KNEE
Increased cartilage volume after injection of hyaluronic
acid in osteoarthritis knee patients who underwent
high tibial osteotomy
Keerati Chareancholvanich •Chaturong Pornrattanamaneewong •
Rapeepat Narkbunnam
Received: 5 March 2013 / Accepted: 14 October 2013 / Published online: 27 October 2013
ÓThe Author(s) 2013. This article is published with open access at Springerlink.com
Abstract
Purpose High tibial osteotomy (HTO) is a surgical pro-
cedure used to correct abnormal mechanical loading of the
knee joint; additionally, intra-articular hyaluronic acid
injections have been shown to restore the viscoelastic
properties of synovial fluid and balance abnormal bio-
chemical processes. It was hypothesized that combining
HTO with intra-articular hyaluronic acid injections would
have benefit to improve the cartilage volume of knee joints.
Methods Forty patients with medial compartment knee
osteoarthritis (OA) were randomly placed into 1 of 2
groups. The study group (n=20) received 2 cycles (at
6-month intervals) of 5 weekly intra-articular hyaluronic
acid injections after HTO operation. The control group
(n=20) did not receive any intra-articular injections after
HTO surgery. Cartilage volume (primary outcome) was
assessed by magnetic resonance imaging (MRI) pre-oper-
atively and 1 year post-operatively. Treatment efficacy
(secondary outcomes) was evaluated with the Western
Ontario and McMaster Universities OA Index (WOMAC)
and by the comparison of the total rescue medication
(paracetamol/diclofenac) used (weeks 6, 12, 24, 48).
Results MRI studies showed a significant increase in total
cartilage volume (p=0.033), lateral femoral cartilage
volume (p=0.044) and lateral tibial cartilage volume
(p=0.027) in the study group. Cartilage volume loss was
detected at the lateral tibial plateau in the control group.
There were significant improvements after surgery in both
groups for all subscales of WOMAC scores (p\0.001)
compared to the baseline. However, no difference was
found between the two groups. The study group had sig-
nificantly lower amounts of diclofenac consumption
(p=0.017).
Conclusion Based on the findings of the present study,
intra-articular hyaluronic acid injections may be beneficial
for increasing total cartilage volume and preventing the
loss of lateral tibiofemoral joint cartilage after HTO.
Level of evidence Therapeutic study, Level I.
Keywords Viscosupplementation Osteoarthritis
knee High tibial osteotomy Cartilage volume
MRI
Introduction
Knee osteoarthritis (OA) is a progressive disease that
results in cartilage degradation due to mechanical and
biochemical factors. The pathology of this disease is
characterized by the degradation of cartilage and hyper-
trophy of the surrounding bone [8,16]. Although the actual
aetiology of osteoarthritis remains unknown, significant
risk factors have been identified, including obesity, mala-
lignment, trauma and genetic abnormalities [19,22].
Malalignment can create abnormal load distribution
through the knee joint, leading to increased stress on a
focal area of articular cartilage. This change is simulta-
neously aggravated by a local biochemical response to an
increased variety of degradation products, such as pro-
K. Chareancholvanich C. Pornrattanamaneewong
R. Narkbunnam (&)
Department of Orthopaedics Surgery, Faculty of Medicine
Siriraj Hospital, Mahidol University, Siriraj Hospital 2 Prannok
Road Bangkoknoi, Bangkok 10700, Thailand
e-mail: mai_parma@hotmail.com
K. Chareancholvanich
e-mail: sikcr@mahidol.ac.th
C. Pornrattanamaneewong
e-mail: tkt108@yahoo.ac.th
123
Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423
DOI 10.1007/s00167-013-2735-1
inflammatory cytokines, free radicals and proteinases,
resulting in an imbalance of the homeostasis of the articular
cartilage and a reduction in synovial fluid viscosity [13,
14].
