Osteoarthritis and Cartilage 25 (2017) 1969e1979
A walking program for people with severe knee osteoarthritis did not
reduce pain but may have benefits for cardiovascular health: a phase II
randomised controlled trial
J.A. Wallis y z *, K.E. Webster y, P. Levinger x, P.J. Singh k, C. Fong ¶, N.F. Taylor y z
y School of Allied Health, La Trobe University, Australia
z Department of Physiotherapy, Eastern Health, Australia
x Institute of Sport, Exercise & Active Living (ISEAL), Victoria University, Australia
k Department of Orthopaedics, Eastern Health, Monash and Deakin University, Australia
¶ Department of Rheumatology, Eastern Health, Monash University, Australia
a r t i c l e i n f o
s u m m a r y
Article history:
Received 31 August 2016
Accepted 14 December 2016
Objective: The primary aim was to evaluate the effect of a dosed walking program on knee pain for
patients with severe knee osteoarthritis (OA). Secondary aims evaluated the effects on cardiovascular
health, function and quality of life.
Design: Participants with severe knee OA and increased cardiovascular risk were randomly assigned to a
12-week walking program of 70 min/week of at least moderate intensity, or to usual care. The primary
outcome was knee pain (0e10). Secondary outcomes were of cardiovascular risk including physical
activity, blood pressure, blood lipid and glucose levels, body mass index and waist circumference;
WOMAC Index scores; physical function; and quality of life.
Results: Forty-six participants (23 each group) were recruited. Sixteen participants (70%) adhered to the
walking program. Intention to treat analysis showed no between-group difference in knee pain. The
walking group had increased odds of achieving a healthy systolic blood pressure (OR ¼ 5.7, 95% CI 1.2
e26.9), and a faster walking speed (Mean Difference (MD) ¼ 0.12 m/s, 95% CI 0.02e0.23). Per protocol
analysis based on participant adherence showed the walking group had more daily steps (MD ¼ 1345
steps, 95% CI 365e2325); more time walking (MD ¼ 18 min/day, 95% CI 5e31); reduced waist circumference (MD ¼ 5.3 cm, 95% CI 10.5 to 0.03); and increased knee stiffness (MD ¼ 0.9 units, 95% CI 0.07
e1.8).
Conclusions: Patients with severe knee OA prescribed a 12-week walking program of 70 min/week may
have had cardiovascular benefits without decreasing knee pain.
Australian New Zealand Clinical Trials Registry ACTRN12615000015549.
© 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords:
Knee osteoarthritis
Physical activity
Cardiovascular health
Introduction
Osteoarthritis (OA) of the knee is a prevalent and debilitating
condition characterised by pain, and difficulty performing normal
daily activities such as walking, which can lead to psychological
distress, and reduced health-related quality of life1. As the majority
of people with knee OA do not meet sufficient levels of physical
* Address correspondence and reprint requests to: J.A. Wallis, Physiotherapy
Department, Eastern Health, Box Hill Hospital, 8 Arnold St, Box Hill, Victoria, 3128,
Australia. Fax: 61-3-9895-4852.
E-mail addresses: Jason.wallis@easternhealth.org.au, jasonwallis23@gmail.com
(J.A. Wallis).
activity2e4 they have high risk of morbidity and mortality from
cardiovascular causes5,6.
Increasing physical activity is therefore important for people
with OA due to their increased cardiovascular risk and low levels of
physical activity. Current physical activity guidelines suggest people with OA be as physically active as their abilities and condition
allows7. This creates uncertainty for health professionals as to how
much physical activity to prescribe for their patients. Also, the
strategy of waiting for total knee replacement for the management
of end stage knee OA may not address this important issue. Total
knee replacement has the potential to improve cardiovascular
health via improved physical activity, reduced use of antiinflammatory medication and reduced psychological distress8.
http://dx.doi.org/10.1016/j.joca.2016.12.017
1063-4584/© 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
1970
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
However, several studies have shown no increase in physical activity levels after knee replacement surgery9e12 and therefore even
after surgery patients may remain at increased risk of mortality
from cardiovascular causes5,6.
Walking programs are known to have beneficial effects on knee
pain and function for people with mild to moderate knee OA13. It is
not known whether patients with end stage knee OA and with
lower cardiovascular health would achieve the same benefits. A
phase I study found people in the community with severe knee OA
tolerated 70 min of walking over one week in sessions lasting at
least 10 min; for higher walking doses there was a risk of exacerbating knee pain14. However, the effects of this dose over a longer
period of time are not known. Therefore, the primary aim of this
phase II study was to evaluate the effect of a 12-week walking
program of 70 min per week on knee pain for people with severe
knee OA and cardiovascular risk, compared to usual care only. The
secondary aims were to evaluate the effects of the walking program on cardiovascular health, function and health-related quality
of life.
Methods
Study design
This was a phase II single-blind randomised controlled trial
design with an intervention group (walking program plus usual
care) and a control group (usual care only). Participants were
randomly assigned using a permuted block design with a computer random number generator using sealed opaque envelopes
prepared by an independent researcher with no role in recruitment or assessment. The health service and university ethics
committees approved this trial in accordance with the Helsinki
Declaration and all participants provided written informed consent. The trial was registered prospectively in the Australian New
Zealand Clinical Trials Registry http://www.ANZCTR.org.au/
ACTRN12615000015549.aspx.
Participants
Adults with severe OA of the knee and increased cardiovascular risk were recruited from a metropolitan health service's OA
hip and knee clinic between April and September 2015. The OA
hip and knee clinic assesses patients for eligibility for total knee
replacement. Patients who attended the service were invited to
participate provided they met the inclusion criteria: aged at least
50 years and living independently in the community; diagnosed
with severe knee OA rated as grade III or IV affecting at least one
of the tibiofemoral compartments determined radiographically15; a cardiovascular risk profile with 2 total risk factors
using stage 2 of the Adult Exercise Screening Tool16; able to
participate safely in the moderate-intensity physical activity trial
using stage 1 of the Adult Exercise Screening Tool16; able to
communicate in English.
Participants were excluded if they: lived in supported accommodation such as a nursing home; reported daily resting level of
pain to be 9 or 10 on a 0 (no pain) to 10 (worst possible pain)
Numerical Pain Rating Scale17 as this level of pain may be indicative
of a more serious pathology; had high levels of psychological
distress as measured by the Kessler 10 questionnaire with a K10
score >2918; had a cognitive impairment measured by the Short
Portable Mental Status Questionnaire with a score of 7 or less19;
had a systemic arthritic condition such as rheumatoid arthritis; had
a neurological condition that affected walking; had knee surgery or
intra-articular corticosteroid injection within past six months; had
used oral corticosteroids within 4 weeks.
