Osteoarthritis and Cartilage 28 (2020) 744e754

Low-dose strength training in addition to neuromuscular exercise and

education in patients with knee osteoarthritis in secondary care e a
randomized controlled trial
P.M. Holm y z *, H.M. Schrøder x, M. Wernbom k ¶, S.T. Skou y z
y Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
z Department of Physiotherapy and Occupational Therapy, Næstved-Slagelse-Ringsted Hospitals, Slagelse & Næstved, Denmark
x Department of Orthopedic Surgery, Næstved-Slagelse-Ringsted Hospitals, Næstved, Denmark
k Center for Health and Performance, Department of Food and Nutrition and Sport Science, University of Gothenburg, Gothenburg, Sweden
¶ Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

a r t i c l e i n f o s u m m a r y

Article history: Objectives: To investigate the effects of lower limb strength training in addition to neuromuscular ex-
Received 12 October 2019 ercise and education (ST þ NEMEX-EDU) compared to neuromuscular exercise and education alone
Accepted 27 February 2020 (NEMEX-EDU) on self-reported physical function in patients with knee osteoarthritis (KOA).
Design: Patient-blinded, parallel-group randomized controlled trial (RCT).
Keywords: Methods: The trial included 90 patients in secondary care with radiographic and symptomatic KOA,
Osteoarthritis
ineligible for knee replacement. Both groups exercised twice weekly for 12 weeks. Additional strength
Knee
training consisted of a single, fatiguing knee extension set (30-60RM) before four sets of leg-press (8-
Exercise
Strength training
12RM). Primary outcome was the between-group difference on the subscale activities of daily living from
Self-reported the Knee Injury and Osteoarthritis Outcome Score (KOOSADL) at 12 weeks. Secondary outcomes included
KOOS symptoms, pain, function in sport and recreation, and quality of life, 40 m walk, stair climb, leg
extension power, EuroQol-5D-5L, pain medication usage, and adverse events.
Results: There was no statistically significant between-group difference in KOOSADL at 12-weeks;
adjusted mean difference 1.15 (6.78 to 4.48). Except for the stair climb test, which demonstrated an
adjusted mean difference of 1.15 (0.09e2.21) in favor of ST þ NEMEX-EDU, all other outcomes showed no
statistically significant between-group differences. Neither group improved leg extension power.
Conclusion: The addition of lower-limb strength training, using a low-dose approach, to neuromuscular
exercise and education carried no additional benefits on self-reported physical function or on most
secondary outcomes. Both groups displayed similar improvements at 12-week follow-up. Hence, the
current low-dose strength training approach provided no additional clinical value in this group of KOA
patients.
Trial identifier (ClinicalTrials.gov): NCT03215602.
© 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Introduction
Osteoarthritis is considered one of the leading causes of
disability worldwide, with knee osteoarthritis (KOA) being the
most frequently reported and disabling OA subgroup1,2. Symptoms
* Address correspondence and reprint requests to: P.M. Holm, Department of
Physiotherapy and Occupational Therapy, Slagelse Hospital, Fælledvej 2C, 4200
Slagelse, Næstved-Slagelse-Ringsted Hospitals, Region Zealand, Denmark. Tel: 45-
61-14-48-33.
E-mail address: pamh@regionsjaelland.dk (P.M. Holm).
include knee pain, loss of lower limb muscle strength, limitations in
physical function and reduced quality of life3,4.
There is no cure for KOA, which means that treatment aims to
improve symptoms and reduce disability5. Exercise is recom-
mended as a core first line management of KOA6,7. However, despite
extensive evidence supporting the positive effects of exercise, un-
certainty persists regarding optimal exercise modes and dose8e10.
This uncertainty is partly due to the limited number of high quality
randomized trials directly comparing different exercise modes9.
Findings from cohorts suggest an association between thigh
muscle strength and symptoms and disability in KOA11,12.

