LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.
The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.
Dr. Michael Stone
How common are atypical femoral fractures?
"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.
"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."
"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.
However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.
Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).
There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.
Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.
What are atypical hip fractures?
Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.
"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.
Dr. Emma Clark
There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.
The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).
The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."