Dietary Supplements in Tendinopathy Sysrev
Dietary Supplements in Tendinopathy Sysrev
Dietary Supplements in Tendinopathy Sysrev
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
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.
2.1.2. 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).
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
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
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
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
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.
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
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
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
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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