# Osteoporosis in Patients with Pre-Existing Diabetes Mellitus and in Women with Estrogen Deficiency: A Molecular and Cellular Perspective

## TL;DR

This review explores how diabetes and estrogen deficiency contribute to osteoporosis by affecting bone remodeling and highlights potential treatments.

## Contribution

The paper provides a comprehensive analysis of molecular and cellular mechanisms linking diabetes and estrogen deficiency to osteoporosis.

## Key findings

- Chronic hyperglycemia and insulin resistance disrupt bone homeostasis, increasing fracture risk in type 2 diabetes.
- Estrogen deficiency accelerates bone resorption and suppresses bone formation through altered cytokine signaling and oxidative stress.
- Emerging diagnostic tools beyond BMD, like trabecular bone score and high-resolution imaging, improve osteoporosis risk assessment.

## Abstract

Osteoporosis is a prevalent metabolic bone disorder characterized by reduced bone mass, compromised microarchitecture, and increased fracture risk. Its pathogenesis extends beyond simple bone mineral density (BMD) loss and reflects complex disruptions in bone remodeling governed by osteoblast–osteoclast coupling and systemic metabolic factors. This review lays particular emphasis on diabetes mellitus-related osteoporosis (DOP) and estrogen deficiency-induced osteoporosis (EDOP), discussing bone remodeling between osteoclastogenesis and osteoblast differentiation regulated by key signaling pathways, including the RANKL/RANK/OPG, Wnt/β-catenin, BMP–Smad, Hedgehog, and inflammatory cytokine networks. This review then explores how chronic hyperglycemia, insulin deficiency or resistance, oxidative stress, ferroptosis, advanced glycation end products, and low-grade inflammation disrupt bone homeostasis in diabetes, resulting in impaired bone quality and elevated fracture risk, particularly in type 2 diabetes. In parallel, we discuss the genomic and non-genomic actions of estrogen in maintaining skeletal integrity and elucidate how estrogen deficiency accelerates bone resorption and suppresses bone formation through altered cytokine signaling, oxidative stress, and impaired mechanotransduction. Advances in diagnostic strategies beyond BMD, including trabecular bone score, high-resolution peripheral quantitative computed tomography, and emerging biomarkers, are reviewed. Finally, this review summarizes current and emerging therapeutic approaches tailored to DOP and EDOP, emphasizing the need for mechanism-based, individualized management. A deeper understanding of these shared and distinct pathways may facilitate improved risk stratification and the development of targeted interventions for osteoporosis.