Progression and Etiology of Cortical Porosity in Diabetic Bone Disease

Overview

Type 2 diabetes is associated with increased cortical bone porosity and increased fracture risk. The goal of this proposed study is to understand the longitudinal evolution of cortical bone porosity and to investigate the underlying biological processes that drive increased cortical porosity and fracture risk in the setting of diabetes. The investigators will apply novel techniques for in vivo imaging of cortical pores to patients with type 2 diabetes and controls in a longitudinal prospective study. This work will establish the longitudinal progression of cortical porosity and determine whether pore content can serve as a predictor of future cortical degradation and bone fragility.

The overall goal of this proposed study is to investigate the underlying biological processes that drive increased cortical porosity in the setting of Type 2 Diabetes and to understand the longitudinal evolution of human diabetic bone disease with a special focus on cortical porosity. The investigators propose the first longitudinal study of pore progression in T2D patients, which will be performed using a novel combined high-resolution peripheral quantitative computed tomography (HR-pQCT) and contrast enhanced magnetic resonance (CE MR) imaging approach. The investigators will use novel image analysis approaches to characterize pore content and spatial distribution of porosity within the cortex, and micro finite element (μFE) analysis to quantify biomechanical impact of porosity. Bone quality deficits underlying increased fragility in T2D are not fully understood. At the tissue level, research evaluating deficits in material properties and fracture resistance is ongoing. At the structural level, increased cortical porosity is a clearly established deficit in bone quality in T2D. Porosity is a major determinant of strength, stiffness, and fracture toughness of cortical tissue, and therefore represents an important target for the prevention or reversal of T2D-associated skeletal fragility. The mechanisms driving increased cortical porosity in T2D are unknown. To develop treatments specifically targeted at the prevention or reversal of pathological porosity, the investigators must understand the biological drivers of porosity. Today these biological drivers are unknown. Within the compact cortex, formation of large cortical pores has been attributed to clustering of osteons and merging of Haversian canals. At the endocortical border, 'trabecularization' or marrow space expansion is hypothesized to drive observed increases in cortical porosity. Multiple mechanisms of pore space expansion likely are at play in diabetic bone disease. Increased marrow adiposity and compromised microvascular health are recognized aspects of T2D mellitus, and may be implicated in the development of pathological porosity. Studies investigating rodent models and humans have established the association of increased marrow fat with T2D. (BMI alone, in contrast, has not been shown to have an association with marrow fat.) Increased marrow fat - in turn - is associated with low Bone Mineral Density (BMD) and poor trabecular microstructure. The investigators have also documented that increased marrow fat is associated with vertebral fracture, independent of BMD. The historic concept of marrow fat as merely a passive filler has been superseded by an appreciation for this fat depot as a dynamic player in bone quality. To date this link has been studied primarily in terms of trabecular bone microstructure; the investigators propose that it could be a player in cortical bone microstructure as well. Microvascular complications of T2D are among the most serious manifestations of the disease. In advanced disease, neovascularization through the process of angiogenesis leads to progression of retinopathy and nephropathy. Recent work has suggested that microvascular pathology also affects trabecular bone quality in diabetes. In cortical bone, where the majority of porosity contains blood vessels, neovascularization necessitates removal of bone tissue. Therefore the investigators hypothesize that microvascular pathology may be influencing cortical microstructural changes in T2D. Content of pathological pore space may indicate drivers of pore space expansion, and lead to strategies for predicting and preventing porosity-related fractures. Characterization of pore content may indicate pore space enlargement by expansion of the marrow cavity, expansion of the vascular network, or both. If the investigators discover that altered marrow distribution or composition is associated with increased porosity in T2D, this suggests that expansion of the marrow cavity may be contributing to pathological porosity. In this case the investigators would direct future efforts towards the emerging topic of fat-bone interactions, specifically: 1) the balance between osteoblast and adipocyte differentiation occurring from a common multipotent precursor; and 2) the action of adipokines on bone remodeling. If the investigators determine that altered vessel distribution or microvascular health is associated with increased porosity in T2D, this suggests that the vascular network may be contributing to pathological porosity. In this case the investigators would direct future research toward the interaction between the vascular system and cortical bone remodeling. The vascular system is known to influence bone remodeling through vasoactive substances released by endothelial cells. In the context of disuse, for example, bone loss is associated with increased vascularity and hyperemia, achieved by the release of vasoactive substances by endothelial cells. As the investigators look at these possible mechanisms of increased cortical porosity, appropriate treatment strategies will be clarified. Specifically, increased porosity related to fat metabolism might indicate interventions focused on directing mesenchymal stem cell differentiation towards osteoblastogenesis or regulating adipokine action on bone remodeling. Alternatively, increased porosity due to microvascular damage might indicate modulation of vasoregulators or anti-angiogenic therapy as used to combat neovascularization and bone erosion in rheumatoid arthritis.