Lin et al.

Journal of Orthopaedic
Journal of Orthopaedic Surgery and Research (2023) 18:694
https://doi.org/10.1186/s13018-023-04182-w Surgery and Research

RESEARCH ARTICLE Open Access

Analgesic efficacy of collagen peptide

in knee osteoarthritis: a meta‑analysis
of randomized controlled trials
Chun‑Ru Lin1, Sung Huang Laurent Tsai2, Ko‑Yen Huang3, Po‑An Tsai1, Hsuan Chou4 and Shu‑Hao Chang5,6*

Abstract
Background The management of knee osteoarthritis involves various treatment strategies. It is important to explore
alternative therapies that are both safe and effective. Collagen peptides have emerged as a potential intervention
for knee osteoarthritis. This study aims to evaluate the analgesic effects and safety of collagen peptide in patients
diagnosed with knee osteoarthritis.
Methods We conducted a systematic literature search following the guidelines of the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses statement. Multiple databases including PubMed, Scopus, EMBASE, Web
of Science, Cochrane, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) published up to 27
May 2023 that focused on the analgesic outcomes and adverse events associated with collagen peptides or hydro‑
lyzed collagen in patients with osteoarthritis. We assessed the quality of the included studies and the strength
of evidence using the Cochrane ROB 2.0 tool and Grading of Recommendations, Assessment, Development,
and Evaluations.
Results Four trials involving 507 patients with knee osteoarthritis were included and analyzed using the random-
effects model. All these trials were considered to have a high risk of bias. Our results revealed a significant difference
in pain relief between the collagen peptide group and the placebo group in patients with knee osteoarthritis (stand‑
ardized mean difference: − 0.58; 95% CI − 0.98, − 0.18, p = 0.004; I2: 68%; quality of evidence: moderate). However,
there was no significant difference in the risk of adverse events between collagen peptide and placebo (odds ratio:
1.66; 95% CI 0.99, 2.78, p = 0.05; I2: 0%; quality of evidence: very low).
Conclusions Our findings demonstrate significant pain relief in patients with knee osteoarthritis who received colla‑
gen peptides compared to those who received placebo. In addition, the risk of adverse events did not differ signifi‑
cantly between the collagen peptide group and the placebo group. However, due to potential biases and limitations,
well-designed randomized controlled trials are needed to validate and confirm these findings.
Keywords Osteoarthritis, Knee osteoarthritis, Collagen peptide, Pain, Adverse events

*Correspondence:
Shu‑Hao Chang
a00414@mail.fjuh.fju.edu.tw
Full list of author information is available at the end of the article

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Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 2 of 11

