# Progress in multiaxial coupling mechanisms of osteoporosis: insights from systems medicine on immune-inflammatory interactions, hormonal regulation, and metabolic imbalance

## TL;DR

This review explores how osteoporosis involves complex interactions between immune, hormonal, and metabolic systems, suggesting a need for multi-axis treatment approaches.

## Contribution

The paper introduces a systems medicine framework for osteoporosis, emphasizing immune-inflammatory, hormonal, and metabolic coupling mechanisms.

## Key findings

- Th17/Treg imbalance and cytokines like IL-17 and IL-35 influence bone remodeling and link autoimmune diseases to bone loss.
- Hormonal axes, including sex and thyroid hormones, regulate bone through signaling networks and circadian rhythms.
- Metabolic imbalances in glucose, lipids, and uric acid affect bone fragility via energy metabolism and gut microbiota.

## Abstract

Osteoporosis (OP) is increasingly recognized as a systemic disorder involving crosstalk among immune-inflammatory, endocrine, and metabolic axes, rather than a condition driven solely by bone-mineral imbalance. This review synthesizes recent advances in understanding these axes and their coupling mechanisms. The immune-inflammatory axis, centered on Th17/Treg imbalance and cytokines such as IL-17 and IL-35, regulates osteoclastogenesis and osteogenesis while linking autoimmune diseases to bone loss. The endocrine axis, encompassing sex hormones, thyroid/adrenal/parathyroid hormones, and receptors such as LGR4, modulates bone remodeling through complex signaling networks and circadian rhythms. The metabolic axis, particularly glucose-lipid-uric acid homeostasis, influences bone fragility via energy metabolism, oxidative stress, and gut microbiota interactions. We propose that OP is best understood as a network disorder manifesting in the skeleton, necessitating a shift from single-target to multi-axis systems medicine approaches. However, much of the mechanistic evidence derives from preclinical models and observational studies; prospective clinical validation remains essential. Future research should prioritize elucidating inter-axis communication in human cohorts and developing integrated, biomarker-stratified therapeutic strategies to advance precision management of osteoporosis.