Epidemiological studies and a recent Mendelian randomization (MR) study have identified an association between low bone mass and an increased risk of scoliosis. Previous research suggests that bone loss in patients with scoliosis may be related to the RANK-RANKL-OPG system. This study is to investigate whether a causal relationship exists between the RANK-RANKL-OPG system and the development of scoliosis. Genome-wide association study (GWAS) data for RANK and RANKL were sourced from the UK Biobank's Pharmaceutical Proteomics Project, while OPG data were derived from 2 independent cohorts, and scoliosis data from the FinnGen R10 database. A bidirectional 2-sample MR framework was applied to investigate causal relationships between OPG, RANK, RANKL, and scoliosis, with inverse variance weighting (IVW) as the main analytical method. Meta-analysis was used to integrate findings across cohorts, and multiple sensitivity analyses were conducted to assess the robustness and reliability of the results. According to the IVW results, there was no significant causal relationship between RANK (OR = 0.973, 95% CI = 0.871-1.087, P = .626) and RANKL (OR = 1.048, 95% CI = 0.938-1.171, P = .411) and scoliosis. OPG is a potential protective factor for scoliosis (Folkersen 2020 OR = 0.739, 95% CI = 0.611-0.893, P = .002; Zhao 2023 OR = 0.833, 95% CI = 0.716-0.968, P = .017).The results of Meta-analysis also showed OPG (P = 1.428e-4) would reduce the risk of scoliosis. Inverse MR analysis showed no statistically significant causal relationship between scoliosis and RANK, RANKL and OPG levels (P > .05). Our study employing MR methodology provides robust evidence supporting a causal relationship between decreased osteoprotegerin (OPG) levels and increased susceptibility to scoliosis. However, no significant relationship was found between scoliosis with the RANK-RANKL-OPG system. This research establishes a basis for further exploration of the pathophysiological mechanisms and potential targeted treatments for scoliosis. Future studies are necessary to understand how OPG influences the development of scoliosis.