Effects of hyperglycemia on the bone microenvironment in diabetic osteoporosis

Abstract

With the global surge in diabetes mellitus prevalence, diabetic osteoporosis (DOP) has become a pressing public health challenge because it markedly increases fracture risk and impairs bone repair capacity. The bone microenvironment, a dynamic ecosystem that maintains skeletal integrity, undergoes profound pathological changes under chronic hyperglycemia: Excessive reactive oxygen species production induced by high glucose and accumulation of advanced glycation end products together trigger oxidative stress and chronic low-grade inflammation in the bone microenvironment (e.g., activation of the nuclear factor-kappa B signaling pathway). These processes, by inhibiting osteoblast differentiation, enhancing osteoclast activity, and damaging microvascular supply, disrupt the coupled balance of bone remodeling. This article aims to systematically review the effects of hyperglycemia on the bone microenvironment and its molecular mechanisms, clarify the pathological basis of DOP, and provide a theoretical foundation for identifying new targets for prevention, treatment, and clinical intervention.

Key Words: Diabetic osteoporosis; Bone microenvironment; Hyperglycemia; Oxidative stress; Inflammation

Core Tip: Diabetic osteoporosis (DOP) poses a major health challenge, elevating fracture risk. Chronic hyperglycemia is central to DOP pathogenesis, instigating oxidative stress via excessive reactive oxygen species and advanced glycation end products, plus inflammation involving the nuclear factor-kappa B signaling pathway within the bone microenvironment. This disrupts bone remodeling. Understanding these molecular mechanisms is crucial for developing innovative prevention and treatment strategies for DOP.

INTRODUCTION

Diabetes mellitus has become the most urgent global public health challenge of the 21^st century[1]. In 2021 there were approximately 537 million adults with diabetes worldwide, and this number is expected to rise to 783 million by 2045, with tens of millions of new cases emerging each year[2,3]. Diabetes and its complications involve multiple systems, including retinopathy, nephropathy, neuropathy, cardiovascular disease, and foot lesions[4,5]. Diabetic osteoporosis (DOP) also significantly increases the risk of fragility fractures and impairs bone healing, and has become an important component of the global public health challenge[6,7]. With population aging and the spread of obesity and metabolic syndrome, the prevalence of DOP is expected to continue rising, approximately 50%-66% of individuals with diabetes exhibit reduced bone mineral density, posing a substantial burden on global health resources and socioeconomic systems and creating an urgent need to deepen understanding of its pathological basis to mitigate long-term impacts.

The bone microenvironment is a highly complex and dynamic mini-ecosystem composed of a mineralized matrix, osteoblasts, osteoclasts, osteocytes, endothelial cells, immune cells, and the bone marrow and vascular networks[8,9]. It is crucial for maintaining skeletal integrity through a fine balance between bone formation and resorption (i.e., the bone remodeling process) and serves as an active site that converts systemic metabolic signals into local cellular responses[10]. Core regulatory pathways such as the receptor activator of nuclear factor-kappa B ligand (RANKL)-osteoprotegerin (OPG) axis, Wnt/β-catenin signaling, the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, and vascular endothelial growth factor-driven vascularization act together to determine bone mass, microarchitecture, and mechanical properties, and are modulated by immune cells, metabolic status, and levels of inflammation[11-13]. Any disruption of this delicate balance can lead to the characteristic structural deterioration of osteoporosis; under pathological conditions such as endocrine disorders, inflammation, or metabolic syndrome, changes in signaling molecules, cellular composition, and blood supply within the microenvironment often serve as key mediators of increased fracture risk[14,15]. Therefore, the stability of the bone microenvironment directly influences the onset and progression of osteoporosis, and understanding its role helps reveal potential shared targets and specific mechanisms.