Intervention
In addition to usual care, participants in the intervention group
were prescribed a walking dose of 70 min per week, of at least
moderate intensity, in bouts of at least 10 min. The weekly dose was
completed for 12 weeks in the community. The participant was
instructed to walk at a moderate level of intensity determined by
the Rate of Perceived Exertion Scale (0e10) where level 3 ¼ “I am
still comfortable but am breathing a little harder”20. No formal instructions on warming up or stretching were provided. The weekly
dose of 70 min was completed in the community; in separate
sessions provided each session was at least 10 min duration. Participants continued taking their usual medications and other nonsurgical treatments to manage their knee OA, and used normal
assistive devices such as a cane.
To increase the likelihood of adherence to the intervention, the
following behavioural change techniques and strategies were
used21. First, each participant had a planning session with a
physiotherapist of up to 30 min to plan the location, day and time
of day for each walk, and reinforce that each walk was moderate
intensity in at least a 10 min bout. Second, there was regular
physiotherapy supervision and monitoring each week, including
one-to-one supervised walking sessions or group supervised
walking sessions based on patient preference, and regular phone
calls or SMS reminders. Third, each participant wore a pedometer
and recorded the number of steps taken and time spent walking
during each session in a logbook. Fourth, participants were
encouraged to engage social supports such as walking with a
friend, family member or other research participants if they
chose to.
Control
Usual care was non-operative management to manage pain and
symptoms including pharmacological and non-pharmacological
interventions. Intervention and control participants were nonblinded to their group allocation. As part of the health service's
OA hip and knee clinic they may have been referred to an orthopaedic surgeon for surgical assessment and/or to a local health
service for conservative management. Participants and their health
professionals were advised with written information not to include
a prescription of physical activity in the 12-week study period. If
requested, the control group participants were provided with a
copy of the walking program that they could take to their health
professional to implement after the final assessment.
Primary outcome
The primary and secondary outcomes were collected at baseline
and post-intervention (week 13) by an assessor blinded to group
allocation.
The primary outcome was average knee pain over the previous
week measured by a valid and reliable Numerical Pain Rating Scale
pain with terminal descriptors 0 (no pain) and 10 (worst possible
pain)22.
Secondary outcomes included modifiable cardiovascular risk
factors of physical activity, blood pressure, body mass index, waist
circumference, and fasting blood lipid and glucose levels. Physical
activity was measured by continuous 24 h recording using
accelerometer-based activity monitors worn for 7-days at baseline
and post intervention (ActivPAL, PAL Technologies, Glasgow)23.
Physical activity measures included the daily number of steps, daily
minutes spent walking, weekly minutes spent walking at moderate
intensity cadence threshold of 80 steps/min24, weekly minutes
spent walking at moderate intensity cadence threshold of 80 steps/
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
1971
Analysed (n=22)
Excluded from analysis (n=1)
Incomplete data at baseline (n=3)
Declined blood tests (n=1)
LDL levels missing (n=2)
Incomplete data at week 13 (n=2)
Declined blood tests (n=2)
Fig. 1. Flow of participants through the trial.
min and at least 10 min of continuous bouts, and daily hours spent
sitting or lying. Resting systolic and diastolic blood pressure
(mmHg) was measured using an electronic blood pressure machine in sitting. Body mass index (kg/m2) and waist circumference
(cm) were measured using standard anthropometric methods25.
Fasting blood lipid levels (total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides (mmol/L)) and fasting
blood glucose level (mmol/L) were collected and reported by the
health service's pathology department or an external pathology
provider.
1972
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
Other secondary outcomes included pain, stiffness and activity
limitation using the Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC)26, performance-based measures of
function, and health-related quality of life. The WOMAC scale has a
5 item likert scale (none ¼ 0, mild ¼ 1, moderate ¼ 2, severe ¼ 3,
extreme ¼ 4) resulting in a pain score (0e20), stiffness score
(0e8), and activity limitation score (0e68) with higher scores
indicating worse function. Performance-based physical function
was measured using the 40 m fast paced walk test and the 30 s
chair stand test27,28. Health-related quality of life was measured by
self-report using the EuroQol (EQ-5D and EQ-VAS) questionnaire29. The EQ-5D is a standardised instrument for measuring
five domains of health-related quality of life providing a single
index of utility estimated using Australian weights29. The EQ-VAS
measures overall health state on a visual analogue scale from
0 (worst imaginable health state) to 100 (best imaginable health
state).
The following demographic factors were collected at baseline:
age, sex, occupation, presence of knee deformity, severity of knee
OA including the compartments affected, medication use, comorbidities such as cardiovascular disorders and smoking status. At
week 13, changes to analgesia use for knee OA, medication use for
cardiovascular health, visits to an orthopaedic specialist, allied
health professional or exercise group regarding their knee OA, and
time off work for those still working during the trial were
recorded.
Adherence
All participants assigned to the intervention group completed a
logbook to record the number of minutes spent walking and
number of steps using a pedometer for each walking session over
the 12 weeks. They also described any changes to their usual care
of their knee OA and any problems with their knee while doing
their walking program each week. The physiotherapist monitored
the participant's logbook at each weekly supervised walking
session.
Table I
Participant characteristics at baseline
Characteristic
Randomised (n ¼ 46)
Exp (n ¼ 23)
Con (n ¼ 23)
Age (yrs), mean (SD), range [minemax]
Sex, n (%) women
Employment, n (%)
Body mass index (kg/m2), mean (SD), range [minemax]
Cardiac risk factors (/7)#, mean (SD)
Kessler (/50), mean (SD)
OA (OA) score
n (%) grade IV
n (%) grade III
n (%) severe MRI
Unilateral or bilateral knee OA
n (%) unilateral OA
n (%) bilateral OA
Main tibiofemoral knee compartment affected by severe OA
n (%) medial
n (%) lateral
Presence of knee alignment deformity
n (%) varus ± fixed flexion
n (%) valgus ± fixed flexion
n (%) fixed flexion only
n (%) nil deformity
Regular daily pain medication use
n (%) Paracetemol and/or codeine
n (%) NSAIDs
n (%) Opioid
Non-regular pain medication use
n (%) Paracetemol and/or codeine
n (%) Non steroidal anti-inflammatory
n (%) Opioid
Regular cardiovascular medication use
n (%) Anti-cholesterol
n (%) Anti-diabetic
n (%) Anti-hypertension
n (%) Anti-arrhythmics
n (%) Anti-angina
n (%) Anti-coagulation
Other medications
n (%) Antidepressant
n (%) Urinary
n (%) Neurological
n (%) Gout
n (%) Gastrointestinal
n (%) Respiratory
n (%) Endocrine/thyroid
n (%) Sleep
n (%) Natural medicines
68 (8), [51e84]
9 (39)
7 (30)
34 (5), [24e45]
3.8 (1.2)
14.6 (5.0)
67 (7), [50e78]
11 (48)
4 (17)
34 (7), [22e53]
3.8 (0.9)
13.7 (4.9)
21 (91)
1 (4)
1 (4)
21 (91)
2 (9)
0 (0)
9 (39)
14 (61)
11 (48)
12 (52)
18 (78)
5 (22)
19 (83)
4 (17)
9
5
5
4
(39)
(22)
(22)
(18)
12 (52)
3 (13)
6 (26)
2 (9)
13 (57)
11 (48)
2 (9)
10 (43)
7 (30)
0 (0)
6 (26)
5 (22)
3 (13)
8 (35)
3 (13)
1 (4)
7 (30)
2 (9)
12 (52)
1 (4)
0 (0)
3 (13)
10 (43)
6 (26)
16 (70)
0 (0)
1 (4)
6 (26)
5
0
1
1
5
1
4
1
7
8
3
1
5
8
3
2
1
4
(22)
(0)
(4)
(4)
(22)
(4)
(17)
(4)
(30)
(35)
(13)
(4)
(22)
(35)
(13)
(9)
(4)
(17)
Exp ¼ experimental group: Con ¼ control group.
