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ABSTRACT Objective: This study sought to determine serum sclerostin (SOST) expression in patients with osteoporotic thoracolumbar vertebral compression fractures before and after percutaneous kyphoplasty (PKP). Methods: Serum SOST levels were quantified with a sandwich enzyme-linked immunosorbent assay (ELISA) preoperatively and six months postoperatively. Anterior vertebral height, kyphotic angles, and Visual Analogue Scale (VAS) scores were also recorded. Results: Serum SOST was highly expressed in patients and remained negatively correlated with bone mineral density (BMD). Vertebral heights, local kyphotic angles, and VAS scores were all significantly improved after PKP. However, serum SOST was positively correlated with BMD six months after surgery. Conclusion: PKP was an effective treatment strategy for osteoporotic thoracolumbar vertebral compression fractures, improving BMD and decreasing serum SOST levels. Level of Evidence II, Prospective comparative study.