Dissecting the role of plasma and urinary metabolites in bone mineral density: Evidence from a bidirectional univariable Mendelian randomization study

BACKGROUND: Plasma and urinary metabolites offer valuable insights into diverse metabolic pathways, potentially playing a pivotal role in osteoporosis pathogenesis. Investigating their association could significantly enhance our comprehension of the underlying mechanisms of osteoporosis. METHODS: This research employed bidirectional univariable Mendelian randomization analyses to causally examine 1296 plasma and 1399 urinary metabolites in relation to estimated bone mineral density (BMD). Subsequent bidirectional univariable Mendelian randomization analyses used these metabolites to further validate these relationships and elucidate the impact of age. RESULTS: 15 plasma and 5 urinary metabolites demonstrated a causal link with estimated BMD. Further analysis identified 3 metabolites with causal associations in at least one age subgroup. Taurocholenate sulfate exhibited a causal association with total body BMD of all age group (β = 0.04, 95 % CI = 0.02-0.06, p = 8.57E-04), 45-60 years group (β = 0.07, 95 % CI = 0.03-0.012, p = 1.40E-03), over 60 years age group (β = 0.06, 95 % CI = 0.02-0.011, p = 3.37E-03). Taurodeoxycholic acid 3-sulfate demonstrated a causal link to total body BMD within the 45-60 group (β = 0.07, 95 %CI = 0.02-0.012, p = 3.21E-03). Octadecadienedioate was related to total body BMD in the 45-60 years group (β = 0.07, 95 %CI = 0.02-0.012, p = 4.61E-03). CONCLUSIONS: This research deepens our insight into metabolite and bone mineral density interactions. The three lipid-related metabolites with causal links to bone density could be potential markers and targets for osteoporosis treatment, especially in middle-aged and older adults.