Bone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes

Abstract

Skeletal fragility is a major complication of type 2 diabetes mellitus (T2D), but there is a poor understanding of mechanisms underlying T2D skeletal fragility. The increased fracture risk has been suggested to result from deteriorated bone microarchitecture or poor bone quality due to accumulation of advanced glycation end-products (AGEs). We conducted a clinical study to determine whether: 1) bone microarchitecture, AGEs, and bone biomechanical properties are altered in T2D bone, 2) bone AGEs are related to bone biomechanical properties, and 3) serum AGE levels reflect those in bone. To do so, we collected serum and proximal femur specimens from T2D (n = 20) and non-diabetic (n = 33) subjects undergoing total hip replacement surgery. A section from the femoral neck was imaged by microcomputed tomography (microCT), tested by cyclic reference point indentation, and quantified for AGE content. A trabecular core taken from the femoral head was imaged by microCT and subjected to uniaxial unconfined compression tests. T2D subjects had greater HbAc (+23%, p ≤ 0.0001), but no difference in cortical tissue mineral density, cortical porosity, or trabecular microarchitecture compared to non-diabetics. Cyclic reference point indentation revealed that creep indentation distance (+18%, p ≤ 0.05) and indentation distance increase (+20%, p ≤ 0.05) were greater in cortical bone from T2D than in non-diabetics, but no other indentation variables differed. Trabecular bone mechanical properties were similar in both groups, except for yield stress, which tended to be lower in T2D than in non-diabetics. Neither serum pentosidine nor serum total AGEs were different between groups. Cortical, but not trabecular, bone AGEs tended to be higher in T2D subjects (21%, p = 0.09). Serum AGEs and pentosidine were positively correlated with cortical and trabecular bone AGEs. Our study presents new data on biomechanical properties and AGEs in adults with T2D, which are needed to better understand mechanisms contributing to diabetic skeletal fragility.

Altered Tissue Composition, Microarchitecture, and Mechanical Performance in Cancellous Bone From Men With Type 2 Diabetes Mellitus

“…These results confirm increased accumulation of the AGE pentosidine and sugars bound to the collagen matrix in cancellous tissue from men with T2DM and are consistent with other reports of bone tissue pentosidine in men and women with and without T2DM . Total fAGE concentration in this study was not different between groups, consistent with another report of tissue fAGEs in proximal femoral cancellous bone in men and women with and without T2DM . In vitro glycosylation/ribosylation studies of human cancellous bone offer the ability to isolate the effects of AGE accumulation.…”

“…Finally, it is important to note that both cancellous and cortical bone contribute to structural performance at the whole‐bone level, and cortical bone is more critical for load‐bearing in the hip . In the first study relating bone tissue AGES to mechanical properties from tissue from patients with T2DM, Karim and colleagues reported a trend toward greater AGEs in the cortex of the femoral neck (+ 19%, P = 0.09) and greater creep indentation distance (+ 18%) and indentation distance increase (+ 20%) in cortical bone from patients with T2DM versus non‐DM controls; however, no relationships between bone AGEs and the indentation variables were observed . These results highlight the complexity of assessing the relationships between AGEs and bone fragility across levels of structural hierarchy and suggest an important area for future investigation.…”

“…Two studies have compared mechanical performance of tissue from men and women with and without T2DM, and the differences were found in cortical tissue. One study reported decreased resistance to in vivo impact indention in cortical bone at the tibial diaphysis in patients with T2DM versus those without T2DM, and the other found decreased resistance to cyclic reference point indentation in cortical proximal femur tissue . With the exception of these two studies, the majority of evidence that T2DM deleteriously affects bone mechanical performance is from rodent models.…”

Bone Quality Sleuths: Uncovering Tissue-Level Mechanisms of Bone Fragility in Human Type 2 Diabetes

“…Although the group size of 31 to 34 in this study is tiny by the standards of large epidemiologic cohorts, it significantly exceeds the standard in a field where conclusions about human bone quality sometimes rely on a handful of specimens. The robust analyses of human bone quality and composition join published studies by Pritchard and colleagues and Karim and colleagues in advancing our understanding of the mechanisms of bone fragility in human diabetes. The results challenge the assumptions based on animal models.…”

Bone Mineral Is More Heterogeneously Distributed in the Femoral Heads of Osteoporotic and Diabetic Patients: A Pilot Study

“…In fact, studies have reported that patients with T2DM have normal to high BMD by DEXA . Recent studies have found that the trabecular microarchitecture and mechanical properties of cancellous bone of T2DM (measured by cyclic reference point indentation and unconfined compression) are indistinguishable from osteoarthritic (OA) controls, whereas the apparent stiffness and yield strength were increased in cancellous cores from the femoral neck of patients with T2DM (and osteoarthritis) compared with OA controls . Impaired mechanical properties (decreased strength, stiffness, and toughness) have been reported for hyperglycemic mouse femurs tested in bending .…”