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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CME Information
CME Released: 03/02/2011; Reviewed and Renewed: 07/25/2012; Valid for credit through 07/25/2013 This activity has expired. The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to the timeliness of expired CME activities.
Target Audience
This activity is intended for clinicians in primary care, emergency care, and rheumatology.
Goal
The goal of this activity is to reinforce and highlight common concepts, situations, and presentations that clinicians will encounter on a regular basis to provide supportive continuing education that illustrates real-world conditions and situations.
Learning Objectives
Upon completion of this activity, participants will be able to: 1. Describe the typical presentation and management of a commonly encountered medical condition in clinical practice
Credits Available
Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™ All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Accreditation Statements
For Physicians
Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity. Medscape, LLC staff have disclosed that they have no relevant financial relationships. Contact This Provider For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
above. For technical assistance, contact [email protected]
Instructions for Participation and Credit
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile.
Hardware/Software Requirements
To access activities, users will need: A computer with an Internet connection. Internet Explorer 7.x or higher, Firefox 4.x or higher, Safari 2.x or higher, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader.
Faculty and Disclosures
As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by 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 approved by 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-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Nallapaneni does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by 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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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
A 49-Year-Old Man Presents With a Fractured Leg
George T. Griffing, MD; Naga Neelima Nallapaneni, MB BS
CME Released: 03/02/2011; Reviewed and Renewed: 07/25/2012; Valid for credit through 07/25/2013
A 49-Year-Old Man Presents With a Fractured Leg Background
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
Figure 1. Radiograph of the femoral fracture showing increased cortical thickness (arrows).
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
(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) Spine (L1-L4) Femoral Neck Femoral Neck T-Score Z-score T-Score Z-score -7 years -4 years +8 months -1.08 0.1 -0.6 -0.92 0.4 -0.1 -1.23 -0.6 -0.3 -0.68 0.1 -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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
Figure 1. Radiograph of the femoral fracture showing increased cortical thickness (arrows).
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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 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* Major
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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 or 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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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 an evolving 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 longterm 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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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.
CME Test
To receive AMA 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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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. Abstract 5. 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 antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11âhydroxysteroid 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;362:18251827. 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-a7022f6eedb8e8f5. 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 1519, 2010; Toronto, Ontario, Canada. Abstract 1201. Available at: http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=05caf316-b73e-47b8-a011bf0766b062c0. 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 Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape CME Case Presentations © 2011 Medscape, LLC
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CME Information
CME Released: 03/02/2011; Reviewed and Renewed: 07/25/2012; Valid for credit through 07/25/2013 This activity has expired. The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to the timeliness of expired CME activities.
Target Audience
This activity is intended for clinicians in primary care, emergency care, and rheumatology.
Goal
The goal of this activity is to reinforce and highlight common concepts, situations, and presentations that clinicians will encounter on a regular basis to provide supportive continuing education that illustrates real-world conditions and situations.
Learning Objectives
Upon completion of this activity, participants will be able to: 1. Describe the typical presentation and management of a commonly encountered medical condition in clinical practice
Credits Available
Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™ All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Accreditation Statements
For Physicians
Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity. Medscape, LLC staff have disclosed that they have no relevant financial relationships. Contact This Provider For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted
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above. For technical assistance, contact [email protected]
Instructions for Participation and Credit
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile.
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To access activities, users will need: A computer with an Internet connection. Internet Explorer 7.x or higher, Firefox 4.x or higher, Safari 2.x or higher, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader.
Faculty and Disclosures
As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by 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 approved by 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-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Nallapaneni does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by 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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A 49-Year-Old Man Presents With a Fractured Leg (printer-friendly)
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
A 49-Year-Old Man Presents With a Fractured Leg
George T. Griffing, MD; Naga Neelima Nallapaneni, MB BS
CME Released: 03/02/2011; Reviewed and Renewed: 07/25/2012; Valid for credit through 07/25/2013
A 49-Year-Old Man Presents With a Fractured Leg Background
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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) Spine (L1-L4) Femoral Neck Femoral Neck T-Score Z-score T-Score Z-score -7 years -4 years +8 months -1.08 0.1 -0.6 -0.92 0.4 -0.1 -1.23 -0.6 -0.3 -0.68 0.1 -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 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* 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 or 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 an evolving 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 longterm 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.
CME Test
To receive AMA 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. Abstract 5. 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 antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11âhydroxysteroid 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;362:18251827. 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-a7022f6eedb8e8f5. 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 1519, 2010; Toronto, Ontario, Canada. Abstract 1201. Available at: http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=05caf316-b73e-47b8-a011bf0766b062c0. 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 Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape CME Case Presentations © 2011 Medscape, LLC
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