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Citation: Qiu, F.; Li, J.; Legerlotz, K.
Does Additional Dietary
Supplementation Improve
Physiotherapeutic Treatment
Outcome in Tendinopathy? A
Systematic Review and
Meta-Analysis. J. Clin. Med. 2022,11,
1666. https://doi.org/10.3390/
jcm11061666
Academic Editor: Marco
Alessandro Minetto
Received: 16 February 2022
Accepted: 15 March 2022
Published: 17 March 2022
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Journal of
Clinical Medicine
Systematic Review
Does Additional Dietary Supplementation Improve
Physiotherapeutic Treatment Outcome in Tendinopathy?
A Systematic Review and Meta-Analysis
Fanji Qiu 1, Jinfeng Li 2and Kirsten Legerlotz 1, *
1Institute of Sport Sciences, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099 Berlin, Germany;
fanji.qiu@student.hu-berlin.de
2Department of Kinesiology, Iowa State University, Ames, IA 50011, USA; jfli@iastate.edu
*Correspondence: kirsten.legerlotz@hu-berlin.de; Tel.: +49-(0)30-2093-46254
Abstract:
A systematic review and meta-analysis of randomized controlled trials was performed to
evaluate the effects of dietary supplements in addition to physiotherapeutic treatment on pain and
functional outcomes. PubMed, The Cochrane Library, Web of Science, and Embase were searched
from inception to November 2021 (Prospero registration: CRD42021291951). Studies were eligible
if the interventions consisted of physiotherapeutic approaches that were combined with dietary
supplementation and if they reported measures of pain and/or function. Six studies were included
in the meta-analysis. Standardized mean differences (SMD) and 95% confidence intervals (CI) were
calculated and analysed using a Review Manager software. Subgroup analysis was performed to
explore possible associations between the study characteristics and the effectiveness of the interven-
tion. Additional dietary supplementation during physiotherapeutic treatment significantly improved
the reduction in pain score (SMD =
−
0.74, 95% CI,
−
1.37 to
−
0.10; p< 0.05), while it had no effect
on functional outcomes (SMD = 0.29, 95% CI, 0.00 to 0.58; p> 0.05). This systematic review and
meta-analysis suggests that additional nutritional interventions may improve physiotherapeutic
treatment outcomes in the management of tendinopathies.
Keywords: nutrition; tendinopathy; tendon pain; exercise therapy; meta-analysis; VISA; VAS
1. Introduction
Tendinopathy is a common tendon disorder accounting for around 30% of com-
plaints related to musculoskeletal pain and functional limitations [
1
]. The aetiology of
this tendon pathology is multifactorial, including mechanical overuse [
1
,
2
] and metabolic
disorders [3–5].
Usually, tendinopathies are characterized by tendon pain and impaired
function, which also leads to a reduction in exercise participation in tendinopathic pa-
tients [
6
]. In the last few years, the incidence of tendinopathies in athletes and in the general
population has increased [
7
], with the increases in physical activity, changes in lifestyle and
side effects of medication being discussed as potentially influencing factors [7–10].
In the management of tendinopathies, a variety of physiotherapy treatment methods
have been applied, including extracorporeal shock wave [
11
] and manual therapy [
12
] as
well as exercise interventions such as heavy slow resistance training [
13
,
14
] and eccentric
training [15,16].
In recent years, dietary supplements have been introduced as an additional therapeu-
tic approach in the treatment of tendinopathies, and their positive curative effects have
been reported for both the general population and athletes [
17
–
20
]. The applied dietary
supplements contained a variety of micronutrients (e.g., bromelain and vitamin C) [
21
–
23
],
which are suggested to reduce the level of inflammation [
24
–
26
] and to promote the healing
of the tendon [
21
,
22
,
27
–
30
]. Because of the suggested anti-inflammatory effects and claimed
J. Clin. Med. 2022,11, 1666. https://doi.org/10.3390/jcm11061666 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2022,11, 1666 2 of 13
improvements in tendon metabolism, treatments that combine dietary supplements with
physiotherapy have been explored in some studies [23,31–36].
The combination treatment of dietary supplementation and physiotherapy has been
evaluated in a series of clinical trials due to these compelling rationales. Considering
that individual trials are unlikely to provide sufficient evidence to guide clinical practice,
we attempted to objectively evaluate the potential impact of this treatment strategy in
tendinopathy management, to provide a higher level of clinical evidence. Thus, we per-
formed a systematic review and meta-analysis of randomized controlled trials to assess the
effect of additional dietary supplementation in combination with physiotherapy treatment
on the key outcomes of tendinopathy treatment such as pain and function in comparison to
physiotherapeutic treatment alone or physiotherapeutic treatment with placebo.
2. Methods
This systematic review and meta-analysis adhered to the PRISMA statement [
37
] and
was registered at Prospero (CRD42021291951) in the international prospective register of
systematic reviews in November 2021.
2.1. Eligibility Criteria
2.1.1. Participants
Studies were eligible if participants were aged under 70 years. No restrictions on
gender, ethnicity, or sport participation were applied.
2.1.2. Interventions
Studies were eligible if the interventions consisted of any kind of physiotherapeutic
approaches (e.g., eccentric training, shockwave or laser therapy), which were combined
with dietary supplementation. The intervention programs were required to last at least 4
weeks and were conducted in any setting (e.g., laboratory, home, gym).
2.1.3. Comparisons
The control groups for comparison were subjected to physiotherapy alone or to phys-
iotherapy and placebo treatment.
2.1.4. Outcomes
Studies were eligible if they reported at least one outcome of interest, which were
measures of pain and/or function. We selected NRS (Numerical Rating Scales) and VAS
(Visual Analogue Scales) scores as assessment of pain. These two measures were synthe-
sized, as recent studies have shown that NRS and VAS scores, both ranging from 0 to
10, correspond to each other [
38
]. In addition, we assessed reliable and valid functional
outcome scores [
39
–
44
], including the Victorian Institute of Sports Assessment for Achilles
or Patellar Tendon (VISA-A and VISA-P), the Shoulder Pain and Disability Index (SPADI)
and the Ankle–Hindfoot Scale (AHS).
2.1.5. Study Design
Inclusion criteria: studies were randomized controlled trials (RCTs) published in
English. Exclusion criteria: (1) duplicate publications; (2) literature review papers; (3letters
to the editor; (4) abstracts published in conference proceedings; (5) animal model studies.
Articles with the full text unavailable were also excluded.
2.2. Search Strategy and Study Selection
We selected relevant studies published before November 2021, by searching PubMed,
Cochrane, Embase, and Web of Science databases. We applied the English language, and the
search keywords included population (e.g., tendinopathy) and intervention (
e.g., dietary
supplement). For PubMed, we used the Mesh Database, combined Mesh terms and
entry terms, and made some adjustments in other databases. Moreover, we applied the
J. Clin. Med. 2022,11, 1666 3 of 13
filters: randomized controlled trial (publication types), randomized (title/abstract), or
placebo (title/abstract) when appropriate. The precise search strategy is described in the
supplemental file (Table S1). All the results were collated by a reference management tool
(Endnote X9, Thomson Reuters, NY, USA), and duplicates were removed. We considered all
potentially eligible studies. In addition, we performed a manual search using the references
of key articles. Two authors (F.Q., J.L.) independently reviewed study titles and abstracts
retrieved, to include the articles that satisfied the requirements, and then read the full
texts for final eligibility. Any disagreements were resolved by consensus with the third
reviewer (K.L.).
2.3. Data Extraction
Data extraction and results compilation were performed by two independent review-
ers (F.Q., J.L.), and data were extracted into Microsoft Excel. In case of disagreement, a
third researcher (K.L.) intervened. As no original data on of pain scores and functional
outcomes were provided in the studies of Juhasz et al. [
31
] and Praet et al. [
35
], the values
were extracted from the reported graphs using Graph digitizer software (Digitizelt, Braun-
schweig, Germany). Data extracted from the studies included the following information:
lead author, year of publication; demographic characteristics (age, gender); sample size in
the experimental and control groups; study groups; intervention characteristics: type of
tendinopathy (e.g., Achilles tendon, rotator cuff), intervention duration (in weeks); type of
population (athletic or non-athletic), type of physiotherapy (e.g., strength training, shock
wave or laser therapy) and reported outcomes (pain and function); symptom duration; time
points of measurement; pharmaceutical company supplying the nutritional supplements;
composition of supplements; assumed effect of supplement.