High tibial osteotomy (HTO) is one of the standard
surgical procedures, which aims to correct abnormal
mechanical axis and unloads excessive stress on the knee
joint. Overall clinical results of HTO surgery have deter-
mined this procedure to be effective in the treatment for
unicompartmental OA of the knee [2,3,17]. Intra-articular
hyaluronan has recently become a widely accepted thera-
peutic option for the treatment for knee pain due to OA [9].
The benefits of intra-articular hyaluronic acid injections
include restoration of the elastic and viscous properties of
the synovial fluid, anti-inflammatory effects, anti-nocicep-
tive effects and normalized hyaluronic acid synthesis [11,
20,27]. Theoretically, these treatment modalities could be
used in combination to create synergistic effects to improve
repair or delay the progression of OA in the knee. To date,
there is no published clinical study evaluating the role of
viscosupplementation in knee OA patients after HTO
operation. The objective of this study was to evaluate the
efficacy of repeated intra-articular hyaluronic acid injec-
tions in the treatment for knee OA patients over a period of
1 year after HTO surgery. We hypothesized that intra-
articular hyaluronic acid may increase the restoration of
cartilage volume and improve the post-operative clinical
outcome after HTO compared to a control group.
Materials and methods
Patients suffering from primary medial compartment knee
OA, who met all of the following inclusion criteria, were
included in this study. The inclusion was between 35 and
65 years of age; pain symptoms greater than 40 mm on a
100-mm visual analogue scale (VAS); knee coronal
deformity not exceeding 15°from normal alignment; knee
range of motion greater than 90°with less than 10°
extension deficit; radiographic evidence of grade 2 or 3
disease severity according to the classification proposed by
Kellgren and Lawrence [18]; failure of conservative treat-
ment; and persistent pain after medical treatment and
physiotherapy for more than 6 months. Exclusion criteria
included prior surgery of the affected knee joint; any intra-
articular injections (including intra-articular hyaluronic
acid, steroid or pain treatment modalities) into the target
joint during the 3 months prior to inclusion; intake of
symptomatic slow-acting drugs for osteoarthritis, (SYSA-
DOA) including chondroitin, glucosamine and diacerein
during the 3 months prior to inclusion; recent or active
history or symptoms suspicious of infection of the target
knee joint; the presence of an underlying disease that could
affect general physical condition or knee function; known
history of allergic reactions; hypersensitivity or any con-
traindication to each medication in study protocol (hyalu-
ronic acid, diclofenac and paracetamol); and history of
allergy to avian proteins. All criteria were assessed for
eligibility by an orthopaedic surgeon (RN).
This study was designed as a randomized, controlled,
observer-blinded study. Patients participating in this study
were placed into control and study groups by block ran-
domization on the selection day. The control group did not
receive any intra-articular hyaluronic acid injections during
the 1-year period of study. The study group received 2
courses of intra-articular hyaluronic acid injections with
sodium hyaluronate (Hyalgan) after surgery at weeks 2, 3,
4, 5 and 6 for the first course and at weeks 24, 25, 26, 27,
28 for the second course. There were 10 total intra-articular
injections. All patients maintained a similar schedule of
visiting the outpatient clinic for a total of 12 visits in the
first year after surgery (weeks 2, 3, 4, 5, 6, 12, 24, 25, 26,
27, 28 and 48). Patients received only the pain medication
mentioned in the study protocol, 25 mg of diclofenac and
500 mg of paracetamol. No other pain medication or
physical modality could be used throughout the study
period.
If any adverse events from intra-articular hyaluronic
acid injection occurred, such as transient pain, joint
swelling or pseudosepsis [1,7,12,21], the patients were
advised to rest and place cold compression on the affected
knee joint. If these problems had not improved before the
next scheduled injection, the patients were asked to stop
the intra-articular hyaluronic acid injection program. Their
outcome measurements and the data were still included in
the intention to perform a complete analysis.
