This application responds to the RFA titled, “Understanding Skeletal Effects of Type 1 Diabetes”, FOA RFA- DK-18-002. Low-trauma (osteoporotic) fractures are epidemic in the U.S. and the world(1-7). About 50% of the variation in risk of these fractures is due to low bone density, and the remaining 50% is due to defective mechanical properties of bone tissue(8). Diabetics suffer a significantly higher incidence of osteoporotic fractures than do non-diabetics(9-13), and their bone densities are higher at the time of fracture than in fracturing non-diabetic patients(13). These mechanical defects may be the result of episodes of hyperglycemia which could cause accumulation of compounds, such as advanced glycation end-products (AGEs) that weaken bone mechanical properties(14-16). These compounds accumulate in many tissues in diabetics(14-18), and this has stimulated some interest in the development of anti-glycation treatments because of their therapeutic potential. Indeed, one approved osteoporosis anti-fracture drug, raloxifene, has been shown to reduce fractures in non-diabetic osteoporotics without the usual accompanying increase in bone mass(19-22). It has also been shown to reduce the concentration AGEs in bone in an animal model(23), and improves bone mechanical strength by increasing matrix-bound water(24). Our hypotheses are: 1. Type 1 diabetics have greater risk of osteoporotic fractures for any given bone density due to reduced mechanical quality of their bone tissue, and 2. This mechanical defect is due to excess accumulation of chemicals such as AGEs, and to loss of bone tissue-bound water(17;24). Our study plan is to recruit 40 female, postmenopausal, type 1 insulin- dependent diabetics, who are over age 50, and have had diabetes for 10 – 30 years. We will perform 2 transilial bone biopsies(25) on each subject, one for mechanical testing(25) and imaging,(26;27), and the other for tissue analysis of AGEs, other candidate chemicals, and bone tissue-bound water(28). A matched, non- diabetic, healthy control will be recruited at the time each diabetic is recruited and biopsied as in our previous study of 60 fracturing patients, each compared with 60 matched controls(25). Heretofore, we have not had FDA approval for the use of agents such as raloxifene(19;21;23;24;29) for prevention of fractures in diabetics, and thus they are rarely prescribed. The ultimate goal of this study is to provide more documentation of the cause of the excess fracture burden in diabetics in order to encourage development of treatment options, i.e. anti-glycation compounds, for their prevention. The absence of approved pharmaceutical options for reduction of fracture-risk in diabetics represents a serious problem for the large population of diabetics, and the results of this work are necessary on behalf of these patients.

This project will contribute knowledge pertinent to the cause of excess risk of osteoporotic fractures in patients with insulin-dependent diabetes mellitus. We will obtain transilial bone biopsies from type-1 diabetics in which to measure content of known chemicals that weaken bones, and compare those same measurements in matched, normal, nondiabetic subjects. Since practitioners and pharmaceutical companies are not yet convinced of their importance, results from this project will encourage performance of the expensive clinical trials needed to provide agents that reduce fracture risk in diabetics.