Chronic hyperglycemia is the primary driver of skeletal degeneration in diabetic patients, acting by profoundly altering the bone microenvironment[16]. Elevated glucose levels promote excessive production of reactive oxygen species (ROS), leading to systemic and local oxidative stress[17,18]. This oxidative milieu, together with accumulation of advanced glycation end products (AGEs) and sustained activation of their receptor for AGEs (RAGE), fosters a chronic low-grade inflammatory state within the bone microenvironment and triggers inflammatory signaling pathways (such as nuclear factor-kappa B)[19-21]. These pathological stimuli jointly impair osteoblast proliferation, differentiation, and mineralization while enhancing osteoclast activity and survival, disrupting the coupling balance between bone formation and resorption[22-24]. In addition, AGEs-mediated protein crosslinking alters the mechanical properties of the bone matrix, and microvascular lesions with reduced blood supply further weaken local reparative capacity and may shift osteoblast lineage differentiation[25-27]. Thus, oxidative stress and inflammatory signaling pathways interact to promote deterioration of bone microarchitecture and loss of bone quality, ultimately leading to DOP and increased fracture risk[28-30]. We systematically categorized and summarized high-quality literature from the past 5 years by searching the Web of Science database using hyperglycemia and osteoporosis as keywords.

This article aims to systematically review the effects of hyperglycemia on the bone microenvironment and new insights into DOP, elucidate its molecular mechanisms, explore clinical application prospects, and provide a theoretical basis and new intervention targets for the prevention and treatment of this disease (Figure 1).

Figure 1 Interactions of bone microenvironmental factors in osteoporosis caused by hyperglycemia. Including functional characteristics of bone microenvironment regulators, molecular mechanisms of bone factors in osteoporosis, inflammation and bone metabolism in osteoporosis, metabolic impacts on osteoporosis, and prevention measures for osteoporosis. AGEs: Advanced glycation end products; BMPs: Bone morphogenetic protein; RANKL: Receptor activator of nuclear factor-kappa B ligand; OPG: Osteoprotegerin.

THE BONE MICROENVIRONMENT: A COMPLEX REGULATORY ECOSYSTEM

Cellular components

The cellular composition of bone is central to maintaining its vitality. Osteoblasts, osteoclasts, and osteocytes constitute the main components of bone remodeling[31-33]. Osteoblasts are responsible for synthesis and mineralization of the bone matrix; their activity directly determines the rate of new bone formation and the accumulation of bone mass. Osteoclasts, by mediating bone resorption, remove aged or damaged bone tissue, providing space for new bone and enabling recycling of minerals. Osteocytes, the most abundant cells within bone, are embedded deeply in the matrix and form a network through their dendritic processes; they sense mechanical stress and local microenvironmental changes and relay signals to osteoblasts and osteoclasts, precisely regulating the initiation and progression of bone remodeling[34-36]. Bone marrow mesenchymal stem cells (BMSCs) are key progenitors for bone formation, possessing multipotent differentiation potential; under specific signaling stimuli they differentiate into osteoblasts and serve as the source of skeletal regeneration and repair[37,38]. In addition, immune cells and endothelial cells are deeply involved in bone metabolism through mechanisms such as osteoimmunology and H-type vessels, immune cells regulate inflammation and the balance of bone resorption/formation by secreting cytokines[39,40], while endothelial cells, via the vascular network, supply nutrients and oxygen and recruit BMSCs, together maintaining homeostasis of the bone microenvironment[41,42].

Non-cellular components

The noncellular components of bone are the cornerstone of its unique mechanical properties and biological activity. The extracellular matrix (ECM) is primarily composed of type I collagen and minerals[43,44]. Type I collagen forms a dense fibrous network that confers toughness and elasticity to bone; the integrity of its structure is critical to bone tensile strength. Minerals such as hydroxyapatite are deposited as microcrystals on the collagen fibers, giving bone its high hardness and compressive strength. The ECM is not only a physical scaffold but also a reservoir for growth factors and signaling molecules, which are gradually released during bone remodeling to finely regulate cellular behavior[45,46]. In addition, various signaling molecules and growth factors act as messengers in bone metabolism. For example, the TGF-β family plays a key role in regulating the proliferation and differentiation of BMSCs and the activity of osteoblasts, promoting matrix synthesis while under certain conditions potentially inhibiting mineralization[47,48]. BMPs are potent osteoinductive agents that promote the differentiation of mesenchymal cells toward the osteogenic lineage and play an important role in fracture healing. These molecules, through a complex network of signaling pathways, jointly maintain the balance between bone formation and resorption[49-51].

