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1.  Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial 
BMJ Open  2012;2(6):e002168.
It is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA).
Methods and analysis
This study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0–100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength.
Ethics and dissemination
This study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014.
Trial registration number
This study is registered with (NCT01535001).
PMCID: PMC3533085  PMID: 23151395
Rheumatology; Rehabilitation Medicine
2.  The efficacy of tourniquet assisted total knee arthroplasty on patient-reported and performance-based physical function: a randomized controlled trial protocol 
Surgical treatment of osteoarthritis with total knee arthroplasty (TKA) usually takes place in a complete bloodless field using a tourniquet. However, doing the surgery without a tourniquet may reduce muscle damage, post-surgery pain and led to improved functional rehabilitation and mobilization.
A prospective, blinded, parallel-group, controlled superiority trial, with balanced randomization [1:1]. Patients aged 50 or older eligible for primary TKA for osteoarthritis will be consecutively recruited from Department of Orthopedic Surgery and Traumatology, Odense University Hospital, Denmark. A total of 80 patients will be randomly allocated to TKA with or without tourniquet application providing 40 patients for each of the two treatment arms. The tourniquet assisted TKA group will have an automatic, micro-processor-based pneumatic tourniquet inflated around the thigh during surgery. The non-tourniquet assisted TKA group will have surgery performed without application of a tourniquet. The primary aim is to compare tourniquet assisted to non-tourniquet assisted TKA on patient-reported physical function (KOOS-ADL). The secondary aim is to compare post-surgery pain, function in sports and recreation, quality of life, and performance-based physical function. The explorative outcomes include; use of pain medication, single-fiber muscle damage, and changes in mechanical muscle function. The primary endpoint will be at 3-months following surgical treatment, and the time-point for analysis of the primary outcome. However, follow-up will continue up to 1 year, and provide medium-term results. The treatment effect (difference in KOOS-ADL) will be analyzed using a random effects regression model, crude and adjusted results will be reported, if needed. Analyses will be based on the intention-to-treat (ITT). Subsequent per-protocol analysis may be necessary in the event of a substantial number of patients (> 15%) being lost during follow-up. The number needed to treat (NNT) for a positive effect of treatment (>10 points on KOOS-ADL) will be reported.
This is the first randomized clinical trial comparing the efficacy of tourniquet assisted TKA on patient-reported physical function supported by a range of performance-based secondary outcome measures. As such it will provide high quality evidence that may help determine whether tourniquet should be used in future TKA procedures in patients with osteoarthritis of the knee.
Trial registration
ClinicalTrials NCT01891266.
PMCID: PMC3978123  PMID: 24678741
Tourniquet; Total knee arthroplasty; Patient-reported; Performance-based; Physical function
3.  Tai Chi for treating knee osteoarthritis: Designing a long-term follow up randomized controlled trial 
Knee Osteoarthritis (KOA) is a major cause of pain and functional impairment among elders. Currently, there are neither feasible preventive intervention strategies nor effective medical remedies for the management of KOA. Tai Chi, an ancient Chinese mind-body exercise that is reported to enhance muscle function, balance and flexibility, and to reduce pain, depression and anxiety, may safely and effectively be used to treat KOA. However, current evidence is inconclusive. Our study examines the effects of a 12-week Tai Chi program compared with an attention control (wellness education and stretching) on pain, functional capacity, psychosocial variables, joint proprioception and health status in elderly people with KOA. The study will be completed by July 2009.
Forty eligible patients, age > 55 yr, BMI ≤ 40 kg/m2 with tibiofemoral osteoarthritis (American College of Rheumatology criteria) are identified and randomly allocated to either Tai Chi (10 modified forms from classical Yang style Tai Chi) or attention control (wellness education and stretching). The 60-minute intervention sessions take place twice weekly for 12 weeks. The study is conducted at an urban tertiary medical center in Boston, Massachusetts. The primary outcome measure is the Western Ontario and McMaster Universities (WOMAC) pain subscale at 12 weeks. Secondary outcomes include weekly WOMAC pain, function and stiffness scores, patient and physician global assessments, lower-extremity function, knee proprioception, depression, self-efficacy, social support, health-related quality of life, adherence and occurrence of adverse events after 12, 24 and 48 weeks.
In this article, we present the challenges of designing a randomized controlled trial with long-term follow up. The challenges encountered in this design are: strategies for recruitment, avoidance of selection bias, the actual practice of Tai Chi, and the maximization of adherence/follow-up while conducting the clinical trial for the evaluation of the effectiveness of Tai Chi on KOA.
Trial registration identifier: NCT00362453
PMCID: PMC2529300  PMID: 18664276
4.  Levels of neuropeptide Y in synovial fluid relate to pain in patients with knee osteoarthritis 
The precise etiology of knee osteoarthritis (KOA) pain remains highly controversial and there is no known effective treatment. Due to the known and suggested effects of neuropeptide Y (NPY) on pain, we have sought to investigate the relationship between the concentration of NPY in synovial fluid of knee, pain of KOA, and structural severity of KOA.
One hundred KOA patients and twenty healthy participants (control group) were recruited. The pain and the radiographic grade of KOA were assessed separately by Hideo Watanabe’s pain score and Tomihisa Koshino’s scoring system. Synovial fluid of knee from all participants was collected with arthrocentesis. Radioimmunoassay was used to examine the concentration of NPY in synovial fluid of knee.
Concentrations of NPY in synovial fluid were significantly higher in KOA patients (124.7 ± 33.4 pg/mL) compared with controls (64.8 ± 26.3 pg/mL) (p = 0.0297). According to Hideo Watanabe’s pain score, 100 KOA patients were divided into 5 subgroups: no pain (n = 12), mild pain (n = 25), moderate pain (n = 37), strong pain (n = 19) and severe pain (n = 7). Within the KOA group, significantly higher concentrations of NPY were found in each subgroup as pain intensified (no pain 81.4 ± 11.7 pg/mL, mild pain 99.1 ± 23.2 pg/mL, moderate pain 119.9 ± 31.5 pg/mL, strong pain 171.2 ± 37.3 pg/mL and severe pain 197.3 ± 41.9 pg/mL). Meanwhile, according to Tomihisa Koshino’s scoring system, 100 KOA patients were divided into 3 subgroups: early stage (n = 30), middle stage (n = 53), advanced stage (n = 17). Concentrations of NPY in middle and advanced stage groups of KOA patients were significant higher than early stage group of KOA patients (early stage 96.4 ± 27.1 pg/mL, middle stage 153.3 ± 16.9 pg/mL, advanced stage 149.5 ± 36.7 pg/mL) (p = 0.0163, p = 0.0352). Concentrations of NPY in advanced stage group of KOA patients has no significant difference compare with middle stage group of KOA patients (p = 0. 2175).
This study demonstrated the presence and variation of concentrations of NPY in the KOA joint fluid, suggesting a role for NPY as a putative regulator of pain transmission and perception in KOA pain.
PMCID: PMC4195915  PMID: 25262001
Pathogenesis; Arthrophlogosis; Synovia; Radioimmunoassay; Regulator
5.  Moxibustion Treatment for Knee Osteoarthritis: A Multi-Centre, Non-Blinded, Randomised Controlled Trial on the Effectiveness and Safety of the Moxibustion Treatment versus Usual Care in Knee Osteoarthritis Patients 
PLoS ONE  2014;9(7):e101973.
This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis (KOA) and evaluated safety.
A multi-centre, non-blinded, parallel-group, randomised controlled trial compared moxibustion with usual care (UC) in KOA. 212 South Korean patients aged 40–70 were recruited from 2011–12, stratified by mild (Kellgren/Lawrence scale grades 0/1) and moderate-severe KOA (grades 2/3/4), and randomly allocated to moxibustion or UC for four weeks. Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s). UC was allowed. Korean Western Ontario and McMaster Universities Questionnaire (K-WOMAC), Short Form 36 Health Survey (SF-36v2), Beck Depression Inventory (BDI), physical performance test, pain numeric rating scale (NRS) and adverse events were evaluated at 5 and 13 weeks. K-WOMAC global score at 5 weeks was the primary outcome.
