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Is long-term physical activity safe for older adults with knee pain?: a systematic review

  • J.G. Quicke
    Correspondence
    Address correspondence and reprint requests to: J.G. Quicke, Arthritis Research UK Primary Care Centre, Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom. Tel: 44-1782-734889; Fax: 44-1782-734719.
    Affiliations
    Arthritis Research UK Primary Care Centre, Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom
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  • N.E. Foster
    Affiliations
    Arthritis Research UK Primary Care Centre, Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom
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  • M.J. Thomas
    Affiliations
    Arthritis Research UK Primary Care Centre, Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom
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  • M.A. Holden
    Affiliations
    Arthritis Research UK Primary Care Centre, Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom
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Open AccessPublished:May 20, 2015DOI:https://doi.org/10.1016/j.joca.2015.05.002

      Summary

      Objective

      To determine whether long-term physical activity is safe for older adults with knee pain.

      Design

      A comprehensive systematic review and narrative synthesis of existing literature was conducted using multiple electronic databases from inception until May 2013. Two reviewers independently screened, checked data extraction and carried out quality assessment.
      Inclusion criteria for study designs were randomised controlled trials (RCTs), prospective cohort studies or case control studies, which included adults of mean age over 45 years old with knee pain or osteoarthritis (OA), undertaking physical activity over at least 3 months and which measured a safety related outcome (adverse events, pain, physical functioning, structural OA imaging progression or progression to total knee replacement (TKR)).

      Results

      Of the 8614 unique references identified, 49 studies were included in the review, comprising 48 RCTs and one case control study. RCTs varied in quality and included an array of low impact therapeutic exercise interventions of varying cardiovascular intensity. There was no evidence of serious adverse events, increases in pain, decreases in physical function, progression of structural OA on imaging or increased TKR at group level. The case control study concluded that increasing levels of regular physical activity was associated with lower risk of progression to TKR.

      Conclusions

      Long-term therapeutic exercise lasting 3 to 30 months is safe for most older adults with knee pain. This evidence supports current clinical guideline recommendations. However, most studies investigated selected, consenting older adults carrying out low impact therapeutic exercise which may affect result generalizability.
      Systematic review registration: PROSPERO 2014:CRD42014006913.

      Keywords

      Introduction

      Knee pain in older adults (aged 45 years and over) is common, with the majority of pain in this age group being attributable to osteoarthritis (OA)
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      Knee pain and osteoarthritis in older adults: a review of the community burden and current use of primary health care.
      • National Institute for Health and Care Excellence
      Osteoarthritis Care and Management in Adults.
      . Physical activity including both local muscle strengthening and increased general physical activity is consistently recommended for older adults with knee pain
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      Osteoarthritis Care and Management in Adults.
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      EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis.
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      OARSI guidelines for the non-surgical management of knee.
      and its effectiveness for pain reduction and physical function improvement has been well established from large, high quality systematic reviews
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      • et al.
      Long-term effectiveness of exercise therapy in patients with Osteoarthritis of the hip or knee: a systematic review.
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      Exercise for osteoarthritis of the knee.
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      Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials.
      . Furthermore, the general health benefits of regular physical activity are unequivocal; it is positively associated with both life expectancy and quality of life
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      A systematic review of the evidence for Canada's physical activity guidelines for adults.
      , as well as being negatively associated with multimorbidity
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      • Doring A.
      • et al.
      Physical activity is inversely associated with multimorbidity in elderly men: results from the KORA-Age Augsburg Study.
      .
      However, physical activity levels in older adults with knee pain are low
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      • Helmick C.G.
      Physical activity in men and women with arthritis national health interview survey, 2002.
      • de Groot I.B.
      • Bussman J.B.
      • Stam H.J.
      • Verhaar J.A.
      Actual everyday physical activity in patients with end-stage hip or knee osteoarthritis compared with healthy controls.
      • Farr J.N.
      • Going S.B.
      • Lohman T.G.
      • Rankin L.
      • Kasle S.
      • Cornett M.
      • et al.
      Physical activity levels in patients with early knee osteoarthritis measured by accelerometry.
      • Holden M.A.
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      • Young J.
      • Hay E.M.
      • Foster N.E.
      Exercise and physical activity in older adults with knee pain: a mixed methods study.
      and both health care professionals and older adults with knee pain express concerns over the safety of long-term physical activity
      • Holden M.A.
      • Nicholls E.E.
      • Young J.
      • Hay E.M.
      • Foster N.E.
      UK-based physical therapists' attitudes and beliefs regarding exercise and knee osteoarthritis: findings from a mixed-methods study.
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      • Hay E.M.
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      Role of exercise for knee pain: what do older adults in the community think?.
      . For example, common and persisting narratives regarding joint “wear and tear” may link to the belief that physical activity will cause further joint damage, whilst pain during activity may be perceived as an indicator of harm
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      • Young J.
      • Hay E.M.
      • Foster N.E.
      Role of exercise for knee pain: what do older adults in the community think?.
      • Hendry M.
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      • Wilkinson C.
      • Maddison P.
      Why should we exercise when our knees hurt? A qualitative study of primary care patients with osteoarthritis of the knee.
      . In addition, some older adults fear adverse events with physical activity, such as falls, which may in turn lead to reductions in physical activity
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      • de Rooij S.E.
      Fear of falling: measurement strategy, prevalence, risk factors and consequences among older persons.
      .
      No systematic review has focussed specifically on the safety of long-term physical activity for older adults with knee pain by collating both randomised control trial (RCT) and observational study evidence from multiple safety outcome domains including adverse events, pain, physical function, structural progression and total knee replacement frequency. Hence, the aim of this systematic review was to synthesise existing literature from multiple safety related outcome domains to determine whether long-term physical activity is safe for older adults with knee pain.

      Method

      Safety definition and systematic review premise

      Within the context of this systematic review, “Safety” is considered as a construct comprising multiple factors relating to harm and condition progression. For physical activity to be considered safe in this population, at a group level, it must not result in; a) serious adverse events; b) increased pain; c) worsening physical function; d) structural progression of OA on imaging; or e) increased incidence of total knee replacements.

