The causal relationship between epigenetic aging and osteoporosis: a bi-directional Mendelian randomization study

Aim: Osteoporosis (OP) is the most common of the musculoskeletal disorders, with decreased bone mineral density (BMD) being the main manifestation and exacerbating fracture susceptibility. OP was once thought to be an inevitable consequence of aging. We conducted a bi-directional Mendelian randomization (MR) for epigenetic age acceleration (EAA) and osteoporosis to accurately assess the interaction between aging and osteoporosis. Methods: This study collected data from genome-wide association studies of EAA and OP and assessed significant genetic variables. Bi-directional MR analyses were performed using random-effects inverse-variance weighting as the primary method, and the interaction of epigenetic age acceleration with OP was assessed using other MRI methods and multiple sensitivity analyses. Results: Inverse-variance weighted (IVW) results suggest that GrimAge acceleration accelerates bone loss in total body bone mineral density [odds ratio (OR) = 1.035, 95% confidence interval (95%CI) = (1.003, 1.069), P = 0.033]. The effect of BMD on EAA was investigated, and a causal relationship was found between forearm bone mineral density and GrimAge acceleration [OR = 0.682, (95%CI) = (0.508, 0.916), P = 0.011]. There was a causal relationship between femoral neck bone mineral density and PhenoAge acceleration [OR = 1.452, (95%CI) = (1.007, 2.096), P = 0.046]. Conclusions: Epigenetic age acceleration was bi-directionally causally associated with osteoporosis. GrimAge acceleration increased the risk of decreased total body bone mineral density. Forearm bone mineral density accelerated GrimAge and femoral neck bone mineral density accelerated PhenoAge acceleration.