#Cardiac risk factors: smoker, hypertension, dyslipidaemia, obesity, low physical activity, family history of cardiac disease, impaired fasting glucose.
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
1973
markers of cardiovascular risk were measured using odds ratio
with logistic regression, adjusting for baseline data.
Adherence was measured as a percentage of weeks that participants completed 70 min ±10 min over 12 weeks. A per protocol
analysis was performed for participants who adhered to at least
75% of the walking program (i.e., completed at least 9 weeks of the
12 week walking program) using the same statistical methods as
for the intention to treat analysis. While the intention to treat
analysis classified participants according to the treatment to
which they were originally randomised and has primacy, in the
exploratory context of a phase II trial, the per-protocol analysis
conveys the effect if a participant adhered to the program and can
be used to generate new hypotheses32. The adhered group were
compared to the non-adhered group to test for any baseline differences using t-tests for continuous data or c2 for dichotomous
data.
Adverse events
A minor adverse event was defined as a short-term exacerbation
of a knee pain levels up to a week after the sessions, trips or falls
without any serious sequelae or hospital admission. A serious
adverse event was defined as a serious medical emergency such as
cardiac arrest or stroke.
Sample size
We aimed to recruit 44 participants (22 in each group allowing
for 10% drop out) providing 80% power of detecting a difference of
2.8 units for the primary outcome of pain, assuming SD of 3.0
units30, at a 5% significance level using a two-tailed test.
Data analysis
Results
Intention to treat analysis was performed as all participants
who were enrolled and randomly allocated were included in the
analysis and were analysed in the groups to which they were
randomised, regardless of adherence. Imputation methods were
not applied as these methods require strong assumptions31.
Analysis of covariance (ANCOVA) was performed using IBM SPSS
version 22 for all the primary and secondary outcome measures
with baseline measures as covariates. Standardised mean differences (SMD) (effect sizes) were calculated for all primary and
secondary outcomes. Proportions of participants with healthy
After screening, 46 participants (20 women, 26 men) aged
between 50 and 84 years met the selection criteria and were
randomly allocated (Fig. 1). Forty-two participants (91%) were
rated grade IV on the KellgreneLawrence scale and 26 (57%) had
severe bilateral knee OA. Thirty-four (74%) had hypertension, 27
(59%) had dyslipidaemia, 36 (78%) were classified as obese (body
mass index 30 kg/m2), 16 (35%) had impaired fasting glucose
level (>6.1 mmol/L), 12 (26%) were current smokers and 6 (13%)
Table II
Intention to treat analysis: mean (SD) of groups, mean (SD) difference within groups, and mean (95% CI, P-value) difference between groups
Outcome
Groups (mean, SD)
Week 0
NRPS pain (0e10)
Steps per day (n)
Time sit or lie per day (hours)
Time walking per day (mins)
Time walking >80 steps/min
per week (mins)
Time walking >80 steps/min in
>10 min bouts per week
(mins)
Waist circumference (cm)
Body mass index (kg/m2)
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
Fasting glucose (mmol/L)
Systolic blood pressure (mmHg)
Diastolic blood pressure
(mmHg)
WOMAC pain (0e20)
WOMAC stiffness (0e8)
WOMAC activity limitation (0
e68)
QOL EQ5D utility (0e1)
QOL EQVAS (0e100)
40 m walk test (m/s)
30s chair stand test (n)
Week 13
Difference within
groups (mean, SD)
Difference between groups^
(MD, 95% CI, P-value)
Week 13 minus Week 0
Week 13 minus Week 0#
Exp (n ¼ 23)
Con (n ¼ 23)
Exp (n ¼ 22)
Con (n ¼ 23)
Exp
Con
Exp minus Con
6.1 (1.9)
6376 (3107)
19 (1.7)
85 (40)
142 (109)
5.3 (1.6)
4989 (2174)
19 (1.7)
67 (28)
82 (52)
6.5 (1.2)
6537 (2816)
19 (1.7)
88 (36)
131 (105)
6.1 (1.7)
4422 (1827)
19 (2.3)
60 (22)
66 (53)
0.5 (1.6)
0.6 (1561)
0.1 (1.2)
0.6 (19)
17 (89)
0.9 (1.6)*
355 (1353)
0.3 (1.6)
4.8 (18)
8.0 (36)
0.04 (0.8 to 0.8, P ¼ 0.918)
784 (95 to 1664, P ¼ 0.079)
0.2 (1.1 to 0.7, P ¼ 0.634)
0.18 (0.003 to 0.37, P ¼ 0.054)
16 (29 to 60, P ¼ 0.481)
41 (65)
6 (16)
26 (35)
5 (12)
17 (50)
0.3 (16)
8.4 (6.3 to 23, P ¼ 0.254)
117 (14)
34 (5.2)
5.2 (1.1)
2.7 (1.0)
1.5 (0.7)
2.2 (1.5)
6.9 (2.8)
