Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: Mechanisms, bone metabolism disruption, and therapeutic strategies

Table 1 Effects of diabetes on bone metabolism

Cell type	Mechanism of action	Influencing factors	Specific manifestations	Ferroptosis-related mechanisms	Ref.
Osteoblasts	High-glucose environments inhibit osteoblast proliferation and differentiation	High glucose, AGEs, oxidative stress	Decreased ALP activity, reduced mineralization capacity	High glucose induces ferroptosis via lipid peroxidation and GPX4 inhibition; AGEs promote ferroptosis, disrupting osteoblast function and mineralization	Wu et al[4], Hygum et al[18]
Osteoclasts	Osteoclast formation and function are suppressed in high-glucose conditions	High glucose, inflammatory factors	Reduced number of osteoclasts, diminished bone resorption function	Iron overload in diabetic conditions enhances osteoclast activity through ferroptosis-associated pathways, increasing bone resorption in some contexts	Bao et al[5], Kim et al[21]
Osteocytes	High glucose and inflammatory environments impair osteocyte function	High glucose, inflammatory factors	Decreased osteocyte activity, reduced bone matrix quality	Ferroptosis induced by high glucose and lipid peroxidation leads to osteocyte death; upregulation of HO-1 and intracellular iron overload exacerbate bone matrix deterioration	Bao et al[5], Saadi et al[25], Yang et al[68]

AGEs: Advanced glycation end products. Metabolic byproducts formed in a hyperglycemic environment that can impair cellular function; ALP: Alkaline phosphatase. An enzyme associated with bone mineralization; GPX4: Glutathione peroxidase 4; HO-1: Heme oxygenase-1; Hyperglycemia: A state of elevated blood glucose levels commonly observed in diabetic patients; Oxidative stress: A condition in which high-glucose environments increase oxidative stress levels, leading to cellular damage.

Table 2 The role of inflammatory response, oxidative stress, and high-throughput sequencing in diabetic osteoporosis

Mechanism type	Key factor	Pathway	Impact on bone metabolism	Ref.
Inflammatory response	TNF-α	Activates NF-κB pathway, promotes osteoclast differentiation and activity	Increases bone resorption, leading to osteoporosis	Qi et al[20]
	IL-6	Stimulates RANKL expression, enhances osteoclast formation	Increases bone resorption, decreases bone density	Wu et al[4]
Oxidative stress	ROS	Damages osteoblasts, inhibits differentiation and function	Reduces bone formation, promotes osteoporosis	Iantomasi et al[53]
	AGEs	Binds to receptors, induces oxidative stress and inflammatory responses	Disrupts bone matrix, reduces bone strength	Wang et al[26], Zhang et al[27]
High-throughput sequencing	miRNAs	Identifies differentially expressed miRNAs (e.g., miR-140-5p, miR-486-3p) involved in bone metabolism pathways like Wnt and TGF-β signaling	Predicts osteoporosis progression; regulates osteoblast and osteoclast activities through gene silencing or activation	Huang et al[110]
RNA-seq	Transcript variants (e.g., ATF3)	Detects oxidative stress-induced transcriptomic changes, including activation of TNF and NRF2 signaling pathways	Highlights mitochondrial dysfunction and inflammation contributing to bone loss	Nyunt et al[111], Chen et al[112]

AGEs: Advanced glycation end products, bind to their receptors to induce oxidative stress and inflammatory responses, disrupting the bone matrix and reducing bone strength; IL-6: Interleukin-6, a pro-inflammatory cytokine that stimulates the expression of receptor activator of nuclear factor-κB ligand, enhancing osteoclast formation; NF-κB: Nuclear factor-κB, a key transcription factor involved in regulating inflammatory responses and immune processes; activation of nuclear factor-κB promotes osteoclast differentiation and activity; RANKL: Receptor activator of nuclear factor-κB ligand; ROS: Reactive oxygen species, high levels of reactive oxygen species damage osteoblasts, inhibit their differentiation and function, and reduce bone formation; TNF-α: Tumor necrosis factor-α, a pro-inflammatory cytokine that activates the nuclear factor-κB pathway, promoting osteoclast differentiation and activity.

