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

Abstract

Diabetic osteoporosis (DOP) is a common complication in diabetes, driven by hyperglycemia-induced metabolic disturbances, chronic inflammation, and oxidative stress. This review describes the critical role of iron metabolism dysregulation in DOP pathogenesis, focusing on ferroptosis, a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species (ROS) overproduction. Diabetic conditions exacerbate iron overload, impairing osteoblast function and enhancing osteoclast activity, while triggering ferroptosis in bone cells. Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption, synergistically promoting bone loss. Furthermore, chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption, with elevated pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6) and ROS exacerbating cellular dysfunction. Therapeutic strategies targeting iron metabolism (e.g., deferoxamine) and ferroptosis inhibition (e.g., nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation, antioxidants like melatonin) demonstrate potential to mitigate DOP progression. Future research should prioritize personalized interventions, clinical trials of iron chelators and antioxidants, and mechanistic studies to refine therapeutic approaches. This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.

Key Words: Bone metabolism; Bone mineral density; Diabetes-related osteoporosis; Hyperglycemia; Inflammatory response; Iron-dependent cell death; Iron metabolism dysregulation; Osteoblasts; Osteoclasts; Oxidative stress

Core Tip: Diabetic osteoporosis (DOP) is becoming increasingly prevalent, driven by global aging and diabetes-related metabolic disturbances. Elevated glucose levels impair osteoblast function and activate osteoclasts via oxidative stress and chronic inflammation, accelerating bone loss. Dysregulated iron metabolism, particularly iron overload, triggers ferroptosis - a novel form of cell death marked by lipid peroxidation and reactive oxygen species production-further exacerbating DOP. Therapeutic strategies targeting iron metabolism and ferroptosis, including antioxidants, iron chelators, and personalized interventions, hold significant potential for improving bone health. Future research should prioritize unraveling underlying mechanisms and refining targeted treatment approaches.

INTRODUCTION

The relationship between diabetes and osteoporosis has received increasing attention, particularly in the context of global aging, as the incidence of diabetes-related osteoporosis (DOP) has risen significantly. Studies have shown that the bone mineral density (BMD) of diabetic patients is generally lower than that of non-diabetic individuals, and as diabetes progresses, the risks of osteoporosis and fractures significantly increase[1-3]. Fracture risk is increased sixfold in patients with type 1 diabetes and twofold in those with type 2 diabetes, which is closely associated with diabetes-induced metabolic changes[2,4].

With the aging global population, the coexistence of diabetes and osteoporosis has become an increasingly prominent issue[5]. Data indicate that approximately 50% to 66% of diabetic patients exhibit decreased BMD, and approximately 33% are diagnosed with DOP[1]. This phenomenon not only affects patients’ quality of life but also imposes a substantial burden on public health systems[1,5,6]. The development of DOP is associated with multiple factors, including chronic inflammation, oxidative stress, and iron metabolism dysregulation[7,8].

The market demand for anti-inflammatory iron preparations continues to significantly expand as healthcare providers increasingly recognize the complex relationship between chronic inflammation and iron metabolism dysregulation. Traditional iron supplements are often ineffective for patients with inflammatory conditions due to inflammation-induced hepcidin upregulation, which leads to functional iron deficiency. This creates a significant unmet need for specialized formulations[9,10]. Recent advancements in intravenous iron treatments, such as ferric carboxymaltose, as well as new oral formulations like malto-ferric iron, are addressing these challenges by offering improved efficacy, safety, and tolerability for patients with inflammatory conditions[11-13]. The projected growth of the global iron preparation market, particularly in regions with high prevalence of inflammatory diseases, underscores the significant commercial opportunity and therapeutic need in this space[11,14]. As research continues to elucidate the intricate connections between inflammation, iron metabolism, and various disease states, we can anticipate further innovations in anti-inflammatory iron preparations that will enhance treatment outcomes and quality of life for patients worldwide[13].

This review aims to explore how diabetes contributes to osteoporosis through mechanisms involving bone metabolism, inflammatory responses, and oxidative stress, with a particular focus on the role of iron metabolism dysregulation in DOP. Research suggests that under hyperglycemic conditions, abnormal iron metabolism may lead to cell death (such as iron-dependent cell death, or ferroptosis), further exacerbating osteoporosis progression[1,5,15]. By analyzing these mechanisms in depth, we hope to provide new insights and strategies for clinical treatment to improve bone health in diabetic patients.

