Impact of Glycemic Control on Skeletal Outcomes in Adults With Type 1 Diabetes (DenSiFy cohort)

Impact of Glycemic Control on Skeletal Outcomes in Adults With Type 1 Diabetes : DenSiFy (Diabetes Spine Fractures) Cohort

Background : Type 1 diabetes (T1D) is associated with an increased risk of fractures. The mechanisms accounting for this bone fragility are not yet fully understood. As T1D is often diagnosed in childhood or early adulthood, the lower bone mineral density (BMD) and deteriorated bone microarchitecture observed in T1D may reflect changes in the bone that occurred before or at the time of peak bone mass achievement. There is a lack of high-quality prospective studies to determine whether adults with T1D continue to lose BMD or deteriorate bone quality compared with controls. Moreover, while chronic hyperglycemia is a risk factor for fracture in T1D, it is unknown if better glycemic control affects bone outcomes.

This prospective multicenter cohort study aims: (1) To compare the changes in the following outcomes over 4 years in adults with T1D and controls without diabetes of similar age, sex and body-mass index distribution: BMD by dual-energy X-ray absorptiometry (DXA) at the femoral neck, hip, spine, and radius, trabecular bone score (TBS) by DXA, and serum biochemical markers of bone turnover (BTMs); (2) To evaluate whether long-term glycemic control or the presence of a microvascular complication are independent predictors of the changes in BMD and TBS in people with T1D.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes Mellitus, Type 1; Bone Diseases, Metabolic; Bone Loss; Bone Health; Hyperglycaemia Due to Type 1 Diabetes Mellitus
• Intervention / Treatment: Diagnostic test: Clinical tests; Diagnostic test: Biochemical tests; Diagnostic test: DXA scan with TBS and VFA; Diagnostic test: AGEReader

• Study Type: Observational
• Enrollment (Estimated): 163

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H2W 1R7
      • Institut de recherches cliniques de Montréal (IRCM)
    • Quebec City, Quebec, Canada, G1V 4G2
      • Centre de recherche du CHU de Québec-Université Laval

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

127 individuals with type 1 diabetes and 65 healthy subjects from the DenSiFy (Diabetes Spine Fractures) study (NCT04064437)

Description

Individuals with type 1 diabetes who have participated in the DenSiFy (Diabetes Spine Fractures) study (NCT04064437)

Inclusion Criteria:

• Diagnosis of type 1 diabetes for at least 5 years;
• Age 20 years and older.

Exclusion Criteria:

• Pregnancy, delivery or breastfeeding in the past 6 months;
• Conditions associated with bone disease (significant liver disease, intestinal malabsorption other than celiac disease, organ transplant, active cancer, rheumatoid arthritis, hyperthyroidism, hypothyroidism with abnormal TSH, hyperparathyroidism, hypoparathyroidism, hypogonadism, acromegaly, Cushing syndrome, adrenal insufficiency);
• Any of these medications since the first DenSiFy study visit : biphosphonates, teriparatide, denosumab, calcitonin, glucocorticoids ≥ 7,5 mg prednisone/day or equivalency ≥ 3 months, aromatase inhibitors, antiandrogens, antiepileptic drugs, anticoagulants, thiazolidinediones;
• Inability to consent.

Healthy controls who have participated in the DenSiFy (Diabetes Spine Fractures) study (NCT04064437)

Inclusion Criteria:

• Age 20 years and older.

Exclusion Criteria :

• As above (as individuals with diabetes), and :
• Diagnosis of diabetes or prediabetes;
• Celiac disease;
• Chronic kidney disease (CrCl < 60 mL/min).

