Osteoporosis is characterized by low bone mineral density (BMD). The advancement of high-throughput technologies and integrative approaches provided an opportunity for deciphering the mechanisms underlying osteoporosis. Here, we generated genomic, transcriptomic, methylomic, and metabolomic datasets from 119 subjects with high (n = 61) and low (n = 58) BMDs. By adopting sparse multiple discriminative canonical correlation analysis, we identified an optimal multi-omics biomarker panel with 74 differentially expressed genes (DEGs), 75 differentially methylated CpG sites (DMCs), and 23 differential metabolic products (DMPs). By linking genetic data, we identified 199 targeted BMD-associated expression/methylation/metabolite quantitative trait loci (eQTLs/meQTLs/metaQTLs). The reconstructed networks/pathways showed extensive biomarker interactions, and a substantial proportion of these biomarkers were enriched in RANK/RANKL, MAPK/TGF-β, and WNT/β-catenin pathways and G-protein-coupled receptor, GTP-binding/GTPase, telomere/mitochondrial activities that are essential for bone metabolism. Five biomarkers (FADS2, ADRA2A, FMN1, RABL2A, SPRY1) revealed causal effects on BMD variation. Our study provided an innovative framework and insights into the pathogenesis of osteoporosis.

骨质疏松症的特征是骨矿物质密度（BMD）低。高通量技术和集成方法的进步为破译骨质疏松症的机制提供了机会。在这里，我们从119名BMD高（n = 61）和低（n = 58）的受试者中产生了基因组，转录组，甲基组学和代谢组学数据集。通过采用稀疏的多判别典型相关分析，我们确定了具有74个差异表达基因（DEG），75个差异甲基化CpG位点（DMC）和23个差异代谢产物（DMP）的最佳多组学生物标志物组。通过链接遗传数据，我们确定了199个与BMD相关的表达/甲基化/代谢物定量性状位点（eQTLs / meQTLs / metaQTLs）。重建的网络/通路显示出广泛的生物标记物相互作用，这些生物标记物中的很大一部分富含RANK / RANKL，MAPK /TGF-β和WNT /β-catenin途径以及G蛋白偶联受体，GTP结合/ GTPase，端粒/线粒体活性，这些活性对骨骼至关重要代谢。五个生物标志物（FADS2，ADRA2A，FMN1，RABL2A，SPRY1）显示出对BMD变异的因果关系。我们的研究为骨质疏松症的发病机理提供了创新的框架和见解。