The primary objective of this study was to determine the differences in efficacy between denosumab and zoledronate in preventing secondary vertebral compression fractures (VCFs). Our findings demonstrate that twice-yearly administration of denosumab compared with conventional zoledronate significantly reduces the early risk of secondary VCFs among postmenopausal women following vertebroplasty. However, this advantage was confined to the first year and was not sustained at 24 months. Clinicians should consider denosumab as a preferential option over bisphosphonates when managing osteoporotic women at high risk of early secondary VCFs.

Denosumab and zoledronate, both recognized as first-line antiresorptive agents, are among the most widely administered drugs for osteoporotic patients experiencing vertebral compression fractures (VCFs). To date, no head-to-head study has been individually powered to compare their efficacy in secondary VCF prevention.

To evaluate the comparative preventive efficacy of denosumab versus zoledronate against secondary VCFs in postmenopausal women with primary osteoporosis and pre-existing VCFs.

Postmenopausal women who underwent vertebroplasty for osteoporotic VCFs at our medical center were prospectively enrolled. Eligible participants were randomly assigned to receive either the denosumab regimen (Den-arm) or the zoledronate regimen (Zol-arm) following spinal intervention for a duration of 2 years. The primary endpoint was the occurrence of new morphometric VCFs identified on lateral radiographs. Secondary endpoints included new clinical VCFs, bone mineral density (BMD), and serum bone turnover markers.

As of December 2025, complete study follow-up was confirmed for 313 subjects (155 randomized to the Den-arm and 158 to the Zol-arm). New morphometric VCFs occurred significantly less frequently in the Den-arm compared with the Zol-arm at 12 months (2.0% vs. 7.6%, P = 0.031), but the overall incidence was comparable at 24 months (5.8% vs. 8.2%, P > 0.05). The 24-month Kaplan–Meier analysis estimated a lower cumulative incidence of new clinical VCFs in the Den-arm versus the Zol-arm (2.0% vs. 6.9%, log-rank P = 0.030). Significant differences were observed in the percent change in lumbar BMD from baseline, favoring the Den-arm over the Zol-arm at 6 and 12 months after treatment initiation (P < 0.001 and P < 0.05, respectively). The Den-arm also showed greater decreases in the bone resorption marker s-CTX from baseline compared with the Zol-arm at 3 and 6 months after treatment (P < 0.05).

Among postmenopausal women with prevalent osteoporotic VCFs, the administration of denosumab versus zoledronate demonstrated superior efficacy in preventing early secondary VCFs within the first year. However, this short-term advantage was not maintained at 24 months, as both agents showed comparable overall morphometric VCF incidence by the end of the study period. Further research with extended follow-up is warranted to clarify the long-term comparative efficacy of denosumab versus other anti-osteoporosis agents.