BackgroundIndividuals’ peak bone mineral density (BMD) achieved and maintained at ages 20–40 years is the most powerful predictor of low bone mass and osteoporotic fractures later in life. The aim of this study was to identify metabolomic factors associated with peak BMD variation in US Caucasian women.MethodsA total of 136 women aged 20–40 years, including 65 subjects with low and 71 with high hip BMD, were enrolled. The serum metabolites were assessed using a liquid chromatography-mass spectrometry (LC-MS) method. The partial least-squares discriminant analysis (PLS-DA) method and logistic regression models were used, respectively, to examine the associations of metabolomic profiles and individual metabolites with BMD.ResultsThe low and high BMD groups could be differentiated by the detected serum metabolites using PLS-DA (P permutation = 0.008). A total of 14 metabolites, including seven amino acids and amino acid derivatives, five lipids (including three bile acids), and two organic acids, were significantly associated with the risk for low BMD. Most of these metabolites are novel in that they have never been linked with BMD in humans earlier. The prediction model including the newly identified metabolites significantly improved the classification of the groups with low and high BMD. The area under the receiver operating characteristic curve without and with metabolites were 0.88 (95% CI: 0.83–0.94) and 0.97 (95% CI: 0.94–0.99), respectively (P for the difference = 0.0004).ConclusionMetabolomic profiling may improve the risk prediction of osteoporosis among Caucasian women. Our findings also suggest the potential importance of the metabolism of amino acids and bile acids in bone health.

Osteoporosis is a highly prevalent chronic aging-related disease that frequently is only detected after fracture. We hypothesized that aminobutyric acids could serve as biomarkers for osteoporosis. We developed a quick, accurate, and sensitive screening method for aminobutyric acid isomers and enantiomers yielding correlations with bone mineral density (BMD) and osteoporotic fracture. In serum, γ-aminobutyric acid (GABA) and (R)-3-aminoisobutyric acid (D-BAIBA) have positive associations with physical activity in young lean women. D-BAIBA positively associated with hip BMD in older individuals without osteoporosis/osteopenia. Lower levels of GABA were observed in 60-80 year old women with osteoporotic fractures. Single nucleotide polymorphisms in seven genes related to these metabolites associated with BMD and osteoporosis. In peripheral blood monocytes, dihydropyrimidine dehydrogenase, an enzyme essential to D-BAIBA generation, exhibited positive association with physical activity and hip BMD. Along with their signaling roles, BAIBA and GABA might serve as biomarkers for diagnosis and treatments of osteoporosis.

Osteoporosis is characterized by low bone mineral density (BMD). The advancement of highthroughput 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-b, and WNT/b-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.

Bone mineral density (BMD) is a complex trait with high missing heritability. Numerous evidences have shown that BMD variation has a relationship with coronary artery disease (CAD). This relationship may come from a common genetic basis called pleiotropy. By leveraging the pleiotropy with CAD, we may be able to improve the detection power of genetic variants associated with BMD. Using a recently developed conditional false discovery rate (cFDR) method, we jointly analyzed summary statistics from two large independent genome wide association studies (GWAS) of lumbar spine (LS) BMD and CAD. Strong pleiotropic enrichment and 7 pleiotropic SNPs were found for the two traits. We identified 41 SNPs for LS BMD (cFDR<0.05), of which 20 were replications of previous GWASs and 21 were potential novel SNPs that were not reported before. Four genes encompassed by 9 cFDR-significant SNPs were partially validated in the gene expression assay. Further functional enrichment analysis showed that genes corresponding to the cFDR-significant LS BMD SNPs were enriched in GO terms and KEGG pathways that played crucial roles in bone metabolism (adjP < 0.05). In protein-protein interaction analysis, strong interactions were found between the proteins produced by the corresponding genes. Our study demonstrated the reliability and high-efficiency of the cFDR method on the detection of trait-associated genetic variants, the present findings shed novel insights into the genetic variability of BMD as well as the shared genetic basis underlying osteoporosis and CAD.

Both loss of muscle mass and strength are important sarcopenia-related traits. In this study, we investigated both specific and shared serum metabolites associated with these two traits in 136 Caucasian women using a liquid chromatography-mass spectrometry method. A joint analysis of multivariate traits was used to examine the associations of individual metabolites with muscle mass measured by the body mass index-adjusted appendicular lean mass (ALM/BMI) and muscle strength measured by hand grip strength (HGS). After adjusting for multiple testing, nine metabolites including two amino acids (aspartic acid and glutamic acid) and an amino acid derive (pipecolic acid), one peptide (phenylalanyl-threonine), one carbohydrate (methyl beta-D-glucopyranoside), and four lipids (12S-HETRE, arachidonic acid, 12S-HETE, and glycerophosphocholine) were significant in the joint analysis. Of them, the two amino acids (aspartic acid and glutamic acid) and two lipids (12S-HETRE and 12S-HETE) were associated with both ALM/BMI and HGS, and the other five were only associated with ALM/BMI. The pathway analysis showed the amino acid metabolism pathways (aspartic acid and glutamic acid) might play important roles in the regulation of muscle mass and strength. In conclusion, our study identified novel metabolites associated with sarcopenia-related traits, suggesting novel metabolic pathways for muscle regulation.