Abstract Purpose: Osteoporosis is characterized by a loss of bone mass, increased bone fragility and susceptibility to fracture. Sequential treatment with bisphosphonates or denosumab (Dmab) after teriparatide (TPT) discontinuation may represent a valid treatment option, but the optimal sequential treatment strategy is unknown. Methods: This retrospective study enrolled 56 osteopenic/osteoporotic patients with fragility fractures who received 24 months of treatment with TPT followed by 24 months of treatment with zoledronic acid (ZOL) (TPT+ZOL) or Dmab (TPT+Dmab). Clinical features, incident fractures, bone mineral density (BMD) measurements, and bone marker profiles were characterized. Ordinary one-way ANOVA adjusted for multiple testing analyzed the difference between median T-scores at baseline, after 24 months of TPT, and after 2 doses of ZOL or at least 3 doses of Dmab when variables failed the normality test. Results: Twenty-three patients received TPT+ZOL (19 females, 4 males; median [IR] age, 74.3 [66.9, 78.6] years) and 33 patients received TPT+Dmab (31 females, 2 males; mean±SD age, 66.6±11.3 years). Mean lumbar and hip T-scores were significantly higher after sequential treatment with both TPT+ZOL and TPT+Dmab (all p<0.05 vs baseline). In particular, the mean lumbar T-score increased in about 80% of patients by 8.5±58% after ZOL, while after Dmab, the mean lumbar T-score was -9.6±36%. Mean±SD femur neck and hip T-scores increased by 12±13% and 9±31%, respectively, after treatment with ZOL, while the change in femur neck and hip T-scores after Dmab were 5±41% and 27±36%, respectively, No significant between-group differences were identified. Fragility fractures occurred in 3 (13%) patients treated with TPT+ZOL and in 5 (15%) patients treated with TPT+Dmab. Conclusion: Sequential therapy with TPT+ZOL increased bone mineralization at the lumbar level and stabilized bone mineralization at the femoral level. Both ZOL and Dmab are effective sequential treatments after TPT.