Full Length ArticleBone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes
Introduction
Individuals with type 2 diabetes mellitus (T2D) have an increased risk of fracture, despite having normal or high bone mineral density (BMD) [[1], [2], [3], [4], [5]]. While falls are more common among T2D patients, fracture risk remains increased even after accounting for the higher incidence of falls within this group [6]. Thus, it has been suggested that the increased fracture risk seen in T2D may be due to altered bone microarchitecture and/or poor bone quality (i.e. matrix properties) [7,8]. Notably, some but not all, studies report altered cortical bone microarchitecture in T2D [[7], [8], [9]]. However, very little is known about the contribution of poor bone quality to reduced bone strength in T2D. Thus, mechanisms underlying diabetic skeletal fragility are poorly understood, making it difficult to develop appropriate strategies to diagnose and prevent fractures in this population.
Specifically, the accumulation of advanced glycation end-products (AGEs) by non-enzymatic glycation, a spontaneous reaction between amino acid residues on collagen fibers and extracellular sugars [10,11], can lead to poor bone tissue matrix composition. Literature indicates that AGEs can adversely affect mechanical properties, which may ultimately contribute to increased skeletal fragility [[12], [13], [14]]. However, the limited data available regarding the effect of AGEs on bone mechanical properties is contradictory. For example, one study showed that human trabecular bone specimens with AGEs induced by in vitro incubation had lower post-yield strain energy compared to vehicle-incubated specimens [15], but there was no difference in post-yield strain energy due to induced AGEs in bovine cortical bone [16]. Further, two ex vivo studies in human trabecular and cortical bone showed negative relationships between AGE content and ultimate strain and stress [17,18], while a study in human trabecular bone reported no relationships between AGEs and biomechanical properties [19]. Therefore, the effect of AGEs on bone mechanical properties, and especially in diabetic bone, remains unclear.
Further, a few studies report increased pentosidine (an AGE) in urine or serum of individuals with T2D who experience fractures compared to those without fractures [20,21]. One study reported that in bone retrieved during total knee replacement, pentosidine content was higher in patients with T2D than in non-diabetics [22]. However, this study was conducted in a small, homogenous sample of men, and did not assess bone biomechanical properties. Moreover, given that pentosidine composes only 1% of total fluorescent AGEs [23], it may be important to assess the total amount of AGEs in bone. Furthermore, it is not known whether the amount of AGEs in other biological sources (e.g. serum) are associated with the amount of bone AGEs and/or bone biomechanical properties.
Thus, our goals were to: 1) investigate whether bone microarchitecture, AGEs, and bone biomechanical properties are altered in diabetic bone, 2) determine if bone AGEs relate to bone biomechanical properties, and 3) determine whether serum AGEs reflect those in bone. We hypothesized that bone specimens from patients with T2D would have increased cortical porosity but similar trabecular microarchitecture, increased AGE content, and deteriorated biomechanical properties compared to non-diabetic specimens. We also hypothesized that higher HbA1c and bone AGEs would be associated with worse bone biomechanical properties, and that bone and serum AGE content would be associated with each other.
Section snippets
Subject recruitment and specimen collection
We sequentially recruited patients undergoing elective total hip replacement surgery at Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA, USA. The protocol was approved by the BIDMC Institutional Review Board, and all subjects provided written informed consent prior to participation. Subjects were considered to have T2D if: 1) they had an HbA1c ≥6.5% in their medical record within the past 2 years; 2) they had an HbA1c ≥6.5% more than 2 years ago and are currently using T2D
Sample size
Several bone specimens (5 T2D, 10 non-T2D) were mishandled or unavailable for use due to logistical issues in the pathology department after surgery, resulting in 15 T2D and 23 non-T2D specimens available for RPI and AGE measurement. Additional specimens were excluded from microCT imaging due to unavailability of the posterior-medial portion of the femoral neck for imaging (3 T2D, 4 non-T2D), resulting in 12 diabetics and 19 non-diabetics whose bone specimens were imaged by microCT. Finally,
Discussion
Despite increased fracture risk among individuals with T2D, there is limited information on how bone microarchitecture and bone quality components contribute to bone mechanical properties in patients with T2D. By studying bone specimens from the proximal femur, our first objective was to provide new information on bone structure, mechanical properties, and AGE content in patients with and without T2D. Our second goal was to determine if AGE content in bone was related to bone mechanical
Acknowledgements
We would like to thank Dr. Anne Breggia from Maine Medical Center for measurement of serum AGEs and pentosidine. Financial support for this work was provided by NIH-T32AG023480, a pilot and feasibility grant from the Boston Area Diabetes and Education Center (NIH-P30DK057521), the Harvard Catalyst Early Clinical Data Support for Grant Submissions (NIH-NCRR and NIH-NCATS Award UL1TR001102), NIH-1K01AR069685-01A1, NIH-R21AR070366, and the NIDDK Diabetic Complications Consortium grant DK076169.
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