Metabolism plays a critical role in bone homeostasis, regeneration, and healing. This study explores the potential of biomaterials to modulate metabolic processes during bone healing as a clinically relevant strategy for biomaterial development. To this end, metabolic changes occurring during bone regeneration were characterized, and the findings were applied to tissue engineering strategies. Metabolomic profiling was performed using samples from rat calvarial critical-sized defects and sheep tibial defect animal models to better understand systemic metabolic changes during bone regeneration. The results revealed that glutamate and glutamine were significantly downregulated during the healing process. Given the widespread use of calcium phosphate-based biomaterials as bone fillers in tissue engineering, the interaction between cells and materials was investigated using fibroblast cell lines exposed to various calcium phosphate compounds. The findings demonstrated that ceramic biomaterials can adsorb a broad range of small molecules from their microenvironment. Additionally, exposure to calcium phosphate-based materials influenced cellular amino acid levels and energy metabolism. A novel amorphous calcium phosphate material synthesized from a glutamate source (ACP-Glu) was developed based on the insights from the critical-sized defect models. This new biomaterial was extensively characterized through osteogenesis and metabolomics studies. ACP-Glu exhibited superior performance in enhancing cellular energy metabolism and promoting osteogenic activity. The increased energy metabolism, particularly the tricarboxylic acid cycle, appeared to compensate for anaerobic glycolysis, providing the necessary energy to support tissue repair. As a result, ACP-Glu shows promise as a biomaterial for bone regeneration, potentially accelerating the healing process by promoting more efficient in situ energy metabolism. This material could replace biologically inactive bone fillers, enhancing regenerative outcomes. Moreover, utilizing endogenous metabolites to modulate biological responses offers a safer alternative to bioactive additives such as cytokines and growth factors. The key practical contribution of this study is the development of ACP-Glu, which could assist patients with bone defects by accelerating hard tissue repair through replenishing depleted nutrients. The biomaterial design and evaluation methodology, particularly the metabolomic approaches employed in this research, could serve as a valuable reference for future work in the field.