Bone remodeling homeostasis

Bone remodeling homeostasis refers to the dynamic balance by which the skeleton, throughout the life cycle, continually renews itself through precisely regulated processes of resorption and formation to adapt to physiological needs and mechanical loading while maintaining structural integrity and mechanical strength[52,53]. This process is driven by tight coupling and signaling interactions among osteoblasts, osteoclasts, and osteocytes. When bone tissue experiences microdamage or changes in mechanical stress, osteocytes sense the signals and transmit them to osteoblasts and osteoclasts, prompting initiation of local remodeling. Multiple systemic and local regulatory factors including hormones (such as parathyroid hormone and estrogen), vitamin D, cytokines (such as RANKL/OPG), and local growth factors (such as TGF-β and BMPs) jointly participate in modulating this balance. Any factor that disrupts the balance between bone formation and resorption such as aging, hormonal imbalances, malnutrition, or chronic disease can lead to bone loss and deterioration of bone microarchitecture, thereby increasing fracture risk[54-56]. Therefore, understanding the complex regulatory network of bone remodeling homeostasis is key to preventing and treating skeletal diseases.

PATHOPHYSIOLOGICAL IMPACT OF HYPERGLYCEMIA ON THE BONE MICROENVIRONMENT

AGEs accumulation

In a hyperglycemic environment, sugar molecules undergo non-enzymatic glycation with proteins in bone (especially type I collagen), leading to the formation of AGEs[57]. These AGEs accumulate in the bone matrix, causing abnormal covalent cross-linking of collagen fibers. This non-enzymatic cross-linking alters the structure and function of collagen, reducing its elasticity and increasing its brittleness, directly impairing bone toughness and making it more susceptible to microcracks or fractures under stress[58]. AGEs not only physically affect the bone matrix but also bind to the RAGE on cell surfaces, activating downstream signaling pathways. Activation of RAGE signaling triggers a cascade of pathological reactions, including oxidative stress, inflammation, and apoptosis, directly damaging osteoblasts, osteocytes, and bone marrow stem cells, inhibiting their proliferation, differentiation, and function, ultimately leading to impaired bone formation and increased bone resorption, further deteriorating bone quality[59].

Oxidative stress and ROS

Chronic hyperglycemia is a major inducer of oxidative stress. In a high-glucose environment, cellular metabolic disturbances lead to mitochondrial electron transport chain dysfunction, increased glucose autoxidation, and enhanced formation of AGEs, producing excess ROS[60,61]. These excess ROS accumulate in the bone microenvironment, attack cellular macromolecules, causing DNA damage and lipid peroxidation, disrupting cell membrane integrity and protein function, and exert direct cytotoxicity on osteoblasts, osteocytes, and BMSCs[62,63]. In addition, hyperglycemia downregulates the expression and activity of endogenous antioxidant enzymes in bone cells [such as superoxide dismutase (SOD) and glutathione peroxidase], further weakening the skeleton’s ability to clear ROS and creating a vicious cycle[64,65]. Sustained oxidative stress not only directly inhibits osteoblast activity and differentiation but also promotes osteoclast formation and function, thereby disrupting bone remodeling balance, accelerating bone loss, and exacerbating diabetic bone disease.

Chronic low-grade inflammation

Patients with diabetes often have systemic chronic low-grade inflammation, a condition that is particularly pronounced in the bone marrow microenvironment. Hyperglycemia-induced oxidative stress and accumulation of AGEs activate various immune and non-immune cells, which release large amounts of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6[66,67]. These pathophysiological processes together disrupt the dynamic balance of bone remodeling, adversely affecting osteoblast differentiation and osteoclast activity. More importantly, by activating the RANKL/receptor activator of nuclear factor-kappa B (RANK) signaling pathway, they strongly promote osteoclastogenesis and enhance bone-resorbing activity[68,69]. This inflammation-driven increase in bone resorption coupled with impaired bone formation is referred to as osteoinflammation, a key component in the pathophysiology of diabetic bone disease. Chronic inflammation not only leads to bone loss and deterioration of microarchitecture but may also impair stem cell function in the bone marrow microenvironment, further hindering bone repair and regenerative capacity[70,71].

