Osteoporotic bone defect is a major challenge in clinics for bone regeneration. Under the condition of osteoporosis, excessive bone absorption and impaired osteogenesis resulted in unexpected long healing procedure of defects. In order to simultaneously enhance bone formation and reduce bone resorption, a polydopamine-coated porous titanium scaffold was designed to be integrated with the anti-catabolic drug zoledronic acid nanoparticles (ZOL loaded gelatin NPs), which was able to achieve a local sustained-release of ZOL as expected. The in-vitro study demonstrated that the extracts of the composite scaffolds would stimulate the osteoblast differentiation; meanwhile, they also inhibited osteoclastogenesis at a ZOL loading concentration of 50μmo/L. In vivo study, thereafter, the composite scaffolds were implanted into the ovariectomy-induced osteoporotic rabbits suffering from femoral condyles defects. The results indicated that the composite scaffolds without ZOL loaded gelatin NPs only induced callus formation mainly at the interface margin between the implant and bone, whereas the composite scaffolds with ZOL loaded gelatin NPs were capable to further enhance osteogenesis and bone growth into the scaffolds. Moreover, the research proved that the promoting effect was optimal at a ZOL loading concentration of 50μmo/L. In summary, the present research indicated that a new type of porous titanium scaffold integrated with ZOL loaded gelatin NPs inherited a superior biocompatibility and bone regeneration capability. It would be an optimal alternative for the reconstruction of osteoporosis-related defects than the traditional porous titanium implant; in other words, the new type of scaffold would offer a new effective and practical procedure option for patients suffering from osteoporotic bone defects.Creative Commons Attribution license.