2.4. Quality Assessment and Risk of Bias
The included studies were assessed according to the Cochrane Risk of Bias tool [
45
].
The following domains were assessed: (1) random sequence generation; (2) concealment of
allocation; (3) blinding of participants, investigators, and assessors; (4) blinding of outcome
assessment; (5) incomplete outcome data processed; (6) selective reporting bias; (7) other
bias. The domains were given a rating of low (+), unclear (?), or high risk (−) of bias.
No funnel plots were graphed for any of the comparisons, given that the number of
studies in each comparison was less than 10 [
46
]. For sensitivity analysis [
47
], we evaluated
the robustness of the pooled results by exclusion-by-exclusion, removing one study data
from the pooled analysis at a time to evaluate the consistency between the pooled results of
the remaining studies and the pooled results of all studies.
2.5. Statistical Analysis
The meta-analysis was performed using the Review Manager software version 5.4
(The Cochrane Collaboration, Copenhagen, Denmark). As the Victorian Institute of Sports
Assessment–Achilles questionnaire (VISA-A), the Shoulder Pain and Disability Index
(SPADI) and the Ankle–Hindfoot Scale (AHS) were not assessed by using consistent forms
of measurement, standardized mean differences (SMD) were applied. All results are ex-
pressed as mean difference (MD) with standard deviation (SD) and were reported with 95%
confidence intervals (CIs). The interquartile ranges and 95% CIs with standard errors were
calculated with the appropriate formulas to convert them to means and standard errors
(SDs) [
48
]. Random-effects and fixed-effects models were used to estimate pooled effects
by accounting for study differences and weighting each study accordingly. We used the
Cochran Q test [
49
] and I
2
testing [
50
] to assess the magnitude of the heterogeneity between
studies, with I
2
greater than 50% or a pvalue at or less than 0.10 in Q test, indicating
the presence of moderate-to-high heterogeneity. Subgroup analyses were conducted to
explore possible associations between the study characteristics and the effectiveness of the
intervention. Study characteristics included type of tendinopathy (Achilles tendon, other
type), intervention duration (
≤
8 weeks or >8 weeks), type of physiotherapy (exercise ther-
J. Clin. Med. 2022,11, 1666 4 of 13
apy, ultrasound (US), extracorporeal shockwave therapy (ESWT)) and type of population
(athletic, non-athletic). For subgroup analysis, statistical significance was established at an
alpha level of 0.05.
3. Results
3.1. Search Yield
We identified a total of 94 potentially eligible articles during the trial selection process.
Sixty-two articles remained for screening after removing duplicates. After screening titles
and abstracts, six articles [
23
,
31
–
36
] were included in the meta-analysis (Figure 1). From all
included studies, an experimental group of 123 people and a control group of 118 people
were evaluated in this meta-analysis.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 14
were calculated with the appropriate formulas to convert them to means and standard
errors (SDs) [48]. Random-effects and fixed-effects models were used to estimate pooled
effects by accounting for study differences and weighting each study accordingly. We
used the Cochran Q test [49] and I2 testing [50] to assess the magnitude of the
heterogeneity between studies, with I2 greater than 50% or a p value at or less than 0.10 in
Q test, indicating the presence of moderate-to-high heterogeneity. Subgroup analyses
were conducted to explore possible associations between the study characteristics and the
effectiveness of the intervention. Study characteristics included type of tendinopathy
(Achilles tendon, other type), intervention duration (≤8 weeks or >8 weeks), type of
physiotherapy (exercise therapy, ultrasound (US), extracorporeal shockwave therapy
(ESWT)) and type of population (athletic, non-athletic). For subgroup analysis, statistical
significance was established at an alpha level of 0.05.
3. Results
3.1. Search Yield
We identified a total of 94 potentially eligible articles during the trial selection
process. Sixty-two articles remained for screening after removing duplicates. After
screening titles and abstracts, six articles [23,31–36] were included in the meta-analysis
(Figure 1). From all included studies, an experimental group of 123 people and a control
group of 118 people were evaluated in this meta-analysis.
Figure 1. Study selection process (according to the PRISMA guidelines).
3.2. Characteristics of Included Studies
Summed up, the six studies (Table 1) included 241 participants, with the mean (SD)
age ranging from 14.8 (1.6) to 55.8 (13.2) years. The six studies applied six different
commercially available dietary supplements (Table 2). The duration of the intervention in
the six articles ranged from 4 to 12 weeks, while the symptom duration ranged from 4
Figure 1. Study selection process (according to the PRISMA guidelines).
3.2. Characteristics of Included Studies
Summed up, the six studies (Table 1) included 241 participants, with the mean (SD) age
ranging from 14.8 (1.6) to 55.8 (13.2) years. The six studies applied six different commercially
available dietary supplements (Table 2). The duration of the intervention in the six articles
ranged from 4 to 12 weeks, while the symptom duration ranged from 4 weeks to 3 years.
The time from the start of the intervention to the end point of the intervention or follow-up
respectively ranged from 32 days to 1 year. Five of the included studies examined indices of
pain [
23
,
31
,
32
,
34
,
36
], and four examined indices of function [
23
,
34
–
36
]. The interventions
in all six studies compared dietary supplementation combined with physiotherapy and
placebo combined with physiotherapy or physiotherapy alone. Two trials combined
dietary supplementation with ESWT (extracorporeal shockwave therapy) or therapeutic
ultrasound; four trials combined dietary supplementation with exercise therapy. In the
study by Balius et al. [
23
], before being randomly assigned to the intervention group, the
subjects were classified according to the pathology model of Cook and Purdam [
51
] as
suffering from reactive or degenerative tendinopathy. Data of six experimental groups were
included in the pooled analysis of the pain score, and data of five groups were included in
the pooled analysis of the functional outcome.
J. Clin. Med. 2022,11, 1666 5 of 13
Table 1. Characteristics of included studies.
First Author (Year) Tendon Investigated Study Groups Sample Size
(n) Type of Population Mean Age (Years;
Mean ±SD)
Intervention
Duration (Weeks)
Symptom Duration
(Months) Time Points of
Measurement
Balius et al. (2016) Achilles tendon
(mid-portion) MCVC + EC 17 non-athletic 43.5 ±14.5 12 >3 baseline, 6 and 12 w
EC 20 38.9 ±6.6
Juhasz et al. (2018) Musculus flexor
hallucis longus Creatine 9 athletic 15.5 ±1.4 6 1–1.5 2, 4 and 6 w
Placebo 9 14.8 ±1.6
Mavrogenis et al.
(2004) Patellar & several
upper body tendons * EFA, AO and US 17 athletic 31 5 >3 8, 16, 24 and 32 d
Placebo and US 14 32
Notarnicola et al.
(2012) Achilles tendon
(insertional) ESWT and tenosan 32 non-athletic 55.8 ±13.2 8 >6 2 and 6 m
ESWT and placebo 32
Praet et al.
(2019) Achilles tendon
(mid-portion) TENDOFORTE + EccEx 10 non-athletic 45.3 ±6.4 12 18 3 and 6 m
Placebo + EccEx 10 42.0 ±9.4
Sandford et al. (2018) Rotator cuff PUFAs 38 non-athletic 52.2 ±12.0 8 >3 8 w, 3, 6 and 12 m
Placebo 35 52.0 ±16.2
d, days; m, months; w, weeks; AO, antioxidants; EC/EccEx, eccentric exercise; EFA, essential fatty acids; ESWT, extracorporeal shockwave therapy; MCVC, mucopolisaccharides, type I
collagen, and vitamin C; PUFAs, polyunsaturated fatty acids; US, ultrasound; *, upper body tendons: supraspinatus, biceps, lateral epicondyle extensormedial epicondyle flexor, and
infraspinatus.
