a 49-year-old man presents with a fractured leg (printer-friendly)

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10/13/13 A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)

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Author(s)

George T. Griffing, MD

Professor of Medicine, Department of Internal Medicine, Saint Louis University, St. Louis, Missouri

Disclosure: George T. Griffing, MD, has disclosed no relevant financial relationships.

Dr. Griffing does not intend to discuss off-labeluses of drugs, mechanical devices, biologics, or diagnostics not

approvedby the US Food and Drug Administration (FDA) for use in the United States.

Dr. Griffing does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not

approvedby the FDA for use in the United States.

Naga Neelima Nallapaneni, MB BS

Department of Internal Medicine, Saint Louis University, St. Louis, Missouri

Disclosure: Naga Neelima Nallapaneni, MB BS, has disclosed no relevant financial relationships.

Dr. Nallapaneni does not intend to discuss off-labeluses of drugs, mechanical devices, biologics, or diagnostics noapprovedby the FDA for use in the United States.

Dr. Nallapaneni does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not

approvedby the FDA for use in the United States.

Editor(s)

Craig A. Goolsby, MD

Director, eMedicine Case of the Week; Staff Physician, Department of Emergency Medicine, Wilford Hall Medical

Center, Lackland Air Force Base, San Antonio, TX

Disclosure: Craig A. Goolsby, MD, has disclosed no relevant financial relationships.

Joseph U. Becker, MD

Chief Resident, Division of Emergency Medicine, Department of Surgery, Yale New Haven Medical Center, New

Haven, CT

Disclosure: Joseph U. Becker, MD, has disclosed no relevant financial relationships.

Herbert S. Diamond, MD

Professor of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; Chairman Emeritus,

Department of Internal Medicine, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania

Disclosure: Herbert S. Diamond, MD, has disclosed no relevant financial relationships.

Eugene Lin, MD

Clinical Assistant Professor, Department of Radiology, University of Washington Medical Center; Attending

Physician, Virginia Mason Medical Center, Seattle, Washington

Disclosure: Eugene Lin, MD, has disclosed no relevant financial relationships.


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Luis M. Soler, BA

Associate Editor, eMedicine/Medscape

Disclosure: Luis M. Soler, BA, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

From Medscape CME Case Presentations

George T. Griffing, MD; Naga Neelima Nallapaneni, MB BS

A 49-Year-Old Man Presents With a Fractured Leg

Background

A 49-Year-Old Man Presents With a Fractured Leg

CME Released: 03/02/2011; Reviewed and Renewed: 07/25/2012; Valid for credit through 07/25/2013
http://www.medscape.org/index/list_3253_0


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Figure 1. Radiograph of the femoral fracture showing increased cortical thickness (arrows).


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Figure 2. The arrow shows the medial spike.

A 49-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.

On 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


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(Figure 1). The sclera and tympanic membranes are clear. Gonadal examination demonstrates bilaterally descended

and normal-sized testicles.

On 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-L4)

T-Score

Spine (L1-L4)

Z-score

Femoral Neck

T-Score

Femoral Neck

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

Which of the following most likely contributed to this man's atypical midshaft femoral fracture?

Hint: Note the fracture pattern on the femoral x-ray.

Bony metastases

Osteomalacia

Pycnodysostosis

Primary hyperparathyroidism

Alendronate therapy

Save and Proceed

Discussion


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Figure 1. Radiograph of the femoral fracture showing increased cortical thickness (arrows).


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Figure 2. The arrow shows the medial spike.

In this case, the patient, who was in relatively stable medical health, experienced an atypical midshaft femoral

fracture (Figures 1 and 2). 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 diaphysea

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*

Major


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Features Located anywhere along the femur from just distal to the lesser 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

Features Localized periosteal reaction of the lateral cortex

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"

Data from US Food and Drug Administration. [1]

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 o

osteogenesis imperfecta.

This patient had been taking alendronate as part of an HIV bone-protection study. Recently, 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). [2]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.[2]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). [3]

Accumulation of this microdamage can reduce bone strength, thereby increasing the risk for fracture, especially in

areas of high mechanical stresses (eg, femur).

