Background <p>Spinal stenosis is a common disease in clinical practice, and drug use is one of its potential predisposing factors. Alendronate, a widely used clinical drug for osteoporosis treatment, has the potential to trigger spinal stenosis. Based on the real world, this study aims to deeply investigate the association between spinal stenosis and alendronate, and to explore novel drug targets against spinal stenosis at the genetic level.</p> Methods <p>Alendronate patient data from the FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024 were included in the study, and four pharmacovigilance analytic methods and Bonferroni corrected P-values were applied to the baseline data, and subgroups of data were analyzed. Complementarily, Weibull distribution were applied to further parse the data. Meanwhile, in order to explore therapeutic targets against spinal stenosis, Mendelian randomization analyses were carried out based on eQTLGen consortium data as well as genome-wide association study (GWAS) data from two large independent cohorts. Subsequently, the medicinal value of the identified drug targets was verified by drug prediction and molecular docking techniques.</p> Results <p>Pharmacovigilance analysis showed a strong positive signal between alendronate and spinal stenosis, especially in females and older patients. Fourteen significant drug targets were identified. Their medicinal value was verified by drug prediction and molecular docking, obtaining four protein-drug docking model structures.</p> Conclusions <p>This study reveals an alendronate-spinal stenosis association, offering insights for clinical prevention. It also identifies new genetic drug targets, opening new treatment pathways for spinal stenosis.</p> Trial registration <p>Not applicable.</p>