Children with type 1 diabetes (T1D) experience an increased risk of fracture, which may be related to altered bone development. We aimed to assess differences in bone, muscle and physical activity (PA), and explore if better muscle and PA measures would mitigate bone differences between children and adolescents with T1D and typically developing peers (TDP). We matched 56 children and adolescents with T1D (mean age 11.9 yrs) and 56 TDP (11.5 yrs) by sex and maturity from 171 participants with T1D and 66 TDP (6-17 yrs). We assessed the distal radius and tibia with high-resolution peripheral quantitative computed tomography (HR-pQCT), and the radius and tibia shaft bone and muscle with pQCT. We also measured muscle function from force-related measures in neuromuscular performance tests (push-up, grip test, countermovement and long jump). We compared PA based on questionnaire scores and accelerometers between groups. Bone, muscle, and neuromuscular performance measures were compared using MANOVA. We used mediation to explore the role of PA and muscle in bone differences. Children and adolescents with T1D had 6-10 % lower trabecular density, bone volume fraction, thickness and number at both distal radius and tibia, and 11 % higher trabecular separation at the distal radius than TDP. They also had 3-16 % higher cortical and tissue mineral density, and cortical thickness at the distal radius, 5-7 % higher cortical density and 1-3 % higher muscle density at both shaft sites compared to TDP. PA mediated the between-group difference in trabecular number (indirect effect -0.04) at the distal radius. Children and adolescents with T1D had lower trabecular bone density and deficits in trabecular micro-architecture, but higher cortical bone density and thickness at the radius and tibia compared to TDP. They engaged in less PA but had comparable muscle measures to those of TDP. PA participation may assist in mitigating deficit in trabecular number observed in children and adolescents with T1D.

Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, and biochemical and imaging studies. Bone mineral density, bone geometry, and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.

The purpose of this review is to highlight the evidence of microvascular dysfunction in bone and marrow and its relation to poor skeletal outcomes in diabetes mellitus.

Diabetes mellitus is characterized by chronic hyperglycemia, which may lead to microangiopathy and macroangiopathy. Micro- and macroangiopathy have been diagnosed in Type 1 and Type 2 diabetes, coinciding with osteopenia, osteoporosis, enhanced fracture risk and delayed fracture healing. Microangiopathy has been reported in the skeleton, correlating with reduced blood flow and perfusion, vasomotor dysfunction, microvascular rarefaction, reduced angiogenic capabilities, and augmented vascular permeability. Microangiopathy within the skeleton may be detrimental to bone and manifest as, among other clinical abnormalities, reduced mass, enhanced fracture risk, and delayed fracture healing. More investigations are required to elucidate the various mechanisms by which diabetic microvascular dysfunction impacts the skeleton.

To evaluate the use of QUS for the bone status assessment in children cared because of a chronic disease such as: inherited metabolic disorder, kidney disease and endocrine defect and considered by the attending physician as at specific risk.

QUS outputs were calculated for each disorder and compared to: sex, age, Tanner stage, Z-score for height, weight and BMI (body mass index).

One-hundred-sixty-eight subjects aged between 3.5 and 18 years met the inclusion criteria. The overall bone quality indexes were under the normal range in all the groups considered. Impairment of bone quality parameters was more evident in the group of patients with inherited metabolic disorders, in which 65% of patients in charge were studied by QUS. Older age and sexual development were associated with less pronounced bone quality impairment, as measured by QUS, in the vast majority of conditions. Overall, the diseases for which the prediction of outcome was the strongest were: hyperphenylalaninemia, nephrotic syndrome and insulin dependent diabetes mellitus.

QUS is capable to provide information on skeletal status in children. Initial evaluation by QUS may allow defining patients with chronic disorders who deserve further, more invasive diagnostic studies. Inherited metabolic disorders warrant specific attention and strict monitoring for their potential effect on bone.

To describe bone mineral density (BMD), bone structure, and fracture prevalence in adolescents with type 1 diabetes (T1D) and explore their associations with glycemic control and microvascular complications.

Cross sectional study of 64 adolescents (38 males) with T1D duration >10 years who underwent dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), fracture survey, plantar fascia thickness, and microvascular complications assessment.

Mean age was 16.6 ± 2.1 years, diabetes duration 12.8 ± 2.2 years and HbA1c 8.9 ± 1.7% (74 mmol/mol). Fracture prevalence was 50%. DXA areal BMD (Z-score) was reduced for femoral neck (-0.5 ± 1.3, p = 0.008) and arm (-0.4 ± 1.0, p < 0.001), while total areal BMD and lumbar spine BMD were normal. In pQCT (Z-score), trabecular volumetric BMD (vBMD) was reduced for tibia (-0.4 ± 0.8, p < 0.001) and radius (-0.8 ± 1.4, p < 0.001) whereas cortical vBMD was increased at both sites (tibia: 0.5 ± 0.6, p < 0.001, radius: 0.7 ± 1.5, p < 0.001). Muscle cross-sectional area (CSA) was reduced for upper (-0.6 ± 1.2, p < 0.001) and lower (-0.4 ± 0.7, p < 0.001) limbs. DXA total areal BMD was positively correlated with BMI (p < 0.01) and age at T1D diagnosis (p = 0.04). Lower radial bone CSA, total and lumbar spine BMD were associated with autonomic nerve dysfunction. HbA1c, diabetes duration, fracture history and other microvascular complications were not significantly associated with bone parameters.

Adolescents with childhood-onset T1D have site-specific bone deficits in upper and lower limbs but normal total and lumbar spine BMD. T1D appears to have differential effects on trabecular and cortical bone compartments. Future longitudinal analysis is warranted to examine whether these changes translate in to increased fracture risk.

Higher prevalence of overweight and obesity in children and adolescents with type 1 diabetes (T1D) suggests alterations are required in body composition. However, differences in body composition between children with T1D and typically developing children (TDC) have not been synthesized using meta-analysis. Therefore, we conducted a systematic review and meta-analysis to compare body composition between children with T1D and TDC, and to explore the role of disease and non-disease related factors in potential body composition differences.

Studies were performed comparing dual-energy x-ray absorptiometry-acquired total body fat and lean mass, absolute (kg) and relative (%) values, between children with T1D and TDC. We reported mean differences with 95% confidence intervals (CI) from meta-analysis and relative between-group %-differences. We used meta-regression to explore the role of sex, age, height, body mass, body mass index, Hemoglobin A1c, age of onset, disease duration, and insulin dosage in the potential body composition differences between children with T1D and TDC, and subgroup analysis to explore the role of geographic regions (p < 0.05).

