UNLABELLED: Chronic use of morphine is a risk factor for endocrinopathy and osteoporosis. Bisphosphonates accentuated the protective effect to develop osteoporosis in female patients with malignancy with morphine treatment. INTRODUCTION: This study investigates the risk of osteoporosis associated with morphine use by comparing the incidence of osteoporosis in female cancer patients treated with and without morphine. METHODS: A population-based nested case-control retrospective analysis was performed using the Longitudinal Health Insurance Database 2000 and Registry for Catastrophic Illness Patients of Taiwan. A malignancy cohort of 12,467 female patients without a history of osteoporosis during 1998-2010, and then 639 patients who subsequently developed osteoporosis as the osteoporosis group, were evaluated. Control-group patients were selected from the malignancy cohort without osteoporosis and frequency matched to each osteoporosis case 2:1 for age, year of cancer diagnosis, and index year. Logistic regression was used to estimate the odds ratios and 95% confidence intervals, and the multivariable model was applied to control for age. RESULTS: Female cancer patients who received morphine had a 10% lower risk of developing osteoporosis than non-morphine users, but this risk reduction was not significant. For patients treated with bisphosphonates, the morphine group had significantly lower odds in developing osteoporosis than the non-morphine group. CONCLUSION: Morphine treatment is not associated with the incidence of osteoporosis, and bisphosphonates accentuated the protective effect of morphine in the development of osteoporosis in female patients with malignancy in Taiwan.