EFFECTS OF DIABETES ON BONE METABOLISM

Basic concepts of bone metabolism

Bone metabolism represents the dynamic balance between bone formation and resorption, primarily governed by the coordinated activities of osteoblasts, osteoclasts, and osteocytes. Under normal physiological conditions, this balance ensures skeletal health and stability[16,17]. However, in pathological conditions such as diabetes, bone resorption frequently outpaces bone formation, leading to bone loss and the development of osteoporosis. Table 1 provides an overview of the effects of diabetes on bone metabolism.

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.

Osteoblasts are responsible for synthesizing and mineralizing the bone matrix and play a pivotal role in bone formation. They secrete collagen and non-collagenous proteins while regulating mineralization. Research indicates that hyperglycemia impairs osteoblast proliferation and function, resulting in diminished new bone formation[4,18]. Moreover, osteoblast function relies on critical signaling molecules such as insulin and insulin-like growth factor-1 (IGF-1), and deficiencies in these factors exacerbate the risk of osteoporosis in individuals with diabetes[19,20].

Conversely, osteoclasts are specialized cells that degrade bone tissue by secreting acidic substances and enzymes, facilitating the remodeling process. In diabetic patients, osteoclast activity is often heightened, driven by the upregulation of osteoclast-promoting factors such as receptor activator of nuclear factor-κB ligand (RANKL) and tumor necrosis factor-α (TNF-α). Elevated levels of these factors enhance osteoclast function, accelerating bone resorption[20-22].

Osteocytes are mature osteoblasts embedded within the mineralized bone matrix, where they act as mechanosensors to detect changes in mechanical stress and coordinate osteoblast and osteoclast activities. They release signaling molecules that influence nearby cells to maintain the delicate balance of bone metabolism[23,24]. However, in diabetic patients, oxidative stress and chronic inflammation can impair osteocyte function, further disrupting overall bone metabolic equilibrium[8,25].

In addition to cellular-level disruptions, hyperglycemia also affects the periosteum, a highly vascularized membrane that envelops bones and contains progenitor cells essential for bone growth and repair. In diabetic conditions, the vascular network and cellular activity within the periosteum are significantly impaired, leading to reduced osteogenic capacity and delayed fracture healing. Hyperglycemia-induced microangiopathy and inflammation in the periosteum compromise nutrient delivery and stem cell function, thereby exacerbating bone loss and reducing regenerative potential in diabetic patients[23-25].

The mechanisms through which hyperglycemia disrupts bone metabolism are depicted in Figure 1, highlighting the multifactorial impacts of diabetes on skeletal health.

Figure 1 Mechanism diagram of high glucose-induced osteoporosis. This schematic illustrates hyperglycemia-induced disruption of bone metabolism through advanced glycation end-products and reactive oxygen species signaling pathways. Hyperglycemia promotes the accumulation of advanced glycation end products (AGEs), which bind to receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) receptors, activating the bone resorption process. AGE-mediated signaling is mediated via the mitogen-activated protein kinase mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, and nuclear factor kappa B pathways, which in turn upregulate pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6, promoting osteoclast differentiation and activation, thereby increasing their number and function. Osteoclast formation is regulated by the balance between RANKL and osteoprotegerin (OPG), with OPG acting as a decoy receptor to inhibit osteoclastogenesis. Meanwhile, hyperglycemia generates reactive oxygen species (ROS) through the Fenton reaction, leading to pancreatic β-cell apoptosis and causing iron overload by increasing intestinal iron absorption. The liver responds to iron overload by upregulating hepcidin, which exacerbates iron accumulation and further disrupts bone metabolism. Additionally, AGEs and ROS inhibit osteoblast function by activating molecules such as gasdermin D, Gaspase-1, IL-1, and bone morphogenetic protein-2, leading to reduced runt-related transcription factor 2 expression and impaired osteoblast activity, thereby hindering bone formation. ROS and iron accumulation also promote ferroptosis, further exacerbating osteoblast dysfunction, which results in an imbalance between bone resorption and formation, ultimately leading to osteoporosis and other bone-related complications associated with diabetes. AGEs: Advanced glycation end products; BMP-2: Bone morphogenetic protein-2; GSDMD: Gasdermin D, a protein associated with programmed necrosis, playing a key role in the release of inflammatory factors such as interleukin-1β; IL-1: Interleukin-1; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor kappa B; OPG: Osteoprotegerin; PI3K/AKT: Phosphoinositide 3-kinase/protein kinase b; RANK: Receptor activator of nuclear factor-κB; RANKL: Receptor activator of nuclear factor-κB ligand; ROS: Reactive oxygen species; RUNX2: Runt-related transcription factor 2, a key transcription factor for osteoblast differentiation, regulating the expression of bone formation-related genes; TNF-α: Tumor necrosis factor-α.

