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Fragility fractures are a major problem in our aging society leading to early death and loss of independence for activities of daily living. Physical activity in a long-term follow-up of Portuguese women over 50 years with a fragility fracture was associated with better physical function and quality of life., Purpose: To evaluate the long-term impact of physical activity on physical function and health-related quality of life (HRQoL) in women ≥ 50 years old who suffered a fragility fracture., Methods: We evaluated the association of physical activity with physical function and HRQoL in women ≥ 50 years old who self-reported at least one low-impact fracture ≥ 40 years old from the EpiDoC cohort, a population-based cohort. Self-reported data regarding sociodemographics, clinical, and lifestyle behaviors were collected through a semi-structured questionnaire at baseline during a face-to-face clinical interview. During a long-term follow-up, a phone interview was conducted to evaluate physical activity (using a non-validated scale developed for the EpiDoC study), physical function (Health Assessment Questionnaire), and HRQoL (European Quality of Life - 5 Dimension). Women were divided into three groups according to the frequency of physical activity (non-frequent = 0 times/week, frequent = 1-2 times/week, or very frequent =  ≥ 3 times/week). The association of physical activity frequency (non-frequent, frequent, and very frequent) with physical function and HRQoL over time was assessed through linear mixed models considering varying intercepts for each woman., Results: This study followed 323 post-fracture women, during a mean follow-up of 3.9 ± 3.5 years. Frequent (β =  - 0.1419 [- 0.2783, - 0.0064]) and very frequent (β =  - 0.1908 [- 0.2944, - 0.0881]) physical exercise were associated with improvements in physical function relative to non-frequent physical exercise adjusted for BMI, multimorbidity, hospitalizations, alcohol and smoking habits, and the number of fragility fractures at baseline. As for HRQoL, a positive association was found for exercise frequency, specifically frequent (β = 0.1305 [0.0646, 0.1958]) and very frequent (β = 0.1354 [0.0856, 0.1859]) suggesting improvements for HRQoL, in this follow-up period., Conclusions: These findings based on longitudinal data with long-term follow-up suggest that regular physical activity is associated with better function and HRQol among middle-aged and older post-fracture osteoporotic Portuguese women., Competing Interests: Declarations. Conflict of interest: David G. Lopes, Carolina Mazeda, Jaime Cunha Branco, and Helena Canhão declare that they have no conflict of interest. Ana Rodrigues reports grants from Amgen and Pfizer. Anabela Barcelos has received honoraria for presentations from Janssen and support for attending meetings and/or travel from Amgen, Janssen, and Novartis., (© 2024. The Author(s).)