Background <p>Osteoporosis, a widespread metabolic bone disorder, leads to diminished bone density, heightened susceptibility to fractures, and overall skeletal fragility. As the world’s population continues to age, this condition has emerged as a pressing public health issue. Recent research has explored the possible link between <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection and various systemic diseases beyond the stomach. Yet, the connection between <i>H. pylori</i> and osteoporosis remains hotly debated, with the exact biological mechanisms still unclear. Methods: The study recruited participants from Taizhou Hospital who underwent routine health evaluations, including hematological assessment, urea breath tests, and bone density evaluations using dual-energy X-ray absorptiometry. Logistic regression models were used to investigate the relationship between <i>H. pylori</i> infection and osteoporosis. Additionally, mediation analysis was performed to determine the potential mediating role of inflammation in this association. Results: Logistic regression analysis identified <i>H. pylori</i> infection as a risk factor for osteoporosis. A subsequent cohort study provided additional evidence that chronic <i>H. pylori</i> infection is associated with an increased risk of osteoporosis. Mediation analysis revealed that inflammatory responses partially mediate the association between <i>H. pylori</i> and osteoporosis. Conclusion: This study suggests that <i>H. pylori</i> infection may be associated with an elevated risk of osteoporosis in postmenopausal women, with inflammatory response potentially acting as a partial mediating pathway.</p>