Study medication
Hyalgan
Ò
is a viscous solution consisting of an optimal
molecular weight (500,000–730,000 Da) fraction of highly
purified sodium hyaluronate (20 mg/2 ml) in a buffered
physiological saline solution with a pH of 6.8–7.5. The
sodium hyaluronate is extracted from rooster combs. Hy-
algan
Ò
is approved by the FDA for the treatment for
painful knee OA.
Surgical technique and rehabilitation program
All patients underwent medial opening-wedge HTO by a
single surgeon (KC). The surgical procedure and post-
operative rehabilitation program were performed in the
same fashion for both groups. An oblique anteromedial
skin incision was made 1 cm above the upper border of pes
anserinus from the medial aspect of the tibial tubercle to
the posterior crest of the tibia. The insertion of the patellar
1416 Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423
123
tendon was identified and retracted. The medial collateral
ligament was released subperiosteally until the medial joint
space was able to be opened by approximately 2–3 mm
when valgus loading was applied. A 2.5-mm Kirschner
wire was placed under fluoroscopic control as a guide for
the desirable osteotomy level. An oblique bone cut was
planned starting from distally and medially at the upper
border of pes anserinus and extending proximally and lat-
erally to the upper third of proximal tibiofibular joint.
Osteotomy was performed in a V-shaped biplanar config-
uration at the anterior aspect (behind the tibial tubercle and
patellar tendon insertion). Osteotomy was angulated at
125°–130°proximal to the protected knee extensor mech-
anism intact with the distal fragment and allowed for a
sufficient area surrounding the proximal fragment for
implant fixation. An oscillating saw and chisel were used to
cut distally to the guided Kirschner wire and to control the
depth of the bone cut, leaving 1 cm of the lateral margin of
the tibia for use as a periosteal hinge so that the osteotomy
was an incomplete wedge cut. A large spreader was placed
into the osteotomy site to control the correction angle until
the mechanical axis was located at the Fugisawa point [10].
Knee extension and tibial slope were determined. Fixation
was achieved with TomoFix
Ò
(Synthes GmbH; Solothurn,
Switzerland) and a locking screw. Distal screws were
placed in a percutaneous fashion. No bone graft or bone
substitute was placed into the osteotomy site. The wound
was closed without a surgical drain (Fig. 1).
Compressive dressing was used for the first day after
surgery. A standard medication regimen for post-operative
pain control was provided by the anaesthesiologist. Active
and passive ranges of motion were encouraged to begin on
the second day after surgery. Partial weight-bearing with
gait aids was allowed as soon as possible. Four to six weeks
after surgery, the patients were expected to achieve a full
range of motion of their knee and to be pain-free. Radio-
graphic studies demonstrated partial healing signs at the
osteotomy site, and then, patients were allowed progressive
weight-bearing until full weight-bearing for an additional
4 weeks.
Data collection
Demographic data and OA parameters were recorded on
the selection day for each patient. These data included sex,
age, body mass index (BMI), number of knee joints
affected by OA, range of motion and severity of
malalignment.
Primary outcome
Cartilage restoration outcomes were assessed by com-
paring MRI measured cartilage volumes (cc) taken at a
pre-operative date (within the 3 months prior to surgery)
and 1 year post-operation. All patients were assessed on
a 3.0T system (Phillips Medical Systems/Alchieva). MR
imaging was performed at a pixel size of 0.286 mm in-
plane resolution and 1.41-mm slice thickness. The MR
images were stored in DICOM format and transferred to
a computer workstation running the MIMICS software
(Materialise, Belgium). The femoral and tibial articular
cartilage structures of each specimen were manually
segmented in the sagittal plane (ranging from 80 to 100
slices) by a single experienced investigator and were
then reconstructed (Fig. 2). The 3D voxel models were
generated and wrapped with a triangular mesh to create a
virtual solid model of each specific structure. The solid
models captured both the articular cartilage volume and
morphology (Fig. 3). The specific region of interest
(ROI) was measured directly using the MIMICS software
(i.e. the values of the areas and the lengths of specific
regions). The 3D models were exported in STL format to
a computer running the computer-aided design (CAD)
software (PowerSHAPE, Delcam, UK) to determine the
circumference and angle of the ROI. The validation of
this method and the use of this computer program for
measuring cartilage volume and bone areas have previ-
ously been described [6,15]. From our previously
unpublished study, reliability tests for intra-class corre-
lation coefficients between assessors and intra-assessor
were 0.76 and 0.89, respectively.