102 patients (73 mild, 29 moderate-severe) were allocated to moxibustion, 110 (77 mild, 33 moderate-severe) to UC. K-WOMAC global score (moxibustion 25.42+/−SD 19.26, UC 33.60+/−17.91, p<0.01, effect size  = 0.0477), NRS (moxibustion 44.77+/−22.73, UC 56.23+/−17.71, p<0.01, effect size  = 0.0073) and timed-stand test (moxibustion 24.79+/−9.76, UC 25.24+/−8.84, p = 0.0486, effect size  = 0.0021) were improved by moxibustion at 5 weeks. The primary outcome improved for mild but not moderate-severe KOA. At 13 weeks, moxibustion significantly improved the K-WOMAC global score and NRS. Moxibustion improved SF-36 physical component summary (p = 0.0299), bodily pain (p = 0.0003), physical functioning (p = 0.0025) and social functioning (p = 0.0418) at 5 weeks, with no difference in mental component summary at 5 and 13 weeks. BDI showed no difference (p = 0.34) at 5 weeks. After 1158 moxibustion treatments, 121 adverse events included first (n = 6) and second degree (n = 113) burns, pruritus and fatigue (n = 2).
Moxibustion may improve pain, function and quality of life in KOA patients, but adverse events are common. Limitations included no sham control or blinding.
Trial Registration
Clinical Research Information Service (CRIS) KCT0000130
PMCID: PMC4111481  PMID: 25061882
6.  Does mild cognitive impairment affect the occurrence of radiographic knee osteoarthritis? A 3-year follow-up in the ROAD study 
BMJ Open  2012;2(6):e001520.
To determine whether mild cognitive impairment (MCI) increases the risk of occurrence or progression of radiographic knee osteoarthritis (KOA) in a general population.
Population-based cohort study.
Residents in mountain and seaside areas of Wakayama Prefecture, Japan.
1690 participants (596 men, 1094 women; mean age 65.2 years old) were enrolled from the large-scale cohort for the Research on Osteoarthritis (OA)/osteoporosis Against Disability (ROAD) study initiated in 2005 to investigate epidemiological features of OA in Japan. Of these, 1384 individuals (81.9%; 466 men, 918 women) completed the second survey including knee radiography 3 years later.
Primary outcome measures
Radiographic KOA was defined as Kellgren-Lawrence (KL) grade ≥ 2 using paired x-ray films. Incidence of KOA during follow-up defined on radiographs as KL grade ≥2, progression of KOA defined as a higher KL grade (either knee) at follow-up compared with baseline. MCI defined as a summary mini-mental state examination (MMSE) score ≤23. Associations between MCI and incidence or progression of KOA were analysed.
The annual cumulative incidence of KOA was 3.3%; for progression of OA it was 8.0%. On logistic regression analysis adjusted for age, gender, regional differences, body mass index, grip strength (worse side), smoking, alcohol consumption, regular exercise and history of knee injury, baseline MMSE summary score was significantly associated with the incidence of KOA (+1 MMSE score; OR 0.83, p=0.010). Baseline MCI was also significantly associated with the incidence of KOA (vs non-occurrence of KOA; OR 4.90, p=0.027). There was no significant association between MMSE scores, the presence of MCI and progression of KOA (+1 MMSE score; OR 0.96, p=0.232; vs non-progression of KOA; OR 1.38, p=0.416).
MCI significantly increases the risk of incident radiographic KOA, but not the progression of KOA.
PMCID: PMC3532983  PMID: 23166128
7.  The attitudes, beliefs and behaviours of GPs regarding exercise for chronic knee pain: a systematic review 
BMC Family Practice  2010;11:4.
Joint pain, specifically chronic knee pain (CKP), is a frequent cause of chronic pain and limitation of function and mobility among older adults. Multiple evidence-based guidelines recommend exercise as a first-line treatment for all patients with CKP or knee osteoarthritis (KOA), yet healthcare practitioners' attitudes and beliefs may limit their implementation. This systematic review aims to identify the attitudes, beliefs and behaviours of General Practitioners (GPs) regarding the use of exercise for CKP/KOA.
We searched four electronic databases between inception and January 2008, using subject headings to identify studies examining the attitudes, beliefs or behaviours of GPs regarding the use of exercise for the treatment of CKP/KOA in adults aged over 45 years in primary care. Studies referring to patellofemoral pain syndrome or CKP secondary to other causes or that occurring in a prosthetic joint were excluded. Once inclusion and exclusion criteria were applied, study data were extracted and summarised. Study quality was independently reviewed using two assessment tools.
From 2135 potentially relevant articles, 20 were suitable for inclusion. A variety of study methodologies and approaches to measuring attitudes beliefs and behaviours were used among the studies. Quality assessment revealed good reporting of study objective, type, outcome factors and, generally, the sampling frame. However, criticisms included use of small sample sizes, low response rates and under-reporting of non-responder factors. Although 99% of GPs agreed that exercise should be used for CKP/KOA and reported ever providing advice or referring to a physiotherapist, up to 29% believed that rest was the optimum management approach. The frequency of actual provision of exercise advice or physiotherapy referral was lower. Estimates of provision of exercise advice and physiotherapy referral were generally higher for vignette-based studies (exercise advice 9%-89%; physiotherapy referral 44%-77%) than reviews of actual practice (exercise advice 5%-52%; physiotherapy referral 13-63%). Advice to exercise and exercise prescription were not clearly differentiated.
Attitudes and beliefs of GPs towards exercise for CKP/KOA vary widely and exercise appears to be underused in the management of CKP/KOA. Limitations of the evidence base include the paucity of studies directly examining attitudes of GPs, poor methodological quality, limited generalisability of results and ambiguity concerning GPs' expected roles. Further investigation is required of the roles of GPs in using exercise as first-line management of CKP/KOA.
PMCID: PMC2826301  PMID: 20082694
8.  Needle-knife therapy improves the clinical symptoms of knee osteoarthritis by inhibiting the expression of inflammatory cytokines 
Knee osteoarthritis (KOA) is a degenerative joint disease that occurs mainly in the elderly population. However, there are currently no effective treatments for treating this condition. In this study, the efficacy of needle-knife therapy, a technique of traditional Chinese medicine that has been widely used to treat KOA was investigated. Patients (n=170) with KOA were randomly divided for needle-knife therapy (treatment group) and acupuncture therapy (control group). Outcome evaluation included stiffness, pain, physiological function, overall changes, total symptom score, clinical curative effects and the concentrations of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the synovial fluid. The trial was completed in 151 patients (233 knees) from a total of 170 patients (264 knees); the treatment group comprised 76 patients (117 knees) who completed the trial and 9 patients (14 knees) who were removed from the study, and the control group comprised 75 patients (116 knees) who completed the trial and 10 patients (17 knees) who were removed from the study. The symptom scores of KOA in stages I–IV were reduced significantly in the treatment group and those of stages I–III were decreased significantly in the control group. The effective rate of the KOA therapy in the patients of stages III and IV in the treatment group was significantly higher than that in the control group. After treatment, the decrements of IL-1β, IL-6 and TNF-α in the treatment group were greater than those in the control group. These results showed that the use of needle-knife therapy to treat KOA effectively improved the clinical symptoms by inhibiting the expression of inflammatory cytokines.
PMCID: PMC3961116  PMID: 24669238
needle-knife therapy; osteoarthritis; knee joint; acupuncture
9.  Clinical effects of Garcinia kola in knee osteoarthritis 
Over the past years, there has been a growing number of knee osteoarthritis (KOA) patients who are not willing to comply with long-term non-steroidal anti-inflammatory drugs (NSAID) treatment and wish to use herbal anti- rheumatic medicine. This study assessed the clinical effects of Garcinia kola (GK) in KOA patients.
Patients and methods
Prospective randomized, placebo controlled, double blind, clinical trial approved by the institutional medical ethics review board and written informed consent obtained from each patient. All KOA patients presenting at the Obafemi Awolowo University Teaching Hospital complex were recruited into the study. The patients were grouped into four (A = Placebo, B = Naproxen, C = Garcinia kola, D = Celebrex). The drugs and placebo were given twice a day per oral route. Each dose consisted of 200 mg of G. kola, Naproxen (500 mg), Celebrex (200 mg) and Ascorbic acid (100 mg). The primary outcome measure over six weeks study period was the change in mean WOMAC pain visual analogue scales (VAS). Secondary outcome measures included the mean change in joint stiffness and physical function (mobility/walking).