      Search strategy and study selection

      The systematic review was developed from a centre protocol and was prospectively registered on PROSPERO (International prospective register of systematic reviews)
      • Quicke J.
      • Foster N.
      • Thomas M.
      • Holden M.
      Is long-term physical activity safe for older adults with knee pain? A systematic review.
      . A comprehensive search strategy was developed combining keywords and database MESH headings for knee pain and OA, exercise and physical activity (shown in Appendix 1). The search was adapted and run in several electronic databases including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, AMED, PEDro, SPORTDiscus, International Occupational Safety and Health Information Centre database (CISDOC), National Institute for Occupational Safety and Health (NIOSHTIC-2) and the Health and Safety Executive database (HSELINE) from inception until May 2013.
      Study inclusion criteria were randomised controlled trials (RCT), prospective cohort studies or case control studies, which included adults of mean age over 45 years old with knee pain or adults with OA, undertaking physical activity over at least 3 months. In addition, included studies had to have measured a safety related outcome (adverse events, pain, physical functioning, structural progression of OA on imaging, or progression to total knee replacement (TKR)). Exclusion criteria were: a) non randomised controlled trials, cross-sectional observational studies and retrospective cohort studies; and b) studies including participants with serious knee pathology not attributable to OA, or mixed participants (for example, some with knee pain and some with other conditions such as rheumatoid arthritis or hip OA without separate knee pain subgroup analysis). Further detail is provided in Table I.
      Table IInclusion and exclusion criteria
      Inclusion criteriaExclusion criteria
      Study Methods
      • RCTs/prospective cohort studies/case control studies
      • Cross-sectional observational studies/retrospective cohort studies/non-randomised controlled trials
      • Knee pain/OA incidence studies
      Publications
      • Full text, published studies
      • All countries/languages
      • Abstracts, posters, non-peer reviewed, thesis, books
      Participants
      • Adults with mean age 45 years old and over with knee pain OR adults with knee OA
      • Serious pathology not attributable to OA (inflammatory arthropathies/fracture/cancer/metabolic disorder)
      • Heterogeneous lower limb joint OA participants
      Intervention
      • Three month or more of physical activity intervention or exposure
      • Physical activity not explicitly carried out for 3 months or more
      Outcomes
      • Contains at least one safety related outcome from: adverse events, pain, physical function, radiographic/MRI biomarkers of structural OA progression
      Abbreviations: MRI = magnetic resonance imaging.
      Two reviewers (JQ and either MH, NF, MT) independently screened all titles, abstracts and full texts for study inclusion and exclusion criteria. Disagreements were resolved by discussion or consensus with a third reviewer where necessary. Reference lists of the included studies were also screened.

      Methodological risk of bias

      Included RCTs were assessed for risk of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias using the Cochrane Risk of Bias Tool
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      • Moher D.
      • Oxman Savovic J.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      . “Other bias” was used to cover aspects of precision (adequate sample size), contamination and issues of sampling frame generalizability. Observational studies were assessed for risk of bias from study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, statistical analysis and reporting using the Quality in Prognostic Studies (QUIPS) tool
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      Assessing bias in studies of prognostic factors.
      .
      Risk of bias assessment was carried out by two independent reviewers. Disagreement was resolved by discussion or consultation with a third reviewer where necessary. Overall risk of bias was used to inform conclusion strength rather than as a cut off inclusion criterion within the systematic review.

      Data extraction

      Safety outcome data extraction was carried out by one reviewer (JQ) and independently verified by a second reviewer (either MH, NF, MT) whilst study descriptive data extraction and physical activity categorisation was carried out by one reviewer (JQ). Information was extracted on: a) study title, authors, year of publication, type, and country; b) participants including total number, key baseline characteristics (e.g., age, specific comorbidities and knee malalignment) and diagnosis method (e.g., knee pain or radiographic OA); c) physical activity type, intensity, session frequency and intervention duration; and d) safety outcome data at baseline and immediately post intervention, including: adverse events, pain and function (statistical significance performed, in comparison with either a non-physical activity control group post-intervention or within group over time), radiographic/MRI structural OA progression, and TKR data. Numbers of TKRs occurring during RCTs within physical activity and non-physical activity intervention/control groups were extracted. Adjusted odds ratios and confidence intervals for progression to TKR for varying levels of physical activity exposure were also extracted from case control studies.

      Narrative synthesis

      Narrative synthesis was completed rather than meta-analysis due to the substantial heterogeneity within studies and the focus on safety rather than treatment effect size. The synthesis included collating and summarising safety outcomes from separate domains and subsequently integrating the results from different domains to draw conclusions about safety. Within each safety outcome domain, patterns of physical activity and exercise safety were summarised. In order to allow comparisons between individual studies, intensity of physical activity interventions were categorised into low, moderate and vigorous using a combination of reported target maximum heart rate percentage and activity metabolic equivalent of task (MET) whilst impact of physical activity was classified into low and high impact (see Appendix 2 for detail). In addition, RCT adverse events were categorised into mild, moderate and severe by one reviewer (JQ) and independently verified by a second reviewer (MH)
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      Clinical analysis of adverse drug reactions: a primer for clinicians.
      . Mild adverse events were defined as bothersome but not requiring change in therapy, moderate adverse events were those requiring change in therapy, additional therapy or hospitalisation whilst severe adverse events were defined as disabling or life threatening.

