Effects of type 2 diabetes on bone quality

Abstract

Individuals with type 2 diabetes mellitus (T2D) have a three-fold greater hip fracture risk than those without diabetes, independent of dual-energy x-ray absorptiometry (DXA) determined bone mineral density (BMD) [1]. Previous large studies explain the BMD T-score inability, a quantitative measure, to accurately predict fracture risk in T2D [2,3]. Mechanisms underlying the inferior bone quality and skeletal fragility in diabetes are not fully understood, making the clinical identification of individuals at risk for fractures difficult [4]. Therefore, we aimed to investigate the comprehensive multiscale bone quality parameters such as biomechanical, microstructural, material, and compositional bone properties in a rodent model and clinical populations with and without T2D. In a rodent study, we have used a combination of a high-fat diet (4 weeks, 58% kcal as fat) and low dose streptozotocin (one time, 35 mg/kg) treatment to develop T2D in female Sprague Dawley rats. In contrast, the control animal received a normal pellet diet (4 weeks, 12% kcal as fat) and an equivalent volume of vehicle (one time, 0.9% saline solution). After eight weeks of establishing the T2D model, the femoral bones were excised, and multiscale bone quality parameters were investigated. We found that the non-enzymatic crosslink ratio (NE-xLR) is elevated in the T2D group. NE-xLR is strongly and negatively correlated with post-yield-displacement, which directly relates to bone fragility. Along with that, the decreased mineral-to-matrix ratio (Fourier transform infrared spectroscopy), decreased nanoindentation determined modulus, increased indentation distance (cyclic reference point indentation), and wider mineral crystal size (x-ray diffraction) in the T2D group compared to non-diabetic, evidenced that the diabetic bone compositional and material properties have changed (diminished), and diabetic bone became weaker and tends to fracture easily. Altogether, our rodent model simulates the disease characteristics of late-stage (insulin resistance and later hypoinsulinemia) for non-obese young T2D and provides potential evidence of diabetic bone fragility at various organization levels [5]. In another study, the femoral head bone tissue specimens were collected from patients with diabetes and known fragility fracture status. Trabecular bone quality parameters were compared in samples of two groups: non-diabetic (n=40) and diabetic (n=30) with a mean duration of disease 7.5±2.8 years. As a result, no significant difference was observed in DXA determined BMD. Bone volume fraction was lower for the diabetic group. Apparent-level (strength) and tissue-level (nanoindentation determined) modulus and hardness were lower in those with diabetes. Compositional differences between the non-diabetic and diabetic groups included lower mineral-to-matrix ratio (gravimetric), wider mineral crystals, and bone collagen modifications assessed as higher total fluorescent advanced glycation end-products (fAGEs) and non-enzymatic crosslink ratio (NE-xLR). Our findings provide evidence of hyperglycemia’s and AGEs detrimental effects on trabecular bone quality at multiple length scales leading to lower energy absorption and toughness, indicative of an increased propensity to bone fragility [6]. After understanding the negative impact of T2D on bone quality, we aim to explore further possibilities of identifying a non-invasive, low-cost diagnostic technique that can help clinicians to predict bone quality beyond bone mineral density accurately. Therefore, first, the multiscale fingernail plate quality is investigated for healthy (HbA1c ≤ 5.9%), diabetic controlled (HbA1c < 7.5%), and uncontrolled diabetic (HbA1c ≥ 7.5%) groups. It was found that T2D had an adverse effect on the human fingernail plate quality too. The parameters of fingernail plate quality were degraded in a pattern among all the three groups, where the degradation was highest in the case of severity of T2D (uncontrolled) as compared to the healthy group (healthy<diabetic controlled<uncontrolled) [7]. Secondly, the material and compositional properties of bone/fingernail were investigated using nanoindentation studies, and Fourier transform infrared spectroscopy, respectively, and a link in degradation pattern of both compositional/material properties of bone and fingernail plate quality was established. Both bone/fingernails in T2D had lower reduced modulus (Er), hardness (H), lower Amide I and Amide II area ratio (protein content), higher sugar-to-matrix ratio, and relatively high carboxymethyl-lysine (CML) content compared with non-diabetic patients. Sugar-to-matrix ratio and relative carboxymethyl-lysine (CML) content were strongly and positively correlated with HbA1c for both bone/fingernail. There was a positive correlation between bone and fingernail glycation content. Our findings provide evidence that the degradation pattern of bone and fingernail properties go hand-in-hand in individuals with T2D. Thus, with these two studies, we concluded that the small-scale properties of the fingernail have the potential to serve as a non-invasive surrogate marker of bone quality in T2D [8]. Altogether, this thesis presents the multiscale characterization of bone as a material, the role of bone quality in diabetic fractures, and elucidates the importance of assessment of bone quality to clinicians in understanding and assessing type 2 diabetic fragility fractures. This thesis concluded that diabetes is detrimental to bone quality. The accumulation of AGEs is one of the processes that favor deterioration of bone quality in diabetes leading to material, structural, compositional, and biomechanical dysfunctionality. Thus, highlight the need for more specific measures to understand and diagnose the bone quality and bone fragility in T2D.