Introduction <p>To compare 12-month real-world treatment persistence and compliance in postmenopausal women prescribed denosumab or alendronate for osteoporosis in Asia–Pacific.</p> Materials and methods <p>This prospective cohort study enrolled women aged ≥ 50 years from Australia, Taiwan, South Korea, Hong Kong and Singapore between 2019–2021. Study participants were prescribed bi-annual denosumab injection or weekly alendronate, based on physicians’ decision. Medication persistence and compliance were estimated over 12 months of follow-up. Multivariable logistic regression was used to determine if treatment type (denosumab or alendronate) was significantly associated with persistence and compliance, while adjusting for age, fracture history, baseline BMD, prior osteoporosis treatment, and prior treatment with oral glucocorticoids. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated.</p> Results <p>Among 686 enrolled women, 580 completed their 12-month visit (301 in denosumab and 279 in alendronate group). At baseline, those in the denosumab group were older and more likely to have received prior osteoporosis treatment. Overall treatment persistence and compliance were 72.4% and 70.7%, respectively. Patients receiving denosumab exhibited higher persistence (82.7% vs. 61.3%,<i> P</i> &lt; 0.001) and compliance (86.0% vs. 54.1%, <i>P</i> &lt; 0.001), versus those on alendronate. Regression results also showed that patients on denosumab were more likely to be persistent (aOR = 3.08; 95% CI 2.04–4.63) and compliant (aOR = 5.32; 95% CI 3.45–8.21) with treatment. Gastrointestinal disorders were more frequently reported in the alendronate group, while bone and joint injuries were more common in the denosumab group.</p> Conclusion <p>Postmenopausal women with osteoporosis were more likely to be persistent and compliant with denosumab, compared with weekly oral alendronate.</p>