Abstract
In observational studies, associations between osteoporosis (OP) and gastroesophageal reflux disease (GERD) have been found. We conducted a 2-way, 2-sample Mendelian randomization (MR) analysis to determine whether these associations have a causal relationship. Data on GERD at the summary-level were sourced from extensive genome-wide association studies encompassing 129,080 cases and 473,524 control subjects. Bone mineral density (BMD) served as the phenotypic indicator for OP. BMD metrics were compiled from a cohort of 537,750 individuals, encompassing total body BMD (TB-BMD) and stratified TB-BMD across age groups, along with BMD measurements at 4 anatomical locations: lumbar spine, femoral neck, heel, and ultra-distal forearm. Multiple MR approaches, such as the inverse-variance weighted (IVW) method, MR-Egger regression, and the MR-PRESSO test, were employed, among which findings obtained by IVW method were designated as the primary outcomes. For quality assurance, sensitivity analyses were conducted using the MR-Egger intercept, Cochran Q, and leave-one-out test. There were no significant causal links between genetic inclination towards GERD and reduced BMD levels. Nonetheless, the genetic evidence suggests a causal link between higher BMD levels and lower incidence of GERD [TB-BMD: OR = 0.941, 95% confidence intervals (CI) = 0.910-0.972, P < .001; TB-BMD-1: OR = 0.919, 95% CI = 0.885-0.954, P < .001; TB-BMD-3: OR = 0.945, 95% CI = 0.915-0.977, P = .001; TB-BMD-4: OR = 0.926, 95% CI = 0.896-0.957, P < .001]. Sensitivity analyses corroborate our findings. The MR analysis indicates no significant causal link between genetic inclination towards GERD and OP or reduced BMD within the European demographic. In addition, the study suggests that lower BMD or OP, as predicted by genetics, may contribute to the development of GERD.