Atypical femur fractures: Refining the clinical picture

Atypical femur fractures are a growing clinical concern. Unfortunately, studies with access to a substantial number of femur X-rays from fracture patients have been limited by short-term drug history data. Although studies with long-term drug-dispensing information exist, they have had to rely on diagnosis codes, so atypical femur fractures could not be distinguished from other subtrochanteric or diaphyseal femur fractures. The former type of study may show correct incidence rates yet provide odds ratios (OR) that are too high because of the undercapture of past drug exposure, whereas the latter type of study will provide incidence rates that are too high and odds ratios that are too low because they include fractures that may not be atypical. Recent work using data from Kaiser Permanente Northwest and conducted in collaboration with Merck, published in this issue of JBMR, provides new information that helps fill this epidemiological gap. Although not a case-control study in a strict sense, this study provides interesting insights that add to those from the Swedish national register data published last year in the New England Journal of Medicine by Schilcher and colleagues. Briefly, the Swedish Schilcher study suggested a rapid, reversible, and above all very pronounced increase in atypical femur fractures among bisphosphonate (BP) users. Thus, the OR for these fractures was 1.3 (95% confidence interval [CI] 1.1–1.6) per 100 prescribed daily doses, corresponding to an almost 10-fold increase in risk within the first 2 years of treatment and a 120-fold increase in the first 5 years. If one compares this risk with the rate of hip fractures of 1510 per 100,000 BP users in the study, it seems that harm could outweigh benefit at the hip after approximately 7 years, but the confidence interval becomes very wide on extrapolation with the OR at 5 years ranging between 7 and 5300. At first glance, the two studies havemany features in common. The US study reviewed 864 X-rays from patients with fractures of the femoral shaft or subtrochanteric femur and found 75 atypical fractures, whereas the Swedish study reviewed 1234 X-rays and found 59 atypical fractures. The study populations differed slightly in demographics; the Swedish data set was for women aged 55þ years, whereas the US data set included men aged 65þ years and women aged 50þ years. The Swedish study used a national data set that covered a background population almost 20 times the size of the Kaiser Permanente Northwest HMO but was constrained by having access to less than 3 years of medication history. The lack of long-term exposure data when a long-term outcome is examined is troublesome, not the least when BP users often have substantial gaps in their treatment so that what would appear to be a new user with limited BP exposure could in fact be a patient who had used BPs or glucocorticoids for many years but done so at a time when prescriptions were not yet captured. A current BP user is far more likely to have used BP in the past than is a control subject drawn from the background population, and this could inflate risk estimates. The good news is that the study by Feldstein and colleagues had access to 5þ years of medication history for more than 85% of fracture cases, and study power was boosted by including several years of fracture outcomes (January 1996 to June 2009). Two findings from the Feldstein study are particularly interesting and may help advance our understanding of these fractures. First, we may have to subdivide atypical femur fractures into those that display ASBMR major features only and into those that also satisfy one or more minor criteria. Only the latter subtype of fractures—22 fractures in the radiology review— appeared to show an increasing time trend and an association with BP use. This not only affects the incidence rate and the strength of the association but also potentially our understanding of the biomechanics and pathophysiology. The question of the significance of cortical thickening and how the mode of action of bisphosphonates can be reconciled with cortical expansion has attracted particular attention. Second, even in the subgroup of patients who had fractures that satisfied one or more minor criteria, BP use was far from obligatory. The odds ratio of ever having used a BP in patients who had an atypical rather than a typical femoral shaft fracture was a modest 2.11 (95% CI 0.99–4.49). Where 78% of Swedish patients with atypical femur fractures had a history of BP use, the US study found this to be the case for 62% of patients with COMMENTARY JBMR