Zhou Wei, van de Laarschot Denise M, van Rooij Jeroen G J, Koedam Marijke, Nguyen Hanh H, Uitterlinden André G, Ebeling Peter R, Thakker Rajesh V, Geusens Piet, van der Eerden Bram C J, Verkerk Annemieke J M H, Zillikens M Carola
Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, 3015 GD, the Netherlands.
Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.
J Bone Miner Res. 2024 Dec 31;40(1):69-78. doi: 10.1093/jbmr/zjae175.
Atypical femur fractures (AFFs) are rare adverse events associated with bisphosphonate use, having unclear pathophysiology. AFFs also cluster in families and have occurred in patients with monogenetic bone diseases sometimes without bisphosphonate use, suggesting an underlying genetic susceptibility. Our aim was to identify a genetic cause for AFF in a Caucasian family with 7 members affected by osteoporosis, including 3 siblings with bisphosphonate-associated AFFs. Using whole-exome sequencing, we identified a rare pathogenic variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the 3 siblings with AFFs. The same variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF and in 1 of 73 unrelated European AFF patients. LOXL4 is involved in collagen cross-linking and may be relevant for microcrack formation and bone repair mechanisms. Preliminary functional analysis showed that skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with 2 controls. In conclusion, this LOXL4 variant may underlie AFF susceptibility possibly due to abnormal collagen metabolism, leading to increased formation of microdamage or compromised healing of microcracks in the femur.
非典型股骨骨折（AFFs）是与双膦酸盐使用相关的罕见不良事件，其病理生理学尚不清楚。AFFs在家族中也有聚集现象，并且在一些单基因骨病患者中也有发生，有时这些患者并未使用双膦酸盐，这表明存在潜在的遗传易感性。我们的目的是在一个有7名成员患骨质疏松症的白种人家族中确定AFF的遗传原因，其中包括3名患有双膦酸盐相关AFF的兄弟姐妹。通过全外显子测序，我们在3名患有AFF的兄弟姐妹共有的64个杂合罕见、蛋白质改变变体中，鉴定出赖氨酰氧化酶样4（LOXL4）基因中的一个罕见致病变体c.G1063A（p.Gly355Ser）。在第四名膝盖上方发生低创伤性股骨骨折、未完全符合AFF所有美国骨矿研究学会（ASBMR）标准的兄弟姐妹以及73名无关的欧洲AFF患者中的1名患者中也发现了相同的变体。LOXL4参与胶原蛋白交联，可能与微裂纹形成和骨修复机制有关。初步功能分析表明，来自携带LOXL4变体的无关患者的皮肤成纤维细胞来源的成骨细胞表达的I型胶原蛋白和弹性蛋白较少，而成骨分化和矿化与2名对照相比有所增强。总之，这种LOXL4变体可能是AFF易感性的基础，可能是由于胶原蛋白代谢异常，导致股骨微损伤形成增加或微裂纹愈合受损。
