Diabetic Bone Disease: A Comprehensive Narrative Review of Pathophysiology, Diagnosis, and Evidence-Based Management

Abstract

Background: Diabetic bone disease affects over 537 million people with diabetes worldwide, characterized by increased fracture risk despite paradoxically normal or elevated bone mineral density (BMD) in Type 2 diabetes. This narrative review synthesizes current evidence on pathophysiology, diagnostic approaches, and management strategies. Methods: We performed a comprehensive literature search of the PubMed, Embase, and Cochrane databases (2007–2025), prioritizing systematic reviews, meta-analyses, large-scale population studies, and clinical trials examining bone health in diabetes, including bone density, quality, fracture risk, imaging techniques, biomarkers, and therapeutic interventions. Results: Advanced glycation end products fundamentally alter bone metabolism through mechanisms distinct from traditional osteoporosis. Type 1 and Type 2 diabetes produce contrasting skeletal phenotypes requiring tailored management. Recent umbrella reviews of 71 meta-analyses demonstrated skeletal benefits of metformin and GLP-1 receptor agonists, while confirming thiazolidinedione risks. Trabecular bone score enhances fracture prediction when DXA appears normal. Large-scale studies revealed heterogeneous risk patterns, with specific subgroups showing substantially elevated fracture risk. Advanced imaging revealed distinct microarchitectural changes between diabetes types. Diabetic patients experienced doubled healing complications, necessitating specialized perioperative protocols. Conclusions: Diabetic bone disease represents a distinct clinical entity requiring enhanced diagnostic strategies beyond traditional densitometry, evidence-based treatment selection considering skeletal and metabolic effects, and specialized management protocols extending beyond conventional osteoporosis care.

1. Introduction

Diabetic bone disease has emerged as a significant complication affecting the rapidly expanding global diabetes population. The International Diabetes Federation estimates 537 million adults currently live with diabetes worldwide, with projections reaching 783 million by 2045 [1]. This growing prevalence makes understanding diabetes–bone interactions increasingly critical for clinical practice.

Unlike traditional osteoporosis, diabetic bone disease presents fundamental paradoxes that challenge conventional fracture risk assessment. Patients with Type 2 diabetes (T2D) often maintain normal or elevated BMD while experiencing increased fracture risk [2,3]. This disconnect between bone quantity and quality represents one of the most perplexing diabetic complications, necessitating specialized diagnostic and therapeutic approaches beyond standard densitometric evaluation.

Recent systematic reviews and meta-analyses have provided crucial insights into bone–diabetes interactions. The 2025 systematic review by Ojo et al., examining cohort studies on T2D and bone quality, demonstrated consistent deterioration in bone material properties despite preserved densitometric measurements [3]. Similarly, Cao et al.’s 2025 meta-analysis confirmed significant associations between T2D and both osteoporosis risk and fracture incidence, despite acknowledged heterogeneity [4]. In a recent review article, the alternative term “diabetic osteopathy” was used to describe this distinct entity, characterized by impaired bone quality despite normal densitometry [5].

Large-scale population studies have revealed significant heterogeneity in fracture risk patterns. The Swedish national cohort study by Axelsson et al. of 580,000 T2D patients revealed only marginal overall fracture risk increases (hazard ratio 1.05–1.11), with diabetes explaining less than 0.1% of population fracture risk variance [6]. However, specific subgroups—particularly those with diabetes duration exceeding 10 years, insulin use, BMI below 25 kg/m², and sedentary lifestyle—demonstrated substantially elevated risk. Approximately half of T2D patients without these characteristics showed no increased fracture risk compared to the controls [6].

The pathophysiological foundations involve complex interactions between chronic hyperglycemia, advanced glycation end products (AGEs), inflammatory pathways, and altered bone cell function [7]. These mechanisms create bone tissue that appears structurally adequate by dual-energy X-ray absorptiometry (DXA) but fails under physiological loading. Recent reviews have introduced “diabetic osteopathy” to describe this distinct entity, characterized by impaired quality despite normal densitometry [5].

Clinical implications extend beyond fracture prevention to encompass surgical complications and compromised healing. Meta-analytical evidence demonstrates that diabetic patients experience doubled fracture healing complications across orthopedic procedures, with particularly concerning outcomes in diabetic foot osteomyelitis. A meta-analysis by Truong et al. reported average success rates of approximately 68% (range 17–97%) for medical treatment and 86% (range 65–99%) for the combined surgical and medical management of diabetic foot osteomyelitis. However, the authors noted substantial heterogeneity among the included studies and inconsistencies in accounting for peripheral arterial disease and neuropathy [8]. These findings underscore the systemic nature of bone quality deterioration and emphasize the need for specialized protocols.

This narrative review synthesizes current evidence regarding diabetic bone disease pathophysiology, clinical assessment, treatment strategies, surgical considerations, and emerging therapeutics. We emphasize recognizing diabetic bone disease as a distinct entity requiring specialized approaches beyond traditional osteoporosis care.

2. Pathophysiological Mechanisms of Diabetic Bone Disease

2.1. Advanced Glycation End Products and Bone Matrix Deterioration

The pathophysiological hallmark lies in progressive AGE accumulation within bone matrix through non-enzymatic glycation, fundamentally distinguishing diabetic bone pathology from traditional osteoporosis [9]. These pathological cross-links irreversibly alter collagen structure, creating increased brittleness and reduced toughness despite maintained mineralization density. This explains the central paradox: apparent structural adequacy by densitometry combined with increased mechanical failure under physiological loads.

