Objective Recent clinical case reports have been controversial regarding the adverse events(AEs) of amputation associated with sodium-glucose co-transporter 2 inhibitors(SGLT2i). We assessed the risk of osteomyelitis AE reporting associated with SGLT2i or SGLT2i-metformin co-medication. Method We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) for SGLT2i-associated or SGLT2i-metformin co-medication osteomyelitis-relevant AEs from the second quarter of 2013 to the first quarter of 2023. The safety signals of osteomyelitis were detected using comprehensive disproportionality analysis by reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma passion shrinker (MGPS), and Bayesian confidence propagation (BCPNN) methods. The additive interaction model (RERI), multiplicative interaction model (eβ3) and Ω shrinkage measures (Ω025) were employed to explore the latent interactions on osteomyelitis adverse events between SGLT2i and metformin. We also focused on the characteristics and correlation between SGLT2i-associated osteomyelitis and amputation by estimating the overlap rate of relevant AE records. Results Out of 2569 SGLT2i-associated osteomyelitis AEs investigated, we identified 2509 canagliflozin-associated reports (ROR 104.47, 95%CI 100.10-109.03; PRR 99.70, 95%CI 95.54-104.04, χ2=214840.90; EBGM 87.45, EBGM05=84.38; IC 6.45, IC025=4.78). There are 103 SGLT2i-metformin compound-associated reports. The outcomes of the drug-drug interaction assessment showed negative correlation(RERI=-21.73, eβ3=0.699, Ω025=-1.370). The concordance between SGLTi-associated osteomyelitis and amputation AE reports was 80%. Conclusion This study showed a significantly increased risk of SGLT2i-associated osteomyelitis, mainly focusing on canagliflozin, and presented a potential association between amputation and osteomyelitis, providing a reference for the clinical practice of diabetes with SGLT2i medication.