Lin Xiaojing, Zuo Yaqi, Hu Hongbo, Zhou Jie
Guangdong Medical University, Zhanjiang, China.
Yuebei People's Hospital, Guangdong Medical University, Shaoguan, China.
Front Genet. 2024 Sep 13;15:1393106. doi: 10.3389/fgene.2024.1393106. eCollection 2024.
Observational studies have found associations between reproductive factors and bone density in women. However, the causal relationships are not well understood. This study aims to investigate whether various reproductive factors are causally related to bone density at different skeletal sites using both univariable and multivariable Mendelian randomization (MR) methods.
The study incorporated four reproductive factors, namely, age at menarche (AAM), age at first live birth (AFB), age at menopause (ANM), and age at last live birth (ALB), as well as five distinct skeletal sites, including bone mineral density (BMD), heel calcaneus BMD, ultradistal forearm bone mineral density (FA-BMD), lumbar spine bone mineral density (LS-BMD), and femoral neck bone mineral density (FN-BMD). Univariable two-sample MR and multivariable MR analyses were conducted using data from published genome-wide association studies (GWASs). A total of 150 single nucleotide polymorphisms (SNPs) associated with the four reproductive factors were extracted from GWAS databases. The primary statistical analysis method utilized in this study was the inverse variance weighted (IVW) method.
In the univariate MR analysis, we observed causal connections between four reproductive factors and bone density. Specifically, AAM had a significant impact on BMD and heel calcaneus BMD. Age at first live birth was negatively associated with FA-BMD. Age at last live birth showed a negative correlation with BMD and heel calcaneus BMD. ANM exhibited positive associations with BMD, heel calcaneus BMD, FA-BMD, and LS-BMD. Subsequently, we performed a multivariable MR analysis to examine the combined effects of multiple variables, which confirmed the persistence of associations between age at menopause and bone density at various sites. Additionally, we found a negative correlation between age at last live birth and heel calcaneus BMD.
This study offers a fresh perspective on the prevention of osteoporosis in women, explicitly stating that reproductive factors such as early menopause and late childbirth play a significant predictive role in individual bone density decline. Therefore, when developing osteoporosis screening and management protocols, reproductive factors should be included for a more comprehensive guidance of clinical practice.
观察性研究发现女性生殖因素与骨密度之间存在关联。然而，因果关系尚不清楚。本研究旨在使用单变量和多变量孟德尔随机化（MR）方法，研究各种生殖因素与不同骨骼部位骨密度之间是否存在因果关系。
该研究纳入了四个生殖因素，即初潮年龄（AAM）、首次生育年龄（AFB）、绝经年龄（ANM）和末次生育年龄（ALB），以及五个不同的骨骼部位，包括骨矿物质密度（BMD）、跟骨骨矿物质密度、超远端前臂骨矿物质密度（FA-BMD）、腰椎骨矿物质密度（LS-BMD）和股骨颈骨矿物质密度（FN-BMD）。使用已发表的全基因组关联研究（GWAS）数据进行单变量双样本MR和多变量MR分析。从GWAS数据库中提取了总共150个与这四个生殖因素相关的单核苷酸多态性（SNP）。本研究采用的主要统计分析方法是逆方差加权（IVW）法。
在单变量MR分析中，我们观察到四个生殖因素与骨密度之间存在因果联系。具体而言，初潮年龄对骨矿物质密度和跟骨骨矿物质密度有显著影响。首次生育年龄与超远端前臂骨矿物质密度呈负相关。末次生育年龄与骨矿物质密度和跟骨骨矿物质密度呈负相关。绝经年龄与骨矿物质密度、跟骨骨矿物质密度、超远端前臂骨矿物质密度和腰椎骨矿物质密度呈正相关。随后，我们进行了多变量MR分析，以检验多个变量的综合影响，这证实了绝经年龄与不同部位骨密度之间的关联持续存在。此外，我们发现末次生育年龄与跟骨骨矿物质密度呈负相关。
本研究为女性骨质疏松症的预防提供了新的视角，明确指出绝经早和生育晚等生殖因素在个体骨密度下降中起重要的预测作用。因此，在制定骨质疏松症筛查和管理方案时，应纳入生殖因素，以更全面地指导临床实践。