Mitochondrial dysfunction and metabolic rewiring

One of the most profound impacts of hyperglycemia on osteocytes is the disruption of mitochondrial function and the reprogramming of cellular metabolism. Prolonged exposure to high glucose environments damages the mitochondrial electron transport chain in bone cells, particularly osteoblasts, leading to decreased activity of respiratory chain complexes and a significant reduction in adenosine triphosphate (ATP) production efficiency[72,73]. This ATP deficiency directly affects various energy-dependent cellular activities, including anabolism, ion pump function, and signal transduction. To cope with this energy crisis, the metabolic mode of osteoblasts shifts from efficient oxidative phosphorylation towards glycolysis[74,75]. While this metabolic reprogramming can provide energy in the short term, it is inefficient and produces more lactate, further exacerbating microenvironmental acidification. Such widespread metabolic dysregulation is not limited to osteoblasts but also extends to endothelial cells. In the diabetic context, hyperglycemia-induced metabolic shifts in endothelial cells directly impair their function, leading to compromised angiogenesis and a significant reduction in the formation of type H vessels. These specialized vessels are crucial for angiogenesis-osteogenesis coupling, as they provide essential signals and nutrients for bone formation, thus their impairment profoundly impacts skeletal health. Furthermore, hyperglycemia affects the metabolic crosstalk of BMSCs, promoting their differentiation from osteogenesis towards adipogenesis, leading to increased bone marrow fat accumulation. This further encroaches on osteogenic space and impairs skeletal health[76,77].

Impaired autophagy and increased apoptosis

Under hyperglycemic conditions, autophagy in bone cells is suppressed while apoptosis is markedly increased, leading to a disruption of the balance between cell survival and death[78,79]. Autophagy is a cellular self-cleaning and recycling process for damaged organelles and misfolded proteins that is critical for maintaining cellular homeostasis and responding to stress[80]. In a high-glucose environment, autophagy pathways are inhibited, causing accumulation of harmful substances such as damaged mitochondria and proteins within cells, which exacerbates oxidative stress and inflammatory responses and ultimately leads to cellular dysfunction[79,81,82]. At the same time, hyperglycemia promotes osteoblast and osteocyte entry into programmed cell death by activating multiple apoptotic signaling pathways (such as the intrinsic mitochondrial pathway and the extrinsic death receptor pathway). The reduction in osteoblast number decreases bone formation capacity; increased osteocyte apoptosis weakens the skeleton’s mechano-sensing and signaling network, reducing its ability to repair damage[83,84]. This vicious cycle of impaired autophagy and increased apoptosis accelerates bone loss and microstructural damage in patients with diabetes and is an important pathological mechanism in the progression of diabetic bone disease[24,85].

MOLECULAR SIGNALING PATHWAYS ALTERED BY HIGH GLUCOSE

Wnt/β-catenin

The Wnt/β-catenin pathway is the central switch that determines the osteogenic differentiation of BMSCs[86,87]. In a hyperglycemic environment, oxidative stress and accumulation of AGEs induce high expression of endogenous antagonists of this pathway (such as dickkopf-related protein 1 and sclerostin), leading to increased phosphorylation and degradation of cytoplasmic β-catenin, preventing its nuclear translocation to activate osteogenic target genes like Runx2[88,89]. This inhibitory effect not only directly impairs osteoblast proliferation and matrix mineralization but also induces metabolic reprogramming of BMSCs, shifting their differentiation potential from osteogenesis toward adipogenesis[90,91]. Inactivation of this pathway is the molecular basis for insufficient bone formation and decreased bone quality in diabetic bone disease and is an important current target for drug intervention.

RANKL/OPG

Bone remodeling homeostasis depends heavily on the dynamic ratio of RANKL to OPG[92,93]. Under hyperglycemic pathological conditions, expression of RANKL (the osteoclast-promoting factor) secreted by osteoblasts and osteocytes is upregulated, while secretion of OPG (the osteoclast-inhibiting decoy receptor) is markedly reduced, leading to a pathologically elevated RANKL/OPG ratio[94,95]. This imbalance activates RANK receptors on osteoclast precursors, triggering downstream signaling cascades that strongly induce osteoclast recruitment, fusion, and functional activation[96,97]. This glucose-mediated “pro-resorptive” state disrupts the finely tuned balance of bone remodeling, causing excessive erosion of bone microarchitecture and increased porosity, and is a key dynamic driver of increased bone fragility and accelerated bone loss in patients with diabetes[98-100].

BMP/Smad

The BMP/Smad pathway is a potent driving system for inducing osteogenesis and promoting bone repair[101,102]. A high-glucose environment interferes with the binding efficiency of BMPs (such as BMP-2, BMP-7) to their receptors and inhibits phosphorylation and nuclear translocation of downstream key transcription factors Smad1/5/8[103,104]. This signaling disruption blocks the directed differentiation of osteoprogenitor cells, preventing effective activation of key osteogenic transcription factors such as Osterix[105,106]. In addition, metabolic disturbances caused by high glucose are often accompanied by abnormal crosstalk between BMP signaling and other pathways (such as Notch), further weakening the bone tissue’s self-renewal and regenerative capacity[107-109]. This pathway suppression provides a molecular explanation for the slow callus formation and high risk of nonunion during fracture healing in patients with diabetes.