Table 3 The role of iron metabolism dysregulation in diabetic osteoporosis

Mechanism type	Key factors	Pathway	Impact on bone metabolism	Ref.
Iron overload	Iron ions (Fe2+/Fe3+)	Excess iron generates ROS via the Fenton reaction, causing oxidative stress and lipid peroxidation	Damages osteoblasts, inhibits their differentiation and function, reduces bone formation; promotes osteoclast differentiation, increasing bone resorption	Zang et al[59], Liu et al[62], Harrison et al[65]
Ferroptosis (iron-dependent cell death)	GPX4, SLC7A11, ROS	Iron-dependent cell death involving lipid peroxidation and antioxidant system imbalance	Induces bone cell death, disrupts bone tissue structure, and promotes the progression of osteoporosis	Yang et al[68]
Hepcidin dysregulation	Hepcidin, FPN1	Overexpression of hepcidin inhibits iron export protein FPN1, leading to intracellular iron accumulation	Increases iron content in bone marrow mesenchymal stem cells, inhibits their differentiation into osteoblasts, reduces bone formation	Zang et al[59]
Hyperglycemia-induced dysregulation	Hyperglycemia, AGEs, ROS	High-glucose environment promotes AGEs formation; AGEs bind to their receptors, inducing ROS production and iron metabolism dysregulation	Causes osteoblast dysfunction, enhances osteoclast activity, and exacerbates osteoporosis	Xie et al[71], Dludla et al[72], Zhao et al[73]

AGEs: Advanced glycation end products, glycation products formed in a hyperglycemic environment that bind to their receptors, inducing oxidative stress and inflammatory responses; Fenton reaction: A reaction where Fe²⁺ interacts with hydrogen peroxide (H₂O₂) to produce hydroxyl radicals (·OH), triggering oxidative stress; GPX4: Glutathione peroxidase 4, a key antioxidant enzyme that inhibits lipid peroxidation and prevents ferroptosis; Hepcidin: A hormone secreted by the liver that regulates systemic iron balance by binding to the iron export protein ferroportin 1, controlling iron absorption and distribution; SLC7A11: Encodes the light chain subunit of system Xc^-, facilitating the exchange of intracellular glutamate for extracellular cystine to maintain intracellular glutathione levels.

Table 4 Current treatment strategies and future research directions

Treatment strategy/research direction	Mechanism of action	Clinical effect	Challenges and prospects
Bisphosphonates	Inhibit osteoclast activity, reduce bone resorption	Increase bone density, reduce fracture risk	Long-term use may lead to side effects such as osteonecrosis of the jaw; risks need to be balanced
Calcitonin	Inhibit osteoclasts, promote osteoblast activity	Relieve bone pain, increase bone density	Limited efficacy; long-term use may lead to drug resistance
Selective estrogen receptor modulators	Mimic estrogen effects, reduce bone resorption	Increase bone density, lower risk of spinal fractures	May increase risk of thrombosis; use with caution
Choice of anti-diabetic drugs	Different drugs have varying impacts on bone metabolism	Metformin may benefit bone health; thiazolidinediones may increase fracture risk	Need to select appropriate medications based on the patient's specific condition
Vitamin D and calcium supplementation	Provide raw materials for bone mineralization, promote calcium absorption	Improve bone density, prevent osteoporosis	Excessive supplementation may lead to hypercalcemia; dosage needs monitoring
New anti-osteoporosis drugs	Agents like denosumab inhibit RANKL, reducing osteoclast formation	Significantly increase bone density, reduce fracture risk	Long-term safety requires further research
Personalized treatment strategies	Develop comprehensive plans based on the patient's specific situation	Improve treatment effectiveness, reduce side effects	Requires multidisciplinary collaboration to formulate individualized plans
Traditional Chinese medicine therapy	Improve bone metabolism through multi-target regulation	Some herbal medicines show potential to enhance bone density	Lack of large-scale clinical research data; further validation needed
Gene therapy	Target specific genes to regulate bone metabolism pathways	Potentially curative treatment method	Technology is not yet mature; ethical and safety issues need to be addressed
Stem cell therapy	Use stem cells to differentiate into osteoblasts and repair bone tissue	Animal studies show some efficacy	Clinical application is still in early stages; more research is necessary

Bisphosphonates: Commonly used for treating osteoporosis by inhibiting osteoclast activity and reducing bone resorption; Calcitonin: A hormone-based medication that inhibits osteoclasts and promotes osteoblast activity; Gene therapy: Targets specific genes to regulate bone metabolism pathways; however, the technology remains immature; Personalized treatment strategies: Develop comprehensive treatment plans based on the patient's specific conditions to enhance effectiveness and reduce side effects; SERMs: Selective Estrogen Receptor Modulators, mimic estrogen effects to reduce bone resorption but may increase the risk of thrombosis; Stem cell therapy: Uses stem cells to differentiate into osteoblasts for bone tissue repair, though clinical applications are still in early stages; Traditional Chinese medicine therapy: Improves bone metabolism through multi-target regulation but lacks large-scale clinical research data; Vitamin D and calcium supplementation: Provide essential materials for bone mineralization, though excessive supplementation may lead to hypercalcemia; Choice of anti-diabetic drugs: Different anti-diabetic medications have varying effects on bone metabolism and should be selected based on the patient's specific needs; New anti-osteoporosis drugs: For example, denosumab reduces osteoclast formation by inhibiting receptor activator of nuclear factor-κB ligand; RANKL: Receptor activator of nuclear factor-κB ligand.