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

## TL;DR

This paper explores how mast cell disorders affect bone health and highlights new treatments, including KIT inhibitors, that could reverse bone disease in systemic mastocytosis.

## Contribution

The paper introduces KIT-targeted therapies like avapritinib as a novel approach to reverse both osteoporosis and osteosclerosis in systemic mastocytosis.

## Key findings

- Neoplastic mast cells disrupt bone homeostasis by upregulating RANKL and secreting Wnt antagonists like DKK1 and sclerostin.
- KIT inhibitors, such as avapritinib, can reverse molecular alterations and restore bone remodeling in systemic mastocytosis.
- Machine learning models are proposed for individualized prediction of osteoporosis and fracture risk in systemic mastocytosis.

## Abstract

What are the main findings?
Neoplastic mast cells disrupt bone homeostasis by upregulating RANKL and secreting Wnt antagonists (DKK1 and sclerostin), cytokines, and microRNAs that inhibit osteoblast differentiation and promote osteoclastogenesis.KIT-targeting inhibition with selective tyrosine kinase inhibitors (TKIs), such as avapritinib, harbors the potential to reverse these molecular alterations and restore balanced bone remodeling by reducing mast cell burden in systemic mastocytosis.

Neoplastic mast cells disrupt bone homeostasis by upregulating RANKL and secreting Wnt antagonists (DKK1 and sclerostin), cytokines, and microRNAs that inhibit osteoblast differentiation and promote osteoclastogenesis.

KIT-targeting inhibition with selective tyrosine kinase inhibitors (TKIs), such as avapritinib, harbors the potential to reverse these molecular alterations and restore balanced bone remodeling by reducing mast cell burden in systemic mastocytosis.

What are the implications of the main findings?
Targeting KIT-driven signaling offers a mechanism-based strategy to treat SM-related bone disease, addressing both osteoporosis and osteosclerosis.Understanding mast cell-mediated modulation of RANKL/OPG and Wnt pathways opens avenues for precision therapies, including KIT inhibitors and Wnt modulators.

Targeting KIT-driven signaling offers a mechanism-based strategy to treat SM-related bone disease, addressing both osteoporosis and osteosclerosis.

Understanding mast cell-mediated modulation of RANKL/OPG and Wnt pathways opens avenues for precision therapies, including KIT inhibitors and Wnt modulators.

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.