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KEYWORDS: Collagen peptides, osteoarthritis, joint pain, healthy ageing, nutraceutical
AbstractAs the global population gets older, joint-related health concerns are increasingly common, such as
osteoarthritis causing pain and reducing mobility. Collagen peptides have been proposed as
nutraceuticals to improve joint health in patients with osteoarthritis. We performed a prospective, randomized, double-blind, placebo-
controlled study in elderly women with mild-to-moderate knee osteoarthritis and showed that the oral intake of collagen peptides
(Peptan®) for a duration of 6 months significantly reduces joint pain and improves physical mobility as assessed by two well-
established scoring systems (WOMAC and Lysholm score). This study confirms that collagen peptides are a highly efficient
nutraceutical to improve joint health which can help to maintain an active lifestyle throughout ageing.
Collagen peptides improve knee
osteoarthritis in elderly women
A 6-month randomized, double-blind, placebo-controlled study
INTRODUCTION
Population ageing
Worldwide, the population is increasingly ageing, with a
greater proportion of people getting old and old people
reaching an even higher age than before. In 2009,
10% of the population were 60 years and older and this
fraction is estimated to increase up to 20% by 2050 (1).
This demographic development is associated with an
increase in age-related diseases (2) concurrently building
a strong case for the maintenance of health throughout
ageing and the focus of interest of the pharmaceutical
and nutraceutical industry.
Osteoarthritis
One age-related disease with rising prevalence is
osteoarthritis with 10% of all men and 20% of all women
over 60 years old already suffering from it today (3).
Osteoarthritis is a degenerative disease of the articular
cartilage in joints of the knee, hip, spine and hand.
Pain, stiffness and locking of the joint are key symptoms
reducing mobility and strongly impacting on the quality of
life of the patient.
The hyaline cartilage of the joint consists mainly of
extracellular matrix composed of collagen, proteoglycans
(e.g. aggrecan) and glycosaminoglycans such as
hyaluronic acid. Chondrocytes present in the cartilage
maintain the matrix in a finely-tuned turnover process
balancing synthesis and breakdown. In osteoarthritis,
a dysregulation of this balance leads to a shift towards
degradation with a subsequent loss of cartilage. In
addition to cartilage degradation, the inflammation
of the lining surrounding the joint space, the synovium,
as well as alterations in the bone underlying the
joint cartilage, such as sclerosis and the formation
of osteophytes, are involved in the pathological
manifestation of osteoarthritis (4).
Currently, osteoarthritis cannot be cured and available
treatment is mostly symptomatic. To treat pain, mainly
analgesics and non-steroidal anti-inflammatory drugs
(NSAIDs) are used, which at long-term or high-dose use
may cause heavy side effects, such as gastrointestinal
bleeding and cardiovascular disease (5, 6). Suggested as
a safe alternative, the dietary supplements glucosamine
and chondroitin sulfate have been used to treat
osteoarthritis. However, a systematic, multi-centred study
at a large scale did not find a general beneficial effect of
glucosamine or chondroitin sulfate. Only a small subgroup
of patients with moderate-to-severe pain significantly
benefited from a combined treatment with glucosamine
HEALTHY AGEING
JIAN-XIN JIANG1, SHEN YU1, QI-REN HUANG2, XIAN-LONG ZHANG1,
CHANG-QING ZHANG1, JIAN-LIE ZHOU3*, JANNE PRAWITT4*
*Corresponding authors
1. Department of Osteology, Shanghai 6th People’s Hospital,
Jiaotong University, 600 Yishan Road, Shanghai 200233, PR China
2. Department of Osteoporosis, Shanghai 6th People’s Hospital,
Jiaotong University, 600 Yishan Road, Shanghai 200233, PR China
3. Medical Consultant of Rousselot AP, 25/A,
18 North Cao Xi Road, Shanghai 200230, PR China
4. Rousselot BVBA, Meulestedekaai 81, B-9000 Gent, Belgium
Jiaotong University, 600 Yishan Road, Shanghai 200233, PR China
Jian-Xin Jiang
Jian-Lie Zhou
Janne Prawitt
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Agro FOOD Industry Hi Tech - vol 25(2) - March/April 2014
sclerosis and possible deformation of the bone contour;
grade IV - marked narrowing of the joint space, large
osteophytes, severe sclerosis and definite deformation
of the bone contour. Only subjects with a Kellgren-
Lawrence score of 0-I to III (excluding stage IV of severe
osteoarthritis), without allergies and with normal liver
and kidney function were included, who had not used
nutraceuticals or analgesics within the last 6 months.