      Results

      Study characteristics

      In total, 8,614 unique references were identified from the electronic databases which reduced to 715, 168 and 46 after screening titles, abstracts and full texts respectively. Two further studies were identified following reference list screening and one from peer review, resulting in 49 included studies (see Fig. 1).
      The included studies comprised 8,920 participants from 48 RCTs
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      • Wright A.A.
      • Leon de la Barra S.
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      Manual therapy, exercise therapy, or both, in addition to usual care, for osteoarthritis of the hip or knee: a randomized controlled trial. 1: clinical effectiveness.
      • Aglamis B.
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      The effect of a 12-week supervised multicomponent exercise program on knee OA in Turkish women.
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      The effect of adding whole-body vibration to squat training on the functional performance and self-report of disease status in elderly patients with knee osteoarthritis: a randomized controlled clinical study.
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      • Layne J.E.
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      • Roubenoff R.
      The efficacy of home based progressive strength training in older adults with knee osteoarthritis: a randomized controlled trial.
      • Bautch J.C.
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      Effects of exercise on knee joints with osteoarthritis: a pilot study of biologic markers.
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      • McConnell J.
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      Efficacy of physiotherapy management of knee joint osteoarthritis: a randomised, double blind, placebo controlled trial.
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      • Hunter D.J.
      • McManus F.J.
      • Hodges P.W.
      • et al.
      Hip strengthening reduces symptoms but not knee load in people with medial knee osteoarthritis and varus malalignment: a randomised controlled trial.
      • Brismee J.-M.
      • Paige R.L.
      • Chyu M.-C.
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      Group and home-based tai chi in elderly subjects with knee osteoarthritis: a randomized controlled trial.
      • Dias R.C.
      • Dias J.M.
      • Ramos L.R.
      Impact of an exercise and walking protocol on quality of life for elderly people with OA of the knee.
      • Durmus D.
      • Alayli G.
      • Bayrak I.K.
      • Canturk F.
      Assessment of the effect of glucosamine sulfate and exercise on knee cartilage using magnetic resonance imaging in patients with knee osteoarthritis: a randomized controlled clinical trial.
      • Ettinger W.H.
      • Burns R.
      • Messier S.P.
      • Applegate W.
      • Rejeski W.J.
      • Morgan T.
      • et al.
      • Farr J.N.
      • Going S.B.
      • McKnight P.E.
      • Kasle S.
      • Cussler E.C.
      • Cornett M.
      Progressive resistance training improves overall physical activity levels in patients with early osteoarthritis of the knee: a randomized controlled trial.
      • Fitzgerald G.K.
      • Piva S.R.
      • Gil A.B.
      • Wisniewski S.R.
      • Oddis C.V.
      • Irrgang J.J.
      Agility and perturbation training techniques in exercise therapy for reducing pain and improving function in people with knee osteoarthritis: a randomised clinical trial.
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      Progressive resistance training and dynamic alignment in osteoarthritis: a single blind randomised controlled trial.
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      Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the look AHEAD trial.
      • Hasegawa R.
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      • Tomiyama N.
      • Lee S.C.
      • Koizumi D.
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      Effects of combined balance and resistance exercise on reducing knee pain in community-dwelling older adults.
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      • Avery A.J.
      • Read A.
      • Taylor M.A.
      • Sach T.H.
      • et al.
      Effects of dietary intervention and quadriceps strengthening exercise on pain and function in overweight people with knee pain: randomised controlled trial.
      • Kawasaki T.
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      Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial.
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      Therapeutic home exercise versus intraarticular hyaluronate injection for osteoarthritis of the knee: 6 month prospective randomized open-labeled trial.
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      Effects of spouse-assisted coping skills training and exercise training in patients with osteoarthritis knee pain: a randomized controlled study.
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      A randomized trial of arthroscopic surgery for osteoarthritis of the knee.
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      A comparison of strength training, self-management, and the combination for early osteoarthritis of the knee.
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      Exercise and weight loss in obese older adults with knee osteoarthritis: a preliminary study.
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      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
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      Effects of strength training on the incidence and progression of knee osteoarthritis.
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      Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis.
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      • Huang C.-H.
      • Lin J.-H.
      Tai chi improves physical function in older Chinese women with knee osteoarthritis.
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      Effectiveness of home exercise on pain and disability from osteoarthritis of the knee: a randomised controlled trial.
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      • Pisters M.F.
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      • Schellevis F.G.
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      • Dekker J.
      Long-term effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a randomised controlled trial comparing two different physical therapy interventions.
      • Rejeski W.J.
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      • Penninx B.
      Obese, older adults with knee osteoarthritis: weight loss, exercise and quality of life.
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      • Marchetti G.
      The effects of group cycling on gait and pain-related disability in individuals with mild-to moderate knee osteoarthritis: a randomized controlled trial.
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      • Cook C.R.
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      Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
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      Pain coping skills training and lifestyle behavioural weight management in patients with knee osteoarthritis; a randomized controlled study.
      • Song R.
      • Lee E.-O.
      • Lam P.
      • Bae S.-C.
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      • Huynh T.N.
      • Metter E.J.
      A home-based pedometer-driven walking program to increase physical activity in older adults with osteoarthritis of the knee: a preliminary study.
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      • O'Reilly S.C.
      • Bassey E.J.
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      The effect of dynamic versus isometric resistance training on pain and functioning among adults with osteoarthritis of the knee.
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      • Rones R.
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      Tai chi is effective in treating knee osteoarthritis: a randomized controlled trial.
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      • Wu S.F.
      • Lin Y.P.
      Comparing the efficacy of aquatic exercises and land-based exercises for patients with knee osteoarthritis.
      and a single case control study
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      • Heliovaara M.
      • Suomalianen O.
      Physical activity and risk of severe knee osteoarthritis requiring arthroplasty.
      . Supplementary online material gives a full table of included studies including intervention detail (Table SI). The studies were undertaken in 16 different countries. All of the included studies were written in English except Olejarova et al., 2008 which was translated from Czech. Participants included those with knee pain and/or a diagnosis of OA with severity of OA ranging from Kellgren Lawrence I–IV in those studies utilising radiographs. Four studies specifically included participants with knee pain/OA who were overweight or obese
      • Jenkinson C.M.
      • Doherty M.
      • Avery A.J.
      • Read A.
      • Taylor M.A.
      • Sach T.H.
      • et al.
      Effects of dietary intervention and quadriceps strengthening exercise on pain and function in overweight people with knee pain: randomised controlled trial.
      • Miller G.D.
      • Nicklas B.J.
      • Davis C.
      • Loeser R.F.
      • Lenchik L.
      • Messier S.P.
      Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis.
      • Rejeski W.J.
      • Focht B.C.
      • Messier S.P.
      • Morgan T.
      • Pahor M.
      • Penninx B.
      Obese, older adults with knee osteoarthritis: weight loss, exercise and quality of life.
      • Somers T.J.
      • Blumenthal J.A.
      • Guilak F.
      • Kraus V.B.
      • Schmitt D.O.
      • Babyak M.A.
      • et al.
      Pain coping skills training and lifestyle behavioural weight management in patients with knee osteoarthritis; a randomized controlled study.
      and one additional study included overweight participants who also had Type II diabetes
      • Foy C.G.
      • Lewis C.E.
      • Hairston K.G.
      • Miller G.D.
      • Lang W.
      • Jakicic J.M.
      • et al.
      Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the look AHEAD trial.
      . Levels of individual comorbidities varied within the remaining studies although many excluded participants who had cardiovascular disease or those who were deemed “unfit to exercise” for other health reasons.
      The RCTs included 78 physical activity intervention groups. Physical activity type, intensity and duration varied widely. All of the RCTs investigated therapeutic exercise physical activity. “Mixed” exercise interventions combining strengthening, stretching and aerobic elements were most common and were investigated within 46 intervention groups. 17 intervention groups focussed on strengthening exercises, five on aerobic exercises (including walking and cycling), five on balance and agility, whilst four included Tai Chi and a single intervention carried out range of motion exercises. Two RCT physical activity interventions were classified as low cardiovascular intensity, 71 as moderate intensity and five as vigorous intensity. All of the physical activity interventions were considered low impact. RCT physical activity intervention duration ranged from 3 months to 30 months whilst frequency varied from one to three sessions per week.