Table 2. Details of dietary Supplements.
First Author (Year) Dietary Supplements (Company) Ingredients of Dietary Supplement Assumed Effect of Supplement
Balius et al. (2016) TendoActive
(Bioiberica SA, Palafolls, Spain) mucopolysaccharides, collagen type I, vitamin C suppression of NF-κB mediated IL-1ß catabolic
signalling pathways in tenocytes
Juhasz et al. (2018) Micronized Cr monohydrate
(BioTech, Inc., Ft. Lauderdale, FL, USA) Cr monohydrate, dextrose, and vitamin C reduction of inflammatory markers
Mavrogenis et al. (2004) Bio-Sport
(Pharma Nord ApS, Vejle, Denmark) EPA, DHA and GLA. selenium, zinc, vitamin A,
vitamin B6, vitamin C and vitamin E reduction of inflammation caused by essential
fatty acids and antioxidants
Notarnicola et al. (2012) Tenosan
(Agave s.r.l., Prato, Italy) arginine-L-alpha-ketoglutarate, MSM, hydrolysed
collagen type I, Vinitrox, bromelain, and vitamin C stimulation of metabolism and proliferation;
reduction of inflammation and neoangiogenesis
Praet et al. (2019) TENDOFORTE®(GELITA AG,
Eberbach, Germany) Hydrolysed specific collagen peptides
stimulation of collagen type I and III,
proteoglycans and elastin content synthesis by
sCPs; reduction of TNF-alpha, matrix
metalloproteases and stimulation of tissue
inhibitors of metalloproteinases by Glycine
Sandford et al. (2018) MaxEPA
(Seven Seas Ltd., Hull, UK) EPA, DHA and vitamin E acetate reduction of inflammation
Cr, creatine; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GLA, gamma-linolenic acid; sCP, specific collagen peptides.
J. Clin. Med. 2022,11, 1666 6 of 13
3.3. Assessment of Risk of Bias
According to the Cochrane Risk of Bias tool, one article was evaluated as high risk of
bias in randomization for grouping patients according to age (Table 3). Group allocation
was clearly stated in half of the included articles [
32
,
35
,
36
]. Three studies were evaluated as
low risk in terms of blinding. Regarding detection bias, three articles were evaluated as low
risk. One study was assessed as high risk in reporting bias, as the overall effect of treatment
was not reported. Two articles were evaluated as high risk of bias due to the financial
support from the pharmaceutical company that was supplying the nutritional supplement.
Table 3. Risk of bias assessment for RCTs according to the Cochrane Risk of Bias Tool.
First Author (year)
Random
Sequence
Generation
(Selection Bias)
Allocation
Concealment
(Selection Bias)
Blinding of
Participants and
Personnel
(Performance
Bias)
Blinding of
Outcome
Assessment
(Detection Bias)
Incomplete
Outcome Data
(Attrition Bias)
Selective
Reporting
(Reporting Bias)
Other Bias
Balius et al. (2016) + - - - ? - -
Juhasz et al. (2018) ? ? ? ? + + +
Mavrogenis et al.
(2004) + + + + - + ?
Notarnicola et al.
(2012) - ? + ? - + -
Praet et al. (2019) + + + + + + +
Sandford et al. (2018) + + + + + + +
-, high risk of bias; +, low risk of bias; ?, unclear risk of bias, as paper contained insufficient information to
permit judgement.
Further sensitivity analysis and exclusion-by-exclusion of the literature led to signifi-
cant changes in the results of the pain score and functional outcomes, which were caused by
the studies by Notarnicola et al. [
34
] and Sandford et al. [
36
], respectively. Although high
heterogeneity (I2 = 77%) was found in the pain score, all five trials showed a significant
reduction in the pain score with additional dietary supplementation.
3.4. Meta-Analysis
3.4.1. Analysis of Pain Score at Rest
Five experiments with a total of 221 participants provided data on pain score at
rest. The pooled analysis of five trials (Figure 2) revealed that the combination of dietary
supplementation and physiotherapy led to a greater mean reduction in pain score than
physiotherapy alone (SMD =
−
0.74, 95%CI,
−
1.37 to
−
0.10). In the subgroup analysis
(Table 4) of types of tendinopathy, intervention duration, physiotherapy type, and type of
population, we observed no significant effects.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 7 of 14
-, high risk of bias; +, low risk of bias; ?, unclear risk of bias, as paper contained insufficient
information to permit judgement.
3.4. Meta-Analysis
3.4.1. Analysis of Pain Score at Rest
Five experiments with a total of 221 participants provided data on pain score at rest.
The pooled analysis of five trials (Figure 2) revealed that the combination of dietary
supplementation and physiotherapy led to a greater mean reduction in pain score than
physiotherapy alone (SMD = −0.74, 95%CI, −1.37 to −0.10). In the subgroup analysis (Table
4) of types of tendinopathy, intervention duration, physiotherapy type, and type of
population, we observed no significant effects.
Figure 2. Forest plot of the meta-analysis on pain score at rest. Pain score measurement include NRS
and VAS scales.
Table 4. Results of subgroup analysis.
Study Characteristics Studies Pain at Rest p Value Functional Outcomes
Effect Size (95%CI) Studies Effect Size (95%CI) p Value
Type of Tendinopathy
Achilles Tendon 2 −0.41 (−0.83, 0.00) >0.05 3 0.53 (0.16, 0.90) 0.005
Other Type 2 −1.72 (−3.72, 0.28) >0.05 - - -
Intervention Duration
≤8 weeks 4 −0.88 (−1.78, 0.08) >0.05 2 0.28 (−0.06, 0.62) >0.05
>8 weeks 2 0.32 (−0.22, 0.86) >0.05
Type of physiotherapy
Exercise therapy 3 −0.26 (−0.62, 0.09) >0.05 3 0.09 (−0.26, 0.44) > 0.05
ESWT/US 2 −1.53 (−3.83, 0.78) >0.05 - - -
Type of population
Athletic 2 −1.72 (−3.72, 0.28) >0.05 - - -
Non-athletic 3 −0.26 (−0.57, 0.05) >0.05 4 0.29 (0.00, 0.58) >0.05
3.4.2. Analysis of Functional Outcomes
Four RCTs with a total of 194 participants provided data on functional outcomes. The
pooled analysis (Figure 3) revealed that the combination of dietary supplementation and
physiotherapy led to no superior improvement in functional outcomes compared to
physiotherapy alone (SMD = 0.29, 95%CI, 0.00 to 0.58). In the subgroup analysis (Table 4),
we observed a greater effect of physiotherapy alone in Achilles tendinopathy (p = 0.005).
Figure 2.
Forest plot of the meta-analysis on pain score at rest. Pain score measurement include NRS
and VAS scales.
J. Clin. Med. 2022,11, 1666 7 of 13
Table 4. Results of subgroup analysis.
Study Characteristics Studies
Pain at Rest
pValue
Functional Outcomes
Effect Size
(95%CI) Studies Effect Size
(95%CI) pValue
Type of Tendinopathy
Achilles Tendon 2−0.41 (−0.83, 0.00) >0.05 3 0.53 (0.16, 0.90) 0.005
Other Type 2−1.72 (−3.72, 0.28) >0.05 - - -
Intervention Duration
≤8 weeks 4−0.88 (−1.78, 0.08) >0.05 2 0.28 (−0.06, 0.62) >0.05
>8 weeks 20.32 (−0.22, 0.86) >0.05
Type of physiotherapy
Exercise therapy 3−0.26 (−0.62, 0.09) >0.05 3 0.09 (−0.26, 0.44) > 0.05
ESWT/US 2−1.53 (−3.83, 0.78) >0.05 - - -
Type of population Athletic 2−1.72 (−3.72, 0.28) >0.05 - - -
Non-athletic 3−0.26 (−0.57, 0.05) >0.05 4 0.29 (0.00, 0.58) >0.05
3.4.2. Analysis of Functional Outcomes
Four RCTs with a total of 194 participants provided data on functional outcomes.