142 (10)
82 (10)
113 (14)
34 (7.4)
4.8 (1.1)
2.7 (1.0)
1.4 (0.4)
1.6 (0.6)
6.1 (1.2)
138 (24)
81 (11.1)
114 (12)
34 (5.4)
5.2 (1.5)
3.0 (1.2)
1.4 (0.5)
1.9 (1.0)
6.4 (1.9)
134 (13)
79 (10)
115 (17)
34 (7.3)
4.9 (1.3)
2.8 (1.2)
1.4 (0.4)
1.6 (0.6)
6.5 (1.9)
136 (21)
78 (13)
3.2 (9.4)
0.2 (0.5)
0.03 (1.2)
0.3 (0.9)
0.08 (0.7)
0.3 (1.3)
0.5 (1.9)
8.1 (12)*
3.4 (9)
1.5 (4.9)
0.0 (1.1)
0.02 (0.5)
0.01 (0.4)
0.00 (0.1)
0.03 (0.5)
0.4 (1.2)
2.5 (18)
2.4 (11)
4.3 (8.7 to 0.2, P ¼ 0.061)
0.2 (0.7 to 0.3, P ¼ 0.417)
0.04 (0.5 to 0.6, P ¼ 0.882)
0.3 (0.1 to 0.8, P ¼ 0.177)
0.05 (0.3 to 0.2, P ¼ 0.719)
0.02 (0.4 to 0.5, P ¼ 0.909)
0.6 (1.4 to 0.3, P ¼ 0.200)
4.0 (12 to 4.0, P ¼ 0.328)
0.5 (6.3 to 5.2, P ¼ 0.856)
11 (2.3)
4.7 (1.6)
37 (10)
8.8 (3.2)
4.4 (1.0)
34 (9)
11 (3.3)
4.9 (1.6)
38 (9)
9.7 (2.9)
4.0 (1.1)
34 (11)
0.5 (2.9)
0.0 (1.5)
0.6 (7.4)
0.9 (2.7)
0.3 (1.4)
0.0 (7.8)
0.3 (1.4 to 2.0, P ¼ 0.738)
0.7 (0.2 to 1.5, P ¼ 0.117)
1.5 (3.0 to 5.9, P ¼ 0.507)
0.54 (0.2)
63 (18)
1.3 (0.3)
8.2 (3.3)
0.64 (0.2)
60 (11)
1.2 (0.4)
8.5 (2.2)
0.63 (0.2)
63 (16)
1.3 (0.4)
9.2 (3.0)
0.62 (0.2)
62 (14)
1.1 (0.3)
8.9 (2.4)
0.07 (0.2)
0.05 (21)
0.03 (0.2)
1.0 (2.6)
0.03 (0.1)
1.5 (12)
0.07 (0.2)
0.4 (1.6)
0.05 (0.06 to 0.2, P ¼ 0.363)
0.2 (8.4 to 8.9, P ¼ 0.959)
0.1 (0.02e0.2, P ¼ 0.024)*
0.5 (0.6 to 1.7, P ¼ 0.350)
^Based on estimated marginal means from ANCOVA; Exp ¼ experimental group, Con ¼ control group; *P < 0.05.
#Data included for between group analyses where there was missing data.
Steps per day, time sit or lie per day, time walking per day
Time walking >80 steps/min and >80 steps/min in 10 min bouts
Total cholesterol, HDL, triglycerides
LDL
Fasting glucose
n
n
n
n
n
¼
¼
¼
¼
¼
22
21
20
18
20
exp,
exp,
exp,
exp,
exp,
n
n
n
n
n
¼
¼
¼
¼
¼
20
19
22
22
23
con
con
con
con
con
1974
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
CI 0.01e0.35). All other comparisons were not significant
(Supplementary Table I).
Three participants in the walking group had minor adverse
events; two reported increased knee pain and were not able
to continue the program after week 1, and one tripped during
a supervised walking session and had to seek medical management due to knee pain. This participant continued the
program following 2 days of rest. There were no serious adverse
events.
had previous cardiac surgery. On average, participants were taking
5 medications (range 1e9) and the most common cardiovascular
medication was antihypertensive medication used for 28 participants (61%). Twenty-three participants (50%) were taking regular
paracetemol to control their knee pain (Table I).
Baseline measures demonstrated similarity between the groups
based on sex, age, body mass index, cardiovascular risk factors,
severity of OA and compartments affected, health-related quality of
life and medication usage (Tables I and II). The walking group
appeared to be more physically active and perhaps have more pain
than the control group at baseline (Table II). Participants had
moderate to severe levels of pain at baseline (Table II).
Primary outcomes
There was no between-group difference in knee pain at week 13
for both the intention to treat analysis and the per protocol analysis
(Tables II and III).
Adherence and adverse events
Sixteen participants allocated to the walking group (70%)
completed at least 9 out of 12 of the weekly dose of 70 min. One
participant (4%) withdrew before starting the walking program
and was lost to follow up. Four participants (17%) discontinued due
to unrelated medical or family reasons after completing less than
four of the weeks. Two (9%) started but did not complete the first
week due to knee pain and were recorded as minor adverse events.
Comparison of adherers and non-adherers demonstrated that
non-adherers were more likely to be female than male (c2(1) ¼ 4.4,
P ¼ 0.036), and had poorer performance in the chair stand test
(Mean Difference (MD) ¼ 3.8 repetitions, 95% CI 1.1e6.5),
and lower levels of health-related quality of life (MD ¼ 0.18, 95%
Secondary outcomes
In the intention to treat analysis there were no significant
between-group differences for the secondary outcomes, except for
increased walking speed favouring the walking group
(MD ¼ 0.12 m/s, 95% CI 0.02e0.23) (Table II), and 5.7 times (95% CI
1.2e26.9) increased odds of lowering systolic blood pressure below
the healthy marker of 140 mmHg (Table IV).