https://doi.org/10.1016/j.joca.2020.02.839
1063-4584/© 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754
Furthermore, recent systematic reviews have shown that reduced
knee extensor muscle strength is an important risk factor for the
incidence of KOA as well as for the symptomatic and functional
decline13,14. As such, improving lower limb muscle strength, with a
particular focus on knee extensor strength, may be a key factor in
improving symptoms and function in KOA. Accordingly, interna-
tional guidelines recommend strength training as part of the core
exercise treatment, appropriate for all patients with KOA15,16.
However, despite the strong recommendations, a recent systematic
review found a very low adherence to recommended strength
training principles in studies of patients with KOA, indicating that
the effects from properly designed strength training interventions
may be underestimated in KOA17.
In Denmark, Good Life with Osteoarthritis in Denmark (GLA:D®)
is the first line non-surgical treatment of patients with KOA, and
Canada, Australia, China, Switzerland and New Zealand are
currently implementing the treatment program18,19. The GLA:D®
treatment consists of disease-specific education and neuromus-
cular exercise (NEMEX-TJR) to improve sensorimotor control (i.e.,
through improved proprioception) and achieve compensatory
functional stability20,21. These exercises are feasible in KOA and
have demonstrated positive effects on self-reported and perfor-
mance-based measures20,22,23. A recent systematic review also
supports a role for improvements in proprioception along with
increased lower limb muscle strength as potential working mech-
anisms in the beneficial effects of exercise on pain and function in
symptomatic OA24. However, low intensities in therapeutic exer-
cises may result in suboptimal stimuli for improving lower limb
muscle strength25,26. Considering the apparent role of the thigh
muscles, and especially the knee extensors, in symptoms and
function in KOA, further investigations of the potentially additive
effects of focused lower limb strength training in this group of
patients is warranted.
Therefore, the aim of this study was to investigate the effects of
focused knee extensor strength training, using a pragmatic, low-
dose approach, in addition to 12 weeks of neuromuscular exercise
and education compared to 12 weeks of neuromuscular exercise
and education alone on self-reported physical function at 12 weeks.
Methods
This was a patient-blinded, parallel-group randomized
controlled trial (RCT) conforming to the CONSORT statement for
reporting RCTs27. The primary endpoint was at 12 weeks with
secondary endpoints after 6 weeks of exercise and 12 months after
completion of the exercise program (ClinicalTrials.gov ID:
NCT03215602). Results from the 12-months follow-up will be re-
ported in a later publication.
Ethics
This study complied with the principles of the declaration of
Helsinki and was approved by the Danish Scientific Ethical Com-
mittee, Region Zealand (SJ-517) as well as by the Danish Data
Protection Agency (REG-61-2016).
Patient and public involvement
In order to evaluate the clinical feasibility of the strength
training, two feasibility studies, including a total of 25 patients with
KOA, were conducted prior to conducting this trial (unpublished
data). Feedback from the patients involved in these trials was used
to develop the current strength training set-up.
745
Patients
From July 18, 2017 to October 3, 2018, we enrolled 90 patients
with symptomatic and radiographic (Kellgren and Lawrence  2)
KOA deemed ineligible for knee replacement surgery by orthopedic
surgeons in the orthopedic outpatient clinic at Næstved Hospital28.
Specifically, patients who had been assessed by an orthopedic
surgeon and deemed ineligible for knee replacement surgery were
approached by study staff at the orthopedic outpatient clinic and
invited to take part in this study. The decision not to list patients for
surgery was based on a combination of criteria, which primarily
included radiographic severity, symptomatic severity, and the pa-
tient's willingness to undergo surgery. Further exclusion criteria
were less than “mild” symptoms (score >75 in 0e100) on the
subscale activities of daily living from the Knee Injury and Osteo-
arthritis Outcome Score (KOOSADL)29; morphine usage for pain
other than knee joint pain; previous ipsilateral knee arthroplasty;
rheumatoid arthritis; inability to comply with the protocol; and
inadequacy in written and spoken Danish.
Randomization and allocation concealment
Patients were randomized (1:1 ratio) using permuted block
randomization (blocks of 4 and 6). An external staff member
administered the randomization list. Another external staff mem-
ber put group allocation into sequentially numbered, sealed opaque
envelopes, which the patients opened after baseline testing. The
envelopes contained only the group allocation number without
further details on the allocated exercise group.
Interventions
The reporting of the exercises in this study adhered to guide-
lines provided by the Consensus on Exercise Reporting Template
(CERT), and recommendations for the reporting of strength training
interventions, provided by Toigo & Boutellier (see Appendix 1)30,31.
The interventions were group sessions led by the same set of six
physiotherapists throughout the study period. The physiotherapists
were certified in the GLA:D® exercise and education program and
specifically trained in the strength training protocol for the inter-
vention group. The training sessions took place at the exercise fa-
cilities in the Departments of Physiotherapy and Occupational
Therapy at Næstved and Slagelse Hospitals, respectively. Patients
were encouraged to carry on with their daily-life activities outside
the exercise sessions as long as it did not interfere with perfor-
mance during the exercise sessions. No home exercises were
prescribed.
Education
In the first week, the two exercise sessions in both groups were
preceded by the educational sessions from GLA:D®, focusing on
disease management and self-help strategies18. The first session
consisted of OA disease features and symptoms, risk factors and
introduction to treatment options. The second session focused
specifically on exercise as a treatment strategy as well as coping
strategies and disease management.
Neuromuscular exercise
Both groups performed neuromuscular exercises (NEMEX-TJR)
twice weekly (60 min sessions) for 12 weeks (same as GLA:D® but 6
weeks longer). The neuromuscular exercises consisted of three
parts; warm-up (z10 min), circuit exercises (z40 min) and cool-
down/stretching (z10 min). The circuit exercises consisted of a
746 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754
total of 10 exercises, two for each domain of core stability, postural
orientation, and functional exercises and four for leg muscle