The pooled analysis (Figure 3) revealed that the combination of dietary supplementation
and physiotherapy led to no superior improvement in functional outcomes compared to
physiotherapy alone (SMD = 0.29, 95%CI, 0.00 to 0.58). In the subgroup analysis (Table 4),
we observed a greater effect of physiotherapy alone in Achilles tendinopathy (p= 0.005).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 8 of 14
Figure 3. Forest plot of the meta-analysis on functional outcomes. Functional outcomes include
VISA-A, SPADI and AHS.
4. Discussion
In the management of tendinopathy, the reduction of pain and the improvement of
function are the aims of different treatment methods [6,52–58]. Within this context, a novel
strategy that applied dietary supplementation additional to physiotherapy was evaluated.
Our meta-analysis has shown that additional nutritional interventions can reduce pain
further than physiotherapy alone, while a significant improvement in function could not
be detected.
Additional nutritional interventions may be an effective strategy to improve pain
reduction in patients with tendinopathies. The mechanism by which the ingestion of
nutritional supplements improves tendinopathy symptoms may be linked to the capacity
of certain ingredients in affecting inflammation. While all six RCTs included in our meta-
analysis applied a different supplement, five studies [23,31,32,34,36] applied supplements
which contained substances of known anti-inflammatory function, and all six papers
explained assumed effects with a reduction in inflammation or inflammatory markers.
Inflammation is strongly associated with pain production [59,60]. In addition, it may
play an important role in the development of tendinopathies [14,61]. Therefore,
downregulation of inflammation levels induced by anti-inflammatory ingredients could
be a potential mechanism to consider in tendinopathy management. The pain-reducing
effect of nutritional interventions addressing inflammation has been shown for a variety
of supplements in a variety of tendon related pathologies. In patients with lateral
epicondylitis and shoulder and Achilles tendinopathy [62], Tendisulfur
®
supplementation
for 60 days led to a drop in VAS, possibly due to the downregulation of NF-κB, TNF-α
and IL-6. Furthermore, in patients subjected to supraspinatus tendon repair [33], two
months of supplementation with Tendisulfur
®
resulted in a significant reduction in the
VAS score, which was assumed to be related to the inhibition the NF-κB pathway by
boswellia serrata and curcuma longa within the supplement. In patients with shoulder,
knee, elbow and hip tendinopathy, a recent study [63] has shown that one-month
supplementation with curcuminoids and boswellia serrata extracts significantly reduced
the VAS score. They explained this effect by the anti-inflammatory activity of curcuma
longa and boswellia serrata extracts. In patients subjected to rotator cuff tear repair [64],
a three-month supplementation with tenosan significantly reduced the pain scores in
patients. The authors suggested that the supplement may have resulted in an inhibitory
effect on the generation of bradykinin and catabolic signalling pathways in tenocytes [64].
In patients with Achilles tendinopathy, a 12-week intervention with a supplement
containing collagen peptide type-1, low molecular weight chondroitin sulphate, sodium
hyaluronate, and vitamin C led to a significant decrease in the VAS score [65]. The authors
suggested that the therapeutic effects may be associated with an improvement in the
glycosaminoglycan composition and collagen synthesis of the tendon by the ingredients
of the supplementation [65].
The pain-reducing effects of nutritional supplements have also been observed in
patients with other musculoskeletal injuries. In patients with mild knee pain, using low-
Figure 3.
Forest plot of the meta-analysis on functional outcomes. Functional outcomes include
VISA-A, SPADI and AHS.
4. Discussion
In the management of tendinopathy, the reduction of pain and the improvement of
function are the aims of different treatment methods [
6
,
52
–
58
]. Within this context, a novel
strategy that applied dietary supplementation additional to physiotherapy was evaluated.
Our meta-analysis has shown that additional nutritional interventions can reduce pain
further than physiotherapy alone, while a significant improvement in function could not
be detected.
Additional nutritional interventions may be an effective strategy to improve pain
reduction in patients with tendinopathies. The mechanism by which the ingestion of
nutritional supplements improves tendinopathy symptoms may be linked to the capacity
of certain ingredients in affecting inflammation. While all six RCTs included in our meta-
analysis applied a different supplement, five studies [
23
,
31
,
32
,
34
,
36
] applied supplements
which contained substances of known anti-inflammatory function, and all six papers
explained assumed effects with a reduction in inflammation or inflammatory markers.
Inflammation is strongly associated with pain production [59,60]. In addition, it may
play an important role in the development of tendinopathies [
14
,
61
]. Therefore, down-
regulation of inflammation levels induced by anti-inflammatory ingredients could be a
potential mechanism to consider in tendinopathy management. The pain-reducing effect of
nutritional interventions addressing inflammation has been shown for a variety of supple-
ments in a variety of tendon related pathologies. In patients with lateral epicondylitis and
shoulder and Achilles tendinopathy [
62
], Tendisulfur
®
supplementation for 60 days led to
a drop in VAS, possibly due to the downregulation of NF-
κ
B, TNF-
α
and IL-6. Furthermore,
J. Clin. Med. 2022,11, 1666 8 of 13
in patients subjected to supraspinatus tendon repair [
33
], two months of supplementation
with Tendisulfur
®
resulted in a significant reduction in the VAS score, which was assumed
to be related to the inhibition the NF-
κ
B pathway by boswellia serrata and curcuma longa
within the supplement. In patients with shoulder, knee, elbow and hip tendinopathy, a
recent study [
63
] has shown that one-month supplementation with curcuminoids and
boswellia serrata extracts significantly reduced the VAS score. They explained this effect by
the anti-inflammatory activity of curcuma longa and boswellia serrata extracts. In patients
subjected to rotator cuff tear repair [
64
], a three-month supplementation with tenosan sig-
nificantly reduced the pain scores in patients. The authors suggested that the supplement
may have resulted in an inhibitory effect on the generation of bradykinin and catabolic
signalling pathways in tenocytes [
64
]. In patients with Achilles tendinopathy, a 12-week
intervention with a supplement containing collagen peptide type-1, low molecular weight
chondroitin sulphate, sodium hyaluronate, and vitamin C led to a significant decrease in
the VAS score [
65
]. The authors suggested that the therapeutic effects may be associated
with an improvement in the glycosaminoglycan composition and collagen synthesis of the
tendon by the ingredients of the supplementation [65].
The pain-reducing effects of nutritional supplements have also been observed in pa-
tients with other musculoskeletal injuries. In patients with mild knee pain, using low-fat
yoghurt supplemented with rooster comb extract for 12 weeks led to a significant im-
provement in pain, possibly caused by a decrease in inflammation [
66
]. In patients with
fibromyalgia syndrome (FMS), 12 weeks supplementation with an extract of salmon’s
milt reduced the pain severity score significantly [
67
]. This may have been caused by an
inhibition of inflammation, as indicated by dropped serum levels of the tumour necrosis
factor (TNF) and substance P [
67
]. While further research is needed to explore the effec-
tiveness of the specific components within the supplementation, it appears that nutritional
interventions, which contain substances addressing inflammation, have the potential to
speed up the recovery of musculoskeletal injuries and to improve the therapeutic response
in terms of pain reduction [23,31–36,62,68].
Despite a reduction in pain, nutritional supplementation during exercise therapy does
not seem to further enhance functional outcomes in tendinopathy patients. While two
comparative studies [
28
,
62
] have reported significant improvements in functional scales
and pain in patients with Achilles, patellar and rotator cuff tendinopathy after receiving
nutritional supplementation, the results of the RCTs do not point in the same direction.
