Bone-targeting β-cyclodextrin phosphate has anti-resorptive activity and thereby prevents osteoporosis

Osteoporosis is a common bone disease that weakens and fragilizes the bones. A wide variety of osteoporosis medicines are available; however, the long-term use of such medicines is not recommended because of major adverse effects. Therefore, the development of effective and safe therapeutic drugs is urgently required. Here, we developed a bone-targeting drug delivery system with anti-resorptive activity for potential osteoporosis treatment. A phosphate-functionalized β-Cyclodextrin (β-CDP) derivative exhibited strong binding to hydroxyapatite surfaces in vitro and bone-targeting property in vivo. Furthermore, β-CDP successfully delivered a compound to the bone. Hydroxyapatite surface-immobilized β-CDP significantly suppressed osteoclastic bone resorption in RAW264.7 cells, while preserving differentiation. Mechanistically, β-CDP reduced the mature V-ATPase proton pump in the lipid raft fractions. Finally, systemic β-CDP administration effectively prevented ovariectomized-induced bone loss and structural deterioration of the trabecular bone in mice. Our results suggest that β-CDP is a promising platform for bone-targeting therapy in osteolytic conditions.