Findings
In children with type 1 diabetes, we identified reduced estimated bone strength measured as failure load in both tibia and radius. This reduced bone strength might be explained by a reduced trabecular bone mineral density, adverse microarchitecture and reduced cortical area. Moreover, increasing latest year HbA1c was associated with reduced trabecular number and increased inhomogeneity and in tibia also with reduced bone strength, trabecular vBMD and trabecular bone volume to tissue volume fraction.
In support of our findings, a recently published study by Mitchell et al examining young girls with type 1 diabetes using HR-pQCT likewise reported reduced estimated failure load and reduced trabecular vBMD, along with associations between increased HbA1c and decreased trabecular vBMD and altered microarchitecture.31 Earlier studies using pQCT have also reported trabecular bone deficits in young patients with type 1 diabetes.17 32 33 Our findings are in keeping with others studies in young patients with type 1 diabetes, where aBMD, vBMD or trabecular vBMD were negatively correlated to HbA1c and/or poor glycemic control.17 18 32
HR-pQCT supplied multiple data on early deficits in bone quality in children with type 1 diabetes. The trabecular number was reduced and the inhomogeneity was increased in both radius and tibia when having diabetes, consistent with deficiency in bone modeling. Interestingly, these two bone parameters were increasingly affected with increasing latest year HbA1c. HbA1c for the entire disease period showed similar trend, but the findings were only statistically significant for inhomogeneity in radius. Mean HbA1c for the entire disease period could be confounded by factors present within this period of possibly many years and is influenced by high HbA1c measurements at the time of diagnosis followed by a patient/parent learning curve. We believe that latest year HbA1c is the most interesting and relevant to report. Latest year HbA1c is reflecting recent glycemic control and likely superior to the most recently measured HbA1c value as one measurement may not reflect the more overall glycemic control of the child. We recognize that other observation periods than the latest year may be relevant to future research. Microarchitecture being affected by glycemic control of the latest year, but not necessarily the entire disease period is supporting a dynamic nature of bone modeling in children and adolescents and a potential for reversibility with improving HbA1c which have also been suggested earlier.34
In our study, we did not find any association between age of diabetes onset and bone parameters. All our cases were diagnosed with childhood onset type 1 diabetes. A study by Shah et al suggested that childhood onset type 1 diabetes has more deleterious effect on the bones than adult onset type 1 diabetes, but it is still unclear if this difference is the effect of diabetes during bone accrual or may be due to longer duration of diabetes.35
We have previously examined the same cohort described in this study using DXA evaluation but were not able to demonstrate decreased aBMD in the children with type 1 diabetes.12 Within this HR-pQCT study, the particularly trabecular bone changes were further supported by our finding of reduced trabecular bone vBMD, without significant reductions in cortical bone vBMD. The differential reduction in vBMD may contribute to the explanation of why the aBMD by DXA was normal in our cohort (and in other studies), as most of the mineral is found in the bone cortex. Whereas cortical bone vBMD was unchanged, the cortical bone area was reduced in our participants. The reduced bone area has been described in other studies,11 14 even though children with type 1 diabetes reach a normal final height.36 This reduced bone size could also be a confounder to aBMD by DXA. We believe our current findings demonstrate the superiority of HR-pQCT compared with DXA scan in identifying bone complications in type 1 diabetes at an early stage.
Strenghts and limitations
The principal strength of our study was the use of HR-pQCT to assess bone strength in children and adolescents with type 1 diabetes. HR-pQCT accurately assesses bone microarchitecture and also provides a novel way to non-invasively assess bone strength.37 To our knowledge, this method is the most accurate method to assess bone strength in vivo, but for technical reasons, only the distal peripheral skeleton can be assessed by this method. This scan technique provides a lot of parameters with the calculated failure load being the most interesting with the potential to predict fracture risk and therefore the focus of our attention. Our secondary outcomes were chosen to provide a possible explanation for differences in failure load, describing specific bone geometric parameters and microarchitecture parameters which we had predetermined before conducting the study. When having a lot of outcomes, there can be a risk of chance findings. We have limited our conclusions by only incorporating significant findings made in both tibia and radius. As these two measurements are independent of each other, the risk of having a chance finding in the same parameter at both sites would be small.
