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 2 and Kirsten Legerlotz 1, *

1 Institute of Sport Sciences, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099 Berlin, Germany;
[email protected]
2 Department of Kinesiology, Iowa State University, Ames, IA 50011, USA; [email protected]
* Correspondence: [email protected]; 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
Citation: Qiu, F.; Li, J.; Legerlotz, K. the reduction in pain score (SMD = −0.74, 95% CI, −1.37 to −0.10; p < 0.05), while it had no effect
Does Additional Dietary on functional outcomes (SMD = 0.29, 95% CI, 0.00 to 0.58; p > 0.05). This systematic review and
Supplementation Improve meta-analysis suggests that additional nutritional interventions may improve physiotherapeutic
Physiotherapeutic Treatment treatment outcomes in the management of tendinopathies.
Outcome in Tendinopathy? A
Systematic Review and Keywords: nutrition; tendinopathy; tendon pain; exercise therapy; meta-analysis; VISA; VAS
Meta-Analysis. J. Clin. Med. 2022, 11,
1666. https://doi.org/10.3390/
jcm11061666

Academic Editor: Marco 1. Introduction

Alessandro Minetto Tendinopathy is a common tendon disorder accounting for around 30% of com-
plaints related to musculoskeletal pain and functional limitations [1]. The aetiology of
Received: 16 February 2022
Accepted: 15 March 2022
this tendon pathology is multifactorial, including mechanical overuse [1,2] and metabolic
Published: 17 March 2022
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-
Publisher’s Note: MDPI stays neutral tients [6]. In the last few years, the incidence of tendinopathies in athletes and in the general
with regard to jurisdictional claims in
population has increased [7], with the increases in physical activity, changes in lifestyle and
published maps and institutional affil-
side effects of medication being discussed as potentially influencing factors [7–10].
iations.
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
Copyright: © 2022 by the authors.
training [15,16].
Licensee MDPI, Basel, Switzerland.
In recent years, dietary supplements have been introduced as an additional therapeu-
This article is an open access article tic approach in the treatment of tendinopathies, and their positive curative effects have
distributed under the terms and been reported for both the general population and athletes [17–20]. The applied dietary
conditions of the Creative Commons supplements contained a variety of micronutrients (e.g., bromelain and vitamin C) [21–23],
Attribution (CC BY) license (https:// which are suggested to reduce the level of inflammation [24–26] and to promote the healing
creativecommons.org/licenses/by/ of the tendon [21,22,27–30]. Because of the suggested anti-inflammatory effects and claimed
4.0/).

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 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 ther-
 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
J. Clin. Med. 2022, 11, 1666 Q test, indicating the presence of moderate-to-high heterogeneity. Subgroup analyses 4 of 13
were conducted to explore possible associations between the study characteristics and the
effectiveness of the intervention. Study characteristics included type of tendinopathy
(Achilles
apy,tendon, other(US),
ultrasound type),extracorporeal
intervention duration (≤8 weeks
shockwave therapyor (ESWT))
>8 weeks), type
and of of population
type
physiotherapy (exercise therapy, ultrasound (US), extracorporeal shockwave therapy
(athletic, non-athletic). For subgroup analysis, statistical significance was established at an
(ESWT)) and type of population (athletic, non-athletic). For subgroup analysis, statistical
alpha level of 0.05.
significance was established at an alpha level of 0.05.
3. Results
3. Results
3.1. Search Yield
3.1. Search Yield
We identified a total of 94 potentially eligible articles during the trial selection process.
We identified a total of 94 potentially eligible articles during the trial selection
Sixty-two
process. Sixty-twoarticles remained
articles remainedforfor
screening after
screening removing
after removing duplicates.
duplicates.After
Afterscreening titles
screening titles and abstracts, six articles [23,31–36] were included in the meta-analysis 1). From all
and abstracts, six articles [23,31–36] were included in the meta-analysis (Figure
included
(Figure 1). Fromstudies, an experimental
all included group of 123
studies, an experimental grouppeople
of 123and a control
people group of 118 people
and a control
were evaluated in this meta-analysis.
group of 118 people were evaluated in this meta-analysis.

