DFUs are open wounds that occur in individuals with type 1 or type 2 diabetes, commonly in the setting of peripheral neuropathy, poor glycemic control and PAD (26). These ulcers represent one of the most frequent and severe complications of diabetes, affecting ~1/3 of patients during their lifetime. Globally, ~18.6 million individuals are affected each year including ~1.6 million cases in the United States and~50% of DFUs become infected, with ~20% of infected cases progressing to partial or total foot amputation (27).

The development of DFUs is driven by factors such as neuropathy, vascular insufficiency, trauma and impaired immunity (28). Neuropathy contributes to sensory loss and abnormal foot mechanics, increasing ulcer risk (29) and affects ~60% of diabetic patients (8). Vascular disease further impairs circulation and delays healing (30). Foot deformities and visual impairment, particularly in older adults, elevate the likelihood of unnoticed injuries (31). These risks are exacerbated by hyperglycemia and prolonged diabetes duration (32). In this setting, chronic hyperglycemia serves as the upstream metabolic abnormality linking vascular dysfunction and immune dysregulation in the diabetic wound microenvironment (33-35).

Chronic hyperglycemia activates alternative metabolic pathways, such as the polyol and hexosamine pathways, which contribute to the overproduction of reactive oxygen species and the formation of AGE products, both of which are key mediators of cellular damage in diabetes (36). AGEs accumulate in hyperglycemic environments through non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids (37). These AGEs exert their pathological effects primarily through interaction with the receptor for AGE (RAGE), a multiligand pattern recognition receptor expressed on endothelial cells, macrophages and fibroblasts (38). Binding of AGEs to RAGE triggers intracellular signaling cascades, including NF-κB, MAPK and JAK/STAT pathways (39,40). These cascades upregulate pro-inflammatory cytokines such as TNF-α and IL-6, promote oxidative stress via NADPH oxidase activation and suppress reparative cell behaviors (41-43).

Metabolic injury then converges with vascular and immune dysfunction. In chronic wounds such as DFUs, persistent inflammatory signaling impairs fibroblast migration, disrupts ECM turnover and compromises angiogenesis (44). At the same time, AGE-related redox imbalance and inflammatory activation sustain chronic inflammation and oxidative stress (45,46), while diabetic wound healing is further impaired through AGE-RAGE-associated mechanisms (40,47). Rather than acting sequentially, these metabolic, vascular and immune abnormalities reinforce one another: Metabolic stress damages endothelial and stromal function, vascular insufficiency worsens tissue hypoxia and repair failure, and chronic inflammation further compromises microvascular integrity and tissue regeneration. Together, these processes create a wound environment that predisposes to ulceration and delays healing (Fig. 1).

Bone involvement in DFUs is frequently overlooked, yet it plays an important role in maintaining the structural integrity of the foot and supporting the regenerative processes of the wound bed. In individuals with diabetes, both metabolic and mechanical factors compromise the bone-soft tissue unit, creating an environment that fosters chronic wound formation and hinders effective healing (48,49).

Cortical thinning in DFU is a key pathological feature driven by a complex interplay of metabolic, neurological and vascular factors (50). Hyperglycemia negatively affects bone health by impairing the function of osteoblasts and osteocytes, the primary cells involved in bone formation and maintenance (51). This metabolic disturbance disrupts normal bone metabolism by decreasing the production of ECM components and hindering mineralization (52). Beyond reducing bone formation and increasing fragility, it accelerates the apoptosis and senescence of osteoblasts, further contributing to bone loss (53). By perturbing the delicate balance between bone-forming osteoblasts and bone-resorbing osteoclasts, diabetes impairs bone remodeling and contributes to cortical bone thinning and reduced bone mineral density (54).

