Objective To investigate the enhancing effect of sikuximab in combination with iguratimod on the serum levels of osteopontin （SOST）， Dickkopf-1 related protein （DKK-1）， type Ⅰ collagen C-terminal peptide （CTX-I）， and spinal function in patients with ankylosing spondylitis （AS）. Methods A total of 150 patients with AS who were admitted to our hospital from January 2023 to December 2024 were selected as the research subjects. They were randomly assigned to three groups， namely Group A （50 cases）， Group B （50 cases）， and Group C （50 cases）， using the random number table method. Among them， 2 cases in Group A， 1 case in Group B， and 1 case in Group C were lost to follow-up. Finally， 48 cases were included in Group A， 49 cases in Group B， and 49 cases in Group C. Group A received iguratimod， Group B received sikuximab， and Group C received sikuximab in combination with iguratimod. All three groups received continuous treatment for 6 months. The clinical efficacy after 6 months of treatment was compared among the three groups， including spinal function before and after treatment， duration of morning stiffness， disease activity， magnetic resonance imaging （MRI） sacroiliac joint score， inflammatory response， and levels of serum SOST， DKK-1， CTX-I before and after 6 months of treatment， as well as safety during treatment. Results After 6 months of treatment， the total effective rate of group C was 93.88%， which was higher than those of group A （60.42%） and group B （79.59%）. Moreover， the total effective rate of group B was higher than that of group A （P < 0.05）. Compared with the pre - treatment values， after 6 months of treatment， the Bath AS Functional Index （BASFI）， Bartholomew's AS Disease Activity Inventory （BASDAI）， MRI sacroiliac joint scores， the levels of serum C-reactive protein （CRP）， tumor necrosis factor - α （TNF-α）， interleukin-1β （IL-1β）， DKK-1， and CTX-I in all three groups decreased. The values in group C were lower than those in group A and group B， and the values in group B were lower than those in group A. The duration of morning stiffness in all three groups was shortened. The duration in group C was shorter than those in group A and group B， and the duration in group B was shorter than that in group A. The levels of serum SOST in all three groups increased. The levels in group C were higher than those in group A and group B， and the levels in group B were higher than those in group A （P < 0.05）. There were no significant differences in the incidences of adverse reactions among the three treatment groups （P > 0.05）. Conclusions Compared to monotherapy， the combination of sikuximab and iguratimod can significantly alleviate the symptoms of patients with AS， reduce their inflammatory response， effectively regulate the levels of serum SOST， DKK-1， and CTX-I， improve spinal function， and enhance clinical efficacy without increasing the incidence of adverse reactions. Nevertheless， sikuximab monotherapy is more effective than iguratimod monotherapy.