Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients
Osteoporosis and its associated fractures are the most common postmenopausal bone problems, affecting women and men of all ethnic groups. Nitrogen-containing bisphosphonates (N-BPs), including alendronate, risendronate, ibandronate and zolendronate figure as the most widely used osteoporosis treatments in millions of patients worldwide. Despite the significant anti-fracture efficacy of BPs, which has been widely demonstrated in several clinical trials and systematic reviews, some infrequent adverse effects associated with prolonged use have been described, including atypical femur fractures (AFFs). These fractures are non-traumatic and characterized by their subtrochanteric location or in the diaphysis of the femur, and are frequently bilateral.
AFFs’ pathogenic mechanisms are not completely known and much has been speculated about their causes. An excessive suppression of bone resorption by N-BPs could trigger an AFF but its pathophysiology is complex and other important factors are reportedly involved. Some proposed risk factors are cortical thickness and pelvic geometry. In addition, cases of AFF have been described in patients affected by other monogenic bone diseases, such as hypophosphatasia, osteogenesis imperfecta or the syndrome of osteoporosis pseudoglioma.