Fig. 1 High tibial osteotomy was performed by the medial opening-
wedge technique
Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423 1417
123
Secondary outcomes
The clinical function and the efficacy of treatment were
recorded. The following parameters were compared for the
difference from the baseline (week 2) to weeks 6, 12, 24
and 48: (1) Western Ontario and McMaster Universities
OA Index (WOMAC), with the subscales of pain, stiffness
and physical function; and (2) rescue medication (25 mg
diclofenac tablet and a paracetamol 500 mg tablet) use per
day.
Safety and tolerability of intra-articular hyaluronic acid
treatments were recorded to determine an incidence of
adverse effects of hyaluronic acid injections during the
1-year duration of the study.
Surgical intervention outcomes were evaluated by
comparison of the measurements of the angles of deformity
correction taken pre-operatively and post-operatively as the
degree of femorotibial angle (FTA) and the angle formed
by the mechanical axis of the femur (from the centre of the
femoral head to the top of the femoral notch) and the tibia
(from the centre of the ankle to the centre of the tibial
spine). Radiographic studies were performed in the stand-
ing scanogram anteroposterior view. Post-operative range
of motion, evidence of radiographically observable bridg-
ing callus or trabeculae between fragments at 1-year post-
operative and post-operative complications were recorded.
The present study was registered in the public registry
ClinicalTrial.gov (number NCT01267214). Ethical
Fig. 2 Femoral and tibial articular cartilage structures of each subject were manually segmented in the sagittal plane slide by slide (range
80–100 slides per subject)
Fig. 3 The 3D voxel models
were generated and wrapped
with a triangular mesh to create
a virtual solid model of each
specific structure
1418 Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423
123
committee approval for the study was obtained from the
ethical review board of Siriraj hospital, Mahidol Univer-
sity, Bangkok, Thailand (495/2551(EC3)). Informed con-
sent documentation was obtained from all participants after
a complete explanation of the study protocol was given by
the study nurse.
Statistical analysis
Sample size calculation
Power analysis determined the sample size necessary to
detect differences between 1 units of cartilage volume (cc),
collected pre-operatively, and 1 year after HTO surgery.
The following assumptions were made to compute the
sample size: standard deviation (SD) of 1; a two-sided
significance level of 5 %. A resulting sample size of
approximately 34 patients (17 patients per group) provided
80 % power to detect a difference between study and
control groups.
A patient who fulfilled the inclusion and exclusion cri-
teria and received at least one intra-articular injection of
Hyalgan was included in the intent-to-treat (ITT) group of
subjects.
Characteristics of knee OA patients with proximal tibial
osteotomy, such as age, gender, weight, height, BMI and
medical history, were analyzed between the study group
and the control group by using descriptive statistics. The
baseline characteristics between the study and the control
groups were compared using a Chi square test and an
independent ttest.
The WOMAC osteoarthritis indices and other efficacy
variables for the baseline (week 2 and the date of the first
intra-articular hyaluronic acid injection) and weeks 6, 12,
24 and 48 were compared with a parametric method using
repeated measures ANOVA. Bonferroni test was used for
post hoc comparisons. Independent ttests were used to
compare WOMAC scores between the study group and the
control group. Nonparametric statistics and Mann–Whitney
Utests were used to compare the ordinal efficacy scale of
patients and the investigator global efficacy and tolerability
assessments between the study and control groups. A
pvalue of less than 0.05 was considered to be a statistically
significant difference.
Results
Patient recruitment started in February 2009, and the last
follow-up visit for all patients was completed in June 2011.
