Highlights
· Type 1 diabetes impairs bone formation through insulin deficiency and disrupted insulin-like growth factor-1 signaling, leading to reduced bone mineral density and altered microarchitecture.
· Type 2 diabetes paradoxically presents with normal or elevated bone mineral density but increased fracture risk, attributed to compromised bone quality from advanced glycation end-product accumulation.
· Early identification using advanced imaging techniques (trabecular bone score, high-resolution peripheral quantitative computed tomography) combined with comprehensive management strategies is essential to optimize peak bone mass during critical developmental periods.
Introduction
The global burden of diabetes mellitus among children and adolescents has risen dramatically in recent decades, presenting major challenges for long-term health outcomes, including skeletal health [1,2]. According to the International Diabetes Federation, the global prevalence of type 1 diabetes (T1D) in children and adolescents (age, 0–19 years) was estimated to be 1.57 million in 2023, with approximately 108,200 new cases diagnosed annually in children under 15 years of age [1]. Additionally, the emergence of type 2 diabetes (T2D) among youth, which was previously rare, has become increasingly common, paralleling the childhood obesity epidemic [3].
In Korea, epidemiological data have shown significant changes in both T1D and T2D prevalence among youth. The incidence increased by 3% to 4% each year from 2007 to 2017 [4]. While this rate is still lower than in Western populations, the trend reflects global patterns. More dramatically, the prevalence of T2D in young Koreans increased more than 4.4-fold from 2002 to 2016, with the increase beginning in the early 2000s among younger age groups and in low-income families [5].
The timing of diabetes onset during childhood and adolescence is especially important for skeletal health, as these years are critical for bone mass acquisition and skeletal development. Approximately 90% of peak bone mass is attained by early adulthood, which establishes the foundation for lifelong skeletal health [6]. Peak bone mass is a key factor in determining future fracture risk, with higher peak bone mass providing a protective reserve against age-related bone loss [6].
The impact of diabetes on skeletal health manifests through distinct pathophysiological mechanisms in T1D and T2D. In T1D, insulin deficiency directly affects bone formation by disrupting the insulin/insulin-like growth factor-1 (IGF-1) signaling axis, which is fundamental to osteoblast differentiation and function [7]. T1D is associated with significantly elevated fracture risk, low bone mineral density (BMD), reduced levels of bone formation markers, and altered bone microarchitecture [8].
Conversely, T2D presents a more complex picture regarding bone health. Despite often normal or elevated BMD measurements, bone quality is frequently compromised [9]. The accumulation of advanced glycation end products (AGEs) in bone tissue alters collagen crosslinking and reduces bone strength independently of mineral density [10]. Additionally, inflammatory processes appear to modulate bone metabolism in T2D and contribute to compromised bone integrity through altered remodeling mechanisms [11].
Technological advances have significantly improved the assessment and management of bone health in diabetic youth. Traditional methods such as dual-energy xray absorptiometry (DXA) are now complemented by newer techniques, including trabecular bone score (TBS) and high-resolution peripheral quantitative computed tomography (HR-pQCT), which provide deeper insights into bone quality and microarchitecture [12]. These advances have revealed that the impact of diabetes on bone extends beyond simple density measurements to include complex alterations in bone quality and strength [13].
Given the potential long-term implications for skeletal health, understanding these effects is crucial. Studies suggest that compromised bone health in youth may increase the risk of osteoporosis and fractures later in life, representing a major public health concern as the diabetic population ages [14]. This review aims to comprehensively examine current evidence regarding bone health in pediatric diabetes, exploring pathophysiological mechanisms, assessment methods, and management strategies while highlighting areas requiring further research.
Pathophysiological mechanisms
The mechanisms behind bone impairment in diabetes are complex and multifaceted, and distinct pathways are dominant in T1D compared to T2D (Fig. 1). Understanding these mechanisms is crucial for developing targeted interventions and identifying key periods for prevention [7]. The primary pathophysiological mechanism in T1D focuses on insulin deficiency and its direct effects on bone metabolism, while T2D presents a more intricate picture involving insulin resistance, obesity, and inflammation [10].
In T1D, lack of insulin greatly affects skeletal development through various pathways, with the insulin/IGF-1 axis playing a central role. Insulin stimulates IGF-1 production, which is essential for normal bone formation and growth. Abnormalities in the growth hormone/IGF-1 axis in children with T1D lead to stunted pubertal growth and decreased peak bone mass acquisition [15-18]. Additionally, insulin signaling directly impacts osteoblast differentiation and activity by regulating Runx2 and other important transcription factors [19,20].
