Osteoarthritis (OA) affects the daily lives of millions of people in terms of pain, limited range of motion, reduced workability, and reduced quality of live in general. In addition to the physical impairments, the lack of effective treatment beyond symptom control may leave patients with limited optimism. For society, this contributes to a socioeconomic burden of arthritis estimated to be between 1% and 2.5% of the gross national product of Western countries ( ).
The development of new treatments is hindered by the complex and heterogeneous pathogenesis of OA. In addition to the limited understanding of the disease’s etiology, treatment development is also challenged by a lack of appropriate, quantitative markers of disease state and treatment efficacy ( ). For a slowly progressing disease, inappropriate study end-goal markers imply a need for lengthy clinical trials with a large number of subjects—making development slow and costly. Therefore, novel analysis tools and biomarkers are essential both for furthering the etiology understanding and conducting clinical trials effectively ( ).
Much research has been devoted to the development of biochemical biomarkers based on systemic fluids such as serum and urine ( ). These turnover biomarkers are highly effective for examining changes over a short period in preclinical models of OA. They are also appropriate for quantifying the current disease activity or burden of disease in human clinical trials. Potentially, they can also be very appropriate for study population selection, ensuring a population with high risk of progression ( ). However, systemic biochemical markers do not directly reveal where in the body the turnover originates, and they may be less optimal for quantifying changes over the duration of years.
As a complement to biochemical markers, quantification based on imaging receives much research attention. Imaging offers direct visualization and quantification of the individual anatomic structures. For OA, the gold standard marker for progression of the disease in clinical trials is the joint space width (JSW) measured from radiographs. Although joint space narrowing (JSN) is definitely a typical result of OA—and therefore very reasonable to use for monitoring progression—this marker is not ideal for clinical studies. In addition to the targeted cartilage loss, JSN also captures meniscal extrusion. Furthermore, it is a one-dimensional measurement from two-dimensional data (the radiograph), whereas the process of cartilage loss is inherently three-dimensional (3D). Additionally, JSW is problematic for investigating etiology because of the lack of identification of the underlying cause for the narrowing (cartilage loss or meniscal extrusion).
Furthermore, the pathogenesis of OA is much more complex than just loss of cartilage. Apart from the biochemical changes in cartilage and bone turnover mentioned previously, there are many other central effects, such as the presence and growth of osteophytes, that have also traditionally been observed from radiographs (eg, in the Kellgren and Lawrence index) ( ). Also, the full 3D shape of the cartilage/bone surfaces that are related to the joint biomechanics and thereby the congruity ( ) and stability of the joint. These biomechanical changes are likely linked to focal cartilage lesions, bone marrow lesions, and thickening of the subchondral plates. In general, there is a growing impression that the processes of degradation and repair are closely linked as well as the processes undergoing in bone and cartilage ( ).
This complex setting of interdependent tissues and processes makes it highly challenging to achieve a proper understanding of the etiology of OA, and therefore much more data are needed. Histology can provide direct inspection of both the cell-level status and the structure and shape of the central tissues. However, because performing histology analysis is mainly possible for joints that have undergone replacement surgery, the analysis is naturally focused on late-stage pathology. To understand the development and variation among healthy joints, large-scale studies on healthy and early-stage subjects are needed—increasing the need for noninvasive and inexpensive modalities.
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