Abstract: Objective To evaluate the effects of sequential administration of different anti-resorptive agents (denosumab/zoledronic acid) following initial alendronate sodium therapy on bone metabolism in patients with primary osteoporosis (POP). Methods A total of 102 patients with POP who were prospectively enrolled and under regular follow-up at Civil Aviation General Hospital from June 2019 to December 2023 were randomized, using a random number table, into the denosumab group (alendronate sodium followed by denosumab, n = 57) and the zoledronic acid group (alendronate sodium followed by zoledronic acid, n= 45). The clinical efficacy was compared between the two groups. Results The average daily drug costs in the denosumab group were lower than those in the zoledronic acid group. At 3, 6, 12, and 18 months post-treatment, serum levels of calcium, procollagen type I N-terminal propeptide (PINP), β isomer of C-terminal telopeptide of type I collagen (β-CTX), and osteocalcin (OC), as well as the visual analogue scale (VAS) scores were significantly lower than those at baseline in both groups (P < 0.05). At 12 and 18 months of treatment, the lumbar spine and femoral neck bone mineral density (BMD) T-scores in both groups were significantly higher than those at baseline and at 6 months (P < 0.05). The levels of PINP, β-CTX, and OC in the denosumab group were significantly lower than those in the zoledronic acid group at 3, 6, 12, and 18 months post-treatment (P < 0.05). The VAS scores in the denosumab group were significantly lower than those in the zoledronic acid group at 3 and 6 months post-treatment (P < 0.05). There was no statistically significant difference in the BMD T-scores at lumbar spine and femoral neck between the two groups at 6, 12, and 18 months post-treatment (P > 0.05). The overall incidence of adverse reactions in the denosumab group was significantly lower than that in the zoledronic acid group (P < 0.05). Conclusion Sequential treatment with denosumab or zoledronic acid following initial alendronate sodium therapy can effectively improve bone metabolism. Compared with zoledronic acid, denosumab was associated with lower medication costs, better therapeutic efficacy, and a more favorable safety profile.