Unlocking bone repair in osteoporosis by targeting the angiogenic niche

Osteoporosis (OP) and its related fragility fractures represent a significant global health burden, primarily characterized by reduced bone mass, deteriorated microarchitecture, and compromised self-repair capacity. While current mainstream therapies focusing on anti-resorption and anabolic pathways can slow bone loss, they often fall short in reversing established skeletal deficits and, particularly, in facilitating fracture healing. Growing evidence underscores that angiogenesis is fundamentally coupled with osteogenesis, forming the cornerstone of bone homeostasis and injury repair. However, developing therapeutic strategies targeting this "vascular-bone" axis remains a relatively nascent and underexplored area in the clinical management of both systemic osteoporosis and osteoporotic fractures. This review aims to provide a comprehensive synthesis of dual strategies targeting angiogenesis for the treatment of systemic osteoporosis and the enhancement of osteoporotic fracture healing. We first analyze the pivotal role and regulatory networks of angiogenesis in maintaining bone homeostasis and within the fracture repair microenvironment. Subsequently, we systematically categorize and critically evaluate various intervention strategies based on this approach, including mesenchymal stem cells and their exosomes with paracrine functions, phytochemicals and traditional Chinese medicine compounds possessing dual regulatory activities, non-coding RNAs (miRNAs, lncRNAs, circRNAs) that modulate key signaling pathways, proteins or peptides with defined pro-angiogenic activity, repurposed clinical drugs with potential vascular-modulating properties, and non-invasive physical therapies. The article further compares and contrasts the application of these strategies for systemic bone mass restoration versus localized fracture repair, discussing differences in delivery methods, molecular targets, and expected outcomes. Finally, we address the current challenges in the field-such as target specificity, translational barriers, and the lack of robust clinical evidence-and outline future research directions. By integrating existing knowledge, this review seeks to provide a theoretical foundation and novel perspectives for developing next-generation, synergistic therapies centered on vascular regeneration, designed to concurrently improve bone mineral density and bone quality.