Background Osteoporosis (OP) is one of the most common chronic diseases, but the drugs used to treat OP have strong side effects. Recently, bone regeneration in stem cell derivatives represented by extracellular vesicles (EVs) has provided a new strategy for the prevention and treatment of OP. EVs derived from mouse mesenchymal stem cells (mMSCs) have a positive effect on bone regeneration, yet their clinical application has been hampered by the lack of bone-targeting. Alendronate (Ale) has a specifically affinity for bone tissue through a high affinity with hydroxyapatite. Herein, we used copper-free "click chemistry” to combine EVs with Ale together for OP targeted therapy. Bone targeting was facilitated via Ale binding to hydroxyapatite, which is highly expressed on the bone surface. Methods In vitro, bone targeting of Ale-EVs was confirmed by flow cytometry. Also, Ex vivo fluorescent imaging data revealed strong fluorescent signals in bone tissues in mice treated with Ale-EVs-DiD compared to bone tissues of mice treated with EVs-DiD. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Besides, our results showed that Ale-EVs could promote the proliferation and differentiation of mouse mesenchymal stem cells in vitro. And it had the antiosteoporotic effects in ovariectomy (OVX)-induced osteoporosis rat model. Conclusions A novel bone-targeting nanoparticle delivery system was developed for osteoporosis therapy. We used the Ale-N3 to modify mMSCs derived EVs by copper-free "click chemistry” to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.