Abstract: Objective Based on the U. S. Food and Drug Administration Adverse Event Reporting System(FAERS) database, this study aims to detect adverse drug reaction(ADR) risk signals of two antiresorptive drugs, zoledronic acid and denosumab, so as to provide reference for clinical safe medication. Methods Adverse drug event(ADE) reports of zoledronic acid and denosumab in the FAERS database from January 2004 to September 2024 were extracted, and the reporting odds ratio(ROR) and proportional reporting ratio(PRR) methods were adopted for ADE signal mining. Results A total of 212 622 ADE reports related to the two commonly used antiresorptive drugs were identified, including 1 311 positive ADE signals for zoledronic acid and 683 for denosumab. There were significant differences in ADE signal profiles between the two drugs. Exposed mandibular bone and bone sequestrum showed the strongest correlation with zoledronic acid, while giant cell tumor of bone and malignant giant cell tumor of bone were strongly associated with denosumab. The ADEs of zoledronic acid mainly involved musculoskeletal and connective tissue disorders, systemic disorders, and administration site reactions; while those of denosumab mainly involved injuries, poisoning and procedural complications, as well as musculoskeletal and connective tissue disorders. Several new ADE signals were also identified in this study, such as skeletal disorders and mandibular disorders. Conclusion The ADE signals of zoledronic acid and denosumab detected in this study are generally consistent with those recorded in the package inserts. In clinical practice, in addition to focusing on known adverse reactions such as death and osteonecrosis of the jaw, close attention should also be paid to new potential adverse reaction signals not mentioned in the package inserts, including various musculoskeletal and connective tissue disorders.