Genetic Risk Factors for Atypical Femoral Fractures (AFFs)

A Systematic Review

Hanh Huu Nguyen, Denise M van de Laarschot, Annemieke JMH Verkerk, Frances Milat, M Carola Zillikens, Peter Robert Ebeling

Research output: Contribution to journalReview ArticleResearchpeer-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.
Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalJBMR Plus
Volume2
Issue number1
DOIs
Publication statusPublished - Jan 2018

Keywords

  • Fracture
  • genetics

Cite this

Nguyen, Hanh Huu ; van de Laarschot, Denise M ; JMH Verkerk, Annemieke ; Milat, Frances ; Zillikens, M Carola ; Ebeling, Peter Robert. / Genetic Risk Factors for Atypical Femoral Fractures (AFFs) : A Systematic Review. In: JBMR Plus. 2018 ; Vol. 2, No. 1. pp. 1-11.
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title = "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‐na{\"i}ve 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‐na{\"i}ve 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. {\circledC} 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.",
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Nguyen, HH, van de Laarschot, DM, JMH Verkerk, A, Milat, F, Zillikens, MC & Ebeling, PR 2018, 'Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review', JBMR Plus, vol. 2, no. 1, pp. 1-11. https://doi.org/10.1002/jbm4.10024

Genetic Risk Factors for Atypical Femoral Fractures (AFFs) : A Systematic Review. / Nguyen, Hanh Huu; van de Laarschot, Denise M ; JMH Verkerk, Annemieke; Milat, Frances; Zillikens, M Carola ; Ebeling, Peter Robert.

In: JBMR Plus, Vol. 2, No. 1, 01.2018, p. 1-11.

Research output: Contribution to journalReview ArticleResearchpeer-review

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T1 - Genetic Risk Factors for Atypical Femoral Fractures (AFFs)

T2 - A Systematic Review

AU - Nguyen, Hanh Huu

AU - van de Laarschot, Denise M

AU - JMH Verkerk, Annemieke

AU - Milat, Frances

AU - Zillikens, M Carola

AU - Ebeling, Peter Robert

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

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KW - genetics

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DO - 10.1002/jbm4.10024

M3 - Review Article

VL - 2

SP - 1

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JO - JBMR Plus

JF - JBMR Plus

SN - 2473-4039

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