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Bisphosphonates and Nonhealing Femoral Fractures: Analysis of the FDA Adverse Event Reporting System (FAERS) and International Safety EffortsA Systematic Review from the Research on Adverse Drug Events And Reports (RADAR) Project
Beatrice J. Edwards, MD, MPH1; Andrew D. Bunta, MD1; Joseph Lane, MD2; Clarita Odvina, MD3; D. Sudhaker Rao, MD4; Dennis W. Raisch, RPh, PhD5; June M. McKoy, MD, MPH, JD, MBA6; Imran Omar, MD7; Steven M. Belknap, MD8; Vishvas Garg, PhD5; Allison J. Hahr, MD9; Athena T. Samaras, BA10; Matthew J. Fisher, BA11; Dennis P. West, PhD, FCCP, CIP8; Craig B. Langman, MD12; Paula H. Stern, PhD13
1 Bone Health and Osteoporosis Center, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 1350, Chicago, IL 60611
2 Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY 10021
3 University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
4 Division of Endocrinology, Diabetes, and Bone and Mineral Metabolism, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202
5 Department of Pharmacy Practice and Administrative Sciences, Nursing/Pharmacy Building, Room B94, University of New Mexico, Albuquerque, NM 87131
6 Division of Geriatric Medicine, Feinberg School of Medicine, Northwestern University, 645 North Michigan, Suite 630, Chicago, IL 60611
7 Department of Radiology, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 800, Chicago, IL 60611
8 Department of Dermatology, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 1600, Chicago, IL 60611
9 Division of Endocrinology, Department of Medicine, Feinberg School of Medicine, Northwestern University, 645 North Michigan, Suite 530, Chicago, IL 60611
10 Robert H. Lurie Comprehensive Cancer Center, 676 North Saint Clair, Suite 1600, Chicago, IL 60611
11 Division of Geriatric Medicine, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 1600, Chicago, IL 60611
12 Ann and Robert H. Lurie Children’s Hospital of Chicago, Box MS37, 225 East Chicago Avenue, Chicago, IL 60611
13 Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, 645 North Michigan, Suite 630, Chicago, IL 60611
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  • Disclosure statement for author(s): PDF

Investigation performed at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago, Illinois

A commentary by Michael J. Klein, MD, is linked to the online version of this article at jbjs.org.



Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, one or more of the authors has had another relationship, or has engaged in another activity, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Feb 20;95(4):297-307. doi: 10.2106/JBJS.K.01181
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Abstract

Background: 

In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts.

Methods: 

We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012).

Results: 

The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures.

Conclusions: 

Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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