      Study safety outcome domain results

      The number of RCTs within the review that provided information on each safety outcome domain are shown in Fig. 2.
      Figure thumbnail gr2
      Fig. 2Bar chart of RCTs providing safety outcome domain evidence.

      Adverse events

      Adverse events were explicitly reported in only 22 of the included RCTs (see Table II for details). Some authors reported adverse events generally without attributing severity whilst others split adverse events into “minor” or “mild” and “serious”, however, definitions of these terms were often lacking. According to the standardised adverse event categorisation
      • Calis K.A.
      Clinical analysis of adverse drug reactions: a primer for clinicians.
      , no studies reported serious adverse events related to physical activity. Moderate adverse events were rare being reported in between 0 and 6% of physical activity intervention participants in any included study. These included five falls with one resulting in a fractured wrist and one a head laceration, one foot fracture (caused by a participant dropping a weight on their foot), four drop outs related to increased knee or other joint pain and one inguinal hernia attributed to physical activity. Mild adverse events were reported in between 0 and 22% of physical activity participants within individual studies and usually involved muscle soreness and temporary or mild joint pain increase.
      Table IIAdverse events
      Study authorAdverse event outcomes from physical activity groups
      DescriptionFrequency and severity summary
      Abbott et al., 2013One inguinal hernia related to physical activity.very rare/moderate
      Baker et al., 2001No adverse events due to physical activity.N/A
      Bennell et al., 2005Minor pain with physical activity reported in 22% of the physical activity group.minority/mild
      Bennell et al., 2010Three participants reported back pain, one back and hip pain, one aggravated varicose veins/knee pain.minority/mild
      Brismee et al., 2007Minor muscle soreness, foot and knee pain reported.minority/mild
      Ettinger et al., 1997+Two falls in I1 and I2, one participant dropped weight on foot causing foot fracture in I2.very rare/moderate
      Faroughi et al., 2011Two minor adverse events.very rare/mild
      Fitzgerald et al., 2011No adverse events reported.N/A
      Hasegawa et al., 2010No adverse events reported.N/A
      Kawasaki et al., 2009No subjects needed to halt treatment due to severe adverse events.unclear
      Lim et al., 2008Four reported increased knee pain and two reported hip and groin pain attributed to the intervention in I1

      Three had increased knee pain and one withdrew with neck pain in I2

      Two participants (one from each alignment group) stopped the treatment due to increased knee pain
      minority/mild-moderate
      McKnight et al., 201015 adverse events were definitely related to the study, 13 were probably related 30 were possibly related.

      These consisted of: increased knee pain, accident/injury related to strength training and pain/soreness from strength training. One participant withdrew due to exacerbating pre-existing back pain.
      minority/mild

      very rare/moderate
      Mikesky et al., 2006One participant dropped out due to increased knee pain with strength trainingvery rare/moderate
      Miller et al., 2006No serious adverse eventsunclear
      Ni et al., 2010Five subjects complained of minor muscle soreness, foot and knee painvery rare/mild
      Peloquin et al., 1999One participant dropped out due to knee inflammation from physical activityvery rare/moderate
      Rejeski et al., 2002+One adverse event during physical activity- a participant tripped and sustained a laceration to his headvery rare/moderate
      Rogind et al., 1998No adverse events were reportedN/A
      Song et al., 2003Temporary mild pain in I1. Dropouts were mainly due to personal reasons not activity related factors.unclear/mild
      Thomas et al., 2002Fifty two (11%) of those in the physical activity group reported minor side effects.very rare/mild
      Wang et al., 2009One participant in I1 reported an increase in knee pain. #very rare/mild
      Wang et al., 2011One participant in I1 reported dizziness during physical activity. Two I2 participants reported increased pain after physical activity.very rare/mild
      Key: + = findings from primary paper and follow up papers; I1 = physical activity intervention group 1, I2 = physical activity intervention group 2, N/A = none reported, very rare = 0–15%, minority = 16–25% (modified from Hubal and Day 2006), mild= bothersome but requiring no change in therapy, moderate= requiring change in therapy, additional treatment, or hospitalisation, severe = disabling or life-threatening (Calis 2004), unclear = Insufficient adverse event reporting detail, # = one participant reported a newly diagnosed cancer that was not attributed to physical activity.