Introduction However, the efficacy and potential benefits of colla-

Knee osteoarthritis, a chronic degenerative joint disor- gen peptides in various applications remain a subject of
der, can have a significant impact on the lives of those ongoing scientific research and debate. Further studies
affected [1]. The condition involves gradual degradation are needed to better understand the effects and safety of
of knee cartilage, accompanied by development of oste- collagen peptides in the management of knee osteoar-
ophytes and remodeling of the subchondral bone. This thritis and other conditions [10].
leads to chronic pain, limited mobility, and decreased Previous studies have reported the potential pain-
mental well-being, greatly affecting the overall quality of relieving effects of collagen peptide or hydrolyzed colla-
life for individuals with knee osteoarthritis [2]. Various gen in people diagnosed with knee osteoarthritis [11, 12].
treatment options are available, ranging from lifestyle However, there is no meta-analysis or systematic review
modifications and oral medications to intra-articular to evaluate the efficacy and safety of collagen peptides in
injections and surgical interventions in severe cases [1]. this patient population. Therefore, to assess the efficacy
Factors such as age, presence of infrapatellar synovitis, of collagen peptide in relieving pain and reducing inci-
comorbidities, ethnicity, body mass index, joint effu- dence of adverse events in patients with knee osteoarthri-
sion, and severity of knee osteoarthritis at baseline can tis, we conducted a meta-analysis of relevant literature.
influence the prognosis of patients with this condition
[3]. Approximately, knee osteoarthritis affected 10% of Methods
men and 13% of women aged 60 years or older in the Research protocol and search question
USA [4]. The economic burden of knee osteoarthritis is The study was completed based on the guidelines of the
substantial, with estimated lifetime care costs ranging Preferred Reporting Items for Systematic Reviews and
from $12,400 to $16,000 [5]. The substantial economic Meta-Analyses (PRISMA) statement. The protocol of this
burden of knee osteoarthritis underscores the need for systematic review and meta-analysis study has been reg-
cost-effective and sustainable therapeutic options. In this istered in PROSPERO (CRD42023429790). The target of
context, collagen peptides have emerged as a promising this study was to evaluate the efficacy of collagen peptide
intervention due to their availability and potential bene- or collagen hydrolysate in pain reduction and to assess
fits in promoting joint health. By addressing the pain and potential risks compared to placebo in patients with oste-
functional limitations associated with knee osteoarthri- oarthritis of the knee. PICO were defined as patients with
tis, collagen peptides have the potential to improve the knee OA (P), using collagen peptide or collagen hydro-
overall well-being of affected individuals while potentially lysate (I), placebo (C), and pain score or adverse effect
reducing the financial strain associated with long-term (O).
care. Understanding the efficacy and safety of collagen
peptides in the management of knee osteoarthritis can Eligibility criteria and primary outcome
contribute valuable insights to optimize treatment strate- Types of studies
gies and provide relief to those impacted by this preva- The included studies must be a randomized controlled
lent condition. trial (RCT). The study outcomes must include pain
Collagen peptides are substances derived from hydro- scores, such as visual analog scale (VAS), or adverse
lyzed collagen and are also known as collagen hydro- events. Trials were excluded if they were (1) single-arm
lysate. They are the basic building blocks that form the follow-up studies, (2) case series, case reports, basic sci-
triple helix structure of collagen proteins, a promi- ence experiments, reviews, or non-human studies, (3)
nent protein component of various connective tissues conference abstracts, and (4) non-English articles.
including skin, bones, tendons, and ligaments [6]. Col-
lagen peptides are primarily composed of three amino Types of participants
acids: proline, hydroxyproline, and glycine, and can be The participants in the study must be diagnosed with
extracted from bovine hides, fish scales, or chicken skins knee osteoarthritis with either Kellgren-Lawrence grade
[7]. Collagen peptides are believed to improve overall I to III or functional class I to III.
health and appearance via stimulation of new collagen
production in skin, maintaining its elasticity and firmness Types of interventions
[8]. As a result, collagen peptides are often incorporated For a study to be included, its intervention must include
into cosmetic formulations, including creams, lotions hydrolyzed collagen as part of the intervention, and a
and oral supplements that aim to reduce wrinkles and matching amount of placebo as control. The substance
improve skin hydration [9]. Furthermore, Collagen pep- used as placebo in the included studies involve lactose,
tides are believed to reduce joint pain and inflammation, maltodextrin, glucosamine sulfate, or a combination of
enhance mobility, and support cartilage regeneration. maltodextrin, xanthan gum, and yeast extract.
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 3 of 11