Effects of diabetes on osteoblasts

A hyperglycemic environment significantly impairs osteoblast proliferation and differentiation. Studies have revealed that under high-glucose conditions, osteoblasts exhibit diminished proliferative capacity, reduced matrix synthesis, and delayed mineralization. This suppression is partially attributed to elevated levels of advanced glycation end products (AGEs) in diabetic patients. AGEs not only directly damage osteoblasts but also activate inflammatory pathways, ultimately leading to cell apoptosis[26,27].

Hyperglycemia specifically promotes inflammatory cytokine release, such as interleukin-1β (IL-1β), through activation of the caspase-1/Gasdermin D (member of Gasdermin family D)/IL-1 signaling pathway. These inflammatory mediators further inhibit osteoblast proliferation and functionality. Research indicates that high glucose concentrations (e.g., 25 mmol/L) suppress osteoblast proliferation and mineralization while reducing the expression of key osteogenic markers, including runt-related transcription factor 2 (RUNX2), alkaline phosphatase, and osteocalcin[28-30]. Furthermore, AGE accumulation is a critical contributor to osteoblast dysfunction, as it induces oxidative stress and exacerbates inflammatory responses, thereby compounding osteoblast damage[31,32].

Insulin plays an essential role in promoting osteoblast proliferation and differentiation. Its absence or insufficiency can result in osteoblast dysfunction. Insulin stimulates the expression of key genes such as RUNX2, facilitating osteoblast differentiation and mineralization[31]. In diabetic models, insulin significantly restores osteoblast function, enhancing their proliferation and differentiation capabilities. These findings underscore insulin's crucial physiological role in regulating bone metabolism[33].

Moreover, hyperglycemia may disrupt osteoblast function by interfering with other signaling pathways. For instance, studies have shown that a high-glucose environment suppresses the bone morphogenetic protein-2 (BMP-2) signaling pathway, which is pivotal for osteoblast differentiation. Under hyperglycemic conditions, BMP-2 levels are significantly diminished, leading to reduced expression of downstream target genes, such as RUNX2, ultimately impairing osteoblast mineralization[26,27].

Effects of diabetes on osteoclasts

Diabetes significantly increases osteoclast activity and accelerates bone resorption. Under hyperglycemic conditions, the expression levels of osteoclast-promoting factors, such as RANKL and TNF-α, are markedly elevated. These factors enhance osteoclast differentiation and activity through the RANK/RANKL/Osteoprotegerin signaling pathway[34,35]. RANKL is secreted by osteoblasts and binds to the receptor RANK on osteoclast precursors, driving their maturation into active osteoclasts[21].

In diabetic models, elevated RANKL and TNF-α levels have been directly linked to increased osteoclast activity[36]. For instance, studies show that diabetic rats exhibit significantly higher TNF-α levels than controls. TNF-α further promotes RANKL expression by activating the nuclear factor-κB (NF-κB) signaling pathway, enhancing osteoclastogenesis and activity. This mechanism not only accelerates bone resorption but also exacerbates chronic inflammation, thereby hastening DOP progression[37,38].

Additionally, a hyperglycemic environment exacerbates osteoclast function by elevating oxidative stress, leading to more pronounced bone loss. Oxidative stress impacts bone metabolism through various pathways, including increasing osteoclast activity and apoptosis. Research indicates that AGE accumulation in diabetic patients stimulates osteoclast activity by activating specific signaling pathways, such as MAPK and PI3K/Akt[26,27].

Moreover, persistently elevated levels of inflammatory cytokines in diabetic patients, such as IL-6, IL-1β, and TNF-α, directly enhance osteoclastogenesis. These inflammatory mediators also impair osteoblast function, indirectly exacerbating the imbalance between bone resorption and formation[19]. The resulting disruption leads to reduced BMD and osteoporosis progression.