Araújo et al (52) demonstrated that high-glucose conditions substantially disrupt the bone ECM. Specifically, glucose exposure promotes increased collagen deposition but results in a disorganized fibril structure and deficient collagen crosslinking. This structural deterioration yields a more brittle, less resilient matrix, ultimately compromising mechanical strength and increasing fracture risk (52). Bone quality is heavily dependent on collagen crosslinking, which occurs via enzymatic lysyl oxidase pathways or non-enzymatic processes that generate AGEs. For instance, the AGE pentosidine is a known marker of increased fracture risk in elderly patients with type 2 diabetes (55). Although AGEs typically interfere with primary mineralization, a positive association has also been reported between collagen crosslink ratios and mineral layer thickness in trabecular bone (56). Furthermore, excessive non-enzymatic crosslinking impairs cancellous bone quality in osteoporotic patients, independent of mineral content (57). Collectively, these findings suggest that abnormal collagen crosslinking, particularly in the setting of AGE accumulation, weakens the structural integrity of the bone matrix and contributes to bone fragility.

Neuropathy, a prevalent complication in DFU, further exacerbates cortical thinning (58). These sensory and motor deficits lead to abnormal mechanical loading of the foot, driven by altered gait mechanics and loss of protective sensation, which ultimately impairs bone remodeling responses (59). Beyond mechanical stress, compromised neural signaling disrupts the intricate neurovascular regulation of local blood flow and nutrient delivery, hindering the bone's ability to repair and maintain its structural integrity (60). Similarly, autonomic dysfunction can dysregulate circulatory responses, diminishing the supply of oxygen and nutrients essential for maintaining skeletal health (61).

PAD, a frequent comorbidity in DFU, substantially exacerbates cortical thinning by compromising the local blood supply (62). Reduced vascularity limits the delivery of oxygen, growth factors and nutrients essential for osteoblast function and bone matrix synthesis (63). The resulting chronic ischemia impairs bone repair processes and promotes a catabolic environment within bone, thereby accelerating cortical loss (64). Collectively, the interplay of hyperglycemia, AGEs, neuropathy and PAD creates a vicious cycle that progressively depletes cortical bone mass, increasing bone fragility and the risk of further complications in patients with DFU (Fig. 2).

Beyond impaired remodeling, diabetes perturbs the bone marrow stem/progenitor niche, reducing the availability and fitness of osteogenic progenitors. Osteogenesis is severely hindered in diabetic individuals by osteoblast dysfunction and the exhaustion of bone marrow stromal cells (BMSCs), both of which are key for bone regeneration (65). In the context of DFU, this BMSC exhaustion contributes to impaired repair and delayed wound healing (66-68), further compromising overall bone health (69). Aging further compounds this issue, driving a lineage shift whereby BMSCs preferentially differentiate into adipocytes rather than osteoblasts, a hallmark of age-related bone loss (70,71). Key to this balance are CXCL12-abundant reticular (CAR) cells, which regulate the transition between osteogenesis and adipogenesis (72). Disruptions in CAR-hematopoietic cell communication promote marrow adipogenesis through the direct conversion of CXCL12+ preadipocyte-like cells into lipid-laden marrow adipocytes (72). This suggests a cell-nonautonomous mechanism in which CXCL12-dependent physical coupling with hematopoietic cells helps prevent premature adipocytic differentiation.

The chronic inflammation, oxidative stress and compromised microenvironment surrounding the ulcer create a hostile setting for BMSCs, which are essential for bone regeneration (73). Pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IL-8, secreted by immune cells such as macrophages and neutrophils, activate inflammatory pathways such as NF-κB and MAPK, thereby promoting BMSC senescence (74-76). This impairs the ability of BMSCs to proliferate and differentiate into osteoblasts, while the upregulation of cell-cycle inhibitors p16INK4a and p21CIP1 serves as a marker of cellular aging (77). Simultaneously, oxidative stress generated by immune-cell activity produces reactive oxygen species, including O²⁻, H₂O₂, and OH^•. These reactive oxygen species damage cellular components, particularly mitochondria (78-80) and further impair BMSC function (81,82). Dysregulation of Nrf2, a key regulator of antioxidant defenses, exacerbates this oxidative damage and further limits the regenerative capacity of these cells (83).