Search strategy and study selection clinical heterogeneity among the studies included in this
We comprehensively searched the following data- meta-analysis, we used a random-effects model to esti-
bases: PubMed, Scopus, EMBASE, Web of Science, and mate the aggregated results. A p-value of less than 0.05
The Cochrane Library on May 27th, 2023. We used the was set as the threshold for statistical significance for all
Boolean algebra to explore the relevant keywords, and analyses. RevMan 5.4.1 was used to analyze the data.
the search strategy was offered in Additional file 1. More-
over, the reference lists of the identified studies were Results
screened to ensure a comprehensive search. Three indi- Literature search and selection process
vidual reviewers (CRL, KYH, HC) assessed the eligibility After an extensive search of multiple databases, a total of
of articles based on their titles and abstracts. The same 2974 records were identified. A strict screening process
reviewers then carried out an in-depth evaluation of the of titles and abstracts excluded duplicate and unrelated
full-text articles to make the final decision on inclusion. studies, resulting in 18 full-text articles being assessed
Any disagreements between reviewers were resolved for suitability. Four trials were eventually included in this
through a process of discussion and consensus. meta-analysis, which comprised a total sample size of 507
patients diagnosed with knee osteoarthritis. (Fig. 1).
Data collection and quality assessment
Relevant data from the included trials were extracted Study characteristics
by three independent reviewers (CRL, KYH, PAT). The Table 1 summarizes the study characteristics of the
extracted data included various study characteristics, included studies. The four studies were carried out in dif-
including author details, year of publication, study loca- ferent countries, namely Ecuador (n = 207) [12], Taiwan
tion, data source, study design, sample size, patient age, (n = 113) [11], China (n = 94) [16], and the Czech Repub-
inclusion criteria used in each study, and specific defi- lic (n = 93) [17]. The interventions used in all trials were
nitions for each treatment. Besides, the reviewers care- collagen peptides or hydrolyzed collagen, and each study
fully documented outcomes of interest, such as pain was published as a full article. One study had two differ-
scales (VAS) and the occurrence of adverse events. The ent intervention groups, hydrolyzed collagen type II and
efficacy of collagen peptides should be compared to the a combination of chicken essence and hydrolyzed col-
placebo group and only evaluated by VAS score on the lagen type II. [11]. All four studies used VAS to assess
100-mm scale after intervention at the endpoint. The the analgesic effect of collagen peptides [11, 12, 16, 17].
safety of collagen peptides was defined as any adverse One of the studies used VAS to rate pain intensity on
events after administration at the endpoint of those stud- several dimensions. These dimensions included current
ies. Two reviewers (CRL, PAT) assessed the risk of bias in pain status, typical and average pain experiences, pain
the included studies and the quality of evidence for the intensity at its peak, and pain intensity at its lowest point
study outcomes. The Cochrane ROB 2.0 framework [13] [17]. Table 2 reports the information on the formulation,
was used to evaluate the risk of bias, while the Grading source, and components used in the included studies.
of Recommendations, Assessment, Development, and
Evaluations (GRADE) system [14] was used to assess the Methodological quality and assessment of risk of bias
quality of evidence. Any disagreements between review- As shown in Figs. 2 and 3, all four studies included in this
ers were resolved through discussion and consensus. analysis were assessed as having an overall high risk of
bias using the ROB 2.0 tool [13]. Specifically, in terms of
bias due to deviations from the intended interventions,
Statistical analysis and quantitative data synthesis
none of the four studies provided an adequate analysis
A pairwise meta-analysis was performed to evaluate
to estimate the effect of non-adherence [11, 12, 16, 17].
and compare the efficacy and safety of collagen peptides
Furthermore, in terms of risk of bias in the selection of
in people with knee osteoarthritis. We used standard-
reported outcomes, one study did not present all relevant
ized mean differences (SMDs) to assess the mean differ-
data in precise numerical values but relied on graphical
ence (MD) of analgesic effect of collagen peptides and
representations [11].
odds ratio (OR) to examine the risk of adverse events
of collagen peptides in knee osteoarthritis patients. The
statistical heterogeneity of the results was assessed by Pain
categorizing the ­I2 values into different ranges. I­2 values A total of three studies with 375 patients with knee oste-
of 25% to 50%, 51% to 75%, and 76% to 100% were consid- oarthritis were included in the evaluation of the analgesic
ered to indicate low, moderate, and high levels of statis- efficacy of collagen peptides. In Fig. 4, our meta-analysis
tical heterogeneity, respectively [15]. Given the expected reported a statistically significant difference in pain con-
trol in patients with knee osteoarthritis when comparing
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 4 of 11

Fig. 1 Flow of identification, screening, eligibility, and inclusion

the collagen peptide and placebo groups (SMD: − 0.58; gastrointestinal morbidities, respiratory infections,
95% CI − 0.98, − 0.18, p = 0.004; I2: 68%; quality of evi- septic arthritis, and lateral thigh pain. The difference
dence: moderate). in adverse events between the collagen peptide and
placebo groups is shown in Fig. 5. Our meta-analysis
showed no significant difference in the risk of adverse
Adverse event events between the collagen peptide and placebo
A total of four studies with 507 patients with knee oste- groups in patients with knee osteoarthritis (OR 1.66;
oarthritis were included in the evaluation of the risk of 95% CI 0.99, 2.78, p = 0.05; ­I2:0%; quality of evidence:
adverse events of collagen peptides. The adverse events very low).
reported in the studies include migraine headache,
Table 1 Study characteristics of the included studies
Study Design Location Drug Inclusion Experimental Experimental Control group Age (yrs) Sex Outcome Follow-up
type criteria group 1 group 2 (M/F)

Benito- Randomized, double-blind, Ecuador Oral Primary 10 g hydro‑ NA A matching 59 15/192 VAS (100 scale), Baseline, 3 months,
Ruiz P controlled multicentre trial knee lyzed collagen amount of pla‑ WOMAC, SF-36 5 months
2009 osteo‑ for once-daily cebo (lactose) score
arthritis administration, for once-daily
(Kellgren- 111 partici‑ administration,
Lawrence pants 96 participants
grade
Lin et al. Journal of Orthopaedic Surgery and Research