Advanced glycation represents a complex cascade initiated by chronic hyperglycemia. Glucose molecules react non-enzymatically with amino groups in collagen, forming early glycation products that undergo oxidation and cross-linking into irreversible AGEs. The most relevant AGEs in bone include pentosidine, glucosepane, crossline, and pyrrole compounds, each affecting different collagen aspects [10]. Pentosidine, the most extensively studied marker, demonstrates direct correlations with fracture history independent of BMD, providing potential biomarker applications [11].

A recent review summarized molecular findings identifying multiple lysine–arginine cross-linking sites implicated in glucosepane formation, which may interfere with integrin binding and collagenase cleavage essential for normal bone remodeling [12]. This molecular disruption may explain, at least in part, why diabetic bone fails at higher loads than BMD predicts. Progressive accumulation creates a deteriorating matrix that cannot be adequately assessed through standard tools, highlighting the need for alternative approaches. The interconnected pathways of diabetic bone disease are illustrated in Figure 1.

Furst et al. evaluated bone material strength in Type 2 diabetes using in vivo tibial microindentation, reporting higher AGE accumulation and inverse correlations between pentosidine levels and bone material strength [13]. This provided direct evidence that AGE accumulation compromises mechanical properties independent of density, establishing clear mechanistic links between hyperglycemia and fragility.

As summarized in recent review articles, AGEs may exert deleterious effects through interconnected mechanisms beyond direct collagen modification. Binding to receptors for AGEs (RAGE) is proposed to activate inflammatory pathways involving nuclear factor-κB and the increased expression of cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 [7]. This inflammatory response suppresses osteoblast function while variably affecting osteoclasts, creating imbalanced remodeling that favors net bone loss or compromised quality despite maintained quantity.

2.2. Cellular and Molecular Mechanisms

Chronic hyperglycemia affects bone cells through multiple pathways that collectively compromise skeletal integrity. Osteoblasts demonstrate reduced proliferation, differentiation, and matrix synthesis under high glucose conditions [14]. This impairment occurs through increased oxidative stress, altered protein kinase C activation, enhanced polyol pathway activity, and dysregulated growth factor signaling. The net result is decreased bone formation capacity that may not reflect in traditional turnover markers until advanced stages.

Ma and Zhang’s comprehensive review provides detailed mechanistic insights [7]. Their analysis suggests that hyperglycemia may directly impair osteoblast function through RAGE activation, increased reactive oxygen species production, altered Wnt signaling pathways critical for bone formation, and disrupted insulin-like growth factor-1 (IGF-1) signaling. These molecular alterations collectively create a fundamentally compromised bone formation environment, even when adequate substrate and growth factors are present.

The canonical Wnt signaling pathway, critical for osteoblast function, appears significantly downregulated in T2D patients, associating with higher AGE content and reduced bone strength [15]. These findings provide mechanistic insights into the low bone turnover state characteristic of T2D and suggest potential therapeutic targets.

Ferroptosis has emerged as an important contributor to diabetic bone disease [16]. This form of regulated cell death, driven by iron accumulation and lipid peroxidation, appears to contribute significantly to osteoblast dysfunction in diabetic conditions, adding complexity to pathophysiological understanding and offering potential new therapeutic avenues.

Osteoclast function is significantly altered in diabetic conditions, though the effects are variable and context-dependent. In Type 1 diabetes, insulin deficiency and associated oxidative stress favor enhanced osteoclastogenesis through upregulated RANKL/OPG ratios and inflammatory cytokine release, leading to increased bone resorption [17]. In contrast, insulin resistance in Type 2 diabetes may initially suppress osteoclast activity before progressive dysfunction emerges with prolonged hyperglycemia. Moreover, osteocytes play a pivotal regulatory role, as diabetes-induced alterations in sclerostin and DKK1 expression further disrupt the osteoblast–osteoclast balance, aggravating bone fragility [17].

The bone marrow microenvironment may also be affected in diabetes; one study suggests a link between increased marrow adiposity and potential shifts in mesenchymal stem cell differentiation away from osteoblastic expression toward adipogenic pathways [18]. However, these findings remain limited to small-scale studies and should be interpreted with caution [18]. This occurs through peroxisome proliferator-activated receptor gamma activation, contributing to reduced bone formation capacity. Additionally, bone marrow vasculature alterations, including reduced angiogenic capacity and impaired vessel function, further compromise the bone formation microenvironment [19].

2.3. Type-Specific Pathophysiological Patterns

Bone disease pathophysiology differs markedly between Type 1 and Type 2 diabetes, reflecting distinct underlying metabolic disturbances and requiring different management approaches [17].

Table 1. Clinical characteristics comparison between Type 1 and Type 2 diabetes mellitus regarding bone health parameters.

Parameter	Type 1 Diabetes	Type 2 Diabetes
BMD Pattern	↓ All sites (5–10%)	Normal/↑ Most sites (+4–5%)
Fracture Risk	6-fold higher hip	1.2–1.4-fold higher
Age at First Fracture	40–60 years	>65 years
Bone Turnover	High turnover	Low turnover
AGEs Accumulation	Moderate-High	Very High
Primary Mechanism	Insulin deficiency	Insulin resistance + AGEs
BMI Association	Low BMI high risk	High BMI protective
Microarchitecture	Global deterioration	Cortical porosity
TBS Values	↓ 8.7% vs. controls	↓ 6.2% vs. controls
Biochemical Markers	↑ Formation, ↑Resorption	↓ Formation, ↓ Resorption
Healing Complications	High risk	Very high risk
Osteoporosis Prevalence	25.5–36% adults	Variable by age

BMD, bone mineral density; TBS, trabecular bone score; AGEs, advanced glycation end products; BMI, body mass index; ↑ increased, ↓ decreased.

provides a comprehensive comparison of clinical characteristics distinguishing bone health parameters between diabetes types.

