Determinants of structural changes in the knee joint in a middle-aged cohort with a low prevalence of osteoarthritis

Osteoarthritis (OA) is the most common joint disorder in adults around the world. Knee OA is the most common form of OA in weight-bearing joints and results in deterioration of knee structures and function in older adults for which there is no cost-effective treatment currently available. The natural history of knee OA is highly variable and can involve any part of the joint including the articular cartilage, meniscus, sub-chondral bone and synovium. Use of MRI has revolutionised the understanding of knee OA disease process but there is limited long-term data available in middle-aged adults with early disease changes, as most studies have focused on older adults with established disease. Identifying modifiable risk factors early in life has the potential to prevent or delay the development of knee OA in later life. This thesis aims to investigate the long-term knee structural natural history data in middleaged adults and subsequent correlations with frequent knee symptoms. A population-based sample of middle-aged adults (mean age 45(26‚Äö-61) years; 58% females participated at baseline and approximately 2 and 10 years later. Matched sampling was used to recruit the study participants. Half of the participants were the adult offspring of patients who had a knee replacement performed for idiopathic knee OA at any Hobart hospital from 1996 to 2000. The other half were age and sex matched controls, randomly selected from the population (using electoral rolls) with no history of knee OA in either parent. Cartilage volume, cartilage defects, bone area, bone marrow lesions (BMLs), meniscal tears, meniscal extrusion and effusion were determined using magnetic resonance imaging (MRI). X-ray was used to assess radiographic OA [joint space narrowing (JSN) and osteophytes]. Multiple questionnaires were used to assess pain, function, history of knee joint injury/surgery and physical activity. The first study examined the cross-sectional association between history of knee injury and knee structural damage assessed on MRI in middle-aged adults from the Offspring study and in a random community based sample of older adults. In middle-aged adults, BML presence, tibial bone area and meniscal extrusion presence were significantly higher in those with knee injury, whereas in older adults, cartilage defect presence, cartilage volume, BML presence and tibial bone area were significantly associated with knee injury. This was the first study to look at the association between history of knee injury and knee joint structural changes assessed on MRI and found that the association between knee injury and MRI-assessed structural pathology in the knee joint is moderate and appears to be stronger in older adults compared to middle-aged adults. In the second study, a family history of knee joint replacement due to OA increased the risk of radiographic OA (JSN and osteophytes) and medial tibial cartilage volume loss over 10 years compared to community acquired controls with no family history of OA. Most of these changes were mediated by differences in baseline characteristics of offspring and controls except for increase in medial JSN. Third study looked at the natural history of BMLs in middle-aged adults and found that the natural history of knee BMLs was unstable. BMLs were common in middle-aged adults at baseline. 24% of these BMLs at baseline increased in size, 55% remained stable and 21% decreased in size or resolved completely over 8 years. Change in BMLs was predicted by BMI and strenuous physical activity. An increase in BML size or a new BML resulted in an increase in pain especially in males and those with a family history of OA. Fourth study looked at the natural history of meniscal tears. Only 22% of the participants had a meniscal tear at baseline. Over 8 years, 16 % of the participants had an increase in severity of meniscal tears while none improved. Change in meniscal tears shared common risk factors with knee OA and was independently associated with worsening knee pain and structural damage suggesting that meniscal tears are on the knee OA causal pathway and not just a result of mechanical factors. Fifth study looked at the natural history of cartilage defects. 44% of the participants had at least one cartilage defect at any site at baseline. Most of these defects remained stable, whereas 26% increased and 13% decreased in severity over 10 years. Cartilage defects independently predicted cartilage volume loss in the lateral compartment only. Change in cartilage defects on the other hand was associated with changes in BMI and structural changes/symptoms mostly in the lateral compartment, suggesting a more crucial role of cartilage defects in the development of lateral compartment knee OA. Sixth study examined the correlation between changes in structural abnormalities assessed on MRI and change in radiographic OA over 10 years. Change in JSN was correlated with change in meniscal tears and, to a lesser extent, with meniscal extrusion and cartilage defects. In this sample, change in JSN was a composite measure that did not reflect cartilage volume loss prompting the review of the use of JSN as an outcome measure in chondro-protective drug trials. In conclusion, this series of related studies detail the natural history of knee structural progression in middle-aged adults. Structural changes such as BMLs and cartilage defects have the potential of reversibility in early disease and should be targeted in disease modifying clinical trials. Meniscal tears and BMLs should be targeted in symptom modifying clinical trials especially in those with a family history of OA. Lastly findings from this thesis suggest that the use of JSN as an outcome measure in chondro-protective trial should be reviewed.