Thomas Funck-Brentano1, Agnes Ostertag2, Francoise Debiais3, Patrice Fardellone4, Corinne Collet2, Etienne Mornet5, Martine Cohen-Solal6. 1. Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France; Department of rheumatology, Lariboisière hospital, université Paris Diderot, 75010 Paris, France. 2. Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France. 3. Department of rheumatology, Poitiers university hospital, 86021 Poitiers, France. 4. Department of rheumatology, Amiens university hospital, 8000 Amiens, France. 5. Unité de génétique constitutionnelle, centre hospitalier de Versailles, 78150 Le Chesnay, France. 6. Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France; Department of rheumatology, Lariboisière hospital, université Paris Diderot, 75010 Paris, France. Electronic address: martine.cohen-solal@inserm.fr.
Abstract
OBJECTIVES: Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment. METHODS: Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures. Genetic screening for ALPL, SOX9, COL1A1 and COL1A2 variants was performed after patient's information and consent. RESULTS: A total of 389 cases were identified and 268 were ruled out according to the ASBMR Task Force recommendations. On the remaining 121, 14 (11.6%) were AFF. Anti-osteoporotic drugs were more frequent in the AFF group compared to the typical fracture group (35% vs 5%, P<0.001) but only 4 (28.6%) patients with AFF had been exposed to bisphosphonates. Genetic analysis performed in 5 patients found one with a heterozygous mutation in COL1A2 (rs72658163, NM_000089.3:c.2123G>A, p.Arg708Gln). This rare variant (Minor Allele Frequency=0.0008) causes a missense mutation that alters collagen fibrillogenesis. Eight heterozygous polymorphisms for ALPL were also found in 3 patients. CONCLUSION: Genetic screening for variants in only 4 genes and 5 patients with AFF resulted in the identification of genetic variants in 3 patients including a rare variant in COL1A2, suggesting a possible genetic susceptibility to AFF. This finding should encourage clinician to further genotype patients with AFF in a collaborative multicentric project.
OBJECTIVES: Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment. METHODS: Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures. Genetic screening for ALPL, SOX9, COL1A1 and COL1A2 variants was performed after patient's information and consent. RESULTS: A total of 389 cases were identified and 268 were ruled out according to the ASBMR Task Force recommendations. On the remaining 121, 14 (11.6%) were AFF. Anti-osteoporotic drugs were more frequent in the AFF group compared to the typical fracture group (35% vs 5%, P<0.001) but only 4 (28.6%) patients with AFF had been exposed to bisphosphonates. Genetic analysis performed in 5 patients found one with a heterozygous mutation in COL1A2 (rs72658163, NM_000089.3:c.2123G>A, p.Arg708Gln). This rare variant (Minor Allele Frequency=0.0008) causes a missense mutation that alters collagen fibrillogenesis. Eight heterozygous polymorphisms for ALPL were also found in 3 patients. CONCLUSION: Genetic screening for variants in only 4 genes and 5 patients with AFF resulted in the identification of genetic variants in 3 patients including a rare variant in COL1A2, suggesting a possible genetic susceptibility to AFF. This finding should encourage clinician to further genotype patients with AFF in a collaborative multicentric project.
Authors: Wei Zhou; Jeroen G J van Rooij; Peter R Ebeling; Annemieke J M H Verkerk; M Carola Zillikens Journal: Curr Osteoporos Rep Date: 2021-02-15 Impact factor: 5.096
Authors: Wei Zhou; Hanh H Nguyen; Denise M van de Laarschot; Tet Sen Howe; Joyce S B Koh; Frances Milat; Jeroen G J van Rooij; Joost A M Verlouw; Bram C J van der Eerden; Mark Stevenson; Rajesh V Thakker; M Carola Zillikens; Peter R Ebeling Journal: JBMR Plus Date: 2022-07-03
Authors: Hanh H Nguyen; Denise M van de Laarschot; Annemieke JMH Verkerk; Frances Milat; M Carola Zillikens; Peter R Ebeling Journal: JBMR Plus Date: 2018-01-03
Authors: Denise M van de Laarschot; Malachi J McKenna; Bo Abrahamsen; Bente Langdahl; Martine Cohen-Solal; Núria Guañabens; Richard Eastell; Stuart H Ralston; M Carola Zillikens Journal: J Clin Endocrinol Metab Date: 2020-05-01 Impact factor: 5.958
Authors: Manuela G M Rocha-Braz; Monica M França; Adriana M Fernandes; Antonio M Lerario; Evelin A Zanardo; Lucas S de Santana; Leslie D Kulikowski; Regina M Martin; Berenice B Mendonca; Bruno Ferraz-de-Souza Journal: J Endocr Soc Date: 2020-10-07