In the per protocol analysis, the walking group were more
physically active than the control group following the intervention
completing 1345 more daily steps (95% CI 365e2325), 18 more daily
Table III
Per protocol analysis based on participant adherence: mean (SD) of groups, mean (SD) difference within groups, and mean (95% CI, P-value) difference between groups
Outcome
Groups (Mean, SD)
Week 0
NRPS pain (0e10)
Steps per day (n)
Time sit or lie per day (hours)
Time walking per day (mins)
Time walking >80 steps/min
per week (mins)
Time walking >80 steps/min in
>10 min bouts per week
(mins)
Waist circumference (cm)
Body mass index (kg/m2)
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
Fasting glucose (mmol/L)
Systolic blood pressure (mmHg)
Diastolic blood pressure
(mmHg)
WOMAC pain (0e20)
WOMAC stiffness (0e8)
WOMAC activity limitation (0
e68)
QOL EQ5D utility (0e1)
QOL EQVAS (0e100)
40 m walk test (m/s)
30s chair stand test (n)
Week 13
Difference within
groups (mean, SD)
Difference between groups^
(MD, 95% CI, P-value)
Week 13 minus Week 0
Week 13 minus Week 0#
Exp (n ¼ 16)
Con (n ¼ 23)
Exp (n ¼ 16)
Con (n ¼ 23)
Exp
Con
Exp minus Con
5.8 (1.8)
6972 (2677)
18 (1.7)
93 (35)
156 (101)
5.3 (1.6)
4989 (2174)
19 (1.7)
67 (28)
82 (52)
6.5 (1.1)
7304 (2380)
18 (1.7)
98 (32)
151 (105)
6.1 (1.7)
4422 (1827)
19 (2.3)
60 (22)
66 (53)
0.7 (1.5)
331 (1586)
0.0 (1.3)
4.8 (19)
5.1 (94.9)
0.9 (1.6)*
355 (1353)
0.3 (1.6)
4.8 (18)
8.0 (36.3)
0.1 (0.7 to 1.0, P ¼ 0.780)
1345 (365e2325, P ¼ 0.009)*
0.4 (1.4 to 0.6, P ¼ 0.442)
18.0 (5.4e30.6, P ¼ 0.006)*
31.1 (20.1 to 82.3, P ¼ 0.225)
44 (68)
6 (16)
28 (33)
5 (12)
16.0 (56.4)
0.34 (16.0)
13.1 (2.8 to 28.9, P ¼ 0.102)
119 (15)
35 (5.8)
5.0 (1.0)
2.5 (0.9)
1.5 (0.8)
2.2 (1.8)
7.3 (3.2)
140 (9)
83 (10)
113 (14)
34 (7.4)
4.8 (1.1)
2.7 (1.0)
1.4 (0.4)
1.6 (0.6)
6.1 (1.2)
138 (24)
81 (11)
115 (12)
35 (5.8)
4.8 (0.9)
2.7 (1.0)
1.3 (0.3)
1.8 (0.9)
6.7 (2.1)
132 (12)
79 (11)
115 (17)
34 (7.3)
4.9 (1.3)
2.8 (1.2)
1.4 (0.4)
1.6 (0.6)
6.5 (1.9)
136 (21)
78 (13)
4.4 (10.8)
0.3 (0.5)*
0.2 (0.8)
0.3 (0.7)
0.2 (0.8)
0.4 (1.5)
0.6 (2.2)
8.7 (13.5)*
3.4 (10)
1.5 (4.9)
0.0 (1.07)
0.02 (0.5)
0.01 (0.4)
0.0 (0.1)
0.03 (0.5)
0.4 (1.2)
2.5 (17.8)
2.4 (11)
5.3 (10.5 to 0.03, P ¼ 0.049)*
0.3 (0.9 to 0.3, P ¼ 0.319)
0.2 (0.7 to 0.3, P ¼ 0.376)
0.3 (0.1 to 0.6, P ¼ 0.191)
0.2 (0.4 to 0.06, P ¼ 0.149)
0.03 (0.5 to 0.4, P ¼ 0.901)
0.6 (1.6 to 0.5, P ¼ 0.283)
5.3 (14.7 to 4.0, P ¼ 0.256)
0.4 (7.1 to 6.3, P ¼ 0.905)
10.4 (1.7)
4.6 (1.2)
35 (8)
8.8 (3.2)
4.4 (1.0)
34 (9)
10.8 (3.3)
5.1 (1.6)
38 (7)
9.7 (2.9)
4.0 (1.1)
34 (11)
0.4 (3.2)
0.4 (1.5)
2.3 (6.0)
0.9 (2.7)
0.3 (1.4)
0.0 (7.8)
0.2 (1.6 to 2.1, P ¼ 0.797)
0.9 (0.07e1.8, P ¼ 0.034)*
2.5 (2.1 to 7.1, P ¼ 0.278)
0.59 (0.15)
65 (17)
1.4 (0.4)
9.4 (3.0)
0.64 (0.15)
60 (12)
1.2 (0.4)
8.5 (2.2)
0.63 (0.16)
63 (16)
1.4 (0.4)
10.2 (2.7)
0.62 (0.20)
62 (14)
1.1 (0.3)
8.9 (2.4)
0.03 (0.24)
2.3 (21.4)
0.07 (0.1)
0.8 (3.0)
0.03 (0.14)
1.5 (12.3)
0.07 (0.2)
0.35 (1.6)
0.03 (0.08 to 0.2, P ¼ 0.573)
0.8 (10.4 to 8.8, P ¼ 0.864)
0.2 (0.06e0.3, P ¼ 0.003)*
0.8 (0.5 to 2.2, P ¼ 0.232)
^Based on estimated marginal means from ANCOVA; Exp ¼ experimental group, Con ¼ control group, *P < 0.05.
#Data included for between group analyses where there was missing data.
Steps per day, time sit or lie per day, time walking per day
Time walking >80 steps/min and >80 steps/min in 10 min bouts
Total cholesterol, HDL, triglycerides
LDL
Fasting glucose
n
n
n
n
n
¼
¼
¼
¼
¼
16
16
15
13
15
exp,
exp,
exp,
exp,
exp,
n
n
n
n
n
¼
¼
¼
¼
¼
20
19
22
22
23
con
con
con
con
con
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
minutes walking (95% CI 5e31), had a greater reduction in waist
circumference of 5.3 cm (95% CI 10.5 to 0.03), increased walking
speed of 0.17 m/s (95% CI 0.06e0.28), increased knee stiffness using
the WOMAC stiffness subscale of 0.9 units (95% CI 0.07e1.8)
(Table III), and 10.3 times (95% CI 1.6e68.6) increased odds of
lowering systolic blood pressure below the healthy marker of
140 mmHg (Table V). Eleven of the secondary outcomes showed at
least a small effect (effect size greater than 0.2) favouring the
walking group (Fig. 2).
Additional outcomes
There were very few changes to analgesia use and cardiovascular medications in both groups. Few participants (n ¼ 3 walking
1975
group (14%), n ¼ 1 control group (4%)) consulted with a specialist
during the trial period. Similar numbers per group attended an
allied health professional or exercise sessions (n ¼ 9 walking
group (41%), n ¼ 8 control group (35%)) (Supplementary Table II).
Discussion
This randomised controlled trial showed no decrease in knee
pain levels following a 12-week moderate intensity walking program based on the maximal tolerated dose of 70 min per week
compared to usual care alone for people with severe knee OA and
increased cardiovascular risk. The prescribed dose may be sufficient
to improve cardiovascular health as participants from the walking
program increased their walking speed by 0.12 m/s and had almost
Table IV
Intention to treat analysis: proportions of participants (n, %) with healthy markers of cardiovascular risk and odds (OR 95% CI) of achieving health marker at week 13
Health markers of cardiovascular risk
Total cholesterol < 5.2 mmol/L
LDL cholesterol < 2.5 mmol/L
HDL cholesterol >0.9 mmol/L
Triglycerides < 1.5 mmol/L
Fasting glucose < 6.1 mmol/L
Systolic blood pressure < 140 mmHg
Diastolic blood pressure < 90 mmHg
Waist circumference < 94 cm men, < 80 cm
women
Body mass index < 25 kg/m2
Physical activity >150 min week at least
moderate intensity in >10 min bouts
Week 0#
Week 13#
OR Exp/Con 95% CI
Exp n of 23 (%)
Con n of 23 (%)
Exp n of 22 (%)
Con n of 23 (%)
13 (62)
9 (47)
20 (95)
8 (38)
12 (57)
9 (39)
17 (74)
0 (0)
14 (61)
10 (43)
21 (91)
13 (57)
14 (61)
14 (61)
19 (83)
0 (0)
13 (65)
9 (45)
17 (85)
8 (40)
12 (60)
17 (77)
20 (91)
0 (0)
14 (64)
9 (41)
19 (86)
11 (50)
15 (65)
12 (52)
20 (87)
0 (0)
1.1 (0.3e4.5)
1.08 (0.1e8.7)
0.5 (0.04e5.4)
1.4 (0.2e8.7)
0.8 (0.2e3.3)
5.7 (1.2e26.9)*
1.7 (0.3e12.1)
NC
1 (4)
3 (14)
2 (9)
0 (0)
1 (5)
0 (0)
1 (4)
0 (0)
NC
NC
NC ¼ Odds ratio not calculated due to small number per cell; *P < 0.05.