The DFU microenvironment is further compromised by hypoxia and nutrient deprivation (3). While poor vascularization initially activates hypoxia-inducible factor-1α(HIF-1α) signaling (84,85), prolonged oxygen deficiency eventually impairs BMSC metabolism (86). These local deficits are compounded by systemic metabolic disturbances that reduce the availability of essential glucose and amino acids, depriving BMSCs of the substrates required for repair (87). Together with chronic inflammation and oxidative stress, these stressors establish a feedback loop in which BMSC exhaustion diminishes the regenerative potential of bone tissue. Consequently, bone repair becomes less efficient, further weakening the capacity of diabetic bone to support local healing. Ultimately, BMSC exhaustion in DFUs impairs bone regeneration and may increase vulnerability to further complications, including infection (Fig. 3).

Diabetic foot osteomyelitis (DFO) represents a severe complication affecting 20-68% of patients with diabetic foot ulcers, considerably increasing the risk of lower-extremity amputation (88). While neuropathy and vascular insufficiency create the general conditions for ulcer formation (89), impaired wound healing and microbial persistence, diabetes-related changes in bone may further increase susceptibility to osteomyelitis (90). Cortical bone deterioration, driven by intracortical remodeling, can thin the cortex from within through cavitation and coalescing pores, increasing cortical porosity and compromising bone strength and structural integrity (91-93). Consistent with this, regions with lower cortical thickness and higher cortical porosity represent structurally and mechanically weaker sites within bone (94). In parallel, marrow stromal dysfunction may impair the local supportive capacity of the marrow microenvironment (95-98). In this context, BMSC exhaustion/senescence is associated with impaired self-renewal and reduced osteogenic differentiation, thereby diminishing osteogenic repair capacity (99). Once DFU extends into deep soft tissue adjacent to bone (100), these bone-specific abnormalities may leave the subjacent bone less able to withstand and recover from contiguous bacterial insult, thereby facilitating progression to established infection (100).

The progression from superficial ulceration to bone infection follows a predictable cascade driven by the unique pathophysiological environment of the diabetic foot. Superficial DFUs typically begin as neuropathic ulcerations that, when left untreated or inadequately managed, provide a direct pathway for bacterial invasion (101). Loss of protective sensation due to peripheral neuropathy allows repetitive microtrauma to go unnoticed, while impaired immune function and chronic hyperglycemia create conditions favorable for bacterial proliferation and biofilm formation (3).

Bacteria penetrate compromised soft tissues, initially colonizing the wound bed before extending into subcutaneous tissues and eventually reaching the underlying bone (102). This progression is accelerated by PAD, which reduces perfusion and oxygen delivery required for effective immune cell function (103). In addition, the polymicrobial nature of the majority of DFIs, commonly involving Staphylococcus aureus, Pseudomonas aeruginosa and anaerobic species, further complicates the infectious process (104,105). Once bacteria establish infection within bone tissue, they form resilient biofilms that resist both host immune responses and antibiotic penetration, leading to chronic, difficult to treat osteomyelitis (106,107). Diagnosis of DFO remains challenging because systemic inflammatory markers may be absent or minimal in diabetic patients despite severe bone infection (108). A positive probe to bone test in the setting of a chronic ulcer is highly suggestive of underlying osteomyelitis and often necessitates aggressive intervention, including surgical debridement and prolonged antimicrobial therapy, to prevent progression to major amputation (109). This progression highlights the importance of early intervention, revascularization and appropriate infection control as part of the wound healing strategy (Fig. 4). It also defines an important practical boundary for bone-origin repair, since suspected osteomyelitis should first undergo appropriate diagnostic evaluation, confirmed osteomyelitis should be treated before bone-targeted intervention is considered (102) and any subsequent reconstruction should follow only after infection control has been achieved (110).