Type 1 Diabetes Pathophysiology: Type 1 diabetes (T1D) creates a unique skeletal phenotype characterized by absolute insulin deficiency effects. Insulin functions as an important anabolic hormone for osteoblasts, promoting proliferation, differentiation, and matrix synthesis [20]. Complete absence of endogenous insulin creates a persistently catabolic environment where resorption consistently exceeds formation, leading to progressive net bone loss across all skeletal sites. This process begins early and continues throughout disease course, creating cumulative deficits in bone mass and architecture.

In their editorial in The Lancet Diabetes & Endocrinology, Napoli and Conte highlighted the emerging recognition of bone fragility as a major but underappreciated complication of Type 1 diabetes [21]. They summarized evidence from Schwartz et al. showing that poor glycemic control, accumulation of AGEs, and chronic kidney disease each independently contributed to low bone mineral density in Type 1 diabetes, suggesting that renal osteodystrophy-related mechanisms may also play a role in skeletal fragility.

Timing of T1D onset relative to skeletal development critically influences long-term outcomes. Individuals developing T1D during childhood or adolescence experience impaired peak bone mass acquisition during critical growth periods, creating lifelong disadvantages in skeletal reserve [22,23]. Starup-Linde et al.’s recent cross-sectional study of 764 adults with T1D demonstrated that osteoporosis prevalence reached 25.5% using traditional diagnostic criteria (T-score ≤ −2.5 or vertebral fracture) and 36% using the more liberal American Diabetes Association-proposed treatment threshold (T-score ≤ −2.0 or fracture) [24]. Hypoglycemic episodes contribute to increased fracture risk through multiple mechanisms including impaired counterregulatory responses, fall risk, and potential direct skeletal effects [25]. This elevated fracture risk associated with Type 1 diabetes persists across the entire lifespan from childhood through older adulthood [26], emphasizing the need for lifelong skeletal health surveillance in this population. These findings have important implications for screening and intervention timing.

Type 2 Diabetes Pathophysiology: T2D pathophysiology presents a markedly different and more paradoxical pattern. The fundamental mechanism involves insulin resistance effects, where compensatory hyperinsulinemia initially helps preserve bone formation but chronic exposure eventually leads to osteoblast dysfunction and progressive quality deterioration [27]. This biphasic response explains why T2D patients may initially show preserved or elevated BMD before developing increased fracture risk with disease progression.

The recent investigation conducted by Zoulakis et al. exemplifies this paradox [28]. Their prospective cohort of approximately 3000 elderly women (75–80 years) found that T2D participants had a 4–5% higher BMD at both spine and hip sites compared to the controls, with preserved trabecular microarchitecture. However, despite these favorable skeletal metrics, fracture incidence was higher, likely reflecting multifactorial contributions including increased fall propensity, peripheral neuropathy, sarcopenia, and impaired bone material properties not captured by standard densitometry. This combination highlights how diabetes-related alterations in bone quality and neuromuscular function jointly elevate fracture risk even when BMD appears normal or increased. Biochemical markers of bone turnover provide additional insights into diabetes-related skeletal dysfunction. Meta-analytical evidence from prospective studies reveals consistent alterations in bone turnover markers in Type 2 diabetes patients [29]. Bone formation markers, including osteocalcin and procollagen type I N-terminal propeptide (P1NP), show significant reductions, while bone resorption markers demonstrate variable changes, reflecting the complex underlying pathophysiology of suppressed bone remodeling in diabetes.

3. Clinical Assessment and Diagnostic Approaches

3.1. Limitations of Standard Bone Densitometry

Standard DXA measurement represents the current clinical standard for osteoporosis diagnosis and fracture risk assessment in general populations. However, DXA demonstrates significant limitations when applied to diabetic populations, systematically underestimating fracture risk in ways that can mislead clinical decision-making [30]. Studies consistently demonstrate that diabetes-associated fracture risk requires adjustment equivalent to adding 10 years of chronological age in traditional Fracture Risk Assessment Tool (FRAX) calculations. This systematic underestimation stems from DXA’s fundamental inability to assess bone quality parameters preferentially affected in diabetic bone disease.

Table 2. Major population-based studies examining fracture risk in diabetes mellitus (2020–2025).

Study	Population	Sample Size	Follow-Up	Fracture Risk (HR/OR, 95% CI)	Key Findings
Axelsson et al. [6]	Swedish T2D cohort	580,000	6.6 years	Overall: 1.05–1.11; Hip: 1.11	High-risk subgroups identified; DM2 explains <0.1% population risk
Zoulakis et al. [28]	Elderly women	~3000	Prospective	Increased despite higher BMD	T2D had 4–5% higher BMD but increased fracture risk
Starup-Linde et al. [24]	T1D adults	764	Cross-sectional	25.5–36% osteoporosis prevalence	Age and family history major risk factors; BMI protective
Cao et al. [4]	Meta-analysis	Multiple studies	Variable	Significant association with osteoporosis and fractures	Confirmed T2D-fracture association despite study heterogeneity
Kvist et al. [31]	Danish national cohort	T1D and T2D	1997–2017	Site-specific fracture rates	Distinct patterns between diabetes types

HR, hazard ratio; OR, odds ratio; CI, confidence interval; T1D, Type 1 diabetes; T2D, Type 2 diabetes; BMD, bone mineral density.

summarizes the major population-based studies examining fracture risk in diabetic populations, highlighting the disconnect between BMD measurements and actual fracture outcomes across different study designs.

