Causal Association Between Bone Mineral Density and the Risk of Joint Replacement in Patients with Osteoarthritis: a Mendelian Randomization Study

Population-based studies have been inconsistent in terms of the relationship between bone mineral density (BMD) and the progression of osteoarthritis. This study aimed to evaluate the causal relationship between BMD and the risk of joint replacement in patients with osteoarthritis. We performed a two-sample Mendelian randomization (MR) analysis to determine the association of BMD of the total body, femoral neck, and lumbar spine with the risk of hip and knee replacements. Inverse variance weighting (IVW) was used as the main analysis method. Heterogeneity and horizontal pleiotropy were checked. Multivariable MR analysis was performed by adjusting for hip/knee pain, body mass index (BMI), estrogen levels, BMI-based sex hormone-binding globulin (SHBG) levels, and physical activity. BMD of the total body and the lumbar spine were significantly associated with higher risks of both knee (IVW odds ratios (ORs) = 1.08-1.10, p = 4.62E-03) and hip replacements (IVW ORs = 1.19-1.37, P = 3.23E-09). Femoral neck BMD was significantly associated with the risk of hip but not knee replacement (IVW OR = 1.27, 95% confidence interval 1.13 to 1.43, p = 9.15E-05). Multivariable MR analyses produced similar results compared to the univariable analyses. No evidence of heterogeneity and horizontal pleiotropy were found, except that there was heterogeneity in the association between total body BMD and the risk of knee replacement. BMD is significantly associated with an increased risk of both knee and hip replacement, and the association is stronger for hip replacement. These findings suggest a causal relationship between BMD and the progression of osteoarthritis. Key Points • BMD is associated with an increased risk of hip and knee joint replacement. • BMD was more strongly associated with hip replacement risk.