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

Aalborg University Hospital300 enrolled

Overview

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 Type

OBSERVATIONAL

Enrollment

300

Conditions

Type 2 Diabetes Bone Disease Osteoporosis Diabetic Neuropathy Peripheral

Interventions

Dual Energy X-ray Absorbtiometry scanDIAGNOSTIC_TEST

Evaluation of body composition and bone mass density

High-resolution peripheral quantitative computed tomographyDIAGNOSTIC_TEST

High-resolution peripheral quantitative computed tomography (HR-pQCT) assesses both volumetric bone mineral density (vBMD) and trabecular and cortical microarchitecture.

MicroindentationDIAGNOSTIC_TEST

Measures Bone Material Strength Index (BMSi) of cortical bone.

Thermal perception thresholdsDIAGNOSTIC_TEST

Heat and cold perception thresholds

Nerve conduction studiesDIAGNOSTIC_TEST

Nerve conduction and amplitude of sural nerve

Composite Autonomic Symptom Score 31DIAGNOSTIC_TEST

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 densityDIAGNOSTIC_TEST

Skin biopsy

Perception Threshold TrackingDIAGNOSTIC_TEST

Transcutaneous stimulation of large and small nerve fibres using weak electrical currents

Assessment of cardiovascular autonomic neuropathyDIAGNOSTIC_TEST

Electrocardiographic recordings at rest and during cardiovascular autonomic reflex tests.

Handgrip strengthDIAGNOSTIC_TEST

Evaluation of muscle strength

Force plate platformDIAGNOSTIC_TEST

Evaluation of balance while standing still

Biospecimen collectionDIAGNOSTIC_TEST

Biochemistry including bone turnover markers, glycemic status, inflammation markers i.e

Isometric leg extension strengthDIAGNOSTIC_TEST

Evaluation of muscle strength

Michigan Neuropathy Screening InstrumentDIAGNOSTIC_TEST

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.

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

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.