Correspondence
More on Atypical Fractures of the Femoral Diaphysis
N Engl J Med 2008; 359:316-318July 17, 2008
- Article
To the Editor:
Our experience has been very similar to that described by Lenart et al. (March 20 issue)1 in their report on atypical fractures of the femoral diaphysis. These fractures have a distinctive pattern and most likely represent completion of a stress fracture (Figure 1Figure 1
Radiograph Showing a Subtrochanteric Stress Fracture Associated with a Typical Cortical Stress Reaction.). In our series,2 64.3% of the patients had involvement of the contralateral femur. In addition, 76% of the patients had documented prodromal symptoms of thigh pain, vague discomfort, or subjective weakness; these symptoms were often dismissed or treated as symptoms of spinal stenosis. “Giving way” of the involved limb immediately preceded the fall in 23.1% of the patients.3 We suggest that any patient receiving bisphosphonates who has thigh pain should undergo radiographic examination of the femur, and patients with a documented fracture should undergo radiographic examination of the contralateral femur. Prefracture diagnosis is challenging, as is defining the need for prophylactic fixation of a lateral cortical stress reaction that has been characterized by means of computed tomographic and magnetic resonance imaging (MRI) studies as a callus forming over an incomplete stress fracture.3 ReferencesErnest B.K. Kwek, M.B., B.S.
Joyce S.B. Koh, M.B., B.S.
Tet Sen Howe, M.B., B.S.
Singapore General Hospital, Singapore S169608, Singapore
kwekasc@pacific.net. sg 1
Lenart BA ,Lorich DG ,Lane JM . Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358:1304-1306
Full Text | Web of Science | Medline2
Kwek EBK ,Goh SK ,Koh JS ,Png MA ,Howe TS . An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 2008;39:224-231
CrossRef | Web of Science | Medline3
Goh SK ,Yang KY ,Koh JS , et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007;89:349-353
CrossRef | Web of Science | Medline
To the Editor:
We previously reported a case similar to those reported by Lenart et al. Our patient, a 73-year-old woman, sustained multiple atraumatic femoral insufficiency fractures while receiving alendronate therapy.1 The bone-specific alkaline phosphatase level was 7.9 μg per liter (range, 3.8 to 22.6), and the ratio of urinary deoxypyridinoline to creatinine was suppressed, at a value of less than 3 nmol per millimole. Although suppressed bone turnover theoretically raises the possibility of bisphosphonate-related “frozen bone,” as previously reported,2 histomorphometrically proven suppression of bone formation was incompatible with the demonstration of normal bone-turnover markers in the series reported by Odvina et al.
Femoral insufficiency fractures are associated with increased mortality, and they are probably markers of ill health with multifactorial causes.1 These fractures are not limited to patients who are receiving bisphosphonates. Nonadherence to prescribed bisphosphonates is associated with a 15 to 20% increase in rates of subsequent fractures. We agree that clinicians should be cautious about the hazards of long-term administration of bisphosphonates. However, until further studies can provide definitive evidence of bisphosphonate-associated fractures, it is premature to attribute atypical fractures to oversuppression of bone turnover alone, while disregarding secondary and patient-related factors. The fractures in our patient healed while alendronate therapy was continued.
2 ReferencesPaul Lee, M.B., B.S.
Markus J. Seibel, M.D., Ph.D.
Concord Repatriation General Hospital, Sydney, NSW 2139, Australia
p.lee@garvan. org. au 1
Lee P ,van der Wall H ,Seibel MJ . Looking beyond low bone mineral density: multiple insufficiency fractures in a woman with post-menopausal osteoporosis on alendronate therapy. J Endocrinol Invest 2007;30:590-597
Web of Science | Medline2
Odvina CV ,Zerwekh JE ,Rao DS ,Maalouf N ,Gottschalk FA ,Pak CY . Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Kwek et al. and with Lee and Seibel that stress fractures of the femoral diaphyses commonly occur in association with prolonged bisphosphonate use. We also agree with Kwek et al. that careful scrutiny of the contralateral femur is important, but radiography may not be adequate. A painful limb may require additional imaging. MRI and bone scanning have greater sensitivity than radiography for an incipient stress fracture.
In response to Lee and Seibel: low bone turnover may not be the only cause of stress fractures associated with prolonged bisphosphonate use. In our series, markers of bone turnover were not directly measured, since diagnosis-related groups did not cover a workup for metabolic bone disease, including markers of bone turnover, for the care of patients with fractures. Microfractures, inadequate mineralization, and outdated collagen are several candidate causes. Although the fractures reported by Lee et al. healed with continued bisphosphonate treatment, an anabolic agent such as parathyroid hormone (1-34) may be preferable. Parathyroid hormone not only has activated bone-formation markers in trials in humans but has also enhanced the healing of fractures in studies in animals.1,2
2 ReferencesBrett A. Lenart, M.D.
Dean G. Lorich, M.D.
