PRIMER

Tendinopathy
Neal L. Millar   1 ✉, Karin G. Silbernagel2, Kristian Thorborg3, Paul D. Kirwan4,
Leesa M. Galatz5, Geoffrey D. Abrams6, George A. C. Murrell7, Iain B. McInnes   1
and Scott A. Rodeo   8
Abstract | Tendinopathy describes a complex multifaceted pathology of the tendon, characterized
by pain, decline in function and reduced exercise tolerance. The most common overuse
tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar
tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular
features of tendinopathy include disorganization of collagen fibres, an increase in the
microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis,
increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although
diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking
tests and imaging might be necessary. Management consists of different exercise and loading
programmes, therapeutic modalities and surgical interventions; however, their effectiveness
remains ambiguous. Future research should focus on elucidating the key functional pathways
implicated in clinical disease and on improved rehabilitation protocols.

1
Institute of Infection,
Immunity and Inflammation,
University of Glasgow,
Glasgow, UK.
2
Department of Physical
Therapy, University of
Delaware, Newark, DE, USA.
3
Institute of Clinical Medicine,
Copenhagen University,
Copenhagen, Denmark.
4
School of Physiotherapy,
Royal College of Surgeons
in Ireland, Dublin, Ireland.
5
Department of Orthopaedic
Surgery, Icahn School of
Medicine, Mount Sinai Health
System, New York, NY, USA.
6
Department of Orthopaedic
Surgery, Stanford University
School of Medicine, Stanford,
CA, USA.
7
Orthopaedic Research
Institute, Sydney, Australia.
8
Hospital for Special Surgery,
New York, NY, USA.
✉e-mail: neal.millar@
glasgow.ac.uk
https://doi.org/10.1038/
s41572-020-00234-1
Tendinopathy describes a spectrum of changes that
occur in damaged and diseased tendons, leading to pain
and reduced function. Tendinopathy is characterized by
abnormalities in the microstructure, composition and
cellularity of tendon. A normal tendon is composed of
highly arranged collagen fibres with sparse cells (mostly
tenocytes), aligned along the length of the collagen
fibres (Fig. 1). However, an ‘altered’ tendon consists of
fragmented collagen fibres, disorganized collagen bun-
dles, accumulation of glycosaminoglycans and increased
microvasculature associated with neoinnervation1, lead-
ing to adverse changes in the material properties of the
tendon. Tendons require the ability to withstand, store
and then deliver substantial force to perform day-to-day
activities. During sports-related activities, where the rep-
etition and speed of the loading is drastically increased,
the mechanical force placed on the tendon becomes
substantially amplified, in turn, demanding an increased
capacity of the tendon2. In most cases of tendinopathy,
injury is associated with overuse, resulting in multiple
overlapping pathological processes, which leads to pain,
diffuse or localized swelling, loss of tissue integrity and
impaired performance1.
Despite >600 muscle–tendon units in the human
body, tendinopathy tends to affect two distinct anatomi-
cal locations — the upper limb (in particular, the shoul-
der and elbow) and the lower limb (especially, the knee,
ankle and hip), whereby the collagen matrix is in a state
of disrepair3. Interestingly, all tendons may undergo
tendinopathic changes under certain insults3, and tendi-
nopathy can occur without the classic signs of overuse
and can be associated with certain drug treatments, such
as fluoroquinolone antibiotics and excess corticosteroid
use, metabolic or medical disorders (for example, seron-
egative spondyloarthropathies) and genetic alterations
(for example, polymorphisms in COL5A1 (ref.4)).
Approaches to the diagnosis and management of
tendinopathy are divergent between clinicians owing to
historical inconsistencies in clinical nomenclature, which
includes the terms tendinitis, tenosynovitis and tendi-
nosis, and also owing to a lack of pathophysiological
understanding. These disputes initially led to a decreased
recognition of tendinopathy in the musculoskeletal com-
munity and, consequently, tendon research has lagged
behind other musculoskeletal therapeutic advances, such
as in inflammatory arthritis and osteoarthritis.
Knowledge of risk factors for tendinopathy, patho-
physiology and enhanced definitions are still emerging.
However, since the early 2000s, the research commu-
nity has provided new clinical and pathogenetic insights,
which have contributed to a remarkable evolution of the
field. Nevertheless, to date, tendinopathy remains a chal-
lenge to treat with many documented treatments failing
to achieve 100% success. A large proportion of patients
still fail to attain complete resolution of tendon sympto-
mology and, therefore, more work is required to afford
therapeutic success in these patients.
In this Primer, we review the latest insights in the epi-
demiology, pathophysiology, diagnosis, clinical assess-
ment and management of tendinopathy. In addition,
we aim to consolidate and interpret the as-yet-unmet
needs in the field and provide an outlook to address