#Week 0 data included in analyses where there was missing data.
Total cholesterol, fasting glucose, triglycerides, HDL
LDL
Physical activity
#Week 13 data included in analyses where there was missing data.
n ¼ 21 exp, n ¼ 23 con
n ¼ 19 exp, n ¼ 23 con
n ¼ 22 exp, n ¼ 22 con
n ¼ 20 exp, n ¼ 22 con
n ¼ 20 exp, n ¼ 23 con
n ¼ 21 exp, n ¼ 20 con
Total cholesterol, LDL, HDL, triglycerides
Fasting glucose
Physical activity
Table V
Per protocol analysis based on participant adherence: proportions of participants (n, %) with healthy markers of cardiovascular risk and odds (OR 95% CI) of achieving health
marker at week 13
Health markers of cardiovascular risk
Week 0#
Week 13#
Exp n of 16 (%)
Con n of 23 (%)
Exp n of 16 (%)
Con n of 23 (%)
Total cholesterol < 5.2 mmol/L
LDL cholesterol < 2.5 mmol/L
HDL cholesterol >0.9 mmol/L
Triglycerides < 1.5 mmol/L
Fasting glucose < 6.1 mmol/L
Systolic blood pressure < 140 mmHg
Diastolic blood pressure < 90 mmHg
Waist circumference < 94 cm men, <80 cm
women
Body mass index < 25 kg/m2
Physical activity >150 min week at least
moderate intensity in >10 min bouts
10 (67)
7 (54)
15 (100)
7 (47)
8 (53)
7 (44)
11 (69)
0 (0)
14 (61)
10 (43)
21 (91)
13 (57)
14 (61)
14 (61)
19 (83)
0 (0)
11 (73)
7 (47)
13 (87)
7 (47)
8 (53)
14 (88)
15 (94)
0 (0)
14 (64)
9 (41)
19 (86)
11 (50)
15 (65)
12 (52)
20 (87)
0 (0)
1.5 (0.3e7.9)
0.5 (0.04e6.5)
0.3 (0.03e4.2)
1.5 (0.2e9.7)
0.6 (0.1e3.0)
10.3 (1.6e68.6)*
2.3 (0.2e25.7)
NC
1 (6)
2 (13)
2 (9)
0 (0)
1 (6)
0 (0)
1 (4)
0 (0)
NC
NC
NC ¼ Odds ratio not calculated due to small number per cell; *P < 0.05.
#Week 0 data included in analyses where there was missing data.
Total cholesterol, HDL, fasting glucose, triglycerides
LDL
Physical activity
#Week 13 data included in analyses where there was missing data.
Total cholesterol, HDL, LDL, triglycerides
Fasting glucose
Physical activity
n ¼ 15 exp, n ¼ 23 con
n ¼ 13 exp, n ¼ 23 con
n ¼ 16 exp, n ¼ 22 con
n ¼ 15 exp, n ¼ 22 con
n ¼ 15 exp, n ¼ 23 con
n ¼ 16 exp, n ¼ 20 con
OR Exp/Con 95% CI
1976
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
Outcomes
SMD (95% CI)
NRPS Pain
0.23 (-0.36 to 0.82)
Steps per day
0.24 (-0.37 to 0.84)
Time walking per day
0.28 (-0.32 to 0.89)
Time walking per week at > 80 steps/min
-0.12 (-0.74 to 0.50)
Time walking per week at > 80 steps/min > 10 min bouts
-0.44 (-1.06 to 0.19)
Time sitting or lying per day
0.11 (-0.50 to 0.72)
Waist circumference
0.62 (0.02 to 1.22)
Body mass index
0.23 (-0.35 to 0.82)
Total cholesterol
-0.01 (-0.62 to 0.59)
LDL cholesterol
-0.45 (-1.08 to 0.18)
HDL cholesterol
-0.15 (-0.76 to 0.45)
Triglycerides
0.37 (-0.24 to 0.98)
Fasting glucose
0.53 (-0.08 to 1.14)
Systolic blood pressure
0.36 (-0.23 to 0.95)
Diastolic blood pressure
0.10 (-0.49 to 0.68)
WOMAC pain
0.16 (-0.43 to 0.74)
WOMAC stiffness
-0.20 (-0.79 to 0.39)
WOMAC activity limitation
-0.08 (-0.66 to 0.51)
Quality of life utility score EQ5D
0.50 (-0.09 to 1.10)
Quality of life EQVAS
Secondary
outcomes:
Measures of
cardiovascular
risk
Other
secondary
outcomes
-0.09 (-0.67 to 0.50)
40 m walk test
0.54 (-0.05 to 1.14)
30s chair stand test
0.30 (-0.29 to 0.89)
-1.5
Primary outcome
-1
-0.5
favours control group
0
0.5
1
1.5
favours experimental group
Fig. 2. Forest plot of intention to treat analysis of intervention vs control group: standardised mean difference (SMD, 95% CI).
6 times increased odds of lowering systolic blood pressure below
the healthy marker of 140 mmHg. Participants who completed the
walking program had a 5 cm greater reduction of waist circumference, 1345 more daily steps, 18 more minutes spent walking per
day, faster walking speed of 0.17 m/s and 10 times increased odds of
lowering systolic blood pressure below the healthy marker of
140 mmHg.
A common concern for patients with severe knee OA is their
knee pain. Indeed this concern may have been a factor in why a
relatively high proportion of potential participants who were
screened declined to participate. While it is known that walking
programs have beneficial effects on knee pain for people with mild
to moderate knee OA13, it is unknown whether the population in
the current study with severe knee OA would achieve the same
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
benefits. Results from this trial suggests this moderate intensity,
low volume walking dosage did not decrease their knee pain when
prescribed in addition to having usual care such as physiotherapy
and analgesia medication. However, seventy per cent of the participants allocated to the walking program were adherent, and
across the whole sample there were no serious adverse events, and
no observed difference in changes to use of pain medications.
