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. In this work, we aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites in 1552 Framingham Offspring study participants with measured femoral neck and lumbar spine BMD as well as osteoporotic fractures. We identified 27 BMD-associated metabolites. Incorporating the selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors. We replicated our results in the Hong Kong Osteoporosis Study (HKOS). We further illustrated potential causal mechanisms with Mendelian randomization analysis.