Bone-origin repair, if translated into clinical practice, should be layered onto standard DFU management rather than introduced in parallel without prior optimization of vascular, infectious and mechanical factors (148,149). Current DFU management is based on systematic assessment of perfusion, infection and mechanical loading, followed by regular wound evaluation, serial debridement, appropriate moist dressings and pressure off-loading. When PAD is present, revascularization should be performed when indicated, whereas adjunctive therapies such as negative pressure wound therapy are generally considered only after standard care has been optimized and wound healing remains inadequate (149). In practical terms, revascularization and infection assessment come first: Ischemic or neuro-ischemic ulcers should undergo prompt vascular evaluation and revascularization when indicated before elective bone-targeted stimulation is considered (150,151), while clinically uninfected ulcers should not receive antibiotics solely to promote healing and suspected or confirmed infection should undergo guideline-based antimicrobial and, when necessary, surgical management before any bone procedure is contemplated (152,153). Local wound care should continue throughout, including regular inspection, debridement and appropriate dressings; negative pressure wound therapy may be considered mainly for post-operative wounds or selected cases, but not as a substitute for infection control or vascular optimization (154). Mechanical protection also remains essential, with ongoing off-loading or protected weight-bearing determined by ulcer location, foot stability and procedural extent; any progression in loading after a bone-targeted intervention should be individualized and deferred until both soft-tissue and structural conditions are clinically stable (155,156).

Following a controlled cortical or subcortical injury, callus formation proceeds through overlapping phases of inflammation, soft callus formation, hard callus maturation and remodeling. Each phase is defined by a characteristic 'cellular cast' (159). Early on, platelets and neutrophils dominate the hematoma, providing hemostasis and releasing a first wave of chemokines and growth factors. Monocytes subsequently differentiate into macrophages, which are key regulators of the switch from inflammation to repair (160); their phenotype transitions from predominantly pro-inflammatory to pro-reparative as healing progresses and that disruption of this switch leads to delayed or abnormal callus formation (160,161).

Mesenchymal stromal cells (MSCs) are recruited from periosteum, endosteum and bone marrow and migrate into the hematoma, where they proliferate and differentiate along chondrogenic and osteogenic lineages (128). After the early inflammatory events, fracture repair progresses into the soft-callus stage (162). This stage usually begins a few days following the fracture. During this time, MSCs migrate to the injury site and differentiate into chondrocytes and osteoblasts. These newly formed cells generate a fibrocartilaginous callus, which plays a vital role in stabilizing the fractured bone. The soft callus functions as a temporary support structure, connecting the broken bone fragments and creating a foundation for subsequent bone repair (163). As the healing process advances, the soft callus is slowly converted into a hard callus during the stage referred to as hard callus formation (Fig. 5) (164). During this stage, osteoblasts deposit osteoid, which subsequently mineralizes to create a woven bone scaffold. At the same time, osteoclasts resorb both cartilage and immature bone, contributing to callus remodeling and restoration of normal bone architecture (163).

The developing callus becomes highly vascularized, with endothelial cells and pericytes working together to form and stabilize new blood vessels. Recent studies have also identified a specialized subset of endothelial cells, known as 'type H' cells, which are associated with osteoprogenitor cells and may serve as key regulators of angiocrine signaling during bone repair (165,166). In addition to these classical bone and vascular cells, immune cell subsets, including macrophages, T cells and innate lymphoid populations, contribute to callus quality (167). Macrophages play pivotal roles throughout healing, with M1 macrophages dominating early inflammation and M2 macrophages promoting resolution and osteogenesis (168). Osteoimmunology studies indicate that macrophages regulate both osteoblast and osteoclast activity throughout bone repair, and that sustained pro-inflammatory macrophage phenotypes or defective efferocytosis can impair callus maturation (161,167,169). These osteal macrophages are located adjacent to osteoblasts and regulate bone formation through efferocytosis and paracrine signaling (170). Taken together, these observations suggest that immune and stromal cell behavior is likely to be an important determinant of callus quality in any bone-targeted reparative response.

Callus formation is orchestrated by an integrated network of signaling pathways. Members of the TGF-β and bone morphogenetic protein (BMP) families are among the earliest and most prominent (171). They drive MSC recruitment, proliferation and differentiation, and regulate the balance between chondrogenesis and osteogenesis; canonical Smad-dependent TGF-β/BMP signaling is essential for normal bone repair and perturbation of these pathways has been linked to non-union and impaired callus quality (172,173).

