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INTRODUCTION
Osteoarthritis (OA) of
the main joints is a
diffuse
social problem altering
the quality of life of
millions
of older inhabitants in
the most industrialized
countries
and, at a younger age,
of inhabitants of
developing
countries (where severe
bone and joint
abnormalities
may be associated with
nutritional and
developmental
problems). The increase
in the average weight
with
age, the diffusion of
sedentary habits, the
decrease in
regular exercise
patterns cause a
progressive decrease
in physical fitness has
contributed to aggravate
the problems
due to OA.
A multitude of treatment
and management options
are available to manage
the symptoms of OA,
particularly
pain, and the
disabilities related to
this disease.
The quantitative
evaluation of the
effects of OA
on the quality of life
of patients and a
standardized
quantification of the
effects of treatments
has been an
important problem,
considering the
widespread clinical
signs associated with
several levels of
handicap and
alterations in the
quality of life.
The WOMAC (Western
Ontario and McMaster
Universities) index is
now generally used to
assess patients
with OA of the hip or
knee – two of the joints
causing
the most frequent and
severe motion handicaps
– using
24 main parameters
(Baron et al., 2007).
The WOMAC
can be used to monitor
the course of the
disease and
how OA affects the life
of patients or to
determine the
efficacy of
antirheumatic/antiinflammatory
treatments.
As a combination between
OA and arterial or
venous
vascular problems and
concomitant metabolic
syndrome
is relatively frequent,
so the vascular aspects
should be
also considered in the
management of these
subjects.
Impaired motion causes
some level of edema of
the
affected limbs (i.e. in
patients with chronic
venous
insufficiency or in
subjects treated with
antihypertensive
drugs). Stasis and low
mobility cause a chronic
increase
in local, distal venous
pressure, therefore
transforming
a mild level of venous
disease into a severe,
chronic
venous hypertension,
often causing
ulcerations. These,
in turn, may contribute
to the signs and
symptoms
of OA, altering mobility
and social life and
causing
further handicaps.
Therefore, vascular
complications should be
evaluated
together with aspects
specifically concerning
OA (i.e. pain,
mobility) to judge the
quality of life of OA
patients.
Four main components –
all contributing to the
clinical
picture – may be
considered in the
treatment management
of OA: 1. specific,
OA-related,
signs/symptoms
(described by
the WOMAC score);
2. inflammation causing
a progression in the
disease;
3. alteration (and
improvement by
treatment) of
fatigue resistance and
muscular performance;
4. reversing and
blocking the vascular
problems
associated with altered
mobility (i.e. often
leading
to edema and sometimes
even to venous and
stasis
ulcerations).
These four aspects can
all be considered as
targets of
a treatment evaluation.
Theoretically, treatment
with a compound
specifically
active on all these four
aspects could be highly
effective.
Therefore, a study
involving Pycnogenol® –
as the
main treatment – was
planned to evaluate
changes in
these main clinical
aspects of OA.
Pycnogenol® is the
trademark of Horphag
Research
Ltd, UK for a
standardized extract
from the bark of
the French maritime
pine. The extract is a
concentrate
of plant polyphenols,
predominantly
procyanidins.
This compound has
antiinflammatory actions
in vitro
and in vivo and
scavenges free radicals
(Rohdewald,
2005; Devaraj et al.,
2002; Durackova et al.,
2003). In
the context of treatment
of OA, inhibition of
matrix
metalloproteases (MMPs)
is of great interest.
After the
intake of Pycnogenol®,
release of MMP9 from
macrophages
is inhibited (Cisar et
al., 2006), thus
blocking
the destructive activity
of MMP on cartilage.
Pycnogenol inhibits in
vitro the activation of
NFκB,
a key element of
inflammation (Grimm et
al., 2006).
Furthermore, plasma from
volunteers inhibited
significantly
the activation of NFκB
in inflammatory cells
ex vivo, blocking
subsequent steps of the
inflammatory
reactions (Grimm et al.,
2006). Cyclooxygenases
initiate
the production of
pain-producing
prostaglandins.
