Xiaojing Lin ¹ Yaqi Zuo ¹ Hongbo Hu ^2* Jie Zhou ²

• ¹ Guangdong Medical University, Zhanjiang, Guangdong, China
• ² Yuebei People's Hospital, Shaoguan, China

Objective: 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.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.Results: 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.