Targeting the osteoporotic bone microenvironment: Mechanistic insight and therapeutic biomaterials for accelerating bone regeneration

Osteoporotic bone defects (OBD) present a major clinical challenge, largely due to a pathological bone microenvironment that severely compromises regenerative capacity. Moving beyond conventional classification schemes that often fail to capture this pathological complexity, our review establishes a conceptual framework that categorizes emerging biomaterials by mirroring the intrinsic functional components of the bone microenvironment itself—namely, ion-releasing, metabolite-based, extracellular matrix (ECM)-mimetic, and cytokine-loaded systems. The component-centric taxonomy not only systematizes a disparate field but also directly links material design to underlying pathological mechanisms. Accordingly, these materials are engineered not merely as structural replacements but as active modulators designed to reprogram the pathological niche by concurrently targeting key mechanisms such as cellular dysfunction and immune-metabolic dysregulation. Furthermore, we explore the emerging roles of bone organoids and artificial intelligence (AI) in refining preclinical models. By integrating a deep biological understanding of the niche with engineering innovation, our work aims to provide a cohesive framework and forward-looking perspective to guide the development of effective, microenvironment-targeted regenerative strategies. Scheme 1: Schematic overview of the osteoporotic bone microenvironment and therapeutic strategies using engineered biomaterials. The figure emphasizes the central role of cellular dysfunction in osteoporosis, characterized by an imbalance between enhanced osteoclastic activity and diminished osteoblastic function. This dysfunction occurs within, and is aggravated by, a chronic inflammatory immune microenvironment featuring increased pro-inflammatory cytokine levels, decreased anti-inflammatory cytokine levels, and abnormal immune cell activation, which further disrupts bone homeostasis. To reverse this pathological milieu, a diverse array of biomaterials is illustrated, such as ion-releasing, metabolite-based, ECM-mimetic, and cytokine-loaded biomaterials. This figure was created in BioRender.com . • The review elucidates how cellular, signaling, and immune imbalances drive osteoporotic bone microenvironment pathology. • A component-centric taxonomy categorizes biomaterials into ion, metabolite, ECM-mimetic, and cytokine systems. • Material design strategies for reprogramming the pathological niche to enhance bone regeneration are evaluated. • Translational hurdles and the role of bone organoids and AI in accelerating therapeutic development are discussed.