Sclerostin

Sclerostin is a potent Wnt pathway antagonist primarily secreted by osteocytes and acts as a brake in the regulation of bone metabolism[110,111]. Clinical studies show that sclerostin levels in the circulation and local bone tissue of diabetic patients are significantly elevated, which is closely related to hyperglycemia-induced oxidative stress and stimulation by AGEs[112,113]. High levels of sclerostin competitively bind LRP5/LRP6 receptors, strongly blocking osteoblastogenic signaling. More importantly, sclerostin can indirectly regulate osteoclast activity, exacerbating the negative balance of bone remodeling[114-116]. This pathologic overexpression of an osteocyte-derived inhibitory factor in a high-glucose environment is not only a core mechanism behind suppressed bone formation but also makes sclerostin a central target for antibody-based drug development against diabetic bone disease[117-119].

FOXO and Nrf2

The FOXO family and the Nrf2 pathway are intrinsic stress-defense barriers within osteocytes, responsible for initiating antioxidant responses, autophagy, and DNA repair programs to counter metabolic stress[120,121]. However, under sustained oxidative damage induced by hyperglycemia, these defense mechanisms often become inactivated or sluggish in their response. Reduced FOXO activity leads to diminished autophagic clearance capacity for damage, while impairment of the Nrf2 pathway hinders the synthesis of antioxidant enzymes such as SOD[122,123]. This defense collapse renders osteoblasts and osteocytes extremely vulnerable to ROS attack, accelerating premature cellular senescence and apoptosis. This not only explains the comprehensive decline in repair capacity in the diabetic bone microenvironment but also underscores the potential value of activating intrinsic protective pathways to combat diabetic bone injury[124-126] (Table 1).

Table 1 The impact of different hypoglycemic drugs on bone metabolism.

Hypoglycemic/bone-targeted class	Main mechanism of action	Effects on bone metabolism	Clinical trial/clinical evidence	Clinical note (relevance to diabetic osteoporosis)
Metformin	Activates AMPK; improves insulin sensitivity; reduces hepatic glucose output	Bone formation: May support osteogenic differentiation and bone formation	Observational studies and some clinical evidence suggest potential fracture-risk reduction or neutral-to-beneficial effects, though results are heterogeneous across cohorts/trials	Widely used as first-line therapy; bone-protective potential makes it relevant for diabetic osteoporosis management
Thiazolidinediones e.g., pioglitazone, rosiglitazone	Activate PPARγ, improving insulin sensitivity but shifting marrow fate toward adipogenesis	Bone resorption: May increase osteoclastogenic signaling	Multiple clinical studies consistently show increased fracture risk, particularly in women and at specific fracture sites (e.g., distal extremities)	Effective glycemic control comes with clear skeletal risks; limits suitability in high-risk bone disease populations
Sclerostin inhibitors (e.g., romosozumab)	Block sclerostin activate Wnt/β-catenin signaling enhance osteoblast function	Bone formation: Strong stimulation of bone formation	Phase 3 trials (e.g., FRAME/ARCH/BRIDGE) show significant increases in bone mineral density and reductions in vertebral and non-vertebral fractures. FDA-approved for osteoporosis in patients at high fracture risk	Potentially attractive for diabetic osteoporosis because of potent anabolic effects; cardiovascular risk stratification is important
GLP-1 receptor agonists	Activate GLP-1 receptor; glucose-dependent insulin secretion; reduce glucagon; slow gastric emptying	Bone formation: May enhance osteogenic signaling in some contexts	Clinical data remain more limited than for osteoporosis drugs; available evidence does not clearly indicate increased fracture risk, and some studies suggest possible bone benefits	Often chosen in diabetes patients with weight and cardiometabolic benefits; bone outcomes are still an active evidence area
SGLT2 inhibitors	Inhibit renal SGLT2 increase urinary glucose excretion	Bone formation: Net effects remain complex/uncertain	Earlier concerns (e.g., canagliflozin) suggested possible fracture risk; later evidence is more mixed and does not consistently show major harm. Further studies are needed	Strong cardio-renal advantages; bone-related outcomes require ongoing clarification in diabetic osteoporosis
		Bone resorption/mineral metabolism: Altered urinary calcium handling may affect bone remodeling, long-term effects are debated
Emerging therapies	Examples: RANKL/OPG-axis modulation, other osteoanabolic/anti-resorptive targets (e.g., novel pathway inhibitors)	Intended to restore the disequilibrium between bone formation and resorption	Mostly preclinical or early-phase clinical studies; evidence is still evolving	May broaden future treatment options once robust clinical outcome data become available

