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This study identifies mitochondrial oxidative phosphorylation (OXPHOS) as a tractable metabolic target for antiresorptive therapy. A literature\u2010guided drug repurposing screen focused on compounds reported to affect OXPHOS or related energy metabolism identified cloperastine (Clo) as a potent suppressor of receptor activator of nuclear factor \u03baB ligand\u2010induced osteoclastogenesis. Clo reduces mitochondrial respiration, downregulates OXPHOS complex proteins, decreases mitochondrial reactive oxygen species (ROS), dissipates the mitochondrial membrane potential, disrupts mitochondrial dynamics, and collectively impairs osteoclast differentiation and bone resorption in vitro. Asp8\u2010modified methionine\/lysine\u2010based ROS\u2010responsive polyethylene glycol micelles encapsulating Clo (Clo\/Asp8\u2010PMK\u2010MCs) were developed for potential bone\u2010directed delivery. These micelles (\u223c220\u00a0nm; \u22123.60 \u00b1 0.09\u00a0mV) exhibit ROS\u2010triggered disassembly and accelerated Clo release under oxidative conditions. Fluorescence tracking of DID\u2010labeled micelles shows stronger skeletal signals with Asp8 modification than without it. Clo\/Asp8\u2010PMK\u2010MCs inhibit osteoclast differentiation and bone resorption, whereas bioactive Asp8\u2010PMK\u2010MCs simultaneously promote osteoblast differentiation and matrix mineralization. In ovariectomized mice, Clo\/Asp8\u2010PMK\u2010MCs attenuate ovariectomy\u2010induced bone loss, preserve trabecular bone microarchitecture, reduce osteoclast\u2010related parameters and serum bone resorption markers, and enhance bone formation. These findings support Clo\/Asp8\u2010PMK\u2010MCs as a potential OXPHOS\u2010targeted nanomedicine integrating Clo\u2010mediated antiresorptive activity with carrier\u2010mediated osteogenic activity to attenuate estrogen deficiency\u2010induced bone loss.<\/jats:p>","DOI":"10.1002\/advs.78205","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:03:33Z","timestamp":1791777813000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Reactive Oxygen Species\u2010Responsive Bone\u2010Targeted Nanoplatform Based on Cloperastine Attenuates Ovariectomy\u2010Induced Bone Loss by Inhibiting Osteoclast Oxidative Phosphorylation"],"prefix":"10.1002","author":[{"given":"Haibo","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Key Laboratory of Orthopaedics of Zhejiang Province The Second Affiliated Hospital and Yuying Children's Hospital of 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