We included 24 studies (1,017 children with T1D, 1,045 TDC) in the meta-analysis. Children with T1D had 1.2 kg more fat mass (kg) (95%CI 0.3 to 2.1; %-difference = 9.3%), 2.3% higher body fat % (0.3-4.4; 9.0%), but not in lean mass outcomes. Age of onset (β = -2.3, -3.5 to -1.0) and insulin dosage (18.0, 3.5-32.6) were negatively and positively associated with body fat % mean difference, respectively. Subgroup analysis suggested differences among geographic regions in body fat % (p < 0.05), with greater differences in body fat % from Europe and the Middle East.

This meta-analysis indicated 9% higher body fat in children with T1D. Earlier diabetes onset and higher daily insulin dosage were associated with body fat % difference between children with T1D and TDC. Children with T1D from Europe and the Middle East may be more likely to have higher body fat %. More attention in diabetes research and care toward body composition in children with T1D is needed to prevent the early development of higher body fat, and to minimize the cardiovascular disease risk and skeletal deficits associated with higher body fat.

Type 1 diabetes (T1DM) is associated with an increased fracture risk, specifically at nonvertebral sites. The influence of glycemic control and microvascular disease on skeletal health in long-standing T1DM remains largely unknown. We aimed to assess areal (aBMD) and volumetric bone mineral density (vBMD), bone microarchitecture, bone turnover, and estimated bone strength in patients with long-standing T1DM, defined as disease duration ≥25 years. We recruited 59 patients with T1DM (disease duration 37.7 ± 9.0 years; age 59.9 ± 9.9 years.; body mass index [BMI] 25.5 ± 3.7 kg/m² ; 5-year median glycated hemoglobin [HbA1c] 7.1% [IQR 6.82-7.40]) and 77 nondiabetic controls. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultradistal radius and tibia, and biochemical markers of bone turnover were assessed. Group comparisons were performed after adjustment for age, gender, and BMI. Patients with T1DM had lower aBMD at the hip (p < 0.001), distal radius (p = 0.01), lumbar spine (p = 0.04), and femoral neck (p = 0.05) as compared to controls. Cross-linked C-telopeptide (CTX), a marker of bone resorption, was significantly lower in T1DM (p = 0.005). At the distal radius there were no significant differences in vBMD and bone microarchitecture between both groups. In contrast, patients with T1DM had lower cortical thickness (estimate [95% confidence interval]: -0.14 [-0.24, -0.05], p < 0.01) and lower cortical vBMD (-28.66 [-54.38, -2.93], p = 0.03) at the ultradistal tibia. Bone strength and bone stiffness at the tibia, determined by homogenized finite element modeling, were significantly reduced in T1DM compared to controls. Both the altered cortical microarchitecture and decreased bone strength and stiffness were dependent on the presence of diabetic peripheral neuropathy. In addition to a reduced aBMD and decreased bone resorption, long-standing, well-controlled T1DM is associated with a cortical bone deficit at the ultradistal tibia with reduced bone strength and stiffness. Diabetic neuropathy was found to be a determinant of cortical bone structure and bone strength at the tibia, potentially contributing to the increased nonvertebral fracture risk. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The type 1 diabetes mellitus (T1DM) is a chronic systemic autoimmune-mediated disease characterised by the insulin deficiency and hyperglycaemia. Its deleterious effect on bones concerns not only bone mass, density, and fracture risk but also may involve the linear growth of long bones. Studies on the lower leg in children with T1DM by pQCT have generated conflicting results, and most of the studies published so far focused only on a selected features of the bone. An additional information about growth, modelling, and remodelling processes can be gathered by the bone turnover marker measurement. The objective of the study was to evaluate bone mineral density, mass, and geometry using peripheral quantitative computed tomography as well as bone turnover markers in the patients with type 1 diabetes mellitus. Material and Methods. Bone mineral density, mass, and geometry on the lower leg using peripheral quantitative computed tomography and serum osteocalcin (OC) and carboxyterminal cross-linked telopeptide of type 1 collagen (CTx) were measured in 35 adolescents with T1DM (15 girls) aged 12.3-17.9 yrs. The results were compared to age- and sex-adjusted reference values for healthy controls.

Both sexes reveal lower than zero Z-scores for lower leg 66% total cortical bone cross-sectional area to muscle cross-sectional area ratio (-0.97 ± 1.02, p = 0.002517 and -0.98 ± 1.40, p = 0.007050, respectively) while tibia 4% trabecular bone density Z-score was lowered in boys (-0.67 ± 1.20, p = 0.02259). In boys in Tanner stage 5 bone mass and dimensions were diminished in comparison to Tanner stages 3 and 4, while in girls, such a phenomenon was not observed. Similarly, bone formation and resorption were decreased in boys but not in girls. Consistently, bone turnover markers correlated positively with bone size, dimensions, and strength in boys only.

T1DM patients revealed a decreased ratio of cortical bone area/muscle area, reflecting disturbed adaptation of the cortical shaft to the muscle force. When analyzing bone mass and dimensions, boys in Tanner stage 5 diverged from "less-mature" individuals, which may suggest that bone development in these individuals was impaired, affecting all three: mass, size, and strength. Noted in boys, suppressed bone metabolism may result in impairment of bone strength because of inadequate repair of microdamage and accumulation of microfractures.

Skeletal fragility is now recognized as a significant complication of type 1 diabetes (T1D). Many patients with T1D develop the disease in childhood and prior to the attainment of peak bone mass and strength. This manuscript will review recent studies investigating the effects of T1D on skeletal development.

Mild-to-moderate deficits in bone density, structure, and mineral accrual were reported early in the course of T1D in some but not all studies. Childhood-onset disease was associated with a more severe skeletal phenotype in some adult studies. Lower than expected bone mass for muscle size was been described. Hemoglobin A1c was negatively associated with bone density and structure in several studies, though the mechanism was not clear.

The use of advanced imaging techniques has shown that the adverse effects of T1D on the developing skeleton extend beyond bone density to include abnormalities in bone size, shape, microarchitecture, and strength. Despite these gains, a uniform understanding of the pathophysiology underlying skeletal fragility in this disorder remains elusive. Longitudinal studies, especially in association with interventions to reduce hyperglycemia or improve muscle strength, are needed to inform bone healthcare in T1D.

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of low-trauma fractures. However, the effect of antidiabetic medication in relation to glycemic control on the risk of fracture is poorly understood.

This work aimed to evaluate the association between the level of glycemic control, use of antidiabetic medication, and risk of low-trauma fractures in patients with newly diagnosed T2DM.

We conducted a nested case-control analysis among individuals registered in the Clinical Practice Research Datalink. The base population consisted of patients with newly diagnosed T2DM from 1995 to 2017. Cases were patients with a low-trauma fracture after T2DM diagnosis. We matched 4 controls to each case. Exposures of interest were glycemic control (last glycated hemoglobin [HbA1c] level before fracture) and type of diabetes treatment. We conducted conditional logistic regression analyses adjusted for several confounders.