The impact of chronic hyperglycemia extends beyond its metabolic effects, leading to the accumulation of AGEs in bone tissue [21]. These AGEs form irreversible cross-links with collagen fibers, altering the mechanical properties of bone independently of BMD [22].
In contrast, the pathophysiology of bone impairment in T2D is particularly complex due to the interplay among insulin resistance, obesity, and inflammation [23]. Unlike T1D, insulin levels are typically elevated in early T2D; however, insulin resistance can compromise bone quality and strength even if BMD is normal or elevated. Other factors, such as bone quality, microarchitecture, and metabolic influences, also contribute to bone health [24]. Obesity, a common characteristic in youth-onset T2D, adds another level of complexity to bone metabolism. While mechanical loading from increased body weight has traditionally been seen as beneficial for bone mass, recent evidence suggests more nuanced effects [25].
Both T1D and T2D are marked by chronic low-grade inflammation, although their underlying mechanisms vary. In T1D, autoimmune-mediated inflammation primarily targets pancreatic β-cells but also affects bone metabolism through heightened levels of inflammatory markers like interleukin (IL)-1β and tumor necrosis factor‑alpha (TNF-α) [24]. In T2D, the inflammatory response is more closely associated with adipose tissue dysfunction and insulin resistance, creating a proinflammatory environment that negatively impacts bone metabolism through various pathways [25].
Vitamin D metabolism and calcium homeostasis are other crucial aspects of bone health in diabetic youth. The results of a meta-analysis indicated that the proportion of vitamin D deficiency among children and adolescents with T1D was 45% [26]. This deficiency can be particularly harmful during periods of rapid bone growth and mineralization, as vitamin D plays essential roles in calcium absorption and bone mineralization. The mechanisms leading to altered vitamin D metabolism in diabetes include impaired vitamin D hydroxylation, reduced calcium absorption, altered parathyroid hormone secretion, and compromised vitamin D receptor function [27].
Evidence indicates that the timing of T1D onset significantly influences skeletal development. With peak onset occurring between the ages of 10 and 14 [28], the diagnosis of T1D aligns with critical periods of bone mass acquisition, during which about 25% of peak bone mass is established [29,30]. This temporal overlap may interfere with normal skeletal development due to prolonged exposure to hyperglycemia and insulin deficiency, potentially compromising bone microarchitecture and strength. As a result, early-onset T1D may lead to inadequate bone mass accrual during developmental phases, which could explain the heightened risk of osteoporosis and fractures noted in the adult T1D population [31].
The intricate relationship between diabetes and puberty adds another layer of complexity to bone metabolism. Pubertal hormones, especially sex steroids, play a crucial role in normal bone development and acquiring peak bone mass. Research has demonstrated that diabetes can significantly influence the timing of puberty onset and disrupt the hormonal environment essential for optimal skeletal development [32].
Oxidative stress is a significant factor in diabetes-related bone disease. Hyperglycemia-induced oxidative stress results in increased production of reactive oxygen species, reduced antioxidant defenses, enhanced AGE formation, and prolonged inflammation [33]. These changes can directly affect osteoblast function and survival, potentially contributing to reduced bone formation and stimulating the differentiation of osteoclast precursors into mature osteoclasts, thereby accelerating bone tissue breakdown in diabetic patients [33]. A recent clinical study showed that young adults with T1D have high blood levels of pro-inflammatory cytokines TNF-α and IL-6, which correlate with increased bone resorption markers and decreased bone density, linking inflammation directly to bone loss [11].
The role of incretins and other gut hormones in bone metabolism has gained increasing attention. Glucagonlike peptide-1 and gastric inhibitory polypeptide, which are altered in diabetes, have been shown to influence bone turnover both directly and indirectly. Research indicates that disruption of these incretin pathways may contribute to the bone phenotype observed in diabetes, particularly in T2D [34]. Furthermore, emerging evidence has suggested that alterations in the gut microbiome associated with diabetes may affect bone metabolism through impacts on calcium absorption and immune regulation [33,35].
Clinical manifestations
The clinical presentation of diabetes-related bone disease in children and adolescents shows various patterns that differ between T1D and T2D. Understanding these manifestations is essential for early identification and appropriate intervention strategies.
