Cistanche Glycosides As A Natural Therapeutic Agent For Osteoporosis: Mechanisms, Signaling Pathways, And Clinical Potential
Jul 14, 2025
2. Key Signaling Pathways in Osteoporosis
2.1 OPG/RANKL/RANK Pathway
The OPG/RANKL/RANK signaling axis plays a pivotal role in bone metabolism by mediating communication between osteoblasts (OBs) and osteoclasts (OCs), thereby regulating bone remodeling [40–43].
RANKL is expressed by osteoblasts and activated T cells, while RANK is expressed on osteoclasts and their precursors.
Osteoprotegerin (OPG), a glycoprotein secreted by OBs, binds to RANKL and prevents its interaction with RANK, thereby inhibiting osteoclastogenesis.
Activation of RANK by RANKL initiates intracellular signaling cascades, including the NF-κB and JNK pathways, promoting OC differentiation and activation.
High-affinity binding of OPG to RANKL suppresses bone resorption and maintains bone metabolism homeostasis [44].
This pathway represents a central mechanism in bone turnover and is a key target for osteoporosis therapies.
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2.2 Wnt/β-Catenin Pathway
The Wnt/β-catenin signaling pathway is crucial for various physiological functions and is closely linked to OP pathogenesis. It includes both canonical (β-catenin-dependent) and non-canonical branches such as Wnt/Ca²⁺ and planar cell polarity (PCP) signaling [45].
Wnt signaling can enhance the expression of Runx2, a key transcription factor that promotes osteoblast differentiation and accelerates fracture healing [46].
Activation of this pathway stimulates bone formation and inhibits resorption, contributing to increased bone mass during OP treatment [47].
Parathyroid hormone (PTH) exerts part of its anabolic effect on bone by activating the Wnt/β-catenin pathway [48].
Studies confirm that this pathway is central to mesenchymal stem cell (MSC) osteogenic differentiation, and its activity can be modulated by numerous biological and environmental factors [49, 50].
3. GCs Regulate Key Osteoporotic Signaling Pathways
3.1 Inhibition of Bone Resorption
Bone resorption is a major pathological hallmark of OP. Cathepsin K (CK), a lysosomal protease expressed by OCs, is an important marker of bone resorption [51, 52]. Research shows that GCs can inhibit CK activity, thereby reducing osteoclastic bone degradation [53].
Herbal remedies that "tonify the kidney" in TCM, including Cistanche, have been shown to modulate the OPG/RANKL/RANK pathway [54]. GCs may exert their anti-OP effects by:
Suppressing RANKL expression
Enhancing OPG secretion
Reducing the RANKL/OPG ratio, leading to decreased OC activation and a shift toward bone formation [55]
3.2 Promotion of Bone Formation
GCs also stimulate bone matrix synthesis and mineralization by upregulating bone-specific proteins like bone gla protein (BGP) and osteopontin (OPN).
Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive factor, and alkaline phosphatase (ALP) is a key marker of OB differentiation [56–59].
Studies suggest that GCs increase BMP-2, BGP, and OPG expression, while reducing RANKL and phosphorylated β-catenin (p-β-catenin), thereby activating the Wnt/β-catenin pathway [60, 61].
These changes promote bone formation, improve microstructural integrity, and delay OP progression.
4. Clinical Applications and Safety Profile of GCs
4.1 Clinical Applications
GCs have demonstrated promising clinical effects in OP management due to their ability to:
Promote osteoblast activity
Inhibit osteoclast-mediated resorption
Increase bone mineral density (BMD)
Reduce fracture risk
In addition to their osteoprotective effects, GCs exhibit anti-inflammatory properties, making them beneficial in managing arthritis and cardiovascular inflammation. They also modulate immune function, enhance overall vitality, and show anti-aging effects by reducing oxidative stress.
Notably, GCs have shown potential benefits for male reproductive health by improving Leydig cell proliferation, sperm motility, and testosterone levels [62].
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4.2 Toxicological Evaluation
Toxicity studies demonstrate that GCs are safe and well-tolerated:
Acute and genetic toxicity tests returned negative results [63].
90-day oral toxicity studies in rats showed no adverse effects on growth, hematology, serum biochemistry, or organ histopathology [64].
No drug-related adverse reactions have been reported in clinical trials to date, supporting the excellent safety profile of GCs [65].
These findings reinforce the feasibility of GCs as a safe herbal candidate for long-term OP treatment.
5. Future Prospects
GCs have shown multi-target, multi-pathway regulatory effects on bone metabolism, particularly in modulating osteoblast and osteoclast activity. Despite encouraging results in animal models, several research gaps remain:
Mechanistic clarity: While some signaling pathways (e.g., OPG/RANKL/RANK, Wnt/β-catenin) have been identified, the complete molecular regulatory network of GCs remains to be elucidated.
Advanced technologies such as single-cell sequencing and CRISPR could help uncover detailed mechanisms and support precision therapy for OP.
Clinical Translation Needs
Current clinical studies on GCs are limited in sample size and scope.
There is a pressing need for large-scale, multi-center, randomized controlled trials to evaluate efficacy, safety, and optimal dosage in humans.
Formulation and Drug Development
Improving purity and stability of GCs is key to pharmaceutical development.
Innovative delivery systems may enhance bioavailability and therapeutic outcomes.
With deeper investigation, GCs may become a safe and effective natural agent for OP, offering novel therapeutic pathways for patients worldwide. Their continued development could also advance the modernization of TCM and promote its global integration.
6. Conclusion
GCs have demonstrated significant therapeutic potential in the treatment of osteoporosis:
Bone Formation: Stimulate osteoblast proliferation and differentiation; upregulate BMP, ALP, and OPN expression; enhance bone density.
Bone Resorption Inhibition: Reduce osteoclast activity; suppress inflammatory mediators and oxidative stress.
Hormonal and Mineral Regulation: Influence the HPG axis, optimize calcium and phosphorus metabolism, and improve skeletal strength.
Animal and clinical studies confirm that GCs can significantly improve bone mass and quality, reduce fracture risk, and enhance quality of life in OP patients.
As research progresses, GCs are poised to become a next-generation herbal therapy for osteoporosis, with the potential to transform the bone health supplement market and contribute to evidence-based modernization of traditional Chinese medicine.
