Microarchitecture, Bone Strength and Fracture Risk in Long-term Type 1 Diabetes

Study Overview
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Brief Summary
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This single center case control study will assess differences in bone structure between women and men with longstanding type 1 diabetes (diabetes duration>/= 25 years) and healthy controls.

Detailed Description
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Based on a cross-sectional approach the investigators aim to assess microstructural, biomechanical and densitometric bone characteristics in patients with longstanding type 1 diabetes and age- and sex-matches controls. The investigators examine whether the presence of microvascular disease and/or poor diabetic control is associated with an altered bone microarchitecture and whether any such effect is independent of bone mineral density. Furthermore, the investigators aim to look into the relationship between an altered bone microarchitecture and advanced glycation end product (AGE) formation as well as biochemical markers of bone formation and bone turnover. The study aims to identify type 1 diabetic patients with high fracture risk by assessing the discriminatory power of parameters of cortical and trabecular microstructure measured via high resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and tibia and high resolution quantitative computed tomography (HR-QCT) of the proximal femur and tibia with and without adjustment for bone density.

Official Title
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Microarchitecture, Bone Strength and Fracture Risk in Long-term Type 1 Diabetes

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Diagnostic Test: Biochemical Tests
* Diagnostic Test: Osteodensitometry
* Diagnostic Test: Clinical Tests
* Diagnostic Test: HR-QCT
* Diagnostic Test: HR-pQCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: women and men with longstanding type 1 diabetes (age 40-80 years, BMI 18-37 kg/m2 and age- and sex matched non-diabetic controls presence of type 1 diabetes for at least 25 years (defined by history of Insulin treatment) Exclusion Criteria: Patients unable to give written informed consent, e.g. with severe dementia or patients not understanding German (or other local language) Any medical or psychiatric condition which would preclude the participant from adhering to the protocol Idiopathic or premenopausal osteoporosis or coexisting metabolic bone disease (e.g. Paget´s disease, primary hyperparathyroidism) Previous treatment with osteoporosis medication (bisphosphonates, denosumab) or intake of medications that are known to affect bone metabolism (e.g. steroids, anticonvulsants) within 6 months prior to enrollment Patients with medical conditions known to affect bone health ( e.g. metastatic bone disease, celiac disease, inflammatory bone disease, hypogonadism, thyrotoxicosis, hypercortisolism, chronic kidney disease stage IV and V (KDIGO), liver dysfunction (serum aspartate amino transferase (ASAT) >3 times the upper limit of normal) Inability to keep the extremities still for a few minutes of an HR-pQCT examination (e.g. Parkinson disease, spastic syndrome) Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: Identical diagnostic procedures will be performed in participants with type 1 diabetes and age- and sex-matched controls.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic<br>The investigators will examine all participants in the same way by performing biochemical tests, clinical tests, osteodensitometry, HRQCT and HRpQCT measurements. | Diagnostic Test: Biochemical Tests<br>* The investigators will perform blood tests in every participant.<br>Diagnostic Test: Osteodensitometry<br>* The investigators will perform an osteodensitometry in every participant.<br>* Other names: dual energy x-ray absorptiometry (DXA scan);Diagnostic Test: Clinical Tests<br>* The investigators perform the following clinical tests: vibration threshold test, monofilament test, chair rise test and timed up and go test in every participant.<br>Diagnostic Test: HR-QCT<br>* The investigators will perform HR-QCT measurements of the proximal femur and tibia in every participant.<br>Diagnostic Test: HR-pQCT<br>* The investigators will perform HR-pQCT measurements of the distal radius and distal tibia in every participant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| volumetric bone mineral density in mg hydroxyapatite (HA)/ccm | measured by HR-pQCT at the distal radius and tibia | through study completion, an average of 6 months | 
| cortical porosity in % | measured by HR-pQCT at the distal radius and tibia | through study completion, an average of 6 months | 
| bone stiffness in kilonewton (kN)/mm | a measure of bone strength, measured by HR-pQCT at the distal radius and tibia | through study completion, an average of 6 months | 
| failure load in kN | a measure of bone strength, measured by HR-pQCT at the distal radius and tibia | through study completion, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| areal bone mineral density of the spine in g/cm2 | measured by osteodensitometry (DXA) | through study completion, an average of 6 months | 
| areal bone mineral density of the proximal femur in g/cm2 | measured by osteodensitometry | through study completion, an average of 6 months | 
| areal bone mineral density of the distal radius in g/cm2 | measured by osteodensitometry | through study completion, an average of 6 months | 
| trabecular bone score of the spine | a measure of bone texture, measured by osteodensitometry | through study completion, an average of 6 months | 
| cortical thickness at the mid tibia in cm | the cortical thickness will be measured by pulse-echo ultrasound and high resolution quantitative computed tomography (HR-QCT) | through study completion, an average of 6 months | 
| density weighed cortical thickness at the mid tibia in cm | the density weighed cortical thickness will be measured by pulse-echo ultrasound and HR- QCT | through study completion, an average of 6 months | 
| bone marrow adiposity in mg/cm3 | measured by HR-pQCT | through study completion, an average of 6 months | 
| measurement of serum carboxy-terminal collagen crosslinks (CTX) in pg/ml | biochemical marker of bone resorption | through study completion, an average of 6 months | 
| measurement of serum n-terminal procollagen type 1 (P1NP) in mcg/l | biochemical marker of bone formation | through study completion, an average of 6 months | 
| measurement of serum pentosidine in pmol/m | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum carboxymethyl-lysine (CML) in pmol/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum insulin in mU/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum sclerostin in pg/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum adiponectin in ng/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum insulin like growth factor -1 (IGF1) in nM | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum ultrasensitive c-reactive protein (usCRP) in mg/l | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum interleukin 6 (IL6) in pg/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months | 
| measurement of serum periostin in ng/ml | biochemical marker associated with bone fragility | through study completion, an average of 6 months |