Skeletal Involvement in Systemic Mastocytosis: Pathophysiology, Clinical Management, Standards of Care, and Novel Therapeutic Strategies

Systemic mastocytosis comprises a group of clonal mast cell disorders characterized by multisystem involvement. Bone involvement represents a major source of morbidity, particularly in young men affected by indolent systemic mastocytosis. This review provides an integrated and up-to-date overview of SM-related bone disease. We dissect the dual and context-dependent role of mast cells in bone remodeling, detailing how they promote osteoclastogenesis, suppress osteoblast function, and, in advanced disease, drive osteosclerosis. We critically appraise available treatments, including classic anti-resorptive therapy and emerging anabolic strategies. We further discuss the transformative impact of KIT-directed tyrosine kinase inhibitors, particularly avapritinib, which has demonstrated for the first time the ability to reverse not only osteoporosis but also osteosclerosis. Finally, we explore the emerging role of machine learning models in SM, proposing their application to individualized prediction of osteoporosis and fracture risk in SM. By bridging clinical care, bone biology, and therapeutic advances, this review underscores the need for a paradigm shift in which SM-related bone disease is recognized as a dynamic process requiring early identification, integrated risk stratification, and coordinated use of anti-resorptive, disease-modifying, and data-driven precision approaches to prevent fractures and improve long-term outcomes and quality of life in this delicate category of patients.