We identified 8809 cases and 35 219 controls. Patients with current metformin use and HbA1c levels of less than 7.0% and between 7.0-8.0% had a reduced risk of fractures (adjusted odds ratio 0.89; 95% CI, 0.83-0.96 and 0.81; 95% CI, 0.73-0.90, respectively) compared with untreated patients. However, in patients receiving metformin plus 1 or 2 other antidiabetic drugs, or insulin (alone or in addition to other antidiabetic medication), the level of glycemic control was not associated with the risk of fracture compared with untreated patients.

While patients with good or medium glycemic control receiving current metformin monotherapy had a lower risk of fracture compared with untreated patients, glycemic control in patients receiving treatment other than metformin was not associated with risk of fracture.

Evidence about bone microarchitecture in Asian type 1 diabetes (T1D) patients is lacking. We assessed the bone microarchitecture in T1D patients versus controls and compare the differences between juvenile-onset and adult-onset T1D patients.

This cross-sectional study recruited 32 Asian males with T1D and 32 age-, sex-, and body mass index (BMI)-matched controls. Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) for ultradistal nondominant radius and tibia were performed. The data were analyzed using Student's t test and analysis of covariance.

Among the patients, 15 had juvenile-onset T1D, with a median disease duration of 11 years, and 17 had adult-onset T1D, with a median disease duration of 7 years. At the radius, adult-onset and juvenile-onset T1D patients had lower total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction (BV/TV), and trabecular thickness (Tb.Th) (p < 0.05) than the control subjects. After adjusting for BMI, disease duration, and insulin dose, juvenile-onset patients tended to have lower trabecular vBMD, BV/TV, Tb.Th, and intracortical porosity (Ct.Po) than adult-onset patients. At the tibia, adult-onset patients displayed lower total vBMD, lower Ct. vBMD, and higher Ct.Po (p < 0.05), while juvenile-onset patients had lower Tb.Th and standard deviation of trabecular number (1/Tb.N.SD) (p < 0.05) than control subjects. After adjustment for covariates, adult-onset patients tended to have higher cortical pore diameter (Ct.Po.Dm) than juvenile-onset patients.

T1D patients were associated with compromised bone microarchitecture, adult-onset and juvenile-onset T1D patients demonstrated some differences in cortical and trabecular microarchitecture.

Patients with type 1 diabetes has an increased risk of fracture. We wished to evaluate estimated bone strength in children and adolescents with type 1 diabetes and assess peripheral bone geometry, volumetric bone mineral density (vBMD) and microarchitecture.

In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) was performed of the radius and tibia in 84 children with type 1 diabetes and 55 healthy sibling controls. Estimated bone strength was assessed using a microfinite element analysis solver. Multivariate regression analyses were performed adjusting for age, sex, height and body mass index.

The median age was 13.0 years in the diabetes group vs 11.5 years in healthy sibling controls. The median (range) diabetes duration was 4.2 (0.4-15.9) years; median (range) latest year Hb1Ac was 7.8 (5.9-11.8) % (61.8 (41-106) mmol/mol). In adjusted analyses, patients with type 1 diabetes had reduced estimated bone strength in both radius, β -390.6 (-621.2 to -159.9) N, p=0.001, and tibia, β -891.9 (-1321 to -462.9) N, p<0.001. In the radius and tibia, children with type 1 diabetes had reduced cortical area, trabecular vBMD, trabecular number and trabecular bone volume fraction and increased trabecular inhomogeneity, adjusted p<0.05 for all. Latest year HbA1c was negatively correlated with bone microarchitecture (radius and tibia), trabecular vBMD and estimated bone strength (tibia).

Children with type 1 diabetes had reduced estimated bone strength. This reduced bone strength could partly be explained by reduced trabecular bone mineral density, adverse microarchitecture and reduced cortical area. We also found increasing latest year HbA1c to be associated with several adverse changes in bone parameters. HR-pQCT holds potential to identify early adverse bone changes and to explain the increased fracture risk in young patients with type 1 diabetes.

Adults with type 1 diabetes mellitus (T1D) have decreased bone mineral density (BMD). Our study aimed at determining BMD and the association to metabolic control in children and adolescents with T1D.

244 patients (113 girls) with a median age of 14.3 years and T1D duration of 1-16 years were included. A dual-energy X-ray absorptiometry scan assessed BMD Z-scores excluding the head (total body less head, TBLH). TBLH-BMD were then investigated for associations to diabetes relevant variables such as HbA1c, insulin treatment, anthropometry and physical activity.

In all participants the TBLH-BMD Z-score (0.22 ± 0.96) was significantly higher than the references. Separated by sex, TBLH-BMD Z-score in boys (0.11 ± 0.84) was no different from healthy peers whereas TBLH-BMD Z-score was significantly higher in girls (0.36 ± 1.09). The higher TBLH-BMD Z-score in girls were explained by higher BMI Z-scores. Participants with assumed final height (based on age) had an average TBLH-BMD Z-score of 0.78 ± 1.06, significantly higher than references independent of gender, HbA1c, height- and weight Z-scores. Multiple regression analyses showed that TBLH BMD Z-score associated negatively to HbA1c (P = 0.003), pump treatment (P = 0.019) and screen-time (P = 0.005) and positively to weight Z-score (P < 0.001). Physical activity, sex and puberty did not significantly associate to TBLH-BMD Z-score.

Unlike adults with T1D, BMD is not decreased in children and adolescents with T1D and even elevated after attained final height. As HbA1c negatively associates to BMD, decreased BMD may progress over time. Whether changes in microarchitecture or bone metabolism precede changes in BMD needs further investigation.

Fracture risk in people with type 1 diabetes (T1D) is higher than their peers without diabetes.

To compare bone mineral density (BMD) across the lifespan in individuals with T1D and age- and sex-matched healthy controls.

Cross-sectional.

Subjects (5-71 years) with T1D and matched controls from ongoing research studies at Barbara Davis Center for Diabetes.

Participants with lumbar spine BMD by dual X-ray absorptiometry (DXA) were divided into 2 groups: children ≤20 years and adults >20 years.

None.

Comparison of BMD by diabetes status across age groups and sex using a linear least squares model adjusted for age and body mass index (body mass index (BMI) for adults; and BMI z-score in children).

