Skeletal Fragility in Type 2 Diabetes Mellitus

Recent studies have shown that individuals with type 2 diabetes mellitus (T2DM) have increased fracture risk, despite being obese and having normal to high bone mineral density, both of which are presumed to protect against fractures(1). The public health impact of skeletal fragility in this group will only grow due to the aging of the population and the significantly increasing prevalence of diabetes. Over the next fifty years the largest increase in diabetes will be in those aged 75 years and greater, with increases projected as high as 336% for this oldest age group (2). To date, there is a very poor understanding of the mechanisms underlying skeletal fragility in adults with T2DM. Several mechanisms have been proposed to contribute to the increased fracture risk seen in individuals with T2DM, including an increased propensity to fall, altered bone microarchitecture, and poor bone quality, due to an accumulation of advanced glycation endproducts (AGE) that decrease bone strength (3). In particular, in vitro incubation of bone with ribose has confirmed that AGE accumulation negatively impacts bone biomechanical properties (4,5). However, no studies have investigated bone samples from patients with diabetes to determine whether AGE content is higher and bone mechanical properties are deteriorated. We propose to determine the contribution of AGE accumulation to altered bone biomechanical properties by studying femoral neck bone specimens retrieved from T2DM and control patients (n=20/group) undergoing total hip replacement. We will measure biomechanical properties of the bone tissue using reference point indentation, a novel technique for directly assessing the mechanical behavior of the bone matrix (6,7). After mechanical testing, proteins will be extracted from bone specimens and used to measure collagen and AGEs content (8). In addition, we will collect blood from each patient in order to relate serum pentosidine, insulin and HbA1c to levels of AGE in the bone itself. Access to the patients and bone specimens is made feasible by colleagues in the Department of Orthopedic Surgery. Results from this study will provide novel information on the potential contribution of poor bone quality to skeletal fragility in patients with T2DM.