Objective: To investigate the effect of calcitriol on the expression of serum sclerotin (SOST) and fibroblast growth factor 23 (FGF23) in postmenopausal women with osteoporosis. Methods: A total of 100 menopausal women with osteoporosis were recruited and randomly divided into a control group and a treatment group (50 cases in each group). The treatment group was treated with calcitriol for 12 weeks, while the control group was treated with placebo. The changes of blood biochemical markers and bone turnover markers were recorded before and after treatment. Results: Compared with the control group, the expression levels of parathyroid hormone (PTH) and SOST decreased, uric acid and urinary calcium increased in the treatment group after the treatment, the difference was statistically significant (P<0.05); the expression levels of FGF23 did not change significantly before and after treatment in both groups (P>0.05). In the treatment group, SOST was positively correlated with PTH (r=0.28, P=0.01) and negatively correlated with urinary calcium (r=−0.22, P=0.04); FGF23 were negatively correlated with serum cross-linked C-terminal telopeptide of type I collagen (r=−0.33, P=0.02) and urinary calcium (r=−0.36, P=0.01). Conclusion: The use of calcitriol in menopausal women with osteoporosis can reduce the expression of serum SOST, but it has no significant effect on FGF23.