FigureFigure Study selection

1. Study1.selection process (according
process (according to the
to the PRISMA PRISMA guidelines).
guidelines).

3.2. Characteristics
3.2. Characteristics of Included
of Included Studies Studies
Summed Summed
up, theup,
six the six studies
studies (Table 1)(Table 1) included
included 241 participants,
241 participants, with(SD)
with the mean the mean (SD) age
rangingfrom
age ranging from14.8
14.8(1.6)
(1.6)toto55.8
55.8 (13.2)
(13.2) years.
years. The
The six
six studies applied six
studies applied six different
different commercially
available
commercially dietarydietary
available supplements (Table
supplements 2). The
(Table duration
2). The of of
duration thethe
intervention
interventionininthe six articles
the sixranged
articlesfrom 4 to
ranged 12 weeks,
from while the
4 to 12 weeks, symptom
while duration
the symptom ranged
duration from
ranged 4 weeks
from 4 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.

Sample Size Mean Age (Years; Intervention Symptom Duration Time Points of
First Author (Year) Tendon Investigated Study Groups (n) Type of Population Mean ± SD) Duration (Weeks) (Months) Measurement
Achilles tendon MCVC + EC 17 43.5 ± 14.5
Balius et al. (2016) EC 20 non-athletic 38.9 ± 6.6 12 >3 baseline, 6 and 12 w
(mid-portion)
Musculus flexor Creatine 9 15.5 ± 1.4
Juhasz et al. (2018) 9 athletic 14.8 ± 1.6 6 1–1.5 2, 4 and 6 w
hallucis longus Placebo
Mavrogenis et al. Patellar & several EFA, AO and US 17 31
upper body tendons * 14 athletic 32 5 >3 8, 16, 24 and 32 d
(2004) Placebo and US
Notarnicola et al. Achilles tendon ESWT and tenosan 32
ESWT and placebo 32 non-athletic 55.8 ± 13.2 8 >6 2 and 6 m
(2012) (insertional)
Praet et al. Achilles tendon TENDOFORTE + EccEx 10 45.3 ± 6.4
(2019) (mid-portion) Placebo + EccEx 10 non-athletic 42.0 ± 9.4 12 18 3 and 6 m

PUFAs 38 52.2 ± 12.0

Sandford et al. (2018) Rotator cuff 35 non-athletic 52.0 ± 16.2 8 >3 8 w, 3, 6 and 12 m
Placebo
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
TendoActive suppression of NF-κB mediated IL-1ß catabolic
Balius et al. (2016) (Bioiberica SA, Palafolls, Spain) mucopolysaccharides, collagen type I, vitamin C
signalling pathways in tenocytes
Micronized Cr monohydrate
Juhasz et al. (2018) (BioTech, Inc., Ft. Lauderdale, FL, USA) Cr monohydrate, dextrose, and vitamin C reduction of inflammatory markers

Bio-Sport EPA, DHA and GLA. selenium, zinc, vitamin A, reduction of inflammation caused by essential
Mavrogenis et al. (2004) (Pharma Nord ApS, Vejle, Denmark) vitamin B6, vitamin C and vitamin E fatty acids and antioxidants
Tenosan arginine-L-alpha-ketoglutarate, MSM, hydrolysed stimulation of metabolism and proliferation;
Notarnicola et al. (2012) (Agave s.r.l., Prato, Italy) collagen type I, Vinitrox, bromelain, and vitamin C reduction of inflammation and neoangiogenesis
stimulation of collagen type I and III,
proteoglycans and elastin content synthesis by
Praet et al. (2019) TENDOFORTE® (GELITA AG, Hydrolysed specific collagen peptides sCPs; reduction of TNF-alpha, matrix
Eberbach, Germany)
metalloproteases and stimulation of tissue
inhibitors of metalloproteinases by Glycine
MaxEPA
Sandford et al. (2018) (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.

Blinding of
Random Blinding of
Allocation Participants and Incomplete Selective
Sequence Outcome
First Author (year) Concealment Personnel Outcome Data Reporting Other Bias
Generation Assessment
(Selection Bias) (Performance (Attrition Bias) (Reporting Bias)
(Selection Bias) (Detection Bias)
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.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 7 of 14

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
-, high
the risk ofbybias;
studies +, low risk et
Notarnicola of al.
bias; ?, unclear
[34] risk of bias,
and Sandford as[36],
et al. paperrespectively.
contained insufficient
Although high
information to permit judgement.
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. Meta-Analysis
3.4.1. Analysis of Pain Score at Rest
3.4.1. Five
Analysis of Pain Score
experiments with aattotal
Restof 221 participants provided data on pain score at rest.
The Five experiments
pooled analysis ofwith
fiveatrials
total (Figure
of 221 participants
2) revealed provided data on painofscore
that the combination at
dietary
rest. The pooled analysis of five trials (Figure 2) revealed that the combination
supplementation and physiotherapy led to a greater mean reduction in pain score than of dietary
supplementation
physiotherapy aloneand(SMD
physiotherapy led to−1.37
= −0.74, 95%CI, a greater mean
to −0.10). Inreduction in pain
the subgroup score(Table
analysis than
physiotherapy
4) of types of alone (SMD = −intervention
tendinopathy, −1.37 to −
0.74, 95%CI,duration, 0.10). In the subgroup
physiotherapy type, andanalysis
type of
(Table 4) of types
population, of tendinopathy,
we observed intervention
no significant effects. duration, physiotherapy type, and type of
population, we observed no significant effects.