GLP-1: Glucagon-like peptide 1; SGLT2: Sodium-dependent glucose transporters 2; AMPK: Adenosine 5’-monophosphate-activated protein kinase; PPAR: Peroxisome proliferators-activated receptor; RANKL: Receptor activator of nuclear factor-kappa B ligand; OPG: Osteoprotegerin; FDA: Food and Drug Administration.

CLINICAL IMPLICATIONS AND FUTURE THERAPEUTIC TARGETS

Pathological changes in the bone microenvironment caused by diabetes have significant clinical implications and provide clear directions for future therapeutic strategies. Commonly used glucose-lowering drugs have varied effects on bone, for example, metformin, a first-line agent, has been shown to potentially improve bone metabolism to some extent by activating the adenosine 5’-monophosphate-activated protein kinase pathway and may have bone-protective effects[127,128]. By contrast, thiazolidinediones increase fracture risk because they promote differentiation of BMSCs into adipocytes and suppress osteoblast activity, so their use in diabetic patients with osteoporosis requires cautious evaluation[129,130]. Understanding the skeletal effects of these drugs helps clinicians consider patients’ bone health when formulating glycemic control regimens and achieve individualized treatment. At the same time, because of the complex pathophysiology of diabetic bone disease such as AGE accumulation, oxidative stress, and chronic inflammation single-target interventions are often of limited effectiveness[131-133]. Therefore, developing new drugs that both control blood glucose and protect bone, and evaluating the skeletal safety of existing drugs, are important current research directions.

Future therapeutic strategies will increasingly focus on directly targeting multiple pathological facets of the diabetic bone microenvironment[124,134]. To counter hyperglycemia-induced oxidative stress, antioxidants such as Nrf2 pathway activators or direct ROS scavengers are expected to protect bone cells from damage. Given the accumulation of senescent cells in diabetic bone disease, senolytics (agents that eliminate senescent cells) may promote skeletal repair by improving the bone marrow microenvironment[125,135,136]. In addition, AGEs inhibitors, such as aminoguanidine derivatives, by preventing AGE formation and crosslinking, are expected to improve the mechanical properties of the bone matrix and mitigate RAGE-mediated cellular damage[137,138]. More promisingly, developing bone-anabolic therapies particularly activators of the Wnt/β-catenin and BMP/Smad pathways, as well as sclerostin inhibitors could directly enhance osteoblast activity and osteogenic differentiation of BMSCs[139,140]. These novel interventions aim to reverse, at the molecular level, the adverse effects of hyperglycemia on bone and provide more comprehensive skeletal health protection for patients with diabetes[141,142] (Table 2).

Table 2 Molecular pathway effects on osteoblasts/osteoclasts.

