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

February 5, 2024 updated by: Julie Lindgård Nielsen, Aalborg University Hospital

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Julie Lindgård Graversen, MD
  • Phone Number: +45 97663651
  • Email: j.lindgaard@rn.dk

Study Locations

  • Denmark
      • Aalborg, Denmark, 9000
        • Recruiting
        • Steno Diabetes Center Nordjylland
        • Contact:
          • Julie Lindgård Graversen, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

T2D with and without fractures and neuropathy.

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of differences in bone microarchitecture between T2D patients with and without previous fractures assessed by HRpQCT.
Time Frame: 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.
Through study completion, estimated 3.5 years
Differences in Bone material strength index (BMSi) between T2D patients with and without previous fractures measured by microindentation.
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years
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).
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The impact of autonomic neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.
Time Frame: 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).
Through study completion, estimated 3.5 years
The impact of autonomic neuropathy on bone material strength in T2D assessed by microindentation.
Time Frame: 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).
Through study completion, estimated 3.5 years
The impact of autonomic neuropathy on bone turnover markers in T2D.
Time Frame: 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)
Through study completion, estimated 3.5 years
The impact of peripheral neuropathy on bone microarchitecture in T2D assessed by HR-pQCT.
Time Frame: 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)
Through study completion, estimated 3.5 years
The impact of peripheral neuropathy on bone material strength in T2D assessed by microindentation.
Time Frame: 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)
Through study completion, estimated 3.5 years
The impact of peripheral neuropathy on bone turnover markers in T2D.
Time Frame: 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).
Through study completion, estimated 3.5 years
Compare postural control between T2D patients with and without fractures assessed by force platform.
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years
Compare postural control between T2D patients with and without peripheral/autonomic neuropathy.
Time Frame: 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.
Through study completion, estimated 3.5 years
Compare muscle mass and strength in T2D patients with and without fractures
Time Frame: 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.
Through study completion, estimated 3.5 years
Compare muscle mass and strength in T2D patients with and without neuropathy
Time Frame: 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).
Through study completion, estimated 3.5 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Co-existence of peripheral and autonomic neuropathy
Time Frame: 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.
Through study completion, estimated 3.5 years
The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone microarchitecture (assessed by HR-pQCT) in T2D.
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years
The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone material strength (assessed by microindentation) in T2D.
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years
The impact of insulin resistance (assessed by HOMA-IR and -%B) on bone turnover markers in T2D.
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years
The correlation between levels of Advanced Glycation End Products (AGEs) (assessed by skin autofluorescence) and bone material strength (assessed by microindentation).
Time Frame: Through study completion, estimated 3.5 years
Through study completion, estimated 3.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Aalborg University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 24, 2023

Primary Completion (Estimated)

April 1, 2026

Study Completion (Estimated)

April 1, 2026

Study Registration Dates

First Submitted

November 4, 2022

First Submitted That Met QC Criteria

November 29, 2022

First Posted (Actual)

December 8, 2022

Study Record Updates

Last Update Posted (Estimated)

February 7, 2024

Last Update Submitted That Met QC Criteria

February 5, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • N-20220038

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Potential analysis of skin biopsies in external lab

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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