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Metabolomics Insights into Osteoporosis Through Association With Bone Mineral Density.

ABSTRACT: Osteoporosis, a disease characterized by low bone mineral density (BMD), increases the risk for fractures. Conventional risk factors alone do not completely explain measured BMD or osteoporotic fracture risk. Metabolomics may provide additional information. We aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 1552 Framingham Offspring Study participants, and measured femoral neck (FN) and lumbar spine (LS) BMD 2 to 10 years later using dual-energy X-ray absorptiometry. We assessed osteoporotic fractures up to 27-year follow-up after metabolomic profiling. We identified 27 metabolites associated with FN-BMD or LS-BMD by LASSO regression with internal validation. Incorporating selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors (area under the curve [AUC] = 0.74 for the model with identified metabolites and risk factors versus AUC = 0.70 with risk factors alone, p = .001; net reclassification index = 0.07, p = .03). We replicated significant improvement in fracture prediction by incorporating selected metabolites in 634 participants from the Hong Kong Osteoporosis Study (HKOS). The glycine, serine, and threonine metabolism pathway (including four identified metabolites: creatine, dimethylglycine, glycine, and serine) was significantly enriched (false discovery rate [FDR] p value = .028). Furthermore, three causally related metabolites (glycine, phosphatidylcholine [PC], and triacylglycerol [TAG]) were negatively associated with FN-BMD, whereas PC and TAG were negatively associated with LS-BMD through Mendelian randomization analysis. In summary, metabolites associated with BMD are helpful in osteoporotic fracture risk prediction. Potential causal mechanisms explaining the three metabolites on BMD are worthy of further experimental validation. Our findings may provide novel insights into the pathogenesis of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

SUBMITTER: Zhang X

PROVIDER: S-EPMC8488880 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Project description:BackgroundOsteoporosis (OP), affecting millions around the globe, is a prevalent degenerative condition of the bones characterized by a decrease in bone mineral density (BMD) and an increase in bone fragility. A novel anthropometric measure, the Body Roundness Index (BRI), provides a more accurate assessment of body fat distribution compared to traditional metrics. Using data from the National Health and Nutrition Examination Survey (NHANES), this study aims to explore the relationship between BRI and total BMD in U.S. adults aged 20 and above.MethodsData from NHANES (2011-2018) were examined, encompassing 9,295 participants following exclusions. Dual-energy X-ray absorptiometry (DXA) was employed to measure BMD. BRI was calculated using waist circumference (WC) and height. The study accounted for variables such as demographic traits, physical exam results, lab test findings, and survey responses. Weighted multivariable linear regression models and smooth curve fitting methods were utilized to assess the relationship between BRI and total BMD.ResultsThe research found a notable inverse relationship between BRI and total BMD. In the model with full adjustments, an increase of one unit in BRI was linked to a 0.0313 g/cm2 reduction in total BMD (P < 0.0001). Moreover, an inflection point was identified at BRI = 9.5229, where each one-unit rise in BRI beyond this threshold corresponded to a more substantial decrease in total BMD (0.0363 g/cm2). Analysis by subgroups revealed that this negative association was consistent across most demographic and health-related categories.ConclusionsThe results demonstrate a notable inverse relationship between BRI and total BMD, indicating that a higher BRI could be associated with lower BMD and a potentially greater risk of developing OP. This underscores the significance of accounting for body fat distribution in preventing OP and advocates for the use of BRI as a valuable marker for early intervention approaches.

Project description:BackgroundPerfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), are detectable in the serum of 95% of the U.S.ObjectiveConsidering the role of PFASs as endocrine disruptors, we examined their relationships with bone health.MethodsThe association between serum PFAS concentration and bone mineral density at total femur (TFBMD), femoral neck (FNBMD), lumbar spine (LSBMD), and physician-diagnosed osteoporosis was assessed in 1,914 participants using data from the National Health and Nutritional Examination Survey 2009-2010.ResultsThe mean age of the participants was 43 years. Men had higher serum PFAS concentrations than women (p < 0.001) except for PFNA. In both sexes, serum PFOS concentrations were inversely associated with FNBMD (p < 0.05). In women, significant negative associations were observed for natural log (ln)-transformed PFOS exposure with TFBMD and FNBMD, and for ln-transformed PFOA exposure with TFBMD (p < 0.05). In postmenopausal women, serum PFOS was negatively associated with TFBMD and FNBMD, and PFNA was negatively associated with TFBMD, FNBMD, and LSBMD (all p < 0.05). With one log unit increase in serum PFOA, PFHxS, and PFNA, osteoporosis prevalence in women increased as follows: [adjusted odds ratios (aORs)] 1.84 (95% CI: 1.17, 2.905), 1.64 (95% CI: 1.14, 2.38), and 1.45 (95% CI: 1.02, 2.05), respectively. In women, the prevalence of osteoporosis was significantly higher in the highest versus the lowest quartiles of PFOA, PFHxS, and PFNA, with aORs of 2.59 (95% CI: 1.01, 6.67), 13.20 (95% CI: 2.72, 64.15), and 3.23 (95% CI: 1.44, 7.21), respectively, based on 77 cases in the study sample.ConclusionIn a representative sample of the U.S. adult population, serum PFAS concentrations were associated with lower bone mineral density, which varied according to the specific PFAS and bone site assessed. Most associations were limited to women. Osteoporosis in women was also associated with PFAS exposure, based on a small number of cases.CitationKhalil N, Chen A, Lee M, Czerwinski SA, Ebert JR, DeWitt JC, Kannan K. 2016. Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the U.S. population in NHANES 2009-2010. Environ Health Perspect 124:81-87; http://dx.doi.org/10.1289/ehp.1307909.

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Metabolomics Insights into Osteoporosis Through Association With Bone Mineral Density.

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