Forty-two patients were enrolled in this study, but 2
patients were screening failures as they denied informed
consent. Thus, a total of 40 patients were randomly
assigned to one of the two groups to be analyzed: 20
patients assigned to the study group received intra-articular
hyaluronic acid injections, while the remaining 20 patients
assigned to the control group did not receive any intra-
articular injections. All patients completed the study
Fig. 4 Study flow chart. IA intra-articular, HAs hyaluronic acid
Table 1 Demographic and baseline characteristics of the study and
control groups
Characteristics Study group
(n=20)
Control
group
(n=20)
pvalue
a
Number of male patients
(%)
2 (10) 2 (10) n.s.
Mean age ±SD (years) 57.7 ±5.3 58.8 ±4.0 n.s.
Mean BMI ±SD (kg/m
2
) 29.1 ±3.7 27.9 ±4.2 n.s.
Number of patients with
bilateral osteoarthritis
(%)
17 (85) 13 (65) n.s.
b
Number of left knees (%) 10 (50) 7 (35) n.s.
b
X-ray grade (Kellgren–
Lawrence criteria)
n.s.
b
Grade II (%) 7 (35) 8 (40)
Grade III (%) 13 (65) 12 (60)
Mean minimal JSW ±SD
(mm)
1.3 ±1.0 1.6 ±2.4 n.s.
Mean joint range of
motion ±SD (°)
119.0 ±12.6 124.5 ±10.7 n.s.
WOMAC score at the
selection day
Pain (0–100) 48.4 ±15.6 46.6 ±14.8 n.s.
Stiffness (0–100) 56.0 ±26.7 55.8 ±20.5 n.s.
Physical function
difficulty (0–100)
53.6 ±23.4 52.5 ±16.7 n.s.
Overall WOMAC
(0–100)
52.7 ±21.2 51.5 ±15.4 n.s.
JSW joint space width, WOMAC Western Ontario and McMaster
Universities Osteoarthritis Index, n.s. not significant
a
Independent ttest
b
Chi square
Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423 1419
123
protocol. No patients were lost to follow-up during the
1-year study period (Fig. 4).
There were no statistically significant differences
between the 2 groups of patients for the baseline charac-
teristics, radiographic grading and functional scores
(Table 1).
MRI evaluation
Structural restoration was assessed by the change in carti-
lage volume from the baseline (pre-operative) to 1-year
after HTO surgery. Patients in the study group had a sig-
nificantly higher cartilage volume (p\0.05) in the entire
compartment of the knee (distal femur, tibial plateau and
patella), whereas patients in the control group had a
slightly decreased cartilage volume (-0.02 cc, SD =0.39)
of the lateral tibial plateau compared to the baseline MRI.
However, the cartilage volume was higher in the remaining
compartments of the knee, including the distal femur,
medial tibial plateau and patella.
Comparison of the change in cartilage volume between
the study and control groups revealed a significant increase
in the total cartilage volume (p=0.033), lateral femoral
volume (p=0.044), tibial plateau volume (p=0.035) and
lateral tibial volume (p=0.027) in the study group com-
pared to the control group (Table 2).
Treatment efficacy
After HTO surgery, there was a significant reduction in the
WOMAC pain score, stiffness score, physical function
difficulty score and mean overall WOMAC score from the
baseline (week 2, the first injection) to weeks 6, 12, 24 and
48 (p\0.001) in both groups. The WOMAC score
progressively improved with time until 24 weeks post-
surgery, after which the results remained stable (Table 3).
There were no significant differences in the WOMAC pain
score, stiffness score, physical function difficulty score and
mean overall WOMAC score between the study group
(receiving Hyalgan injections) and the control group for the
5 visits (week 2, week 6, week 12, week 24 and Week 48)
during the 12 months of knee osteoarthritis treatment
(Table 3).