Lumbar spine BMD from 194 patients with T1D and 156 controls were analyzed. There was no difference in age- and BMI-adjusted lumbar spine BMD between patients with T1D and controls: among male children (least squares mean ± standard error of the mean [LSM ± SEM]; 0.80 ± 0.01 vs 0.80 ± 0.02 g/cm2, P = .98) or adults (1.01 ± 0.03 vs 1.01 ± 0.03 g/cm2, P = .95), and female children (0.78 ± 0.02 vs 0.81 ± 0.02 g/cm2, P = .23) or adults (0.98 ± 0.02 vs 1.01 ± 0.02 g/cm2, P = .19). Lumbar spine (0.98 ± 0.02 vs 1.04 ± 0.02 g/cm2, P = .05), femoral neck (0.71 ± 0.02 vs 0.79 ± 0.02 g/cm2, P = .003), and total hip (0.84 ± 0.02 vs 0.91 ± 0.02, P = .005) BMD was lower among postmenopausal women with T1D than postmenopausal women without diabetes.

Across age groups, lumbar spine BMD was similar in patients with T1D compared with age- and sex-matched participants without diabetes, except postmenopausal females with T1D had lower lumbar spine, femoral neck, and total hip BMD.

There is a need for a non-invasive, affordable, and reliable method for bone health screening in pediatric patients at risk.

To assess Bone Health Index (BHI) in pediatric patients with type 1 diabetes (T1D) and its relation to bone metabolism, age at onset, duration, control, and insulin dose.

Left-hand radiographs were obtained from 65 patients with T1D, mean age 11.23 ± 3.89 years, mean disease duration 5.23 ± 3.76 years and mean glycosylated hemoglobin (HbA1c)-83 mmol/mol (9.7%). Blood and 24 hours urine samples were collected for bone and mineral metabolism assessment. BoneXpert was used to determine BHI, Bone Health Index standard deviation score (BHI SDS), and bone age.

Mean BHI SDS was -1.15 ± 1.19 (n = 54). In 20.37% (n = 11) BHI SDS was < -2SD with mean value -2.82 ± 0. 69, P < .001. These patients had lower levels of beta cross laps (0.77  ± 0.33 ng/mL vs 1.17 ± 0.47 ng/mL), osteocalcin (47.20 ± 14.07 ng/mL vs 75.91 ± 32.08 ng/mL), serum magnesium (0.79 ± 0.05 mmol/L vs 0.83 ± 0.06 mmol/L) and phosphorus (1.48 ± 0.29 mmol/L vs 1.71 ± 0.28 mmol/L) but higher ionized calcium (1.29 ± 0.04 mmol/L vs 1.26 ± 0.05 mmol/L), P < .05, compared to patients with BHI SDS in the normal range. We found a positive correlation between BHI SDS and age at manifestation (r = 0.307, P = 0.024) and a negative one with disease duration (r = -0.284, P = .038). No correlations were found with HbA1c, insulin dose, height, weight, BMI.

To the best of our knowledge, this is the first study to assess bone health in pediatric patients with T1D using BHI. We found significantly decreased cortical bone density and bone turnover in 20.37%. Earlier age at onset and diabetes duration may have a negative impact on cortical bone density in patients with poor control. Longitudinal studies are needed to follow changes or to assess future interventions.

Type 1 diabetes (T1D) is associated with an increased fracture risk across the life course. The effects on bone accrual early in the disease are unknown.

To characterize changes in bone density and structure over the year following diagnosis of T1D and to identify contributors to impaired bone accrual.

Prospective cohort study.

Academic children's hospital.

Thirty-six children, ages 7 to 17 years, enrolled at diagnosis of T1D.

Whole body and regional dual-energy X-ray absorptiometry and tibia peripheral quantitative computed tomography obtained at baseline and 12 months. The primary outcome was bone accrual assessed by bone mineral content (BMC) and areal bone mineral density (aBMD) velocity z score.

Participants had low total body less head (TBLH) BMC (z = -0.46 ± 0.76), femoral neck aBMD (z = -0.57 ± 0.99), and tibia cortical volumetric BMD (z = -0.44 ± 1.11) at diagnosis, compared with reference data, P < 0.05. TBLH BMC velocity in the year following diagnosis was lower in participants with poor (hemoglobin A1c ≥7.5%) vs good (hemoglobin A1c <7.5%) glycemic control at 12 months, z = -0.36 ± 0.84 vs 0.58 ± 0.71, P = 0.003. TBLH BMC velocity was correlated with gains in tibia cortical area (R = 0.71, P = 0.003) and periosteal circumference (R = 0.67, P = 0.007) z scores in participants with good, but not poor control.

Our results suggest that the adverse effects of T1D on BMD develop early in the disease. Bone accrual following diagnosis was impaired in participants with poor glycemic control and appeared to be mediated by diminished bone formation on the periosteal surface.

This study compared bone health in youth with type 1 diabetes and celiac disease (CD) versus type 1 diabetes alone.

This was a case-control study of 42 youth with coexisting type 1 diabetes and CD and 40 with type 1 diabetes matched for age, sex, diabetes duration, and HbA_1c. Bone mineral density (BMD), bone mineral content (BMC), and BMC-to-lean tissue mass (LTM) ratio were measured using DXA and reported as z-scores for height. Total, trabecular, and cortical bone and muscle parameters were measured using peripheral quantitative computed tomography (pQCT) and reported as z-scores for age.

Mean age at assessment was 14.3 ± 3.1 years; diabetes duration, 8.0 ± 3.5 years; HbA_1c, 8.2 ± 1.5% (66 ± 5 mmol/mol); and 25-hydroxy vitamin D, 71 ± 21 nmol/L. Comparing youth with coexisting CD versus type 1 diabetes alone, DXA showed lower BMC-to-LTM ratio (0.37 ± 1.12 vs. 0.73 ± 2.23, P = 0.007) but no difference in total BMD. Youth with coexisting CD also had lower BMC-to-LTM ratio versus the general population (P = 0.04). Radial pQCT showed lower total BMC (-0.92 ± 1.40 vs. -0.26 ± 1.23, P = 0.03) despite similar bone and muscle cross-sectional area. In multivariable linear regression, lower BMC was associated with higher insulin dose (P = 0.03) but not HbA_1c.

Youth with both type 1 diabetes and CD have lower BMC relative to LTM and lower BMC, indicating abnormal trabecular and cortical bone development despite similar bone and muscle size. These findings suggest that the two conditions confer a lower bone turnover state. We recommend further examination of bone health in this population; future research should examine early interventions to improve bone health.

