CONTEXT Metabolomics is an emerging tool that provides insights into the dynamics of phenotypic changes. It is a potential method for the discovery of novel serum markers of fracture.

OBJECTIVE To identify metabolite parameters that can be used as a proxy for osteoporotic fracture risk.

DESIGN Prospective study based on the Ansung cohort in Korea.

SETTING The general community.

PARTICIPANTS A total of 1504 participants with metabolomic analyses.

INTERVENTIONS None.

MAIN OUTCOME MEASURE Fragility fractures.

RESULTS We measured 135 baseline metabolite profiles in fasting serum of the participants. The participants had a mean age of 60.2 years and were comprised of 585 (38.9%) men. During a mean 9-year follow-up, 112 osteoporotic fracture events occurred. Of all metabolites measured, only serum spermidine concentrations were positively associated with the risk of fracture (hazard ratio [HR] per 1 μM of spermidine 1.35, 95% confidence interval [CI] = 1.03-1.65, P = 0.020) after adjusting for age, sex, body mass index, diabetes, hypertension, smoking status, previous fracture history, and baseline tibial quantitative ultrasound. Participants with spermidine concentrations >1.57 μM had a 2.2-fold higher risk of fractures (95% CI 1.08-4.51, P = 0.030) compared with those with concentrations ≤1.57 μM after adjustment. In a subgroup analysis, women with baseline spermidine concentrations >1.57 μM also had a 2.4-fold higher risk of fracture than those with concentrations ≤1.57 μM (95% CI 1.02-5.48, P = 0.047).

CONCLUSIONS Increased baseline spermidine concentrations were associated with a risk of osteoporotic fracture during a mean 9-year follow-up. The biological significance of the metabolites in the musculoskeletal system could be a subject for future studies.