Short summary

The effect of Type 1 Diabetes Mellitus (T1DM) on bone properties in children and adolecents is unclear. It may be that a loss in bone density and strength is already present before adulthood. A loss that may be life-long. The aim of this study is to explore the density and structure of bones in children with T1DM. 80 children and adolescents will be recruited and examined with multiple scanning modalities in search of signs of a decreased bone density and strength. This will provide important insight into the effect of T1DM on the growing bone.

Rationale

T1DM is a severe, autoimmune chronic disease with increasing incidence, currently affecting approximately 3800 children and adolescents in Denmark. T1DM imposes significant risks of long-term complications, including nephropathy, neuropathy and vascular complications. Less well-known, patients with T1DM also have an up to six-fold increased fracture risk. A large cohort study has shown this risk to begin in childhood and extending across lifespan. The fragility fractures and delayed bone healing resulting from low bone strength in T1DM are clinical relevant, as major skeleton complications reduce quality of life in T1DM patients.

The mechanism underlying diabetic osteopenia and bone fragility is still not fully understood and is probably multifactorial.

Adult patients with T1DM seem to have impaired bone formation with low levels of osteocalcin and increased bone resorption. Hyperglycaemia may damage the osteoblasts, inhibit osteoblast differentiation and activity and might also result in increase osteoclast formation and activity. Insulin is likely to have an anabolic effect on the bone, which may be suppressed in the hypoinsulinemic state of T1DM. Moreover, s-Insulin-like Growth Factor-1 (IGF-1) is decreased in patients with T1DM, which may result in low peak bone mass.

The incidence of T1DM in childhood and adolescence peaks between the ages of 10-14 years, but may be present in preschool children. Accordingly, bone effects may occur before the attainment of peak bone mass, which potentially may worsen the diabetic osteopenia. In spite of this, there is little knowledge regarding the bone structure and quality in children and adolescents with T1DM.

Recent studies have shown that children and adolescents with T1DM also have impaired bone metabolism with reduced osteoblast and increased osteoclast signalling. As bones are extensively modelled in childhood and adolescence it may be hypothesized that the bone mineral density (BMD) and structure would be altered in children with T1DM, but the few studies on the topic have conflicting results and most studies are of an older date.

A few studies have found a risk of smaller bone size.

By Dual-energy X-ray Absorptiometry (DXA) scan, some studies have found an association between children and adolescents with T1DM and a lower BMD or bone mineral content (BMC), while others failed to find such associations.

Peripheral Quantitative Computed Tomography (pQCT) scan is a useful method to investigate BMD in diabetes patients. However, only a few previous studies have used this method. One study found the trabecular bone to be significantly decreased, but with only insignificant decreases in cortical bone and total bone density, potentially due the small sample size, n=21(15). Other studies found both trabecular and cortical BMC to be lower in T1DM patients , while another study found no difference in BMD by pQCT. Saha et al. found the most pronounced reduction in BMC among T1DM patients in the radial shaft, after controlling for child's sex. Boys were more affected than girls.

Description of the cohort

Population/participation:

Children and adolescents diagnosed with T1DM seen in the outpatient clinic at Hans Christian Andersen Children's Hospital, OUH (currently approximately 145 children and adolescents).

Based on power calculations, we aim to include 80 participant to the study cohort.

Inclusion criteria:

- Children and adolescents diagnosed with T1DM at Hans Christian Andersen Children's Hospital, OUH

- Current age 6-17 years

Exclusion criteria:

- Primary bone disease, e.g. infantile osteopetrosis

- Presence of other chronic diseases that may affect bone metabolism, e.g. celiac disease, thyroid disorder

- Previous and current treatment with medication that could alter the bone metabolism, e.g. systemic glucocorticoids (local glucocorticoid e.g. inhalation is not an exclusion criteria)

- The child is unable to corporate to the scanning procedures

Control Group :

As the pQCT-scan has never been preformed on children before, we will have a control group of up to 80 children without T1DM. 

When inviting the patients with T1DM we will also invite their siblings to participate as a control group for the pQCT scan. 

Inclusion criteria:

- Siblings to patients diagnosed with T1DM at Hans Christian Andersen Children's Hospital, OUH

- Current age 6-17 years

Exclusion criteria:

- Any kind of Diabetes Mellitus

- Primary bone disease, e.g. infantile osteopetrosis

- Presence of other chronic diseases that may affect bone metabolism, e.g. celiac disease, thyroid disorder

- Previous and current treatment with medication that could alter the bone metabolism, e.g. systemic glucocorticoids (local glucocorticoid e.g. inhalation is not an exclusion criteria)

- The child being unable to corporate to the scanning procedures

Data and biological material

Basic:  sex, weigth, Hight, tanner status

Medication, dietary supplements

Fractures

Debut of diabetes, HbA1C

Results from DXA scan and pQCT-scan

Collaborating researchers and departments

Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark

• Undergraduate student, Gitte Bjerg Fuusager
• Professor, PhD, MD, Henrik Thybo Christesen
• PhD, MD, Anders Jørgen Schou

Department of Endocrinology, Odense University Hospital, Odense, Denmark 

• PhD, MD, Anne Pernille Hermann

Department of Endocrinology, Odense University Hospital, Odense, Denmark

• PhD, MD, Vikram Shanbhogue