Causal association analysis between blood metabolomes and osteopenia and therapeutic target prediction for mechanomedicine

Ruobing Liu; Yaru Huang; Maogang Jiang; Fei Xu; Qilin Pei; Jiajun Ma; Youru Li; Siqi Shen; Bo Zhang; Xiangyang Guo; Jing Cai; Wenwen Wang

doi:10.1016/j.mbm.2025.100137

Causal association analysis between blood metabolomes and osteopenia and therapeutic target prediction for mechanomedicine

Mechanobiol Med. 2025 Jun 9;3(3):100137. doi: 10.1016/j.mbm.2025.100137. eCollection 2025 Sep.

Authors

Ruobing Liu¹, Yaru Huang², Maogang Jiang³, Fei Xu⁴, Qilin Pei¹, Jiajun Ma⁵, Youru Li¹, Siqi Shen¹, Bo Zhang¹, Xiangyang Guo¹, Jing Cai^{1

6}, Wenwen Wang²

Affiliations

¹ Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, 710032, China.
² Department of Health Statistics, School of Preventive Medicine, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Key Lab of Environmental Health Hazard Assessment and Protection of Shaanxi Province, Key Lab of Free Radical Biology and Medicine of Shaanxi Province, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
³ Department of Medical Engineering, The Second Affiliated Hospital of Air Force Medical University, Xi'an, 710038, China.
⁴ Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
⁵ Department of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
⁶ College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, China.

Abstract

Blood metabolomes have been linked to osteoporosis, yet the precise causal relationship with osteopenia, its preventable early stage, remains unclear. This study aimed to uncover the genetic causality between blood metabolomes and osteopenia, pinpointing potential targets for mechanomedicine. Utilizing genome-wide association study summary statistics, we analyzed 1091 metabolites and 309 metabolite ratios from 8299 individuals, correlating them with total body bone mineral density (BMD) from 56,284 individuals in the IEU GWAS database and osteopenia data from 408,961 European populations. Through two-sample Mendelian randomization, we investigated the association between blood metabolomes and skeletal characteristics. We then conducted summary-data-based Mendelian randomization (MR) analysis and colocalization analyses to identify causal genes related to skeletal phenotypes, predicting therapeutic targets for osteopenia. Expression of potential targets in osteocytes under fluid shear stress (FSS) stimulation was tested using qRT-PCR to explore mechanical sensitivity and bone health mechanisms. Our findings revealed five metabolites affecting total body BMD and osteopenia, with biliverdin emerging as a potential protective factor against osteopenia (OR = 0.93, 95 %CI = 0.88-0.98, P = 0.009). Additionally, three genes-LRRC14, SLC22A16, and TNFRSF1A-were identified as potential therapeutic targets for osteopenia. Notably, LRRC14 and TNFRSF1A are also associated with other musculoskeletal diseases. In vitro experiments showed that FSS significantly increased LRRC14 expression in osteocytes, suggesting its potential as a mechanosensitive factor. This study identifies candidate blood metabolites and mechanomedicine targets for osteopenia, offering a scientific basis for new diagnostic and treatment strategies and deepening our understanding of bone mechanics response characteristics.

Keywords: Blood metabolomes; Bone mineral density; Genome-wide association study; Mechanomedicine; Mendelian randomization; Osteopenia.