1. Exercise therapy in Knee Osteoarthritis Marike van der Leeden PT PhD 0 Amsterdam Rehabilitation Research Center | Reade

2. Osteoarthritis Prevalence symptomatic OA in among adults aged ≥45 years Knee 16.7% Hip 9.2% Top 10 of most disabling diseases in European region Most important cause of pain and disability in the elderly Jordan et al, 2007 WHO, 2008 Conaghan et al, 2008 1

3. Total joint failure 2 Bijlsma et al, Lancet, 2011

4. Impairments of cartilage and bone Findings on X-rays, MRI Physical impairments Muscle weakness, instability Sensory impairments Pain, stiffness Limitations in activity and functioning Walking, rising Problems in participation Work Osteoarthritis – multiple levels 3

5. Exercise therapy in knee OA Exercise is dominant intervention Pain relieve Improved performance of activities Exercise recommended in all major guidelines Franssen, 2008, 2009 4

6. Definition and types of exercise Definition: ‘a planned, structured and repetitively movement designed to improve or maintain one or more components of physical fitness’ Types of exercises: Muscle strenghtening: strength: maximum amount of force a muscle can generate endurance: ability of muscles to sutain muscle action Aerobic: improvement of aerobic capacity, eg walking, cycling Flexibility: stretching exercises to increase ROM Functional exercises: train problematic activities 5

7. Cochrane Review “Exercise for Osteoarthritis of the Knee” Fransen M et al., January 2015 Evidence? 4

8. Objectives Update of Cochrane review of 2008 ‘To determine whether land-based therapeutic exercise is beneficial for people with knee OA in terms of reduced joint pain or improved physical function and quality of life’ 5

9. Data collection and analysis A systematic review and meta-analysis was conducted Five databases were searched from their inception until May 2013 Inclusion of all randomised controlled trials (RCTs) recruiting people with knee OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in the water) with a non-exercise or non-treatment (or waiting list) intervention were included (n =54) 6

10. Main results on pain High-quality evidence from 44 trials (3537 participants) indicates that exercise reduced pain (SMD -0.49, 95% CI -0.39 to -0.59) immediately after treatment Pain was estimated at 44 points on a 0 to 100-point scale (0 indicated no pain) in the control group; exercise reduced pain by an equivalent of 12 points (95% CI 10 to 15 points). 7

11. Moderate-quality evidence from 44 trials (3913 participants) showed that exercise improved physical function (SMD -0.52, 95% CI -0.39 to -.064) immediately after treatment Physical function was estimated at 38 points on a 0 to 100-point scale (0 indicated no loss of physical function) in the control group; exercise improved physical function by an equivalent of 10 points (95% CI 8 to 13 points) 10 Main results on physical function

12. Treatment content 11 10

13. Conclusion Cochrane review High-quality evidence indicates that land-based therapeutic exercise provides short-term benefit in terms of reduced knee pain, and moderate-quality evidence shows improvement in physical function among people with knee OA. The magnitude of the treatment effect would be considered moderate (immediate) to small (two to six months) but comparable with estimates reported for non-steroidal anti- inflammatory drugs. 12

14. Optimization of effectiveness Effects are small to moderate Optimization of effects through targeted exercise programs for specific subgroups

15. Targeted exercise therapy Pain Pain medication and exercise Muscle weakness Vitamin D, strength training Comorbidity Exercise adapted to comorbidity Depressive mood and avoidance Exercise plus graded increase of physical activity level Instability of the knee joint Proprioceptive exercise, strength training 14 Veenhof et al, Arthritis Care Res, 2006 Knoop et al, Osteoarthritis Cartilage, 2013 van Tunen et al, submitted de Zwart et al, accepted de Rooij et al, in progress

16. Stability trial 15

17. Muscle weakness Laxity Poor proprioception Varus-valgus knee motion during walking (In)stability knee van der Esch et al,’06/’07 Activity limitations Instability of knee joint:  >60% of knee OA patients 1,2  associated with activity limitations 1,2 1 van der Esch et al, ’12; 2 Fitzgerald et al, ‘04

18. 159 knee OA with knee joint instability: randomized 12 weeks with 2 sessions + home exercises; 6-8 patients per group, supervised by two pt’s; gradual increase in intensity and knee loading; exercises linked to daily activities; patients encouraged to remain physically active after treatment Minimal intensity/loadingIncreasing intensity and loading Muscle endurance Week 1-4 Week 9-12 Week 5-8 Week 1-8 Focus on muscle strengthening Week 9-12 Focus on performance daily activities Control program Functional training + maximal strength + aerobic training Exercise programs Minimal muscle training + education Minimal intensity/loading Increasing intensity and loading Muscle enduranceFunctional training + maximal strength + aerobic training Week 1-4 Focus on knee stabilization Week 5-8 Focus on muscle strengthening Week 9-12 Focus on performance daily activities Experimental program Knee stabilization training + education Week 1-4 Week 9-12 Week 5-8

19. Knee joint stabilization training -feedback by PT’s -use of mirrors -specific exercises

20. Amsterdam Rehabilitation Research Center | Reade Study design Randomized controlled trial (single-blinded) two exercise programs. Inclusion criteria: diagnosis of knee OA (ACR) knee instability age 40-75 years. Outcome measures: WOMAC, physical function (primary) NRS pain, GUG- test, global perceived effect, self-reported knee instability, muscle strength, proprioception measurements at baseline, 6-week (mid-treatment), 12-week (post- treatment) and 38-week follow-up (6 months post-treatment) assessor blinded for treatment allocation.

