Background: The relationship between hormone replacement therapy (HRT) and osteoarthritis is controversial in epidemiological studies. With the aim of better understanding the effect of HRT use, this first meta-analysis was implemented to explore the association of HRT and knee OA. Methods: A series of data is retrieved from Web of Science, PubMed, and Embase databases to observe the association of HRT and knee osteoarthritis up to December 2021. Two separated reviewers chose the research, extracted the data, and evaluated the study quality. Pooled estimates of 95% CI and HRs were acquired through a random-effects model. Results: Finally, there existed 13 pieces of research, containing one case-control research, four cross-sectional pieces of research, as well as eight cohort pieces of research, involving 2573,164 participants. The overall results showed that the use of HRT was related to a raised risk of knee OA (HR = 1.24, 95% CI 1.07–1.45). And the pooled analysis showed a statistically significant raised risk of knee joint replacement (HR = 1.30, 95% CI 1.09–1.54) when using HRT. In addition, the outcome exhibits the raised knee OA risk for the present users of HRT (HR = 1.40, 95% CI 1.16–1.68) according to HRT status. In the past users of HRT, the augment of knee OA risk was not statistically evident (HR = 1.16, 95% CI 0.94–1.42). Conclusion: We observed that HRT use was related to a raised knee OA risk. Furthermore, future studies might focus on relevant mechanistic to verify our observed associations.
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