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Healthy tendon

Interfascicular matrix
Type I collagen fibril
Immune cell

Muscle
Nerve fibre Tenocyte

Tendon Blood vessel

Bone
Tendinopathy

Myotendinous
junction
Type III collagen fibril

Enthesis
Neovessel

Rotator cuff impingement

Previously used term to
describe rotator cuff
tendinopathy, that is, pain and
weakness, most commonly
experienced with movements of
Degenerative type I collagen fibril
shoulder external rotation and
elevation, as a consequence of
Fig. 1 | Structural changes of tendons in tendinopathy. Normal tendon is a well-organized network of collagen fibrils.
excessive load on the rotator The extracellular matrix (ECM) is dense, with a fibrillary network of predominantly parallel-aligned collagen fibres,
cuff tissue. principally consisting of type I collagen. The ECM is composed of proteoglycans, glycosaminoglycans and glycoproteins
including small leucine-rich proteoglycans. In tendinopathy, tenocytes are decreased in volume, becoming longer and
Subacromial pain syndrome slender, have an increased nucleus to cytoplasm ratio and produce less ECM but with an increase in type III collagen
Pain, weakness and loss of density (mostly owing to less degradation). Histological examination of patient biopsy sample has shown intratendinous
function of the shoulder collagen degeneration with fibre disorientation and glycosaminoglycan accumulation between the thinning fibrils with
usually resulting from inflammatory cell infiltrates. Neovascularization and neoinnervation are also frequently found in the diseased tendon.
overhead activities.

Plantar fascia
Thick, web-like ligament that
connects the heel to the front
of the foot. This ligament
acts as a shock absorber
and supports the arch of
the foot, facilitating walking.
Achilles tendon
A strong fibrous cord that
connects the muscles
in the back of the calf
to the calcaneus bone.
Greater trochanter
The attachment site for
five muscles: the gluteus
medius, gluteus minimus,
piriformis, obturator externus
and obturator internus.
Patellar tendon
The tendon running inferiorly
from the patella bone to the
tibial tuberosity.
Tibialis posterior tendon
The tendon on the inner side
of the ankle that assists in
maintaining the arch of the
foot as well as the ability to
turn the ankle inwards.
the outstanding issues to attain better outcomes in all
patients with tendinopathy.
Epidemiology
Since the early 2000s, the prevalence of tendinopathy has
been increasing worldwide, resulting in long-term or per-
manent deficits in function in both athletic individuals
and non-athletic individuals of all ages5. Additionally, the
incidence and prevalence of tendinopathy varies widely
between different parts of the body and according to age,
sex, type of sports and physical activity, occupational
setting and specific disease condition.
Tendinopathies are commonly observed in the lower
and the upper extremities of the body5 (Fig. 2). The inci-
dence of lower limb tendinopathy is reported to be
10.52 per 1,000 person-years, which even exceeds the
incidence of osteoarthritis (8.4 per 1,000 person-years)6,7.
In the upper extremity, tendinopathies in the supra­
spinatus within the shoulder (rotator cuff) and the elbow
(common flexors and extensors) are the most common.
Among these, rotator cuff impingement or subacromial pain
syndrome, with or without tendon degeneration, is the
most common8,9. In the lower extremity, the most com-
mon tendinopathies occur at the heel (plantar fascia and
Achilles tendon), the greater trochanter (that is, the gluteal
insertional complex), the knee (patellar tendon) and the
ankle (tibialis posterior tendon)7. Reports based upon the
general population and patients seen in general prac-
tice suggest that 1–2% of adults (18–65 years of age)
present with lower extremity tendinopathy during their
lifetime7–9. The lifetime prevalence of Achilles tendinop-
athy in athletes was found to be 23.9% compared with
5.9% in the general population10. Although tendinopa-
thy can occur at an early age, it occurs most commonly
between 18 and 65 years of age and tendinopathy in this
age group accounts for more than two thirds of the cases
across all age groups5,7. The prevalence of tendinopathy
increases with increasing age, and women are more
prone to tendinopathy than men7. In children and ado-
lescents (<18 years of age), the prevalence ranges from
8% to 33% and is higher in boys11.
Risk factors
Multifactorial elements including modifiable risk fac-
tors and non-modifiable intrinsic and extrinsic risk
factors are involved in the development of tendinopathy
(Box 1). In a subset of patients, hormonal and metabolic
conditions, such as obesity12, cholesterol and diabe-
tes mellitus13, have been shown to influence the inci-
dence and severity of injury and the patient response
to physical therapy14. Furthermore, tendinopathy is
more prevalent in individuals with diabetes mellitus15,