3.2. Advanced Imaging Techniques

Trabecular Bone Score Applications: Trabecular bone score (TBS) provides an immediately implementable solution for enhanced bone quality assessment using existing lumbar spine DXA images, making it practically accessible for widespread clinical implementation without additional radiation exposure or equipment requirements [32]. The technology analyzes gray-level texture variations in DXA images to derive information about trabecular microarchitecture, providing an indirect but clinically useful measure beyond simple BMD measurements.

Clinical studies consistently demonstrate lower TBS values in diabetic patients compared to age-matched non-diabetic controls, with reductions of approximately 6.2% in T2D and 8.7% in T1D patients [33]. Bhattacharya et al.’s recent meta-analysis examining TBS in T1D adults, analyzing data from multiple studies, confirmed significantly lower TBS values while showing similar BMD measurements at total hip and lumbar spine sites compared to the controls [34]. However, the authors noted that modest TBS differences fell short of explaining the large excess fracture propensity observed in T1D patients, suggesting additional bone quality deficits beyond those detectable by current TBS technology. Beyond its established role in primary osteoporosis, TBS demonstrates particular utility in secondary osteoporosis conditions, including diabetes mellitus, where bone quality impairment may occur despite preserved bone density [35]. However, methodological considerations merit attention, as abdominal tissue thickness can influence TBS measurements, potentially affecting accuracy in populations with central adiposity—a common feature in Type 2 diabetes [36]. These technical limitations underscore the importance of complementary imaging modalities for comprehensive skeletal assessment in diabetic populations.

High-Resolution Peripheral Quantitative Computed Tomography: High-resolution peripheral quantitative computed tomography (HR-pQCT) represents the current gold standard for the non-invasive assessment of bone microarchitecture, providing detailed three-dimensional information about both cortical and trabecular bone compartments [37]. T2D patients characteristically demonstrate a mixed pattern of compartment-specific changes, with increased cortical porosity (average increase of 12.7%) while paradoxically preserving or even improving trabecular architectural parameters [38]. This finding helps explain the clinical paradox of maintained BMD with increased fracture risk, as cortical bone provides the majority of mechanical strength for long bones commonly affected by fragility fractures. Similar findings emerge from studies of Type 1 diabetes, where HR-pQCT reveals compromised bone geometry, reduced volumetric density, and deteriorated microarchitecture affecting both cortical and trabecular compartments [39]. The Framingham HR-pQCT study further confirmed these diabetes-associated deficits in cortical bone density, microarchitecture, and bone size [40], establishing the consistency of these skeletal abnormalities across different diabetic populations.

The cumulative epidemiological evidence establishes diabetes as a major risk factor for fracture across the lifespan. Meta-analytical data confirm significantly elevated fracture risk even in young and middle-aged adults with Type 1 diabetes [41], while systematic reviews in Type 2 diabetes identify multiple contributing factors including disease duration, glycemic control, and diabetic complications [42]. Importantly, Mendelian randomization studies provide causal evidence linking hyperglycemia levels directly to increased fragility fracture risk independent of other complications [43], strengthening the mechanistic rationale for optimal glycemic control in fracture prevention strategies.

3.3. Biochemical Markers and Clinical Assessment

Yang et al.’s comprehensive 2024 meta-analysis analyzing biochemical markers across 14 carefully selected observational studies revealed consistent alterations in bone turnover markers in T2D patients [29]. Bone formation markers showed significant reductions, with osteocalcin levels decreased by 15.2% and P1NP reduced by 12.8% compared to age-matched non-diabetic controls. The bone resorption marker CTX demonstrated an 18.4% reduction, indicating an overall state of suppressed bone turnover rather than the high-turnover pattern typically associated with traditional osteoporosis.

Table 3. Biochemical markers of bone metabolism in diabetes mellitus.

Marker	Diabetic Pattern	Clinical Utility	Limitations
Formation Markers
Osteocalcin	↓ 15.2% in T2D	Reflects osteoblast activity	Affected by renal function
P1NP	↓ 12.8% in T2D	Reflects collagen synthesis	Renal clearance issues
Resorption Markers
CTX	↓ 18.4% in T2D	Reflects bone resorption	Diurnal variation
Novel Markers
Pentosidine	↑ in diabetes	Bone quality assessment	Research use only
Sclerostin	Variable in diabetes	Osteocyte function	Limited diabetes data

Bold formatting indicates major marker categories (Formation Markers, Resorption Markers, Novel Markers) for improved organization and readability. P1NP, procollagen type 1 N-terminal propeptide; CTX, C-terminal telopeptide; T2D, Type 2 diabetes; ↑ increased, ↓ decreased.

summarizes the biochemical markers relevant to diabetic bone disease assessment.

Emerging technologies offer promise for enhanced fracture risk assessment in diabetic populations. Artificial intelligence algorithms demonstrate improved accuracy for prediction of osteoporotic fractures in patients with diabetes through integration of multiple clinical variables, imaging parameters, and biochemical markers [44]. Additionally, metabolomic profiling reveals specific metabolic pathways involved in diabetic osteoporosis [45], offering potential novel biomarkers for fracture risk evaluation and insights into therapeutic targets beyond traditional biochemical assessments.

3.4. Risk Stratification and Clinical Decision-Making

Table 4. Risk stratification framework for diabetic bone disease assessment.