Children and adolescents with T1D exhibit significant abnormalities in bone health that may have lifelong implications for skeletal integrity and fracture risk. A comprehensive meta-analysis of 36 studies involving 2,222 children with T1D and 2,316 typically developing children revealed consistent deficits in bone mineral content (BMC) and areal BMD (aBMD) [36]. Total body BMC showed a standardized mean difference (SMD) of -0.21 (95% confidence interval [CI], -0.37 to -0.05), while total body aBMD demonstrated an SMD of -0.30 (95% CI, -0.50 to -0.11). Similar deficits were noted at the lumbar spine, with a BMC SMD of -0.17 (95% CI, -0.28 to -0.06), an aBMD SMD of -0.20 (95% CI, -0.32 to -0.08), and a bone mineral apparent density SMD of -0.30 (95% CI, -0.48 to -0.13). The femoral neck also showed reduced aBMD with an SMD of -0.21 (95% CI, -0.33 to -0.09). These deficits of 0.2–0.3 standard deviations are clinically significant, as they are comparable to deficits observed in children with a history of fractures (-0.3 SMD) [36,37].
Advanced imaging techniques have revealed specific microarchitectural abnormalities in the bones of children with T1D. pQCT and HR-pQCT studies showed deficits in distal radius trabecular density (SMD, -0.38; 95% CI, -0.64 to -0.12) and trabecular bone volume fraction (SMD, -0.33; 95% CI, -0.56 to -0.09) [36]. Similar deficits were observed in the distal tibia, with reduced trabecular density (SMD, -0.35; 95% CI, -0.51 to -0.18), trabecular bone volume fraction (SMD, -0.37; 95% CI, -0.60 to -0.14), and trabecular thickness (SMD, -0.41; 95% CI, -0.67 to -0.16). Additionally, tibia shaft cortical content was lower (SMD, -0.33; 95% CI, -0.56 to -0.10), suggesting that both trabecular and cortical bone compartments are affected in pediatric T1D. A small study of 32 children with T1D compared to age- and sex-matched healthy children used skeletal magnetic resonance imaging of the proximal tibia to demonstrate lower trabecular number, lower trabecular volume, and higher trabecular separation in diabetic children [38].
Importantly, meta-regression analyses indicated that bone deficits in T1D increase with age and disease duration [36]. Older age was associated with a larger SMD in total body BMC (β=-0.13; 95% CI, -0.21 to -0.04) and total body aBMD (β=-0.09; 95% CI, -0.17 to -0.01). Additionally, longer disease duration correlated with greater deficits in total body aBMD (β=-0.14; 95% CI, -0.24 to -0.04). These findings suggest that experiencing T1D during adolescence, a crucial period for bone mass accumulation, may hinder optimal peak bone mass achievement and contribute to lifelong skeletal fragility.
The underlying pathophysiology includes a low bone turnover state, as shown by altered biochemical markers in children with T1D [39]. Reduced levels of osteocalcin and procollagen type 1 N-terminal peptide (P1NP) indicate decreased bone formation, while findings related to C-terminal telopeptide (CTX) levels are variable [39,40]. One study noted lower P1NP without differences in CTX, suggesting impaired bone formation with relatively preserved bone resorption [40].
The clinical significance of these bone deficits is reflected in the increased fracture risk among youth with T1D. Population-based cohort studies demonstrate hazard ratios for incident fractures of 1.14 in males and 1.35 in females under the age of 20 with T1D compared to their nondiabetic peers [41]. A prospective study from the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort further showed that each standard deviation decrease in size-adjusted BMC is associated with an 89% increase in risk of fractures [37].
Youth with T2D display a paradoxical pattern of bone health characterized by normal or increased BMD despite a higher risk of fractures. In the cross-sectional study by Kindler et al. [42], youth with T2D (n=180) exhibited notably higher BMD z-scores (0.88±1.02) compared to healthy weight controls (0.47±0.87, P<0.001), with obese youth showing similar increases (0.87±0.93). This pattern demonstrated age-dependent variations, with predicted aBMD z-scores at age 10 being 0.36, 0.78, and 1.30 for healthy weight, obese, and T2D groups, respectively. At age 24, these scores converged to 0.57, 0.94, and 0.57, indicating a decline in the relative bone density advantage among T2D patients during adolescence [42].
Despite normal BMD, bone quality is compromised in T2D. Multiple studies report increased cortical porosity in T2D patients [43,44], with Patsch et al. [44] demonstrating significantly higher cortical porosity in T2D individuals who experience fragility fractures. TBS, which evaluates bone microarchitecture, is significantly lower in T2D patients, even with normal BMD [43]. Bone material strength is also impacted, with studies indicating an approximately 10% lower bone material strength index in T2D patients compared to controls [43].