      Pain

      In total, 46 studies measured pain. The Western Ontario and McMaster Arthritis Index (WOMAC) pain scale
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to anti-rheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      and numerical pain scales were the two most common outcome measures. No studies found significantly higher pain with physical activity (Table III). Only 29 carried out between group statistical testing comparing physical activity to non-physical activity interventions. Of these, 19 showed pain to be significantly lower in the physical activity groups whilst seven found no significant difference between groups and two showed a combination of significantly lower and non-significant difference with multiple physical activity intervention groups.
      Table IIISummary of RCT pain and physical function outcomes
      Study author N = 48PainPhysical function
      Between group N = 29Within group N = 28Between group N = 28Within group N = 28
      Abbott et al., 2013
      Aglamis et al., 2008
      Avelar et al., 2011#
      Baker et al., 2001
      Bautch et al., 1997
      Bennell et al., 2005
      Bennell et al. 2010
      Brismee et al., 2007
      Dias et al., 2003
      Durmus et al., 2012
      Ettinger et al., 1997+
      Farr et al., 2010
      Fitzgerald et al., 2011
      Foroughi et al., 2011
      Foy et al., 2011
      Hasegawa 2010
      Jenkinson et al., 2009
      Kawasaki et al., 2008
      Kawasaki et al. 2009
      Keefe et al., 2004
      Kirkley et al., 2008
      Lim et al., 2008
      McCarthy et al., 2004
      McKnight et al., 2010
      Messier et al., 2000#
      Messier et al. 2007#
      Mikesky et al., 2006
      Miller et al., 2006
      Ni et al., 2010
      Olejerova et al., 2008
      O'Reilly et al., 1999
      Osteras et al., 2012
      Peloquin et al., 1999##
      Pisters et al., 2010
      Rejeski et al., 2002+###
      Rogind et al., 1998##
      Salancinski et al., 2012
      Sayers et al., 2012
      Schlenk et al., 2011
      Silva et al., 2008
      Simao et al., 2012#
      Somers et al., 2012##
      Song et al., 2003
      Talbot et al., 2003
      Thomas et al., 2002
      Topp et al., 2002#
      Wang et al., 2009
      Wang et al. 2011
      Key: + = findings from primary paper and follow up papers, ✓ = significantly lower pain in physical activity group over time or compared to non-physical activity group/significantly better physical function in physical activity group over time or compared to non-physical activity group. ↔ = no significant difference over time or between groups. # = mixed significant improvements and non-significant results across multiple physical activity interventions. All significance tests set at α=0.05.
      Of the studies that statistically explored change in pain over time within physical activity group (n = 28), most showed significant improvement (n = 20) with only five studies showing no significant change and three showing mixed improvement and no change within multiple physical activity interventions.

      Physical function

      In total, 43 studies measured physical function with WOMAC function
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to anti-rheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      and various objective function tests being the most common outcome measures. No studies found physical function to be lower with physical activity (see Table III). Only 28 carried out between group statistical testing comparing physical activity to non-physical activity interventions. The majority showed physical function was significantly better in physical activity groups (n = 15) whilst a minority found no significant difference between groups (n = 11) and two studies a combination of significantly better and non-significant difference with multiple physical activity intervention groups.
      Of the studies that explored change in function over time within physical activity groups (n = 28), most showed significant improvement (n = 19) with only two studies showing no significant change and seven showing mixed improvement and no change within multiple physical activity interventions.

      Structural OA biomarker imaging

      Six studies reported heterogeneous measures of OA from imaging of the tibiofemoral joint, including: Kellgren and Lawrence score, joint space width, joint space narrowing, OA severity and cartilage volume (see Table IV). Of the five RCTs that measured changes in radiographic OA using imaging, none provided any evidence of significantly greater structural progression of OA between those in physical activity vs non-physical activity groups or those within physical activity group over time. A single small RCT found trends for improvements in the majority of OA parameters measured using MRI over time within the physical activity group
      • Durmus D.
      • Alayli G.
      • Bayrak I.K.
      • Canturk F.
      Assessment of the effect of glucosamine sulfate and exercise on knee cartilage using magnetic resonance imaging in patients with knee osteoarthritis: a randomized controlled clinical trial.
      whilst a single RCT found trends towards joint space narrowing within physical activity groups
      • Mikesky A.E.
      • Mazzuca S.A.
      • Brandt K.D.
      • Perkins S.M.
      • Damush T.
      • Lane K.A.
      Effects of strength training on the incidence and progression of knee osteoarthritis.
      .
      Table IVSummary of osteoarthritis biomarker imaging results
      Study authorRadiographic or MRI biomarker outcomes
      Outcome measureResult
      Bautch et al., 1997Radiographic/tibiofemoral/antero-posterior/KL severityNo within physical activity group change over time
      Durmus et al., 2012MRI/tibiofemoral/cartilage volumeSome MRI parameter improvements within physical activity group over time
      Ettinger et al., 1997+Radiographic/tibiofemoral/antero-posterior and lateral/OA severityNo between group difference post intervention
      Mikesky et al., 2006Radiographic/tibiofemoral/antero-posterior/joint space width, joint space narrowing and osteophytosis severityBoth physical activity groups showed non-significant trends towards joint space width narrowing over time
      Kawasaki et al., 2008Radiographic/tibiofemoral/anteroposterior/joint space widthNo between group difference post intervention
      Rejeski et al., 2002+Radiographic/tibiofemoral and patellofemoral/anteroposterior and sunrise/joint space width and KLNo between group difference post intervention

      No within physical activity group change over time
      Key: + = results were taken from the primary trial paper and additional follow up papers pertaining to the same trial. Abbreviations: MRI = magnetic resonance imaging; KL= Kellgren and Lawrence OA grading.

      Total knee replacement

      Four RCTs reported TKRs within the study intervention period in enough detail to permit data extraction
      • Bennel K.L.
      • Hinman R.S.
      • Metcalf B.R.
      • Buchbinder R.
      • McConnell J.
      • McColl G.
      • et al.
      Efficacy of physiotherapy management of knee joint osteoarthritis: a randomised, double blind, placebo controlled trial.
      • Fitzgerald G.K.
      • Piva S.R.
      • Gil A.B.
      • Wisniewski S.R.
      • Oddis C.V.
      • Irrgang J.J.
      Agility and perturbation training techniques in exercise therapy for reducing pain and improving function in people with knee osteoarthritis: a randomised clinical trial.
      • Jenkinson C.M.
      • Doherty M.
      • Avery A.J.
      • Read A.
      • Taylor M.A.
      • Sach T.H.
      • et al.
      Effects of dietary intervention and quadriceps strengthening exercise on pain and function in overweight people with knee pain: randomised controlled trial.
      • McKnight P.E.
      • Kasle S.
      • Going S.
      • Villanueva I.
      • Cornett M.
      • Farr J.
      • et al.
      A comparison of strength training, self-management, and the combination for early osteoarthritis of the knee.
      , as did the case control study
      • Manninen P.
      • Riihimaki H.
      • Heliovaara M.
      • Suomalianen O.
      Physical activity and risk of severe knee osteoarthritis requiring arthroplasty.
      . Summing the four RCTs, there was no evidence of more TKRs within physical activity groups compared to non-physical activity groups (n = 8 and 10 respectively). The case control study
      • Manninen P.
      • Riihimaki H.
      • Heliovaara M.
      • Suomalianen O.
      Physical activity and risk of severe knee osteoarthritis requiring arthroplasty.
      investigated cases of Finnish adults who underwent TKR and age matched controls. They concluded that TKR risk decreased with increasing recreational physical activity. Using adults with a history of no regular physical activity as a reference, adjusted odds ratios (and 95% confidence intervals) of TKR were 0.91 (0.31–2.63) in men with low cumulative hours of physical activity and 0.35 (0.12–0.95) in those with a high number of accumulative hours. In women the respective results for low and high cumulative hours of physical activity were 0.56 (0.30–0.93) and 0.56 (0.32–0.98).