Women with type 1 diabetes (T1D) are at increased risk for fracture. We studied the association of T1D and young age at T1D onset (T1D onset before 20 years) on bone structural quality. 24 postmenopausal women with T1D (mean age 60.9 years, mean T1D duration 41.7 years) and 22 age, sex- and body mass index (BMI)-matched controls underwent dual X-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the lumbar spine, hip and distal radius. Bone mass, geometry and estimated bone strength were assessed at distal and shaft of non-dominant radius and tibia using peripheral quantitative computed tomography (pQCT). Postmenopausal women with T1D had lower trabecular volumetric bone mineral density (vBMD) (LSM ± SEM; 166.1 ± 8.2 vs 195.9 ± 8.3 mg/cm3, p = 0.02) and compressive bone strength (24.6 ± 1.8 vs 30.1 ± 1.9 mg2/mm4, p = 0.04) at the distal radius compared to controls adjusting for age, BMI and radius length. At the distal radius, patients with young onset T1D had lower total vBMD (258.7 ± 19.7 vs 350.8 ± 26.1 mg/cm3, p = 0.02) and trabecular vBMD (141.4 ± 11.6 vs 213.6 ± 15.4 mg/cm3, p = 0.003) compared to adult onset T1D patients adjusting for age, BMI and the radius length. At the tibial shaft, young onset T1D patients had larger endosteal circumference (39.1 ± 1.2 vs 32.1 ± 1.6 mm, p = 0.005) with similar periosteal circumference (67.1 ± 0.9 vs 65.1 ± 1.2 mm, p = 0.2) resulting in reduced cortical thickness (4.4 ± 0.1 vs 5.2 ± 0.1 mm, p = 0.004) compared to adult onset T1D patients adjusting for age, BMI and the tibia length. There was no difference in the lumbar spine, femoral neck, total hip and distal radius DXA-measured aBMD between subjects with T1D and controls. T1D is associated with lower trabecular vBMD at the distal radius. T1D onset before age 20 is associated with cortical bone size deficits at the tibial shaft.

Diabetes mellitus (DM) has been associated with an increased risk of fractures. However, the effect of glycemic control on the risk of fracture is not well understood.

To evaluate the association between glycemic control and the risk of low-trauma fractures in patients with type 1 DM (T1DM) and type 2 DM (T2DM).

Nested case-control analysis.

UK-based Clinical Practice Research Datalink.

The study population was patients whose T1DM or T2DM had been newly diagnosed between 1995 and 2015. The cases were patients with a low-trauma fracture after DM onset. We matched four controls to each case by age, sex, general practice, fracture date, and DM type and duration.

Conditional logistic regression analyses were performed, adjusted for covariates, including body mass index, smoking, DM complications and medications.

The study population included 3329 patients with T1DM and 44,275 patients with T2DM. The median duration between DM onset and fracture date was 4.5 years for both T1DM and T2DM. The risk of fracture was increased in the patients with T1DM with a mean hemoglobin A1c >8.0% (adjusted OR, 1.39; 95% CI, 1.06 to 1.83) compared with those patients with T1DM and a mean hemoglobin A1c ≤7.0%. No such effect was found in the patients with T2DM. Independently of glycemic control, the risk of fracture was elevated in patients with T2DM and the current use of rosiglitazone and pioglitazone.

The effect of glycemic control on the risk of low-trauma fracture differs between patients with T1DM and T2DM. Poor glycemic control increased the risk of fractures in patients with T1DM but not in those with T2DM.

To understand the effect of type 1 diabetes (T1D) on bone mineral content (BMC) and bone density (BMD), we studied 125 T1D adolescents and 80 pubertal stage matched controls. T1D was associated with lower whole-body BMC and BMD compared to controls, even when adjusted for age, sex and sex hormones.

Disturbed bone turnover, osteoporosis, and increased fracture risk are late complications of insulin-dependent diabetes mellitus. Little is known about how far and to what extent can glycaemic control of type 1 diabetes mellitus (T1DM) prevent disturbances of bone health and body composition during the growth and maturation period.

The aim of this cross-sectional study was to compare the skeletal status outcomes and body composition between patients stratified by glycaemic control (1-year HbA1c levels) into well- and poorly-controlled subgroups in a population of T1DM adolescents, that is, <8% and ≥8%, respectively.

Skeletal status and body composition were evaluated in 60 adolescents with T1DM (53.3% female; mean aged: 15.1 ± 1.9 years; disease duration: 5.1 ± 3.9 years) using dual energy X-ray absorptiometry (GE Prodigy). The results were compared to age- and sex-adjusted reference values for healthy controls. The calculated Z-scores of different metabolic control subgroups were compared. Clinical data was also assessed.

As evidenced by Z-scores, patients with T1DM revealed a significantly lower TBBMD (total body bone mineral density), TBBMC (total body bone mineral content), S24BMD (bone mineral density of lumbar spine L2-L4), and TBBMC/LBM ratio (total body bone mineral content/lean body mass), but higher FM (fat mass) and FM/LBM ratio (fat mass/lean body mass) values compared to an age- and sex-adjusted general population. The subset (43.3% patients) with poor metabolic control (HbA1c ≥ 8%) had lower TBBMD, TBBMC, and LBM compared to respective values noted in the HbA1c < 8% group, after adjusting for confounders (mean Z-scores: -0.74 vs. -0.10, p = 0.037; -0.67 vs. +0.01, p = 0.026; and -0.45 vs. +0.20, p = 0.043, respectively). Additionally, we found a significant difference in the TBBMC/LBM ratio (relative bone strength index) between the metabolic groups (-0.58 vs. -0.07; p = 0.021). A statistically significant negative correlation between 1-year HbA1c levels and Z-scores of TBBMD, TBBMC, and LBM was also observed. In patients with longer disease duration, a significant negative correlation was established only for TBBMD, after adjusting for confounders. The relationships between densitometric values and age at onset of T1DM and sex were not significant and showed no relation to any of the analysed parameters of the disease course.

Findings from this study of adolescents with T1DM indicate that the lower Z-scores of TBBMD, TBBMC, and LBM as well as the TBBMC/LBM ratio are associated with increased HbA1c levels. Their recognition can be crucial in directing strategies to optimise metabolic control and improve diabetes management for bone development and maintenance in adolescents with T1DM.

In a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD.

To determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers.

Longitudinal observational study.

Urban community.

Forty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later.

BMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers.

After adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies.

There is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.

Substantial evidence exists that diabetes mellitus is associated with an increased risk of osteoporotic fractures. Low bone strength as well as bone extrinsic factors are probably contributing to the increased bone fragility in diabetes. Bone density and quality are important determinants of bone strength. Although bone mineral density (BMD) and the fracture risk assessment tool (FRAX) are very useful clinical tools in assessing bone strength, they may underestimate the fracture risk in diabetes mellitus. Through advances in new technologies such as trabecular bone score (TBS) and peripheral quantitative computed tomography (pQCT), we can better assess the bone quality and fracture risk of patients with diabetes mellitus. Invasive assessments such as microindentation and histomorphometry have been great complement to the existing bone analysis techniques. Bone turnover markers have been found to be altered in diabetes mellitus patients and may be associated with fractures. This review will give a brief summary of the current development and clinical uses of these assessments.