THE INFLAMMATORY RESPONSE AND OXIDATIVE STRESS IN DOP

Inflammatory response

Chronic low-grade inflammation associated with diabetes is a key mechanism in the development of DOP[39]. Diabetic patients often exhibit a persistent inflammatory state driven by obesity, insulin resistance, and metabolic dysfunction. This state is characterized by elevated levels of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α[40,41]. These cytokines directly affect bone metabolism but also disrupt the balance between bone formation and resorption by impairing osteoblast and osteoclast functions[42] (Table 2).

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.

Elevated IL-6 levels are a hallmark of diabetes and play a pivotal role in DOP. IL-6 promotes osteoclastogenesis while inhibiting osteoblast differentiation and function. Specifically, IL-6 enhances osteoclast activity by upregulating RANKL expression, thereby accelerating bone resorption[4,43]. Similarly, TNF-α is a significant driver of osteoclastogenesis, further stimulating osteoclast activity through activation of the NF-κB signaling pathway. In a chronic inflammatory state, sustained elevation of these cytokines contributes to progressive bone loss and worsening osteoporosis[44,45].

In experimental models of diabetes, there is a strong correlation between inflammatory cytokines and bone metabolism markers[46]. For instance, elevated TNF-α levels are inversely correlated with BMD, underscoring the critical role of inflammation in DOP[47,48]. Furthermore, persistent low-grade inflammation may increase osteoblast apoptosis, leading to reduced bone formation and exacerbating DOP progression[4,27].

Oxidative stress

Hyperglycemia significantly increases reactive oxygen species (ROS) production, which represents another critical mechanism in DOP pathogenesis[49,50]. Research indicates that hyperglycemia induces ROS generation through multiple pathways, including the accumulation of AGEs, mitochondrial dysfunction, and activation of the polyol pathway[51]. Excessive ROS production causes oxidative damage to cells and disrupts the function of both osteoblasts and osteoclasts[49,52].

In osteoblasts, ROS inhibits proliferation and differentiation while inducing apoptosis. For example, under high-glucose conditions, MC3T3-E1 osteoblasts undergo increased rates of apoptosis and decreased mineralization capacity[27]. This effect is partially attributed to ROS-induced mitochondrial dysfunction, which reduces ATP synthesis and leads to cellular energy deficiency[31]. Additionally, ROS activates signaling pathways such as MAPK and NF-κB, further promoting osteoblast apoptosis and inhibiting differentiation[53].

In osteoclasts, ROS enhances activity and function. Studies have shown that hyperglycemia-induced ROS amplifies osteoclast responsiveness to RANKL, promoting their differentiation and activity. This process accelerates bone resorption, resulting in more severe bone loss[54,55].

Thus, hyperglycemia-induced oxidative stress in diabetic patients exerts a dual impact: Impairing osteoblast function and enhancing osteoclast activity. This imbalance exacerbates DOP progression, highlighting oxidative stress as a key therapeutic target in managing diabetes-related bone disorders[56].

IRON METABOLISM DYSREGULATION IN DOP

Basic concepts of iron metabolism

Iron is an essential element in the body, playing a pivotal role in various physiological processes such as oxygen transport, DNA synthesis, and energy production. Iron metabolism involves several key stages: absorption, transport, utilization, recycling, regulation, and storage. Iron is primarily absorbed in the small intestine, where it enters cells in its ferrous form (Fe²⁺) and is transported throughout the body via transferrin, a carrier protein in the bloodstream[57]. Within cells, iron can be stored as ferritin or utilized in the synthesis of hemoglobin and other iron-dependent enzymes[58].

Iron homeostasis is tightly regulated by hepcidin, a hormone produced by the liver. Under normal conditions, increased hepcidin levels inhibit intestinal iron absorption and reduce iron release from storage sites, thereby preventing iron overload[59]. Conversely, during hypoxic conditions, hepcidin expression decreases, facilitating iron release and utilization. This dynamic regulatory mechanism ensures that the body’s iron demands are met under varying physiological conditions while protecting against the toxicity associated with excessive iron levels[59,60].

The relationship between diabetes and iron metabolism

The interplay between diabetes and iron metabolism is complex and multifaceted. Studies have revealed that diabetic patients frequently exhibit abnormalities in iron metabolism, manifesting as either iron overload or iron deficiency. These conditions are often associated with inflammation, insulin resistance, and metabolic dysregulation[61-63]. Specifically, iron metabolism disturbances in diabetes can be categorized into two main categories: Iron overload and iron deficiency. Table 3 provides a summary of the relationship between diabetes and iron metabolism.

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.