I-III)
Chen CC Randomized, double-blind, Taiwan Oral Mild Hydrolyzed Essence 6.8 g malto‑ 45– 17/96 VAS pain score, WOMAC score at 8,
2023 four-arm, pilot study to moder‑ collagen type of chicken + hydro‑ dextrin, 0.007 g 75 years WOMAC score, 16, and 24 weeks;
ate knee II, 38 partici‑ lyzed collagen type xanthan gum, fat-free mass, VAS pain score
osteoar‑ pants II, 37 participants and 0.43 g grip strength, at 7 and 14 days;
thritis ( yeast extract, 38 SF-36 grip strength, FFM
(2023) 18:694

Kellgren– participants at 24 weeks

Lawrence
grade I
to III)
JX Jiang Prospective,single- China Oral Knee Peptan B 2000 NA Maltodex‑ 40–70 0/94 WOMAC 3 months,6 months
2014 centre,randomized,doulble- osteo‑ of bovine ori‑ trin,8 g per day and the Lysholm
blind,placebo-controlled arthritis gin,8 g per day for 6 months,48 scoring system
trial (Kellgren- for 6 months, participants
Lawrence 46 paticipants
score
of 0-I
to III)
Trč T 2011 Prospective, multicentre, Czech Oral Knee 10 g enzymatic NA 1.5 g glucosa‑ 40 years NA VAS (100 scale), − 7, 0, 15, 30, 60,
randomized, parallel, Republic osteo‑ hydrolyzed mine sulfate or older WOMAC, SF-36 and 90 days
double-blind study arthritis collagen once daily for 90 score, self-
(func‑ once daily consecutive assessment,
tional for 90 con‑ day, 46 partici‑ the investigator’s
class I, II, secutive day, pants overall opinion,
or III) 47 participants and reduction
of the use of res‑
cue medication
Page 5 of 11
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 6 of 11

Table 2 Patented formulations, botanical or chemical of medications from the included studies
Study Formulation Source Component Quality control Chemical
reported? (Y/N) analysis
reported? (Y/N)

Benito 2009 Colnatur (Protein SA, Girona, Colnatur (Protein SA, Girona, natural hydrolyzed collagen N N
Spain), a powdered hydrolyzed Spain)
natural collagen with a mean
molecular weight of 3,500 Da;
10 g hydrolyzed collagen
for once-daily administra‑
tion dissolved in a liquid
of the patient’s choice
Chen CC 2023 Essence of Chicken-hydrolyzed Suntory Beverage and Food Hydrolyzed collagen type II: N Y
collagen type II doses: 2.0 g Asia (Changhua Taiwan, Good derived from chicken sternal
of hydrolyzed collagen type II Hygiene Practice certified) cartilage; Essence of Chicken:
collagen and 5.81 g of Essence extracted from chicken meat
of Chicken with proteins
and peptides/hydrolyzed
collagen type II doses: 2.0 g
of hydrolyzed collagen type II
collagen
JX jiang 2014 Hydrolyzed collagen bovine Peptan B 2000,Rousselot Food grade Bovine Collagen Y N
100% Peptides
Trč T 2011 10 g enzymatic hydrolyzed Colatech® (trade name, uncer‑ Enzymatic hydrolyzed collagen N N
collagen tain company)

Fig. 2 ROB2, risk of bias assessment of the included studies, and the summary of domains

Post hoc analysis (SMD: − 0.63; 95% CI − 0.86, − 0.39, p < 0.00001; I2: 52%;
The study conducted by Trč and BohmováIn reported an quality of evidence: moderate).
analgesic effect in 4 different conditions, including VAS
in pain right now, typical or average pain, pain level at its
best and pain level at its worst [17]. Thus, in our addi- Discussion
tional analysis, we extracted the data of the other groups Our study yielded promising findings regarding the
from the study conducted by Trč and Bohmová [17]. The potential clinical benefits of collagen peptides in provid-
difference in analgesic effect between the collagen pep- ing pain relief for individuals with knee osteoarthritis.
tide and placebo groups is shown in Fig. 6. Our meta- The analysis showed a significant difference in pain relief
analysis revealed a statistically significant difference in between the collagen peptide group and the placebo
pain control in patients with knee osteoarthritis when group. Importantly, the study also revealed that the risk
comparing the collagen peptide and placebo groups of adverse events did not significantly differ between the
two groups. The most commonly reported adverse events
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 7 of 11

