This study aims to investigate the effect of iguratimod, a novel disease-modifying antirheumatic drug, alone or combined with methotrexate (MTX), on the serum levels of regulators of bone remodeling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and Dickkopf-1 (DKK-1)) and bone remodeling markers (C-telopeptide of type I collagen (CTX-I) and procollagen type I N-terminal propeptide (PINP)) in patients with rheumatoid arthritis (RA). Patients with RA were treated with iguratimod, MTX, or their combination for 12months. Serum samples were collected before treatment and 6 and 12months afterwards. RANKL, OPG, DKK-1, CTX-I, and PINP levels were measured, and radiographic progression was assessed. The serum RANKL levels decreased after treatment for 6 and 12months with iguratimod (median: baseline 565.00pmol/L vs. 6months 411.00pmol/L vs. 12months 212.00pmol/L), MTX (median: baseline 562.50pmol/L vs. 6months 399.50pmol/L vs. 12months 163.50pmol/L), and their combination (median: baseline 971.00pmol/L vs. 6months 272.50pmol/L vs. 12months 241.50pmol/L). Combination therapy showed greater effects 6months post-treatment compared to single-drug therapy. PINP levels increased significantly 12months post-treatment with all therapies, but only the combination therapy led to decreased CTX-I levels. OPG and DKK-1 levels showed no significant changes. The three treatments showed no significant differences in radiographic progression. Iguratimod could stimulate bone formation and regulate the RANKL/RANK/OPG system rather than DKK-1levels. Its effects are comparable to those of MTX, and combination therapy showed stronger effects.