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

Abstract

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.