      Risk of bias assessment

      Risk of bias from included studies varied widely. 18 studies (38%) were judged to be at high risk of bias in one or more risk of bias domains. The risk of bias domains of “sequence generation”, “allocation concealment”, and “incomplete outcome data” were assessed as low risk of bias in 31 (65%), 16 (33%) and 19 (40%) of studies respectively. Blinding of participants to physical activity intervention was not possible and hence judged as unclear throughout, whilst blinding of “outcome assessment” was assessed as low risk of bias in 26 (54%) of studies. Only four studies published protocols hence selective reporting was unclear for most studies and only low in three (6%). Fig. 3 shows the RCT Cochrane risk of bias tool summary scores for each outcome domain (Table SII in the supplementary online material shows individual study scores). Studies were not excluded on the basis of methodological risk of bias and although there was wide variation in the risk of bias within included studies, safety findings were consistent for studies at both low and high risk of bias.
      Figure thumbnail gr3
      Fig. 3Summary of risk of bias within the 47 included RCTs.
      Using the QUIPs tool, the case control study
      • Manninen P.
      • Riihimaki H.
      • Heliovaara M.
      • Suomalianen O.
      Physical activity and risk of severe knee osteoarthritis requiring arthroplasty.
      was considered at moderate risk of bias in four domains (attrition, prognostic factor measurement, confounding and statistical analysis and reporting) and low risk in two (selection, and statistical analysis and reporting).

      Discussion

      This systematic review is the first to specifically investigate whether long-term physical activity is safe for older adults with knee pain. However, the vast majority of evidence meeting our inclusion criteria related specifically to therapeutic exercise hence our conclusions relate to therapeutic exercise rather than physical activity more generally. Based on consistent evidence from 49 included studies we conclude that long-term therapeutic exercise is safe for most older adults with knee pain. At the group level, there was no evidence of serious adverse events, increases in pain, worsening of physical function, progression of structural OA on imaging or higher rates of TKR associated with therapeutic exercise. Moderate adverse events, such as falls or pain that resulted in participants dropping out of studies, were very rare, whilst a minority of individuals experienced mild adverse events.
      This evidence builds on previous expert consensus that exercise appears to be safe for adults with knee pain attributable to OA
      • Roddy E.
      • Zhang W.
      • Doherty M.
      • Arden N.K.
      • Barlow J.
      • Birrell F.
      • et al.
      Evidence-based recommendations for the role of exercise in the management of osteoarthritis of the hip or knee-the MOVE consensus.
      . Together with existing systematic reviews that evidence the effectiveness of therapeutic exercise in improving pain and physical functioning
      • Fransen M.
      • McConnell S.
      • Harmer A.R.
      • Van der Esch M.
      • Simic M.
      • Bennell K.L.
      Exercise for osteoarthritis of the knee.
      • Juhl C.
      • Christensen R.
      • Roos E.M.
      • Zhang W.
      • Lund H.
      Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials.
      • Uthman O.A.
      • van der Windt D.A.
      • Dziedzic K.S.
      • Healey E.L.
      • Peat G.M.
      • Foster N.E.
      Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis.
      , and those showing physical activity is not associated with condition progression
      • Belo J.N.
      • Berger M.Y.
      • Reijman M.
      • Koes B.W.
      • Biernma-Zeinstra S.M.
      Prognostic factors of progression of osteoarthritis of the knee: a systematic review of observational studies.
      • Chapple C.M.
      • Nicholson H.
      • Baxter D.
      • Abbott J.H.
      Patient characteristics that predict progression of knee osteoarthritis: a systematic review of prognostic studies.
      , the findings reinforce clinical guidelines recommending therapeutic exercise as a core part of condition management
      • National Institute for Health and Care Excellence
      Osteoarthritis Care and Management in Adults.
      • Fernandes L.
      • Hagen K.B.
      • Bijlsma J.W.J.
      • Andreassen O.
      • Christensen P.
      • Conaghan P.G.
      • et al.
      EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis.
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee.
      .
      Long-term therapeutic exercise (up to 30 months), was consistently safe across a broad range of types and intensities of interventions. However, no studies focussed on domestic physical activity, occupational physical activity, travel activity or sports. Whilst various types and intensities of therapeutic exercise within this systematic review may be similar to physical activities within these different categories, caution is required in drawing inferences from the findings. For example, cycling on an exercise bike is safer than on roads due to the risk of road traffic accidents. Varying therapeutic exercise frequencies, ranging from one to 3 h per week, and cardiovascular intensities from low to vigorous were also safe regardless of level. Hence, all these components can be considered in therapeutic exercise programs for older adults with knee pain. However, given that all the studies included in the review included low impact interventions, it is not possible to confidently draw conclusions about the safety of higher impact exercise, such as running.
      Long-term therapeutic exercise was also safe across a broad range of study populations including older adults with varying levels of knee pain severity, those diagnosed with both radiographic OA and clinical OA, varus malalignment
      • Lim B.-W.
      • Hinman R.S.
      • Wrigley T.V.
      • Sharma L.
      • Bennell K.L.
      Does knee malalignment mediate the effects of quadriceps strengthening on knee adduction moment, pain, and function in medial knee osteoarthritis? A randomized controlled trial.
      , and common comorbidity subgroups such as overweight and Type II diabetic participants
      • Foy C.G.
      • Lewis C.E.
      • Hairston K.G.
      • Miller G.D.
      • Lang W.
      • Jakicic J.M.
      • et al.
      Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the look AHEAD trial.
      • Jenkinson C.M.
      • Doherty M.
      • Avery A.J.
      • Read A.
      • Taylor M.A.
      • Sach T.H.
      • et al.
      Effects of dietary intervention and quadriceps strengthening exercise on pain and function in overweight people with knee pain: randomised controlled trial.
      • Miller G.D.
      • Nicklas B.J.
      • Davis C.
      • Loeser R.F.
      • Lenchik L.
      • Messier S.P.
      Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis.
      • Rejeski W.J.
      • Focht B.C.
      • Messier S.P.
      • Morgan T.
      • Pahor M.
      • Penninx B.
      Obese, older adults with knee osteoarthritis: weight loss, exercise and quality of life.
      • Somers T.J.
      • Blumenthal J.A.
      • Guilak F.
      • Kraus V.B.
      • Schmitt D.O.
      • Babyak M.A.
      • et al.
      Pain coping skills training and lifestyle behavioural weight management in patients with knee osteoarthritis; a randomized controlled study.
      • Kadam U.
      • Jordan K.
      • Croft P.
      Clinical comorbidity in patients with osteoarthritis: a case-control study of general practice consulters in England and Wales.
      • Nieves-Plaza M.
      • Castro-Santana L.E.
      • Font Y.M.
      • Mayor A.M.
      • Vila L.M.
      Association of hand or knee osteoarthritis with diabetes mellitus in a population of Hispanics from Puerto Rico.
      . However, despite exercise being a core part of cardiac rehabilitation recommended for multiple cardiovascular diseases
      • National Institute for Health and Care Excellence
      Cardiac Rehabilitation Services.
      , many RCTs excluded older adults with a history of cardiovascular disease or those considered “unfit for exercise” which is a limitation in generalising the results to this comorbid subgroup.
      Falling was the most common moderate severity adverse event (n = 5). Falls are a common problem for older adults, with 30% of adults over the age of 65 falling at least once a year
      • Gillespie L.D.
      • Robertson M.C.
      • Gillespie W.J.
      • Sherrington C.
      • Gates C.
      • Clemson L.M.
      • et al.
      Interventions for preventing falls in older people living in the community.
      • National Institute for Health and Care Excellence
      Falls: Assessment and Prevention of Falls in Older People.
      . Although existing systematic review evidence has shown therapeutic exercise reduces the number of falls in community dwelling older adults
      • National Institute for Health and Care Excellence
      Falls: Assessment and Prevention of Falls in Older People.
      , five falls appears relatively low for the number of included participants and may also be explained by the different characteristics of RCT participants compared to adults in the general population or under reporting of falls. Adverse events were only explicitly reported in 22 of the 48 RCTs hence it is not clear whether they occurred in the remaining studies. Finally, although only a minority of older adults experienced mild or temporary increases in pain with therapeutic exercise (ranging from 0 to 22% of participants within individual RCT exercise groups), this finding is still clinically meaningful, especially if it contributes to physical activity avoidance behaviour through fear of “hurt meaning harm”
      • Holden M.A.
      • Nicholls E.E.
      • Young J.
      • Hay E.M.
      • Foster N.E.
      Role of exercise for knee pain: what do older adults in the community think?.
      • Hendry M.
      • Williams N.H.
      • Markland D.
      • Wilkinson C.
      • Maddison P.
      Why should we exercise when our knees hurt? A qualitative study of primary care patients with osteoarthritis of the knee.
      • Heuts P.H.T.G.
      • Vlaeyen J.W.S.
      • Roelofs J.
      • de Bie R.A.
      • Aretz K.
      • van Weel C.
      • et al.
      Pain-related fear and daily functioning in patients with osteoarthritis.
      .