Our subgroup analysis of RCTs investigating Achilles tendinopathy was in favour of phys-
iotherapy alone. A reduction in pain does not necessarily translate into an improvement in
function, which has been reported in various studies. In patients with Achilles tendinopathy,
treatment with nonsteroidal anti-inflammatory medication (NSAIDs) for 1 week resulted
in an improvement in VAS, while no significant changes in the VISA-A were detected [
69
].
In patients with temporomandibular joint osteoarthritis [
70
], the ingestion of a supplement
containing glucosamine, chondroitin sulphate, and methylsulfonylmethane for 3 months
led to a reduction in VAS but not to a significant change in mandibular mobility, suggesting
that the supplementation was not able to trigger an adequate adaptive response to improve
joint function. In adolescent swimmers with muscle damage induced by high-intensity
interval swimming, supplementation with whey protein caused a significant decrease in
pain score, while no beneficial effect on swimming performance was observed [
71
]. While
a reduction in pain may be a necessary prerequisite to improve function, these studies
suggest that pain relief is by no means automatically associated with an improvement in
function or performance.
Although human and
in vitro
studies have shown that vitamin C has the potential
of stimulating collagen synthesis [
18
] and Tendoactive
®
has the potential to inhibit the
NF-
κ
B-mediated IL-1ß catabolic signalling pathway in tendon cells [
24
], it appears that the
acceleration of collagen synthesis is not necessarily reflected in scales measuring function.
In addition, it needs to be considered, that by reducing inflammation, the adaptive
response could be impaired. Anti-inflammatory supplements have been found to suppress
J. Clin. Med. 2022,11, 1666 9 of 13
the production of prostaglandin E2 (PGE2) [
72
,
73
], and such changes can affect matrix
remodelling and thus lead to impairments in tendon healing [
74
,
75
]. In healthy adults,
one week of NSAID administration has been shown to cause a reduction in PGE2 and to
minimize the adaptive increase in collagen synthesis in human patellar tendons induced
by exercise [
76
]. Furthermore, not all patients suffering from tendinopathy present with
signs of inflammation such as increased IL6 levels [
14
], and suppression of inflammation in
those patients may not be warranted. This may explain why nutritional supplements aim-
ing to reduce inflammation work poorly in patients with degenerative tendinopathy [
23
].
It may also explain why NSAID treatment, as a commonly applied approach to reduce
musculoskeletal pain, does not necessarily lead to symptom improvement in tendinopathic
patients. In a randomized controlled trial with 70 Achilles tendinopathy patients, a
28-day
long treatment with the NSAID piroxicam did neither improve pain nor function compared
to the placebo-treated group [
77
]. In this context, it needs to be highlighted that long-term
oral NSAID intake may result in significant adverse effects, e.g., related to the gastrointesti-
nal system [
78
]. The advantage of nutritional supplementation as an alternative to NSAID
treatment may therefore be inherent in the lower risk to induce significant adverse side
effects. However, when using additional nutritional supplementation as an intervention, it
is noteworthy to pay attention to how functional parameters are affected by pain and how
the reduction of inflammation may affect tendon metabolism.
5. Limitations
Overall, the number of studies included in this meta-analysis is small. As a result,
subgroup analyses of some study characteristics were prevented, and no funnel plot could
be graphed because the number of studies was small such that the test power was too
low to distinguish chance from real asymmetry [
46
]. Second, included studies embraced a
diverse range of dietary supplements with different ingredients and physiotherapy types
and with a wide range of intervention durations (6 weeks to 6 months), which makes
it difficult to draw any definitive conclusions on the use of combination treatment in
tendinopathies. Third, potential factors such as funding from pharmaceutical companies
and lack of random sequence generation might have affected the risk of bias.
The study by Balius et al. [
23
] was assessed to be at “high risk” of bias in five of seven
evaluated areas, which may affect the final results. Since two studies [
23
,
34
] reported
receiving funding from pharmaceutical companies, it cannot be excluded that the results
of current research may be influenced by financial bias. In sensitivity analysis, the poor
robustness of the pooled results in pain scores resulted from the methodology in the
Notarnicola et al. [
34
] study, with only two of seven evaluated areas assessed as “low risk”,
while the poor robustness of the pooled results in functional outcomes was caused by the
sample size in the Sandford et al. [
36
] study, which was the highest within all included
studies. The high heterogeneity of the Mavrogenis et al. [
32
] study stems from the diverse
types of tendinopathies they explored within one study. Compared to exploring only one
type of tendinopathy, including diverse types of tendinopathies, will affect the accuracy of
the meta-analysis results.
6. Conclusions
In the management of tendinopathy, dietary supplementation in addition to phys-
iotherapeutic treatment may be an effective strategy to reduce pain. However, more
high-quality methodology RCTs with a sufficiently large sample size are required to con-
firm and establish a more definitive conclusion. With regard to the efficacy of dietary
supplements combined with physiotherapy, studies have frequently used supplements
which contain diverse components and which are supposed to fulfil multiple functions
such as an improvement of collagen fibre organization [
79
] and downregulation of the
level of oxidative stress and inflammation [
24
,
27
], limiting the evaluation of each single
ingredient’s effect. Future studies should aim to limit the kinds of ingredients in dietary
supplements for more targeted results.
J. Clin. Med. 2022,11, 1666 10 of 13
Clinical implications of additional nutritional interventions in the management of
tendinopathies are the potential to allow for a reduction of the use of painkillers and
faster recovery.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jcm11061666/s1, Table S1: search strategy.
Author Contributions:
K.L. and F.Q. had the idea for the study conception and design. F.Q., K.L.
and J.L. selected the studies for inclusion and abstracted data. F.Q. performed the statistical analyses
and wrote the first draft. K.L. critically revised the paper for important intellectual content. The
corresponding author had full access to all the data in the study and had final responsibility for the
decision to submit for publication. All authors have read and agreed to the published version of
the manuscript.
Funding:
Fanji Qiu is supported by a grant from the China Scholarship Council (grant no. 202106520004).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest:
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this paper.
References
1.
Fusini, F.; Bisicchia, S.; Bottegoni, C.; Gigante, A.; Zanchini, F.; Busilacchi, A. Nutraceutical supplement in the management of
tendinopathies: A systematic review. Muscles Ligaments Tendons J. 2016,6, 48–57. [CrossRef] [PubMed]
2. Xu, Y.; Murrell, G.A.C. The basic science of tendinopathy. Clin. Orthop. Relat. Res. 2008,466, 1528–1538. [CrossRef] [PubMed]
3.
Skovgaard, D.; Siersma, V.D.; Klausen, S.B.; Visnes, H.; Haukenes, I.; Bang, C.W.; Bager, P.; Gravare Silbernagel, K.; Gaida, J.;
Magnusson, S.P.; et al. Chronic hyperglycemia, hypercholesterolemia, and metabolic syndrome are associated with risk of tendon
injury. Scand. J. Med. Sci. Sports 2021,31, 1822–1831. [CrossRef] [PubMed]
4.
Squier, K.; Scott, A.; Hunt, M.A.; Brunham, L.R.; Wilson, D.R.; Screen, H.; Waugh, C.M. The effects of cholesterol accumulation on
Achilles tendon biomechanics: A cross-sectional study. PLoS ONE 2021,16, e0257269. [CrossRef] [PubMed]
5.
Ranger, T.A.; Wong, A.M.Y.; Cook, J.L.; Gaida, J.E. Is there an association between tendinopathy and diabetes mellitus? A
systematic review with meta-analysis. Br. J. Sports Med. 2015,50, 982–989. [CrossRef] [PubMed]
6.
Millar, N.L.; Silbernagel, K.G.; Thorborg, K.; Kirwan, P.D.; Galatz, L.M.; Abrams, G.D.; Murrell, G.A.C.; McInnes, I.B.; Rodeo, S.A.
Tendinopathy. Nat. Rev. Dis. Prim. 2021,7, 1. [CrossRef] [PubMed]
7.
Maffulli, N.; Wong, J.; Almekinders, L.C. Types and epidemiology of tendinopathy. Clin. Sports Med.
2003
,22, 675–692. [CrossRef]
8.