Fig. 3 The summary of domains of the risk of bias

Fig. 4 Forest plot demonstrating overall pain scores comparing between collagen peptides and placebo. Better pain control is shown if favor
collagen peptides or placebo

associated with collagen peptide administration were osteoarthritis [20]. In addition, a previous study which
gastrointestinal disorders, migraines, and collagen pep- contained more than 60 studies (in vitro, in vivo, clin-
tide-related infections including respiratory infection and ics and on bioavailability) exploring the impact of col-
septic arthritis. These results suggest that collagen pep- lagen peptides on cartilage damage, joint erosions, and
tides may offer a safe and effective therapeutic option for joint pain reported consistent intake of collagen peptides
managing knee osteoarthritis symptoms. have benefit in prevention and relief of joint discomfort,
With the trend of the global population aging, the reducing bone density loss, and slowing skin aging pro-
prevalence of osteoarthritis patients rose, highlighting cess [21].
the urgent need for effective osteoarthritis treatment and Collagen peptide products have long been used in
prevention strategies. Owing to the potential adverse pharmaceuticals, biomaterials, and foods [7]. Our meta-
effects associated with the use of analgesics and anti- analysis revealed an analgesic effect of collagen peptide
inflammatory drugs for the treatment of osteoarthritis, in patients with knee osteoarthritis compared to the
it is necessary to explore safe therapeutic ingredients to placebo groups. Multiple studies demonstrated possible
replace or minimize reliance on currently used treatment cellular mechanisms of the beneficial effects of collagen
modalities [18, 19]. Collagen derivatives, including col- peptides on alleviating pain and improving joint condi-
lagen hydrolysate, undenatured collagen, and gelatine, tion in knee osteoarthritis. These mechanisms include
are candidates for use as disease-modifying drugs for the anti-inflammatory and antioxidant capacities of
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 8 of 11

Fig. 5 Forest plot demonstrating overall adverse events between collagen peptides and placebo. Lower adverse event is shown if favor collagen
peptides or placebo

Fig. 6 Post hoc analysis of pain scores including data in all different conditions in Trč 2011 between collagen peptide and placebo. Better pain
control is shown if favor collagen peptides or placebo. Trč 2011: VAS measured in pain right now. Trč 2011*: VAS measured of typical or average pain
Trč 2011**: VAS measured of pain level at its best. Trč 2011***: VAS measured of pain level at its worst

collagen peptides, and its ability to stimulate collagen content as well as bone mineral density in the femur of
synthesis and promote bone formation [22–24]. In vitro rats [27]. Bovine collagen hydrolysate was shown to
and in vivo studies showed a reduction of pro-inflamma- stimulate osteoblast differentiation and mineralized
tory cytokines, including IL-1β, IL-6, and TNF-α after bone matrix formation through increased runt-related
collagen peptide administration [22, 25]. Collagen pep- transcription factor 2 (Runx2) expression and activity
tide also displays antioxidant activities measured by oxy- [23], and may serve as an effective supplement for pre-
gen radical absorbance capacity and radical scavenging venting bone loss by significantly enhancing the organic
assay [24]. Furthermore, evidence has shown that orally substance content of bone [28]. The promotion of bone
administered collagen hydrolysate stimulates a signifi- formation could be further explained by the downregula-
cant increase in type II collagen synthesis by chondro- tion of the aforementioned pro-inflammatory molecules,
cytes [26]. Animal studies demonstrated the efficacy of because these cytokines are responsible for the upregu-
gelatin to increase type I collagen and glycosaminoglycan lation of receptor activator for nuclear factor kappa-B
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 9 of 11

