Abstract
BACKGROUND: Osteoporosis imposes a substantial fracture burden, yet scalable and dynamic biomarkers for risk stratification remain limited. Serum creatinine-routinely assayed and capturing intertwined muscle and renal signals-has been little studied for incident osteoporosis or fractures. METHODS: In the UK Biobank, covariate-adjusted Cox models and restricted cubic splines assessed associations of baseline creatinine with incident osteoporosis and fractures. Creatinine was modeled categorically (six strata; G4 [70-80 μmol/L] as reference) and continuously. The pre-defined analysis was stratified by sex and age (>65) as well as the three tertiles of the polygenic risk score for osteoporosis (PRS); the multiplicative interaction term examined the relationship between creatinine and PRS. RESULTS: Creatinine showed a U-shaped association with osteoporosis, with a nadir near 80 μmol/L (overall P<0.001; nonlinearity P<0.001). In piecewise models, each 1-μmol/L increase corresponded to a 2.0% lower osteoporosis risk within 25-80 μmol/L (HR = 0.980, 95% CI 0.978-0.982) and a 1.1% higher risk within 80-130 μmol/L (HR = 1.011, 95% CI 1.006-1.017). For fractures, the dose-response was J-shaped around the same nadir: risk decreased by 1.0% per μmol in 25-80 μmol/L (HR = 0.990, 95% CI 0.988-0.992) and increased by 0.3% per μmol in 80-130 μmol/L (HR = 1.003, 95% CI 0.999-1.006). Sex-stratified patterns were directionally concordant. In PRS-stratified categorical analyses (vs G4), the low-creatinine stratum (G1) carried higher osteoporosis risk across tertiles (HRs 1.925, 1.811, and 1.592 for low, intermediate, and high PRS). Creatinine×PRS interactions were not significant (osteoporosis P = 0.132; fractures P = 0.210). CONCLUSIONS: Baseline serum creatinine was significantly and nonlinearly associated with incident osteoporosis (U-shaped pattern) and fractures (J-shaped pattern), with the lowest risk observed at approximately 80 μmol/L, and there was a notable sex difference (higher in males). These associations were independent of genetic susceptibility, suggesting that serum creatinine may serve as a low-cost adjunct marker for clinical risk stratification and surveillance of osteoporosis.