      Study risk of bias

      Of particular concern to the validity of the conclusions was the unclear or high risk of attrition bias due to incomplete outcome data in just over half of the studies. Even low numbers of unexplained loss to follow up may bias the conclusions if they were associated with adverse events or increased pain. However, safety findings were consistent regardless of individual study risk of bias. For example, three large RCTs with low risk of attrition bias still found safe outcomes and no serious adverse events after 2 years of moderate intensity strengthening and mixed exercise
      • Jenkinson C.M.
      • Doherty M.
      • Avery A.J.
      • Read A.
      • Taylor M.A.
      • Sach T.H.
      • et al.
      Effects of dietary intervention and quadriceps strengthening exercise on pain and function in overweight people with knee pain: randomised controlled trial.
      • McKnight P.E.
      • Kasle S.
      • Going S.
      • Villanueva I.
      • Cornett M.
      • Farr J.
      • et al.
      A comparison of strength training, self-management, and the combination for early osteoarthritis of the knee.
      • Thomas K.S.
      • Muir K.R.
      • Doherty M.
      • Jones A.C.
      • O'Reilly S.C.
      • Bassey E.J.
      Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial.
      .

      Strengths and limitations of the systematic review

      Systematic review strengths included the prospective registration with PROSPERO which offered transparency in the planned method and reduced the chance of the research being duplicated. The search strategy was comprehensive and included double author screening, data extraction and quality assessment to decrease the risk of individual subjectivity and human error
      • Higgins J.P.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions.
      . The safety conclusions were triangulated from multiple safety outcome domains including adverse events hence strengthening their validity.
      There are several limitations. Firstly, despite efforts to include observational studies, all but one of the studies meeting the inclusion criteria were RCTs. This may lead to a participant selection bias. Participants who consent and are included in therapeutic exercise intervention trials may be systematically different from the wider population of older adults with knee pain. Furthermore, RCT evidence pertained to therapeutic exercise carried out for up to 30 months, hence any conclusions for longer periods must be made with caution. Secondly, although there was no evidence of increased frequency of TKR or increased OA structural progression with physical activity, these results should also be interpreted with caution. This is because relatively few studies (five and six for each respective safety domain) contributed extractable data whilst the responsiveness of radiographs to detect OA structural change over periods less than 2 years is suboptimal
      • Reichmann W.M.
      • Maillefert J.F.
      • Hunter D.J.
      • Katz J.N.
      • Conaghan P.G.
      • Losina E.
      Responsiveness to change and reliability of measurement of radiographic joint space width in osteoarthritis of the knee: a systematic review.
      which would tend to bias these safety outcomes towards the null. Thirdly, two studies were identified through the reference list search and one from peer review so the electronic database search, despite being comprehensive, was not exhaustive. Fourthly, there is a possibility of publication bias with studies showing positive outcomes more likely to be published
      • Rosenthal R.
      The file drawer problem and tolerance for null results.
      . If a small number of unpublished studies exist that show therapeutic exercise to be unsafe this could alter the conclusions, however, given the large number of papers investigating a broad range of exercise yielding similar safety findings this situation seems unlikely. Finally, caution is required in inferring safety to subgroups and physical activity categories not included within the review.