Rescue medication utilization during the 1-year study
period showed that a significantly higher (p=0.017)
amount of diclofenac (250 mg/tab) was consumed in the
control group (mean 1.11 tabs/day, SD 0.76) compared to
the study group (mean 0.63 tabs/day, SD 0.59). No dif-
ference in paracetamol (500 mg/tab) consumption was
found between the two groups (mean =0.43, 0.44 tabs/
day, SD =0.44, 0.6 for the study and control groups,
respectively) (Table 4).
Safety
There were no serious adverse effects related to the study
treatments or procedures. Two patients (10 %) in the study
group reported local allergic reactions and mild swelling
after intra-articular injection in the first course of injec-
tions. After conservative treatment by rest and cold com-
pression, the symptoms resolved within 1 week and before
the next scheduled injection. There were no reports of any
adverse reactions in the second cycle of injections.
Results of HTO surgery
Mean pre-operative/post-operative FTAs from the study
and control groups are shown in Table 5. There was no
Table 2 Magnetic resonance imaging outcome: cartilage volume
Cartilage volume (cc) Study group Control group Value
a
(D1-D2)
Baseline (SD) 48 weeks (SD) D1
b
(SD) Baseline (SD) 48 weeks (SD) D2
b
(SD)
Total volume 4.1 (0.8) 6.2 (1.6) 2.1 (0.9)** 3.7 (1.2) 5.0 (1.7) 1.3 (1.3)** 0.03*
Distal femur 2.8 (0.6) 4.4 (1.2) 1.6 (0.7)** 2.4 (0.9) 3.6 (1.2) 1.2 (0.8)** n.s.
Medial femur 1.0 (0.3) 1.4 (0.5) 0.4 (0.4)** 0.9 (0.4) 1.2 (0.4) 0.3 (0.4)** n.s.
Lateral femur 1.8 (0.4) 3.1 (0.9) 1.2 (0.6)** 1.6 (0.5) 2.3 (1.0) 0.8 (0.8)** 0.04*
Tibial plateau 1.3 (0.4) 1.8 (0.5) 0.5 (0.4)** 1.2 (0.5) 1.4 (0.6) 0.2 (0.6) 0.03*
Medial tibia 0.6 (0.2) 0.9 (0.3) 0.3 (0.3)** 0.5 (0.2) 0.6 (0.3) 0.2 (0.2)** n.s.
Lateral tibia 0.6 (0.2) 0.9 (0.3) 0.3 (0.3)** 0.8 (0.4) 0.7 (0.4) -0.1 (0.4) 0.03*
Patella 1.2 (0.4) 1.6 (0.5) 0.4 (0.2)** 0.9 (0.3) 1.2 (0.4) 0.3 (0.4)** n.s.
D1, 48 weeks—baseline (study group); D2, 48 weeks—baseline (control group)
* Significant difference at p\0.05
** Significant difference at p\0.01
a
Independent ttest
b
Paired ttest
1420 Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423
123
difference between the two groups for the degree of cor-
rection angle after HTO surgery (mean =12.45, 11.75;
SD =1.50, 1.25 for the study and control groups, respec-
tively). At the final study visit, all of the patients had
regained a knee range of motion (ROM) equal to their pre-
operative ROM. Osteotomy sites showed a good progres-
sion of bone healing, which tolerated full weight-bearing in
all patients (Fig. 5). Four (10 %) patients (2 in the study
group and 2 in the control group) experienced skin dis-
comfort upon palpability of the surgical implants. No
serious complications of the surgical wounds were
reported.
Discussion
The efficacy of intra-articular hyaluronic acid injections in
pain relief and improvement of joint function in patients
with knee OA has been well established [4,5,23,26].
Table 3 Clinical efficacy outcomes: WOMAC Osteoarthritis Index
WOMAC Osteoarthritis Index Baseline (SD) Week 6 (SD) Week 12 (SD) Week 24 (SD) Week 48 (SD) pvalue
a
Pain score
Study group 36.7 (16.5) 26.8 (14.5) 23.8 (15.1) 16.5 (10.5) 16.0 (13.5) \0.001**
Control group 39.9 (22.6) 23.3 (16.7) 19.1 (18.9) 12.1 (13.2) 15.3 (20.3) \0.001**
pvalue
b
n.s. n.s. n.s. n.s. n.s.