T2D is characterized by suppressed bone turnover markers (BTMs). Across various studies, osteocalcin and P1NP levels were notably lower in T2D patients [43]. Resorption markers, such as CTX, were lower in T2D patients than controls [43]. Wang et al. [45] reported an inverse relationship between hemoglobin A1c and osteocalcin levels.
Despite higher BMD, T2D increases fracture risk [43]. The combination of T2D and chronic kidney disease further elevates fracture risk, with hazard ratios exceeding 2.0 in some studies [43]. In youth with T2D, failing to achieve optimal peak bone mass during crucial developmental periods, alongside progressive deterioration of bone quality and accumulation of AGEs, may contribute to fracture risk later in life [42,43].
These findings highlight that conventional BMD measurements are often inadequate for evaluating fracture risk in T2D patients, as they obscure underlying qualitative defects in bone structure, turnover, and strength that contribute to skeletal fragility despite seemingly normal bone mass.
Assessment methods
Diabetes mellitus increases the risk of fragility fractures in patients, requiring comprehensive diagnostic approaches to evaluate bone health in pediatric and young adult populations with diabetes.
DXA-measured BMD represents the traditional gold standard for osteoporosis assessment. However, its diagnostic utility exhibits significant limitations in diabetic populations. In T1D, BMD is typically lower than in nondiabetic controls, yet fragility fracture risk exceeds what would be predicted by DXA measurements alone [46]. More problematically, patients with T2D often present with normal or elevated BMD despite increased fracture incidence, indicating that BMD insufficiently captures diabetic bone pathology [28].
The diagnostic criteria for pediatric osteoporosis have evolved to address these limitations. The International Society of Clinical Densitometry (ISCD) recommends that individuals under 19 years of age should not be diagnosed with osteoporosis based solely on densitometric criteria [47]. Instead, a history of clinically significant fractures, particularly vertebral compression fractures, serves as a diagnostic criterion regardless of BMD measurements [48].
For young adults with diabetes, z-scores rather than t-scores should be evaluated when interpreting DXA results. ISCD emphasizes that in patients younger than 25, BMD assessment requires adjustment for height, bone size, and skeletal maturity to avoid diagnostic misclassification [47]. This is particularly relevant in diabetic populations, where growth and maturation may be affected by disease chronicity and glycemic control.
The Fracture Risk Assessment Tool (FRAX) has limited diagnostic accuracy in diabetic populations because it fails to include diabetes as an independent risk factor [49]. Research in Canadian cohorts showed that FRAX consistently underestimated fracture probability in diabetic patients, emphasizing the need for diabetesspecific adjustments to risk calculation algorithms. Proposed modifications to the methodology include increasing the calculated patient age by 10 years or adjusting the BMD t-score by -0.5 standard deviations [50].
TBS represents a diagnostic advancement that evaluates microarchitectural deterioration from standard lumbar spine DXA images. Multiple cross-sectional studies demonstrated significantly lower TBS values in diabetic patients compared with controls, indicating its usefulness in detecting qualitative bone abnormalities not captured by conventional densitometry [51]. Integrating TBS with standard BMD assessment may improve diagnostic sensitivity for fracture risk in diabetes patients who otherwise have normal BMD parameters.
QCT and HR-pQCT facilitate volumetric BMD assessment and 3-dimensional evaluation of bone microarchitecture. Previous HR-pQCT studies revealed diabetesspecific deficits in bone microstructure, particularly increased cortical porosity and decreased cortical density, correlating with fracture risk independently of BMD [13]. In a cross-sectional analysis of patients with T1D, Sewing et al. [52] documented reduced cortical thickness and volumetric BMD at the ultradistal tibia, along with corresponding reductions in calculated bone strength parameters.
BTMs demonstrate limited diagnostic utility as standalone tests but may provide supplementary information in comprehensive assessment. The diabetic bone phenotype is characterized by a consistent pattern of suppressed bone formation markers (osteocalcin, P1NP) combined with normal or reduced resorption markers (CTX) [53]. However, the wide reference ranges and significant biological variability of these markers limit their utility in individual patient assessment.
In specialized diagnostic circumstances, transiliac crest bone biopsy with tetracycline labeling remains the definitive assessment method for determining bone cellular activity and microstructure. While limited by its invasiveness, this approach may clarify equivocal cases and distinguish between low turnover and high turnover bone disease in complex patients with diabetes [54].