Another strength was our focus on patients with type 1 diabetes without comorbidities and the use of healthy siblings as our control group. Genetics account for a majority of the variations in bone structure and healthy siblings are in general more comparable in terms of genetics, lifestyle and socioeconomic status. Therefore, we chose siblings as the control group despite the possible limitations including missing populations-based differences.
Last, our cohort had no overt selection bias from non-participating Danish children with type 1 diabetes without comorbidity. 64% of the invited patients participated in the study. The main reasons for non-participation were comorbidities (17%) and lack of consent (16%) (figure 1). The latter was predominantly justified by lack of time on behalf of the participant or their parents, as the examinations were performed in daytime school and working hours.
Our study also had limitations. The CIs for many of our reported variables are wide. This is in part explained by the limitations in the size of our cohort; however, many of the reported bone variables also seem to be very varying across the cohort even after adjustment for known confounder such as age and sex. We recognize that this makes the study prone to type 2 error, and more associations may be discovered in a larger study. Despite of these limitations, many outcomes of interest, including failure load, have 95% CIs that does not include 0 and hence are statically significant. Also, some changes in microarchitecture might be harder to detect in the radius do to the greater amount of motion artifacts in this region.
Another limitation was the mean age difference of 1 year between the patients with diabetes and their sibling controls. We therefore adjusted for age, among other group differences, in our linear regression analyses, assuming linearity with age. Overall, the choice of sibling controls both had strengths and limitations. We were not able to report on pubertal stage at debut of diabetes. However, the mean age at debut was 7.9 years, allowing the assumption that the majority of the participants were prepubertal at diabetes debut. Even though we adjusted for sex and our analyses showed no interaction between diabetes and sex in relation to bone parameters, larger studies with stratification of sex would be preferred.
Our findings may not be valid in other cohorts with higher or lower HbA1c means as result of differences in blood glucose control. The population of our uptake region was by far of Danish ethnic origin and therefore the study may loss validity in other populations.
Moreover, daily insulin dose may be an important parameter to include in analyses, as bone size is positively influenced by insulin. This was not included in our study. Children with type 1 diabetes have obtained a normal final height after improvement of diabetes regulation by modern insulin therapy.36 In our cohort, the vast majority of children were treated with continuous subcutaneous insulin infusion (CSII) and therefore did not allow for analyses between treatment with multiple daily injections and CSII.
No difference in self-reported fracture prevalence was detected between patients and controls. However, this study was not designed to detect a difference in fracture between the groups due to low participant numbers and short observation time. Follow-up studies and large-scale studies are needed to address this question.
Future research
The mechanism behind the fragility of bones in type 1 diabetes is still not fully understood. Hyperglycemia may lead to increased production of advanced glycation end products, which may lead to osteoblastic apoptosis, decreased osteoblast proliferation and increased osteoclast activation.16 38 Reduced osteoblast and increased osteoclast signaling has been described in children and adolescents with type 1 diabetes,4 5 but further studies with bone turnover markers are needed to elucidate the underlying mechanisms causing altered bone structure in patients with type 1 diabetes.
The increased fracture risk in type 1 diabetes is highly relevant due to the morbidity and mortality associated with fractures. Fragility fractures resulting from low bone strength may be a significant cause of major skeleton complications, which reduces quality of life in patients with type 1 diabetes.39
Estimation of bone strength by aBMD from DXA scan is probably insufficient for patients with type 1 diabetes, as poor bone quality is a more likely cause for the elevated fracture risk.16 Our study highlights the limitations of DXA compared with HR-pQCT in children and adolescents. Although currently a research tool, HR-pQCT holds potential for use in the clinical diagnosis and management in osteoporosis and in type 1 diabetes. Prospective studies are needed to evaluate HR-pQCT as a tool to identify the fracture risk in individuals with type 1 diabetes.