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

Type 2 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05642143
• Other study ID #: N-20220038
• Status: Recruiting
• Start date: February 24, 2023
• Est. completion date: April 2026

Study information

• Verified date: February 2024
• Source: Aalborg University Hospital
• Contact: Julie Lindgård Graversen, MD
• Phone: 97663651
• Email: j.lindgaard[@]rn.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: April 2026
• Est. primary completion date: April 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Autonomic Neuropathy, Diabetic
• Bone Disease
• Bone Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diabetic Neuropathies
• Diabetic Neuropathy Peripheral
• Osteoporosis
• Peripheral Nervous System Diseases
• Type 2 Diabetes

Intervention

Diagnostic Test:
• Dual Energy X-ray Absorbtiometry scan
Evaluation of body composition and bone mass density
• High-resolution peripheral quantitative computed tomography
High-resolution peripheral quantitative computed tomography (HR-pQCT) assesses both volumetric bone mineral density (vBMD) and trabecular and cortical microarchitecture.
• Microindentation
Measures Bone Material Strength Index (BMSi) of cortical bone.
• Thermal perception thresholds
Heat and cold perception thresholds
• Nerve conduction studies
Nerve conduction and amplitude of sural nerve
• Composite Autonomic Symptom Score 31
A validated self-assessment questionnaire quantifying the severity and distribution of autonomic symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor functions) by scoring 31 clinically selected questions
• Skin biopsies with quantification of intra-epidermal nerve fibre density
Skin biopsy
• Perception Threshold Tracking
Transcutaneous stimulation of large and small nerve fibres using weak electrical currents
• Assessment of cardiovascular autonomic neuropathy
Electrocardiographic recordings at rest and during cardiovascular autonomic reflex tests.
• Handgrip strength
Evaluation of muscle strength
• Force plate platform
Evaluation of balance while standing still
• Biospecimen collection
Biochemistry including bone turnover markers, glycemic status, inflammation markers i.e
• Isometric leg extension strength
Evaluation of muscle strength
• Michigan Neuropathy Screening Instrument
MNSI is used to assess status of peripheral neuropathy. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes.

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center Nordjylland	Aalborg

Sponsors (1)

Lead Sponsor	Collaborator
Aalborg University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Co-existence of peripheral and autonomic neuropathy	Presence of autonomic neuropathy (assessed by CAN-score from Vagus™ device, COMPASS31-score, intraepidermal nerve fiber density, orthostatic BP and ECG) will be compared with presence of peripheral neuropathy (assessed by PTT, QST, sural nerve conduction test and intraepidermal nerve fiber density) in T2D.	Through study completion, estimated 3.5 years
Other	The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone microarchitecture (assessed by HR-pQCT) in T2D.		Through study completion, estimated 3.5 years
Other	The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone material strength (assessed by microindentation) in T2D.		Through study completion, estimated 3.5 years
Other	The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone turnover markers in T2D.		Through study completion, estimated 3.5 years
Other	The correlation between levels of Advanced Glycation End Products (AGEs) (assessed by skin autofluorescence) and bone material strength (assessed by microindentation).		Through study completion, estimated 3.5 years
Primary	Evaluation of differences in bone microarchitecture between T2D patients with and without previous fractures assessed by HRpQCT.	Bone microarchitecture is a composite outcome assessed by HRpQCT at radius and tibia: Total volumetric mineral density, Trabecular volumetric mineral density, Cortical volumetric mineral density, Trabecular number, Trabecular thickness, Cortical thickness, Trabecular separation, Cortical porosity, bone stiffness and failure load.	Through study completion, estimated 3.5 years
Primary	Differences in Bone material strength index (BMSi) between T2D patients with and without previous fractures measured by microindentation.		Through study completion, estimated 3.5 years
Primary	Evaluation of differences in bone turnover markers between T2D patients with and without previous fractures by biochemical analysis of different bone markers (CTX, P1NP, osteocalcin (OC), ucOC, sclerostin, osteoglycin and osteopontin).		Through study completion, estimated 3.5 years
Secondary	The impact of autonomic neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.	Compare bone microarchitectural parameters (assessed by HR-pQCT) in T2D patients with and without autonomic neuropathy (assessed by CAN-score from Vagus™ device, COMPASS31-score, intraepidermal nerve fiber density, orthostatic BP and ECG).	Through study completion, estimated 3.5 years
Secondary	The impact of autonomic neuropathy on bone material strength in T2D assessed by microindentation.	Compare bone material strength (assessed by microindentation) in T2D patients with and without autonomic neuropathy (assessed by CAN-score from Vagus™ device, COMPASS31-score, intraepidermal nerve fiber density, orthostatic BP and ECG).	Through study completion, estimated 3.5 years
Secondary	The impact of autonomic neuropathy on bone turnover markers in T2D.	Compare bone turnover markers in T2D patients with and without autonomic neuropathy (assessed by CAN-score from Vagus™ device, COMPASS31-score, intraepidermal nerve fiber density, orthostatic BP and ECG)	Through study completion, estimated 3.5 years
Secondary	The impact of peripheral neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.	Compare bone microarchitectural parameters (assessed by HR-pQCT) in T2D patients with and without peripheral neuropathy (assessed by MNSI, PTT, QST, sural nerve conduction study and intraepidermal nerve fiber density)	Through study completion, estimated 3.5 years
Secondary	The impact of peripheral neuropathy on bone material strength in T2D assessed by microindentation.	Compare bone material strength (assessed by microindentation) in T2D patients with and without peripheral neuropathy (assessed by MNSI, PTT, QST, sural nerve conduction study and intraepidermal nerve fiber density)	Through study completion, estimated 3.5 years
Secondary	The impact of peripheral neuropathy on bone turnover markers in T2D.	Compare bone turnover markers in T2D patients with and without peripheral neuropathy (assessed by MNSI, PTT, QST, sural nerve conduction study and intraepidermal nerve fiber density).	Through study completion, estimated 3.5 years
Secondary	Compare postural control between T2D patients with and without fractures assessed by force platform.		Through study completion, estimated 3.5 years
Secondary	Compare postural control between T2D patients with and without peripheral/autonomic neuropathy.	Neuropathy assessed by PTT, QST, sural nerve conduction study, skin biopsies, COMPASS-31, MNSI and Vagus device. Postural control assessed by force platform.	Through study completion, estimated 3.5 years
Secondary	Compare muscle mass and strength in T2D patients with and without fractures	Compare muscle mass (assessed by DXA scan) and muscle strength (assessed by hand grip, leg extension strength and functional tests) in T2D patients with and without fractures.	Through study completion, estimated 3.5 years
Secondary	Compare muscle mass and strength in T2D patients with and without neuropathy	Compare muscle mass (assessed by DXA scan) and muscle strength (assessed by hand grip, leg extension strength and functional tests) in T2D patients with and without neuropathy (assessed by PTT, QST, sural nerve conduction study, skin biopsies, COMPASS-31, MNSI and Vagus device).	Through study completion, estimated 3.5 years