Iron overload and diabetes: Chronic low-grade inflammation in diabetic patients may elevate hepcidin levels, a key hormone responsible for regulating iron homeostasis. Increased hepcidin inhibits intestinal iron absorption and reduces the release of stored iron, potentially leading to inadequate iron availability. Furthermore, oxidative stress, which is increased in diabetes, exacerbates iron metabolism dysregulation[5]. Elevated ROS levels promote iron release and enhance its bioavailability, contributing to iron overload. The detailed process of iron absorption is illustrated in Figure 2.

Figure 2 The process of iron absorption in the small intestine. Iron is primarily absorbed in the upper small intestine through an energy-dependent active transport process involving two key steps: Uptake of iron from the intestinal lumen by mucosal cells and its subsequent transport into the plasma. This process requires the participation of multiple transport proteins. Divalent metal transporter 1, located on the apical membrane of mucosal cells, facilitates the H⁺-dependent active transport of Fe²⁺ into intestinal epithelial cells. On the basolateral membrane, FPN1 mediates the export of Fe²⁺ from the cells into the bloodstream, also via an H⁺-dependent mechanism. Any inorganic iron that remains within the mucosal cells without being exported can be oxidized to Fe³⁺ and stored temporarily as ferritin by binding to apoferritin. This stored iron is slowly released into the bloodstream over time. Iron that is not utilized is eventually lost with the natural turnover and shedding of mucosal cells, preventing excessive accumulation. This sophisticated balance ensures efficient iron absorption by the intestinal mucosa while protecting the body from iron overload. Under normal conditions, iron homeostasis is regulated by hepcidin, a liver-secreted hormone that modulates iron availability. Elevated ROS can further promote iron release and increase its bioavailability, potentially exacerbating iron overload. DMT1: Divalent metal transporter 1; FPN1: Ferroportin 1; ROS: Reactive oxygen species.

Iron overload intensifies oxidative stress, aggravating insulin resistance and impairing β-cell function, thereby complicating diabetes management. Excessive iron facilitates ROS production through the Fenton reaction, which is toxic to β-cells, resulting in their dysfunction and apoptosis[1,64]. Additionally, studies indicate that iron overload disrupts insulin signaling pathways in the liver and adipose tissue, further exacerbating insulin resistance[65].

Iron deficiency and diabetes: Conversely, diabetic patients may also experience iron deficiency. Chronic inflammation and elevated hepcidin levels are contributors to functional iron deficiency in diabetes. This condition impairs erythropoiesis and may lead to complications such as anemia[66,67]. Furthermore, iron deficiency can adversely affect insulin secretion, as β-cells rely on sufficient iron to maintain their functional and secretory capacities[68].

In diabetic models, iron deficiency has been shown to diminish the glucose-stimulated response of β-cells, thereby reducing insulin secretion. These findings highlight the critical importance of maintaining optimal iron levels in diabetes management to preserve β-cell functionality and ensure metabolic stability[69,70].

The impact of abnormal iron metabolism on bone metabolism

Recent research highlights a strong relationship between abnormal iron metabolism and bone metabolism, particularly in the context of DOP. Iron-dependent cell death, or ferroptosis, has emerged as a critical mechanism underlying DOP. Ferroptosis is a novel form of programmed cell death characterized by the accumulation of lipid peroxides and ROS generation[68]. Under hyperglycemic conditions, ferroptosis is significantly elevated in diabetic patients, closely linked to bone cell death and the development of osteoporosis[71-73].

Definition of ferroptosis and its association with DOP: Ferroptosis is an iron-dependent form of cell death that differs from traditional mechanisms such as apoptosis, necrosis, and autophagy. It is defined by lipid peroxidation triggered by intracellular iron overload, which ultimately causes membrane rupture and cell death. In diabetic patients, hyperglycemia increases ROS generation, driving ferroptosis[74]. Studies suggest that both osteoblasts and osteoclasts are affected by ferroptosis under hyperglycemic conditions[75].

For instance, one study demonstrated that osteoblasts exposed to high glucose levels exhibit substantial lipid peroxidation and apoptosis, effects that can be mitigated by inhibiting ferroptosis[74]. Furthermore, iron overload amplifies this process, as excessive iron enhances ROS generation, further promoting ferroptosis[76].