143 patients were recruited, 84 (58.7%, males – 24, females – 60) satisfied the selection criteria and completed the study. The effect of knee osteoarthritis bilateralism among the subjects was not significant on their outcome (p > 0.05). The change in the mean WOMAC pain VAS after six weeks of G. kola was significantly reduced compared to the placebo (p < 0.001). Multiple comparisons of the mean VAS pain change of G. kola group was not lowered significantly against the naproxen and celebrex groups (p > 0.05). The onset of G. kola symptomatic pain relief was faster than the placebo (p < 0.001). However, it was slower than the active comparators (p > 0.05). The duration of therapeutic effect of Garcinia kola was longer than the placebo (p > 0.001). G. kola period of effect was less than naproxen and celebrex (p < 0.001). G. kola subjects had improved mean change mobility/walking after six weeks better than the control group(p < 0.001). The mean change in mobility of the G. kola group when compared to the active comparators was not significantly better (p < 0.05). The mean change of knee joint stiffness (p < 0.001) and the change of mean WOMAC score (p < 0.001) were improved on Garcinia kola as compared to the placebo. The mid term outcome of eleven Garcinia kola subjects after cessation of use had a mean pain relief period of 17.27 +/- 5.15 days (range: 9–26 days). There was no significant cardiovascular, renal or drug induced adverse reaction to Garcinia kola.
Garcinia kola appeared to have clinically significant analgesic/anti-inflammatory effects in knee osteoarthritis patients. Garcinia kola is a potential osteoarthritis disease activity modifier with good mid term outcome. Further studies are required for standardization of dosages and to determine long-term effects.
PMCID: PMC2526991  PMID: 18667082
10.  The Dutch version of the knee injury and osteoarthritis outcome score: A validation study 
The Knee Injury and Osteoarthritis Outcome Score (KOOS) was constructed in Sweden. This questionnaire has proved to be valid for several orthopedic interventions of the knee. It has been formally translated and validated in several languages, but not yet in Dutch. The purpose of the present study was to evaluate the clinimetric properties of the Dutch version of the KOOS questionnaire in knee patients with various stages of osteoarthritis (OA).
The Swedish version of the KOOS questionnaire was first translated into Dutch according to a standardized procedure and second tested for clinimetric quality. The study population consisted of patients with different stages of OA (mild, moderate and severe) and of patients after primary TKA, and after a revision of the TKA. All patients filled in the Dutch KOOS questionnaire, as well as the SF-36 and a Visual Analogue Scale for pain. The following analyses were performed to evaluate the clinimetric quality of the KOOS: Cronbach's alpha (internal consistency), principal component analyses (factor analysis), intraclass correlation coefficients (reliability), spearman's correlation coefficient (construct validity), and floor and ceiling effects.
For all patients groups Cronbach's alpha was for all subscales above 0.70. The ICCs, assessed for the patient groups with mild and moderate OA and after revision of the TKA patients, were above 0.70 for all subscales. Of the predefined hypotheses 60% or more could be confirmed for the patients with mild and moderate OA and for the TKA patients. For the other patient groups less than 45% could be confirmed. Ceiling effects were present in the mild OA group for the subscales Pain, Symptoms and ADL and for the subscale Sport/Recreation in the severe OA group. Floor effects were found for the subscales Sport/Recreation and Qol in the severe OA and revision TKA groups.
Based on these different clinimetric properties within the present study we conclude that the KOOS questionnaire seems to be suitable for patients with mild and moderate OA and for patients with a primary TKA. The Dutch version of the KOOS had a lower construct validity for patients with severe OA on a waiting list for TKA and patients after revision of a TKA. Further validation studies on the Dutch version of the KOOS should also include a knee specific questionnaire for assessing the construct validity.
PMCID: PMC2289810  PMID: 18302729
11.  Association between disease-specific quality-of-life and magnetic resonance imaging outcomes in a clinical trial of prolotherapy for knee osteoarthritis 
Archives of physical medicine and rehabilitation  2013;94(11):10.1016/j.apmr.2013.06.025.
To assess the relationship between knee osteoarthritis (KOA)-specific quality-of-life (QoL) and intra-articular cartilage volume (CV) in participants treated with prolotherapy. KOA is characterized by CV loss and multifactorial pain. Prolotherapy is an injection therapy reported to improve KOA-related QoL compared to blinded saline injections and at-home exercise but the mechanism of action is unknown.
Two-arm (Prolotherapy, Control), partially blinded, controlled trial.
37 adults with ≥3 months of symptomatic KOA.
Prolotherapy: 5 monthly injection sessions; Control: blinded saline injections or at-home exercise.
Outcome Measures
Primary: KOA-specific QoL scores (baseline, 5, 9, 12, 26, 52 weeks; Western Ontario McMaster University Osteoarthritis Index, WOMAC). Secondary: KOA-specific pain, stiffness, function (WOMAC subscales), magnetic resonance imaging (MRI)-assessed CV (baseline, 52 weeks).
Knee-specific QoL improvement among Prolotherapy participants exceeded that of Controls (17.6±3.2 versus 8.6±5.0 points, p=0.05) at 52 weeks. Both groups lost CV over time (p<0.05); no between-group differences were noted (p=0.98). While Prolotherapy participants lost CV at varying rates, those who lost the least CV (“Stable CV”) had the greatest improvement in pain scores. Among Prolotherapy, but not Control participants, the change in CV and the change in pain (but not stiffness or function) scores were correlated; each 1% CV loss was associated with 2.7% less improvement in pain score (p<0.05).
Prolotherapy resulted in safe, substantial improvement in KOA-specific QoL compared to Control over 52-weeks. Among prolotherapy participants, but not Controls, MRI-assessed CV change (CV stability) predicted pain severity score change, suggesting prolotherapy may have pain-specific disease-modifying effect. Further research is warranted.
PMCID: PMC3812343  PMID: 23850615
knee osteoarthritis; prolotherapy; dextrose; cartilage volume; magnetic resonance imaging
12.  Patellar resurfacing in posterior cruciate ligament retaining total knee arthroplasty (PATRES): design of a randomized controlled clinical trial 
Anterior knee pain may occur after total knee arthroplasty (TKA). Patellar resurfacing, which is considered to lower the incidence of anterior knee pain after TKA, remains controversial. In the present study clinical and radiological outcomes after TKA performed on patients with clinical and radiological signs of femorotibial and patellofemoral osteoarthritis (OA) with and without patellar resurfacing will be compared.
Fifty patients will be included in a randomized controlled trial. Patients scheduled for TKA with clinical and radiological signs of femorotibial and patellofemoral OA will be included. Arthritis of the patellofemoral joint was determined based on the preoperative Baldini and Merchant X-ray views, which is assessed by the orthopaedic surgeon who treats the patient. Exclusion criteria are rheumatoid arthritis, history of patellar fracture, tuberosity transposition, high tibial osteotomy (HTO), hip arthroplasty and posterior cruciate ligament insufficiency. Patients will be randomized to undergo TKA either with or without patellar resurfacing. Outcomes will be assessed preoperatively, at 6 weeks and at 6, 12, 18 and 24 months postoperatively. Primary outcome measure is the patellofemoral scoring system according to Baldini. Secondary outcome measures are the Knee Society clinical rating system (KSS) and the Knee Osteoarthritis Outcome Scale (KOOS) scores. Conventional weight-bearing radiographs, and views according to Baldini will be used to asses component loosening, wear, and patellofemoral problems including fracture or loosening of resurfaced patellae, subluxation and wear of non-resurfaced patellae.
There is no consensus regarding patellar resurfacing during primary TKA. Current prospective studies fail to determine any differences in clinical outcome among patients after TKA with or without patellar resurfacing. This randomized controlled trial has been designed to determine the effectiveness of patellar resurfacing during TKA in patients undergoing TKA who have clinical and radiological signs of tibiofemoral and patellofemoral OA, using a specific patellofemoral outcome measurement.
Trial registration
Netherlands Trial Registry NTR3108
PMCID: PMC4232658  PMID: 25351573
13.  Association between knee alignment and knee pain in patients surgically treated for medial knee osteoarthritis by high tibial osteotomy. A one year follow-up study 
The association between knee alignment and knee pain in knee osteoarthritis (OA) is unclear. High tibial osteotomy, a treatment option in knee OA, alters load from the affected to the unaffected compartment of the knee by correcting malalignment. This surgical procedure thus offers the possibility to study the cross-sectional and longitudinal association of alignment to pain. The aims were to study 1) the preoperative association of knee alignment to preoperative knee pain and 2) the association of change in knee alignment with surgery to change in knee pain over time in patients operated on for knee OA by high tibial osteotomy.
182 patients (68% men) mean age 53 years (34 - 69) with varus alignment having tibial osteotomy by the hemicallotasis technique for medial knee OA were consecutively included. Knee alignment was assessed by the Hip-Knee-Ankle (HKA) angle from radiographs including the hip and ankle joints. Knee pain was measured by the subscale pain (0 - 100, worst to best scale) of the Knee injury and Osteoarthritis Outcome Score (KOOS) preoperatively and at one year follow-up. To estimate the association between knee alignment and knee pain multivariate regression analyses were used.