21. Amsterdam Rehabilitation Research Center | Reade Flow chart 61% female age: 62 ± 7 yr 69% K/L ≥ 2

22. Results (1) Mean difference: B (95% CI) = -0.26 (-0.76-0.23) Mean difference: B (95% CI) = -0.01 (-2.58-2.57) Primary outcome: WOMAC, physical function (0-68) Secundary outcome: NRS knee pain (0-10) No difference in effectiveness between programs

23. Result on muscle strength 22

24. Result on knee stability 23

25. Results (2) Both exercise programs are highly effective and safe: effect size: 0.9 for pain and 0.7-0.8 for function effects unharmed after 6 months no adverse events

26. No added value of additional knee joint stabilization treatment, which is consistent with literature: No differences between: strength only vs. proprioceptive/balance + strength training (Diracoglu, ‘05) strength only vs. agility/perturbation + strength training (Fitzgerald, ‘11) strength only vs. neuromuscular + strength training (Bennell, ‘14) Conclusion Stability trial (1)

27.  Important role of muscle strength in knee stabilization: a)Most important mechanoreceptors for proprioception located inside muscles: muscle spindles. b)Self-reported knee instability associated with muscle weakness, while not with poor proprioception or high laxity (Knoop et al. Arthritis Care Res, 2012 Jan; 64(1)-38-45). Conclusion Stability trial (2)

28. Implications for exercises Exercising knee OA patients starts with muscle strengtening exercises (focus on quadriceps strength) and additional attention on knee joint stability It seems that specific attention for knee stability is neccessarry in case of sufficient muscle strength or high laxity AND knee joint instability 18

29. Is the severity of knee OA on MRI associated with outcome of exercise therapy? Knoop et al, 2014

30. Background Effectiveness and safety of exercise therapy for OA patients with severe joint damage have been questioned Randomized clinical trial to compare two exercise programs (Knoop et al, Osteoarthritis Cartilage 2013) The two 12-week, supervised exercise programs (with/without knee stabilization training) were equally effective From the total group of (ranging from K/L grade 0-4), baseline MRIs were obtained in a random subsample (n=95)

31. Aim of study To explore whether the severity of knee OA on MRI is associated with treatment outcome in knee OA patients treated with exercise therapy

32. Study sample (n=95) MRI features * Cartilage loss: grade 0 grade 1 grade 2 grade 3 7% 8% 31% 54% Bone marrow lesions: grade 0 grade 1 grade 2 grade 3 17% 25% 27% 31% Osteophytes: grade 0 grade 1 grade 2 grade 3 15% 38% 33% 15% MRI features * Effusion: grade 0 grade 1 grade 2 grade 3 34% 30% 23% 13% Synovitis: absent present 66% 34% Meniscal lesions: grade 0 grade 1 grade 2 grade 3 7% 13% 22% 58% * highest regional grade per knee MRI protocol: 3.0 Tesla MRI (GEMS) 5 sequences one index knee Boston Leeds Osteoarthritis Scoring (BLOKS) system, in which knee is subdivided into multiple regions; each region scored for severity of MRI-feature (Hunter et al, 2008).

33. Results (1/3) Outcome of exercise therapy independent of severity of knee OA in any MRI-feature Example: With two exceptions

34. Results (2/3) PF cartilage loss p=0.01 for WOMAC physical function p=0.04 for upper leg muscle strength

35. Results (3/3) PF osteophyte formation p<0.01 for upper leg muscle strength

36. Conclusions First study to explore the role of OA severity on MRI in the effectiveness of exercise therapy Outcome of exercise therapy is independent of OA severity Only exception seems to be advanced PF OA, in which effects might be reduced; this needs replication for validation

37. Implications Referral to exercise therapy needs to be considered prior to total knee arthroplasty in patients with ‘end- stage’ knee OA Also in patients with severe knee OA, weightbearing intense exercises can be provided, if gradually increased and professionally supervised

38. Future research Effects on inflammation Exercise more effective in inflammatory phenotype of OA? 37

39. Summary Exercise therapy is effective to reduce pain and improve function Targeting exercise therapy to specific groups seems promising for patients with severe pain, comorbidities, and probably inflammation No added value of additional knee joint stabilization treatment in patients with knee instability Exercise therapy can be effective in all grades of OA severity 38

40. Questions: m.vd.leeden@reade.nl