Abstract
Weight loss, whether resulting from disease-related conditions or intentional interventions, has been increasingly recognized as a significant risk factor for compromised skeletal integrity. While moderate weight reduction may yield metabolic benefits, rapid or sustained weight loss is frequently associated with decreased bone mineral density, deterioration of bone microarchitecture, and heightened fracture risk. The mechanisms underlying weight loss-induced bone loss are complex and multifactorial. Emerging evidence highlights a range of contributing factors, including reduced mechanical loading, increased bone marrow adiposity, hormonal and endocrine alterations, nutritional deficiencies, and disruptions in energy metabolism. These mechanisms are intricately interconnected, ultimately impairing bone remodeling and homeostatic balance. In this review, we provide a comprehensive analysis of the current literature on the mechanistic pathways, clinical consequences, and therapeutic strategies related to weight loss-induced bone loss. We further differentiate the skeletal effects of disease-associated versus intervention-induced weight loss, with a focus on their distinct molecular underpinnings. Our goal is to offer novel insights into the optimization of bone health management in the context of weight loss, guided by a translational medicine perspective.