Effects of abnormal iron metabolism on osteoblast and osteoclast function: In diabetic models, both osteoblasts and osteoclasts are vulnerable to ferroptosis. Elevated glucose levels and iron overload increase ROS levels in osteoblasts, inducing ferroptosis. For example, studies have shown that MC3T3-E1 osteoblasts exposed to high glucose concentrations accumulate lipid peroxides, experience mitochondrial dysfunction, and undergo apoptosis[77]. These changes not only impair osteoblast proliferation and differentiation but also reduce bone matrix synthesis, exacerbating osteoporosis[78,79].

Similarly, in osteoclasts, iron overload induces ferroptosis and enhances osteoclast activity. Under high iron conditions, osteoclasts demonstrate increased responsiveness to RANKL, which promotes their differentiation and activity. This accelerates bone resorption and exacerbates bone loss. Studies in rat models have shown that in diabetes, osteoclast activity is significantly elevated and strongly correlated with increased iron levels[78].

CLINICAL TREATMENT STRATEGIES AND FUTURE RESEARCH DIRECTIONS

Current treatment approaches

The clinical management of DOP primarily involves pharmacological interventions and lifestyle modifications. Current pharmacological strategies focus on the combined use of antidiabetic and anti-osteoporotic drugs, aiming to control blood glucose levels while simultaneously enhancing bone metabolism.

Regarding pharmacotherapy, antidiabetic agents such as metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors are considered relatively safe for bone health[80]. Research has demonstrated that metformin not only effectively reduces blood glucose levels but may also offer protective effects on bone density[80-82]. Furthermore, GLP-1 receptor agonists promote bone quality by stimulating osteoblast proliferation and differentiation, whereas SGLT-2 inhibitors exhibit bone-protective effects and also lower blood glucose levels[81].

Anti-osteoporotic treatments typically include bisphosphonates and RANKL inhibitors, such as denosumab. Bisphosphonates work by inhibiting osteoclast activity, thereby reducing bone resorption, while RANKL inhibitors prevent the binding of RANKL to its receptor RANK, further suppressing osteoclastogenesis[83,84]. Calcium and vitamin D supplementation also constitute a core treatment component, collectively supporting bone health in patients[80,85].

Lifestyle interventions are crucial for enhancing both overall and bone health. These include a balanced diet, regular exercise, and avoiding smoking. A nutritious diet provides the necessary nutrients to maintain bone strength, while moderate physical activity, especially weight-bearing exercises, helps increase bone density and decrease osteoporosis risk[82,86]. Additionally, healthy lifestyle habits contribute to better blood glucose control. A study on postmenopausal women demonstrated that rigorous dietary and exercise management significantly improved bone density in patients with both type 2 diabetes and osteoporosis[87].

Future research directions

Future research should prioritize the areas discussed below to improve the management and treatment outcomes of DOP (summarized in Table 4).

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.

The role of ferroptosis in DOP: Ferroptosis is a novel form of programmed cell death and is characterized by the accumulation of lipid peroxides and ROS generation[88]. Recent findings suggest that ferroptosis is a critical mechanism underlying DOP onset and progression. While preliminary studies have highlighted the influence of ferroptosis on bone cells in the diabetic microenvironment, its precise molecular mechanisms remain incompletely understood[68,89]. Future research should explore the following areas:

(1) Regulating ferroptosis to protect bone cells: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that orchestrates cellular antioxidant defenses. Under oxidative stress, Nrf2 dissociates from its inhibitor Keap1 and translocates to the nucleus, where it induces the expression of antioxidant genes such as heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPX4)[90,91]. These genes mitigate iron-dependent lipid peroxidation, thereby inhibiting ferroptosis.

Nrf2 plays a protective role in osteoblasts and osteoclasts by modulating intracellular free iron levels and lipid metabolism, effectively decelerating DOP progression[92,93]. Therapeutic approaches targeting pathways like the Nrf2/HO-1 signaling axis to suppress ferroptosis could offer innovative strategies for bone cell protection and DOP mitigation. For example, previous studies have demonstrated that Nrf2 activation decreases iron-dependent lipid peroxidation, significantly reducing ferroptosis[94].

(2) Application of antioxidants and iron chelators; the role of antioxidants Glutathione (GSH) and melatonin: GSH is a pivotal intracellular antioxidant that protects cells from oxidative damage by scavenging ROS. Studies indicate that GSH deficiency can trigger ferroptosis, as GSH is an essential substrate for GPX4, an enzyme responsible for detoxifying lipid peroxides[95,96].

