Epidemiology, Radiology and Histology of Atypical Femoral Fractures : Development of understanding

Abstract: Bisphosphonates have been used successfully in the prevention of osteoporosis-related fractures for over two decades. Only recently an association between bisphosphonate use and femoral insufficiency fractures – atypical femoral fractures – has been found.Bone remodeling is necessary to maintain a healthy skeleton. With age this process can get out of balance and bone resorption can outweigh formation of new bone. This can lead to osteoporosis and fractures that occur after minor trauma. Almost half of all women 50 years of age or older will suffer an osteoporosis related fracture during their remaining life. Bisphosphonates inhibit bone resorption, and after some years of treatment an increase in bone mass can be noted. This increase in bone mass can reduce fracture risk by as much as  half. However, bisphosphonate use seems associated with the development of femoral insufficiency fractures, so called atypical femoral fractures. This thesis aimed to estimate the risk of atypical femoral fractures in the population and its association with bisphosphonate use. It also describes the radiographic and histologic features of these fractures in order to improve our understanding of the pathophysiological background.Study 1)  All women 55 years of age and older, who had sustained a femoral shaft fracture during 2008, were identified through the Swedish National Patient Register. Radiographs of 1234 women were reviewed, and 59 patients with atypical fractures and 263 control patients with common femoral shaft fractures were identified. Atypical femoral fractures were defined by their stress fracture-like appearance. In a cohort analysis, we estimated an age-adjusted relative risk of 47 for bisphosphonate users to suffer an atypical femoral fracture compared to non-users. A total of 78% of the patients with an atypical fracture and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33. The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. These results indicate that bisphosphonate use is strongly associated with atypical femoral fractures. The absolute risk is low and benefits of treatment will outweigh the risks.Study 2)  A transverse fracture line and a small but visible callus reaction are well established radiographic features of stress fractures. Radiographs from 59 atypical fracture patients and 218 control patients from Study 1 were re-reviewed to measure fracture angles and to detect callus reactions. The majority of the patients with a transverse fracture angle used bisphosphonates. Fracture angle and callus reaction had a high specificity to detect bisphosphonate treatment. When an oblique fracture line was chosen to define atypical femoral fractures in the cohort from Study 1, the association of atypical femoral fractures to bisphosphonate use became attenuated. Therefore, a correct case definition of atypical femoral fractures is necessary for adequate risk calculations.Study 3)  Bone biopsies from 8 patients with atypical femoral fractures were obtained during surgical fixation. The histological analysis of the fracture site itself showed a thin fracture line running perpendicular to the long axis of the femur. Despite ongoing remodeling in the bone adjacent to the fracture gap, no healing occurred within the gap itself. Necrotic material in the gap suggests that strains within the gap might prohibit ingrowth of cells necessary for healing. This mechanism of inhibited healing might share similarities with that of stress fractures in athletes. Although it is highly likely that bisphosphonates play a causative role, the pathogenesis of these fractures is still unclear. It may involve a reduced capacity for targeted remodeling.