Sphingolipid Metabolism in Bone Homeostasis: From Mechanisms and Functional Insights to Clinical Implications

Bone homeostasis is a dynamic process governed by the balanced activity of osteoblasts and osteoclasts, tightly regulated through complex signaling networks. Emerging evidence highlights sphingolipid metabolism as a critical modulator of skeletal integrity, influencing bone remodeling in both health and disease. Each individual step, however, appears to have a unique role in these processes, with some overlap in function that is not well understood yet. This review explores the interplay between sphingolipid metabolism and bone homeostasis. It provides a comprehensive overview of the diverse roles of the various sphingolipid metabolic enzymes in bone remodeling and the maintenance of bone health. Special focus is given to the key enzymes from the de novo and turnover pathways that have been shown to play a pivotal role in modulating osteoblast and osteoclast differentiation, survival, and function, thereby impacting bone formation and resorption. Emerging data also suggest that alterations in sphingolipid metabolism may serve as biomarkers or therapeutic targets in metabolic bone diseases. Understanding these sphingolipid-mediated mechanisms opens new avenues for targeted interventions in bone disorders. It also highlights the need for further research into the therapeutic potential of modulating the sphingolipid metabolic pathway.