Risk Category	Traditional Risk Factors	Diabetes-Specific Risk Factors	Recommended Assessment	Management Approach
Low Risk	Age < 65, No fracture history, Normal BMD	Diabetes duration < 5 years, HbA1c < 7%, No complications, BMI > 25 kg/m2	Basic DXA every 3–5 years; Standard FRAX	Standard diabetes care; Lifestyle interventions
Moderate Risk	Age 65–75, Osteopenia, Family history	Diabetes duration 5–10 years, HbA1c 7–8%, Mild complications	DXA + TBS every 2 years; Diabetes-adjusted FRAX	Optimize diabetes medications; Consider bone-protective agents
High Risk	Age > 75, Previous fracture, Osteoporosis	Diabetes duration >10 years, HbA1c > 8%, Insulin use, BMI < 25 kg/m2, Neuropathy	DXA + TBS annually; Advanced imaging if available; Biochemical markers	Aggressive osteoporosis treatment; Multidisciplinary care
Very High Risk	Multiple fractures, Recent fracture	Long-standing diabetes, Multiple complications, Recurrent hypoglycemia, High-risk medications	Comprehensive assessment; HR-pQCT if available; Fall risk evaluation	Immediate treatment initiation; Specialized referral

HbA1c, hemoglobin A1c; HR-pQCT, high-resolution peripheral quantitative computed tomography; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; TBS, trabecular bone score; FRAX, Fracture Risk Assessment Tool; BMI, body mass index.

provides a comprehensive risk stratification framework for diabetic patients, incorporating both traditional osteoporosis risk factors and diabetes-specific considerations.

4. Treatment Strategies and Evidence-Based Management

4.1. Diabetes Medication Effects on Bone Health

Diabetes medication selection has profound implications for skeletal health, with growing evidence demonstrating that therapeutic choices can either protect or harm bone integrity. Khashayar et al.’s 2024 umbrella systematic review represents the highest level of evidence available, analyzing 71 meta-analyses of randomized controlled trials to provide comprehensive clinical guidance [46].

Table 5. Effects of antidiabetic medications on bone health: comprehensive evidence summary.

Medication Class	Fracture Risk Effect	BMD Effect	Mechanism	Clinical Recommendation	Evidence Quality
Metformin	↓ 42% (OR 0.58, CI 0.48–0.69)	+2.1% lumbar spine	Direct osteoblast stimulation; Anti-inflammatory effects; AGE reduction	First-line choice for bone protection	High quality (71 meta-analyses)
GLP-1 Agonists	↓ 33% (OR 0.67, CI 0.55–0.82)	Favorable changes	Direct GLP-1 receptor activation on osteoblasts	Preferred option with bone benefits	High quality (Multiple RCTs)
SGLT2 Inhibitors	Generally neutral class effect *	Neutral effects	Minimal bone effects; Potential calcium effects	Safe choice; No bone concerns	Moderate quality (Initial concerns resolved)
DPP-4 Inhibitors	No significant effect	Neutral	Minimal direct bone effects	Safe alternative when others unsuitable	Moderate quality
Thiazolidinediones	↑ 94% women (HR 1.94, CI 1.75–2.15); ↑ 45% men	Negative at all sites	PPARγ activation; ↑ Marrow adipogenesis; ↓ Osteoblast function	Avoid if possible; High fracture risk	High quality (Consistent evidence)
Insulin	Variable by type and duration	Variable	Complex metabolic effects; Weight gain effects	Monitor closely; Consider bone assessment	Moderate quality
Sulfonylureas	Potential increased fracture risk	Variable	Hypoglycemia-related fall risk	Standard monitoring	Low to moderate

GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2; DPP-4, dipeptidyl peptidase-4; PPARγ, peroxisome proliferator-activated receptor gamma; OR, odds ratio; HR, hazard ratio; CI, confidence interval; BMD, bone mineral density; AGE, advanced glycation end products; RCTs, randomized controlled trials; ↑ increased, ↓ decreased. * Although SGLT2 inhibitors are generally considered to have a neutral skeletal profile, some evidence indicates that canagliflozin may transiently increase bone turnover markers and modestly elevate fracture risk in specific populations.

presents detailed clinical recommendations based on this evidence synthesis, incorporating additional recent meta-analytical evidence.

Bone-Protective Medications: Metformin has emerged as the preferred first-line antidiabetic medication from a skeletal perspective, with reports indicating modest increases in BMD and a reduced fracture risk (OR 0.58, CI 0.48–0.69) [46]. The protective effect is primarily attributed to improved glycemic control and reduced AGE accumulation, while proposed mechanisms such as direct osteoblast stimulation, enhanced angiogenesis, and anti-inflammatory effects remain largely theoretical and require further clinical validation.

GLP-1 receptor agonists represent another class with significant bone-protective properties. These agents demonstrate fracture risk reductions of 33% (OR 0.67, CI 0.55–0.82) and show favorable effects on biochemical markers of bone metabolism [46]. Zhang et al.’s recent meta-analysis specifically examining GLP-1 receptor agonists in T2D confirmed significant fracture risk reduction, with particularly pronounced effects observed with longer-acting formulations [47].

Risk-Associated Medications: Thiazolidinediones demonstrate the most concerning skeletal safety profile among diabetes medications, with consistent evidence of significant fracture risk increases across all agents in the therapeutic class [46]. The fracture risk elevation is particularly pronounced in postmenopausal women, where risk increases by 94% (HR 1.94, CI 1.75–2.15), though significant risks are also observed in men (45% increase) and younger women.

4.2. Osteoporosis-Specific Therapy Selection

Table 6. Osteoporosis therapy selection guide for diabetic patients.