Patients were randomly assigned to receive a daily
oral dose of 8g collagen peptides or 8g placebo for a
duration of 6 months. The administered collagen peptide
was Peptan®B 2000 (Rousselot) of bovine origin, while
maltodextrin was used as placebo. Compliance was
defined as the percentage of those subjects who took the
treatment in agreement with the protocol guidelines of all
subjects designated to the respective treatment group.
Assessment of safety parameters and treatment efficacy
Patients were examined at baseline as well as 3 and
6 months after the start of the treatment. Blood and
urine were sampled for the analysis of liver and kidney
parameters by standard biochemical procedures.
Joint pain and function were assessed using two well-
established scoring systems based on standardized
questionnaires, the WOMAC (23) and the Lysholm score
(24). The primary endpoint of the study was defined as the
difference of the WOMAC and Lysholm score between
the placebo and the collagen peptide group after 6
months of treatment. The WOMAC score evaluates 24
parameters for pain, stiffness and physical function of
the joint which are recorded on a visual analogue scale
with a high score indicating more severe symptoms of
osteoarthritis. The Lysholm score assesses 6 parameters for
knee joint function (e.g. limping, stair climbing, running,
jumping). A high score is associated with a better knee
function.
Statistical analysis
All values are indicated as mean with standard deviation
unless indicated otherwise. Statistical analysis was
performed by means of Student’s T-Test , repeated
measurement ANCOVA or Fisher’s exact test. Differences
were considered significant when p<0.05.
RESULTS
Patient characterisation and adherence
The hundred osteoarthritis patients that entered the study
and chondroitin sulfate (7). Thus, the strong need for
alternative symptom-modifying therapies has created a
highly active field of research.
Collagen peptides
Collagen peptides are a specific mix of peptides of
different length, obtained by the enzymatic hydrolysis
of native collagen coming from animal connective
tissues, with a high abundance of the amino acids
hydroxyproline, glycine and proline. Used as a food
ingredient, collagen peptides are proven to be safe (8)
and to have a high bioavailability (9). They have been
shown to exert a beneficial effect on bone and skin (10,
11) and have been proposed as a candidate therapy for
osteoarthritis (12).
Studies in rodents have demonstrated that radio-actively
labeled collagen peptides accumulate in cartilage upon
ingestion (13, 14). Since collagen is the major protein
component of the extracellular matrix in cartilage,
collagen peptides have been suggested to stimulate the
formation of cartilage by simply providing building blocks.
In addition, collagen peptides have been shown to
enhance the synthesis of collagen (15) and proteoglycans
(16) in primary chondrocytes as well as the secretion of
hyaluronic acid from synovial fibroblasts (17) and might
thus be able to actively shift the balance of cartilage
turnover in osteoarthritis towards net formation.
Indeed, several clinical studies have investigated the
effect of collagen peptide treatment in individuals with
joint discomfort or osteoarthritis, reporting different levels
of joint pain improvement upon treatment (18-21) but
with conflicting results on the effect on joint function
(19 - 21). The aim of the present study was to assess the
effect of collagen peptide ingestion on knee joint pain
and function in patients with mild-to-moderate knee
osteoarthritis.
STUDY DESIGN
A prospective, single-centre, randomized, double-
blind, placebo-controlled trial was conducted between
January and July 2012 at the 6th People’s Hospital
affiliated to Shanghai Jiaotong University, China. The
study protocol was approved by the hospital’s ethical
committee which works according to the guidelines of
Good Clinical Practice and the study was registered in
the hospital’s database (Clinical Trial Registration No.
2011-51). All participants gave their informed consent.
Patient recruitment, inclusion criteria and treatment
Hundred women between the age of 40 and 70
presenting themselves with knee joint pain or discomfort
were recruited to participate in the study. This effect
size assures, at a significance level of a=0.05, a power
of 90% for WOMAC score, and of more than 80% for
Lysholm score. Osteoarthritis was diagnosed by x-ray and
quantified using the Kellgren-Lawrence x-ray classification
(22). According to the guidelines the scores were defined
based on the following symptoms: grade I - doubtful
narrowing of the joint space and possible osteophytes
lipping; grade II - definite narrowing of the joint space
and definite osteophytes; grade III - definite narrowing
of the joint space, moderate multiple osteophytes, some
Table 1. Baseline characteristics of the recruited patients.
Values are presented as means ± standard deviation.
Statistical signicance of differences was calculated by
Student’s T-Test. BMI=body mass index.
