Molecular mechanism of icariin in prevention and treatment of osteoporosis

Abstract

BACKGROUND: Pharmacodynamic characteristics and mechanisms of action of icariin in combating osteoporosis gradually gain recognition within the academic community. Related basic research and clinical translation efforts are increasingly becoming the focal point of research. OBJECTIVE: To summarize the research progress of icariin on anti-osteoporosis. METHODS: China National Knowledge Infrastructure (CNKI) and PubMed databases were searched for relevant literature. Chinese and English search terms included “icariin, osteoporosis, Chinese medicine compound, pathogenesis, signal path, BMSCs, osteoblast, osteoclast.” Based on inclusion criteria, 90 articles were ultimately included in the review. RESULTS AND CONCLUSION: Icariin treatment increased alkaline phosphatase activity and induced the expression of core binding factor α1, bone morphogenetic protein 2, and bone morphogenetic protein 4 in bone marrow mesenchymal stem cells in a dose-dependent manner. Icariin promoted fracture healing by increasing serum levels of osteocalcin, bone-specific alkaline phosphatase, N-terminal peptide of type I collagen, C-terminal peptide of type I collagen, and tartrate-resistant acid phosphatase 5b, thereby enhancing osteocalcin secretion at the fracture site. Icariin promoted proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells in ovariectomized osteoporotic rats by upregulating alkaline phosphatase and osteocalcin levels and inhibiting the expression of Notch-1, CBF1, and Jagged-1 proteins in the Notch pathway, thus achieving prevention and treatment of osteoporosis. Icariin regulates bone metabolism through multiple signaling axes including Wnt/β-catenin, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, osteoprotegerin/receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB, and Notch. Among these, the Wnt/β-catenin pathway and the osteoprotegerin/receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB axis constitute the core regulatory mechanism, modulating the osteoblast-osteoclast dynamic balance through synergistic interactions. Icariin can influence the biological behavior of osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells through multidimensional interventions including regulation of mRNA expression modifications, inhibition of oxidative stress, and improvement of the inflammatory microenvironment.

1. Introduction

Osteoporosis is a systemic metabolic bone disease characterized by progressive loss of bone mass and deterioration of bone microarchitecture. It typically progresses insidiously and chronically. In the early stages, most patients lack specific clinical manifestations, leading to a high rate of missed diagnosis. As the pathological process advances, patients may develop pain, spinal deformities, and an increased risk of fractures at multiple sites. Epidemiological surveys indicate that approximately 200 million people worldwide suffer from osteoporosis. Therefore, a deep understanding of the pathological mechanisms and the exploration of optimized diagnostic and therapeutic strategies are of great value in improving disease prognosis.

In current clinical practice, bone metabolism regulators such as aminobisphosphonates, denosumab, and abaloparatide, which possess dual mechanisms of inhibiting bone resorption and promoting bone formation, have become the first-line treatment for most osteoporosis patients. However, long-term use of these drugs is limited by safety concerns and adverse reactions, prompting the search for safer and more effective interventions. The development of novel therapeutic approaches that combine efficacy and safety is of significant clinical value. Traditional Chinese medicine has gained widespread attention for its clinical value in treating osteoporosis. Although the term "osteoporosis" does not appear in ancient medical texts, its clinical manifestations fall under categories such as "bone wilting," "bone dryness," and "bone bi" in traditional Chinese medicine. Through syndrome differentiation and treatment, ancient physicians used compound formulations to intervene in osteoporosis, accumulating rich clinical experience. Modern pharmacological research has further confirmed that Chinese herbal compounds have multi-target regulatory effects and low incidence of adverse reactions, making them suitable for long-term management of chronic diseases.

The herb Epimedium (Berberidaceae) is a perennial herb, and its leaves are used medicinally. It was first recorded in the "Shennong's Classic of the Materia Medica" and is known for its effects of tonifying the liver and kidney and strengthening bones and tendons. Icariin, the main active flavonoid glycoside isolated from Epimedium, exhibits multiple pharmacological activities including anti-osteoporosis, anti-tumor, antioxidant, anti-inflammatory, and cardiovascular protection. These pleiotropic effects endow icariin with potential for clinical application and new drug development. In recent years, with breakthroughs in bone tissue engineering, the combination of active ingredients from traditional Chinese medicine with biomaterial scaffolds has shown promise in enhancing bone regeneration and biomechanical strength.