Metabolomic patterns, redox-related genes and metals, and bone fragility endpoints in the Hortega Study

Free Radic Biol Med. 2023 Jan:194:52-61. doi: 10.1016/j.freeradbiomed.2022.11.007. Epub 2022 Nov 9.


Background: The potential joint influence of metabolites on bone fragility has been rarely evaluated. We assessed the association of plasma metabolic patterns with bone fragility endpoints (primarily, incident osteoporosis-related bone fractures, and, secondarily, bone mineral density BMD) in the Hortega Study participants. Redox balance plays a key role in bone metabolism. We also assessed differential associations in participant subgroups by redox-related metal exposure levels and candidate genetic variants.

Material and methods: In 467 participants older than 50 years from the Hortega Study, a representative sample from a region in Spain, we estimated metabolic principal components (mPC) for 54 plasma metabolites from NMR-spectrometry. Metals biomarkers were measured in plasma by AAS and in urine by HPLC-ICPMS. Redox-related SNPs (N = 341) were measured by oligo-ligation assay.

Results: The prospective association with incident bone fractures was inverse for mPC1 (non-essential and essential amino acids, including branched-chain, and bacterial co-metabolites, including isobutyrate, trimethylamines and phenylpropionate, versus fatty acids and VLDL) and mPC4 (HDL), but positive for mPC2 (essential amino acids, including aromatic, and bacterial co-metabolites, including isopropanol and methanol). Findings from BMD models were consistent. Participants with decreased selenium and increased antimony, arsenic and, suggestively, cadmium exposures showed higher mPC2-associated bone fractures risk. Genetic variants annotated to 19 genes, with the strongest evidence for NCF4, NOX4 and XDH, showed differential metabolic-related bone fractures risk.

Conclusions: Metabolic patterns reflecting amino acids, microbiota co-metabolism and lipid metabolism were associated with bone fragility endpoints. Carriers of redox-related variants may benefit from metabolic interventions to prevent the consequences of bone fragility depending on their antimony, arsenic, selenium, and, possibly, cadmium, exposure levels.

Keywords: Bone mineral density; Candidate genes; Metabolomics; Metals; Osteoporosis-related bone fractures; Redox.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimony
  • Arsenic*
  • Bone Density / genetics
  • Cadmium
  • Fractures, Bone*
  • Humans
  • Oxidation-Reduction
  • Selenium*


  • Cadmium
  • Arsenic
  • Antimony
  • Selenium