      Research and clinical implications

      Future research needs to investigate the safety of physical activity for specific subgroups of older adults with knee pain such as those with cardiovascular conditions and multimorbidities. Research into the safety of physical activity associated with sport, travel, occupation and domestic tasks is also warranted in this patient group. Future RCTs should ensure adverse events are both explicitly monitored and clearly reported even if none occurred.
      Many types of long-term therapeutic exercise have been shown to be safe for most older adults with knee pain regardless of pain severity. This allows choice in therapeutic exercise selection based on individual health goals, preferences and factors likely to facilitate adherence such as enjoyment
      • Hendry M.
      • Williams N.H.
      • Markland D.
      • Wilkinson C.
      • Maddison P.
      Why should we exercise when our knees hurt? A qualitative study of primary care patients with osteoarthritis of the knee.
      • Jordan J.L.
      • Holden M.A.
      • Mason E.E.
      • Foster N.E.
      Interventions to improve adherence to exercise for chronic musculoskeletal pain in adults.
      . Patients can be reassured that mild or temporary increases in pain with therapeutic exercise occur in a minority of individuals but pain does not equal harm or mean structural progression of knee OA and most will experience less pain if they persist with long-term exercise.
      The long-term therapeutic exercise safety profile and risk of serious adverse events appears favourable when compared to common pharmacological treatment options such as paracetamol and non-steroidal anti inflammatories
      • National Institute for Health and Care Excellence
      Osteoarthritis Care and Management in Adults.
      • Adbulla A.
      • Adams N.
      • Bone M.
      • Elliott A.M.
      • Gaffin J.
      • Jones D.
      • et al.
      Guidance on the management of pain in older people.
      . Our findings may increase the frequency and confidence with which therapeutic exercise is recommended and offer reassurance to some clinicians and older adults with knee pain who perceive that knee pain attributed to OA is a “wear and tear” condition that deteriorates with time and is made worse by regular physical activity
      • Holden M.A.
      • Nicholls E.E.
      • Young J.
      • Hay E.M.
      • Foster N.E.
      UK-based physical therapists' attitudes and beliefs regarding exercise and knee osteoarthritis: findings from a mixed-methods study.
      • Holden M.A.
      • Nicholls E.E.
      • Young J.
      • Hay E.M.
      • Foster N.E.
      Role of exercise for knee pain: what do older adults in the community think?.
      • Hendry M.
      • Williams N.H.
      • Markland D.
      • Wilkinson C.
      • Maddison P.
      Why should we exercise when our knees hurt? A qualitative study of primary care patients with osteoarthritis of the knee.
      • Cottrell E.
      • Roddy E.
      • Foster N.
      The attitudes, beliefs and behaviours of GPs regarding exercise for chronic knee pain: a systematic review.
      .
      To conclude, the findings from this systematic review suggest that long-term therapeutic exercise can safely be recommended for older adults with knee pain. However, there are limitations in generalising the safety findings to all types of patient subgroups and physical activity as a result of the current available evidence.

      Contributions

      Jonathan Quicke was the overall lead for the work for the systematic review and was involved at all stages of the paper. The lead author can be contacted by email: [email protected] or at Primary Care and Health Science building, Keele University, Keele, Staffordshire, United Kingdom, ST5 5BG.
      Jonathan Quicke, Prof Nadine Foster and Dr Melanie Holden were involved with the conception of the design. Jonathan Quicke, Prof Nadine Foster, Dr Melanie Holden and Dr Martin Thomas were involved in study searching, quality assessment and data extraction checking and editing drafts of the paper.

      Role of the funding source

      J.G.Quicke is funded by a Keele University ACORN studentship in conjunction with Arthritis Research UK. Neither funder had involvement in the study design, collection, data analysis, writing or publishing of this paper.
      N.E Foster is supported through a National Institute for Health Research (NIHR) Research Professorship (NIHR-RP-011-015).
      M.J Thomas was supported by West Midlands Strategic Health Authority through a Nursing, Midwifery, and Allied Health Professionals Doctoral Research Training Fellowship (NMAHP/RFT/10/02).
      M.A Holden is supported by the National Institute for Health Research (NIHR) School for Primary Care Research.
      The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

      Competing interests

      There is no conflict of interest for any of the authors.

      Acknowledgements

      We would like to thank Jo Jordan for her protocol feedback and systematic review methodological advice. We would also like to thank Professor Peter Croft for his peer review of the initial submitted manuscript, ongoing support and Socratic questions and, last but not least, we would like to thank the journal peer reviewers who helped with important contributions towards the final paper.

      Appendix A. Supplementary data

      The following are the supplementary data related to this article:

      Appendix 1. Medline search filter.

      Appendix 2. Cardiovascular intensity and physical activity impact categorisation

      Cardiovascular intensity and physical activity impact categorisation were carried out by one author (JQ). Where target heart rates were stipulated, <50% of maximum heart rate was defined as low intensity, 50–70% as moderate intensity, and >70–85% as vigorous intensity
      • Centers for Disease Control and Prevention
      Physical Activity: Target Heart Rate and Estimated Maximum Heart Rate.
      . If no target heart rate information was available physical activities were classified by MET score. A MET score of <3 was defined as low intensity, 3–6 as moderate intensity whilst >6 was considered vigorous
      • Ainsworth B.E.
      • Haskell W.L.
      • Herrmann S.D.
      • Meckes N.
      • Bassett Jr., D.R.
      • Tudor-Locke C.
      • et al.
      2011 Compendium of physical activities: a second update of codes and MET values.
      . Physical activity intervention impact was categorised on a case by case basis into high and low impact based on the likely amount of compressive load and whether both feet were intermittently off the ground. For example, jogging, running and jumping were considered high impact whilst cycling, swimming and walking were considered low impact.

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