strength. All exercises were performed in 2e3 sets of 10e15 repe-
titions with three levels of difficulty20. A complete description of
the neuromuscular exercise set-up as well as further description of
the GLA:D® program is provided elsewhere20,19.
Strength training
To maintain the clinical feasibility of the overall intervention,
the aim of the strength training protocol was to keep additional
exercise time to a minimum without substantially compromising
potential clinical effects of the strength training program. Leg press
is a functionally relevant movement both as a measure of perfor-
mance in a KOA population32 and as a strength training exercise33.
Therefore, leg press was chosen as the primary strength training
exercise.
Patients in the group receiving additional strength training
performed one set of low-intensity, high-repetition (30-60RM)
knee extensions followed by 4 sets of high-intensity (8-12RM) leg-
press in gym machines. This was done approximately 10 min after
cessation of the neuromuscular exercise session. Performing a
high-repetition set prior to high-intensity strength training is
aimed at causing muscular fatigue principally in lower threshold
motor units (consisting of type I muscle fibers) in order to facilitate
increased recruitment of higher threshold motor units (with type II
fibers) in the high-intensity training sets34. The combination of a
single set of low-intensity, fatiguing strength training prior to
traditional high-intensity strength training has previously proven
to be a potent method to enhance gains in muscle mass and
strength compared with high-intensity training alone in young
men34. For a complete description of the strength training protocol,
including load progression and pain monitoring strategies, please
see Appendix 1.
The group receiving strength training in addition to neuro-
muscular exercise and education is here referred to as ST þ NEMEX-
EDU, while the group receiving neuromuscular exercise and edu-
cation alone is termed NEMEX-EDU.
Outcomes
Follow-up assessments were performed after 6 weeks of exer-
cise (corresponding to the length of the GLA:D® program) and after
completing 12 weeks of exercise. Self-reported outcomes were
assessed using online questionnaires sent to the patient's email
addresses. The same trained assessor conducted all performance-
based tests and muscle function tests at the department of Phys-
iotherapy and Occupational Therapy, Slagelse Hospital.
Primary outcome
The primary outcome was the between-group difference in
KOOSADL after completion of the 12-week exercise program. KOO-
SADL consists of 17 questions regarding knee problems during
various forms of daily physical function and is scored on a Likert-
type scale, ranging from zero (no problems) to four (extreme
problems) for each question29. A normalized score for the entire
subscale was calculated and reported, ranging from zero (extreme
symptoms) to 100 (no symptoms)29. The reliability and construct
validity of KOOS has been extensively demonstrated in recent
years35.
Secondary outcomes
The remaining four KOOS subscales (pain, symptoms, function in
sport and recreation, and quality of life) were all completed and
reported using the same approach as for the primary outcome. The
patients also completed a 5-level version of EuroQol 5-dimension
questionnaire (EQ-5D-5L)36. The EQ-5D-5L is a measure of general
health status, containing both an index score (ranging from -0.59 to
1.00) and a visual analog scale (0e100), with higher scores indicating
better quality of life. As a measure of dynamic (isotonic) muscle ac-
tions, leg extension power was assessed using a Nottingham Power
Rig (NPR) (University of Nottingham Medical School, Queen's Med-
ical Centre, Nottingham NG7 2UH, United Kingdom)37. The power
output normalized to kilo body mass (Watt/kg) for the symptomatic
leg was derived and used for the between group analysis. Functional
performance was assessed using the performance-based tests 40-
m walk test (time to complete 40 m of walking in seconds) and stair
climb test (time to descend and ascend a 9-step stairway in sec-
onds)38. The quantity of pain medication usage during the last month
was recorded by self-report at each follow-up. Usage of pain medi-
cation was defined as responding “yes” to using any kind of pain
medication (with and without prescription) within the last month.
The number of adverse events (AE) (any contact to the health care
system) and serious adverse events (SAE) (prolonged treatment,
hospitalization or permanent damage/disability and death) was
recorded by self-report at each follow-up by the treating physio-
therapists and by reviewing the patient's hospital records39.
Blinding
By exercising on separate days, patients were kept unaware of
the content of exercise in the comparator group and therefore did
not know if they had been randomized to the intervention or
comparator exercises. The assessor conducting all performance-
based and muscle function tests was blinded to group allocation
and the patients were carefully instructed not to reveal any details
of the content of their exercise sessions to the assessor. A blinded
interpretation of findings (group allocation unknown) was also
performed in order to avoid biased interpretation of results from
this study40. This blinded interpretation was made publicly avail-
able prior to breaking the randomization code (see Appendix 2).
Sample size
Using a common standard deviation (SD) of 15 and the recom-
mended minimal clinically important difference of 10 for KOOS, the
sample size needed to detect a 10-point between-group difference
at 12-week follow-up, was 37 patients in each group (power: 80%;
a ¼ 0.05 (two-sided))29. Accounting for a dropout rate of 20%, 90
patients (45 in each group) were recruited for this study.
Statistical analysis
A pre-defined, detailed statistical analysis plan was made pub-
licly available prior to commencement of the analysis of the results
(see Appendix 3). An independent statistician, unaware of group
allocation performed all analyses in this study.
The primary pre-specified analysis was Intention-To-Treat (ITT)
analysis, including all randomized patients in the analysis. A sec-
ondary per protocol analysis was performed, including only pa-
tients from both groups, who attended 75% (18 of 24) exercise
sessions and, for ST þ NEMEX-EDU, only patients who completed
the strength training at the pre-specified intensities in 75% of the
attended exercise sessions. Adherence to pre-specified strength
training intensities was defined as completing one set of low-in-
tensity knee extensions and 3 of 4 sets in high-intensity leg press.
Accordingly, adherence below 75% to pre-specified strength
training intensities in the ST þ NEMEX-EDU group was defined as a
major protocol deviation. Patients undergoing knee joint
 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754 747