Knapik, J.J.; Pope, R. Achilles Tendinopathy: Pathophysiology, Epidemiology, Diagnosis, Treatment, Prevention, and Screening. J.
Spec. Oper. Med. 2020,20, 125–140. [PubMed]
9.
Sobhani, S.; Dekker, R.; Postema, K.; Dijkstra, P.U. Epidemiology of ankle and foot overuse injuries in sports: A systematic review.
Scand. J. Med. Sci. Sports 2012,23, 669–686. [CrossRef] [PubMed]
10.
Bidell, M.R.; Lodise, T.P. Fluoroquinolone-Associated Tendinopathy: Does Levofloxacin Pose the Greatest Risk? Pharmacotherapy
2016,36, 679–693. [CrossRef]
11.
Mani-Babu, S.; Morrissey, D.; Waugh, C.; Screen, H.; Barton, C. The Effectiveness of Extracorporeal Shock Wave Therapy in Lower
Limb Tendinopathy: A Systematic Review. Am. J. Sports Med. 2014,43, 752–761. [CrossRef] [PubMed]
12.
Desjardins-Charbonneau, A.; Roy, J.-S.; Dionne, C.E.; Fremont, P.; MacDermid, J.C.; Desmeules, F. The Efficacy of Manual Therapy
for Rotator Cuff Tendinopathy: A Systematic Review and Meta-analysis. J. Orthop. Sports Phys. Ther.
2015
,45, 330–350. [CrossRef]
[PubMed]
13.
Beyer, R.; Kongsgaard, M.; Hougs Kjær, B.; Øhlenschlæger, T.; Kjær, M.; Magnusson, S.P. Heavy Slow Resistance Versus Eccentric
Training as Treatment for Achilles Tendinopathy: A Randomized Controlled Trial. Am. J. Sports Med.
2015
,43, 1704–1711.
[CrossRef] [PubMed]
14.
Radovanovi´c, G.; Wolfarth, B.; Legerlotz, K. Interleukin-6 levels drop after a 12 week long physiotherapeutic intervention in
patients with Achilles tendinopathy—A pilot study. Transl. Sports Med. 2019,2, 233–239. [CrossRef]
15.
Woodley, B.L.; Newsham-West, R.J.; Baxter, G.D. Chronic tendinopathy: Effectiveness of eccentric exercise. Br. J. Sports Med.
2007
,
41, 188–198. [CrossRef] [PubMed]
16.
van der Vlist, A.C.; Winters, M.; Weir, A.; Ardern, C.L.; Welton, N.J.; Caldwell, D.M.; Verhaar, J.A.N.; de Vos, R.J. Which
treatment is most effective for patients with Achilles tendinopathy? A living systematic review with network meta-analysis of 29
randomised controlled trials. Br. J. Sports Med. 2021,55, 249–256. [CrossRef] [PubMed]
J. Clin. Med. 2022,11, 1666 11 of 13
17.
Maughan, R.J.; Burke, L.M.; Dvorak, J.; Larson-Meyer, D.E.; Peeling, P.; Phillips, S.M.; Rawson, E.S.; Walsh, N.P.; Garthe, I.;
Geyer, H.; et al
. IOC consensus statement: Dietary supplements and the high-performance athlete. Br. J. Sports Med.
2018
,52,
439–455. [CrossRef] [PubMed]
18.
Shaw, G.; Lee-Barthel, A.; Ross, M.L.; Wang, B.; Baar, K. Vitamin C–enriched gelatin supplementation before intermittent activity
augments collagen synthesis. Am. J. Clin. Nutr. 2017,105, 136–143. [CrossRef] [PubMed]
19.
Clark, K.L.; Sebastianelli, W.; Flechsenhar, K.R.; Aukermann, D.F.; Meza, F.; Millard, R.L.; Deitch, J.R.; Sherbondy, P.S.; Albert, A.
24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr. Med.
Res. Opin. 2008,24, 1485–1496. [CrossRef] [PubMed]
20.
Zdzieblik, D.; Oesser, S.; Gollhofer, A.; König, D. Improvement of activity-related knee joint discomfort following supplementation
of specific collagen peptides. Appl. Physiol. Nutr. Metab. 2017,42, 588–595. [CrossRef] [PubMed]
21.
Aiyegbusi, A.I.; Duru, F.I.; Awelimobor, D.; Noronha, C.C.; Okanlawon, A.O. The role of aqueous extract of pineapple fruit parts
on the healing of acute crush tendon injury. Niger. Q. J. Hosp. Med. 2010,20, 223–227.
22.
Kao, W.W.-Y.; Flaks, J.G.; Prockop, D.J. Primary and secondary effects of ascorbate on procollagen synthesis and protein synthesis
by primary cultures of tendon fibroblasts. Arch. Biochem. Biophys. 1976,173, 638–648. [CrossRef]
23.
Balius, R.; Álvarez, G.; Baró, F.; Jiménez, F.; Pedret, C.; Costa, E.; Martínez-Puig, D. A 3-Arm Randomized Trial for Achilles
Tendinopathy: Eccentric Training, Eccentric Training Plus a Dietary Supplement Containing Mucopolysaccharides, or Passive
Stretching Plus a Dietary Supplement Containing Mucopolysaccharides. Curr. Ther. Res. Clin. Exp. 2016,78, 1–7. [CrossRef]
24.
Shakibaei, M.; Buhrmann, C.; Mobasheri, A. Anti-inflammatory and anti-catabolic effects of TENDOACTIVE
®
on human
tenocytes in vitro. Histol. Histopathol. 2011,26, 1173–1185. [CrossRef] [PubMed]
25.
Bassit, R.A.; Curi, R.; Costa Rosa, L.F. Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2
after a half-ironman competition. Amino Acids 2008,35, 425–431. [CrossRef] [PubMed]
26.
DePhillipo, N.N.; Aman, Z.S.; Kennedy, M.I.; Begley, J.P.; Moatshe, G.; Laprade, R.F. Efficacy of Vitamin C Supplementation on
Collagen Synthesis and Oxidative Stress After Musculoskeletal Injuries: A Systematic Review. Orthop. J. Sports Med.
2018
,6,
2325967118804544. [CrossRef] [PubMed]
27.
Ömero˘glu, S.; Peker, T.; Türközkan, N.; Ömero˘glu, H. High-dose vitamin C supplementation accelerates the Achilles tendon
healing in healthy rats. Arch. Orthop. Trauma Surg. 2009,129, 281–286. [CrossRef] [PubMed]
28.
Puig, D.M.; Arquer, A.; García, M.; Laucirica, J.A.; Rius, M.; Blàvia, M.; Fontserè, J.; Hernández, C.; Boluda, J.; Kranjcec, T. The
efficacy and safety of oral mucopolysaccharide, type I collagen and vitamin C treatment in tendinopathy patients. Apunt. Med.
De L’esport 2014,49, 31–36.
29.
Chisari, E.; Rehak, L.; Khan, W.S.; Maffulli, N. Tendon healing in presence of chronic low-level inflammation: A systematic review.
Br. Med. Bull. 2019,132, 97–116. [CrossRef] [PubMed]
30.
Fu, S.C.; Cheng, W.-H.; Cheuk, Y.-C.; Mok, T.-Y.; Rolf, C.; Yung, S.-H.; Chan, K.-M. Development of vitamin C irrigation saline to
promote graft healing in anterior cruciate ligament reconstruction. J. Orthop. Transl. 2013,1, 67–77. [CrossRef]
31.
Juhasz, I.; Kopkane, J.P.; Hajdu, P.; Szalay, G.; Kopper, B.; Tihanyi, J. Creatine Supplementation Supports the Rehabilitation of
Adolescent Fin Swimmers in Tendon Overuse Injury Cases. J. Sports Sci. Med. 2018,17, 279–288. [PubMed]
32.
