping it (in most cases).
Ultimately, this patient had an open reduction and internal fixation of the femoral fracture, and
he had an uncomplicated postoperative course. Alendronate therapy was stopped, and he was
started on teriparatide. A repeat BMD after 15 months showed osteopenia. He has had no further
fractures or leg pain.
A noncomminuted fracture is one of the major criteria for an atypical femoral fracture. The other
factors are all expected with atypical fractures.
The prolonged inhibitory action of bisphosphonates on bone remodeling is thought to decrease
the repair process, leading to the accumulation and eventual coalescence of microfractures into a
complete transverse fracture.