Deep Phenotyping of Bone Disease in Type 2 Diabetes and Relations to Diabetic Neuropathy

Aalborg University Hospital

Status: Enrolling

Conditions: Osteoporosis; Bone Disease; Type 2 Diabetes; Autonomic Neuropathy, Diabetic; Diabetic Neuropathy Peripheral

Treatments: Diagnostic Test: Biospecimen collection; Diagnostic Test: Force plate platform; Diagnostic Test: Michigan Neuropathy Screening Instrument; Diagnostic Test: Thermal perception thresholds; Diagnostic Test: Perception Threshold Tracking; Diagnostic Test: Nerve conduction studies; Diagnostic Test: High-resolution peripheral quantitative computed tomography; Diagnostic Test: Assessment of cardiovascular autonomic neuropathy; Diagnostic Test: Dual Energy X-ray Absorbtiometry scan; Diagnostic Test: Isometric leg extension strength; Diagnostic Test: Handgrip strength; Diagnostic Test: Composite Autonomic Symptom Score 31; Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density; Diagnostic Test: Microindentation

Study type: Observational

Funder types: Other

Identifiers

NCT05642143

N-20220038

Details and patient eligibility

About

Objectives:

The goal of this cross sectional clinical trial is to examine the phenotype of bone disease in type 2 diabetes.The main aims are to:

1. Compare bone microarchitecture, bone biomechanical competence, and bone turnover markers as well as postural control in T2D patients with and without fractures.
2. Examine how autonomic and peripheral neuropathy affects bone microarchitecture, bone material strength and bone turnover markers as well as postural control in T2D.

Methods:

The trial is of cross-sectional design and consists of examinations including

• Blood samples to analyze bone markers, glycemic state i.e.
• Bone scans including dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT) to evaluate Bone Mineral Density, t-score and bone structure.
• Microindentation to evaluate bone material strength
• Skin autofluorescence to measure levels of advanced glycation endproducts (AGEs) in the skin
• Assesment of nerve function (peripheral and autonomic)
• Assesment of postural control, muscle strength and gait

Participants:

A total of 300 type 2 diabetes patients divided to three groups:

• 160 with no history of fractures or diabetic neuropathy
• 100 with a history of fracture(s)
• 40 with autonomic neuropathy or severe peripheral neuropathy

Enrollment: 300 estimated patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Men and women with minimum 40 years of age.

2. Diagnosis of T2D. At least one of the following criteria must be met at diagnosis:

   1. HbA1c ≥ 48 mmol/mol (6,5 %)
   2. Plasma glucose ≥ 11,1 mmol/l
   3. Fasting plasma glucose ≥7,0 mmol/l Clinical effect of oral antidiabetic medication strengthens the diagnosis.

3. Diagnosis of diabetes at least one year prior to inclusion of the study to avoid honeymoon diabetes.

4. A history of fracture(s) (confirmed by radiographs analyzed by radiologist) following the diabetes diagnosis (T2D F+ group)

5. Diagnosed with severe peripheral (VPT ≥ 50) or autonomic neuropathy defined by cardiac autonomic reflex tests or severe abnormalities in orthostatic blood pressure (T2D N+ group)

6. Signed the informed consent.

7. Not defined by the exclusion criteria.

Exclusion criteria

1. Severe decreased liver function (Alanin amino-transaminase (ALAT) >250 U/l, Gamma-Glutamyltransferase (GGT) >150 U/l).
2. Moderate to severe kidney dysfunction, estimated Glomerular Filtration Rate (eGFR) <15 mmol/L/1,73m2.
3. Pregnancy or breast feeding.
4. Active malignancy or terminal ill.
5. Previous chemotherapy or immunomodulating treatment
6. Known severe vitamin deficiency
7. Current or previous alcohol- or drug abuse.
8. Not being able to understand Danish written and/or verbally.
9. Terms according to investigators judgement that makes subjects unsuitable to participate including lack of ability to understand and comply with instructions and/or reduced physical ability, limiting the ability to participate in the examinations.
10. Participating in other clinical studies utilizing experimental treatment or medication.
11. Subjects with pathologic fractures (defined as fractures due to local tumors, tumor-like lesions, or focal demineralization as visualized on radiographs).
12. Primary hyperparathyroidism, Paget's disease and other metabolic bone diseases, uncontrolled thyrotoxicosis, celiac disease not controlled by diet, known hypogonadism, severe COPD, hypopituitarism, Cushing's disease.
13. Fracture < 6 month ago
14. Initiation of antiresorptive or bone anabolic drugs <12 months ago to ensure stable bone turnover markers.
15. History of fractures following the diagnosis of diabetes (T2D F-/N- and T2D N+ groups).
16. History of peripheral or autonomic neuropathy defined by cardiac autonomic reflex tests or severe abnormalities in orthostatic blood pressure (T2D F-/N- group).

Trial design

300 participants in 3 patient groups

T2D F-/N-

Description:

Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)

Treatment:

Diagnostic Test: Microindentation

Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density

Diagnostic Test: Composite Autonomic Symptom Score 31

Diagnostic Test: Handgrip strength

Diagnostic Test: Isometric leg extension strength

Diagnostic Test: Dual Energy X-ray Absorbtiometry scan

Diagnostic Test: Assessment of cardiovascular autonomic neuropathy

Diagnostic Test: High-resolution peripheral quantitative computed tomography

Diagnostic Test: Perception Threshold Tracking

Diagnostic Test: Nerve conduction studies

Diagnostic Test: Thermal perception thresholds

Diagnostic Test: Michigan Neuropathy Screening Instrument

Diagnostic Test: Force plate platform

Diagnostic Test: Biospecimen collection

T2D F+

Description:

Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)

Treatment:

Diagnostic Test: Microindentation

Diagnostic Test: Composite Autonomic Symptom Score 31

Diagnostic Test: Handgrip strength

Diagnostic Test: Isometric leg extension strength

Diagnostic Test: Dual Energy X-ray Absorbtiometry scan

Diagnostic Test: Assessment of cardiovascular autonomic neuropathy

Diagnostic Test: High-resolution peripheral quantitative computed tomography

Diagnostic Test: Perception Threshold Tracking

Diagnostic Test: Nerve conduction studies

Diagnostic Test: Thermal perception thresholds

Diagnostic Test: Michigan Neuropathy Screening Instrument

Diagnostic Test: Force plate platform

Diagnostic Test: Biospecimen collection

T2D N+

Description:

Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)

Treatment:

Diagnostic Test: Microindentation

Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density

Diagnostic Test: Composite Autonomic Symptom Score 31

Diagnostic Test: Handgrip strength

Diagnostic Test: Isometric leg extension strength

Diagnostic Test: Dual Energy X-ray Absorbtiometry scan

Diagnostic Test: Assessment of cardiovascular autonomic neuropathy

Diagnostic Test: High-resolution peripheral quantitative computed tomography

Diagnostic Test: Perception Threshold Tracking

Diagnostic Test: Nerve conduction studies

Diagnostic Test: Thermal perception thresholds

Diagnostic Test: Michigan Neuropathy Screening Instrument

Diagnostic Test: Force plate platform

Diagnostic Test: Biospecimen collection