Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene

Summary Prior studies have suggested an association between bisphosphonate use and subtrochanteric fractures. This cohort study showed an increased risk of subtrochanteric and femoral shaft fractures both before and after the start of drugs against osteoporosis including bisphosphonates. This may suggest an effect of the underlying disease rather than the drugs used. Introduction The objective of this study is to determine the association between drugs against osteoporosis and the risk of femoral shaft and subtrochanteric fractures. No separation was made between atypical and typical fractures. Methods Nationwide cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n=103,562) as exposed group and three age- and gender-matched controls from the general population (n=310,683). Adjustments were made for prior fracture, use of systemic hormone therapy, and use of systemic corticosteroids. Results After initiation of therapy, an increased risk of subtrochanteric fractures was seen for alendronate (hazard ratio (HR)=2.41, 95% confidence interval (CI) 1.78–3.27), etidronate (HR=1.96, 95% CI 1.62–2.36), and clodronate (HR=20.0, 95% CI 1.94–205), but not for raloxifene (HR= 1.06, 95% CI 0.34–3.32). However, an increased risk of subtrochanteric fractures was also present before the start of alendronate (OR=2.36, 95% CI 2.05–2.72), etidronate (OR= 3.05, 95% CI 2.59–3.58), clodronate (OR=10.8, 95% CI 1.14–103), raloxifene (OR=1.90, 95% CI 1.07–3.40), and strontium ranelate (OR=2.97, 95% CI 1.07–8.27). Similar trends were seen for femoral shaft fractures and overall fracture risk. After the start of etidronate, no dose–response relationship was present (p for trend, 0.54). For alendronate, a decreasing risk was present with increasing average daily dose (p for trend, <0.01). Conclusions Although an increased risk of femoral shaft and subtrochanteric fractures are seen with the use of several types of bisphosphonates, the increased risk before the start of the drugs may point at an effect of the underlying disease being treated. The increased risk may, thus, perhaps be due to confounding by indication.