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Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment

Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, 08003 Barcelona, Spain
Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, 08028 Barcelona, Spain
Department of Rheumatology, Hospital Universitario de La Princesa, IIS-Princesa, Cátedra UAM-Roche, EPID-Future, Universidad Autónoma de Madrid, 28670 Madrid, Spain
Author to whom correspondence should be addressed.
Academic Editor: Zhousheng Xiao
Genes 2022, 13(1), 146;
Received: 10 December 2021 / Revised: 12 January 2022 / Accepted: 13 January 2022 / Published: 14 January 2022
(This article belongs to the Special Issue Genetic Disorders of Bone)
Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication. View Full-Text
Keywords: atypical femoral fractures; bisphosphonates; WES atypical femoral fractures; bisphosphonates; WES
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MDPI and ACS Style

Garcia-Giralt, N.; Roca-Ayats, N.; Abril, J.F.; Martinez-Gil, N.; Ovejero, D.; Castañeda, S.; Nogues, X.; Grinberg, D.; Balcells, S.; Rabionet, R. Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment. Genes 2022, 13, 146.

AMA Style

Garcia-Giralt N, Roca-Ayats N, Abril JF, Martinez-Gil N, Ovejero D, Castañeda S, Nogues X, Grinberg D, Balcells S, Rabionet R. Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment. Genes. 2022; 13(1):146.

Chicago/Turabian Style

Garcia-Giralt, Natalia, Neus Roca-Ayats, Josep F. Abril, Nuria Martinez-Gil, Diana Ovejero, Santos Castañeda, Xavier Nogues, Daniel Grinberg, Susanna Balcells, and Raquel Rabionet. 2022. "Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment" Genes 13, no. 1: 146.

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