Multifactorial Regulation of Inflammatory Bone Loss in Chronic Inflammatory and Immune-Associated Disorders: Osteoimmune Mechanisms and Translational Prospects of Natural Small Molecules.

Inflammatory bone loss is a frequent complication of chronic inflammatory and immune-associated disorders. In this review, we synthesize the osteoimmune mechanisms through which persistent inflammation disrupts coupled bone remodeling, with emphasis on RANKL-dependent osteoclastogenesis, suppressed osteoblast-supportive signaling, cytokine networks, immune-cell plasticity, and lesion microenvironment. We distinguish canonical inflammatory bone-loss settings, such as rheumatoid arthritis, periodontitis, and inflammatory osteolysis, from supportive models, including diabetic, ovariectomy-associated, osteoarthritis-related, and steroid-associated bone pathology. We further discuss local versus systemic bone loss and the emerging concept that osteoclasts arising in inflammatory environments may differ from those in physiological remodeling. Natural small molecules are reviewed as multifunctional candidates, but their therapeutic potential is evaluated cautiously in light of model heterogeneity, limited clinical data, pharmacokinetic constraints, and uncertain lesion-specific exposure. Finally, delivery platforms are considered as disease-context-dependent tools for improving local retention, formulation stability, and potentially lesion-specific exposure to natural small molecules.