Genetic risk factors for atypical femoral fractures (AFFs): Transcontinental AFF Consortium (TrAFFiC) study — ASN Events
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Genetic risk factors for atypical femoral fractures (AFFs): Transcontinental AFF Consortium (TrAFFiC) study (#186)

Hanh H Nguyen 1 2 , Denise M van de Laarschot 3 , Frances Milat 1 2 4 , M Carola Zillikens 3 , Peter R Ebeling 1 2
  1. Department of Medicine, Monash University, Clayton, Victoria, Australia
  2. Department of Endocrinology, Monash Health, Clayton, Victoria, Australia
  3. Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
  4. Hudson Institute, Clayton, Victoria, Australia

Background: Atypical femoral fractures (AFFs) are uncommon associations of long-term anti-resorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenic bone disorders has led to the hypothesis that genetic factors predispose to AFF.

Aim: To review monogenic bone diseases and genetic studies of individuals with AFF.

Method: Structured literature searches (Embase, Medline, Web of Science, Cochrane Central, and Google Scholar), and hand-searching of conference abstracts/reference lists identified 2566 citations. HN and DV independently reviewed citations for (i) cases of AFF in monogenic bone diseases, and (ii) genetic studies in individuals with AFF. Twenty-five citations fulfilled the inclusion criteria.

Results: AFFs were reported in 29 individuals with the following underlying monogenic conditions (gene): osteogenesis imperfecta (COL1A1/2), pycnodysostosis (CTSK), hypophosphatasia (TNSALP), X-linked osteoporosis (PLS3), osteopetrosis, X-linked hypophosphataemia [PHEX gene sequence (Xp.22)] and osteoporosis pseudoglioma syndrome (LRP5) (Table 1). In eight cases (29%), AFF occurred prior to the diagnosis of the monogenic bone disease.

We identified five small cohort studies of AFF patients (n=5-13). A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases. A whole exome sequencing study in 3 sisters with AFFs and in 3 unrelated AFF cases showed a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. In two studies, targeted analyses of the COL1A2 and TNSALP genes identified variants in AFF patients.

Conclusion: These findings imply/suggest genetic susceptibility for AFFs. A large multicenter collaborative (TrAFFiC) study of well-phenotyped AFF cases and controls in sufficient numbers to have the power to detect rare variants associated with AFFs, as well as common variants in multiple genes, will allow targeting of anti-resorptive therapy to those with low AFF risk.

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