Novel Imaging Tracers of Bone Turnover for the Early Diagnosis of Osteoarthritis

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Abstract

Osteoarthritis (OA) is characterized by progressive destruction of articular cartilage, subchondral bone sclerosis, and osteophyte formation. Currently there is no disease modifying drug for treatment of OA. Usually OA is not diagnosed until the advanced stages, where palliative treatment is the only option. Early diagnosis of OA is thought to play a critical role in the management of OA. The etiology of OA is not well-understood, however, studies suggest that early increased turnover in the subchondral bone precedes the degeneration of overlying articular cartilage.

The objectives of this thesis were firstly to develop and characterize an animal model of post-traumatic OA (PTOA), and secondly to develop and characterize novel tracers of bone turnover for early diagnosis of OA.

PTOA was surgically induced in skeletally mature rats. Pathological changes were monitored and characterized utilizing micro-MRI, micro-CT and histology; resulting in development of a comprehensive scoring system for evaluation of OA in pre-clinical animal models. Secondary to the objectives of the thesis, this system was used to evaluate the efficacy of several therapeutic compounds.

The feasibility of using stable strontium as a surrogate for calcium and a tracer of bone turnover was evaluated. After OA induction rats received strontium ranelate as a bioavailable source of elemental strontium at sub-therapeutic doses. Distribution of strontium on bony tissues were assessed ex vivo at 2D and 3D using electron probe micro-analysis (EPMA), and synchrotron dual energy K-edge subtraction micro-CT (KES), respectively. The main bone adaptations detected were formation of osteophytes and subchondral bone sclerosis. Although very sensitive and accurate, these methodologies remain mainly as ex vivo methods. Therefore, we further aimed to develop a bone-targeting MRI contrast agent with potential for in vivo application in humans. For that purpose superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized and subsequently conjugated with bisphosphonate molecules. In vivo micro-MRI revealed accumulation of the tracer in the subchondral bone plate at the early stages of OA progression (i.e., 2-3 weeks post-surgery) before manifestation on radiography. This non-ionizing MR-based bone tracer can provide information on the cellular events at bone (i.e., functional imaging) while providing anatomical information about the cartilage-bone compartment.

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