This article reviews recent publications on the effect of type 1 diabetes (T1D) on fracture risk, bone mineral density (BMD), bone structure, and bone tissue quality. Possible fracture prevention strategies for patients with T1D have also been reviewed.

T1D is associated with substantially elevated fracture risk and modestly low BMD at the femoral neck. However, BMD alone does not explain higher observed fracture risk in T1D. T1D also affects bone macro- and microstructure, characterized by thinner cortices and trabecular bone changes such as thinner and more widely spaced trabeculae. Structural bone deficit is pronounced in the presence of microvascular complications. Tissue-level changes, such as accumulation of advanced glycation endproducts, detrimental alterations of the mineral phase because of low bone turnover, and occlusion of vascular channels in bone by mineralized tissue, are implicated in pathophysiology of bone fragility in T1D. There are no guidelines on screening and prevention of osteoporotic fractures in T1D.

More studies are needed to understand the influence of T1D on structural bone quality and tissue material properties. There is a need for a prospective study to evaluate better screening strategies for diagnosis and treatment of osteoporosis in T1D.

The effects of diabetes and diabetes therapy on bone are less known among clinicians. Traditionally, the emphasis of diabetes therapy has been on reducing cardiovascular risk by facilitating reductions in weight, blood pressure, blood sugar, systemic inflammation, and lipid levels. Now, with ample research demonstrating that patients with diabetes are more susceptible to bone fractures relative to controls, there has been a greater or renewed interest in studying the effects of diabetes therapy on bone. Interestingly, the majority of antidiabetic agents positively affect bone, but a few have detrimental effects. Specifically, although insulin has been demonstrated to be anabolic to bone, the rate of hypoglycemic episodes are increased with exogenous infusion; consequently, there is an increased fall and fracture frequency. Other agents such as thiazolidinediones have more direct negative effects on bone through transcriptional regulation. Even metabolic surgery, to a varying operation-dependent extent, exacerbates bone strength and may heighten fracture rate. The remaining diabetes agents seem to have neutral or positive effects on bone. With the increasing incidence of diabetes, it is more pertinent than ever to fully comprehend the effects of diabetes-related therapeutic modalities.

Adults with Type 1 diabetes mellitus show a high risk of bone fracture, probably as a consequence of a decreased bone mass and microarchitectural bone alterations. The aim of the study was to investigate the potential negative effects of type 1 diabetes on bone geometry, quality, and bone markers in a group of children and adolescents. 96 children, mean age 10.5 ± 3.1 years, agreed to participate to the study. Bone geometry was evaluated on digitalized X-rays at the level of the 2nd metacarpal bone. The following parameters were investigated and expressed as SDS: outer diameter (D), inner diameter (d), cortical area (CA), and medullary area (MA). Bone strength was evaluated as Bending Breaking Resistance Index (BBRI) from the geometric data. Bone turnover markers (PINP, CTX-I, and BAP), sclerostin, Dkk-1, PTH, and 25OH-Vitamin D were also assessed. A group of healthy 40 subjects of normal body weight and height served as controls for the bone markers. D (- 0.99 ± 0.98), d (- 0.41 ± 0.88), CA (- 0.85 ± 0.78), and MA (- 0.46 ± 0.78) were all significantly smaller than in controls (p < 0.01). BBRI was significantly lower (- 2.61 ± 2.18; p < 0.0001). PTH, PINP, and BAP were higher in the diabetic children. Multiple regression analysis showed that CA and D were influenced by insulin/Kg/day and by BMI, while d was influenced by PINP only. Type 1 diabetic children show smaller and weaker bones. The increased bone turnover could play a key role since it might amplify the deficit in bone strength associated with the inadequate osteoblastic activity caused by the disease itself.

We have previously shown that the intertrochanter of young and middle-aged patients with type 1 diabetes mellitus (T1DM) showed higher buckling ratio (an index of cortical instability) and lower volumetric bone mineral density (vBMD). However, we have not yet reported the detailed findings regarding the mechanical and density properties of the femoral neck. Therefore, we present a subanalysis of our previous study with the aim of further evaluating the middle third of the femoral neck via quadrant quantitative computed tomography in young and middle-aged patients with T1DM. Bone parameters in 4 anatomical quadrants (superoanterior [SA], inferoanterior [IA], inferoposterior [IP], and superoposterior [SP]) were cross-sectionally evaluated in 17 male T1DM patients and 18 sex-matched healthy controls aged between 18 and 49 yr using quadrant quantitative computed tomography analysis. Patients with T1DM had a thinner cortical thickness in the SP quadrant and a significantly lower cortical vBMD in the SA quadrant than the controls. The serum insulin-like growth factor-1 values in patients with T1DM were positively correlated with the average cortical thickness in the SA quadrant and the average trabecular vBMD in the SP quadrant of the femoral neck. The cortical thickness in controls was negatively correlated with age in the SP and IP quadrants. The cortical thickness in patients with T1DM showed no correlation with age in all quadrants. The fragility of the femoral neck was remarkable in the superior region of patients with T1DM. Insulin-like growth factor-1 may play an important role in superior cortical thinning and in lowering cortical vBMD. Furthermore, in young and middle-aged men with T1DM, the structure of the femoral neck exhibits similar changes as those observed with aging.

Sarcopenia and osteoporosis are among the late complications of type 1 diabetes (T1D) in adults. Whether and to what extent musculoskeletal impairment is present in childhood and adolescence has yet to be determined. The aim of this study was to assess volumetric bone mineral density (BMD) and dynamic muscle function in adolescents with T1D and to assess the clinical and biochemical predictors of their musculoskeletal system.

Ninety-five children and adolescents (59 boys and 36 girls, mean age 16.2±1.2years) with T1D were included in this cross-sectional study. Study participants were divided into two groups according to the duration of the disease (<6years and >9years, respectively). Volumetric BMD of the non-dominant tibia was assessed using peripheral quantitative computed tomography (pQCT). Dynamic muscle function was evaluated using jumping mechanography. Gender- and height-specific Z-scores were calculated using published reference data. HbA1c was evaluated retrospectively as an average over the past 5years.

Relative muscle power (P_max/mass) and force (F_max/body weight) were significantly decreased in T1D subjects (mean Z-scores -0.4±1.0; p<0.001, and -0.3±1.1; p<0.01, respectively). The duration of T1D negatively affected P_max/mass (p<0.01) but not F_max/body weight (p=0.54). Patients with T1D had also decreased trabecular BMD, the Strength-Strain Index and cortical thickness (mean Z-scores -0.8±1.3; -0.5±0.8 and -1.1±0.8, respectively, p<0.001 for all) whereas cortical BMD was increased when compared to controls (Z-score 1.2±0.90, p<0.001). No association was observed between the HbA1c and 25-hydroxyvitamin D levels and bone or muscle parameters.