ligand (RANKL) for osteoclast recruitment, which may et al. reported limited efficacy of collagen derivatives
lead to bone loss [25]. Current scientific research indi- in osteoarthritis [20]. However, the previous meta-
cates that consistent consumption of collagen peptides analysis included a broader range of collagen deriva-
has been associated with a reduction in joint pain and tives, namely gelatin, undenatured collagen type II, and
bone density loss [21, 22, 29]. The underlying mecha- collagen peptides. In contrast, our study specifically
nisms through which collagen peptides exert these concentrated on evaluating the therapeutic effects of
beneficial effects may involve their ability to diminish collagen peptides alone. This difference in the composi-
proinflammatory molecules, enhance collagen synthesis, tion of collagen derivatives examined could potentially
and facilitate bone formation. contribute to variations in the observed outcomes.
Our results showed no significant difference in the risk Moreover, the previous meta-analysis encompassed
of adverse events between the collagen peptide and pla- osteoarthritis of various organs, while our research
cebo groups in patients with knee osteoarthritis. How- exclusively focused on knee osteoarthritis. Osteoar-
ever, not all of the studies included in our research [11, thritis can affect different joints and organs through-
12, 16, 17] specified the adverse events. In the study by out the body, and the pathophysiological processes and
Benito-Ruiz P et al., the most common adverse event of responses to treatment may vary across these different
collagen peptide was gastrointestinal disorders (n = 29), locations. By narrowing our scope to knee osteoarthri-
followed by migraine headache (n = 14) and respiratory tis, we aimed to provide a more targeted analysis of
infection (n = 10). However, none of the adverse events the specific benefits and effects of collagen peptides in
were obviously associated with the treatment [12]. A pre- this particular context. Therefore, the differences in the
vious RCT of collagen peptides also reported gastroin- types of collagen derivatives examined and the focus
testinal symptoms as the most common adverse events, on knee osteoarthritis specifically are key factors that
which is compatible with our findings. These gastrointes- likely contribute to the contrasting findings between
tinal symptoms, including vomiting and diarrhea, were the previous meta-analysis and our study. It is crucial
of mild to moderate severity, and were cured by medical to consider these distinctions when interpreting the
interventions [10]. Other less common adverse events results and implications of each study.
reported include septic arthritis and allergic peripheral Nevertheless, our study is not without limitations.
edema [10, 16]. A previous RCT demonstrated a signifi- Firstly, the inclusion of only four trials in this meta-anal-
cant improvement in liver function indicators (serum ysis resulted in a relatively small sample size, which may
glutamic oxaloacetic transaminase and serum glutamic impact the generalizability of our findings. In addition,
pyruvic transaminase) and blood urea nitrogen in the the studies included in our analysis had variations in their
collagen peptide group compared to the placebo, indi- design, including differences in the dosage and com-
cating the safety of collagen peptide use for knee osteo- ponents of the collagen peptides used, which may have
arthritis [16]. In another systematic review, none of the influenced the observed analgesic effects. It is important
involved studies reported side effects of collagen peptide to consider the clinical heterogeneity when interpreting
[6], which was similar to our findings. Overall, collagen the results, which is why we employed the GRADE sys-
peptide is safe with a high level of tolerance, making it a tem and a random-effect model for our analysis. Moreo-
potential supplement or medication for long-term use in ver, one study reported pain scores using the VAS across
knee osteoarthritis [21]. multiple dimensions, which may have disproportionately
Our study provides compelling evidence support- influenced the overall results. To address this concern,
ing the therapeutic potential of collagen peptides in a post hoc analysis was performed in our study. Table 3
the treatment of knee osteoarthritis. It is important recapitulates the results of the GRADE assessment [14]
to note that a previous meta-analysis by Van Vijven for the included studies.

Table 3 GRADE (Grading of Recommendations, Assessment, Development and Evaluations) criteria for assessing quality of evidence
Outcome Number Number of Risk of bias Imprecision Inconsistency Indirectness Publication Relative Confidence
of participants bias effect (95% in effect
studies confidence estimate
interval) (Grade)

Pain 3 375 Serious Not serious Moderate Not serious Not serious − 0.63 (95% Moderate
CI − 0.86,
− 0.39)
Adverse 4 507 Serious Not serious Not serious Not serious Serious 1.66 (95% CI Very low
effect 0.99, 2.78)
Lin et al. Journal of Orthopaedic Surgery and Research (2023) 18:694 Page 10 of 11

It is worth highlighting that our meta-analysis repre- 2

Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Kee‑
lung Branch, and Chang Gung University, F7, No 222 Mai‑King Road, Keelung,
sents the first systematic review of randomized controlled Taiwan. 3 Department of Medical Education, Taipei Medical University-Shuang
trials (RCTs) investigating the clinical benefits of collagen Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, New Taipei
peptides for pain relief in patients with knee osteoarthri- City 235041, Taiwan. 4 School of Medicine, College of Medicine, Fu Jen Catholic
University, New Taipei City 242008, Taiwan. 5 Department of Orthopedics, Fu
tis. However, further well-designed RCTs are warranted Jen Catholic University Hospital, Fu Jen Catholic University, No. 69, Guizi Rd.,
in future research to validate and strengthen our findings. Taishan Dist., New Taipei City 24352, Taiwan. 6 School of Medicine, College
Continued investigation will enhance the understanding of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang
Dist., New Taipei City 24205, Taiwan.
of the efficacy and safety of collagen peptides as a thera-
peutic option for knee osteoarthritis, ultimately provid- Received: 4 July 2023 Accepted: 10 September 2023
ing more robust evidence for clinical decision-making.

Conclusion
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