Background Shoulder pain is a prevalent symptom primarily affecting the adult population,
with an incidence of approximately 19 per 1000 and a prevalence ranging from 7 to 26%,
particularly affecting women. The primary cause of shoulder pain is rotator cuff
pathology, characterized by nocturnal pain and weakness, especially during external
rotation and elevation movements of the shoulder, attributable to excessive loading on
the cuff tissues. These symptoms often result in disability and functional impairment.
The etiology of rotator cuff pathology appears multifactorial, often associated with
chronic age-related degeneration characterized by a reduced ability to synthesize
collagen, increased levels of free radicals, and heightened catabolic activity (5).
Tendinopathies exhibit widespread structural changes, including increased apoptosis of
tenocytes, collagen fiber disintegration leading to a decrease in collagen type I, an
increase in collagen type III resulting in a reversal of the collagen I/III ratio, and
ineffective neoangiogenesis.
As tendinopathy primarily represents a degenerative condition where the inflammatory
component plays a minor role, current therapeutic strategies mainly focus on regenerative
approaches. While intra-articular cortisone therapy has historically been utilized to
alleviate pain from rotator cuff injuries, its potential detrimental effect on tendon
collagen limits its long-term efficacy, rendering cortisone therapy beneficial only in
the short term.
Conversely, intra-articular treatment with hyaluronic acid (HA) for rotator cuff injuries
appears promising in reducing pain and improving shoulder function. A recent review
analyzed 11 studies encompassing a total of 1102 patients. Low to medium molecular weight
hyaluronic acids were utilized in these studies, with infiltration performed either via
anatomical landmarks or ultrasound guidance, targeting either intra-articular or
subacromial sites. Moreover, rare minor side effects (such as pain at the injection site
or slight vagal effects) were reported, with no instances of allergic reactions.
Hyaluronic acid (HA) is a carbohydrate, specifically a mucopolysaccharide, naturally
present in all living organisms. When unbound to other molecules, it binds to water,
imparting a rigid viscous 'jelly-like' quality. HA serves as an integral component of
synovial fluid, crucial for joint chondroprotection, and constitutes a significant
portion of the tendon extracellular matrix.
Upon injection into a joint, HA diminishes cytokine-induced responses and reduces
synovial inflammation, ultimately relieving pain and enhancing joint function. Notably,
preclinical in vitro and in vivo studies have demonstrated that exogenous peritendinous
HA possesses the ability to inhibit fibroblast activity and diminish the proinflammatory
M1 activation state of macrophages.
Observations of improved lubrication, chondroprotection, and enhanced synovial fluid
characteristics have also been reported. Additionally, HA facilitates tenocyte
regeneration, modulates the ratio of collagen type I/III, and mitigates apoptosis and
impaired angiogenesis.
It is important to note that in most studies, HA was not injected directly into the
degenerated tendon but rather near and/or into the joint space. While it can be
speculated that alterations in synovial fluid may positively impact the tendon itself, it
remains plausible that clinical improvement could be secondary to the favorable effects
on concomitant arthrosis frequently associated with the condition.
Rationale for Dietary Supplementation of Collagen and HA:
Tendons primarily comprise cells, predominantly tenoblasts along with endothelial cells
and some chondrocytes, as well as proteoglycans, notably decorin and hyaluronic acid, and
collagen, primarily type I. The tendon exhibits a highly organized extracellular matrix
wherein collagen molecules assemble into filamentous collagen fibrils (formed by
microfibrils), which further aggregate to constitute collagen fibers, the principal
structural components.
Various reviews have assessed the effectiveness of oral collagen supplementation in
enhancing tendon structure. Particularly, a review highlights that some studies have
demonstrated promising clinical implications of collagen peptide supplementation in the
prevention and treatment of tendinopathies, although conclusive evidence is still
lacking. Another review indicates that collagen supplementation alongside physical
training significantly influences pain relief, increased cross-sectional area, and tendon
thickness . From a joint perspective, collagen supplementation enhances mobility and
functionality while reducing pain.
Oral supplementation of hyaluronic acid has predominantly been investigated for its
effects on joints. For instance, it has been found effective in ameliorating pain and
enhancing the quality of life in patients with knee arthrosis, with sustained effects
observed at 2 months . Furthermore, the combined administration of HA and collagen orally
has shown to improve functional recovery in patients following anterior cruciate ligament
reconstruction, with evidence from resonance imaging indicating improved neoligament
maturation.
Experimental design In order to conduct this study, we will recruit 50 patients with
rotator cuff injuries from the outpatient clinic of the Santa Lucia Foundation. A
physiatrist from the clinic, participating in the project, will explain the study to the
enrolled individuals and obtain their informed consent.
The enrolled patients will undergo infiltrative treatment with corticosteroids
(Triamcinolone acetonide 40 mg, 1 vial - Kenacort®, BRISTOL-MYERS SQUIBB S.r.l.).
The enrolled patients will be randomized in 2 groups: oral supplements (Group 1 - G1) or
intra-articular hyaluronic acid (Group 2 - G2).
The Experimental Group (G1) will begin taking a supplement called Tendogenial® (B2Pharma
S.r.l.) the day after enrollment. This supplement contains Collagen, Hyaluronic Acid,
Vitamin C, and Manganese. Each day for 28 days, participants in G1 will consume one vial
of Tendogenial®.
Group 2 (G2) will receive three intra-articular injections of Hyalotend® (Fidia), a
viscous solution of sodium salt hyaluronic acid (500-730 kDa) obtained by bacterial
fermentation in buffered saline. The injections will be administered without ultrasound
guidance, using pre-filled 20 mg/2 ml syringes. The route of administration will be
intra-articular via the posterior access route.
Participants will be advised to take only paracetamol as needed for pain relief.
Additionally, they will be instructed not to undergo physiotherapy during the study
period. Any participants who undergo physiotherapy or receive other analgesic therapies
during the study will be excluded from the statistical analysis.
Inclusion Criteria:
Persistent shoulder pain lasting for at least 2 months, unresponsive to conservative
treatment (nonsteroidal anti-inflammatory drugs [NSAIDs] and rehabilitation).
Ultrasound or MRI evidence of a rotator cuff lesion without complete tendon rupture.
Limited active range of motion (ROM) in the shoulder. Age between 30 and 80 years.
Willingness to provide informed consent to participate in the study.
Exclusion Criteria:
Traumatic shoulder injury as the cause of pain. History of shoulder dislocation,
fracture, or previous shoulder surgery. Presence of signs indicating ligamentous
instability. Severe shoulder arthrosis, adhesive capsulitis, or calcific tendinitis.
Previous infiltrative treatment with corticosteroids, hyaluronic acid, or collagen within
the past 6 months.
Diagnosis of rheumatic or neoplastic diseases. Ongoing therapy with anticoagulants.
Cervical radiculopathy. Pregnancy. History of heart, kidney, or liver failure. Cognitive
impairment.
Both study groups will undergo assessment using pain and functional scales by a clinician
who is blinded to the treatment group.
In addition to providing informed consent to participate in the study, participants will
also sign a consent form specifically for infiltration, prepared by the Santa Lucia
Foundation. Any adverse reactions or side effects experienced by participants will be
documented and reported.