1. Prevention and personalized treatments in knee osteoarthritis Synthesis of evidence from systematic literature searches with focus on implications for prevention and personalized treatment WP4 Ewa Roos - Hans Lund SDU

2. General background ESR8 Effectiveness of biomechanical therapies, examples:  Effect of exercise on joint structure or Joint load  Effect of bracing on pain/disability Joint load is crucial in stimulating the cartilage cells and maintaining the homeostasis of the cartilage. Thus physical activity is a potentially important part of maintaining cartilage health, and exercise is indeed a corner stone of knee OA treatment. On the other hand high-level physical activity such as elite sports and long-term knee bending work are risk factors for knee OA development. In summary, a window of optimal knee joint load seems to promote joint health.

3. General Background – ESR7 Evidence synthesis on biomechanical pathways in knee OA, examples  Effect of strengthening exercise on pain/disability  Effect of improved hip abductor strength on knee adduction moment It is not known whether a poor muscle function leads to cartilage degradation / pain and/or disability or cartilage changes lead to poor muscle function. In some situations good muscle strength may diminish the load in the knee joint, while it in other situations it may increase the load. In the same way, muscles around the knee and hip joints may be of importance to secure an even distribution of loads between the medial and lateral knee joint compartment. It is however currently unknown how the muscle function is related to the development and worsening of KOA.

4. Aim ESR7 Overall aim: evidence synthesis on biomechanical pathways in knee OA Specific aim: To identify the optimal muscle function for patients with KOA both in daily activities and when performing exercise. ESR8 Overall aim: compile the existing evidence on the effectiveness of biomechanical therapies in knee OA Specific aim: To provide guidelines for optimal knee joint load in preventing and treating participants at high risk of developing OA and participants with knee OA.

5. Example Methodical background: optimal muscle function  The expanding body of research reports increase the danger of an increasing number of less than meaningful observations are being reported in the literature is a real possibility (Chow 2011)  Fewer than 20% of the papers published in two applied biomechanics serials could be rated highly on rationale, theory and statistical analysis (Knudson 2005). 5

6. Theoretical assumption  By mapping the possible mechanisms it would be possible to examine the evidence for each mechanism.  By dividing each mechanism into deterministic models it is possible to examine the evidence for each part/step of the model

7. Beckwee et al. 2013  Qualitative analysis of the literature aims to provide an overview of theoretical models that are put forward to explain the beneficial treatment effects of exercise in KOA  70 original papers identified from reviews and guidelines  22 had a explanation for why exercise can help diminishing pain in KOA

8. Beckwee 2013 CategoriesTheoretical concepts Neuromuscular components Muscle Proprioception Energy absorption capacity Stability Peri-articular componentsConnective tissue Bone Intra-articular componentsCartilage Inflammation Joint fluid General fitness /health componentsComorbidity Weight loss Aerobic fitness Psychosocial componentsIncrease of well-being Decrease of depression Placebo effect Increase of self-efficacy

9. Deterministic models, muscle and KOA (from Beckwee 2013) Better muscle strength Better cartilage quality Better muscle strength Increased functional capacity Better hip abductor muscle strength Reduce knee adduction moment Less load in medial compartment Mikesky 2006: Hinmann 2007: Røgind 1998: What is the evidence?

10. METHOD STEP 1 Identify the primary goal / primary outcome. Operationalised in KOA: 1.Less pain? 2.Less disability? – patient-reported OR observed 3.Structural changes? 10

11. METHOD STEP 2 Identify the factors that could contribute to this outcome Operationalised in KOA 1.Beckwee's study from 2013 identifies 16 different concepts/mechanisms focusing on reducing pain for patients with KOA 2.Choice: MUSCLE (Neuromuscular components) 11

12. METHOD STEP 3 For each concept/mechanism form a block diagram (deterministic model). The links between each block and the blocks should be all-inclusive and non- redundant. Operationalised in KOA Bradford Hill criteria should be used for each link in the block diagram (deterministic model) 12

13. Bradford Hill criteria In 1965 Austin Bradford Hill proposed a series of considerations to help assess evidence of causation, [21] which have come to be commonly known as the "Bradford Hill criteria".Austin Bradford Hill [21]Bradford Hill criteria In contrast to the explicit intentions of their author, Hill's considerations are now sometimes taught as a checklist to be implemented for assessing causality. [22] Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non." [21] [22] [21] 13

14. Bradford Hill criteria 1.Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. [21] [21] 2.Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. [21] [21] 3.Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship. [21] [21] 4.Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). [21] [21] 5.Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence. [21] [21] 6.Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge). [21] [21] 7.Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations". [21] [21] 8.Experiment: "Occasionally it is possible to appeal to experimental evidence". [21] [21] 9.Analogy: The effect of similar factors may be considered. [21] [21] 14

15. Bradford Hill criteria The consequence of using these criteria is a systematic search for documentation for each link in the block diagram/deterministic model. A strong mechanism (block diagram) is one where every link is supported by earlier studies / Bradford Hill criteria A weak mechanism (block diagram) is one where the support for hub links (i.e. crucial link) is absent or weak according to the Bradford Hill criteria 15

16. Method STEP 4 Comparing each deterministic model – which models have the strongest evidence Operationalized in KOA: The strongest mechanism can show us: 1.The persons with high risk for KOA 2.The best exercise regimes for KOA 16

17. Method STEP 5 A systematic search for all RCTs dealing with the deterministic model(s) with the best evidence PS It would be relevant to search for RCTs for both the strong and weak mechanisms. Sometimes the theoretical foundation is lacking but clinical research indicates an effect 17