Reducing cardiovascular mortality is an important health issue
for people with knee OA because of their increased risk, compared
to people without OA5,6. Hypertension, one of the major risk factors
for coronary heart disease and stroke33, was a health issue for over
70% of participants in this study. One of the key findings was an
increase in the odds of reducing systolic blood pressure to below
140 mmHg for the walking group, both in the intention to treat and
per protocol analyses. This may be consistent with results from a
systematic review and meta-analysis that showed aerobic exercise
could reduce systolic blood pressure by 3e4 mmHg33 and by
6e8 mmHg in people with hypertension34. If these changes were
sustained then it is likely to reduce their risk of mortality35. Our
trial's findings were uncertain regarding changes in lipid and
glucose levels and other markers of cardiovascular risk. It is
possible the dose may have been insufficient and/or exercise in the
form of walking may need to be combined with other lifestyle
intervention such as weight loss to affect other markers of cardiovascular risk34. It is also possible that the relatively small sample
size meant that we did not have sufficient power to detect changes
in lipids and glucose levels.
The walking dose prescribed in our study, based on the
maximum tolerated dose of walking14 and about half of the volume of the current physical activity guidelines7, was likely to be
sufficient to lead to health benefits according to a recent review36.
Small doses of walking for older adults including as little as 6e12
blocks per week has been shown to reduce the risk of cardiovascular disease by 30% and stroke by 40% compared to those walking
less than 5 blocks37. People in the community who exercised as
little as 15 min a day had a 14% reduced risk of all-cause mortality
and a 3 year longer life expectancy than those who were physically
inactive38. Furthermore, older people who walked at 1.3 m/s
compared to people who walked at 0.9 m/s had demonstrated a
50% reduced risk of cardiovascular disease and stroke37. Therefore
the results of our study indicating increased walking speed,
increased daily walking time and improved chance of achieving a
healthy systolic blood pressure below 140 mmHg in the intervention group are consistent with other literature that our dose
was sufficient to result in cardiovascular benefits for people with
knee OA.
Given that joint replacement surgery may not lead to increased
physical activity levels9e12 our findings suggest that a minimum of
10 min walking per day, in addition to usual physical activity, is an
achievable and low cost intervention, that could be prescribed by
health professionals for patients with severe knee OA as part of
routine clinical practice. This could include people awaiting joint
replacement surgery or as part of non-surgical management for
people with severe knee OA and lower cardiovascular health.
Therefore, our study provides preliminary evidence to support
physical activity promotion strategies that emphasise the potential benefits to cardiovascular health, that may be accrued with a
10 min brisk walk per day. However, although participants who
adhered to the program took more steps per day than the control
group at week 13, there was no statistically significant difference
in the amount of moderate intensity activity. It is possible that the
observed increased activity, represented by steps per day, was
not at the same level of moderate intensity as was completed
during the program, when supervision was provided from a
physiotherapist.
1977
Our study has limitations. First, our sample size was powered to
detect a large difference of 2.8 units in knee pain levels and hence
was underpowered to detect clinically important changes in cardiovascular risk factors. However phase II trials estimate the effect
of a treatment39 and the next step is to design a fully powered
phase III trial informed by the results of the current trial with longer
term follow up. Second, medication use such as anti-hypertensive
medications may confound the results. However, in this randomised trial design there were no observed between-group differences in antihypertensive medication use and medication use did
not change in one group more than the other during the trial. Third,
despite concealed randomisation, there were observed differences
in baseline pain and physical activity levels due to chance. Therefore it is possible the control group was more deconditioned than
the intervention group at baseline that could influence outcomes
over this 12-week trial, despite the analysis taking into account
baseline differences. Finally, we did not monitor for disease progression to assess if the walking program had negative physiological effects on knee joint structure. However, there were no
between-group differences in knee pain between the two groups
as well as conflicting evidence in the literature about the effects of
physical activity on disease progression40.
A key strength of our study was the use of a single blind randomised controlled trial design to lower the risk of bias. This is also
the first known trial, to our knowledge, that compared the effects of
a walking program on cardiovascular health for people with severe
end-stage knee OA.
Conclusion
Patients with severe knee OA prescribed a 12-week moderate
intensity walking program did not decrease their knee pain. There
may be cardiovascular benefits in the prescription and completion
of a walking program of 70 min/week for patients with severe knee
OA.
Authors' contributions
All authors contributed to the conception and design, and
contributed to the writing of the paper by revising it critically for
important intellectual content. JAW collected and assembled the
data. JAW, NFT, KEW and PL performed the data analysis and
interpretation of data. All authors read and approved the
manuscript.
Ethics committee approval
La Trobe University and Eastern Health.
Conflict of interest statement
All authors declare that they do not have any potential conflict of
interest.
Role of funding source
The research received $24,704 from La Trobe University's research
focus area on Sport, Exercise and Rehabilitation. The study sponsors
had no role in the study design, in the collection, analysis and
interpretation of data; in the writing of the manuscript; and in the
decision to submit the manuscript for publication.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.joca.2016.12.017.
1978
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
References
1. Dekker J, Boot B, van der Woude LH, Bijlsma JW. Pain and
disability in osteoarthritis: a review of biobehavioural mechanisms. J Behav Med 1992;15(2):189e214.
2. Wallis JA, Webster KE, Levinger P, Taylor NF. What proportion
of people with hip and knee osteoarthritis meet physical activity guidelines? A systematic review and meta-analysis.
Osteoarthritis Cartilage 2013;21(11):1648e59.
3. Dunlop DD, Song J, Semanik PA, Chang RW, Sharma L,
Bathon JM, et al. Objective physical activity measurement in
the osteoarthritis initiative: are guidelines being met? Arthritis
Rheum 2011;63(11):3372e82.
4. Stubbs B, Hurley M, Smith T. What are the factors that influence physical activity participation in adults with knee and hip
osteoarthritis? A systematic review of physical activity correlates. Clin Rehabil 2015;29(1):80e94.
5. Nüesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Jüni P. All
cause and disease specific mortality in patients with knee or
hip osteoarthritis: population based cohort study. BMJ
2011;342:d1165.
6. Veronese N, Cereda E, Maggi S, Luchini C, Solmi M, Smith T,
et al. Osteoarthritis and mortality: a prospective cohort study
and systematic review with meta-analysis. Semin Arthritis
Rheum 2016;46(2):160e7.
7. Global recommendations on physical activity for health: 65
years and above. World Health Organisation, Available from:
http://www.who.int/dietphysicalactivity/factsheet_older
adults/en/.
8. Lin WY, Lee CC, Hsu CW, Huang KY, Lyu SR. Patients with knee
osteoarthritis undergoing total knee arthroplasty have a lower
risk of subsequent severe cardiovascular events: propensity
score and instrumental variable analysis. PLoS One 2015;10(5),
http://dx.doi.org/10.1371/journal.pone.0127454.
