Mendelian randomization to evaluate the relationship between frailty index and the risk of osteoporosis, falls and fractures

Abstract

Background Observational research suggested a suggestive relationship between frailty index (FI) and osteoporosis, falls and fractures. Aims This study aimed to explore genetic causality and identified that higher genetically predicted FI positively correlated with increased risks of osteoporosis, falls, and fractures. Methods Genome-wide association study summary data were used to identify genetic variants strongly related to FI. GWAS data of Heel Bone mineral density, osteoporosis, fall risk and fracture at different site was considered as outcome. Inverse variance-weighted (IVW) analysis was mainly applied; MR-Egger and the weighted median were also used to obtain robust estimates. A series of sensitivity analyses were used to detect pleiotropy or heterogeneity. Then, we adjustment of Body Mass Index (BMI) and type 2 diabetes (T2DM) using multivariable Mendelian randomization (MVMR). Results In the main analysis, a genetically predicted higher Frailty index was associated with a higher risk of Osteoporosis and fall. What’s more, frailty index significantly contributed to an increased risk of Heel Body Mass Density (BMD). In MVMR, after correcting for type 2 diabetes, the causal relationship between FI and Heel BMD has turned into negative regulation. Results of comprehensive sensitivity analysis were consistent with the main causality estimate. Horizontal pleiotropy and heterogeneity were absent in our MR study. Discussion The results provide evidence that offering avenues for interventions alleviates the burden of FI associated with these health concerns. Conclusions Our results suggest a potentially causal relationship between FI and osteoporosis, falls, and fractures.