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

The investigators will enroll 40 female, postmenopausal, patients with T1DM, fracturing or non-fracturing, 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.

• Transilial bone biopsy (Procedure): 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.

Primary outcomes

• Compare cortical bone tissue levels of pentosidine (AGE), pyridinoline (normal enzymatic collagen crosslinks), and matrix-bound water between T1DM and controls. [6-8 weeks]: 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. 1. Pentosidine (PEN) \[ratio\]. PEN (Pentosidine) from the integrated area ratio of bands 1495 (PEN) cm-1 / 1450 cm-1 (methylene side chains (CH2)). 2. Pyrinoline (Pyd) \[ratio\]. The pyridinoline (Pyd; enzymatic trivalent collagen cross-link) content is calculated as the absorbance height

Secondary outcomes

• Compare cortical bone tissue heterogeneity in nanoindentation measures of modulus and hardness between T1DM and controls. [6- 8 weeks]: 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. 1. Hardness \[GPa-giga-pascal-N/m2\] 2. Modulus \[GPa-giga-pascal-N/m2\]

Sex: Female, ages: 50 Years to any, accepts healthy volunteers

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 years post menopausal.

• Mohammed Akhter, PhD, Principal investigator, Creighton University Osteoporosis Research Center