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

Recruiting

• Conditions: Bone Disease; Autonomic Neuropathy, Diabetic; Type 2 Diabetes; Osteoporosis; Diabetic Neuropathy Peripheral
• Interventions: Diagnostic Test: Dual Energy X-ray Absorbtiometry scan; Diagnostic Test: High-resolution peripheral quantitative computed tomography; Diagnostic Test: Microindentation; Diagnostic Test: Thermal perception thresholds; Diagnostic Test: Nerve conduction studies; Diagnostic Test: Composite Autonomic Symptom Score 31; Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density; Diagnostic Test: Perception Threshold Tracking; Diagnostic Test: Handgrip strength; Diagnostic Test: Assessment of cardiovascular autonomic neuropathy; Diagnostic Test: Force plate platform; Diagnostic Test: Biospecimen collection; Diagnostic Test: Isometric leg extension strength; Diagnostic Test: Michigan Neuropathy Screening Instrument

• Registration Number: NCT05642143
• Lead Sponsor: Aalborg University Hospital

Brief 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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-11-04
• Study First Submitted QC: 2022-11-29
• Study First Posted: 2022-12-08
• Study Start: 2023-02-24
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-05
• Last Update Posted: 2024-02-07
• Primary Completion: 2026-04
• Study Completion: 2026-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

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).

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
T2D F+	Handgrip strength	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Composite Autonomic Symptom Score 31	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F-/N-	Nerve conduction studies	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Skin biopsies with quantification of intra-epidermal nerve fibre density	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Force plate platform	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F+	Biospecimen collection	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Michigan Neuropathy Screening Instrument	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D N+	Handgrip strength	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Biospecimen collection	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D F-/N-	Perception Threshold Tracking	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Michigan Neuropathy Screening Instrument	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F+	Dual Energy X-ray Absorbtiometry scan	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Thermal perception thresholds	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Force plate platform	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Isometric leg extension strength	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D N+	Dual Energy X-ray Absorbtiometry scan	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	High-resolution peripheral quantitative computed tomography	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Microindentation	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Composite Autonomic Symptom Score 31	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D F-/N-	Microindentation	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Assessment of cardiovascular autonomic neuropathy	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D N+	Nerve conduction studies	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D F-/N-	Dual Energy X-ray Absorbtiometry scan	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	High-resolution peripheral quantitative computed tomography	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Thermal perception thresholds	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Composite Autonomic Symptom Score 31	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Handgrip strength	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F+	High-resolution peripheral quantitative computed tomography	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Microindentation	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Perception Threshold Tracking	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D N+	Thermal perception thresholds	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Skin biopsies with quantification of intra-epidermal nerve fibre density	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D F-/N-	Biospecimen collection	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D F-/N-	Isometric leg extension strength	Subjects with T2D and no previous history of any fractures or diabetic neuropathy (n=160)
T2D N+	Force plate platform	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Isometric leg extension strength	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D F+	Nerve conduction studies	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D F+	Assessment of cardiovascular autonomic neuropathy	Subjects with T2D with a previous history of a fracture(s) (any fracture, major osteoporotic fracture (MOF) and peripheral) (n=100)
T2D N+	Perception Threshold Tracking	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Assessment of cardiovascular autonomic neuropathy	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)
T2D N+	Michigan Neuropathy Screening Instrument	Subjects with T2D matched by age and sex with severe peripheral (vibration perception threshold (VPT) \> 50) or a history of autonomic neuropathy (n=40)

Primary Outcome Measures

Name	Time	Method
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
Evaluation of differences in bone microarchitecture between T2D patients with and without previous fractures assessed by HRpQCT.	Through study completion, estimated 3.5 years	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.
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

Secondary Outcome Measures

Name	Time	Method
The impact of autonomic neuropathy on bone material strength in T2D assessed by microindentation.	Through study completion, estimated 3.5 years	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).
The impact of autonomic neuropathy on bone turnover markers in T2D.	Through study completion, estimated 3.5 years	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)
The impact of peripheral neuropathy on bone turnover markers in T2D.	Through study completion, estimated 3.5 years	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).
Compare muscle mass and strength in T2D patients with and without neuropathy	Through study completion, estimated 3.5 years	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).
Compare postural control between T2D patients with and without fractures assessed by force platform.	Through study completion, estimated 3.5 years
Compare muscle mass and strength in T2D patients with and without fractures	Through study completion, estimated 3.5 years	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.
The impact of autonomic neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.	Through study completion, estimated 3.5 years	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).
The impact of peripheral neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.	Through study completion, estimated 3.5 years	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)
The impact of peripheral neuropathy on bone material strength in T2D assessed by microindentation.	Through study completion, estimated 3.5 years	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)
Compare postural control between T2D patients with and without peripheral/autonomic neuropathy.	Through study completion, estimated 3.5 years	Neuropathy assessed by PTT, QST, sural nerve conduction study, skin biopsies, COMPASS-31, MNSI and Vagus device. Postural control assessed by force platform.

Trial Locations

Locations (1)

Steno Diabetes Center Nordjylland; 🇩🇰 Aalborg, Denmark