Mean preoperative varus alignment was 170 degrees (153 - 178) and mean preoperative KOOS pain was 42 points (3 - 86). There was no association between preoperative varus alignment and preoperative KOOS pain, crude analysis 0.02 points (95% CI -0.6 - 0.7) change in pain with every degree of HKA angle, adjusted analysis 0.3 points (95% CI -1.3 - 0.6).
The mean postoperative knee alignment was 184 degrees (171 - 185). The mean change in knee alignment was 13 degrees (0 - 30). The mean change in KOOS pain was 32 (-16 - 83). There was neither any association between change in knee alignment and change in KOOS pain over time, crude analysis 0.3 point (95% CI -0.6 - 1.2), adjusted analysis 0.4 points (95% CI 0.6 - 1.4).
We found no association between knee alignment and knee pain in patients with knee OA indicating that alignment and pain are separate entities, and that the degree of preoperative malalignment is not a predictor of knee pain after high tibial osteotomy.
PMCID: PMC2796991  PMID: 19995425
14.  Efficacy and tolerance of enzymatic hydrolysed collagen (EHC) vs. glucosamine sulphate (GS) in the treatment of knee osteoarthritis (KOA) 
International Orthopaedics  2010;35(3):341-348.
This was a 13-week, multicentre, randomised, parallel, double-blind study. One hundred men and women volunteers aged ≥40 years with knee osteoarthritis (KOA) were randomised to once daily enzymatic hydrolysed collagen (EHC) 10 g or glucosamine sulphate (GS) 1.5 g for 90 consecutive days. Follow-up took place after two weeks and after one, two and three months. Primary [visual analogue scale (VAS), Western Ontario and McMaster Universities (WOMAC Index)] and secondary outcomes variables, assessed at weeks two, four, eight and 12, were KOA pain intensity measured by quadruple visual analogue scales in the target knee, the WOMAC total score index, patient’s and investigator’s global assessments of disease activity, joint assessment, use of rescue medication (ibuprofen 400 mg tablets) and assessment of Quality of Life index (SF-36 Questionnaire). Safety and tolerability were also evaluated. Clear improvement was observed in both joint pain and symptoms in patients with KOA treated with EHC (Colatech®) and significant differences were observed. Mean reductions from baseline for EHC 10 g daily and GS 1.5 g, respectively, were KOA pain intensity reduction in the target knee for Colatech® (p < 0.05): WOMAC index decrease ≤ 15 points at the last visit (day 90) for Colatech® in 16 patients (34.04%) (p < 0.05) and for glucosamine in six patients (13.04%); total score index for painful joints: Colatech® 1.6 (p < 0.05) and glucosamine 1.8; total score index for swollen joints: Colatech® 0.5 (p < 0.05) and glucosamine 0.7; patient’s global assessment of efficacy as the sum of improvement good + ideal: 80.8% for Colatech® and 46.6% for glucosamine (p < 0.05). EHC (Colatech®) showed superior improvement over GS in the SF-36 Questionnaire in the Physical Health Index (42.0 for Colatech and 40.0 for glucosamine). The incidence of adverse events was similar in both groups. Both EHC and GS were well tolerated.
PMCID: PMC3047656  PMID: 20401752
15.  Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial 
Objective To compare, in young active adults with an acute anterior cruciate ligament (ACL) tear, the mid-term (five year) patient reported and radiographic outcomes between those treated with rehabilitation plus early ACL reconstruction and those treated with rehabilitation and optional delayed ACL reconstruction.
Design Extended follow-up of prospective randomised controlled trial.
Setting Orthopaedic departments at two hospitals in Sweden.
Participants 121 young, active adults (mean age 26 years) with acute ACL injury to a previously uninjured knee. One patient was lost to five year follow-up.
Intervention All patients received similar structured rehabilitation. In addition to rehabilitation, 62 patients were assigned to early ACL reconstruction and 59 were assigned to the option of having a delayed ACL reconstruction if needed.
Main outcome measure The main outcome was the change from baseline to five years in the mean value of four of the five subscales of the knee injury and osteoarthritis outcome score (KOOS4). Other outcomes included the absolute KOOS4 score, all five KOOS subscale scores, SF-36, Tegner activity scale, meniscal surgery, and radiographic osteoarthritis at five years.
Results Thirty (51%) patients assigned to optional delayed ACL reconstruction had delayed ACL reconstruction (seven between two and five years). The mean change in KOOS4 score from baseline to five years was 42.9 points for those assigned to rehabilitation plus early ACL reconstruction and 44.9 for those assigned to rehabilitation plus optional delayed reconstruction (between group difference 2.0 points, 95% confidence interval −8.5 to 4.5; P=0.54 after adjustment for baseline score). At five years, no significant between group differences were seen in KOOS4 (P=0.45), any of the KOOS subscales (P≥0.12), SF-36 (P≥0.34), Tegner activity scale (P=0.74), or incident radiographic osteoarthritis of the index knee (P=0.17). No between group differences were seen in the number of knees having meniscus surgery (P=0.48) or in a time to event analysis of the proportion of meniscuses operated on (P=0.77). The results were similar when analysed by treatment actually received.
Conclusion In this first high quality randomised controlled trial with minimal loss to follow-up, a strategy of rehabilitation plus early ACL reconstruction did not provide better results at five years than a strategy of initial rehabilitation with the option of having a later ACL reconstruction. Results did not differ between knees surgically reconstructed early or late and those treated with rehabilitation alone. These results should encourage clinicians and young active adult patients to consider rehabilitation as a primary treatment option after an acute ACL tear.
Trial registration Current Controlled Trials ISRCTN84752559.
PMCID: PMC3553934  PMID: 23349407
16.  Short-term functional versus patient-reported outcome of the bicruciate stabilized total knee arthroplasty: prospective consecutive case series 
The main goals of the standard treatment for advanced symptomatic knee osteoarthritis, total knee arthroplasty (TKA), are pain reduction and restoration of knee motion.
The aim of this study was to analyse the outcome of the patient-based Knee Injury and Osteoarthritis Outcome Score (KOOS), and the surgeon-based Knee Society Score (KSS) and its Knee Score (KS) and Knee Functional Score (KFS) components after (TKA) using the Journey knee prosthesis, and to assess the correlation of these scores with range of motion (ROM).
In a prospective case series study between August 1st 2008 and May 31st 2011, 99 patients, all operated by a single surgeon, received Journey bicruciate stabilized total knee prostheses. The female/male ratio was 53/34, the mean patient age at surgery was 68 years (range 41–83 years), and the left/right knee ratio was 55/44. The KOOS, range of motion, and KS and KFS were obtained preoperatively and at 1-year follow-up. The pre- and postoperative levels of the outcome measures were compared using the Wilcoxon signed-rank test. Correlation between ROM and patient outcomes was analysed with the Spearman coefficient.
All KOOS subscores improved significantly. Ninety percent of patients improved by at least the minimum clinically relevant difference of 10 points in stiffness and other symptoms, 94.5% in pain, 94.5% in activities of daily living, 84.9% in sports and recreation, and 90% in knee-related quality of life. The mean passive and active ROM improved from 122.4° (range 90-145°) and 120.4° (range 80-145°) preoperatively to 129.4° (range 90-145°) and 127.1° (range 100-145°) postoperatively. The highest correlation coefficients for ROM and KOOS were observed for the activity and pain subscores. Very low or no correlation was seen for the sport subscore.
There was a significant and clinically relevant improvement of KSS (preop/postop 112.2/174.5 points), and its KS (preop/postop 45.6/86.8 points) and KFS (preop/postop 66.6/87.8 points) components.
The Journey bicruciate stabilized knee prosthesis showed good 1-year postoperative results in terms of both functional and patient-based outcome. However, higher knee ROM correlates only moderately with patient-based outcome, implying that functionality afforded by the Journey bicruciate TKA is not equivalent to patient satisfaction.
PMCID: PMC4300849  PMID: 25515192
Total knee arthroplasty; Knee injury and osteoarthritis outcome score; Knee society score; Journey; Bicruciate stabilized knee prosthesis
17.  Associations for Change in Physical and Psychological Factors and Treatment Response Following Exercise in Knee Osteoarthritis: An Exploratory Study 
Arthritis care & research  2012;64(11):1673-1680.
Understanding how changes in physical and psychological factors following therapeutic exercise are associated with treatment outcome could have important implications for refining rehabilitation programs for knee osteoarthritis (KOA). The objective of the study was to examine the association of changes in these factors with changes in pain and function after an exercise program for people with (KOA).