The diagnostic evaluation of bone health in young diabetic patients requires a multifaceted approach that extends beyond conventional densitometry. Integrating advanced imaging modalities, microstructural assessment techniques, and careful clinical evaluation provides a more comprehensive diagnostic framework for identifying patients at elevated fracture risk despite potentially normal BMD values.
Management strategies
Management and treatment strategies for bone health in pediatric and adolescent patients with diabetes mellitus require a comprehensive, evidence-based approach that addresses both the prevention and intervention of skeletal complications often associated with this chronic endocrine disorder. The pathophysiological mechanisms underlying diabetic bone disease involve complex interactions between hyperglycemia-induced alterations in osteoblast function, impaired collagen crosslinking, advanced glycation end-product accumulation, and microvascular complications that collectively compromise bone quality and strength [55].
Therapeutic management protocols start with stringent glycemic control as the cornerstone intervention, focusing on reducing glycemic variability, which has been recognized as an independent risk factor for diminished bone mineral acquisition in longitudinal pediatric cohort studies. Nutritional optimization serves as a vital second-line intervention, particularly by ensuring age-appropriate calcium intake (ranging from 700 to 1,300 mg/day, depending on developmental stage) and maintaining 25-OH-vitamin D levels above the established threshold of 20 ng/mL (50 nmol/L) through supplementation when indicated [56,57].
Structured weight-bearing physical activity regimens represent the third pillar of management. Systematic reviews have demonstrated significant improvements in BMD parameters following the implementation of supervised exercise protocols incorporating both resistance and impact loading elements appropriately modified to accommodate diabetic complications such as peripheral neuropathy or retinopathy [56,58]. DXA assessment is recommended at diagnosis and sequentially at 12–24-month intervals for surveillance and monitoring. Meticulous attention to appropriate heightadjustment calculations can prevent inaccurate interpretation in patients with diabetes-associated growth impairments [56].
In cases of established osteoporosis meeting the ISCD criteria—specifically vertebral compression fractures regardless of BMD or a clinically significant fracture history (2 or more long bone fractures before age 10, or three or more before age 19) accompanied by BMD z-scores ≤-2.0—pharmacological intervention with bisphosphonates becomes necessary [56,59]. The selection and dosing of bisphosphonates follow standardized pediatric protocols: intravenous zoledronate (0.025–0.05 mg/kg every 3–6 months) is the preferred agent due to superior compliance and reduced administration frequency, while oral alendronate (5–10 mg daily based on weight) provides an alternative for milder cases or when intravenous access is challenging [56]. Implementing this multifaceted management approach requires coordination through a dedicated multidisciplinary team that includes pediatric endocrinologists, diabetes educators, nutritionists, exercise physiologists, and bone health specialists to effectively reduce the significant risk of skeletal complications in this vulnerable population [56].
Fig. 2 illustrates the comparative clinical manifestations and assessment methods in pediatric diabetes related bone disease, highlighting the distinct differences between T1D and T2D in BMD, microarchitecture, BTMs, and fracture risk profiles.
Conclusion
The intricate relationship between diabetes and bone health in children and adolescents represents a major clinical challenge that necessitates careful attention and proactive management. This review highlights the distinct pathophysiological mechanisms underlying bone impairment in T1D and T2D, emphasizing the critical importance of the timing of diabetes onset during skeletal development. The evidence shows that both types of diabetes can significantly impact bone health through different mechanisms, with T1D primarily affecting bone formation due to insulin deficiency and T2D exhibiting more complex mechanisms involving insulin resistance and inflammation.
Recent advances in assessment methods, especially in imaging technologies and biochemical markers, have deepened our understanding of diabetes-related bone disease and enhanced our ability to identify at-risk patients early in the disease course. By integrating traditional and novel assessment tools and considering agespecific factors, we can create a strong framework for monitoring and evaluating bone health in this vulnerable population.
Management strategies should be comprehensive and tailored to each individual, integrating preventive methods, lifestyle changes, and careful consideration of pharmacological options when necessary. The importance of achieving optimal glycemic control while ensuring appropriate levels of physical activity and nutrition cannot be overstated. As our understanding of the complex relationship between diabetes and bone metabolism continues to develop, future research will yield more targeted and effective therapeutic strategies.
The long-term effects of childhood-onset diabetes on skeletal health highlight the necessity of early intervention and ongoing monitoring. As the global prevalence of both T1D and T2D in young people continues to rise, addressing bone health becomes crucial for preventing future complications and maintaining quality of life into adulthood. Ongoing research efforts and clinical vigilance will be vital for optimizing outcomes in this growing patient population.
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