Melatonin is also an effective ferroptosis inhibitor[95]. In addition to its potent antioxidant properties, melatonin enhances cellular antioxidant defenses by activating the Nrf2/HO-1 signaling pathway. Research has demonstrated that melatonin increases GSH and superoxide dismutase levels and reduces the accumulation of lipid peroxides and malondialdehyde, thereby alleviating ferroptosis[97,98].

Role of iron chelators: Deferoxamine (DFO) applications. DFO is a highly effective iron chelator that mitigates ferroptosis by binding free iron and reducing intracellular iron levels[76]. DFO has been extensively studied in various disease models to counteract iron-induced cell death. For example, in osteoarthritis models, DFO inhibits chondrocyte ferroptosis and activates the Nrf2 antioxidant system, thereby protecting cartilage cells[99,100].

DFO shows promise in the treatment of osteoporosis-related conditions. Research indicates that DFO prevents bone loss caused by excessive iron accumulation and improves osteoblast function by inhibiting ferroptosis. These findings suggest new therapeutic opportunities for managing DOP[100].

Combined applications: The simultaneous use of antioxidants and iron chelators may provide synergistic effects, offering enhanced protection against ferroptosis-induced cellular damage. For instance, co-administration of melatonin and DFO could amplify bone cell protection by concurrently reducing ROS levels and alleviating iron overload, thereby improving bone cell functionality[93,101,102].

Developing novel therapies targeting iron metabolism and oxidative stress: With growing insights into the intricate relationship between iron metabolism and oxidative stress, developing targeted therapies has become a critical research priority. Potential approaches include:

(1) Interventions in iron metabolism: Investigating the use of iron chelators in diabetic patients and their potential benefits for bone health. Studies have shown that DFO effectively reduces iron overload and may protect bone cells by mitigating ROS production[93,99,100];

(2) Antioxidant therapies: Antioxidants targeting oxidative stress, such as GSH precursors or small-molecule drugs, represent promising therapeutic options for DOP. These therapies aim to alleviate cellular damage by neutralizing excess ROS, thereby enhancing bone metabolism[103].

Numerous studies have highlighted the antioxidant effects of small-molecule drugs and natural compounds in animal models, demonstrating significant improvements in diabetes-induced bone metabolic abnormalities. For example, the natural polyphenolic compound resveratrol reduces blood glucose levels while promoting osteoblast differentiation and suppressing adipogenesis through activation of the Sirtuin1 signaling pathway, thereby supporting bone health[104,105]. Furthermore, innovative nanomaterials with specific structural properties have shown exceptional antioxidant capabilities, enabling the sustained local release of antioxidant agents, thereby enhancing the repair of diabetic bone defects[106,107].

Personalized treatment strategies: Given the substantial variability among diabetic patients, future efforts should focus on personalized assessments to create more precise treatment plans. This includes selecting the most suitable anti-diabetic and anti-osteoporosis medications based on individual patient conditions, complemented by lifestyle modifications to maximize therapeutic outcomes[68]. For instance, tailoring interventions to address specific iron metabolism imbalances could significantly enhance treatment efficacy.

Clinical trials and long-term observations: Large-scale, long-term clinical trials are essential to evaluate the efficacy of various treatment strategies on bone health and overall quality of life in DOP patients[68]. These trials will provide strong evidence to inform clinical practice. Moreover, studies focusing on emerging therapies, such as drugs targeting ferroptosis and iron metabolism, will deliver crucial data to drive the development of innovative treatment strategies.

Application of high-throughput sequencing technology in ferroptosis and DOP research: High-throughput sequencing technology, especially RNA sequencing (RNA-seq), serves as a powerful tool for exploring the molecular mechanisms of ferroptosis in DOP. This technique allows for the simultaneous detection of millions of DNA molecules, enabling the identification of specific genes or genomic regions, thereby offering profound insights into the role of ferroptosis in DOP[30] (Table 2).

RNA-seq technology offers significant advantages in the study of DOP. It enables a comprehensive analysis of transcriptomic changes in bone tissue, facilitating the identification of differentially expressed genes associated with ferroptosis. For instance, RNA-seq analysis of diabetic bone tissue has led to the identification of key ferroptosis-related genes, including GPX4, Ftl1, Tp53, and GPLD1. These findings suggest that along with the GPI-anchored biosynthesis signaling pathway, ferroptosis plays a crucial role in high-phosphate-induced vascular smooth muscle cell calcification[68,108,109]. These insights provide valuable understanding of the mechanisms underlying ferroptosis in bone cells within the diabetic microenvironment.

