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

Sponsor
Aalborg University Hospital (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05642143
Collaborator
(none)
300
Enrollment
39
Anticipated Duration (Months)

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
  • 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: Assessment of cardiovascular autonomic neuropathy
  • Diagnostic Test: Handgrip strength
  • Diagnostic Test: Force plate platform
  • Diagnostic Test: Biospecimen collection
  • Diagnostic Test: Isometric leg extension strength
  • Diagnostic Test: Michigan Neuropathy Screening Instrument

Study Design

Study Type:
Observational
Anticipated Enrollment :
300 participants
Observational Model:
Case-Control
Time Perspective:
Cross-Sectional
Official Title:
Deep Phenotyping of Bone Disease in Type 2 Diabetes and Relations to Diabetic Neuropathy
Anticipated Study Start Date :
Jan 1, 2023
Anticipated Primary Completion Date :
Apr 1, 2026
Anticipated Study Completion Date :
Apr 1, 2026

Arms and Interventions

Arm Intervention/Treatment
T2D F-/N-

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

Diagnostic Test: Dual Energy X-ray Absorbtiometry scan
Evaluation of body composition and bone mass density
Other Names:
  • DXA

    • Diagnostic Test: 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.
    Other Names:
  • HR-pQCT

    • Diagnostic Test: Microindentation
    Measures Bone Material Strength Index (BMSi) of cortical bone.
    Other Names:
  • Osteoprobe, ActiveLife, Santa Barbara, CA

    • Diagnostic Test: Thermal perception thresholds
    Heat and cold perception thresholds
    Other Names:
  • Quantitative Sensory Testing

    • Diagnostic Test: Nerve conduction studies
    Nerve conduction and amplitude of sural nerve
    Other Names:
  • NCStat-DPN-Check

    • Diagnostic Test: 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
    Other Names:
  • COMPASS 31

    • Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density
    Skin biopsy
    Other Names:
  • PGP9.5, antibodies for subsets of ion-channels ect

    • Diagnostic Test: Perception Threshold Tracking
    Transcutaneous stimulation of large and small nerve fibres using weak electrical currents
    Other Names:
  • PTT

    • Diagnostic Test: Assessment of cardiovascular autonomic neuropathy
    Electrocardiographic recordings at rest and during cardiovascular autonomic reflex tests.
    Other Names:
  • Vagus device, Medicus Engineering ApS, Aarhus, Denmark

    • Diagnostic Test: Handgrip strength
    Evaluation of muscle strength
    Other Names:
  • Hydraulic dynamometer, Saehan Corporation, Gyungnam, South Korea

    • Diagnostic Test: Force plate platform
    Evaluation of balance while standing still
    Other Names:
  • Plux Biosignals, S.A, Arruda dos Vinhos, Portugal

    • Diagnostic Test: Biospecimen collection
    Biochemistry including bone turnover markers, glycemic status, inflammation markers i.e
    Other Names:
  • Blood samples
  • Urine samples

    • Diagnostic Test: Isometric leg extension strength
    Evaluation of muscle strength
    Other Names:
  • EasyForce Digital Dynamometer

    • Diagnostic Test: 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.
    Other Names:
  • MNSI

    		•
    T2D F+

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

    Diagnostic Test: Dual Energy X-ray Absorbtiometry scan
    Evaluation of body composition and bone mass density
    Other Names:
  • DXA

    • Diagnostic Test: 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.
    Other Names:
  • HR-pQCT

    • Diagnostic Test: Microindentation
    Measures Bone Material Strength Index (BMSi) of cortical bone.
    Other Names:
  • Osteoprobe, ActiveLife, Santa Barbara, CA

    • Diagnostic Test: Thermal perception thresholds
    Heat and cold perception thresholds
    Other Names:
  • Quantitative Sensory Testing

    • Diagnostic Test: Nerve conduction studies
    Nerve conduction and amplitude of sural nerve
    Other Names:
  • NCStat-DPN-Check

    • Diagnostic Test: 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
    Other Names:
  • COMPASS 31

    • Diagnostic Test: Perception Threshold Tracking
    Transcutaneous stimulation of large and small nerve fibres using weak electrical currents
    Other Names:
  • PTT

    • Diagnostic Test: Assessment of cardiovascular autonomic neuropathy
    Electrocardiographic recordings at rest and during cardiovascular autonomic reflex tests.
    Other Names:
  • Vagus device, Medicus Engineering ApS, Aarhus, Denmark

