Bisphosphonate-associated Atypical Fractures that are not “Atypical Femoral Fractures”

Abstract

Aims: Responding to the steadily increasing number of unusual subtrochanteric and mid-shaft femoral (ST/FS) fractures in persons treated with the bisphosphonate drugs since the index cases were described in 2003, the American Society of Bone and Mineral Research (ASBMR) convened a committee tasked with finding a precise definition. Their present definition, a composite from two publications, includes the morphological characteristics of low trauma, origin as an insufficiency fracture, transverse/oblique orientation with/without comminution, cortical thickening, and beaking at the cortex when complete. These fractures must occur in mid-femur, below the lesser trochanter and above the supracondylar flare. They became known as Atypical Femur Fractures (AFFs). The index cases included about an equal number of fractures meeting this definition and similar fractures in other locations. Despite this, attention was focused on the ST/FS definition and a large number of publications ensued describing these. However, publications in the medical literature as early as 1986 contained descriptions of non-femur fractures associated with bisphosphonate therapy and the number of these reported has grown slowly contemporaneously with reports of femur fractures meeting the ASBMR definition. The present authors have been following the development of these non-AFF bisphosphonate-associated fractures since 2005 and have collected a large amount of historical and current information on the subject. We find that many useful inferences about the phenomenon can be derived from consideration of it as a systemic rather than localized effect. We aim to provide a summary of this subset up to the present time and to discuss the implications of these data. Methodology: We queried the OVID Medline database as detailed below. Results and Discussion: We identified 102 individual or case series which reported more than 166 atypical non-AFF fractures. In the Discussion, we review the current state of the evidence upon which the assumed antifracture benefit of the drugs rests and show that these atypical fractures, when added to the AFFs, reduce even more the typically claimed benefit-to-harm ratio. Conclusion: We intend this review as a resource for individuals wishing to follow developments in this field. We also present our conclusions about the implications of the accumulated evidence and the general state of associated knowledge.