Plasma from human
volunteers inhibited
cyclooxygenases
I and II following
intake of Pycnogenol®
(Schäfer et al.,
2006). The sum of these
antiinflammatory effects
suggests
that this compound may
have a positive effect
in reducing the symptoms
of mild to moderate
osteoarthritis.
Furthermore, Pycnogenol®
demonstrated in
several clinical trials
its activity against
edema formation
and chronic venous
insufficiency
(Rohdewald, 2005;
Cesarone et al., 2005,
2006a, 2006b, 2006c;
Belcaro et al.,
2006). In a range of
clinical trials, the
unwanted effects
of Pycnogenol were
minimal, mainly mild
gastrointestinal
symptoms or dizziness,
and transient in most
cases
(Cesarone et al., 1999).
In the USA Pycnogenol
obtained
the GRAS status
(Generally Recognized As
Safe).
The aim of this study
was to evaluate the
efficacy
of 100 mg Pycnogenol
(oral capsules) in a
3-month,
double-blind,
placebo-controlled study
in patients
with OA and disability
due to pain of the major
joints
altering their quality
of life. The mobility of
these
patients was also
evaluated by recording
their walking
performance on a
treadmill.
PATIENTS AND METHODS
A total of 156 patients
with osteoarthritis
grade I or II,
confirmed by x-ray
analysis were included
in this study.
Patients were recruited
the San Valentino
vascular
screening project.
Patients were informed
about aim of
the study and treatment
procedure according to
the
declaration of Helsinki
and gave written
informed
consent. The study was
approved by the ethical
committee
of the University of
Pescara. Patients were
informed
that they could leave
the study any time
without
difficulty.
Inclusion criteria.
Primary osteoarthritis
grade I or II
in one or both knees was
diagnosed by x-ray
investigation.
There was mild to
moderate pain not
adequately
controlled with
antiinflammatory drugs.
Subjects had
to be able to perform
the treadmill test and
to understand
all questions from the
questionnaire.
Exclusion criteria.
Cardiovascular disease
requiring drug
treatment, particularly
coronary heart diseases,
diabetes,
overweight, severe
metabolic disorders,
surgery or arthroscopy
3 months before
inclusion or radio- or
chemotherapy.
Pregnancy, breast
feeding, planned
conception.
Randomization. Patients
were allocated to
treatment
groups using
randomization by blocks.
Block allocation
sequences were created
at random by using
randomly
generated numbers from a
computer program. The
randomization list
covered twice the number
of subjects
planned to be recruited.
Each patient enrolled in
the study received the
respective lowest
randomization
number available.
Estimation of size of
treatment groups. A
recent study
with a comparable
population of
osteoarthritis patients
showed a significant
response to Pycnogenol
treatment
using a group size of 37
patients (Farid et al.,
2007).
Taking into
consideration a drop-out
rate of 10–20%
for a treatment period
of 3 months, an alfa of
0.05 and
a beta of 0.20 (power of
80%) a number of about
80 patients in each
group was calculated to
obtain a
significant difference
from the placebo.
Evaluation of symptoms
of osteoarthritis. To
describe
and rate the symptoms of
osteoarthritis the
questionnaire
developed by the Western
Ontario and McMaster
Universities (Baron et
al., 2007) was applied.
The
questionnaire gives
scores for the diverse
symptoms of
osteoarthritis (WOMAC
scores) (Baron et al.,
2007).
The status of
osteoarthritis was
evaluated by the
investigator together
with the patient at the
start of
study and after 3 months
of treatment.
Evaluation of physical
performance. Patients
were trained
how to do the treadmill
test in two tutorial
tests. At the
start and after the end
of treatment, the
patient’s performance
was evaluated by the
treadmill test with a
speed of 3 km/h and an
inclination of 10%. The
total
distance which could be
covered without pain was
noted.
