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Schema diagram of the bioactive composite PTH@PHC hydrogel with osteogenic potency and immunomodulatory property for treating osteoporotic bone defects via improving bone metabolism and sustainable release of PTH. [Display omitted] • Novel composite hydrogel was constructed by tetra-PEG, nanohydroxyapatite, and chitosan. • This composite hydrogel exhibited an effect of inducing M2 macrophage polarization. • The composite had ability of enhancing osteogenesis and reducing osteoclastogenesis. • The hydrogel can load and long-term release PTH, thus improving osteogenesis further. • This hydrogel improved bone regeneration and healing in osteoporotic bone defects. Osteoporotic bone defect is an intractable challenge in clinical practice, involving impaired bone repair ability and abnormal immune response. Despite the development of various tissue-engineered scaffolds for osteoporotic bone repair, the pathogenesis of osteoporosis has been lacking consideration, resulting in poor efficacy. Here, we integrated short-chain chitosan (CS) and nanoparticulate hydroxyapatite (nHAp) into a covalent tetra-armed poly (ethylene glycol) (tetra-PEG) network to create a composite hydrogel (PEG/nHAp/CS, PHC). The constructed PHC hydrogel exhibited ability of enhancing osteogenesis with high mechanical strength, excellent surface properties, and good biocompatibility. PHC hydrogel also had immunomodulatory effects of promoting M2 macrophage polarization and suppressing M1 macrophage polarization via antagonizing TLR4/NF-κB signaling. PHC hydrogel further increased osteogenic capacity and inhibited osteoclast formation and resorption indirectly. Parathyroid hormone (PTH) could be effective loaded and sustainable released in the PHC hydrogel (PTH@PHC), in which the osteogenic ability was further enhanced via activation of cAMP/PKA/CREB signaling. By using an osteoporotic calvaria bone defect rat model, we demonstrated that the PTH@PHC hydrogel was able to improve bone regeneration and bone defects healing. Findings of this study indicated that the bioactive composite hydrogel has powerful osteogenic-promoting potency and immunomodulation, which provides a promising therapeutic strategy for future clinical repair of osteoporotic bone defect. [ABSTRACT FROM AUTHOR]