152 people with KOA completed an exercise program consisting of lower extremity strengthening, stretching, range of motion, balance and agility, and aerobic exercises. Change from baseline to the 2-month follow-up was calculated for physical and psychological factors including self-reported knee instability, quadriceps strength, knee range of motion, lower extremity muscle flexibility, fear of physical activity, anxiety, and depressive symptoms. Treatment response was defined as a minimum of a 20% improvement from baseline in BOTH the Numerical Pain Rating Scale (NKPR) and the WOMAC physical function scale. The association of each factor with treatment response was examined with logistic regression mutually adjusted for age, sex, BMI, radiographic severity and exercise group.
Change in self-reported knee instability (odds ratio (95%CI) = 1.67 (1.13, 2.47) and fear of physical activity (odds ratio (95%CI) = 0.93 (0.88, 1.00) were the only two factors that were significantly associated with treatment response after adjustment for covariates.
Improvement in knee instability and fear of physical activity were associated with an increased odds of a positive treatment response following therapeutic exercise in subjects with KOA.
PMCID: PMC3448876  PMID: 22674892
18.  Intraarticular Botulinum Toxin A for Refractory Painful Total Knee Arthroplasty: A Randomized Controlled Trial 
The Journal of rheumatology  2010;37(11):2377-2386.
To assess short-term efficacy of single intraarticular botulinum toxin (IA-BoNT/A) injection in patients with chronically painful total knee arthroplasty (TKA) in a randomized, placebo-controlled, triple-blind study.
Patients with chronic TKA pain (pain > 6 on 0–10 scale and > 6 months post-TKA) evaluated in and referred from orthopedic surgery clinics were recruited. The primary outcome, proportion of patients with clinically meaningful decrease of at least 2 points on 0–10 visual analog scale (VAS) for pain, was compared between treatment groups at 2 months using comparison of proportions test and for all efficacy timepoints (2, 3, and 4 months) using generalized estimating equations (GEE). Secondary outcomes of global assessment, function, and quality of life were compared using GEE, duration of pain relief by t-test, and adverse events by chi-square test.
In total, 54 patients with 60 painful TKA were randomized, with main analyses restricted to one TKA per patient (49 TKA in 49 patients). Mean age was 67 years, 84% were men, and mean duration of TKA pain was 4.5 years. A significantly greater proportion of patients (71%) in the IA-BoNT/Agroup compared to IA-placebo (35%) achieved clinically meaningful reduction in VAS pain at 2 months (p = 0.028) and at all efficacy timepoints (p = 0.019). Duration of meaningful pain relief was significantly greater after IA-BoNT/A, 39.6 days (SD 50.4) compared to IA-placebo, 15.7 days (SD 22.6; p = 0.045). Statistically significantly better scores were seen in IA-BoNT/A vs IA-place-bo for all efficacy timepoints for the following outcomes: “very much improved” on physician global assessment of change (p = 0.003); Western Ontario McMaster Osteoarthritis Index physical function (p = 0.026), stiffness (p = 0.004), and total scores (p = 0.024); and Short-Form 36 pain subscale score (p = 0.049). Number of total and serious adverse events was similar between groups, with no patients in either group with new objective motor or sensory deficits during followup.
In this single-center randomized trial, single IA-BoNT/A injection provided clinically meaningful short-term improvements in pain, global assessment, and function in patients with chronic painful TKA. A multicenter trial is needed to confirm these findings.
PMCID: PMC3018709  PMID: 20810509
19.  Hypertonic Dextrose Injections (Prolotherapy) for Knee Osteoarthritis: Results of a Single-Arm Uncontrolled Study with 1-Year Follow-Up 
The objective of this study was to determine whether prolotherapy, an injection-based complementary treatment for chronic musculoskeletal conditions, improves pain, stiffness, and function in adults with symptomatic knee osteoarthritis (KOA) compared to baseline status.
This was a prospective, uncontrolled study with 1-year follow-up.
The study was conducted in an outpatient setting.
Adults with at least 3 months of symptomatic KOA, recruited from clinical and community settings, participated in the study.
Participants received extra-articular injections of 15% dextrose and intra-articular prolotherapy injections of 25% dextrose at 1, 5, and 9 weeks, with as-needed treatments at weeks 13 and 17.
Outcome measures
Primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). Secondary outcome measure was the validated Knee Pain Scale (KPS). Tertiary outcome measure was procedure-related pain severity and participant satisfaction.
Thirty-six (36) participants (60±8.7 years old, 21 female) with moderate-to-severe KOA received an average of 4.3±0.7 prolotherapy injection sessions over a 17-week treatment period and reported progressively improved scores during the 52-week study on WOMAC and KPS measures. Participants reported overall WOMAC score improvement 4 weeks after the first injection session (7.6±2.4 points, 17.2%), and continued to improve through the 52-week follow-up (15.9±2.5 points, p<0.001, 36.1%). KPS scores improved in both injected (p<0.001) and uninjected knees (p<0.05). Prescribed low-dose opioid analgesia effectively treated procedure-related pain. Satisfaction was high and there were no adverse events. Female gender, age 46–65 years old, and body–mass index of 25 kg/m2 or less were associated with greater improvement on the WOMAC instrument.
In adults with moderate to severe KOA, dextrose prolotherapy may result in safe, significant, sustained improvement of knee pain, function, and stiffness scores. Randomized multidisciplinary effectiveness trials including evaluation of potential disease modification are warranted to further assess the effects of prolotherapy for KOA.
PMCID: PMC3326267  PMID: 22515800
20.  Arthroscopic Lavage and Debridement for Osteoarthritis of the Knee 
Executive Summary
The purpose of this review was to determine the effectiveness and adverse effects of arthroscopic lavage and debridement, with or without lavage, in the treatment of symptoms of osteoarthritis (OA) of the knee, and to conduct an economic analysis if evidence for effectiveness can be established.
Questions Asked
Does arthroscopic lavage improve motor function and pain associated with OA of the knee?
Does arthroscopic debridement improve motor function and pain associated with OA of the knee?
If evidence for effectiveness can be established, what is the duration of effect?
What are the adverse effects of these procedures?
What are the economic considerations if evidence for effectiveness can be established?
Clinical Need
Osteoarthritis, the most common rheumatologic musculoskeletal disorder, affects about 10% of the Canadian adult population. Although the natural history of OA is not known, it is a degenerative condition that affects the bone cartilage in the joint. It can be diagnosed at earlier ages, particularly within the sports injuries population, though the prevalence of non-injury-related OA increases with increasing age and varies with gender, with women being twice as likely as men to be diagnosed with this condition. Thus, with an aging population, the impact of OA on the health care system is expected to be considerable.
Treatments for OA of the knee include conservative or nonpharmacological therapy, like physiotherapy, weight management and exercise; and more generally, intra-articular injections, arthroscopic surgery and knee replacement surgery. Whereas knee replacement surgery is considered an end-of-line intervention, the less invasive surgical procedures of lavage or debridement may be recommended for earlier and more severe disease. Both arthroscopic lavage and debridement are generally indicated in patients with knee joint pain, with or without mechanical problems, that are refractory to medical therapy. The clinical utility of these procedures is unclear, hence, the assessment of their effectiveness in this review.
Lavage and Debridement
Arthroscopic lavage involves the visually guided introduction of saline solution into the knee joint and removal of fluid, with the intent of extracting any excess fluids and loose bodies that may be in the knee joint. Debridement, in comparison, may include the introduction of saline into the joint, in addition to the smoothening of bone surface without any further intervention (less invasive forms of debridement), or the addition of more invasive procedures such as abrasion, partial or full meniscectomy, synovectomy, or osteotomy (referred to as debridement in combination with meniscectomy or other procedures). The focus of this health technology assessment is on the effectiveness of lavage, and debridement (with or without meniscal tear resection).
Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment.
The keywords searched were: arthroscopy, debridement, lavage, wound irrigation, or curettage; arthritis, rheumatoid, osteoarthritis; osteoarthritis, knee; knee or knee joint.
Time frame: Only 2 previous health technology assessments were identified, one of which was an update of the other, and included 3 of 4 randomized controlled trials (RCTs) from the first report. Therefore, the search period for inclusion of studies in this assessment was January 1, 1995 to April 24, 2005.
