Skeletal Effects of Type 1 Diabetes

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.

Grant Number: 5R01DK122558-05
NIH Institute/Center: NIH
Principal Investigator: MOHAMMED AKHTER