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy controls	Diagnostic test: Clinical tests; The investigators perform the following clinical tests: vibration threshold test, monofilament test, and height, weight and waist circumference measurement in every participant.; Diagnostic test: Biochemical tests; The investigators perform blood and urine tests in every participant.; Diagnostic test: DXA scan with TBS and VFA; The investigators perform a dual energy x-ray absorptiometry (DXA scan or osteodensitometry) including trabecular bone score (TBS) and Vertebral Fracture Assessment (VFA) in every participant.; Diagnostic test: AGEReader; The investigators perform a skin advanced glycation end products (AGEs) measurement with the AGE Reader machine in every participant.
Individuals with type 1 diabetes	Diagnostic test: Clinical tests; The investigators perform the following clinical tests: vibration threshold test, monofilament test, and height, weight and waist circumference measurement in every participant.; Diagnostic test: Biochemical tests; The investigators perform blood and urine tests in every participant.; Diagnostic test: DXA scan with TBS and VFA; The investigators perform a dual energy x-ray absorptiometry (DXA scan or osteodensitometry) including trabecular bone score (TBS) and Vertebral Fracture Assessment (VFA) in every participant.; Diagnostic test: AGEReader; The investigators perform a skin advanced glycation end products (AGEs) measurement with the AGE Reader machine in every participant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in areal bone mineral density (aBMD) at the femoral neck in g/cm2	aBMD measured by DXA scan	Between the baseline and the 4-year visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in areal bone mineral density (aBMD) at the spine in g/cm2	aBMD measured by DXA scan	Between the baseline and the 4-year visit
Change in areal bone mineral density (aBMD) at the total hip in g/cm2	aBMD measured by DXA scan	Between the baseline and the 4-year visit
Change in areal bone mineral density (aBMD) at the distal third of radius in g/cm2	aBMD measured by DXA scan	Between the baseline and the 4-year visit
Change in Trabecular bone score (TBS) (unitless)	TBS with the software TBSinSight	Between the baseline and the 4-year visit
Glycemic control, assessed with mean glycated hemoglobin (HbA1c) of the past 7 years	Mean HbA1c of the past 7 years from all the available HbA1c in the medical record	4-year visit
Glycemic control, assessed with skin advanced glycation end products (AGEs)	Skin AGEs measured with AGEReader (autofluorescence)	4-year visit
Presence of a microvascular complication (neuropathy, nephropathy, retinopathy)	From the information available in the medical record and from monofilament and vibration testing (for neuropathy) and from microalbuminuria (nephropathy)	4-year visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Areal bone mineral density at the femoral neck, g/cm2	Measured by DXA scan	4-year visit
Areal bone mineral density at the femoral neck, T-Score	Measured by DXA scan	4-year visit
Areal bone mineral density at the femoral neck, Z-Score	Measured by DXA scan	4-year visit
Areal bone mineral density at the total hip, g/cm2	Measured by DXA scan	4-year visit
Areal bone mineral density at the total hip, T-score	Measured by DXA scan	4-year visit
Areal bone mineral density at the total hip, Z-score	Measured by DXA scan	4 year visit
Areal bone mineral density at the spine, g/cm2	Measured by DXA scan	4-year visit
Areal bone mineral density at the spine, T-Score	Measured by DXA scan	4-year visit
Areal bone mineral density at the spine, Z-score	Measured by DXA scan	4-year visit
Areal bone mineral density at the distal third of radius, g/cm2	Measured by DXA scan	4-year visit
Areal bone mineral density at the distal third of radius, T-score	Measured by DXA scan	4-year visit
Areal bone mineral density at the distal third of radius, Z-score	Measured by DXA scan	4-year visit
Trabecular bone score (TBS) at the lumbar spine (L1-L4) (unitless)	TBS calculated with the software TBSinSight	4-year visit
Vertebral Fracture Assessment (VFA) from the T4 to L5 vertebrae to detect the presence of vertebral fracture	Image acquired by DXA	4-year visit
Lean mass (arm, leg, trunk, android, gynoid and total) (g)	Body composition measured by DXA scan	4-year visit
Fat mass (arm, leg, trunk, android, gynoid and total) (g)	Body composition measured by DXA scan	4-year visit
C-terminal cross-linking telopeptide of type I collagen (C-telopeptide, CTX) (ng/mL)	Bone turnover marker, bone resorption (serum)	4-year visit
Procollagen type 1 N-terminal propeptide (P1NP) (ng/mL)	Bone turnover marker, bone formation (serum)	4-year visit
Osteocalcin (ng/mL)	Bone turnover marker, bone formation (serum)	4-year visit
Sclerostin (pmol/mL)	Inhibitor of bone formation (serum)	4-year visit
Change in C-terminal cross-linking telopeptide of type I collagen (C-telopeptide, CTX) (ng/mL)	Bone turnover marker, bone resorption (serum)	Between the baseline and the 4-year visit
Change in osteocalcin (ng/mL)	Bone turnover marker, bone formation (serum)	Between the baseline and the 4-year visit
Change in procollagen type 1 N-terminal propeptide (P1NP) (ng/mL)	Bone turnover marker, bone formation (serum)	Between the baseline and the 4-year visit
Change in sclerostin (pmol/mL)	Inhibitor of bone formation (serum)	Between the baseline and the 4-year visit
Skin advanced glycation end-products (AGEs) (arbitrary units)	Measured with AGEReader (autofluorescence)	4-year visit
Glycated hemoglobin (HbA1c, %)	Diabetes control marker	4-year visit
Fasting glucose (mmol/L)	Blood level measurement	4-year visit
Complete blood count	Blood level measurement	4-year visit
Thyroid-stimulating hormone (TSH) (mU/L)	Blood level measurement	4-year visit
Lipid panel (total cholesterol, LDL-cholesterol, HDL-cholesterol, non-HDL-cholesterol, total cholesterol/HDL-cholesterol ratio, triglycerides, in mmol/L)	Blood level measurement	4-year visit
Creatinine (umol/L)	Blood level measurement	4-year visit
Microalbuminuria (mg/mmol)	Urine microalbuminuria/ urine creatinine ratio measurement	4-year visit
Liver enzymes (AST, ALT) (U/L)	Blood level measurement	4-year visit
Calcium (mmol/L)	Blood level measurement	4-year visit
Albumine (g/L)	Blood level measurement	4-year visit
Phosphate (mmol/L)	Blood level measurement	4-year visit
25-hydroxyvitamin D3 (nmol/L)	Blood level measurement	4-year visit
Parathormone (PTH) (ng/L)	Blood level measurement	4-year visit
Antitransglutaminase antibodies (U/mL)	Blood level measurement	4-year visit
Immunoglobulin A (IgA) (g/L)	Blood level measurement	4-year visit
Insulin like growth factor-1 (IGF-1) (ng/mL)	Blood level measurement	4-year visit
Follicle stimulating hormone (FSH, women) (U/L)	Blood level measurement	4-year visit
Total testosterone (men) (nmol/L)	Blood level measurement	4-year visit
Sex hormone-binding globulin (SHBG, men) (nmol/L)	Blood level measurement	4-year visit

Collaborators and Investigators

• Sponsor: CHU de Quebec-Universite Laval
• Collaborators: Diabetes Canada
• Investigators: Principal Investigator: Claudia Gagnon, MD, CHU de Quebec- Université Laval

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2023
• Primary Completion (Estimated): December 22, 2024
• Study Completion (Estimated): August 29, 2025

Study Registration Dates

• First Submitted: April 2, 2024
• First Submitted That Met QC Criteria: April 2, 2024
• First Posted (Actual): April 8, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Bone Diseases; Bone Diseases, Metabolic; Metabolic Diseases
• Other Study ID Numbers: 2024-6819

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No