T1D influences the musculoskeletal system in adolescence. Decreased muscle function could contribute to the osteoporosis reported in adult diabetic patients.

Type 1 and type 2 diabetes are generally accepted to be associated with increased bone fracture risk. However, the pathophysiological mechanisms of diabetic bone disease are poorly understood, and whether the associated increased skeletal fragility is a comorbidity or a complication of diabetes remains under debate. Although there is some indication of a direct deleterious effect of microangiopathy on bone, the evidence is open to question, and whether diabetic osteopathy can be classified as a chronic, microvascular complication of diabetes remains uncertain. Here, we review the current knowledge of potential contributory factors to diabetic bone disease, particularly the association between diabetic microangiopathy and bone mineral density, bone structure, and bone turnover. Additionally, we discuss and propose a pathophysiological model of the effects of diabetic microvascular disease on bone, and examine the progression of bone disease alongside the evolution of diabetes.

The increased fracture risk associated with type 1 diabetes mellitus (T1DM) remains unexplained by traditional risk factors such as low areal bone mineral density (aBMD). Nonetheless, few data exist on other determinants of bone strength in T1DM, including volumetric bone mineral density (vBMD) and bone geometry.

We compared areal and volumetric bone parameters and cortical bone geometry in adult T1DM patients and sex- and age-matched controls.

Cross-sectional study including 64 adult T1DM patients (38 men; mean age, 41.1 ± 8.1 years) and 63 sex- and age-matched controls.

Areal bone parameters using dual-energy X-ray absorptiometry; volumetric bone parameters and cortical bone geometry using peripheral quantitative computed tomography.

T1DM was associated with lower aBMD at the total body, femoral neck, and total hip; lower trabecular vBMD at the distal radius; and higher cortical but lower total vBMD at the radial shaft. In addition, subjects with T1DM had a similar periosteal but larger endosteal circumference, smaller cortical thickness, and lower cortical over total bone area ratio. Differences in bone parameters could not be explained by differences in bone turnover markers or body composition, but cortical area was inversely associated with glycemic variability and long-term glycemic control.

Besides decreased aBMD and trabecular vBMD, adult T1DM patients present with a cortical bone size deficit, which may contribute to their increased fracture risk. This deficit is mainly situated at the endosteal envelope, suggesting imbalanced remodeling rather than compromised modeling processes as the underlying mechanism.

Diabetes mellitus, both type 1 and type 2 (T2DM), is associated with decreased bone strength as well as increased fracture risk. Bone mineral density is decreased in type 1 diabetes but increased in T2DM, compared with controls. This suggests alterations in bone quality are a major player in the pathogenesis of fragility fractures in patients with diabetes. The link between diabetes and bone appears to be mediated by complex pathways, including the insulin-insulin growth factors system, accumulation of advanced glycation end-products in bone collagen, microangiopathy, and increased bone marrow fat content. Bone fragility in T2DM, which is not reflected by bone mineral density and bone mass reduction, depends on deterioration of bone quality. Also, at least in T2DM, the classical diagnosis of osteoporosis by dual-energy X-ray absorptiometry and the fracture risk estimation by FRAX (fracture risk assessment tool) are only partially useful in assessing fracture risk. Trabecular bone score and trabecular bone score-adjusted FRAX offer an enhanced estimation of fracture risk in these patients. Specific risk stratification criteria are needed in the future. The development of improved methods to assess the material properties of bone to better characterize fracture risk is also a priority. Adequate glycemic control is generally associated with decreased fracture risk, with the exception of specific antidiabetics (thiazolidinediones, canagliflozin) that have been shown to have a detrimental effect. Most currently used antiosteoporotic treatments seem equally effective in diabetic patients as compared with patients without diabetes, but clinical data regarding the reduction in fracture risk specifically in patients with diabetes mellitus are lacking.

Streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) decreases trabecular bone volume and bone strength in rodents. The current study investigated the potential protective effects of aerobic endurance training (AET) on bone in STZ-induced T1DM young adult rats. Sixty-four 8-week-old male Sprague-Dawley rats were randomly divided into 4 groups of 16: control non-T1DM sedentary (CS) and exercised (CX), T1DM sedentary (DS) and exercised (DX). Blood glucose was maintained at 9-15 mmol/L using subcutaneously implanted insulin pellets (Linplant, Linshin Canada, Inc.). AET was performed at ~75-85% VO_2max for 1 h/day, 5 day/week for 10 weeks. Areal and volumetric bone mineral density (aBMD and vBMD; excised femur) were measured using dual-energy X-ray absorptiometry (DXA; QDR 4500A) and micro computed tomography (μCT; Aloka). Bone strength was tested using a 3-point bending test (Instron 5544 Load Frame). Two-way ANOVA was used to test for T1DM and exercise differences followed by Tukey's HSD tests for interaction effects; significance was set at P < 0.05. T1DM had lower body weight (18.0%), aBMD (8.6%), cortical vBMD (1.6%), trabecular vBMD (2.1%), maximum load at break (22.2%), and increased elastic modulus (11.3%) vs. control (P < 0.001). Exercise in T1DM further decreased body weight (4.7%) vs. sedentary (P = 0.043) and maximum extension during the bending test that demonstrated DX was increased (7.3%) vs. CX (P = 0.033). There were no other beneficial effects of exercise on bone. These results suggest that 10 weeks of AET in rats do not have protective effects on bone in the short term and that T1DM rats have compromised bone health.

The skeleton is adversely affected by type 1 diabetes (T1D). Patients with T1D of both sexes have an increased risk of fracture that begins in childhood and extends across the entire lifespan. T1D is characterized by mild to modest deficits in bone density, structure, and microarchitecture. Current evidence suggests that the observed bone deficits in T1D are the result of impaired bone formation rather than increased bone resorption. There is emerging data that bone quality is impaired in T1D, which may explain the findings that fracture risk is elevated out of proportion to the degree of bone mineral deficit. In this review, we summarize the current knowledge regarding the epidemiology of skeletal health in T1D. Given the high individual and societal burden of osteoporotic fracture, there is an urgent need to better understand the etiology of T1D-related bone disease so that clinical strategies to prevent fracture can be developed.

Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of "bone quality," rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health.

Peripheral quantitative computed tomography provides an automatical scan analysis of trabecular and cortical bone compartments, calculating not only their bone mineral density (BMD), but also bone geometrical parameters, such as marrow and cortical Cross-Sectional Area (CSA), Cortical Thickness (CoTh), both periosteal and endosteal circumference, as well as biomechanical parameters like Cross-Sectional Moment of Inertia (CSMI), a measure of bending, polar moment of inertia, indicating bone strength in torsion, and Strength Strain Index (SSI). Also CSA of muscle and fat can be extracted. Muscles, which are thought to stimulate bones to adapt their geometry and mineral content, are determinant to preserve or increase bone strength; thus, pQCT provides an evaluation of the functional 'muscle-bone unit', defined as BMC/muscle CSA ratio. This functional approach to bone densitometry can establish if bone strength is normally adapted to the muscle force, and if muscle force is adequate for body size, providing more detailed insights to targeted strategies for the prevention and treatment of bone fragility. The present paper offers an extensive review of technical features of pQCT and its possible clinical application in the diagnostic of bone status as well as in the monitoring of the skeleton's health follow-up.

