Grad Seminar: Oxidative damage of the bone collagen as a cause of reduced fracture resistance in human cortical bone

Abstract

Bone fragility and fracture remain a prominent issue in the populace especially for the older adult population with associated significant health, social and economic implications. The X-ray based clinical tools used to assess bone fracture risk only “see” the mineral and are unable to predict fracture risk accurately in certain individuals especially for those with type 2 diabetes (T2D) and chronic kidney diseases (CKD). This suggest that factors not measured by these X-ray based clinical tools may be important contributors to predicting bone fracture risk. One such factor is bone collagen which forms about 41% by volume of the bone tissue and has been shown to be vital to the fracture resistance of bone consequently an important determinant for bone fracture risk prediction. Ex vivo human bone studies have shown that the quality and integrity of the bone collagen network degrades with age, and this is associated with a reduction in the fracture resistance of cortical bone. However, the exact mechanics that lead to this degradation of quality and connectivity remains inconclusive.

Interestingly, elevated levels of oxidative stress has been implicated in the development and progression of osteoporosis, T2D and CKD, all bone affecting diseases. Oxidative stress is known to cause damage to macromolecules, referred to as oxidative damage, which includes long lived proteins such as collagen. Consequently, the overarching goal of this thesis was to investigate oxidative damage as a cause of collagen network quality and integrity degradation leading to reduced fracture resistance in cortical bone.
However, first, various methods were compared to determine the best way to conduct fracture resistance testing of cortical bone. It was determined that the most widely used approach resulted in errors in these tests. This highlighted a need for rigorous and standardized methods for cortical bone fracture resistance testing. Using results from the prior mentioned study, fracture resistance testing of ex vivo cortical bone specimens from a large heterogenous group of 81 donors with and without a history of T2D and/or CKD were performed.  In addition, various biomarkers of oxidative damage alongside collagen network quality measures, cortical porosity as well as mineralization profiles were measured. From this, it was found that the biomarkers for oxidative damage correlated negatively with measures of crosslinking in the collagen network. Consequently, it was proposed that oxidative damage indirectly impacts collagen network integrity and thereby cortical bone’s fracture resistance by disrupting formation of crosslinks in the collagen network.
This work provides a better understanding of how oxidative stress may contribute to cortical bone fragility and loss of fracture resistance and this new knowledge could be critical towards the development of better means to detect, prevent and treat bone fragility.

Presenter

Daniel Dapaah, PhD candidate in Systems Design Engineering

Attending this seminar will count towards the graduate student seminar attendance milestone!