The Wnt/β-catenin pathway is another major regulator, promoting osteoblast differentiation and maturation while suppressing excessive chondrogenesis (174). Human fracture-callus studies have shown active Wnt signaling in normally healing callus and altered Wnt activity in non-union tissue, underscoring its relevance to callus competence (175,176). Hedgehog and Notch pathways interact with both BMP/TGF-β and Wnt networks, fine-tuning progenitor cell fate and the timing of endochondral ossification. These pathways do not operate in isolation; rather, they form a densely interconnected 'signal grammar' in which changes in one pathway propagate through others, affecting cell recruitment, proliferation and differentiation (177).

The HIF-VEGF axis couples angiogenesis with osteogenesis through oxygen-sensing mechanisms. HIF-1 regulates bone homeostasis and angiogenesis by controlling VEGF expression, with the HIF-1/RANKL/Notch1 pathway bidirectionally regulating macrophage differentiation into osteoclasts under different conditions (178). VEGF serves as the master regulator of vascular development and is required for effective angiogenic-osteogenic coupling, with dose-dependent effects on mesenchymal progenitor differentiation and angiocrine functions of endothelium (179). Notch signaling exhibits stage-specific functions, with Notch1-4 receptors controlling osteoblast differentiation, matrix mineralization and osteoclast recruitment through crosstalk with Wnt/β-catenin, BMP and RANKL/OPG pathways (180).

The ECM adds a further layer of regulation: Its composition, stiffness and degree of cross-linking influence integrin signaling, mechanotransduction and the way cells interpret growth-factor cues. Glycation-related changes and altered collagen cross-linking can therefore have direct consequences for callus architecture and mechanics, beyond their effects on bone cells per se (181,182). ECM stiffness regulates MSC differentiation through mechanotransduction pathways, while glycation-induced matrix modifications alter mechanical properties and cellular interactions (183). The bone ECM guides specific tissue formation at implantation sites through osteoinductive, osteoconductive and osteogenic signals (Fig. 6) (183).

Angiogenesis and osteogenesis are tightly coupled during bone regeneration (179). Newly formed vessels are not only conduits for oxygen and nutrients but also active participants in regulating callus development through 'angiocrine' signals (184). Studies of skeletal vasculature have shown that endothelial cells can directly influence osteoprogenitor proliferation and differentiation via VEGF signaling and other paracrine factors, and that osteoblast-derived HIF-1α-VEGF activity is required to initiate and sustain this angiogenic-osteogenic cascade (63,179,185,186). Vascular-skeletal coupling represents a fundamental requirement for successful callus maturation. Type H vessels, characterized by high CD31 and Endomucin expression, possess unique ability to induce osteogenesis through factors including Platelet-derived growth factor-BB (PDGF-BB), SLIT3, HIF-1α, Notch and VEGF (184,187). PDGF-BB is one of a family member of transmembrane glycoproteins encoded by four genes A, B, C and D. These specialized capillaries support perivascular osteoprogenitor cells and thereby control bone formation, with blood vessels serving as both structural templates around which bone development occurs and conduits delivering essential minerals, growth factors and progenitor cells (179).

Within the callus, spatial organization of vessels and bone-forming cells is non-random (179). VEGF produced by inflammatory cells, MSCs, osteoblasts and hypertrophic chondrocytes promotes endothelial proliferation and sprouting, while reciprocal signals from endothelial cells enhance osteoblast and osteoclast activity (188). Osteoblast-derived VEGF plays key roles at multiple fracture healing stages, promoting macrophage recruitment and angiogenic responses during inflammation, coupling angiogenesis with osteogenesis in areas of intramembranous ossification and stimulating blood vessels and osteoclasts for cartilage resorption during endochondral ossification (189). The intimate bidirectional communication between endothelial cells and bone cells involves angiocrine functions where endothelium regulates osteoprogenitors, while immune cells recruited by the vascular microenvironment modulate both angiogenesis and osteogenesis (190).