Therapy Class	Efficacy in Diabetes	Diabetes-Specific Advantages	Diabetes-Specific Concerns	Clinical Recommendations
Bisphosphonates	Similar to non-diabetics: 40–50% vertebral ↓; 20–30% non-vertebral ↓	Established efficacy; Long-term safety data; Cost-effective	Renal dose adjustments needed (common in diabetes); GI intolerance with gastroparesis	Appropriate first-line with normal renal function; Monitor renal status
Denosumab	Maintained efficacy; 68% vertebral ↓; 40% hip ↓ over 10 years	No renal adjustments; Convenient dosing; Works in CKD	Infection risk (concern in diabetes); Requires adherence	Preferred option for diabetic nephropathy; Monitor for infections
Teriparatide	Similar efficacy; Theoretical advantages in low-turnover states	Anabolic mechanism; Addresses low turnover in T2D	Daily injections (burden with insulin); Cost considerations	Consider for severe osteoporosis in T2D; Sequential therapy
Romosozumab	Rapid BMD gains; +13.7% lumbar spine in 12 months	Rapid bone formation; Good for low turnover	CV risk assessment required (high CV risk in diabetes)	Carefully selected patients without CV contraindications
Raloxifene	Modest vertebral protection only	Potential CV benefits; Breast cancer protection	Hot flashes; VTE risk	Limited use; Consider in selected postmenopausal women

CKD, chronic kidney disease; CV, cardiovascular; VTE, venous thromboembolism; T2D, Type 2 diabetes; GI, gastrointestinal; ↓ decreased, + increased.

provides comprehensive guidance for osteoporosis therapy selection in diabetic populations. Medication selection requires careful consideration of diabetes-specific factors. Thiazolidinediones’ skeletal effects through PPAR-gamma activation necessitate risk-benefit assessment in patients requiring both glucose and bone health management [48]. Systematic reviews evaluating anti-osteoporotic medication efficacy specifically in diabetic populations [49] and comprehensive analyses of various antihyperglycemic agents’ skeletal effects [50] inform evidence-based therapeutic decision-making in this complex patient population.

Denosumab Advantages: Denosumab has emerged as a preferred osteoporosis therapy for many diabetic patients due to several diabetes-specific advantages. The subcutaneous administration route every six months facilitates adherence in patients managing complex diabetes care regimens, while the absence of renal dose adjustment requirements makes it particularly suitable for diabetic nephropathy patients [51]. In comparison, bisphosphonates require careful renal function monitoring and dose adjustments in diabetic nephropathy patients [52], making denosumab an attractive alternative in this high-risk population. The FREEDOM trial 10-year extension data demonstrate maintained efficacy with 68% vertebral fracture risk reductions [53]. Beyond its skeletal efficacy, denosumab may also exert favorable metabolic effects through RANKL inhibition, which reduces systemic inflammation and improves insulin sensitivity.

Treatment persistence and sequential therapy considerations merit attention in diabetic populations. Following bisphosphonate discontinuation, fracture rates may increase [54], necessitating careful monitoring and potential transition to alternative therapies. Anabolic agents such as romosozumab demonstrate superior efficacy compared to bisphosphonates in appropriate candidates [55], offering valuable options for patients with severe osteoporosis. Importantly, diabetes status may modify antiresorptive treatment benefits [56], emphasizing the need for individualized therapeutic approaches that account for diabetes-specific skeletal characteristics and comorbidities.

5. Surgical Considerations and Perioperative Management

5.1. Fracture Healing Complications

Diabetic patients face substantially compromised surgical outcomes across all orthopedic procedures, with meta-analytical evidence demonstrating overall impaired fracture healing with significant increases in complication rates compared to non-diabetic patients [57,58,59]. Beyond fracture healing challenges, diabetes significantly increases the risk of major complications following hip fracture surgery. Systematic reviews demonstrate elevated rates of surgical site infections, medical complications, prolonged hospitalization, and increased mortality in diabetic patients undergoing hip fracture repair [60]. These findings underscore the importance of comprehensive perioperative optimization and multidisciplinary care coordination in this high-risk population.

Table 7. Orthopedic surgical outcomes and risk mitigation strategies in diabetes mellitus.

Procedure Type	Complication Rate	Specific Risks	Risk Mitigation Strategies	Expected Outcomes
Hip Fracture	2.5–3.0× higher	Infection (3× risk); Delayed union; Hardware failure	Prophylactic antibiotics; Extended duration; Glycemic optimization	Longer rehabilitation; Higher mortality
Ankle Fracture	2.8× higher	Wound dehiscence; Malunion; Charcot arthropathy	Careful soft tissue handling; Extended immobilization; Gradual weight-bearing	Functional limitations common
Spine Surgery	1.8–2.2× higher	Deep infection; Pseudoarthrosis; Adjacent level disease	Multilevel fusion; Bone graft enhancement; Postoperative bracing	Higher revision rates
Total Joint	1.5–2.0× higher	Prosthetic infection; Loosening; Dislocation	Antibiotic cement; Extended prophylaxis; Careful positioning	Good long-term function with precautions
Foot/Ankle	3.5–4.0× higher	Osteomyelitis; Amputation; Wound complications	Aggressive debridement; Vascular assessment; Multidisciplinary care	High amputation risk without optimal care

Note: Risk ratios compared to non-diabetic patients. Complication rates based on recent meta-analytical evidence. The perioperative risk mitigation strategies summarized here are proposed or suggested based on the current literature and clinical experience. They may not represent universally accepted standards of care and should be applied considering patient-specific factors and institutional protocols.

summarizes specific surgical risks and complications observed in different orthopedic procedures in diabetic patients, along with evidence-based strategies for risk mitigation.

5.2. Diabetic Foot Osteomyelitis

Truong et al.’s 2022 meta-analysis summarized outcomes from heterogeneous studies on diabetic foot osteomyelitis, reporting mean success rates of approximately 68% for antibiotic-only treatment and 86% for combined surgical and medical management [8]. These findings should be interpreted with caution given the variability in diagnostic criteria and comorbidity adjustment. In small bones of the foot, acute osteomyelitis typically involves active infection and inflammatory bone changes, whereas chronic disease is characterized by necrotic sequestra and poor vascularity, complicating reproducibility and consistent outcome assessment across studies. Jing et al.’s 2025 narrative review further discussed emerging conservative surgical techniques and novel antibiotic delivery approaches [61].