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Agro FOOD Industry Hi Tech - vol 25(2) - March/April 2014
system. The WOMAC score is composed of subscale
scores for pain, stiffness and physical function. As shown
in Figure 1, the values of the WOMAC score decreased
over time in patients treated with collagen peptides
indicating a gradual improvement of joint pain and
function. At 3 months of treatment, a small but already
highly significant effect was visible (treatment difference
of 0.002 in the placebo vs. -1.07 in the collagen peptide
group, p<0.001) which developed into a pronounced
and highly significant improvement of knee osteoarthritis
after 6 months of treatment with collagen peptides
(treatment difference of -0.77 in the placebo vs. -3.93 in
the collagen peptide group, p<0.001).
The difference between the WOMAC scores of the
collagen peptide group and the placebo group after six
months was significant for all three WOMAC subscales
(Table 4), demonstrating an improvement in knee pain
and stiffness as well as in physical function.
The Lysholm score which emphasizes on a comprehensive
evaluation of joint function demonstrated an
improvement over time by gradually increasing values in
patients treated with collagen peptides (Figure 2). In line
with the results of the WOMAC score a highly significant
effect already detectable at 3 months of treatment
(treatment difference of 0.25 in the placebo compared
to 2.39 in the collagen peptide group, p<0.001) further
increased into a clear and significant effect at 6 months
were equally randomized to the two treatment groups,
placebo or collagen peptides.
Over the course of the study, two patients dropped out
of the placebo group (for reasons of non-adherence
and lateral thigh pain), and four patients dropped out
of the collagen peptide group (three had already taken
collagen peptides before the study and one presented
septic arthritis). As shown in Table 1, there were no
significant differences at baseline between both groups
regarding age, height, weight, body mass index (BMI),
WOMAC score and Lysholm score.
Importantly, the level of osteoarthritis quantied using
the Kellgren-Lawrence X-ray classication (Table 2) was
distributed in a comparable manner without signicant
differences between the placebo and the collagen peptide
group. Around half the patients of each group presented
mild osteoarthritis in one or both knees (score I-II).
Treatment safety
At baseline as well as after 6 months of treatment,
parameters of liver function (SGOT, SGPT) and kidney
function (blood urea nitrogen, serum creatinine, serum
uric acid) were within the normal range for all patients
with no significant differences between the placebo and
the collagen peptide group neither at baseline nor after
6 months of treatment (Table 3). Compared to baseline,
the improvement of liver parameters and blood urea
nitrogen was significant in the collagen peptide group,
even though the change from baseline was very
small. Serum creatinine showed a small but significant
increase from baseline in the placebo and to a lesser
extent in the collagen peptide group. Overall, this
result demonstrates that the treatment of osteoarthritis
patients with 8g collagen peptides daily over a duration
of 6 months is safe.
Treatment efficacy
The effect of the treatment on joint pain and function
was evaluated by the WOMAC and the Lysholm scoring
Table 2. Kellgren-Lawrence score of the recruited patients at
baseline. Statistical signicance of differences was calculated by
Fisher’s exact test. Levels of osteoarthritis are dened as 0=None,
I=Doubtful, II=Minimal, III=Moderate (22).
Table 3. Parameters of liver and kidney function were measured in
blood and urine at baseline and after 6 months of treatment with
placebo or collagen peptides. Values are presented as means
± standard deviation. Statistical signicance of differences was
calculated by Student’s T-Test. SGOT=serum glutamic oxaloacetic
transaminase; SGPT=serum glutamic pyruvic transaminase;
BUN=blood urea nitrogen.
Figure 1. Effect of collagen peptide treatment on osteoarthritis
assessed by the WOMAC score. Score values at baseline, after
3 months and 6 months of treatment are presented as mean ±
standard error mean. Statistical signicance of differences was
calculated by ANCOVA. A low WOMAC score indicates a low
degree of osteoarthritis. *** p<0.001.
Table 4. Effect of collagen peptide treatment on the WOMAC
subscale scores for pain, stiffness and function. Score values at
baseline and after 6 months of treatment are presented as mean
± standard deviation. Statistical signicance of differences was
calculated by ANCOVA. A low WOMAC subscale score indicates
a low degree of pain or stiffness, and a lower degree of difculty
in physical function.
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Agro FOOD Industry Hi Tech - vol 25(2) - March/April 2014
of treatment (treatment difference of 0.77 in the placebo
compared to 5.00 in the collagen peptide group,
p<0.001). Thus the beneficial effect of collagen peptide
treatment on joint pain and function in osteoarthritis
patients could be shown independently by two different
evaluation systems.