Excluded were: case reports, comments, editorials, and letters. Identified were 335 references, including previously published health technology assessments, and 5 articles located through a manual search of references from published articles and health technology assessments. These were examined against the criteria, as described below, which resulted in the inclusion of 1 health technology assessment and its corresponding update, and 4 articles (2 RCTs and 2 level 4 studies) for arthroscopic lavage and 8 papers (2 RCTs and 6 level 4 studies) for arthroscopic debridement.
Inclusion Criteria
English-language articles from PubMed, EMBASE, Cochrane Systematic Reviews, and health technology assessments from January 1, 1995 onward
Studies on OA of the knee with a focus on the outcomes of motor function and pain
Studies of arthroscopic procedures only
Studies in which meniscal tear resection/meniscectomy (partial or full) has been conducted in conjunction with lavage or debridement.
Exclusion Criteria
Studies that focus on inflammatory OA, joint tuberculosis, septic joints, psoriatic joints (e.g., psoriatic knee joint synovitis), synovitis, chondropathy of the knee and gonarthrosis (which includes varotic gonarthrosis)
Studies that focus on rheumatoid arthritis
Studies that focus on meniscal tears from an acute injury (e.g., sports injury)
Studies that are based on lavage or debridement for microfracture of the knee
Studies in which other surgical procedures (e.g., high tibial osteotomy, synovectomy, have been conducted in addition to lavage/debridement)
Studies based on malalignment of the knee (e.g., varus/valgus arthritic conditions).
Studies that compare lavage to lavage plus drug therapy
Studies on procedures that are not arthroscopic (i.e., visually guided) (e.g., nonarthroscopic lavage)
Studies of OA in children.
Arthroscopic lavage or debridement, with or without meniscectomy, for the treatment of motor function symptoms and pain associated with OA of the knee.
Studies in which there was a comparison group of either diseased or healthy subjects or one in which subjects were their own control were included. Comparisons to other treatments included placebo (or sham) arthroscopy. Sham arthroscopy involved making small incisions and manipulating the knee, without the insertion of instruments.
Summary of Findings
In early OA of the knee with pain refractory to medical treatment, there is level 1b evidence that:
Arthroscopic lavage gives rise to a statistically significant, but not clinically meaningful effect in improving pain (WOMAC pain and VAS pain) up to 12 months following surgery. The effect on joint function (WOMAC function) and the primary outcome (WOMAC aggregate) was neither statistically nor clinically significant.
In moderate or severe OA of the knee with pain refractory to medical treatment, there is:
Level 1b evidence that the effect on pain and function of arthroscopic lavage (10 L saline) and debridement (with 10 L saline lavage) is not statistically significant up to 24 months following surgery.
Level 2 evidence that arthroscopic debridement (with 3 L saline lavage) is effective in the control of pain in severe OA of the medial femoral condyle for up to 5 years.
For debridement in combination with meniscectomy, there is level 4 evidence that the procedure, as appropriate, might be effective in earlier stages, unicompartmental disease, shorter symptom duration, sudden onset of mechanical symptoms, and preoperative full range of motion. However, as these findings are derived from very poor quality evidence, the identification of subsets of patients that may benefit from this procedure requires further testing.
In patients with pain due to a meniscal tear, of the medial compartment in particular, repair of the meniscus results in better pain control at 2 years following surgery than if the pain is attributable to other causes. There is insufficient evidence to comment on the effectiveness of lateral meniscus repair on pain control.
Arthroscopic debridement of the knee has thus far only been found to be effective for medial compartmental OA. All other indications should be reviewed with a view to reducing arthroscopic debridement as an effective therapy.
Arthroscopic lavage of the knee is not indicated for any stage of OA.
There is very poor quality evidence on the effectiveness of debridement with partial meniscectomy in the case of meniscal tears in OA of the knee.
PMCID: PMC3382413  PMID: 23074463
21.  Total Knee Replacement 
Executive Summary
The aim of this review was to assess the effectiveness, in terms of pain reduction and functional improvement, and costing of total knee replacement (TKR) for people with osteoarthritis for whom less invasive treatments (such as physiotherapy, analgesics, anti-inflammatory drugs, intra-articular steroids, hyaluronic acids, and arthroscopic surgery) have failed.
Clinical Need
Osteoarthritis affects an estimated 10% to 12% of Canadian adults. The therapeutic goals of osteoarthritis treatment are to improve joint mobility and reduce pain. Stepwise treatment options include exercise, weight loss, physiotherapy, analgesics, anti-inflammatory drugs, intra-articular steroids and hyaluronic acids, arthroscopic surgery, and, in severe cases, total joint replacement with follow-up rehabilitation. These treatments are delivered by a range of health care professionals, including physiotherapists, occupational therapists, family physicians, internists, rheumatologists, and orthopedic surgeons. TKR is an end-of-line treatment for patients with severe pain and functional limitations. More women than men undergo knee replacement, and most patients are between 55 and 84 years old.
The Technology
TKR is a surgical procedure in which an artificial joint or prosthesis replaces a damaged knee joint. The primary indication for TKR is pain, followed by functional limitation. Usually, a person’s daily activities must be substantially affected by pain and functional limitations for him or her to be considered a candidate for TKR.
There are 3 different types of knee replacement prostheses. Non-constrained prostheses use the patient’s ligaments and muscles to provide the stability for the prosthesis. Semi-constrained prostheses provide some stability for the knee and do not rely entirely on the patient’s ligaments and muscles to provide the stability. Constrained prostheses are for patients whose ligaments and muscles are not able to provide stability for the knee prosthesis.
The most common risks and complications associated with TKR are deep venous thrombosis, infection, stiffness, loosening, and osteolysis. To prevent deep venous thrombosis, patients are treated with heparin prophylactically and/or given support stockings to wear. Patients are also given antibiotics for 24 hours after surgery to minimize the risk of infection. Stiffness is another associated complication. In most patients, it can be avoided by keeping the knee moving in the days and weeks following surgery.
The National Institutes of Health in the United States concluded that the indications for TKR should include the following: radiological evidence of joint damage, moderate to severe persistent pain that is not adequately relieved by nonsurgical management, and clinically significant functional limitation resulting in diminished quality of life.
Review Strategy
In March 2005, the following databases were searched: Cochrane Library International Agency for Health Technology Assessment (first quarter 2005), Cochrane Database of Systematic Reviews (first quarter 2005), Cochrane Central Register of Controlled Trials (first quarter 2005), MEDLINE (1966 to March 2005), MEDLINE In-Process and Other Non-indexed Citations (1966 to March 14, 2005), and EMBASE (1980 to 2005 week 9). The Medical Advisory Secretariat also searched Medscape on the Internet for recent reports on trials that were unpublished but that were presented at international conferences. In addition, the Web site Current Controlled Trials ( was searched for ongoing trials investigating TKR or unicompartmental knee replacement.
No studies were identified that compared TKR to an alternative treatment. Several studies have been reported that compare preoperative measurement scores on targeted measures of functioning and pain to postoperative measurement scores in patients undergoing various TKR procedures.
In order for the Medical Advisory Secretariat to measure the effectiveness of TKR and to compare the effectiveness of TKR across studies, effect sizes were calculated in studies that reported the standard deviations of the preoperative and postoperative measurement scores. Percent change was also calculated. For this review, a 20% improvement in outcome score was defined as the minimal clinically important difference.
Summary of Findings
Overall, patients who undergo TKR surgery for osteoarthritis have substantial improvements in terms of reduction of pain and improvement of function. A comparison of the mean effect score and the percent change in 19 studies that reported preoperative and postoperative outcome scores for patients who had TKR showed that the procedure is effective. The 19 studies included patients of various ages and used a variety of prostheses and techniques to implant the device. TKR was effective in all of the studies. The revision rates ranged from 0% to 13% in the studies that reported at least 5 years of follow-up.
As for the factors that predict TKR outcomes, a variety of factors have been evaluated, including obesity, age, gender, prosthesis design, and surgical techniques; however, none of these have been shown to predict outcomes (pain or function) consistently across studies. However, the regression analyses identified accounted for only 12% to 27% of the variance, indicating that over 70% of the variance in the outcomes of TKR is unexplained.
In terms of the timing of TKR surgery, 2 studies found that the severity of osteoarthritis does not predict outcome, but 1 study was found that higher functioning patients had significantly less pain and better function up to 2 years after surgery compared with lower functioning patients. It is important to note that the patients in the low and high function groups were evenly matched on comorbid conditions.
Unicompartmental knee replacement surgery seems to be as effective as TKR surgery for people who meet the indications for it. This is a subset of people who have osteoarthritis of the knee, because for unicompartmental knee replacement to be indicated, only 1 (usually the medial) compartment of the knee can be affected. Patients who undergo this kind of surgery seem to have shorter hospital stays and faster recovery times than do patients who have TKR surgery.