Vascular aspects. The
presence of any vascular
(arterial,
venous of lymphatic)
problem was carefully
evaluated
to exclude the influence
of vascular disease on
the
treadmill performance
(i.e. claudication) and
on pain.
Color-duplex, Doppler
(at rest and after the
treadmill
test) excluded the
presence of peripheral
vascular disease.
After a treadmill test,
in the presence of
peripheral
arterial disease, the
Doppler signal at the
distal
tibial arteries may
disappear for a variable
period of
time or become fainter
with a decrease in
tibial pressures
measured by Doppler. In
the case of a normal
arterial
system the distal
pressure is comparable
to the pre-test
value or higher (Belcaro
et al., 1996; Belcaro
and
Nicolaides, 2001). Also
venous diseases and the
possible
presence of venous
obstruction were
evaluated
before the inclusion and
at the end of the study
(Belcaro
et al., 1996).
Edema evaluation. Edema
was scored by the
investigator
using the following
scores: 0, not visible;
1, edema
only visible after long
standing or in the
evening; 2,
edema visible during the
day but relieved
overnight; 3,
edema visible during the
day but only partially
relieved
overnight; 4, edema
present all the time.
Ankle/foot edema.
Ankle/foot edema (foot
edema
levels 2 and 3 only) was
also evaluated in a
quantitative
way by foot volumetry in
a randomly selected
subgroup
of subjects within the
two treatment groups. To
normalize
the values, the actual
foot volume at inclusion
was defined as 100% (by
immersion in water,
using a
water displacement
method) (Belcaro et al.,
1996;
Belcaro and Nicolaides,
2001; Cesarone et al.,
1999).
The intra-individual,
relative percent
variations with this
test were within 8%,
therefore any variation
>10% can
be defined as caused by
external factors
(treatment,
management). The foot
volume values were
defined
at the end of the study
and compared. The
variations in
volume observed with
this method can be
considered
as the measurement of
the level of edema
involving the
distal part of the leg
(Cesarone et al., 1999).
The plastic
leggings included water
up to the level of the
knee
(defined as the lower
edge of the rotula, in
these measurements).
The leg was immersed in
water and the water
level was defined by
eliminating water from a
lower
side tap down to the
lower edge of the
rotula. The
relative volume was
defined as 100%. A
variation
of this volume was
measured as a percentage
of the
individual volume at the
start.
Evaluation of associated
treatments needed to
manage
arthrosis. A diary was
kept to record the use
of any
other drug prescribed by
the patient’s GP, the
use
of which was free (with
only a warning not to
use an
excess of treatment).
Evaluation of costs and
side effects. The cost
of treatments
and other costs
(including working
disruption
and hospital admission)
occurring during the
trial
period were recorded in
a specific costing file.
Medication. Pycnogenol
and placebo tablets were
prepared by Manhattan
Drug Company Inc, New
York,
USA. Verum and placebo
tablets had an identical
appearance, size and
shape. Containers of
study drugs
– verum and placebo –
were delivered by the
producer
labeled as A and B and
were identical in size,
shape
and appearance.
Emergency envelopes were
provided
to identify A and B in
the case of severe
adverse events.
Treatment consisted of
two tablets daily, taken
after
breakfast and after
dinner, consisting
either of placebo
or 50 mg Pycnogenol.
Statistical evaluation.
The results were
evaluated using
analysis of variance
(ANOVA) and the
non-parametric
Mann-Whitney U test.
Table 1. Patient
characteristics at
inclusion
Pycnogenol Placebo
Patient data group group
Age (years) 48.6 SD 8
47.8 SD 7.7
Male/female ratio 39/38
39/40
Mean global WOMAC score
79.2 76.9
Treadmill test mean 68 m
65 m
distance achieveda
(0–133 m) (12–98 m)
a Treadmill 8 km/h with
an inclination of 10%.