Mavrogenis, S.; Johannessen, E.; Jensen, P.; Sindberg, C. The effect of essential fatty acids and antioxidants combined with
physiotherapy treatment in recreational athletes with chronic tendon disorders: A randomised, double-blind, placebo-controlled
study. Phys. Ther. Sport 2004,5, 194–199. [CrossRef]
33.
Merolla, G.; Dellabiancia, F.; Ingardia, A.; Paladini, P.; Porcellini, G. Co-analgesic therapy for arthroscopic supraspinatus
tendon repair pain using a dietary supplement containing Boswellia serrata and Curcuma longa: A prospective randomized
placebo-controlled study. Musculoskelet. Surg. 2015,99 (Suppl. 1), S43–S52. [CrossRef] [PubMed]
34.
Notarnicola, A.; Pesce, V.; Vicenti, G.; Tafuri, S.; Forcignanò, M.; Moretti, B. SWAAT Study: Extracorporeal Shock Wave Therapy
and Arginine Supplementation and Other Nutraceuticals for Insertional Achilles Tendinopathy. Adv. Ther.
2012
,29, 799–814.
[CrossRef]
35.
Praet, S.F.E.; Purdam, C.R.; Welvaert, M.; Vlahovich, N.; Lovell, G.; Burke, L.M.; Gaida, J.E.; Manzanero, S.; Hughes, D.;
Waddington, G. Oral Supplementation of Specific Collagen Peptides Combined with Calf-Strengthening Exercises Enhances
Function and Reduces Pain in Achilles Tendinopathy Patients. Nutrients 2019,11, 76. [CrossRef]
36.
Sandford, F.M.; Sanders, T.; Wilson, H.; Lewis, J.S. A randomised controlled trial of long-chain omega-3 polyunsaturated fatty
acids in the management of rotator cuff related shoulder pain. BMJ Open Sport Exerc. Med. 2018,4, e000414. [CrossRef]
37.
Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.;
Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Int. J. Surg.
2021
,88,
105906. [CrossRef]
38.
Hjermstad, M.J.; Fayers, P.M.; Haugen, D.F.; Caraceni, A.; Hanks, G.W.; Loge, J.H.; Fainsinger, R.; Aass, N.; Kaasa, S.; European
Palliative Care Research Collaborative (EPCRC). Studies Comparing Numerical Rating Scales, Verbal Rating Scales, and Visual
Analogue Scales for Assessment of Pain Intensity in Adults: A Systematic Literature Review. J. Pain Symptom Manag.
2011
,41,
1073–1093. [CrossRef]
39.
Dawson, J.; Hill, G.; Fitzpatrick, R.; Carr, A. The benefits of using patient-based methods of assessment. Medium-term results of
an observational study of shoulder surgery. J. Bone Jt. Surg. Br. Vol. 2001,83, 877–882. [CrossRef]
J. Clin. Med. 2022,11, 1666 12 of 13
40.
Angst, F.; Schwyzer, H.-K.; Aeschlimann, A.; Simmen, B.R.; Goldhahn, J. Measures of adult shoulder function: Disabilities of
the Arm, Shoulder, and Hand Questionnaire (DASH) and its short ver-sion (QuickDASH), Shoulder Pain and Disability Index
(SPADI), American Shoulder and Elbow Surgeons (ASES) Society standardized shoulder assessment form, Constant (Murley)
Score (CS), Simple Shoulder Test (SST), Oxford Shoulder Score (OSS), Shoulder Disability Questionnaire (SDQ), and Western
Ontario Shoulder Instability Index (WOSI). Arthritis Care Res. 2011,63 (Suppl. 11), S174–S188. [CrossRef]
41.
Bot, S.D.; Terwee, C.B.; van der Windt, D.A.; Bouter, L.M.; Dekker, J.; de Vet, H.C. Clinimetric evaluation of shoulder disability
questionnaires: A systematic review of the literature. Ann. Rheum. Dis. 2004,63, 335–341. [CrossRef] [PubMed]
42. Breckenridge, J.D.; McAuley, J.H. Shoulder Pain and Disability Index (SPADI). J. Physiother. 2011,57, 197. [CrossRef]
43.
Murphy, M.; Rio, E.; Debenham, J.; Docking, S.; Travers, M.; Gibson, W. Evaluating the Progress of Mid-Portion Achilles
Tendinopathy during Rehabilitation: A Review of Outcome Measures for Self- Reported Pain and Function. Int. J. Sports Phys.
Ther. 2018,13, 283–292. [CrossRef] [PubMed]
44.
Kostuj, T.; Stief, F.; Hartmann, K.A.; Schaper, K.; Arabmotlagh, M.; Baums, M.H.; Meurer, A.; Krummenauer, F.; Lieske, S. Using
the Oxford Foot Model to determine the association between objective measures of foot function and results of the AOFAS
Ankle-Hindfoot Scale and the Foot Function Index: A prospective gait analysis study in Germany. BMJ Open
2018
,8, e019872.
[CrossRef]
45.
Higgins, J.P.; Altman, D.G.; Gøtzsche, P.C.; Jüni, P.; Moher, D.; Oxman, A.D.; Savovic, J.; Schulz, K.F.; Weeks, L.; Sterne, J.A. The
Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011,343, d5928. [CrossRef]
46.
Sterne, J.A.; Sutton, A.J.; Ioannidis, J.P.; Terrin, N.; Jones, D.R.; Lau, J.; Carpenter, J.; Rücker, G.; Harbord, R.M.; Schmid, C.H.; et al.
Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ
2011,343, d4002. [CrossRef]
47.
Higgins, J.P.T.; Thomas, J.; Chandler, J.; Cumpston, M.; Li, T.; Page, M.J.; Welch, V.A. Cochrane Handbook for Systematic Reviews of
Interventions, 2nd ed.; John Wiley & Sons: Chichester, UK, 2019.
48. Borenstein, M. Introduction to Meta-Analysis; John Wiley & Sons: Chichester, UK, 2009.
49.
Bowden, J.; Tierney, J.F.; Copas, A.J.; Burdett, S. Quantifying, displaying and accounting for heterogeneity in the meta-analysis of
RCTs using standard and generalised Q statistics. BMC Med. Res. Methodol. 2011,11, 41. [CrossRef]
50.
Higgins, J.P.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. Measuring inconsistency in meta-analyses. BMJ
2003
,327, 557–560.
[CrossRef]
51.
Alfredson, H.; Cook, J. A treatment algorithm for managing Achilles tendinopathy: New treatment options. Br. J. Sports Med.
2007,41, 211–216. [CrossRef] [PubMed]
52.
Cardoso, T.B.; Pizzari, T.; Kinsella, R.; Hope, D.; Cook, J.L. Current trends in tendinopathy management. Best. Pract. Res. Clin.
Rheumatol. 2019,33, 122–140. [CrossRef]
53.
Murphy, M.; Travers, M.; Gibson, W.; Chivers, P.; Debenham, J.; Docking, S.; Rio, E. Rate of Improvement of Pain and Function in
Mid-Portion Achilles Tendinopathy with Loading Protocols: A Systematic Review and Longitudinal Meta-Analysis. Sports Med.
2018,48, 1875–1891. [CrossRef] [PubMed]
54.
Vander Doelen, T.; Jelley, W. Non-surgical treatment of patellar tendinopathy: A systematic review of randomized controlled
trials. J. Sci. Med. Sport 2020,23, 118–124. [CrossRef] [PubMed]
55.
Liu, X.; Machado, G.C.; Eyles, J.P.; Ravi, V.; Hunter, D.J. Dietary supplements for treating osteoarthritis: A systematic review and
meta-analysis. Br. J. Sports Med. 2018,52, 167–175. [CrossRef] [PubMed]
56.
Puigdellivol, J.; Comellas Berenger, C.; Perez Fernandez, M.A.; Cowalinsky Millan, J.M.; Carreras Vidal, C.; Gil Gil, I.; Martinez
Pagan, J.; Ruiz Nieto, B.; Jimenez Gomez, F.; Comas Figuerola, F.X.; et al. Effectiveness of a Dietary Supplement Containing
Hydrolyzed Collagen, Chondroitin Sulfate, and Glucosamine in Pain Reduction and Functional Capacity in Osteoarthritis
Patients. J. Diet. Suppl. 2019,16, 379–389. [CrossRef]
57.
