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BACKGROUND: Hip fracture is a major cause of morbidity and mortality in ageing populations. Although emerging evidence suggests a role of metabolomic profiles in osteoporosis, their association with hip fracture risk has not been well established. We aimed to investigate plasma metabolomic profiles associated with risk of hip fracture.METHODS: We conducted a nested case-control analysis (N = 1234) including 617 hip fracture cases and 617 matched controls (discovery data set) and a prospective cohort analysis including 10,031 participants (replication data set; 475 incident hip fractures) within the Nurses' Health Study and the Health Professionals Follow-Up Study. Conditional logistic regression was applied in the case-control analysis to estimate odds ratios (ORs) per 1 SD increase in metabolite levels, and Cox proportional hazards models were used in the cohort analysis. A total of 653 plasma metabolites were examined, with false discovery rate (FDR) correction applied to control for multiple testing.FINDINGS: In the nested-case control analysis, six metabolites related to phospholipid metabolism were consistently associated with hip fracture risk (P < 0.05), with five showing inverse associations. After FDR correction, 1-stearoyl-2-dihomo-linolenoyl-GPC, a phosphatidylcholine metabolite, remained significantly associated with lower hip fracture risk (OR 0.76, 95% CI 0.67-0.87, FDR = 0.02), and this association was replicated in the cohort analysis. At the class level, phosphatidylcholine and phosphatidylethanolamine were associated with reduced hip fracture risk (FDR = 0.01 and 0.05, respectively), with similar patterns in the replication cohort.INTERPRETATION: Plasma metabolomic profiles, particularly phospholipid metabolism pathways and phosphatidylcholine, are associated with hip fracture risk. These findings suggest altered phospholipid metabolism may contribute to the development of hip fracture and highlight potential metabolic targets for prevention.FUNDING: This study was supported by NIH grants.