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Objective To observe the effects of osthol-loaded N-octyl-O-sulfonyl chitosan micelles ( NSC-OST) on bone microstructures and bone resorption in ovariectomized osteoporotic rats, and to explore its molecular mechanism of anti-osteoporosis. Methods Forty female SD rats were randomly divided into 5 groups： sham group (Sham) , model group (Ovx) , nilestriol group (Nil) , osthol ( OST) , osthol/chitosan derivative micelle group (NSC-OST). Except for sham operation group, osteoporosis models were established by removing bilateral ovaries. After 12 weeks of continuous administration, osteoporosis models were established. The effects of drugs on bone microstructures was observed with HE staining and micro-CT detection on two-dimensional and three-dimensional morphological perspectives, respectively. The effects of drugs on osteoclast formation and differentiation were observed with tartrate resistant acid phosphatase (TRAP) staining. The effects of drugs on specific molecules NFATcl, c-fos and CTSK expression were detected using immunohistochemistry. Results HE staining result showed that the osteoporosis-like changes induced by modeling in the drug groups improved significantly, and the effect in Nil group was the most obvious, followed by NSC-OST group and OST group. Micro-CT analysis showed that NSC-OST significantly improved BMD and BV/TV of the femur in rats (P< 0. 05) , and significantly improved Tb. The three indexes Tb.N, Tb.Sp, and Tb.Th (P<0. 05) were better than those in OST group, but slightly worse than those in NIL group. TRAP staining showed that NSC-OST significantly inhibited the osteoclast formation parameters N.Oc/BS and Oc.S/BS (F<0. 05) , and the effect was better than that in OST group, but slightly worse than that in NIL group. Immunohistochemical result showed that NSC-OST inhibited the expression of osteoclast-specific molecules NFATcl , c-fos, and CTSK. The inhibitive effect on the first two indicators was similar in NSC-OST group and in Nil group. When CTSK was inhibited, the efficacy in NSC-OST group was less than that in Nil group but more than that in OST group. Conclusion NSC-OST significantly improves the bone microstructures in ovariectomized rats, and its anti-osteoporosis effect may be related to the inhibition of osteoclast formation and differentiation. [ABSTRACT FROM AUTHOR]