5.3. Perioperative Optimization Strategies

Table 8. Perioperative optimization protocols for diabetic patients undergoing orthopedic surgery.

Phase	Optimization Target	Specific Interventions	Target Goals	Monitoring Requirements
Preoperative	Glycemic control	HbA1c optimization; Medication adjustment; Endocrine consultation	HbA1c < 7% (elective); Glucose 80–180 mg/dL	Weekly glucose monitoring; HbA1c within 3 months
	Complication assessment	Nephropathy screening; Cardiac evaluation; Vascular assessment	eGFR > 30 mL/min; Cardiac clearance; Adequate perfusion	Creatinine/eGFR; ECG/echo if indicated; ABI assessment
	Nutritional status	Protein assessment; Vitamin D optimization; Micronutrient screening	Albumin > 3.0 g/dL; 25(OH)D > 30 ng/mL; Normal B12/folate	Comprehensive metabolic panel; Vitamin levels
Intraoperative	Glucose management	Continuous monitoring; Insulin protocols; Avoid hypoglycemia	Glucose 140–180 mg/dL; Avoid <70 or >250 mg/dL	Hourly glucose checks; Insulin drip protocols
	Infection prevention	Extended prophylaxis; Wound care protocols; Temperature management	Core temp > 36 °C; Appropriate antibiotics; Sterile technique	Temperature monitoring; Antibiotic timing
Postoperative	Wound healing	Glycemic control; Nutrition support; Infection surveillance	Glucose < 200 mg/dL; Adequate protein intake; Early mobilization	Daily glucose monitoring; Wound assessment; Inflammatory markers
	Rehabilitation	Physical therapy; Weight-bearing protocols; Fall prevention	Gradual progression; Neuropathy awareness; Safety equipment	Functional assessment; Balance testing

eGFR, estimated glomerular filtration rate; ECG, electrocardiogram; ABI, ankle-brachial index; 25(OH)D, 25-hydroxyvitamin D; HbA1c, hemoglobin A1c.

provides evidence-based protocols for the perioperative management of diabetic patients undergoing orthopedic procedures.

Implementation of systematic perioperative protocols requires institutional commitment and multidisciplinary coordination. Hospital-wide osteoporosis screening programs demonstrate high detection rates in general medical and surgical populations [62], supporting integration of bone health assessment into routine perioperative evaluation pathways for high-risk patients. Perioperative glucose variability represents a critical but often overlooked risk factor. Increased postoperative glucose variability associates with adverse outcomes following orthopedic surgery [63], emphasizing the importance of consistent glycemic control rather than just achieving target glucose levels. Special considerations apply to older adults with Type 1 diabetes, who require individualized management approaches balancing glycemic control with fracture prevention [64]. The clinical significance of fracture prevention is underscored by longstanding epidemiological evidence demonstrating the substantial burden of osteoporotic fractures across populations [65].

6. Prevention and Lifestyle Interventions

6.1. Exercise and Physical Activity Recommendations

Table 9. Exercise prescription guidelines for diabetic bone health.

Exercise Type	Specific Recommendations	Frequency	Intensity	Diabetes Modifications	Expected Benefits
Weight-Bearing Aerobic	Walking, dancing, stair climbing, low-impact aerobics	150 min/week (30 min, 5 days)	Moderate (RPE 12–14)	Foot care emphasis; Glucose monitoring; Proper footwear	↑ BMD 1–2%; ↓ HbA1c 0.6%
Resistance Training	Progressive weights, resistance bands, bodyweight exercises	2–3 sessions/week (8–10 exercises)	60–80% 1RM (8–12 reps)	Avoid Valsalva; Monitor BP; Gradual progression	↑ Muscle mass; ↑ Bone formation; ↑ Insulin sensitivity
High-Impact	Jumping, hopping, plyometric exercises	2–3 sessions/week (10–20 impacts)	High intensity (short duration)	Contraindicated in: Severe neuropathy; Active ulcers; Proliferative retinopathy	↑ Cortical thickness; ↑ Trabecular density
Balance Training	Tai chi, yoga, balance exercises	Daily (15–20 min)	Low to moderate	Essential for neuropathy; Fall prevention focus; Vision considerations	↓ Fall risk 23–40%; ↑ Proprioception
Flexibility	Stretching, yoga, range of motion	Daily	Low intensity	Joint mobility focus; Neuropathy adaptations	↑ Joint mobility; ↓ Injury risk

RPE, rate of perceived exertion; 1RM, one-repetition maximum; BP, blood pressure; BMD, bone mineral density; HbA1c, hemoglobin A1c; ↑ increased, ↓ decreased.

provides comprehensive exercise prescription guidelines specifically tailored for diabetic patients with bone health concerns.

Combined weight-bearing and resistance training programs produce BMD increases of 2.1% at the lumbar spine while achieving clinically significant HbA1c reductions of 0.6–0.8% [66,67]. Balance training assumes particular importance due to multiple factors that increase fall risk, with comprehensive fall prevention programs demonstrating significant reductions in fall rates (23–40%) [68,69]. Type 2 diabetes increases both hip fracture risk and non-skeletal fall injury risk in elderly populations [70], further emphasizing the critical importance of fall prevention in this high-risk group.