    • Diagnostic Test: Handgrip strength
    Evaluation of muscle strength
    Other Names:
  • Hydraulic dynamometer, Saehan Corporation, Gyungnam, South Korea

    • Diagnostic Test: Force plate platform
    Evaluation of balance while standing still
    Other Names:
  • Plux Biosignals, S.A, Arruda dos Vinhos, Portugal

    • Diagnostic Test: Biospecimen collection
    Biochemistry including bone turnover markers, glycemic status, inflammation markers i.e
    Other Names:
  • Blood samples
  • Urine samples

    • Diagnostic Test: Isometric leg extension strength
    Evaluation of muscle strength
    Other Names:
  • EasyForce Digital Dynamometer

    • Diagnostic Test: 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.
    Other Names:
  • MNSI

    		•
    T2D N+

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

    Diagnostic Test: Dual Energy X-ray Absorbtiometry scan
    Evaluation of body composition and bone mass density
    Other Names:
  • DXA

    • Diagnostic Test: 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.
    Other Names:
  • HR-pQCT

    • Diagnostic Test: Microindentation
    Measures Bone Material Strength Index (BMSi) of cortical bone.
    Other Names:
  • Osteoprobe, ActiveLife, Santa Barbara, CA

    • Diagnostic Test: Thermal perception thresholds
    Heat and cold perception thresholds
    Other Names:
  • Quantitative Sensory Testing

    • Diagnostic Test: Nerve conduction studies
    Nerve conduction and amplitude of sural nerve
    Other Names:
  • NCStat-DPN-Check

    • Diagnostic Test: 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
    Other Names:
  • COMPASS 31

    • Diagnostic Test: Skin biopsies with quantification of intra-epidermal nerve fibre density
    Skin biopsy
    Other Names:
  • PGP9.5, antibodies for subsets of ion-channels ect

    • Diagnostic Test: Perception Threshold Tracking
    Transcutaneous stimulation of large and small nerve fibres using weak electrical currents
    Other Names:
  • PTT

    • Diagnostic Test: Assessment of cardiovascular autonomic neuropathy
    Electrocardiographic recordings at rest and during cardiovascular autonomic reflex tests.
    Other Names:
  • Vagus device, Medicus Engineering ApS, Aarhus, Denmark

    • Diagnostic Test: Handgrip strength
    Evaluation of muscle strength
    Other Names:
  • Hydraulic dynamometer, Saehan Corporation, Gyungnam, South Korea

    • Diagnostic Test: Force plate platform
    Evaluation of balance while standing still
    Other Names:
  • Plux Biosignals, S.A, Arruda dos Vinhos, Portugal

    • Diagnostic Test: Biospecimen collection
    Biochemistry including bone turnover markers, glycemic status, inflammation markers i.e
    Other Names:
  • Blood samples
  • Urine samples

    • Diagnostic Test: Isometric leg extension strength
    Evaluation of muscle strength
    Other Names:
  • EasyForce Digital Dynamometer

    • Diagnostic Test: 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.
    Other Names:
  • MNSI

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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]

    3. 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 Outcome Measures

    1. 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).

    2. 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).

    3. 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)

    4. 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)

    5. 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)

    6. 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).

    7. Compare postural control between T2D patients with and without fractures assessed by force platform. [Through study completion, estimated 3.5 years]

    8. 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.

    9. 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.

    10. 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).

    Other Outcome Measures

    1. Co-existence of peripheral and autonomic neuropathy [Through study completion, estimated 3.5 years]

      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.

    2. 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]

    3. 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]

    4. The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone turnover markers in T2D. [Through study completion, estimated 3.5 years]

    5. 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]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    40 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    3. HbA1c ≥ 48 mmol/mol (6,5 %)

    4. Plasma glucose ≥ 11,1 mmol/l

    5. Fasting plasma glucose ≥7,0 mmol/l Clinical effect of oral antidiabetic medication strengthens the diagnosis.

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

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

    8. 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)

    9. Signed the informed consent.

    10. 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).

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Aalborg University Hospital

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Julie Lindgård Nielsen, Principal Investigator, Aalborg University Hospital
    ClinicalTrials.gov Identifier:
    NCT05642143
    Other Study ID Numbers:
    • N-20220038
    First Posted:
    Dec 8, 2022
    Last Update Posted:
    Dec 12, 2022
    Last Verified:
    Dec 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Osteoporosis
    Bone Diseases
    Peripheral Nervous System Diseases
    Diabetic Neuropathies
    Diabetes Mellitus
    Diabetes Mellitus, Type 2

    Study Results

    No Results Posted as of Dec 12, 2022