DISCUSSION
Collagen peptides are nutraceuticals used in dietary
supplements and as a food ingredient offering health
benefits at different levels. Their positive effect on skin
physiology, increasing skin hydration and elasticity (11),
stimulating synthesis of skin matrix components (25, 26)
and decreasing skin collagen fragmentation (Rousselot,
unpublished data), is well documented. Several in
vivo studies have further reported a positive impact
of collagen peptides on bone formation, resulting in
increased bone strength and bone mineral density
helping to reduce osteoporosis (10, 27, 28). Lately,
collagen peptides have been vividly discussed as a
symptom-modifying agent for osteoarthritis (12). Based
on their application in functional foods as a bioactive
ingredient they are thought to act at a rather early
stage of the disease helping to prevent or delay the
manifestation of osteoarthritis.
We performed a randomized, double-blind, placebo-
controlled trial in elderly women to evaluate the
effect of collagen peptides on the symptoms of knee
osteoarthritis. Since the variability of results in other
clinical trials has been attributed to the investigation
of rather heterogeneous patient cohorts, we recruited
only women within a defined age and BMI range, who
presented with mild knee osteoarthritis. The relative
homogeneity of the study groups was confirmed by
the fact that over 50% of all subjects in each group
presented a rather low score of I-II on the Kellgren-
Lawrence scale, indicating mild osteoarthritis.
In the present study, the administration of collagen
peptides at a dose of 8g/d was highly efficient to
decrease joint pain and stiffness and to improve joint
Figure 2. Effect of collagen peptide treatment on osteoarthritis
assessed by the Lysholm score. Score values at baseline, after
3 months and 6 months of treatment are presented as mean ±
standard error mean. Statistical signicance of differences was
calculated by ANCOVA. A high Lysholm score indicates a low
degree of osteoarthritis. *** p<0.001.
function in comparison to the placebo, with a significant
effect already observed after 3 months of treatment.
The improvement of pain evaluated with the help of the
WOMAC score is in line with the results of several other
clinical studies. Benito-Ruiz et al. observed a decrease
in pain according to two different pain scales (VAS
and WOMAC) in a gender-mixed cohort with mild knee
osteoarthritis (19). Another trial showed that collagen
peptides performed even better than glucosamine in
reducing pain in osteoarthritis patients as early as 3
months after the treatment start (20).
In addition to the WOMAC score, we used the Lysholm
scoring system for the assessment of joint function.
The Lysholm score has been developed specifically
to evaluate knee function, by integrating information
on limping, stair climbing, locking, giving way of the
knee during activity and the ability to squat the joint.
Corresponding to the results of the WOMAC rating, the
Lysholm score significantly improved over the study
duration in patients treated with collagen peptides
in comparison to the placebo group. This finding is
remarkable since only one other study has described
such an effect (20). Two other trials assessed joint
function by WOMAC or Quality of Life scores but did not
find an effect of collagen peptide treatment (19, 21).
However, both studies used a much more heterogeneous
group of subjects presenting with general joint pain, not
diagnosed osteoarthritis, and performed a combined
evaluation of different joints (knee, hip, spine, etc.),
which might explain why no effect on joint function was
observed.
The presented data provide strong evidence for the
symptom-relieving effect of collagen peptides in knee
osteoarthritis, but the study design does not allow to
conclude on potential mechanisms of action. A recent
study has investigated the effect of collagen peptides
on joint structure in a small group of patients using a
MRI technique which can visualise cartilage (29). The
result suggests that collagen peptides increase the
proteoglycan content in knee cartilage after 6 months
of treatment, which is consistent with the in vitro data
showing a stimulation of extracellular matrix synthesis by
collagen peptides (15, 16).
Even if the differences observed after 6 months are
highly significant in the current study, more investigations
should be initiated in future to confirm the efficacy of
collagen peptides as a protective factor of cartilage
in randomized, placebo controlled clinical studies of
bigger scale, and with diverse patient characteristics
to overcome the current study’s limitations of sex,
ethnicity of the subjects and the cause and location of
osteoarthritis. In addition, mechanistic and biochemical
parameters (e.g. MRI, uCTX-I, uCTX-2) could be assessed,
and efforts could be made to investigate the potential
differences between collagen peptide products from
different sources and different production processes.
The present study demonstrates a clear beneficial effect
of collagen peptide (Peptan®) treatment on joint pain
and function in patients with mild knee osteoarthritis.
Their safety record and demonstrated absence of side
effects make collagen peptides a valuable alternative
symptom-modifying treatment for osteoarthritis. Thus, they
present a highly useful nutraceutical to help maintain the
quality of life during ageing.
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ACKLOWLEDGMENTS
The authors thank Hongshan Tan (Department of
Occupational and Environmental Medicine, School of
Public Health, Fudan University, Shanghai, PR China) for
his support of statistical analysis.
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