Pericytes serve dual functions as vascular stabilizers and osteoprogenitor reservoirs. Bone-specific microvascular pericytes, tightly affiliated with capillaries, exhibit multilineage potential and constitute the cellular reserve for bone formation, remodeling and repair (191). Coupling factors and exosomal microRNAs mediate crosstalk between osteoclasts, osteoblasts, vessel-specific endothelial cells and perivascular pericytes, playing central roles in angiogenesis-osteogenesis coupling essential for bone remodeling (192). Perfusion geometry within the callus determines nutrient delivery and waste removal, with adequacy of vascular supply being critically dependent on successful angiogenesis, as fracture healing can be prevented by inhibiting angiogenesis (193).

In bone-origin repair applied beneath DFUs, the interaction between angiogenesis and osteogenesis is a factor to be taken into account. The hope is that a localized callus response can augment perfusion in an otherwise ischemic, microangiopathic environment. However, it is equally plausible that, in advanced diabetic microvascular disease, the ability of bone to mount an effective angiogenic response is constrained, leading to under-perfused or fibrotic callus (194). The balance between these two outcomes likely depends on the degree of vascular compromise and the integrity of HIF-VEGF signaling in diabetic bone (Fig. 7) (34,195).

Diabetes mellitus exerts multifactorial effects on bone regeneration, and these are expected to shape any callus induced by bone-origin repair under a DFU (196,197). Hyperglycemia, AGE accumulation, oxidative stress, low-grade inflammation and vascular damage converge to impair osteoblast differentiation, increase osteoclast activity and alter the function of osteocytes and MSCs (181,196,198). AGEs alter matrix mechanical properties, disrupt molecular conformation, impair enzyme activity and interfere with receptor functioning (199,200). Through interaction with RAGE, these molecules trigger pro-inflammatory signaling and oxidative stress that fundamentally derails normal callus kinetics (201). MSCs exposed to hyperglycemic or AGE-rich environments show impaired proliferation and osteogenic differentiation, increased adipogenic drift and enhanced senescence, while osteoblasts exhibit reduced matrix production and increased susceptibility to apoptosis (182,202).

On the immune side, diabetes alters macrophage plasticity, prolonging pro-inflammatory phenotypes and delaying the transition toward pro-reparative subsets (203). In bone, this can translate into a prolonged inflammatory phase within the callus, with excessive production of reactive oxygen species and pro-inflammatory cytokines that interfere with osteoblast and chondrocyte function (204). Aged and diabetic macrophages show increased sensitivity to inflammatory signals, and failure of M1-to-M2 repolarization leads to persistent inflammation, increased osteoclast activation and decreased osteoblast formation (168). Proper macrophage polarization is essential for successful bone healing, as M2 macrophages promote tissue regeneration while prolonged M1 dominance inhibits repair (205). Microangiopathy compounds these cellular defects by reducing perfusion to fracture sites, with decreased blood supply increasing impaired healing incidence from 10 to 15 to 46% (206). The diabetic microenvironment exhibits reduced VEGF responsiveness, impaired endothelial function and diminished Type H vessel abundance (207).

To facilitate future research design and clinical trial endpoint selection, studies of callus biology in diabetic bone repair should incorporate quantifiable measures across structural, vascular, histologic and circulating domains (208-210). Structural evaluation may include longitudinal CT or micro-CT to quantify callus volume and mineral density (211,212), thereby characterizing the three-dimensional composition and maturation of the regenerative unit. Vascular assessment may include serial local perfusion measurements using laser Doppler-based methods or angiographic techniques to track angiogenic recovery (213). Where tissue-level analysis is feasible, quantification of CD31^hi/Emcn^hi type-H vessels may provide a useful marker of angiogenic-osteogenic coupling (187,214-216). In parallel, serial measurement of PDGF-BB and other candidate osteokines may help characterize temporal circulating response patterns (214,217). At present, such circulating profiles should be interpreted as exploratory biomarkers rather than validated surrogate endpoints.

The recognition of bone as an endocrine organ has fundamentally reshaped the understanding of skeletal biology beyond its traditional structural and mineral storage functions (15,218). Bone cells, osteoblasts, osteocytes and osteoclasts, secrete a constellation of bioactive molecules termed 'osteokines' that exert systemic effects on distant organs through endocrine, paracrine and autocrine mechanisms (222). These bone-derived factors represent key mediators associating skeletal metabolism to wound healing, with particular relevance in the diabetic context where both systems are profoundly dysregulated (222).