RESULTS
The treatment group (77
patients) and placebo
group
(79 patients) did not
differ in respect of
age, male to
female ratio, overall
WOMAC score and
performance
on treadmill test at the
start of the study
(Table 1).
Six patients in the
treatment group and five
patients
in the placebo group
left the study for
non-medical
reasons such as moving
to other places and work
problems.
Two patients had a
localized trauma from
accidents.
Symptoms of
osteoarthritis
The results of the
evaluation of treatment
success after
3 months by WOMAC scores
are given in detail in
Table 2.
Scores for pain dropped
significantly (p < 0.05)
following
Pycnogenol intake from
17.3 to 7.7, the placebo
had no significant
effect.
The scores for stiffness
were reduced
significantly
from 6.6 to 3.1 (p <
0.05), scores for the
placebo
remained unchanged after
3 months.
Also the scores for
physical function were
more
than halved, reducing
from 55.3 at the start
to 23.8 in
the verum group (p <
0.05), the improvement
under
placebo was not
significant.
The global WOMAC score
(Table 2) decreased
following
Pycnogenol treatment
significantly from 79.2
to
34.6, with the placebo
insignificant from 76.9
to 69.5.
Negative alterations of
social functions by OA
decreased significantly
in the treatment group
(p > 0.05),
but not in the placebo
group (details in Table
3).
The well-being of
patients (emotional
function) was
significantly (p < 0.05)
enhanced under verum
treatment,
as reflected in scores
for emotional function
(Table 3),
the placebo produced a
marginal improvement.
In conclusion, all WOMAC
scores improved
significantly
(p < 0.05) after 3
months treatment
relative to
the start and versus the
placebo.
Muscular performance
The results of the
exercise test on the
treadmill demonstrate
a convincing increase of
performance of patients
following the 3 month
treatment with
Pycnogenol
(Table 4). Patients
could walk just 68 m as
mean distance
covered at the start,
but could go for a mean
of
198 m after treatment,
versus only 65 m to 88 m
in the
placebo group. Vascular
problems
A high percentage of
patients (76% in the
Pycnogenol
group and 79% in the
placebo group) showed
visible
ankle and foot edema at
inclusion. At the end of
the treatment period,
edema decreased under
verum in
79% of the patients but
only in 1% of patients
under
placebo.
Foot volume, evaluated
by the
water-displacement
method, decreased in a
subgroup of 40 patients
with
slight to moderate edema
after Pycnogenol (n =
20) by
32% (19–69%), after
placebo (n = 20) by 7%
(0–22%).
The difference with the
placebo was significant
(p >
0.05).
Reduction of concomitant
medication
Patients were allowed to
use concomitant
medication
during treatment. The
use of NSAIDs dropped by
58% during treatment
with Pycnogenol, whereas
under
placebo NSAID use was
reduced by only 1%. The
difference between both
treatments was
significant
(p > 0.05) (Table 5).
Treatment costs
evaluated from
patients files indicate
a decrease in the need
for drugs
(other than NSAIDs) and
treatment by 54% versus
11% in the placebo group
(Table 5).
Decrease of management
costs
The days spent in
hospital and the number
of hospital
admissions decreased
over the study period of
3 months
by 60% in the treatment
group versus 3% in the
placebo
group. The decrease of
non-drug related
treatment costs
as lost working days,
consultations, insurance
costs was
estimated as 55% versus
3.5% with placebo (Table
5).
Unwanted effects
Unwanted effects of
treatment were reported
by patients
in diaries. Evaluation
of data demonstrated a
decrease
of gastrointestinal
complications of 63% in
the Pycnogenol
group versus 3% in the
placebo group.
DISCUSSION
The evaluation of
treatment success of
Pycnogenol by
using the WOMAC scores
resulted in a very
significant
decrease of OA symptoms
by about 50%. This
judgement
by patients was
supported by the
objective test of
treadmill performance of
OA patients, showing
that
patients could walk more
than twice the distance
after
Pycnogenol treatment
compared with placebo.