replacement surgery during the 12-week intervention period were
also excluded from the per protocol analysis.
The primary outcome (KOOSADL) was compared between groups
using a mixed model repeated measurements (MMRM) analysis of
variance with patient as a random factor (assessments at baseline, 6
and 12 weeks), treatment (ST þ NEMEX-EDU, NEMEX-EDU) and
time as fixed factors, treatment-by-time interaction terms, baseline
value included as a covariate, and assuming a covariance structure
with compound symmetry. Baseline values were included as
covariates in the analysis of change from baseline. Between-group
differences were reported using estimated marginal means and
95% CI or P values for superiority assessment. All secondary
continuous variables were analyzed using the same method. Cat-
egorical variables were analyzed using generalized estimating
equation (GEE) logistic regression analysis. These models were,
with the exception that no baseline covariates were included,
structured as the MMRM models with treatment, time, and treat-
ment-by-time interaction terms. The GEE models were fitted using
Stata's xtgee procedure, assuming compound symmetry, binary as
family option and logit link.
All analyses were performed using STATA 15.1 (StataCorp, Col-
lege Station, TX, USA).
Results
See Table I for descriptive summary of baseline characteristics.
Enrollment, adherence and follow-up
In total, 90 patients were randomized to one of the two exercise
groups. 35 patients (78%) in the ST þ NEMEX-EDU group and 42
patients (93%) in the NEMEX-EDU group completed the primary 12-
week follow-up. Patients completing primary follow-up and pa-
tients lost to primary follow-up had similar characteristics at base-
line (Appendix table 2). Two patients, both in the ST þ NEMEX-EDU
group, underwent knee replacement surgery during the interven-
tion period. All randomized patients (n ¼ 90) were included in the
ITT analysis. 28 patients attended 75% (18 out of 24) of the exercise
sessions in the ST þ NEMEX-EDU group and 19 of these patients
completed the strength training at pre-determined intensities in
75% of the attended exercise sessions. In the NEMEX-EDU group,
34 patients attended 75% (18 out of 24) of the exercise sessions.
This resulted in a per protocol analysis set of 19 out of 45 patients
(42%) in the ST þ NEMEX-EDU group and 34 out of 45 patients (76%)
in the NEMEX-EDU group (see flowchart; Fig. 1).
Outcomes
There was no statistically significant or clinically important
difference between groups in the primary outcome, KOOSADL at
12 weeks (or 6 weeks); adjusted mean difference of 1.15 (6.78 to
4.48). The ST þ NEMEX-EDU group improved by 16.5 points while
the NEMEX-EDU group improved by 15.2 points from baseline to
the 12-week follow-up (adjusted values). The stair climb test
revealed a statistically significant between-group difference;
adjusted mean difference of 1.15 s (0.09 to 2.21), indicating faster
test completion in the ST þ NEMEX-EDU group. All other secondary
outcomes failed to demonstrate significant differences between
groups (Tables II and III and Fig. 2). Neither group improved leg
extension power. Analysis of the per protocol populations revealed
similar results on all outcomes except for leg extension power,
which demonstrated a statistically significant between-group dif-
ference in favor of ST þ NEMEX-EDU; adjusted mean difference
of 0.24 (0.42 to 0.06) (Appendix table 1).
Discussion
This was the first RCT on the effects of adding focused lower-
limb strength training to neuromuscular exercise and education in
patients with KOA deemed not eligible for knee replacement