The application of single-cell RNA-seq (scRNA-seq) technology has further advanced the precision of DOP research[110-112]. This technology can distinguish gene expression patterns across different cell types, making it particularly important for studying the ferroptosis status of distinct cell types in the bone marrow microenvironment under diabetic conditions, such as osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells. Studies by Bao et al[5] and Zhang et al[113] have shown that iron metabolism dysregulation in the bone marrow microenvironment is a key factor in developing osteoporosis under diabetic conditions, and scRNA-seq can accurately capture these changes.

In addition, the integration of multi-omics data analysis methods has provided new perspectives for DOP research. Combining RNA-seq data with proteomics and metabolomics data can help construct a comprehensive regulatory network linking ferroptosis and DOP[68,114]. For example, Yang et al[68] performed a joint analysis of RNA-seq and proteomics and found that inhibiting ferroptosis could alleviate glucolipotoxicity in bone cells and improve diabetic osteopathy. This study confirmed the crucial roles of key genes such as MAPK3, CDKN1A, MAP1 LC3A, TNF, RELA, and TGF-β1 in this process[68,115].

Future research should focus on the following key areas: high-throughput sequencing technologies to identify specific biomarkers of ferroptosis, which could facilitate the early diagnosis of DOP. Second, conducting functional genomics studies to validate the roles of key genes in DOP, thereby supporting the discovery of drug targets and the development of personalized treatment strategies. Additionally, the creation of a large-scale database integrating transcriptomic and clinical data will provide a more comprehensive understanding of ferroptosis in DOP pathogenesis, laying a solid foundation for the development of novel ferroptosis-targeted therapies.

DISCUSSION

This study provides a comprehensive analysis of DOP pathogenesis, with a particular emphasis on the roles of iron metabolism dysregulation and ferroptosis, an iron-dependent form of programmed cell death. The findings demonstrate that diabetes adversely affects bone metabolism through multiple interconnected pathways, including impaired osteoblast function, enhanced osteoclast activity, chronic inflammation, persistent oxidative stress, and abnormalities in iron metabolism.

The results further confirm the inhibitory effects of hyperglycemia on bone cell metabolism. Under high-glucose conditions, osteoblasts exhibit significantly reduced proliferation and differentiation, which is closely associated with oxidative stress-induced apoptosis and functional impairment. Simultaneously, pro-inflammatory factors such as RANKL and TNF-α markedly enhance osteoclast activity, leading to accelerated bone resorption and further bone loss. These findings suggest that targeting the dysregulated functions of osteoblasts and osteoclasts may provide novel therapeutic avenues for DOP.

Moreover, the study underscores the pivotal role of iron metabolism dysregulation in DOP, revealing its dual impact on bone metabolism through iron overload and deficiency. In diabetic patients, abnormal iron metabolism not only impairs bone cell function but also exacerbates osteoporosis progression by inducing ferroptosis. Particularly under iron overload conditions, elevated ROS levels intensify lipid peroxidation and lead to bone cell death. This mechanism highlights the importance of addressing iron metabolism abnormalities as part of DOP management.

Ferroptosis has been identified as a key contributor to the detrimental effects of diabetes on bone metabolism, as it accelerates the death of both osteoblasts and osteoclasts while aggravating the overall metabolic imbalance through oxidative stress and lipid peroxidation. These findings suggest that inhibiting ferroptosis could represent a promising therapeutic strategy for the treatment of DOP.

While this study provides valuable insights into DOP pathogenesis, particularly the impact of iron metabolism and ferroptosis on bone metabolism, it has certain limitations. For example, the differences in mechanisms between in vivo and in vitro models may restrict the generalizability of the findings. Additionally, the study does not comprehensively address how various diabetes treatments influence the regulation of iron metabolism and ferroptosis, leaving this as an important area for future research.

CONCLUSION

Future studies should prioritize a detailed exploration of the specific mechanisms underlying iron metabolism dysregulation and ferroptosis in DOP, particularly their interactions with oxidative stress and pro-inflammatory factors. The development of novel therapeutic agents targeting these abnormalities, such as iron chelators and antioxidants, and their validation through large-scale clinical trials will be essential. Furthermore, establishing representative animal models that integrate genetic, metabolic, and environmental factors could facilitate the creation of personalized treatment strategies. Such advancements would support the transition of DOP management toward individualized and precision medicine.