Dragan, S.; Serban, M.C.; Damian, G.; Buleu, F.; Valcovici, M.; Christodorescu, R. Dietary Patterns and Interventions to Alleviate
Chronic Pain. Nutrients 2020,12, 2510. [CrossRef] [PubMed]
58.
Agergaard, A.-S.; Svensson, R.B.; Malmgaard-Clausen, N.M.; Couppé, C.; Hjortshoej, M.H.; Doessing, S.; Kjaer, M.; Magnusson,
S.P. Clinical Outcomes, Structure, and Function Improve with Both Heavy and Moderate Loads in the Treatment of Patellar
Tendinopathy: A Randomized Clinical Trial. Am. J. Sports Med. 2021,49, 982–993. [CrossRef] [PubMed]
59.
Ji, R.R.; Chamessian, A.; Zhang, Y.Q. Pain regulation by non-neuronal cells and inflammation. Science
2016
,354, 572–577.
[CrossRef] [PubMed]
60.
Ronchetti, S.; Migliorati, G.; Delfino, D.V. Association of inflammatory mediators with pain perception. Biomed. Pharm.
2017
,96,
1445–1452. [CrossRef] [PubMed]
61.
Legerlotz, K.; Jones, E.R.; Screen, H.R.; Riley, G.P. Increased expression of IL-6 family members in tendon pathology. Rheumatology
2012,51, 1161–1165. [CrossRef]
62.
Vitali, M.; Naim Rodriguez, N.; Pironti, P.; Drossinos, A.; Di Carlo, G.; Chawla, A.; Gianfranco, F. ESWT and nutraceutical
supplementation (Tendisulfur Forte) vs ESWT-only in the treatment of lateral epicondylitis, Achilles tendinopathy, and rotator
cuff tendinopathy: A comparative study. J. Drug Assess. 2019,8, 77–86. [CrossRef]
63.
Henrotin, Y.; Dierckxsens, Y.; Delisse, G.; Seidel, L.; Albert, A. Curcuminoids and Boswellia serrata extracts combination decreases
tendinopathy symptoms: Findings from an open-label post-observational study. Curr. Med. Res. Opin.
2021
,37, 423–430.
[CrossRef] [PubMed]
J. Clin. Med. 2022,11, 1666 13 of 13
64. Gumina, S.; Passaretti, D.; Gurzi, M.D.; Candela, V. Arginine L-alpha-ketoglutarate, methylsulfonylmethane, hydrolyzed type I
collagen and bromelain in rotator cuff tear repair: A prospective randomized study. Curr. Med. Res. Opin.
2012
,28, 1767–1774.
[CrossRef] [PubMed]
65.
Choudhary, A.; Sahu, S.; Vasudeva, A.; Sheikh, N.A.; Venkataraman, S.; Handa, G.; Wadhwa, S.; Singh, U.; Gamanagati, S.; Yadav,
S.L. Comparing Effectiveness of Combination of Collagen Peptide Type-1, Low Molecular Weight Chondroitin Sulphate, Sodium
Hyaluronate, and Vitamin-C Versus Oral Diclofenac Sodium in Achilles Tendinopathy: A Prospective Randomized Control Trial.
Cureus 2021,13, e19737. [CrossRef] [PubMed]
66.
Morina, D.; Fernandez-Castillejo, S.; Valls, R.M.; Pedret, A.; Taltavull, N.; Romeu, M.; Giralt, M.; Montero, M.; Bernal, G.; Faba, J.;
et al. Effectiveness of a low-fat yoghurt supplemented with rooster comb extract on muscle strength in adults with mild knee
pain and mechanisms of action on muscle regeneration. Food Funct. 2018,9, 3244–3253. [CrossRef] [PubMed]
67.
Tsilioni, I.; Pipis, H.; Freitag, M.S.C.; Izquierdo, M.D.C.; Freitag, K.; Theoharides, T.C. Effects of an Extract of Salmon Milt on
Symptoms and Serum TNF and Substance P in Patients with Fibromyalgia Syndrome. Clin. Ther.
2019
,41, 1564–1574.e1562.
[CrossRef] [PubMed]
68.
Baar, K. Stress Relaxation and Targeted Nutrition to Treat Patellar Tendinopathy. Int. J. Sport Nutr. Exerc. Metab.
2019
,29, 453–457.
[CrossRef] [PubMed]
69.
Heinemeier, K.M.; Øhlenschlæger, T.F.; Mikkelsen, U.R.; Sønder, F.; Schjerling, P.; Svensson, R.B.; Kjaer, M. Effects of anti-
inflammatory (NSAID) treatment on human tendinopathic tissue. J. Appl. Physiol. 2017,123, 1397–1405. [CrossRef] [PubMed]
70.
Cömert Kılıç, S. Does glucosamine, chondroitin sulfate, and methylsulfonylmethane supplementation improve the outcome
of temporomandibular joint osteoarthritis management with arthrocentesis plus intraarticular hyaluronic acid injection. A
randomized clinical trial. J. Cranio-Maxillofac. Surg. 2021,49, 711–718. [CrossRef] [PubMed]
71.
McKinlay, B.J.; Theocharidis, A.; Adebero, T.; Kurgan, N.; Fajardo, V.A.; Roy, B.D.; Josse, A.R.; Logan-Sprenger, H.M.; Falk, B.;
Klentrou, P. Effects of Post-Exercise Whey Protein Consumption on Recovery Indices in Adolescent Swimmers. Int. J. Environ.
Res. Public Health 2020,17, 7761. [CrossRef]
72.
Shahnazi, M.; Mohammadi, M.; Mohaddes, G.; Latifi, Z.; Ghasemnejad, T.; Nouri, M.; Fattahi, A. Dietary omega-3 and -6
fatty acids affect the expression of prostaglandin E2 synthesis enzymes and receptors in mice uteri during the window of
pre-implantation. Biochem. Biophys. Res. Commun. 2018,503, 1754–1760. [CrossRef]
73.
Baugé, C.; Leclercq, S.; Conrozier, T.; Boumediene, K. TOL19-001 reduces inflammation and MMP expression in monolayer
cultures of tendon cells. BMC Complement. Altern. Med. 2015,15, 217. [CrossRef] [PubMed]
74.
Chan, K.-M.; Fu, S.-C. Anti-inflammatory management for tendon injuries-friends or foes? BMC Sports Sci. Med. Rehabil.
2009
,
1, 23. [CrossRef] [PubMed]
75.
Sauerschnig, M.; Stolberg-Stolberg, J.; Schmidt, C.; Wienerroither, V.; Plecko, M.; Schlichting, K.; Perka, C.; Dynybil, C. Effect of
COX-2 inhibition on tendon-to-bone healing and PGE2 concentration after anterior cruciate ligament reconstruction. Eur. J. Med.
Res. 2018,23, 1. [CrossRef] [PubMed]
76.
Christensen, B.; Dandanell, S.; Kjaer, M.; Langberg, H. Effect of anti-inflammatory medication on the running-induced rise in
patella tendon collagen synthesis in humans. J. Appl. Physiol. 2010,110, 137–141. [CrossRef] [PubMed]
77.
Åström, M.; Westlin, N. No effect of piroxicam on Achilles tendinopathy: A randomized study of 70 patients. Acta Orthop. Scand.
1992,63, 631–634. [CrossRef] [PubMed]
78.
Pattanittum, P.; Turner, T.; Green, S.; Buchbinder, R. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow
pain in adults. Cochrane Database Syst. Rev. 2013,5, CD003686. [CrossRef]
79.
Jiang, D.; Gao, P.; Lin, H.; Geng, H. Curcumin improves tendon healing in rats: A histological, biochemical, and functional
evaluation. Connect. Tissue Res. 2016,57, 20–27. [CrossRef] [PubMed]
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