NEMEX-EDU¶ ST þ NEMEX-EDU#

Gender, females(n (%)) 27 (60) 25 (56)

Age, years(mean (SD)) 66.4 (9.3) 63.2 (10.7)
Body mass index(mean (SD)) 29.6 (5.4) 32.2 (6.5)
KOOSADL*(mean (SD)) 54.3 (11.8) 48.2 (14.5)
KOOSSport/recy 19.9 (14.8) 17.0 (13.9)
KOOSQOLz(mean (SD)) 34.9 (14.2) 28.3 (13.5)
KOOSPain (mean (SD)) 49.1 (12.8) 43.4 (16.3)
KOOSSymptoms (mean (SD)) 54.5 (14.7) 49.3 (17.2)
Leg extension power, watt/kg(mean (SD)) 1.5 (0.7) 1.5 (0.7)
Time (s) on the 40-m walk test(mean (SD)) 25.6 (6.6) 27.7 (6.6)
Time (s) on the stair climb test(mean (SD)) 11.9 (4.6) 14.2 (7.3)
EQ-5D-5Lxindex (mean (SD)) 0.7 (0.1) 0.6 (0.2)
EQ-5D-5Lvisual analog scale (mean (SD)) 60.5 (24.3) 61.0 (20.3)
Use of pain medication within the last monthk(n (%)) 21 (47) 25 (56)
*
Subscale activities of daily living from the Knee Injury and Osteoarthritis Outcome Score (KOOS).
y
KOOS subscale function in sport and recreation.
z
KOOS subscale quality of life.
x
EuroQol, five dimensions, five levels.
k
Total number of patients responding “yes” to having used pain medication within the last month.
¶
Neuromuscular exercise and education.
#
Neuromuscular exercise and education and strength training.

Table I Baseline characteristics of patients Osteoarthritis

andCartilage
748 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754

160 patients were assessed for eligibility

15 were unable to participate due to logistical

reasons
6 were not interested
9 had less than mild symptoms
7 had rheumatoid arthritis
5 took morphine for other conditions
3 were unable to write and speak Danish
11 had other reasons

104 were eligible for inclusion in the study

8 did not wish to participate

2 chose other treatment options
4 did not show up for baseline tests

90 underwent randomization

45 were randomized to ST+NEMEX-EDU 45 were randomized to NEMEX-EDU

37 attended 6-week follow-up 43 attended 6-week follow-up

8 did not attend 2 did not attend
3 logistical reasons 1 logistical reasons
1 underwent knee replacement surgery 1 exacerbation of knee pain
2 unable to adhere to intervention procedures
1 unrelated health reasons 42 attended 12-week follow-up
1 unknown reasons 1 did not attend
1 unrelated hospitalization
35 attended 12-week follow-up
2 did not attend
1 underwent knee replacement surgery
1 family reasons

45 were included in the intention-to-treat analysis 45 were included in the intention-to-treat analysis

19 were included in the per protocol analysis 34 were included in the per protocol analysis

