BACKGROUND:Numerous clinical studies have suggested a close relationship between obesity and osteoporosis,but whether there is a genetic causal effect between obesity and osteoporosis remains unclear. OBJECTIVE:To explore the association between obesity and osteoporosis using summary data from a large-scale genome-wide association study(GWAS)through Mendelian randomization analysis. METHODS:Obesity data were derived from summary statistics of the Genetic Investigation of Anthropometric Traits(GIANT)and the UK Biobank(UKBB).Osteoporosis data were obtained from the Genetic Factors for Osteoporosis(GeFOS)consortium,including two bone density phenotypes:total body bone mineral density(BMD)and heel BMD.The inverse variance-weighted method was the primary analysis,with the Mendelian randomization method based on Egger regression(MR-Egger)and weighted median method as supplementary approaches to calculate the causal association between genetic variations related to obesity and osteoporosis.Sensitivity analyses were conducted to validate the reliability of the results.Heterogeneity was assessed using Cochran's Q test.Horizontal pleiotropy was assessed through the MR-Egger intercept test.Leave-one-out analysis was performed to evaluate the potential influence of single nucleotide polymorphisms on the combined inverse variance-weighted estimates. RESULTS AND CONCLUSION:(1)Impact of obesity on osteoporosis:In addition to body mass index and forearm BMD,body mass index,waist-to-hip ratio,body mass index-adjusted waist-to-hip ratio,and whole-body body mass index,heel BMD,forearm BMD,lumbar spine BMD,and femoral neck BMD were causally related to each other.Further Meta-analysis revealed that obesity increased the risk of BMD(odds ratio=1.07,95%confidence interval:1.03-1.12,P<0.01).(2)Impact of osteoporosis on obesity:Apart from arm BMD and lumbar spine BMD as exposure factors showing causal relationships with obesity,other datasets indicated no causal effect between total body BMD,heel BMD,femoral neck BMD,and obesity.Additional meta-analysis demonstrated that BMD did not increase the risk of obesity(odds rate=0.99,95%confidence interval:0.98-1.01,P<0.01).There is a causal relationship between obesity and osteoporosis,suggesting that obesity may be a risk factor for osteoporosis.However,no causal association is found between osteoporosis and obesity.