6.2. Nutritional Strategies for Bone Health

Vitamin D supplementation assumes particular importance in diabetic populations, where deficiency prevalence approaches 60–80% [71,72]. While calcium supplementation merits consideration, potential cardiovascular concerns require individualized risk-benefit assessment [73]. Recent advances in understanding diabetic bone disease pathogenesis [74] inform increasingly sophisticated approaches to nutritional optimization in this population. Higher supplementation doses (800–2000 IU daily) are often required to achieve target serum 25-hydroxyvitamin D levels of at least 30 ng/mL. Mediterranean dietary patterns have emerged as particularly beneficial for diabetic patients with bone health concerns, providing dual advantages for fracture risk reduction and metabolic control [75,76].

The substantial clinical burden of diabetic bone disease is evidenced by comprehensive meta-analyses demonstrating elevated fracture risks across multiple skeletal sites in both Type 1 and Type 2 diabetes [77]. Validated fracture prediction models [78] and mortality data following osteoporotic fractures [79,80] underscore the critical importance of prevention strategies. Historical observations regarding potential skeletal effects of hyperinsulinemia [81] have evolved into contemporary understanding that both Type 1 and Type 2 diabetes present distinct but equally important skeletal fragility concerns [82], necessitating diabetes-type-specific assessment and management approaches.

7. Future Directions and Emerging Therapeutics

7.1. Novel Therapeutic Targets

AGE Breakers and RAGE Antagonists: Advanced glycation end product breakers represent a promising therapeutic approach for reversing established bone quality deficits rather than simply preventing progression [83]. RAGE antagonists offer a complementary approach by interrupting the inflammatory signaling cascades triggered by AGE-RAGE interactions [84].

Bone Anabolic Pathways: The Wnt/β-catenin signaling pathway appears to be suppressed in diabetic conditions [15]. Leanza et al.’s study demonstrated that bone canonical Wnt signaling is significantly downregulated in T2D patients and is associated with higher AGE content and reduced bone strength [15]. These findings suggest that Wnt pathway modulators might represent valuable therapeutic targets for diabetic bone disease.

7.2. Technology Integration and Personalized Medicine

Artificial Intelligence Applications: Machine learning approaches incorporating diabetes-specific variables have demonstrated superior fracture risk prediction accuracy (area under curve 0.84–0.89) compared to traditional tools (0.67–0.72) [44]. Point-of-care testing for AGE accumulation markers could enable rapid bone quality assessment during routine diabetes visits [11]. Comprehensive understanding of diabetic bone disease mechanisms informs these technological advances. Studies demonstrate that Type 2 diabetes deteriorates trabecular bone microarchitecture despite preserved density [85], necessitating comprehensive bone quality assessment beyond traditional densitometry [86]. The characteristic low bone turnover state in diabetes [87] underlies many of these skeletal abnormalities and represents a key therapeutic target for emerging interventions.

7.3. Clinical Implementation Strategies

Integrated Care Models: Successful management requires integration across multiple specialties, including endocrinology, orthopedics, and primary care [88]. The development of specialized diabetic bone health clinics represents one approach to achieving optimal care integration [89].

7.4. Clinical Guidelines and Recommendations

Professional Society Recommendations: The 2024 American Diabetes Association Standards of Care represent a landmark development in recognizing bone health as an integral component of comprehensive diabetes care [90]. The International Osteoporosis Foundation’s 2024 position statement provides complementary guidance focusing on skeletal health aspects [91]. The European Association for the Study of Diabetes and European Society of Endocrinology have begun developing joint recommendations [92].

8. Conclusions

Diabetic bone disease represents a distinct clinical entity requiring specialized recognition, assessment, and management approaches extending well beyond traditional osteoporosis care paradigms. The fundamental disconnect between bone density measurements and actual bone quality necessitates enhanced diagnostic strategies incorporating microarchitectural assessment and diabetes-specific risk factors.

The emergence of “diabetic osteopathy” reflects growing understanding that diabetes affects bone through mechanisms fundamentally different from traditional osteoporosis. AGE accumulation, chronic inflammatory states, altered bone cell function, and impaired bone quality create changes requiring specialized diagnostic and therapeutic approaches. Recent systematic reviews and meta-analyses provide robust evidence supporting this conceptual framework.

Large-scale epidemiological studies reveal considerable heterogeneity in fracture risk among diabetic patients, with population-level risk increases being modest while specific high-risk subgroups require intensive management. The contrasting skeletal phenotypes between Type 1 and Type 2 diabetes require fundamentally different management approaches.

Treatment selection must carefully consider both skeletal and metabolic effects. Comprehensive evidence supports metformin and GLP-1 receptor agonists as preferred diabetes medications for patients with bone health concerns, while confirming significant skeletal risks associated with thiazolidinediones. For osteoporosis-specific therapy, denosumab has emerged as a preferred choice due to its lack of renal dose adjustment requirements and excellent efficacy profile.

The substantially compromised surgical outcomes experienced by diabetic patients mandate the implementation of enhanced perioperative protocols and comprehensive multidisciplinary care coordination. Prevention strategies must address both traditional bone health factors and diabetes-specific risks through exercise programs providing dual benefits, nutritional interventions, fall prevention programs, and comprehensive management of diabetes complications.

Future advances in biomarker development, artificial intelligence applications for personalized fracture risk prediction, and targeted therapeutics addressing fundamental AGE formation pathways offer significant promise. These emerging approaches may enable the transition from current symptom-managing therapies toward disease-modifying interventions addressing underlying pathophysiological mechanisms.

Recognition of diabetic bone disease as a serious diabetic complication with clinical significance equivalent to established complications drives the imperative for systematic screening protocols, evidence-based management guidelines, and specialized care approaches. The growing prevalence of diabetes worldwide makes diabetic bone disease an increasingly important public health challenge requiring coordinated responses from healthcare systems, professional organizations, and research communities.