Fracture risk is significantly increased in both type 1 and type 2 diabetes, and individuals with diabetes experience worse fracture outcomes than normoglycemic individuals. Factors that increase fracture risk include lower bone mass in type 1 diabetes and compromised skeletal quality and strength despite preserved bone density in type 2 diabetes, as well as the effects of comorbidities such as diabetic macro- and microvascular complications. In this Perspective, we assess the developing scientific knowledge regarding the epidemiology and pathophysiology of skeletal fragility in patients with diabetes and the emerging data on the prediction, treatment, and outcomes of fractures in individuals with type 1 and type 2 diabetes.

Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.

Low bone mineral density has been reported in children and adolescents with type 1 diabetes (T1DM). The aims of this cross-sectional study were to study growth, serum IGF1 concentrations and bone health parameters assessed by Dual Energy X-ray Absorptiometry (DXA).

Height was measured and converted to Z scores (HAZ). Serum IGF1 concentrations were measured (ELISA) in a subset. Bone mineral content for total body (less head) (TBBMC) and lumbar spine was measured (n=170, 77 boys, 6-16years old) and converted to Z scores using local normative data.

Mean age was 11.1±3.8years, disease duration was 2.2±2.5years and HbA1C was 10.1±1.8%. Diabetic children were shorter than reference population (HAZ -0.6±1.1); Z scores for height and total body bone area (TBBA) for height were <-2SD in 12% & 6% respectively. Serum IGF1 Z scores were lower amongst group with longer disease duration (-1.58±1.3 vs -2.63±0.7; P=0.037). Disease duration (β=-0.180, P=0.000) and metabolic control (HbA1C; β=-0.096, P=0.042) were negative predictors of HAZ and TBBA for height Z in younger children. Using the Molgaard approach, children with longer disease duration had lower HAZ (-0.31±0.92 vs -1.28±1.11; P=0.000; "short bones") and TBBA for height Z scores (0.12±1.62 vs -0.53±0.94; P=0.044; "slender bones"). Older children (tanner stages 4 and 5) had lower BMC and BA as compared to reference population possibly due to delayed growth spurt.

Longer duration of diabetes was associated with shorter and slender but appropriately mineralized bones. Small and slender bones in diabetic children may increase risk of fragility fractures in the future. This article is part of a Special Issue entitled "Bone and diabetes".

Diabetes adversely impacts many organ systems including the skeleton. Clinical trials have revealed a startling elevation in fracture risk in diabetic patients. Bone fractures can be life threatening: nearly 1 in 6 hip fracture patients die within one year. Because physical exercise is proven to improve bone properties and reduce fracture risk in non-diabetic subjects, we tested its efficacy in type 1 diabetes. We hypothesized that diabetic bone's response to anabolic mechanical loading would be attenuated, partially due to impaired mechanosensing of osteocytes under hyperglycemia. Heterozygous C57BL/6-Ins2(Akita)/J (Akita) male and female diabetic mice and their age- and gender-matched wild-type (WT) C57BL/6J controls (7-month-old, N=5-7 mice/group) were subjected to unilateral axial ulnar loading with a peak strain of 3500 με at 2 Hz and 3 min/day for 5 days. The Akita female mice, which exhibited a relatively normal body weight and a mild 40% elevation of blood glucose level, responded with increased bone formation (+6.5% in Ct.B.Ar, and 4 to 36-fold increase in Ec.BFR/BS and Ps.BFR/BS), and the loading effects, in terms of changes of static and dynamic indices, did not differ between Akita and WT females (p ≥ 0.1). However, loading-induced anabolic effects were greatly diminished in Akita males, which exhibited reduced body weight, severe hyperglycemia (+230%), diminished bone formation (ΔCt.B.Ar: 0.003 vs. 0.030 mm(2), p=0.005), and suppressed periosteal bone appositions (ΔPs.BFR/BS, p=0.02). Hyperglycemia (25 mM glucose) was further found to impair the flow-induced intracellular calcium signaling in MLO-Y4 osteocytes, and significantly inhibited the flow-induced downstream responses including reduction in apoptosis and sRANKL secretion and PGE2 release. These results, along with previous findings showing adverse effects of hyperglycemia on osteoblasts and mesenchymal stem cells, suggest that failure to maintain normal glucose levels may impair bone's responses to mechanical loading in diabetics.

The primary goal of this cross-sectional in vivo study was to assess peripheral bone microarchitecture, bone strength, and bone remodeling in adult type 1 diabetes (T1D) patients with and without diabetic microvascular disease (MVD+ and MVD-, respectively) and to compare them with age-, gender-, and height-matched healthy control subjects (CoMVD+ and CoMVD-, respectively). The secondary goal was to assess differences in MVD- and MVD+ patients. Fifty-five patients with T1DM (MVD+ group: n = 29) were recruited from the Funen Diabetes Database. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal radius and tibia, and biochemical markers of bone turnover were performed in all participants. There were no significant differences in HR-pQCT parameters between MVD- and CoMVD- subjects. In contrast, MVD+ patients had larger total and trabecular bone areas (p = 0.04 and p = 0.02, respectively), lower total, trabecular, and cortical volumetric bone mineral density (vBMD) (p < 0.01, p < 0.04, and p < 0.02, respectively), and thinner cortex (p = 0.03) at the radius, and lower total and trabecular vBMD (p = 0.01 and p = 0.02, respectively) at the tibia in comparison to CoMVD+. MVD+ patients also exhibited lower total and trabecular vBMD (radius p = 0.01, tibia p < 0.01), trabecular thickness (radius p = 0.01), estimated bone strength, and greater trabecular separation (radius p = 0.01, tibia p < 0.01) and network inhomogeneity (radius p = 0.01, tibia p < 0.01) in comparison to MVD- patients. These differences remained significant after adjustment for age, body mass index, gender, disease duration, and glycemic control (average glycated hemoglobin over the previous 3 years). Although biochemical markers of bone turnover were significantly lower in MVD+ and MVD- groups in comparison to controls, they were similar between the MVD+ and MVD- groups. The results of our study suggest that the presence of MVD was associated with deficits in cortical and trabecular bone vBMD and microarchitecture that could partly explain the excess skeletal fragility observed in these patients.