There is substantial evidence to indicate that TKR effectively reduces pain and improves function.
PMCID: PMC3382388  PMID: 23074478
22.  Intra-Articular Viscosupplementation With Hylan G-F 20 To Treat Osteoarthritis of the Knee 
Executive Summary
To assess the effectiveness and cost-effectiveness of hylan G-F 20 as a substitute for existing treatments for pain due to osteoarthritis (OA) of the knee, other viscosupplementation devices, and/or as an adjunct to conventional therapy.
Hylan G-F 20 (brand name Synvisc, which is manufactured by Genzyme) is a high molecular weight derivative of hyaluronan, a component of joint synovial fluid. It acts as a lubricant and shock absorber. It is administered by injection into the joint space to treat pain associated with OA of the knee. Although the injection procedure is an insured service in Ontario, the device, hylan G-F 20, is not.
Clinical Need
Osteoarthritis is prevalent in 10% to 12% of Ontario adults, and exceeds 40% in Ontario residents aged 65 years and older. About one-half of these people have mild, moderate, or severe OA of the knee. Conventional treatment involves a combination of nonpharmacological management (e.g., weight loss, exercise, social support, and patient education), drugs, (e.g., acetaminophen, COX-2 inhibitors, nonsteroidal anti-inflammatory drugs with/without misoprostol, intra-articular glucocorticoids, opioids, and topical analgesics) and surgical interventions, such as debridement and total knee replacement, when pharmacological management fails.
The growing burden of OA of the knee in the aging Ontario population combined with recent safety concerns about COX-2 inhibitors and long wait times for total joint replacement is placing pressure on the demand for new, effective technologies to manage the pain of OA.
The Technology
Hylan G-F 20 is derived from rooster comb hyaluronan (HA). At the time of writing, eight viscosupplement hyaluronic products are licensed in Canada. Hylan G-F 20 is distinguished from the other products by its chemical structure (i.e., cross-linked hyaluronan, hence hylan) and relatively higher molecular weight, which may bestow greater therapeutic viscoelastic properties. A complete treatment cycle of hylan G-F 20 involves an intra-articular injection of 2 ml of hylan G-F 20 once a week for 3 weeks. It is licensed for use for patients in all stages of joint pathology, but should not be used in infected or severely inflamed joints, in joints with large effusion, in patients that have skin diseases or infections in the area of the injection site, or in patients with venous stasis. It is also contraindicated in patients with hypersensitivities to avian proteins.
Review Strategy
The Medical Advisory Secretariat used its standard search protocol to review the literature for evidence on the effectiveness of intra-articular hylan G-F 20 compared with placebo, as a substitute for alternate active treatments, or as an adjunct to conventional care for treatment of the pain of OA of the knee. All English-language journal articles and reviews with clearly described designs and methods (i.e., those sufficient to assign a Jadad score to) published or released between 1966 and February 2005 were included. Two more recently published meta-analyses were also included. The databases searched were Ovid MEDLINE, EMBASE, the Cochrane database and leading international organizations for health technology assessments, including the International Network of Agencies for Health Technology Assessments. The search terms were as follows: hyaluronan, hyaluronate adj sodium, hylan, hylan G-F 20 (Synvisc), Synvisc, Hyalgan, Orthovisc, Supartz, Artz, Artzal, BioHY, NASHA, NRD101, viscosupplementation, osteoarthritis, knee, knee joint. The primary outcome of interest was a clinically significant difference, defined as greater than 10 mm on 100 mm visual analogue scale, or a change from baseline of more than 20% in the mean magnitude of pain relief experienced among patients treated with hylan G-F 20 compared with those treated with the control intervention.
One clinical epidemiologist reviewed the full-text reports and extracted data using an extraction form. Key variables included, but were not limited to, the characteristics of the patients, method of randomization, type of control intervention, outcome measures for effectiveness and safety, and length of follow-up. The quality of the studies and level of the evidence was initially scored by one clinical epidemiologist using the Jadad scale and GRADE approach. Level of quality depends on the amount of certainty about the magnitude of effect and is based on study designs, extent of methodological limitations, consistency of results and applicability (i.e. directness) to the Ontario clinical context. The GRADE approach also permits comment on the strength of recommendations resulting from the evidence, based on estimates of the magnitude of effect relative to the magnitude of risk and burden and the level of certainty around these estimates. The quality assessments were subsequently peer-reviewed.
Summary of Findings
The literature search revealed 2 previous health technology assessments, 3 meta-analyses of placebo-controlled trials, 1 Cochrane review and meta-analysis encompassing 18 randomized controlled trials (RCTs) that compared hylan G-F 20 to either placebo or active treatments, 11 RCTs of hylan G-F 20 (all included in the Cochrane review), and 10 observational studies. Given the preponderance of evidence, the Medical Advisory Secretariat’s analysis focused on studies with Level 1 evidence of effectiveness (i.e., the meta-analyses of RCTs and the RCTs). Only safety data from the observational studies were included.
The authors of the 2 health technology assessments concluded that the data were sparse and poor quality. There was some evidence that hylan G-F 20 delivered a small, clinical benefit at 3 to 6 months after treatment on a magnitude comparable to NSAIDs and intra-articular steroids. Hylan G-F 20 appeared to carry a risk of a local adverse reaction of in the range of 3% to 18% per 100 injections, but there was no apparent risk of a severe adverse event, although the data were limited.
Each of the 3 meta-analyses of placebo-controlled trials of intra-articular hyaluronans had only 3 trials involving hylan G-F 20. There results were inconsistent, with one study concluding that intra-articular hyaluronans were efficacious, whereas the 2 other analyses concluded the effect size was small (0.32) and probably not clinically significant. The risk of a minor adverse event ranged from 8% to 19% per 100 injections. Major adverse events were rare.
The authors of the Cochrane review concluded that a pooled analysis supported the efficacy of hyaluronans, including hylan G-F 20. The 5- to 13-week post-injection period showed an improvement from baseline of 11% to 54% for pain and 9% to 15% for function. Comparable efficacy was noted against NSAIDs, and longer-term benefits were noted in against steroids. Few adverse events were noted.
When the Medical Advisory Secretariat applied the criterion of clinical significance to the magnitude of pain relief reported in the RCTs on hylan G-F 20, the following was noted:
There was inconsistent evidence that hylan G-F 20 was clinically superior to placebo at 5 to 26 weeks after treatment.
There was consistent evidence that, in terms of delivering pain relief, hylan G-F 20 was no better or worse than NSAIDs or intra-articular steroids at 5 to 26 weeks after treatment.
There was consistent evidence that hylan G-F 20 was not clinically superior to other hyaluronic products.
There was consistent evidence that hylan G-F 20 delivered a small magnitude of clinical benefit at 12 to 52 weeks post-injection when administered as an adjunct to conventional care.
There were limitations to the methods in many of the RCTs involving hylan G-F 20. When only the results from the higher-quality studies were considered, there was level 2 evidence that hylan G-F 20 was not clinically superior to placebo (or another hyaluronan) at 1 to 26 weeks after treatment in older patients with advanced disease for whom total knee replacement was indicated. There was level 2 evidence that hylan G-F 2- was comparable to NSAIDs at 4 to 13 weeks after treatment, and level 2 evidence that hylan G-F 20 was superior to placebo as an adjunct to conventional care 4 to 26 weeks after treatment.
With respect to safety, overall, hylan G-F 20 carries a risk of a minor, local adverse event rate of about 8% to 19% per 100 injections. Incidents of moderate-severe post-injection inflammatory joint reactions have been reported, but the likelihood appears to be low (0.15% of patients).
Economic Analysis
Case-costing estimates suggest that the annual cost of 2 treatment cycles of hylan G-F 20 (plus analgesics for breakthrough pain) is almost equivalent to the annual cost of taking a NSAID (with a gastroprotective agent) and is more expensive that taking intra-articular corticosteroids (plus analgesics for breakthrough pain). The estimated cost of funding hylan G-F 20 as an adjunct to conventional therapy (i.e., any of analgesics, NSAIDs, intra-articular steroids, physiotherapy, and surgery) is $700 per patient per year. Given the huge burden of mild to moderate OA among adults who seek medical care for it in Ontario (about 300,000), funding hylan G-F 20 as an adjunct to existing treatment could be expensive, depending on its diffusion and uptake. If only 10% to 30% of patients choose this option, then the estimated budget impact would be $21 million to $63 million (Cdn) per year.