Stiffness score
Study group 43.3 (23.0) 32.7 (18.0) 26.9 (20.8) 18.9 (14.2) 21.7 (17.5) \0.001**
Control group 38.7 (21.8) 24.7 (16.6) 23.2 (23.2) 15.9 (19.3) 17.6 (21.4) \0.001**
pvalue
b
n.s. n.s. n.s. n.s. n.s.
Function score
Study group 47.1 (25.9) 32.3 (18.4) 28.5 (15.8) 21.3 (10.8) 20.3 (14.7) \0.001**
Control group 41.3 (24.0) 23.6 (15.5) 20.0 (21.4) 17.0 (15.9) 19.2 (21.0) \0.001**
pvalue
b
n.s. n.s. n.s. n.s. n.s.
Overall score
Study group 44.6 (21.0) 32.3 (18.4) 27.4 (13.8) 20.1 (9.8) 19.5 (13.4) \0.001**
Control group 40.8 (22.3) 23.6 (15.5) 20.0 (20.2) 15.9 (15.2) 183 (20.4) \0.001**
pvalue
b
n.s. n.s. n.s. n.s. n.s.
** Significant difference at p\0.001
a
Repeated measures ANOVA
b
Independent ttest
Table 4 Clinical efficacy outcomes: rescue medicine used
Rescue
medicine
Mean ±SD (tabs/day) pvalue
a
Study group
(n=20)
Control group
(n=20)
Diclofenac 25 mg
Week 6 1.40 ±1.04 1.99 ±1.22 n.s.
Week 12 0.94 ±1.39 1.47 ±1.20 n.s.
Week 24 0.20 ±0.49 0.90 ±1.00 0.009*
Week 48 0 0.17 ±0.46 n.s.
Total 0.63 ±0.59 1.1 ±0.76 0.017*
Paracetamol 500 mg
Week 6 1.05 ±0.96 0.71 ±0.98 n.s.
Week 12 0.61 ±0.99 0.52 ±0.69 n.s.
Week 24 0.85 ±0.25 0.12 ±0.20 n.s.
Week 48 0 0.51 ±2.06 n.s.
Total 0.43 ±0.44 0.44 ±0.60 n.s.
* Significant difference at p\0.05
a
Independent ttest
Table 5 Radiographic outcome of HTO surgery
Outcomes Study group
(n=20)
Mean ±SD
Control group
(n=20)
Mean ±SD
pvalue
a
Pre-operative
FTA (°)
168.7 ±2.2 170.7 ±2.6 n.s.
Post-operative
FTA (°)
181.8 ±1.9 182.2 ±2.5 n.s.
Correction
angle
a
(°)
12.45 ±1.50 11.75 ±1.3 n.s.
Union rate
b
(%) 100 % 100 % n.s.
FTA femorotibial angle
a
Correction angle =post-operative FTA -pre-operative FTA
b
Union rate =evidence of a radiographic bridging callus or tra-
beculae between fragments at 1 year post-operatively
Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423 1421
123
However, the debate on the structural modifications or
chondroprotective effects of hyaluronic acid is still ongo-
ing without a clear consensus. In recent years, only a few
studies have evaluated a repeated treatment cycle with
intra-articular hyaluronic acid injections using clinical or
MRI assessments [23,26]. In the OsteoArthritis Modifying
Effects of Long-term Intra-articular Adant (AMELIA)
clinical study [23], 4 courses of repeated cycle intra-
articular hyaluronic acid injections over a 40-month period
resulted in a significantly higher number of patients (22 %)
improving with hyaluronic acid treatment compared to a
placebo group (OARSI 2004, p=0.004). The hyaluronic
acid group also showed a marked carryover effect for at
least 1 year after the last injection. Advanced quantitative
MRI is accepted as the most reliable and accurate tool for
the evaluation of structure-modification effects in knee OA
patients [24,25]. Wang et al. [26] reported MRI assessment
results after 4 courses of Hyalgan GF-20 in 78 knee OA
patients (39 patients received Hyalgan injections, 39
patients in the control group did not) during 2 years of
follow-up assessments. The results demonstrated a signif-
icant reduction in cartilage volume loss and cartilage
defects in the injection group.
