Skeletal Effects of Type 1 Diabetes on Low-Trauma Fracture Risk

Patients with Type 1 Diabetes Mellitus (T1DM) have a higher risk of low-trauma (osteoporotic) fracture that is 7-12 times higher than non-diabetics. The bone density of people with Type 1 Diabetes is higher at the time of fracture than in non-diabetics. This suggests the presence of underlying bone tissue mechanical defects. The potential benefits to participants would be knowledge gained about their bone density and the results of laboratory tests. On a wider scale, there may be general benefits to society because the knowledge gained from this study may help better understand the effects of diabetes on bone health

Study Overview

• Status: Recruiting
• Conditions: Fractures, Bone; Type 1 Diabetes; Bone Loss; Osteopenia
• Intervention / Treatment: Procedure: Transilial bone biopsy

Detailed Description

The investigators will enroll 40 female, non-fracturing, postmenopausal, patients with T1DM, who are age 50 and over, and have had diabetes for more than ten years. The investigators will perform 2 transiliac (hip bone) biopsies on each subject, one for mechanical testing, tissue analysis of AGEs, enzymatic crosslinks and bone tissue-bound water in cortical bone, and the other for histomorphometry and high-resolution 3D imaging in trabecular bone. A matched, non-diabetic, healthy control will be enrolled at the time each T1DM is enrolled.

• Study Type: Observational
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julie Stubby; Phone Number: 402-280-4958; Email: jstubby@creighton.edu
• Study Contact Backup: Name: Joan Lappe; Phone Number: 402-280-4646; Email: jmlappe@creighton.edu

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68122
      • Recruiting
      • Creighton University Osteoporosis Research Center
      • Contact: Julie Stubby; Phone Number: 402-280-4958; Email: jstubby@creighton.edu
      • Contact: Joan Lappe; Phone Number: 402-280-4646; Email: jmlappe@creighton.edu
      • Sub-Investigator: Laura Armas, MD
      • Principal Investigator: Mohammed Akhter, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

40 female non-fracturing type 1 diabetics and 40 matched healthy female controls. The investigators will enroll an age-matched, healthy, non-diabetic, non-fracturing female control who is 5 years past the onset of menopause. All of our subjects, diabetics and controls, will be Caucasians, free of diagnoses other than diabetes, and all will have DXA T-scores at the femoral neck and/or total hip and/or lumbar spine between -1.0 and -2.5, (i.e. none will have T-scores in the DXA T-score range of osteoporosis).

Description

Inclusion Criteria:

Criteria for enrollment of female diabetics

1. No chronic disease diagnoses that may affect bone, as confirmed by the PI.
2. Normal clinical history, physical, and clinical laboratory exam (except for usual complications of a 10+-year diabetic, i.e., ~minimal neuropathy or retinopathy, known, but asymptomatic mild vascular disease, etc.)
3. Glomelular Filtration Rate (GFR) >45 ml/min (Renal Association lower limit for "mild" kidney failure).
4. Willingness to sign a consent form.
5. Willingness to undergo a transilial bone biopsy incision that yields 2 bone specimens.
6. No abnormalities in clinical blood chemistry measurements (small, age-related decreases in GFR, will be permitted).
7. Caucasian

Criteria for each non-diabetic subject, compared to their matched diabetic:

1. Dual-energy x-ray absorptiometry (DXA) measures (BMD, gm/cm) must be within +/- 15% in total hip.
2. Body mass index (BMI) must be within +/-10%.
3. Age must be within +/- 5 years.
4. Caucasian

Exclusion Criteria:

1. Women who have had Type 1 diabetes for less than 10 years.
2. Non-insulin dependent Type 1 diabetic.
3. Less than 50 years old.
4. Less than 5 post menopausal.nd have had diabetes for at least 10 years. -

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Type 1 Diabetics; All participants will complete 4 visits over 6-8 weeks. Visit 1 is a screening visit which includes a physical exam, a bone mineral density scan, a blood draw and an EKG. Visit 2 consists of dispensing the Tetracycline antibiotic required for the bone biopsy. Visit 3 is the bone biopsy and includes a blood draw. Visit 4 is to remove the stitches.	Procedure: Transilial bone biopsy; The transiliac bone biopsy will be performed on each subject under local anesthesia, and conscious sedation. From one skin incision located ~2cm posterior and inferior to the anterior-superior pelvic spine on one side of the pelvis, the investigators will obtain two iliac bone specimens, each 7.5 mm in diameter, cylindrical in shape, and including both inner and outer cortices and the intervening trabecular bone.
Non-Type 1 Diabetics; All participants will complete 4 visits over 6-8 weeks. Visit 1 is a screening visit which includes a physical exam, a bone mineral density scan, a blood draw and an EKG. Visit 2 consists of dispensing the Tetracycline antibiotic required for the bone biopsy. Visit 3 is the bone biopsy and includes a blood draw. Visit 4 is to remove the stitches.	Procedure: Transilial bone biopsy; The transiliac bone biopsy will be performed on each subject under local anesthesia, and conscious sedation. From one skin incision located ~2cm posterior and inferior to the anterior-superior pelvic spine on one side of the pelvis, the investigators will obtain two iliac bone specimens, each 7.5 mm in diameter, cylindrical in shape, and including both inner and outer cortices and the intervening trabecular bone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare cortical bone tissue levels of pentosidine (AGE), pyridinoline (normal enzymatic collagen crosslinks), and matrix-bound water between T1DM and controls.	For different advance glycation endproducts (AGEs), a) pentosidine (PEN), b) pyrinoline (Pyd), and c) tissue water (TW), will be measured using Raman spectroscopy technique on bone biopsy tissue obtained from study participants. Raman spectra will be obtained from the embedded block surfaces using a confocal Raman spectrometer (Renishaw InVia Qontor, www.renishaw.de). These spectra will be collected at the interstitial, cement lines, and actively bone forming osteons with evident fluorescent labels. A continuous laser beam with an excitation of 785 nm and power of 10 mW will be focused through a Raman microscope (Leica DM2700M), using the 50x objective, down to a micrometer-sized spot on the sample.; Pentosidine (PEN) [ratio]. PEN (Pentosidine) from the integrated area ratio of bands 1495 (PEN) cm-1 / 1450 cm-1 (methylene side chains (CH2)).; Pyrinoline (Pyd) [ratio]. The pyridinoline (Pyd; enzymatic trivalent collagen cross-link) content is calculated as the absorbance height	6-8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare cortical bone tissue heterogeneity in nanoindentation measures of modulus and hardness between T1DM and controls.	Bone tissue's hardness and modulus will be quantified by using nanoindentation technique. The nanoindentation is a mechanical/material strength testing technique. The technique has been used in bone tissue from bone biopsies.; Hardness [GPa-giga-pascal-N/m2]; Modulus [GPa-giga-pascal-N/m2]	6- 8 weeks

Collaborators and Investigators

• Sponsor: Creighton University
• Investigators: Principal Investigator: Mohammed Akhter, PhD, Creighton University Osteoporosis Research Center

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2019
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: December 21, 2022
• First Submitted That Met QC Criteria: January 17, 2023
• First Posted (Actual): January 27, 2023

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Bone; Cortical Bone; Mechanical Strength
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Wounds and Injuries; Endocrine System Diseases; Musculoskeletal Diseases; Bone Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Fractures, Bone; Bone Diseases, Metabolic; Osteoporotic Fractures
• Other Study ID Numbers: 1425624-3

Drug and device information, study documents

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