# Immune reprogramming in the bone marrow microenvironment: a new perspective on the bone immune microenvironment of postmenopausal osteoporosis

## TL;DR

This paper explores how immune changes in the bone marrow contribute to postmenopausal osteoporosis and suggests new treatment approaches based on these findings.

## Contribution

The paper introduces a novel perspective on PMOP by highlighting immune reprogramming in the bone marrow microenvironment and proposing a three-tiered immunotherapy framework.

## Key findings

- Postmenopausal bone marrow shows myeloid bias and aging of mesenchymal stem cells.
- Immune cell imbalances and altered signaling pathways like RANK/RANKL/OPG drive PMOP.
- A three-tiered immunotherapy approach is proposed for PMOP treatment.

## Abstract

Research on postmenopausal osteoporosis (PMOP), a common bone metabolic disease, has traditionally focused on bone loss and imbalance in bone remodeling. However, with the development of bone immunology, the complex interactions between immune cells and bone cells in the bone marrow microenvironment have gradually been revealed, and “immune reprogramming” is considered a key factor driving the persistent bone loss in PMOP. Current evidence indicates that the postmenopausal bone marrow microenvironment undergoes significant structural and functional changes. These changes are characterized by a myeloid bias in hematopoietic stem/progenitor cells, aging of bone marrow mesenchymal stem cells (BMSCs) with a tendency toward differentiation into the adipocyte lineage, an imbalance of key immune cell subpopulations such as M1 and M2 macrophages and Th17 and regulatory T cells (Treg), as well as remodeling of cytokine and chemokine axis networks. Signaling pathways such as RANK/RANKL/OPG, Wnt/β-catenin, CXCL12–CXCR4, and S1P — along with systemic factors like estrogen deficiency, inflammatory aging, and the gut-bone-immune axis-collectively shape the characteristic bone immune microenvironment of PMOP. Based on this, this article systematically reviews the changes in cell lineage and molecular mechanisms underlying PMOP bone marrow immune reprogramming. It focuses on the key signaling networks in the bone immune microenvironment and their relationship with the mechanisms of existing anti-osteoporosis drugs. Furthermore, it proposes an immunotherapy approach represented by a three-tiered framework: traditional bone-targeted drugs, immune-guided therapy, and comprehensive intervention of the bone marrow microenvironment. Finally, in conjunction with emerging technologies such as multi-omics, single-cell, and spatial omics, this article discusses future directions for constructing a PMOP bone immune map and achieving precise stratification and individualized intervention, aiming to provide a theoretical basis and methodological reference for mechanistic research and bone immune-targeted therapy of PMOP.