The most important finding of the present study dem-
onstrated a significant increase in total cartilage volume,
lateral femoral cartilage volume, tibial plateau cartilage
volume, and lateral tibial cartilage volume in the study
group compared to the control group. Data from this study
also showed that cartilage volumes of the medial tibio-
femoral joint were increased in both groups, which dem-
onstrates the reparative effect of HTO surgery. These
results correlated with the principle of using HTO to
unload the medial compartment and to shift the loading
point to the lateral tibial compartment. Moreover, there was
a trend for a slight loss of cartilage volume at the lateral
tibial plateau in the control group [-0.02 (0.39) cc],
whereas cartilage volume in this region increased in the
study group. This finding can be interpreted as a protective
effect from intra-articular hyaluronic acid injections on the
lateral tibiofemoral joint after HTO in knee OA patients.
The results of the present study demonstrate significant
improvements in clinical outcomes using the WOMAC
score in both groups of patients, but no differences were
determined for pain, stiffness or physical subscales of
WOMAC scores between the study and control groups.
This result confirmed the potential of pain reduction and
functional outcome improvement after HTO surgery, and it
could be speculated that because of the surgical improve-
ments, intra-articular hyaluronic acid injections could not
further improve the WOMAC scores post-operatively.
However, the second clinical outcome showed that intra-
articular hyaluronic acid can reduce the total amount of
NSAID consumption during the first year after surgery.
This study has several strengths. First, all of the patients
completed all of the study components up to the last fol-
low-up visit at 1-year post-surgery. A single experienced
surgeon used the same technique and same post-operative
rehabilitation protocol to perform all of the operations.
Finally, all of the patients showed similar results after HTO
surgery without any serious complication. There were also
some limitations to this study. This study was a single-
blinded pilot study, and the sample size was quite small
(n=40). One year of follow-up assessments was too short
to evaluate the long-term results for the structure-modifi-
cation effect or survival rate after HTO surgery. The results
from this study cannot be extrapolated to recommend the
routine use of intra-articular hyaluronic acid after HTO
surgery, the appropriate treatment cycle and dose or the
course of hyaluronic acid injection. Further studies with a
larger number of patients and a longer follow-up period are
warranted.
Conclusion
High tibial osteotomy is a surgical procedure that results in
significant pain relief and functional improvement by
WOMAC score assessment in patients with OA of the knee
joint. The combination of intra-articular hyaluronic acid
after HTO surgery in this study demonstrated a positive
synergistic effect in structural modifications by signifi-
cantly increasing total cartilage volume and reducing car-
tilage volume loss in the lateral tibiofemoral joint after
HTO. Intra-articular hyaluronic acid improved the clinical
outcome by reducing NSAID consumption without any
Fig. 5 Osteotomy site showing good progression of bone healing at
1 year after surgery
1422 Knee Surg Sports Traumatol Arthrosc (2014) 22:1415–1423
123
severe adverse events, as observed compared to the control
group during 1 year of post-operative study.
Acknowledgments The authors would like to thank Professor
Weerachai Kosuwan and the engineering team from Khon Kean
University for helping to perform the cartilage volume measurement.
This manuscript is based upon the clinical trial results from a study
sponsored by TRB Chemedica. Sponsor has the role to provide all of
the study medication and management of patients’ appointment in the
entire follow-up periods.
Conflict of interest None.
Ethical standard Ethics committee approvals were obtained.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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