Thus,
this double-blind,
placebo-controlled study
confirmed
the hypothesis that
Pycnogenol, due to its
diverse
antiinflammatory
actions, could be used
as an alternative
treatment of OA to
relieve pain and
increase
mobility. The WOMAC
questionnaire revealed
not
only an improvement of
physical function of
patients
but showed a gain of
quality of life, by
enabling the
patients to be engaged
in social activities,
staying in
better mood.
Another important
advantage of the
treatment with
Pycnogenol is the
reduction of unwanted
effects, mainly
gastrointestinal
troubles connected with
the reduced use
of NSAIDs.
The improved symptoms of
OA and enhanced the
well-being of patients
leading to reduced
treatment
costs. The estimation of
the sparing effect of
Pycnogenol
to treatment costs of OA
point to the possibility
of a
better cost management
by adding the pine bark
extract to regular
treatment. However,
studies with a
larger population and
for a longer treatment
period are
needed to confirm the
findings of this study
on a broader
basis.
While some effects of OA
can be easily calculated
as
costs (as medical
care/management) costs
and disrupted
or lost working days,
other costs are not easy
to detect.
These hidden costs
include quality of life,
the need of a
family member support
(who may alter his/her
working
and life habits), the
inability to enjoy
leisure activities
global impact of OA is
often underestimated
because
of the difficulties in
quantifying many of its
consequences.
New safe and
cost-effective methods
of
treatment – not
associated with
complications and side
effects – which may be
directly used by
patients both
as a base treatment or
as a substitute
treatment for a
period of time are
useful for expanding the
therapeutic
range.
In addition to the
amelioration of OA
symptoms, the
study provided
information about
clinical effects which
have been generally
overlooked in previous
studies on
OA. The decrease of limb
mobility is generally
associated
with variable degrees of
edema, limb swelling and
deterioration of
microcirculation, which
in turn leads
to a more severe level
of disability. During
Pycnogenol
treatment, edema of the
lower legs and the foot
volume
were significantly
reduced compared with
placebo,
in accordance with our
previous publications
showing
the high efficacy of
Pycnogenol in edema
reduction
(Cesarone et al., 2005,
2006a, 2006b, 2006c;
Belcaro
et al., 2006).
The medication used in
this protocol was
therefore
not only characterized
by its potential to
improve the
symptoms of OA, but also
by its efficacy in
improving
peripheral vascular
disease and controlling
edema.
The reduction of signs
and symptoms of OA and
of vascular problems may
be attributed to the
diverse
antiinflammatory
mechanisms of
Pycnogenol, as the
unspecific inhibition of
cyclooxygenases I and II
(Schäfer
et al., 2006) and the
inhibition of matrix
metalloproteases
(Grimm et al., 2006).
Further clinical studies
have to clarify whether
the
increase of muscular
performance is due to
inflammation
control or to a direct
action on muscular
function.
CONCLUSIONS
This study provides a
new window to the
management
of OA by showing
significant actions of
Pycnogenol on
four main, clinical
components of OA:
1. the signs/symptoms
and disability;
2. inflammation causing
a progression in the
disease;
3. the altered fatigue
resistance and muscular
performance;
4. severe, vascular
problems associated with
altered
mobility (i.e. sometimes
leading to venous and
stasis
ulcerations).
The study demonstrated
an important clinical
action of
Pycnogenol on OA and
shows an interesting
potential
in the management of
this diffuse disease.
The aspects concerning
cardiovascular toxicity
of
antiinflammatory drugs
used in OA (Stillman and
Stillman, 2007; Rahme
and Nedjar, 2007) have
received
great attention lately.
As many OA patients have
concominant
cardiovascular diseases,
the use of Pycnogenol
may reduce the load of
antiinflammatory agents
and offers important
alternative management
solutions
for cardiovascular
patients.
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