Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Abstract

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition

“…Genetic risk factors may exist as well, although evidence is still developing. (129) It should be noted that in around 70% of the AFF cases reviewed by an expert task force, patients reported a prodrome of thigh or hip pain. (115) Although it is not known whether AFF can be prevented, patients should be told to urgently report thigh or hip pain and should receive radiographic evaluation.…”

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…Such fractures often occur after minimal trauma, are often transverse, are almost always complete, and are non‐ or minimally comminuted, thereby fulfilling four major criteria for establishing a diagnosis of atypical femur fractures, as defined for fractures that occur in the context of postmenopausal osteoporosis . By extension, some case reports and small case series on OI have recently labeled transverse femur fractures as “atypical femur fractures,” especially when they occurred after bisphosphonate use …”

“…(39) By extension, some case reports and small case series on OI have recently labeled transverse femur fractures as "atypical femur fractures," especially when they occurred after bisphosphonate use. (40) However, transverse diaphyseal femur fractures have been one of the most common types of fracture in OI even before the bisphosphonate era ( Fig. 2).…”

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture

“…A recent systematic review found six published studies that investigated the role of genetics on AFF in a total of 44 patients [11]. The review also identified 23 cases of AFF associated with seven different monogenetic bone disorders, of which seven cases had been exposed to a bisphosphonate.…”

“…We performed the largest case-control GWAS to date, to determine whether common genetic variants contribute to risk of bisphosphonate-associated AFF. We also performed candidate gene analyses of 29 genes that have been implicated in AFF [11].…”