Fig. 1 Flowchart of patients throughout the study. Osteoarthritis

andCartilage

surgery. While both groups had clinically important improvements
in self-reported physical function (exceeding 10 points) after 12
weeks, we found no statistically significant or clinically important
between-group differences. The lack of between-group difference
in the primary outcome (KOOSADL) was confirmed by most sec-
ondary outcomes whereas the significant difference on the stair
climb test in favor of strength training was small and may not be
clinically relevant. These findings question the clinical effectiveness
and feasibility of adding the current pragmatic, low-dose strength
training protocol to neuromuscular exercise and education in pa-
tients with KOA in secondary care who are not scheduled for knee
replacement surgery.
 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754 749

Outcomes at 12 weeks mean (95% CI) Adjusted between-group difference**

¶ # (95% CI or P value)
NEMEX-EDU ST þ NEMEX-EDU

Primary outcome
KOOSADL* 68.1 (64e72.2) 67 (63.2e70.8) 1.15 (6.78 to 4.48)
Secondary outcomes
KOOSsport/recy 35.8 (31.2e40.4) 29.1 (24.1e34) 6.74 (0.07 to 13.55)
KOOSQOLz 42.9 (39.4e46.4) 40.4 (36.6e44.2) 2.48 (2.72 to 7.68)
KOOSpain 61.2 (57.2e65.2) 58.5 (54.2e62.8) 2.65 (3.24 to 8.54)
KOOSsymptoms 63.2 (59.5e66.8) 63.9 (60e67.9) 0.77 (6.19 to 4.65)
Leg extension power, watt/kg 1.5 (1.3e1.7) 1.3 (1.2e1.5) 0.19 (0.03 to 0.41)
Time (s) on the 40-m walk test 24.8 (24.2e25.4) 24.2 (23.5e24.9) 0.58 (036 to 1.52)
Time (s) on the stair climb test 10.7 (10e11.4) 9.6 (8.8e10.3) 1.15yy (0.09 to 2.21)
EQ-5D-5Lxindex 0.75 (0.72e0.78) 0.72 (0.69e0.76) 0.03 (0.01 to 0.07)
EQ-5D-5Lvisual analog scale 69.9 (65.0e74.7) 70.1 (64.9e75.3) 0.23 (7.37 to 6.91)
Reduction in the use of pain medication (n)k 7 9 0.357
*
Subscale activities of daily living from the Knee Injury and Osteoarthritis Outcome Score (KOOS).
y
KOOS subscale function in sport and recreation.
z
KOOS subscale quality of life.
x
EuroQol, five dimensions, five levels.
k
Measured as total amount of reduction from baseline in patients responding “yes” to having consumed pain medication within the last month.
¶
Neuromuscular exercise and education.
#
Strength training in addition to neuromuscular exercise and education.
**
Adjusted for baseline.
yy
Significant difference between groups.

Table II All follow-up assessments at primary follow-up (12 weeks) Osteoarthritis

andCartilage

NEMEX-EDU* ST þ NEMEX-EDUy P value

Number of events

Adverse events (in total) 13 17 0.765

Serious adverse events 5 3 0.459
Involving index knee 0 0
Involving other sites 5 3
Renal system 1 2
Deep venous thrombosis 1 0
Other 3 1
Non-serious adverse events 8 14
Involving index knee 5 3
General practitioner consultation 2 1
Consultation in orthopedic outpatient clinic 3 2
Involving other sites 3 11
Musculoskeletal 0 2
Gastrointestinal 1 1
Infection 0 4
Other 2 4
*
Neuromuscular exercise and education.
y
Strength training in addition to neuromuscular exercise and education.

Table III Adverse events, serious adverse events Osteoarthritis

andCartilage
750 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754

Primary outcome, change from baseline to the primary follow-up at 12 weeks for the subscale activities of
daily living on the Knee Injury and Osteoarthritis Outcome Score (KOOS-ADL) for the two groups of patients
Fig. 2 randomly assigned to 12 weeks of neuromuscular exercise and education supplemented by strength Osteoarthritis
training (blue bar) or 12 weeks of neuromuscular exercise and education only (red bar). The KOOS scales andCartilage
ranges from zero (worst) to 100 (best). The error bars represent the 95% confidence intervals.

