Osteoporotic fractures have a tremendous impact on quality of life and may contribute to fatality, but half of patients may discontinue their anti-osteoporosis medication. The study aimed to investigate the factors associated with the persistence of anti-osteoporosis medication. Between June 2016 and June 2018, we recruited 1195 participants discontinuing prior anti-osteoporosis medication. Telephone interviews were conducted to discern the reasons for discontinuation. Comparisons among groups and risks of self-discontinuation were analyzed. Among 694 patients who have no records of continuing anti-osteoporosis medication, 374 (54%) self-discontinued, 64 (9.2%) discontinued due to physicians' suggestion, and 256 (36.8%) with unintended discontinuation. Among patients with self-discontinuation, 173 (46.3%) forgot to visit outpatient clinics; 92 (24.5%) discontinued because of medication-related factors; 57 (15.2%) thought the severity of osteoporosis had improved and therefore discontinued; 30 (8%) stopped due to economic burden; 22 (5.9%) were lost to follow-up because of newly diagnosed diseases other than osteoporosis. Additionally, older age, male gender, calcium supplement, teriparatide therapy and hip fractures in teriparatide users were associated with adherence to anti-osteoporosis drugs. In conclusion, our results indicate that younger age, female gender, non-use of calcium supplements, and anti-resorptive medication were independent risk factors associated with drug discontinuation. Identifying high-risk patients and providing timely health education are crucial for adherence to anti-osteoporosis medication.