The majority of atypical femoral fractures show a common radiographic pattern. Conventional x-rays in the


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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 employed to document the presence of anevolving stress or atypical fracture. In these cases, the scintigraphic appearance will be 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. On occasion, 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.[4]It has been argued that these fractures 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[7]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.[7]

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 fractures 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.[11]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. [11]If for instance alendronate prevents 50% of

these hip fractures, the benefit of preventing 50 of these osteoporotic hip fractures is offset by the risk for 1 atypical

femoral fracture. It is important to note that 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 fracture, 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).[12]Therefore, it may be possible to use shorter durations of

alendronate therapy 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, it seems reasonable to follow the recommendations of


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some of the experts.[13]In patients without an osteoporotic fracture, the recommendations are as follows:

A. 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).

B. Restart bisphosphonate therapy if bone loss resumes, but do so at the lowest possible dose.

C. Bisphosphonate-treated patients with thigh pain may need to be evaluated for a prodromal stress fracture (eg,

x-ray, MRI, and/or bone scanning).

D. 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.

CMETest

To receiveAMA PRA Category 1 Credit, you must receive a minimum score of 70% on the post-test.

You suspect alendronate was associated with a femoral fracture in one of your patients. Which of the

following factors, if seen in this fracture, would make alendronate use the least likely cause?

Long duration of alendronate therapy

Femoral diaphysis location of the fracture

Radiographic characteristics of a transverse fracture pattern with beaking of the cortex and

cortical hypertrophy

Absence of other causes of low-energy femoral fractures

The fracture is comminuted

Alendronate therapy is strongly suspected as the culprit in an atraumatic femoral fracture in one of

your patients. What is the putative mechanism for alendronate-associated atypical femoral fractures?

Decreased vitamin D levels leading to osteomalacia

Decreased bone remodeling leading to the accumulation of microfractures

Increased bone remodeling leading to weakening of cortical bone

A renal phosphate leak leading to increased calcium losses in the urine

Save and Proceed

References

1. US Food and Drug Administration. FDA Drug Safety Communication: Safety update for osteoporosis drugs,

bisphosphonates, and atypical fractures. October 23, 2010 Available at:


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http://www.fda.gov/Drugs/DrugSafety/ucm229009.htm#summary . Accessed February 24, 2011.

2. Shane E, Burr D, Ebeling PR, 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 [published online ahead of print]. J Bone Miner Res. 2010;25:2267-2294. Available at:

http://onlinelibrary.wiley.com/doi/10.1002/jbmr.253/pdf. Accessed September 17, 2010.

3. Stepan JJ, Burr DB, Pavo I, et al. Low bone mineral density is associated with bone microdamage

accumulation in postmenopausal women with osteoporosis. Bone. 2007;41:378-385.Abstract

4. Black DM, Kelly MP, Genant HK, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal

femur. N Engl J Med. 2010;362:1761-1771.Abstract5. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with

alendronate: a register-based national cohort study. J Bone Miner Res. 2009;24:1095-1102.Abstract

6. Abrahamsen B, Eiken P, Eastell R. Cumulative alendronate dose and the long-term absolute risk of

subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol

Metab. 2010;95:5258-5265.Abstract

7. Vestergaard P, Schwartz F, Rejnmark L, Mosekilde L. Risk of femoral shaft and subtrochanteric fractures

among users of bisphosphonates and raloxifene. Osteoporos Int. 2011;22:993-1001.Abstract

8. Sutinen J, Kannisto K, Korsheninnikova E, et al. In the lipodystrophy associated with highly active antiretrovira

therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11-

hydroxysteroid dehydrogenase type 1 in adipose tissue. Diabetologia. 2004;47:1668-1671.Abstract

9. Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med.

2010;362:1848-1849.Abstract

10. Giusti A, Hamdy NA, Papapoulos SE. Atypical fractures of the femur and bisphosphonate therapy: a

systematic review of case/case series studies. Bone. 2010;47:169-180.Abstract

11. Shane, E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med. 2010;362:1825-

1827.Abstract

12. Kelly MP, Wustrack R, Bauer DC, et al. Incidence of subtrochanteric and diaphyseal fractures in older white

women: data from the Study of Osteoporotic Fractures. Program and abstracts of the ASBMR 2010 Annual

Meeting; October 15-19, 2010; Toronto, Ontario, Canada. Poster FR0355. Available at:

http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=8e62e010-dd30-4d4d-a702-

2f6eedb8e8f5. Accessed February 24, 2011.13. Dell R, Greene D, Ott S, et al. A retrospective analysis of all atypical femur fractures seen in a large California

HMO from the years 2007 to 2009. Program and abstracts of the ASBMR 2010 Annual Meeting; October 15-

19, 2010; Toronto, Ontario, Canada. Abstract 1201. Available at:

http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=05caf316-b73e-47b8-a011-

bf0766b062c0. Accessed February 24, 2011.

14. Nieves JW, Cosman F. Atypical subtrochanteric and femoral shaft fractures and possible association with

bisphosphonates. Curr Osteoporos Rep. 2010;8:34-39.Abstract

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