Molecular pathway/axis	Upstream trigger in hyperglycemia (DOP context)	Effects on osteoblasts/osteogenic lineage	Effects on osteoclasts/resorption	Potential therapeutic targets (examples)
AGEs-RAGE axis	Non-enzymatic glycation of bone ECM proteins (especially type I collagen) AGEs accumulation; AGEs binding to RAGE	Impairs proliferation, differentiation, mineralization; promotes apoptosis/senescence through stress signaling	Enhances pro-resorptive inflammatory milieu that favors osteoclast activity; may indirectly upregulate osteoclastogenesis	AGE formation inhibitors; RAGE antagonists or soluble RAGE; agents reducing AGE-protein crosslinking; downstream anti-inflammatory modulation
NF-κB driven inflammatory signaling	ROS/AGEs stimulate inflammatory cascades in bone microenvironment	Inhibits osteoblast differentiation and function; accelerates apoptosis via inflammatory signals	Promotes osteoclastogenesis and survival via inflammatory cytokines	NF-κB pathway inhibitors; cytokine/immune modulators (e.g., TNF-α/IL-1β/IL-6 axis)
Oxidative stress/ROS mitochondria dysfunction (general)	High glucose mitochondrial ETC dysfunction + autoxidation excess ROS; reduced endogenous antioxidant defenses	Cellular damage leads to impaired anabolic programs and energy depletion; increases susceptibility to ROS and apoptosis	ROS supports osteoclast differentiation/function (osteoclast activity rises under oxidative/inflammatory conditions)	Antioxidants; Nrf2 activators; mitochondrial protective strategies; ROS scavengers
FOXO-Nrf2 intrinsic stress-defense network	Sustained oxidative damage under hyperglycemia weakens stress-response programs	Reduced FOXO activity (decrease) autophagic clearance; impaired Nrf2 (decrease) antioxidant enzyme synthesis (e.g., SOD) osteoblast/osteocyte vulnerability	Indirectly supports a higher-resorption phenotype by maintaining high oxidative/inflammatory stress	Activate FOXO/Nrf2 pathways; enhance antioxidant enzyme capacity; autophagy-restoring interventions
Wnt/β-catenin pathway	Oxidative stress/AGEs induce endogenous antagonists (e.g., Dkk1, sclerostin) β-catenin phosphorylation/degradation	Inhibits nuclear translocation of β-catenin downregulation of osteogenic targets (e.g., Runx2); suppresses osteoblast activity and mineralization	Reduced osteogenic signaling may exacerbate remodeling imbalance; osteoclast activity can be indirectly favored	Sclerostin inhibition (e.g., romosozumab); Wnt pathway agonism; block Wnt antagonists (e.g., Dkk1-related strategies)
RANKL/OPG axis	Hyperglycemia alters osteoblast/osteocyte secretion: RANKL (increase), OPG (decrease) elevated RANKL/OPG ratio	Osteogenesis impaired in parallel with inflammatory/oxidative stress, disrupting coupling	Directly promotes osteoclast recruitment, fusion, and activation through RANK receptor signaling	RANKL/RANK blockade strategies; restore OPG-like decoy function; pathway modulation to normalize RANKL/OPG balance
BMP/Smad pathway	High glucose interferes with BMP ligand–receptor binding; disrupts phosphorylation and nuclear translocation of Smad1/5/8	Blocks directed differentiation of osteoprogenitors; prevents activation of osteogenic transcription factors (e.g., Osterix)	Indirectly contributes to altered remodeling balance (weaker bone formation coupled with persistent resorption)	Restore BMP signaling efficiency; target upstream regulators interfering with BMP receptor/Smad activation; osteoanabolic BMP-pathway modulation
Mitochondrial dysfunction and metabolic rewiring (OXPHOS glycolysis)	High glucose damages mitochondrial ETC ATP production inefficiency; energy stress	ATP deficiency compromises energy-dependent anabolic processes; metabolic shift to glycolysis reduces efficiency and promotes lactate/acidification	Metabolic/inflammatory changes in niche favor pro-resorptive remodeling environment	Mitochondria/energy-restoration therapies; metabolic modulators improving OXPHOS efficiency; microenvironment pH/energy-supportive strategies
Osteoimmunology-coupled inflammation (cytokine-driven remodeling)	Hyperglycemia-evoked oxidative stress/AGEs activate immune and non-immune cells in marrow	Inflammatory milieu inhibits osteoblast proliferation/differentiation and promotes apoptosis	Cytokine-driven signaling strongly promotes osteoclastogenesis via RANKL-related mechanisms	Immune modulation; cytokine targeting; integrated multi-pathway anti-inflammatory regimens
Senescence/autophagy apoptosis imbalance	High glucose suppresses autophagy and accelerates apoptosis/senescence in bone cells	Loss of survival/repair capacity; impaired regenerative signaling and osteogenic competence	Osteoclastogenic remodeling environment worsens as niche health declines	Senolytics; autophagy-enhancing agents; anti-apoptotic/repair-supportive approaches
Type H vessels/angiogenesis-osteogenesis coupling (endothelial metabolic dysregulation)	Hyperglycemia-induced endothelial metabolic dysregulation damages angiogenesis	Reduced vessel support weakens nutrient/oxygen delivery and osteogenic signaling in the niche	Indirectly promotes remodeling imbalance by impairing microvascular supply supporting coupling	Target endothelial metabolic dysfunction; promote H-type vessel formation; restore vessel–bone coupling