Comparing different exercise modes in KOA
Two previous RCT's on similar groups of KOA patients (not
candidates for knee replacement surgery) found no additional ef-
fects on self-reported physical function (WOMAC) when investi-
gating the effects of neuromuscular exercises (e.g., joint
stabilization and perturbation training) in addition to a muscle
strengthening program (i.e., the reverse situation compared to our
study design)41,42. This led to speculations that strength training in
itself was sufficient to elicit improvements in joint stability (which
is the main target of neuromuscular exercise21) and that additional
neuromuscular exercises may be redundant41. Furthermore, a sec-
ondary analysis from one of the RCT's41 showed that improved
quadriceps and hamstring muscle strength was associated with
reduced pain and fewer activity limitations, whereas improved
knee joint proprioception was not associated with the outcome,
indicating that increasing muscle strength would be more impor-
tant to improve pain and function43. Our study did not support this,
as we did not demonstrate any additional benefit from strength
training in addition to neuromuscular exercise and education.
Importantly however, our findings might also indicate some over-
lap in the effects for neuromuscular exercises and strength training.
For example, it has been shown that knee extensions performed
with elastic tubing (similar to exercises performed in the NEMEX-
TJR program) can produce comparable levels of muscle activation to
those observed with training in conventional knee extension ma-
chines, provided that the resistance in the elastic tubing is high
enough44.
Our findings are also similar to recent RCT's assessing different
exercise modes in KOA, including, proprioception vs strength
training45, water vs land-based exercises46, and hip-extensor vs
leg-extensor strengthening47, all reporting equal improvements
between groups on self-reported physical function in KOA. One
reason for this lack of differences in effects of different exercise
modes in KOA may be due to the multimodal nature of exercise
effects; affecting muscle and nerve, peri-articular components,
intra-articular components, general fitness and health, and psy-
chosocial factors48. Thus, it is likely that self-reported physical
function will improve by targeting anyone of these factors.
Furthermore, contextual factors are known to be important in the
explanation of treatment effects in OA and are likely to contribute
to the non-significant differences between groups49.
Disease heterogeneity
Due to the multifaceted origin of the disease, KOA patients
represent a heterogeneous patient population, which consists of
several distinct disease subgroups50e52. Notably, a recent system-
atic review and meta-analysis, categorizing patients with mild to
moderate KOA into pre-defined subgroups (chronic pain, mala-
ligned biomechanics, inflammation, metabolic disorder, bone and
cartilage metabolism), found that quadriceps muscle strength (N/
kg.) and self-reported physical function differed significantly across
most of the subgroups53. Therefore, a clinical impact of muscle
strengthening interventions on self-reported physical function in
KOA might only occur in certain subgroups with distinct impair-
ments in muscle strength. It is likely that the study sample has been
comprised of several distinct disease subgroups, thereby affecting
the potential clinical impact of additional strength training across
the included KOA patients. This may therefore be one important
reason for the lack of additional clinical effects of the strength
training intervention.
 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754
Considerations for strength training strategies
We were especially surprised not to find improvements on leg
extension power from either the control or intervention group
exercises. Since the neuromuscular exercises are characterized by
being performed in a slow, controlled manner21, this might explain
the lack of effects on muscle power in the NEMEX-EDU group.
Despite a specific focus on explosive concentric contractions during
leg-press strength training for the majority of the intervention
period in the ST þ NEMEX-EDU group, the velocity of the
contraction phases may still have been insufficient for improve-
ments in explosive muscle force. In the per protocol analysis,
including only patients with adequate strength training protocol
adherence, we did find an added effect on leg extension power
corresponding to a between-group difference of roughly 15%.
However, the lack of significant between-group differences in the
primary outcome and in most secondary outcomes remained un-
changed in the per protocol analysis, indicating a limited clinical
impact of the additional strength training. As per default, the un-
derpowered and unbalanced nature of the per protocol analysis set
should be acknowledged in this interpretation. Furthermore, it is
important to note that greater gains in strength and muscle mass as
well as muscle function in elderly undergoing heavy resistance
training are seen with 24e30 weeks of training compared with
12e15 weeks of training54,55. Thus, it cannot be ruled out that
clinically meaningful increases in primary and secondary outcomes
would have taken place if the intervention period had been longer.
Previously, a meta-analysis found that KOA patients needed to
improve knee extension strength by 30e40% in order to reduce
pain and disability17. Although the estimates may be slightly
different for leg extension power, these findings might suggest that
even when performing the current strength training protocol ac-
