Abstract: Objective: To evaluate whether Lactoferrin (LF) has a therapeutic effect on cartilage and subchondral bone in osteoporotic (OP) rats with osteoarthritis (OA). Methods: Forty female Sprague Dawley rats were stratified into four groups with 10 animals per group: OA, OA+LF, OP+OA, OP+OA+LF. OA was induced 12 weeks after bilateral ovariectomy (OVX) or sham operation. LF dissolved in 2ml 0.9% normal saline was administered by oral gavages at a dose of 85mg/kg/d, starting from the first day after the induction of OA. After 8-week treatment, the proximal tibia was harvested for histology, micro-computed tomography (micro-CT), immunohistochemical staining, real-time polymerase chain reaction, as well as western blot evaluation. Results: Therapeutic effect of LF was mainly observed in OVX rats, which increased BV/TV by 30.2%, the Tb.Th by 33.7%, and decreased Tb.Sp by 50.1% in micro-CT analysis of the subchondral bone. LF treatment also decreased the mRNA and protein expression of matrix metalloproteinase-13 (MMP-13) and tartrate-resistant acid phosphatase (TRAP), as well as increasing the mRNA and protein expression of runt-related transcription factor 2 (Runx2) in OVX rats. Conclusion: LF treatment reduced traumatic osteoarthritis in OVX rats, which was possibly related to the beneficial effect of LF on subchondral bone tissue indirectly, or direct effect on cartilage by decreasing the expression of MMP-13 and TRAP.