ESPE Yearbook of Paediatric Endocrinology

In Brief: Prolonged bisphosphonate treatment is associated with atypical femoral fractures (AFF). However, AFFs also occur in bisphosphonate-naïve patients, so bisphosphonate is not a prerequisite for AFF. This study found a higher yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of monogenic bone disorder, stressing the importance of careful clinical evaluation of patients who present with this condition.

Commentary: Atypical femur fractures (AFFs) are a rare type of fractures, which have been associated with long-term bisphosphonate use. They occur with no or minimal trauma at the femoral shaft from the subtrochanteric region to just above the supracondylar flare. They can be distinguished from typical osteoporotic fractures by specific radiological features, such as a horizontal fracture line originating at the lateral side, no or minimal comminution, and localized cortical thickening.

It has been suggested that AFFs are stress or insufficiency fractures, possibly due to the accumulation of microdamage from suppressed bone remodelling and/or increased homogeneity of bone mineralization caused by long-term bisphosphonate use. Nevertheless, it remains unexplained why AFF occurs in only a minority of patients treated with bisphosphonates. Nor is it been explained why AFFs also occur in patients who never used bisphosphonates. AFF has been reported in monogenic bone disorders, where bisphosphonates are not used, e.g. hypophosphatasia (HPP), X-linked hypophosphatemia, pycnodysostosis, osteopetrosis, osteoporosis pseudoglioma syndrome (OPPG), osteogenesis imperfecta (OI), and X-linked osteoporosis.

This study recruited AFF patients from two specialist bone centers in the Netherlands. Their medical records were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Copy number variants overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprised 60 AFF patients (including two siblings), of whom 95% had received bisphosphonates. Fifteen AFF patients (25%) had clinical features of a monogenic bone disorder. Eight of them (54%), including the 2 siblings, had a (likely) pathogenic variant in PLS3, COL1A2, LRP5, or ALPL. Among patients not suspected of monogenic bone disorders, only one patient (2%) carried a likely pathogenic variant in TCIRG1. In total, nine AFF patients (15%) had a (likely) pathogenic variant. One patient, was found to have 12.7 Mb deletion in chromosome 6, encompassing TENT5A.

In summary, these findings strongly suggest that genetic variants associated with monogenic bone disorders play a role in the pathogenesis of AFF, although the underlying mechanism is still unclear.