Association between the Metabolome and Bone Mineral Density in Chinese

Abstract

Background: Osteoporosis is a common metabolic bone disease, which always leads to osteoporotic fractures especially among the elderly. Biomarkers of bone mineral density (BMD) are helpful for prevention and early diagnosis of osteoporosis. This study aims to identify metabolomic biomarkers of low BMD. Methods: We included 701 participants who had BMD measures by dual-energy X-ray absorptiometry scans and donated fasting plasma samples from three clinical centers as a discovery set and another 278 participants from the fourth center as an independent replication set. We used a liquid chromatography-mass spectrometry-based metabolomics approach to profile the global circulating metabolites. Results: Among the 265 named metabolites identified in our study, six were associated with low BMD (FDR-adjusted P <0.05) in the discovery set and were successfully validated in the independent replication set. The circulating levels of five metabolites, i.e., inosine, hypoxanthine, PC(O-18:0/22:6), SM(d18:1/21:0) and isoleucyl-proline were associated with decreased odds of low BMD, and PC(16:0/18:3) level was associated with increased odds of low BMD. Per one standard deviation increase in a composite metabolite score of these six metabolites was associated with about half decreased odds of low BMD (odds ratio 0.59, 95% confidence interval: 0.52-0.68). Furthermore, introduction of a panel of metabolites selected by elastic net regression to a prediction model of classical risk factors and plasma biomarker of bone resorption substantially improved the prediction performance for low BMD (AUCs: 0.782 vs. 0.698, P =0.002). Conclusions: Metabolomics profiling may help identify novel biomarkers of low BMD and be helpful for early diagnosis of osteoporosis beyond the current clinical index. Funding Statement: This study was supported by the National Key R&D Program of China [2018YFC2001500 to J.S.], the National Natural Science Foundation of China [Key Program, 91749204 to J.S.], the National Natural Science Foundation of China [General Program, 81771491 to J.S.], the Project of Shanghai Subject Chief Scientist [2017BR011 to J.S.], Grants from the TCM Supported Project [18431902300 to J.S.] from the Science and Technology Commission of Shanghai Municipality, and the National Natural Science Foundation of China [General Program, 81972089 to Z.X.]. Y.Z. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Municipal Science and Technology Major Project [2017SHZDZX01 to Y.Z.], and the National Natural Science Foundation of China [81973032]. Declaration of Interests: The authors have nothing to disclose. The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the ethics committee at each center and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.