Figure2.
Figure 2. Forest
Forest plot
plot of
of the
the meta-analysis
meta-analysis on
on pain
pain score
score at
at rest.
rest. Pain score
score measurement
measurement include
includeNRS
NRS
and VAS scales.
and VAS scales.

Table 4. Results of subgroup analysis.

Pain at Rest Functional Outcomes

Study Characteristics Studies p Value
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
J. Clin. Med. 2022, 11, 1666 7 of 13

Table 4. Results of subgroup analysis.

Pain at Rest Functional Outcomes

Study Characteristics Studies Effect Size p Value Effect Size
(95%CI) Studies (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
J. Clin. Med. 2022, 11, x FOR PEER REVIEW to
8 of 14
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
Figure 3.
3. Forest
Forest plot
plot of the meta-analysis
of the meta-analysis on
on functional
functional outcomes.
outcomes. Functional
Functional outcomes
outcomes include
include
VISA-A, SPADI and AHS.
VISA-A, SPADI and AHS.

4. Discussion
4. Discussion
In the
In the management
management of of tendinopathy,
tendinopathy, the reduction
reduction of pain and the improvement
improvement of
function are the aims
function aims ofof different
different treatment
treatment methods [6,52–58]. Within
Within this
this context,
context, aa novel
novel
strategy that
strategy that applied
applied dietary
dietarysupplementation
supplementation additional
additionaltotophysiotherapy
physiotherapywas wasevaluated.
evaluated.
Our meta-analysis
Our meta-analysis has
has shown
shown thatthat additional
additional nutritional
nutritional interventions
interventions can can reduce
reduce pain
pain
further than physiotherapy alone, while a significant improvement in function
further than physiotherapy alone, while a significant improvement in function could not could not
be detected.
be detected.
Additional nutritional
Additional nutritional interventions
interventions may
may bebe an
an effective
effective strategy
strategy toto improve
improve pain
pain
reduction in patients with tendinopathies. The mechanism by which
reduction in patients with tendinopathies. The mechanism by which the ingestion of the ingestion of
nutritional supplements
nutritional supplements improves
improves tendinopathy
tendinopathy symptoms
symptoms may may bebe linked
linked toto the
the capacity
capacity
of certain ingredients in affecting inflammation. While all six RCTs included
of certain ingredients in affecting inflammation. While all six RCTs included in our meta- in our meta-
analysis applied a different supplement, five studies [23,31,32,34,36] applied
analysis applied a different supplement, five studies [23,31,32,34,36] applied supplements supplements
which contained
which contained substances
substances of of known
known anti-inflammatory
anti-inflammatory function,
function, andand all
all six
six papers
papers
explained assumed effects with a reduction in inflammation or inflammatory
explained assumed effects with a reduction in inflammation or inflammatory markers. markers.
Inflammation is strongly associated with pain production [59,60]. In addition, it may
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-
play an important role in the development of tendinopathies [14,61]. Therefore,
regulation of inflammation levels induced by anti-inflammatory ingredients could be a
downregulation of inflammation levels induced by anti-inflammatory ingredients could
potential mechanism to consider in tendinopathy management. The pain-reducing effect of
be a potential mechanism to consider in tendinopathy management. The pain-reducing
nutritional interventions addressing inflammation has been shown for a variety of supple-
effect of nutritional interventions addressing inflammation has been shown for a variety
ments in a variety of tendon related pathologies. In patients with lateral epicondylitis and
of supplements in a variety of tendon related pathologies. In patients with lateral
shoulder and Achilles tendinopathy [62], Tendisulfur® supplementation for 60 days led to
epicondylitis and shoulder and Achilles tendinopathy [62], Tendisulfur® supplementation
a drop in VAS, possibly due to the downregulation of NF-κB, TNF-α and IL-6. Furthermore,
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,
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-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 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-κB-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.

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