Regenerative Strategies for Osteoporotic Craniomaxillofacial Bone Defects: Evidence, Translational Gaps, and Future Directions

Background: Osteoporosis alters bone remodeling, osteogenic competence, redox and inflammatory homeostasis, and vascular support. These abnormalities may compromise healing of craniomaxillofacial defects, but evidence for regenerative interventions is distributed across mechanistic studies, non-craniofacial osteoporotic models, craniofacial models without osteoporosis, and a smaller body of direct osteoporotic craniofacial evidence. Methods: A literature search was conducted using PubMed and Web of Science. Search terms combined osteoporosis-related terms with bone regeneration/defect healing, craniomaxillofacial anatomy, and intervention-specific terms. No strict publication-date restriction was applied, and studies were selected according to their relevance to the predefined scope. Evidence was interpreted using two complementary dimensions: directness to osteoporotic craniomaxillofacial regeneration and translational maturity. Results: Direct osteoporotic craniofacial preclinical evidence is available for selected interventions, including melatonin and injectable platelet-rich fibrin, whereas vitamin D, teriparatide, bone morphogenetic proteins, mesenchymal stem cell-based therapies, exosomes, hydrogels, nanomaterials, and 3D-printed constructs are supported by different combinations of indirect osteoporotic, non-osteoporotic craniofacial, mechanistic, and clinical evidence. Teriparatide and recombinant human bone morphogenetic protein-2 have comparatively mature clinical pathways, but their clinical evidence is not synonymous with efficacy in osteoporotic craniomaxillofacial defects. Emerging biomaterials can address delivery, retention, oxidative stress, inflammation, angiogenesis, and osteogenic deficits simultaneously, but remain predominantly preclinical. Conclusions: Direct evidence for regeneration of osteoporotic craniomaxillofacial defects remains limited and predominantly preclinical. The most useful translational distinction is whether a strategy has demonstrated defect-level regeneration in an osteoporotic craniomaxillofacial setting, whether it has an established delivery pathway, and whether its added complexity produces a clinically meaningful advantage. Anatomically relevant preclinical evidence should be interpreted as proof of concept rather than as evidence of clinical readiness. Future studies should use clinically matched osteoporotic defect models, report concomitant osteoporosis therapy, and standardize direct regenerative endpoints rather than relying on bone mineral density or mechanistic markers alone.