DOP: Diabetic osteoporosis; AGEs: Advanced glycation end products; RAGE: Receptor for advanced glycation end products; NF-κB: Nuclear factor kappa-B; ROS: Reactive oxygen species; BMPs: Bone morphogenetic protein; RANKL: Receptor activator of nuclear factor-kappa B ligand; OPG: Osteoprotegerin; OXPHOS: Oxidative phosphorylation; ETC: Electron transport chain; ATP: Adenosine triphosphate; ECM: Extracellular matrix; Dkk1: Dickkopf-related protein 1; SOD: Superoxide dismutase; RANK: Receptor activator of nuclear factor-kappa B; TNF: Tumor necrosis factor; IL: Interleukin; pH: Potential of hydrogen.

CONCLUSION

In summary, this review systematically examines the multidimensional remodeling effects of hyperglycemia on the bone microenvironment. Hyperglycemia is not merely a metabolic abnormality; through AGEs accumulation causing matrix embrittlement, ROS-induced cellular damage, chronic inflammation-driven osteoclastic activity, and mitochondrial dysfunction-induced metabolic reprogramming, it transforms the healthy bone niche into a pathological “diabetic bone niche.” This process profoundly alters core signaling axes such as Wnt/β-catenin, RANKL/OPG, and BMP, ultimately producing a severe imbalance of suppressed bone formation and enhanced bone resorption. By systematically collating these cellular and molecular alterations, we reveal the core logic behind increased bone fragility in diabetic patients and provide a panoramic theoretical framework for understanding this insidious complication. Although significant progress has been made in understanding the molecular pathology of diabetic bone disease, clinical practice still faces many challenges in fracture risk assessment and effective interventions for diabetic patients. Common bone density measurements currently have limited accuracy in predicting fracture risk in hyperglycemic patients, because diabetes-related bone fragility is not merely reflected by reduced bone mass but, more importantly, by marked deterioration in bone quality, including disruption of bone microarchitecture, loss of bone matrix toughness, and microcirculatory abnormalities. At present, we still lack clinical assessment tools with both high specificity and sensitivity to precisely identify high-risk patients with diabetes-specific bone fragility features. Meanwhile, comprehensive long-term data on the effects of marketed glucose-lowering drugs on the skeleton remain incomplete, and differences in skeletal safety across diabetes types, disease durations, and comorbidity backgrounds are not yet clear. Additionally, it should be noted that a substantial proportion of the current evidence base derives from Asian populations, which may limit the generalizability of findings to other ethnic groups with potentially different genetic backgrounds and metabolic phenotypes. Future research should prioritize diverse global cohorts to ensure the universality of therapeutic recommendations. Therefore, how to effectively translate cutting-edge molecular mechanism research into clinical diagnostic and therapeutic strategies remains an urgent problem. Looking ahead, research should shift from isolated exploration of single pathways to multidimensional systems biology analyses. By integrating transcriptomics, metabolomics, and single-cell sequencing technologies, we can deeply probe the metabolic crosstalk and signaling communication networks among different cell populations in the bone marrow microenvironment under high-glucose conditions (such as immune cells, endothelial cells, and osteogenic lineage cells). Particularly in frontier fields like osteoimmunology and type H vessels, we should explore how precise modulation of the immune microenvironment or remodeling of vessel-osteogenesis coupling can repair the damaged bone niche. In addition, developing novel bone-targeted drug delivery systems such as agents that clear AGEs, senolytics (senescent cell-clearing agents), or new bone anabolic metabolic promoters—will provide more precise molecular tools to reverse diabetic bone disease. With continued deepening of our understanding of the molecular mechanisms of diabetic bone disease and the integrated application of advanced technologies such as biomedical engineering and artificial intelligence, we can look forward to a new era of diabetic skeletal health management. By constructing multidimensional, multi-omics bone health risk assessment models that combine genomics, proteomics, and metabolomics data, truly individualized precision medicine can be achieved. At the same time, based on profound insights into hyperglycemia-induced remodeling of the bone microenvironment, multi-target combined therapeutic strategies that target AGE clearance, oxidative stress inhibition, inflammation modulation, and bone formation promotion will become mainstream. The ultimate goal is not only to effectively control blood glucose but also to comprehensively preserve and restore bone quality and function in diabetic patients, significantly reduce their fracture risk, and thereby greatly improve their quality of life and healthy life expectancy.