Serum Metabolome of Coffee Consumption and its Association With Bone Mineral Density: The Hong Kong Osteoporosis Study

Background: Inconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD. Methods: Two independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001-2010 (N = 329) and 2015-2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography-mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses. Results: 12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10^-5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N'-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (β = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (β = 0.007, SE = 0.003, P = 0.027) and trigonelline (β = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck. Conclusions: 12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.