When the benefits relative to the risks and costs are considered, NSAIDs and hylan G-F 20 appear comparable, as the table shows. Consequently, there’s little evidence on which to recommend hylan G-F 20 over NSAIDs, except perhaps for patients who cannot tolerate NSAIDs, although this evidence is indirect, since no studies looked specifically at this population.
CC indicates conventional care; IA, intra-articular; NSAID, nonsteroidal anti-inflammatory drug.
Intra-articular steroids appear to deliver the same risks and clinical benefits as hylan G-F 20 at a lower cost; therefore, there’s evidence that intra-articular steroids are the preferred option. Hylan G-F 20 as an adjunct to conventional care appears to deliver some clinical benefit, although funding hylan G-F 20 as an adjunct would have considerable budget impact, so the benefits of this option do not clearly outweigh the costs. There’s some uncertainty about the effect of hylan G-F 20 relative to other hyaluronans, mostly because some of the trials of this comparison were not published.
Many of the studies of hylan G-F 20 have considerable methodological limitations that result in uncertainty about the magnitude of effect. An upcoming review of the evidence by the Osteoarthritis Advisory Panel of clinical experts will likely help to reduce some of this uncertainty.
There is moderate evidence that hylan G-F 20 is no more clinically effective than NSAIDs. The evidence that hylan G-F 20 might be an appropriate option for a person with OA of the knee who cannot tolerate NSAIDs is indirect. The possible benefit of fewer cases of NSAID-induced gastropathy in this population must be weighed against the uncertainty of a severe inflammatory adverse reaction to hylan G-F 20.
Similarly, there is moderate evidence that hylan G-F 20 is no more clinically effective than intra-articular corticosteroids. The lower cost of intra-articular corticosteroids makes them the preferred option.
There is moderate evidence that hylan G-F 20 is effective as an adjunct to conventional care, delivering a small magnitude of temporary relief at 4 to 26 weeks after treatment. The estimated additional cost to the system of providing hylan G-F 20 as an adjunct to conventional care is about $700 (Cdn) per patient annually. The magnitude and duration of clinical benefit of hylan G-F 20 must be weighed against the uncertainty and potential magnitude of the budget impact (about $35 million to $105 million (Cdn) per year) of funding this device given the high burden of OA in Ontario adults.
There is level 2 evidence that hylan G-F 20 is not effective in people with advanced OA for whom total knee replacement is indicated.
PMCID: PMC3382385  PMID: 23074461
23.  Osteoarthritis of the knee 
BMJ Clinical Evidence  2007;2007:1121.
Osteoarthritis of the knee affects about 10% of adults aged over 60 years, with risk increased in those with obesity, and joint damage or abnormalities. Progression of disease on x rays is commonplace, but x ray changes don’t correlate well with clinical symptoms.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-surgical treatments for osteoarthritis of the knee? What are the effects of surgical treatments for osteoarthritis of the knee? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, capsaicin, chondroitin, education to aid self-management, exercise and physiotherapy, glucosamine, insoles, intra-articular corticosteroids, intra-articular hyaluronan, joint bracing, knee replacement, non-steroidal anti-inflammatory drugs (including topical non-steroidal anti-inflammatory drugs), opioid analgesics, osteotomy, simple analgesics, and taping.
Key Points
Osteoarthritis of the knee affects about 10% of adults aged over 60 years, with risk increased in those with obesity, and joint damage or abnormalities. Progression of disease on x rays is commonplace, but x ray changes don't correlate well with clinical symptoms.We don't know the long-term effectiveness of any non-surgical treatment in reducing pain and improving function.
Exercise and physiotherapy and joint bracing or taping reduce pain and disability in people with knee osteoarthritis, but we don't know whether patient education or insoles are beneficial.
Oral and topical NSAIDs reduce pain in the short term compared with placebo, but can cause gastrointestinal, renal and cardiac adverse effects. Paracetamol reduces pain in the short term compared with placebo, but may be less effective than NSAIDs. Opioid analgesics reduce pain in knee osteoarthritis but they are associated with serious adverse effects so are not rcommended for first-line treatment.
Intra-articular corticosteroids and intra-articular hyaluronan may improve pain, although most studies are of poor quality. We don't know whether acupuncture, capsaicin, glucosamine, or oral or intramuscularchondroitin improve symptoms in knee osteoarthritis.
Consensus is that total knee replacement is the most clinically effective treatment for severe osteoarthritis of the knee. Unicompartmental knee replacement may be more effective than tricompartmental knee replacement in the long term.Tibial osteotomy may be as effective as unicompartmental knee replacement in reducing symptoms of medial compartment knee osteoarthritis.
PMCID: PMC2943785  PMID: 19450299
24.  Workplace policies and prevalence of knee osteoarthritis: the Johnston County Osteoarthritis Project 
Previous studies on work and knee osteoarthritis (KOA) have been primarily focused on physical demands; very little is known about work-related organisational policies and KOA risks and outcomes. We examined the associations between workplace policies and KOA in a community-based population in the USA.
The associations between employment offering accommodations (switch to physically less demanding jobs; part-time work for people needing reduced time) and benefits policies (paid sick leave; disability payment) with KOA outcomes (knee symptoms; symptomatic KOA [sKOA]; asymptomatic radiographic KOA [rKOA]) were analysed in participants (n = 1639) aged <65 years old and with completed employment histories and knee radiographs at baseline examination of the Johnston County Osteoarthritis Project. Multiple logistic regression models were used to estimate the prevalence odds ratios (ORs) of KOA associated with each workplace policy, adjusting for sociodemographic features, lifestyle factors, knee injuries, body mass index and other workplace characteristics. We used propensity score models to evaluate the differential selection in employment offering favourable policies and adjust for this potential bias accordingly.
Individuals employed in workplaces offering better policies had significantly less knee symptoms. Lower sKOA prevalence was noted in workplaces offering job-switch accommodation (8% vs. 13%), paid sick leave (9% vs. 16%) and disability payment (8% vs. 16%) than their counterparts. In multivariable models, the difference in sKOA prevalence was statistically significant for paid sick leave (adjusted OR 0.58, 95% CI 0.37 to 0.91) and disability payment policies (adjusted OR 0.54, 95% CI 0.35 to 0.85). Even among those without overt knee-related symptoms, a similar pattern of negative association between workplace policies and rKOA was present and remained robust after propensity score adjustment.
The negative associations between KOA and workplace policies raise concerns about possible employment discrimination or beneficial effects of workplace policies. Longitudinal studies are needed to clarify the dynamic complexities of KOA risks and outcomes in relation to workplace policies.
PMCID: PMC2095393  PMID: 17567725
25.  Workplace policies and prevalence of knee osteoarthritis: the Johnston County Osteoarthritis Project 
Previous studies on work and knee osteoarthritis (KOA) have been primarily focused on physical demands; very little is known about work-related organisational policies and KOA risks and outcomes. We examined the associations between workplace policies and KOA in a community-based population in the USA.
The associations between employment offering accommodations (switch to physically less demanding jobs; part-time work for people needing reduced time) and benefits policies (paid sick leave; disability payment) with KOA outcomes (knee symptoms; symptomatic KOA [sKOA]; asymptomatic radiographic KOA [rKOA]) were analysed in participants (n = 1639) aged <65 years old and with completed employment histories and knee radiographs at baseline examination of the Johnston County Osteoarthritis Project. Multiple logistic regression models were used to estimate the prevalence odds ratios (ORs) of KOA associated with each workplace policy, adjusting for sociodemographic features, lifestyle factors, knee injuries, body mass index and other workplace characteristics. We used propensity score models to evaluate the differential selection in employment offering favourable policies and adjust for this potential bias accordingly.
Individuals employed in workplaces offering better policies had significantly less knee symptoms. Lower sKOA prevalence was noted in workplaces offering job-switch accommodation (8% vs. 13%), paid sick leave (9% vs. 16%) and disability payment (8% vs. 16%) than their counterparts. In multivariable models, the difference in sKOA prevalence was statistically significant for paid sick leave (adjusted OR 0.58, 95% CI 0.37 to 0.91) and disability payment policies (adjusted OR 0.54, 95% CI 0.35 to 0.85). Even among those without overt knee-related symptoms, a similar pattern of negative association between workplace policies and rKOA was present and remained robust after propensity score adjustment.
The negative associations between KOA and workplace policies raise concerns about possible employment discrimination or beneficial effects of workplace policies. Longitudinal studies are needed to clarify the dynamic complexities of KOA risks and outcomes in relation to workplace policies.
PMCID: PMC2095393  PMID: 17567725

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