Caffeine intake is inversely associated with osteoporosis risk based on cross-sectional and genetic evidence.

This study aimed to explore the relationship between caffeine intake and osteoporosis (OP) using a combination of cross-sectional research and Mendelian randomization (MR) methods. Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were used to build logistic regression models, conduct restricted cubic spline (RCS) analysis, and perform subgroup analysis to explore the association between caffeine intake and OP. Additionally, MR analysis employed inverse variance weighted (IVW) as the principal technique to confirm the causal association. A total of 2,863 participants were included in the NHANES cross-sectional study, including 157 with osteoporosis. The OP group had significantly lower caffeine intake. After adjusting for all covariates, logistic regression indicated that participants in the highest tertile of caffeine intake (> 166.5 mg/day) had a 60% lower risk of OP than those in the lowest tertile (< 60 mg/day) (odds ratio [OR] = 0.401; 95% confidence interval [CI]: 0.211-0.769; P = 0.049). RCS analysis revealed an L-shaped curve indicating a declining trend in the risk of osteoporosis (P-non-linear = 0.013, P-overall = 0.003). Subgroup analysis identified race, smoking status, phosphorus, and age as the most significant factors influencing the association between caffeine intake and OP (P-interaction < 0.05). Based on the IVW approach, coffee intake was negatively causally associated with OP (OR = 0.982; 95% CI: 0.974-0.990; P < 0.001). This study, through the integration of cross-sectional and MR analyses, provides strong evidence of a negative causal relationship between caffeine intake and OP.