Joseph M. Lane, M.D.
Weill Medical College of Cornell University, New York, NY 10021
lanej@hss.edu 1
Black DM ,Greenspan SL ,Ensrud KE , et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215
Full Text | Web of Science | Medline2
Alkhiary YM ,Gerstenfeld LC ,Krall E , et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am 2005;87:731-741
CrossRef | Web of Science | Medline
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Pongthorn Narongroeknawin, Nivedita M. Patkar, Bita Shakoory, Archana Jain, Jeffrey R. Curtis, Elizabeth Delzell, Philip H. Lander, Robert R. Lopez-Ben, Michael J. Pitt, Monika M. Safford, David A. Volgas, Kenneth G. Saag. (2011) Validation of Diagnostic Codes for Subtrochanteric, Diaphyseal, and Atypical Femoral Fractures Using Administrative Claims Data. Journal of Clinical Densitometry
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Thomas Funck-Brentano, Emmanuel Biver, Florence Chopin, Beatrice Bouvard, Guillaume Coiffier, Jean-Claude Souberbielle, Patrick Garnero, Christian Roux. (2011) Clinical Utility of Serum Bone Turnover Markers in Postmenopausal Osteoporosis Therapy Monitoring: A Systematic Review. Seminars in Arthritis and Rheumatism 41:2, 157-169
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J.R. Caeiro-Rey, I. Etxebarria-Foronda, M. Mesa-Ramos. (2011) Fracturas atípicas relacionadas con el uso prolongado de bifosfonatos. Estado de la situación. Revista Española de Cirugía Ortopédica y Traumatología 55:5, 392-404
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J.R. Caeiro-Rey, I. Etxebarria-Foronda, M. Mesa-Ramos. (2011) Atypical fractures associated with the long term use of bisphosphonates. The current situation. Revista Española de Cirugía Ortopédica y Traumatología (English Edition) 55:5, 392-404
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Seo Young Kim, Sebastian Schneeweiss, Jeffrey N Katz, Raisa Levin, Daniel H Solomon. (2011) Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. Journal of Bone and Mineral Research 26:5, 993-1001
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Kimberly McKenzie, J. Dennis Bobyn, Jacintha Roberts, Dorota Karabasz, Michael Tanzer. (2011) Bisphosphonate Remains Highly Localized After Elution From Porous Implants. Clinical Orthopaedics and Related Research® 469:2, 514-522
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R. Rizzoli, K. Åkesson, M. Bouxsein, J. A. Kanis, N. Napoli, S. Papapoulos, J.-Y. Reginster, C. Cooper. (2011) Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporosis International 22:2, 373-390
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C. Wack, R. Zettl, S. Ruchholtz. (2010) Man lernt nie aus – zu spät erkannt. Trauma und Berufskrankheit 12:S4, 425-429
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Richard S. Yoon, Kathleen S. Beebe, Joseph Benevenia. (2010) Prophylactic Bilateral Intramedullary Femoral Nails for Bisphosphonate-Associated Signs of Impending Subtrochanteric Hip Fracture. Orthopedics
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M. H. Edwards, F. C. McCrae, S. A. Young-Min. (2010) Alendronate-related femoral diaphysis fracture—what should be done to predict and prevent subsequent fracture of the contralateral side?. Osteoporosis International 21:4, 701-703
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Joyce S B Koh, Seo Kiat Goh, Meng Ai Png, Ernest B K Kwek, Tet Sen Howe. (2010) Femoral Cortical Stress Lesions in Long-Term Bisphosphonate Therapy: A Herald of Impending Fracture?. Journal of Orthopaedic Trauma 24:2, 75-81
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Athanassios Kyrgidis, Konstantinos Vahtsevanos. (2009) “Fatigue” having a role in the pathogenesis of osteonecrosis of the jaws. Clinical Oral Investigations 13:4, 479-480
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Athanassios Kyrgidis, Stefanos Triaridis, Kostantinos Vahtsevanos, Kostantinos Antoniades. (2009) Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients. Expert Review of Anticancer Therapy 9:8, 1125-1134
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Kurt A. Kennel, Matthew T. Drake. (2009) Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clinic Proceedings 84:7, 632-638
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K. A. Kennel, M. T. Drake. (2009) Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clinic Proceedings 84:7, 632-638
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Leyla H. Alparslan, Barbara N. Weissman. 2009. Imaging Findings of Drug-Related Musculoskeletal Disorders. , 264-279.
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Jörg Schilcher, Per Aspenberg. (2009) Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthopaedica 80:4, 413-415
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