Immunotherapeutic potential of “Breg-Treg” vs “Th9-Th17” cell axis in post-menopausal osteoporosis

Osteoporosis is a skeletal disease that affects the microarchitecture and mineralization of the bone, reduces bone strength, and lowers bone mineral density (BMD). Post-menopausal osteoporosis (PMO), caused by estrogen deficiency, is the most common type of osteoporosis. Given the chronic nature of PMO, sustained prevention or treatment with targeted bone-specific therapies and comprehensive medical management is crucial. Long-term usage of bone-specific pharmaceutical treatment therapies that include osteoanabolic and anti-resorptive drugs has sparked questions about side effects and possible rebound occurrences following treatment termination. Therefore, new therapy approaches with fewer side effects are needed. Studies in the past decade have demonstrated that immunological factors are crucial in the onset and progression of PMO. Treg and Th17 cells have long been recognized as critical factors in maintaining bone homeostasis, mainly <i>via</i> regulating osteoclast differentiation. However, astonishing data from our recent studies have highlighted the significant role of Breg and Th9 cells in bone homeostasis regulation. Breg and Th9 cells directly influence the development of bone cells and also regulate the Treg-Th17 cell balance to maintain skeletal integrity. We propose that although the Treg-Th17 cell axis is undeniably important in the pathophysiology of osteoporosis, the dynamic interplay between Breg-Treg and Th9-Th17 cells may play an even more pivotal role. This broader immune network likely exerts a greater influence on bone homeostasis and the progression of osteoporosis. However, the interplay between Breg-Treg vs Th9-Th17 cell axis in PMO remains limited. This review summarizes the most recent developments regarding the Breg-Treg vs Th9-Th17 cell axis in PMO and discusses the potential novel therapeutic strategies to address this issue. Novel pathophysiological insights into the Breg-Treg-Th9-Th17 cell axis in bone metabolism may pave the way for improved diagnosis and transformative treatments for PMO.