9. Losina E, Walensky R, Kessler C, Emrani P, Reichmann W,
Wright E, et al. Cost effectiveness of total knee arthroplasty in
the United States patient risk and hospital volume. Arch Intern
Med 2009;169(12):1113e21.
10. Vissers M, Bussmann J, de Groot I, Verhaar J, Reijman M.
Physical functioning four years after total hip and knee
arthroplasty. Gait Posture 2013;38(2):310e5.
11. Harding P, Holland AE, Delany C, Hinman RS. Do activity levels
increase after total hip and knee arthroplasty? Clin Orthop
Relat Res 2014;472(5):1502e11.
12. Arnold JB, Walters JL, Ferrar KE. Does physical activity increase after total hip or knee arthroplasty for osteoarthritis? A
systematic review. J Orthop Sports Phys Ther 2016;46(6):
431e42.
13. Fransen M, McConnell S, Harmer A, Van der Esch M, Simic M,
Bennell K. Exercise for osteoarthritis of the knee. Cochrane
Database Syst Rev 2015;(1)CD004376, http://dx.doi.org/
10.1002/14651858.CD004376.pub3.
14. Wallis JA, Webster KE, Levinger P, Singh PJ, Fong C, Taylor NF.
The maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial. Osteoarthritis
Cartilage 2015;23(8):1285e93.
15. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis 1957;16(4):494e502.
16. Norton KI, Norton L. Pre-exercise Screening. Guide to the
Australian Adult Pre-exercise Screening System. Exercise and
Sports Science Australia; 2011.
17. Farrar JT, Young Jr JP, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured
on an 11-point numerical pain rating scale. Pain 2001;94(2):
149e58.
18. Kessler RC, Barker PR, Colpe LJ, Epstein JF, Gfroerer JC, Hiripi E,
et al. Screening for serious mental illness in the general population. Arch Gen Psychiatry 2003;60(2):184e9.
19. Pfeiffer E. A short portable mental status questionnaire for the
assessment of organic brain deficit in elderly patients. J Am
Geriatr Soc 1975;23(10):433e41.
20. Borg G. Borg's Perceived Exertion and Pain Scales. Champaign,
IL: Human Kinetics; 1998.
21. Greaves C, Sheppard K, Abraham C, Hardeman W, Roden M,
Evans P, et al. Systematic review of reviews of intervention
components associated with increased effectiveness in dietary
and physical activity interventions. BMC Public Health Rep
2011;11:119.
22. Hawker GA, Mian S, Kendzerska T, French M. Measures of
adult pain: Visual analog scale for pain (vas pain), numeric
rating scale for pain (nrs pain), mcgill pain questionnaire
(mpq), short form mcgill pain questionnaire (sf-mpq), chronic
pain grade scale (cpgs), short form-36 bodily pain scale (sf-36
bps), and measure of intermittent and constant osteoarthritis
pain (icoap). Arthritis Care Res 2011;63(S11):S240e52.
23. Ryan C, Grant P, Tigbe W, Granat M. The validity and reliability
of a novel activity monitor as a measure of walking. Br J Sports
Med 2006;40:779e84.
24. Brandes M, Ringling M, Winter C, Hillmann A, Rosenbaum D.
Changes in physical activity and health-related quality of life
during the first year after total knee arthroplasty. Arthritis
Care Res 2011;63(3):328e34.
25. Tolonen H, Kuulasmaa K, Laatikainen T, Wolf H. Recommendation for Indicators, International Collaboration, Protocol and Manual of Operations for Chronic Disease Risk Factor
Surveys. European Health Risk Monitoring (EHRM). Available
from:
http://www.thl.fi/publications/ehrm/product2/title.
htm; 2002.
26. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J,
Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant
outcomes to antirheumatic drug therapy in patients with
osteoarthritis of the hip or knee. J Rheumatol 1988;15(12):
1833e40.
27. Dobson F, Hinman RS, Roos EM, Abbott JH, Stratford P,
Davis AM, et al. OARSI recommended performance-based tests
to assess physical function in people diagnosed with hip or
knee osteoarthritis. Osteoarthritis Cartilage 2013;21(8):
1042e52.
28. Wright AA, Cook CE, Baxter GD, Dockerty JD, Abbott JH.
A comparison of 3 methodological approaches to defining
major clinically important improvement of 4 performance
measures in patients with hip osteoarthritis. J Orthop Sports
Phys Ther 2011;41(5):319e27.
29. The EuroQol Group. EuroQol e a new facility for the measurement of health-related quality of life. Health Policy
1990;16(3):199e208.
30. Hinman RS, McCrory P, Pirotta M, Relf I, Forbes A, Crossley KM,
et al. Acupuncture for chronic knee pain: a randomized clinical
trial. JAMA 2014;312(13):1313e22.
31. Streiner DL. Missing data and the trouble with LOCF. Evid
Based Ment Health 2008;11(1):3e5.
32. Chufal KS, Rastogi M, Singh S, Pant MC, Srivastava M,
Bhatt MLB. Exploring new potentials and generating hypothesis for management of locally advanced head neck cancer:
analysis of pooled data from two phase II trials. J Cancer Res
Ther 2010;6(2):185e93.
33. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on
blood pressure: a meta-analysis of randomized, controlled
trials. Ann Intern Med 2002;136(7):493e503.
J.A. Wallis et al. / Osteoarthritis and Cartilage 25 (2017) 1969e1979
34. Wasfy MM, Baggish AL. Exercise dose in clinical practice. Circulation 2016;133(23):2297e313.
35. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,
Izzo Jr JL, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of
high blood pressure: the JNC 7 report. JAMA 2003;289(19):
2560e71.
36. Warburton DE, Bredin SS. Reflections on physical activity and
health: what should we recommend? Can J Cardiol
2016;32(4):495e504.
37. Soares-Miranda L, Siscovick DS, Psaty BM, Longstreth WT,
Mozaffarian D. Physical activity and risk of coronary heart
disease and stroke in older adults: the Cardiovascular Health
Study. Circulation 2016;133(2):147e55.
1979
38. Wen CP, Wai JPM, Tsai MK, Yang YC, Cheng TYD, Lee MC, et al.
Minimum amount of physical activity for reduced mortality
and extended life expectancy: a prospective cohort study.
Lancet 2011;378(9798):1244e53.
39. Phase II clinical trial. Centre for Clinical Research and Biostatistics (CCRB), Available from: https://www2.ccrb.cuhk.edu.
hk/stat/PhaseII.htm.
40. Kwee RM, Wirth W, Hafezi-Nejad N, Zikria BA, Guermazi A,
Demehri S. Role of physical activity in cartilage damage progression of subjects with baseline full-thickness cartilage defects in medial tibiofemoral compartment: data from the
Osteoarthritis Initiative. Osteoarthritis Cartilage 2016;24(11):
1898e904.