Bisphosphonate Use and Risk of Atypical Femoral Fractures: A Danish Case-Cohort Study With Blinded Radiographic Review

Abstract

Context Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF). Objective To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined. Design Population-based case-cohort study Setting The Danish National Healthcare system maintains longitudinal records of medication use, healthcare utilization, and x-ray images. Participants Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010-2015 (n = 4,973) were identified and compared to a random sample (n = 37,021). Predictors Bisphosphonate use was collected from 1995-2015. Main Outcome Measures Fracture radiographs (n = 4,769) were reviewed by blinded study radiologists to identify AFFs (n = 181) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10. Results Compared to <1 year of BP use, 5-7 years of use was associated with a 7-fold increase in AFF [adjusted HR = 7.29 (CI: 3.07,17.30)]; the risk of AFF fell quickly after discontinuation. The 5-year number-needed-to-harm for one AFF was 1,424, while the 5-year number-needed-to-treat to prevent one hip fracture was 56. Glucocorticoid and proton pump inhibitor use were independently associated with increased AFF risk. Thirty-one percent of those with AFF had no BP exposure. Conclusions The risk of AFF increases with duration of BP use but the beneficial effects of BP therapy in adults ≥50 dramatically exceed this increased risk. Nearly one-third of those with AFF have no BP exposure.

Prevalence and risk factors for atypical femoral fracture among Lebanese patients with hip and shaft fractures

“…Although BP use, specifically prolonged exposure, increases the risk of AFF, the beneficial effects of BP therapy in adults more than 50 dramatically outweigh this increased risk where the ratio of reduced hip fracture to increased AFF risk favors BP treatment in a Danish study. 22 Similar to our study, almost one-third of those with AFF had no BP exposure and other risk factors may be the cause. 22 In addition, discontinuation of BPs leads to a decrease in AFF risk.…”

“… 10 Interestingly, exposure to BP in the AFF population was smaller when compared with 3 other large US and European population-based studies in which 90.5%, 78%, and 69% of AFF patients had evidence of previous BP or Dmab use and a smaller UK study where 70% of AFF patients were previously exposed to BP. 16 , 17 , 22 , 24 However, 3 smaller studies in South Korea and Thailand found a smaller proportion of AFF patients, ranging from 35.3% to 44.4%, with previous exposure to BPs. 14 , 18 , 25 This could be explained by different populations having different baseline risks for AFF, with more at-risk populations having AFFs with less exposure to BP.…”

“…In our study, 42.9% of AFF patients were taking PPIs, which is higher than that seen in Swedish (37.8%), Danish (35%), British (30%), and South Korean (13.3%) studies. 16–18 , 22 There are limited studies, to our knowledge, investigating PPI use in Lebanon or other countries in the MENA region. The literature from Lebanon is mainly focused on patients who were prescribed PPIs, and reports overuse in the outpatient setting.…”

“… 14 , 16 , 18 Interestingly, a study conducted in Denmark found that although a prior fracture increases the risk of future hip and shaft fracture, it does not affect AFF risk. 22 It is therefore unclear as to whether or not the history of fracture acts as a risk factor for AFFs.…”

“…Many studies investigating the risk of AFFs among BP users have found that the use of BP for longer periods significantly increases the risk of AFFs. 22 , 24 This may explain why 3 out of the 5 patients (60%) with bilateral AFFs were long-term users of BP, whereas only 2 of the nine patients (22%) with only one AFF were exposed to BP for over 5 yr.…”