cording to predetermined adherence thresholds, the effects on
muscle power may be too small for a clinical impact. Thus, the
current low-dose, pragmatic short-term strength training approach
may provide suboptimal stimuli for clinically important muscle
function gains in this population.
Future work may need to consider more comprehensive
strength training strategies, including power training, and/or
longer training periods, using an explanatory trial approach to
better understand the efficacy of strength training in improving
muscle strength above certain thresholds for clinical benefits in
KOA patients.
Limitations
The low adherence to the additional strength training at the
prescribed frequencies and intensities (19 out of 45 patients; 42%)
is an important limitation to this study and warrants a careful
interpretation of the results. The robustness of findings from this
study was also affected by a relatively large and differential loss to
follow-up in the group randomized to additional strength training
(10 losses to follow-up vs 3 in the control group). However, reasons
for patients dropping out of the study did not seem to be related to
intervention procedures (see Fig. 1). In addition, post hoc compar-
isons of patients lost to follow-up and patients completing 12-week
follow-up revealed similar baseline characteristics. Thus, we were
unable to determine specific reasons to the uneven study attrition
(Appendix table 2)56.
Clinical implications
The addition of a low-dose lower limb strength training protocol
did not induce harms and can be considered a safe exercise
approach in KOA patients ineligible for knee replacement. However,
751
the lack of adherence to the strength training protocol as well as the
lack of additional clinical benefits suggests a limited relevance of
this intervention as an adjunct to an established neuromuscular
exercise and education program.
Conclusion
In conclusion, supplementing neuromuscular exercise and ed-
ucation with focused lower-limb strength training using a prag-
matic, low-dose approach carried no additional clinical value to
self-reported physical function and most secondary outcomes
compared to neuromuscular exercise and education alone in pa-
tients with KOA not eligible for knee replacement in secondary care.
Patients seem to improve similarly on a wide range of self-reported
domains, covering physical function, quality of life, and general
health, as well as showing similar improvements in walking per-
formance when being prescribed neuromuscular exercise and ed-
ucation alone. Future studies should consider more comprehensive
strength training programs and/or longer training periods as well
as delineating between different subgroups of KOA patients when
investigating the relative effects of exercise in KOA.
Author contributions
Study conception and design: Holm, Schrøder, Wernbom,
Skou.
Recruitment of patients: Holm, Schrøder.
Acquisition of data: Holm.
Analysis and interpretation of data: Holm, Schrøder, Wern-
bom, Skou.
Drafting the article or revising it critically for important in-
tellectual content: Holm, Schrøder, Wernbom, Skou.
Final approval of the article: Holm, Schrøder, Wernbom, Skou.
All authors had full access to all the data (including statistical
reports and tables) in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Declaration of competing interest
Dr. Skou is associate editor of the Journal of Orthopaedic &
Sports Physical Therapy, has received grants from The Lundbeck
Foundation, personal fees from Munksgaard, all of which are
outside the submitted work. He is co-founder of Good Life with
Osteoarthritis in Denmark (GLA:D®), a not-for profit initiative
hosted at University of Southern Denmark aimed at implementing
clinical guidelines for osteoarthritis in clinical practice.
The authors affirm that they have no financial affiliation
(including research funding) or involvement with any commercial
organization that has a direct financial interest in any matter
included in this manuscript, except as disclosed in an attachment
and cited in the manuscript.
Funding/support
We would like to express our gratitude for the financial support
provided by The Danish Rheumatism Association, The Regional
Health Research Grant of Region Zealand and Næstved-Slagelse-
Ringsted Hospitals Research Grant.
The lead author (Holm PM) is funded by a postdoc grant from
Clinical Academic Group (CAG) e Research Osteoarthritis Denmark
(ROAD).
Dr. Skou is currently funded by a grant from the European
Research Council (ERC) under the European Union's Horizon 2020
research and innovation program (grant agreement No 801790).
752 P.M. Holm et al. / Osteoarthritis and Cartilage 28 (2020) 744e754
Role of funding source
The funders did not have any involvement in the study other than
providing funding.
Acknowledgments
A special thank you goes to Mette Nyberg for her relentless work
in the outcome assessment and administrative procedures in this
study, and Professor of Statistics Jonas Ranstam for administering
all aspects of the blinded statistical analyses in this study. We
would also like to thank the physiotherapists in charge of the
intervention procedures as well as nurses and orthopedic surgeons
involved in the recruitment of patients at the Orthopedic Outpa-
tient Clinic at Næstved Hospital. Finally, we would like to appre-
ciate the help provided for various parts of this study by staff at the
Department of Physiotherapy and Occupational Therapy at
Næstved and Slagelse Hospitals as well as at the Department of
Clinical Biomechanics, University of Southern Denmark.
Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.joca.2020.02.839.
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