# The role and mechanisms of bone microenvironment regulators in osteoporosis: novel intervention strategies for addressing the challenges of aging

## TL;DR

This review explores how changes in the bone environment with aging contribute to osteoporosis and highlights new treatment strategies to combat this age-related disease.

## Contribution

The paper provides a comprehensive synthesis of bone microenvironment regulators and proposes novel therapeutic targets for osteoporosis.

## Key findings

- Aging reduces protective factors like osteoprotegerin and BMPs while increasing pro-resorptive mediators like RANKL, IL-6, and TNF-α.
- These changes promote osteoclast activity and hinder osteoblast function, leading to accelerated bone loss.
- Targeting these regulators offers promising strategies to preserve bone health in older adults.

## Abstract

Osteoporosis is an increasingly important global health concern, particularly in aging populations, with prevalence rising markedly after the age of 60. Age-related alterations in the bone microenvironment play a pivotal role in disrupting skeletal homeostasis. Regulators of the bone microenvironment contribute centrally to osteoporosis pathogenesis by modulating bone remodeling through multiple, intersecting mechanisms. Accumulating evidence indicates that aging is accompanied by reduced levels of protective factors, such as osteoprotegerin and bone morphogenetic proteins (BMPs), alongside increases in pro-resorptive mediators, including receptor activator of nuclear factor-κB ligand (RANKL), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). This shift favors osteoclastogenesis and impairs osteoblast function, ultimately accelerating bone loss and increasing the risk of fragility fractures and disability. In this review, we synthesize current evidence on bone microenvironment regulatory factors in osteoporosis, with emphasis on their roles in bone remodeling and downstream cellular signaling pathways. We further discuss emerging intervention strategies that target these regulators to preserve or restore bone health in older adults. By clarifying age-associated microenvironmental changes and the interactions among key regulatory factors, this review aims to identify promising therapeutic targets and provide a conceptual framework to support osteoporosis prevention and treatment in the context of global population aging.