Background <p>Osteoporosis is often underdiagnosed due to limitations in traditional screening methods, leading to missed early intervention opportunities. AI-driven screening using chest radiographs could improve early detection, reduce fracture risk, and improve public health outcomes.</p> Aims <p>To assess the cost-effectiveness of deep learning models (hereafter referred to as AI-driven) applied to chest radiographs for opportunistic osteoporosis screening in German women aged 50 and older.</p> Methods <p>A decision tree and microsimulation Markov model were used to calculate the cost per quality-adjusted life year (QALY) gained (€2024) for screening with AI-driven chest radiographs followed by treatment, compared to no screening and treatment. Patient pathways were based on AI model accuracy and German osteoporosis guidelines. Women with a fracture risk below 5% received no treatment, those with 5–10% risk received alendronate, and women 65 + with a risk above 10% received sequential treatment starting with romosozumab. Data was validated by a German clinical expert, incorporating real-world treatment persistence, DXA follow-up rates, and treatment initiation. Sensitivity analyses assessed parameter uncertainty.</p> Results <p>The cost per QALY gained from screening was €13,340, far below the typical cost-effectiveness threshold of €60,000. Optimizing follow-up, treatment initiation, and medication adherence further improved cost-effectiveness, with dominance achievable by halving medication non-persistence, and in women aged 50–64.</p> Conclusion <p>AI-driven chest radiographs for opportunistic osteoporosis screening is a cost-effective strategy for German women aged 50+, with the potential to significantly improve public health outcomes, reduce fracture burdens and address healthcare disparities. Policymakers and clinicians should consider implementing this scalable and cost-effective screening strategy.</p>