Biomaterials-based engineering of the bone microenvironment for osteoporosis therapy.

Osteoporosis is a progressive skeletal disorder marked by an imbalance between bone resorption and formation, resulting in compromised microarchitecture and increased fracture risk. However, conventional pharmacological therapies have systemic side effects and limited targeting efficiency. Therefore, these limitations highlights the need for innovative strategies, and biomaterials have emerged as versatile tools, offering both structural support and the ability to modulate the osteoporotic bone microenvironment. This review outlines the key pathophysiological changes in osteoporosis including cellular dysregulation, ECM alteration, inflammation, and impaired vascularization underscoring the importance of restoring this niche for effective regeneration. A wide range of biomaterials, including natural/synthetic polymers, bioceramics, and metallic biomaterials and their alloys, are explored for their osteoconductive, osteoinductive, and mechanical features tailored to osteoporotic bone. This review also focuses on the functionalization approaches for the controlled delivery of drugs and growth factors (e.g. BMP-2, VEGF), and emerging gene/RNA therapies. The integration of biomaterials with stem cells and extracellular vesicles is discussed for enhancing osteogenesis, angiogenesis, and immunomodulation. Additionally, immuno-informed scaffold designs and bio-responsive materials responsive to pathological cues such as inflammation and oxidative stress are reviewed. Advanced technologies like three-dimensional printing and sensor-enabled scaffolds for real-time feedback are also addressed. Finally, the review considers translational barriers and highlights future directions combining material science, regenerative medicine, and personalized therapy for osteoporotic bone repair.