OCN, the primary non-collagenous protein in the bone matrix, exists in two major forms with distinct biological associations: The carboxylated form, which facilitates mineralization and the undercarboxylated (ucOCN) form (15), which has been implicated in systemic metabolic regulation (223). While experimental murine models indicate that ucOCN can potently stimulate insulin secretion and peripheral sensitivity (19,224), its endocrine role in humans remains a subject of ongoing debate (225-228). Human clinical data generally show an inverse association between circulating OCN and glycemic indices, such as HbA1c and fasting glucose, but these associations are not uniform and often do not establish ucOCN as a definitive causal mediator (223,226). This clinical discrepancy is illustrated by reports of patients with type 2 diabetes exhibiting lower circulating OCN levels than healthy controls (7.07±3.80 ng/mlvs. 20.41±13.50 ng/ml), alongside inverse associations with glycemic markers (223). Consequently, in the context of DFU pathogenesis, OCN is best interpreted as a plausible metabolic mediator whose reduction in diabetes may reflect altered bone-endocrine function, rather than a fully validated driver of soft-tissue repair.

Sclerostin, encoded by the SOST gene and predominantly secreted by osteocytes, is a potent inhibitor of canonical Wnt/β-catenin signaling (15). By binding to LRP5/6 co-receptors on osteoblasts, it suppresses bone formation, shifting the remodeling balance toward an anti-anabolic state (229).

Beyond these local skeletal effects, circulating sclerostin has been associated with metabolic dysfunction; however, its role as a systemic endocrine mediator remains less clearly defined than its established paracrine action in bone (230). While elevated sclerostin levels in diabetes may contribute to a compromised bone environment (231), direct evidence associating sclerostin to DFU healing remains limited (232,233). Pharmacological inhibition of sclerostin is under clinical investigation, with monoclonal antibodies, including romosozumab, blosozumab, and BPS804 (setrusumab), being explored for their potent anabolic effects (234-237).

FGF-23, produced by osteoblasts and osteocytes, represents a bone-derived endocrine factor that regulates phosphate metabolism primarily through renal actions (238). FGF-23 targets the kidney's proximal tubule, the parathyroid gland and the cardiovascular system; while its primary role is phosphate homeostasis, it has also been implicated in inflammatory and vascular pathways relevant to tissue repair (239,240). In diabetes, however, interpretation of circulating FGF-23 is complicated by the frequent coexistence of chronic kidney disease (CKD), making it difficult to distinguish direct endocrine effects from CKD-related biomarker elevation (15,241-244). Thus, FGF-23 is better interpreted as a context-dependent systemic biomarker rather than an established causal mediator of DFU repair.

By contrast, the RANKL/OPG axis constitutes a fundamental regulatory system linking bone remodeling with immune activation (245). The RANKL/OPG ratio, regulated by osteoblasts and osteocytes, influences immune cell subsets (for example, T cells and dendritic cells) and endothelial cells, contributing to osteoimmune crosstalk within the wound microenvironment. In diabetes, this ratio is elevated, promoting excessive osteoclastogenesis and inflammatory cytokine production (246-249). While RANKL-neutralizing antibodies (for example, denosumab) represent potential strategies to rebalance this signaling, their relevance to DFU remains unproven (250,251). Therapeutic extrapolation must remain cautious regarding potential risks, including increased infection susceptibility, suppression of necessary bone remodeling and impaired skeletal adaptation in the biomechanically complex diabetic foot (252).

LCN2, secreted by osteoblasts, influences energy metabolism by suppressing appetite in the brain and has been linked to inflammatory processes (253). LCN2, can bind bacterial siderophores and has been implicated in matrix degradation; subtly altered LCN2 signaling might therefore affect the protease-antiprotease balance and ECM turnover within chronic DFUs, although this remains speculative.

