Abstract
Background Osteoporosis is a foremost public health challenge, especially with the global aging population. Both frailty and osteoporosis share many risk factors, although the relationship between them remains partially explored. This study aims to explore the correlation between varying frailty statuses and osteoporosis incidence. Methods Participants from the 2017-2018 NHANES were classified into three groups: frailty, prefrailty, and robust, based on the frailty phenotype. The correlation between frailty and osteoporosis prevalence was assessed using weighted multivariate logistic regression models. Causal relationship was verified by Mendelian randomization using frailty data from the U.K. Biobank and osteoporosis data from the FinnGen database. Proteomic analysis including associated protein screening and functional enrichments was performed based on data from the Icelandic cohort. Results The study group comprised 1814 participants. An increased incidence of osteoporosis was observed in older age and lower body mass index populations. A significant frailty-osteoporosis correlation (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.14-1.64; p = 0.001) was indicated both in the crude model and after adjustments (OR: 1.23; 95% CI: 1.01-1.51; p = 0.039). The inverse variance weighting method observed a potential effect of frailty on osteoporosis risk (β/SE, 0.209/0.099; OR: 1.233; 95% CI: 1.014-1.499; p = 0.036). Thirteen frailty-osteoporosis-associated proteins were found, and proteomic enrichment indicated oxidative stress-related pathways as a hypothesis-generating mechanism of frailty-mediated osteoporosis. Conclusions Our findings suggest a potential causal association between frailty and osteoporosis, with risk exacerbating with the progression of frailty severity. Frailty potentially impacts the progression of osteoporosis through response to oxidative stress. </p>