Progression and Etiology of Cortical Porosity in Diabetic Bone Disease
Condition: Type 2 Diabetes
MeSH terms: Bone Diseases
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): XtremeCT
Intervention type(s): Device
Intervention description(s): HRpQCT technology provides information on bone microarchitecture, bone density and bone strength by measuring the cortical and trabecular bone structures with improved spatial resolution and defining the surfaces in three-dimensional manner.
Other intervention name(s): High-resolution peripheral quantitative computed tomography (HRpQCT)
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects with type 2 diabetes will be recruited from primary care clinics all over San
        Francisco;
      
Biospecimen description: 
      Serum will be frozen for future batch analysis of 1.25(OH)2D, sclerostin, the fat-secreted
      hormones (adipokines), adiponectin and leptin, estradiol, angiogenesis markers vascular
      endothelial growth factor (VEGF), angiopoietin-1 and antagonist ang-2, and the bone turnover
      markers C-terminal cross-linking telopeptide of type I collagen (CTX; bone resorption), total
      aminoterminal propeptide of type I collagen (PINP; bone formation), and bone-specific
      alkaline phosphatase (BAP; bone formation). Serum and urine will be stored for possible
      future analyses.