LCN2 also known as neutrophil gelatinase-associated lipocalin, is secreted by osteoblasts (253-255), and various immune cell types (256,257), and has been implicated in energy metabolism, innate immunity (256) and inflammatory signaling (253,258). In the context of bone-derived endocrine signaling, its interpretation remains highly context-dependent. While LCN2 can bind bacterial siderophores (259), and has been associated with matrix remodeling (256,259), its specific causal relevance to DFU repair is not yet established. In diabetes, current evidence suggests that circulating LCN2 levels may reflect a systemic dysmetabolic or inflammatory state rather than act as a primary driver of wound healing (256,260), particularly because its metabolic and immune effects are not consistently unidirectional. Accordingly, LCN2 is best interpreted as a context-dependent osteokine with biomarker relevance, while its direct therapeutic modulation for DFU remains under investigation (254,256,261-263).

PDGF-BB, released locally following bone injury, acts on fibroblasts, endothelial cells and pericytes (220,264). Among the osteokines discussed here, PDGF-BB is more plausibly positioned as a direct paracrine mediator than as an accompanying biomarker, because bone-injury-triggered PDGF-BB signaling is mechanistically linked to angiogenesis, fibroblast activation and improved diabetic wound repair (265,266). PDGF-BB also influences osteoclast precursor behavior, further supporting its role in coordinating reparative responses across bone-associated tissues (220,264). In the diabetic state, impaired PDGF-BB release from bone may compromise this reparative influence on distal soft tissues (220). While topical recombinant PDGF-BB is an established clinical therapy, strategies to leverage bone-derived release mechanisms or targeted delivery platforms remain of interest and should be regarded as investigational within the specific framework of bone-origin repair (267).

To further illustrate the systemic roles of bone-derived signals in diabetic wound healing, Table I summarizes the primary sources, target tissues, functional effects, diabetes-associated alterations and emerging therapeutic strategies for key osteokines implicated in this endocrine network.

The diabetic milieu fundamentally disrupts bone endocrine function, creating a pathological feedback loop wherein skeletal dysfunction exacerbates systemic metabolic derangements that further impair wound healing. Understanding these disease-specific alterations and identifying therapeutic strategies to restore beneficial bone-wound crosstalk represents a frontier in diabetic wound management. The complex interaction between bone-derived signals (osteokines) and diabetic wound healing plays a key role in the pathophysiology of DFU (7,220). Osteoblasts, osteocytes and osteoclasts secrete various osteokines, including OCN, sclerostin, FGF-23, RANKL/OPG and LCN2, which exert systemic effects on metabolism, angiogenesis and immune regulation (Fig. 8) (229,268).

Diabetes is associated with broad alterations in osteokine secretion that may influence both systemic metabolism and the local bone-wound microenvironment (223). Type 2 diabetic patients exhibit reduced circulating OCN levels, specifically the undercarboxylated form, showing substantial inverse associations with glycemic control (223,269,270). Elevated circulating sclerostin, increased FGF-23, frequently confounded by coexisting CKD, dysregulated LCN2 profiles (260,271,272) and a shifted RANKL/OPG balance (273) collectively suggest a catabolic and pro-inflammatory endocrine/paracrine milieu. Although the patterns imply that not only is the bone of the diabetic patient structurally weakened, but it is also endocrinologically abnormal, the relative contribution of each osteokine to the failure of DFU repair remains unequal and, in some cases, needs further mechanistic explanations.

Additional therapeutic considerations involve attempts to modulate OCN biology, for instance, through vitamin K supplementation to optimize carboxylation status, or interventions aimed at reducing bone marrow adiposity (274). However, within the DFU context, such strategies remain biologically plausible but clinically unvalidated, particularly given the unresolved debate surrounding the causal role of undercarboxylated OCN in human metabolic repair (275). Furthermore, while the emerging field of bone-targeted drug delivery, utilizing bisphosphonates or bone-binding peptides, may offer opportunities to localize osteoactive agents (276), its efficacy and potential unintended consequences in the diabetic foot remain insufficiently studied. Finally, the deliberate induction of controlled bone remodeling to trigger osteokine release is a provocative concept (220); its clinical translation would require strict integration with established standards of care, including infection control, vascular assessment and mechanical off-loading (277).