Metal alloys in arthroplasty face limitations including aseptic loosening, material failure, and allergic reactions. High-performance oxide ceramics (HPOCs) represent an alternative but are bioinert, restricting osseointegration and osteoconduction. The aim of this study was to convert bioinert HPOC surfaces into bioactive osteogenic microenvironments through stable peptide-biofunctionalization with cyclic-arginylglycylaspartic acid (cRGD) or modified-hepatocyte growth factor (mod-HGF). In a rabbit femoral defect model, cylindrical ATZ implants were press-fitted into 4.5 × 8 mm defects and examined after 18 weeks. Three groups were compared: uncoated ATZ, cRGD-coated, and mod-HGF-coated implants (n = 8 each). Histomorphometry (Movat Pentachrome, H&E, Alcian Blue), scanning electron microscopy, and energy-dispersive X-ray spectroscopy were performed. Both cRGD- and mod-HGF-coated implants significantly increased bone formation and bone–implant contact relative to controls. Reduced fibrotic encapsulation and enhanced vascularization were observed in both groups, with the strongest effects in the mod-HGF group. Microscopy and spectroscopy confirmed greater mineralization and continuous bone–implant interfaces in coated implants. These results demonstrate that biologically functionalizing ATZ with cRGD or mod-HGF effectively enhances bone formation and implant integration in vivo while reducing fibrotic responses. We proved through the in vivo experiments that bioinert HPOCs obtain osseointegrative behavior due to the hydrolytically stable organo-chemical surface functionalization.