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hypercholesterolaemia16, rheumatic diseases (psoriatic
arthritis) and renal diseases (for example, end-stage
renal disease)5. In non-athletic individuals who develop
tendinopathy, metabolic factors have been suggested to
be more prevalent and can influence the ability to recover
with current exercise treatment17. Additionally, the use of
antibiotics (for example, fluoroquinolones) is associated
with a 2–15% increased risk of tendinopathy and tendon
rupture compared with the risk in control individuals18.
Sports. Most tendinopathies occur in relation to specific
high-load demands that are frequently encountered in
sports and are associated with repetitive loading of the
tendon5. Tendinopathy is one of the most common diag-
noses in people performing elite sports and accounts for
~30% of total injuries diagnosed19. Handball, basketball
and volleyball players are at a high risk of developing
patellar tendinopathy and rotator cuff tendinopathy20
owing to the sport demanding repetitive jumping and
throwing, and smashing and blocking. Runners, however,
are most likely to develop tendinopathies in the knee,
foot or ankle, although Achilles tendinopathy seems to
be the most frequent21. Footballers and ice hockey play-
ers have a higher risk of developing tendinopathy at the
hip and groin region (gluteal tendinopathy), than other
Shoulder
• Rotator cuff
tendons (5.5%) Elbow
• Common extensor
origin (0.7%)
• Common flexor
origin (0.6%)
Hip
• Gluteal
tendons (4.2%)
Knee
• Patellar
PPPskjdbn
tendon (1.6%)
Foot and/or ankle
• Achilles tendon (2.4%)
• Peroneal or posterior
tibial tendons (2.4%)
Fig. 2 | Common sites of tendinopathy. This figure shows the incidence of different types
of tendinopathy in the general population. Most tendinopathies in the lower limbs involve
the Achilles tendons or patellar tendons, although current studies have highlighted the
growing incidence of gluteal tendinopathy. The most frequent tendinopathy in the upper
limbs affects the rotator cuff tendons and the elbow (extensor carpi radialis brevis),
commonly known as tennis elbow or lateral elbow tendinopathy.
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Primer
sportspersons and the general population, most likely
due to excessive kicking and repetitive skating moves20.
Swimming and tennis are typically associated with a
high risk of rotator cuff tendinopathy; tennis is also
associated with an inherent risk of developing tendin-
opathy at the lateral elbow, and hence the popular term
‘tennis elbow’22.
Occupation. Specific occupational settings that include
forceful activities, often with high force and/or repeti-
tion, are associated with an increased risk of developing
tendinopathy. Such physically demanding occupations
include food industry workers, assembly line packers,
construction workers, sewing machine operators, musi-
cians, cooks and surgeons5. These jobs are typically asso-
ciated with repetitive activities in the upper extremity,
especially involving the tendons of the elbow and shoul-
der. Thus, individuals engaged in such occupations have
a higher prevalence and incidence of tendinopathy than
the general population23.
Genetic factors. Genetic factors play an important part
in tendon homeostasis and in the balance between repair
and degeneration following tendon injury4,24. A system-
atic review investigated ~34 different genes and their
relationship to tendon form or function, and identified
polymorphisms in 13 independent genes, which were
associated with tendon injury (tendinopathy or rup-
ture)24. The strongest of these associations was observed
in COL5A1, TNC, MMP3 and ESRRA. Several studies
have consistently found an association between COL5A1
and Achilles tendinopathy 25,26. Indeed, COL5A1 is
known to play a crucial part in fibril formation by inter-
acting with COL1A1 to regulate overall fibril size and
subsequent matrix organization24. Genetic variants in
MMP3 and TIMP2 have been reported to be strongly
associated with the risk of Achilles tendinopathy27.
As most studies were focused on Achilles tendinopa-
thy and were specifically based on South African and
Australian patient groups, the associations might not be
applicable to the development of other tendinopathies.
Indeed, systematic reviews of the genetics of rotator cuff
tendinopathy28,29 have highlighted a role for SASH1 and
SAP30BP (tumour suppressor genes associated with
apoptosis) in tendinopathy pathogenesis.
Despite the above-mentioned findings, there are mul-
tiple proposed aetiologies for tendinopathy, with a lack
of consensus, reflecting the complex polygenic nature of
tendinopathy. Hence, further studies are required to
clarify the complex interaction between genes, encoded
proteins and the environment. This understanding may
ultimately lead to individualized strategies for preven-
tion and herald the potential for a personalized medi-
cine approach involving genetics for the management
of tendinopathy.
Mechanisms/pathophysiology
The pathogenesis of tendinopathy is multifactorial and
complex. Different studies have led to multiple theories
to explain the pathophysiology of tendinopathy (Box 2).
The pathological process seems to be initiated by repet-
itive tendon overload, leading to structural injury of
Primer
Tensile load
The ability of a material to
withstand a pulling force.
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Box 1 | Risk factors for tendinopathy
Intrinsic factors
• Systemic diseases
-- Metabolic disorders such as diabetes mellitus,
obesity and hyperlipidaemia
-- Inflammatory conditions
• Family history
• Obesity
• Age
• Limited or excessive joint mobility
• Muscle weaknesses
• Deficits in neuromuscular control
• Tendinosis and altered tendon structure
Extrinsic risk factors
• Overuse
• Sudden increase in activity or intensity of activity
• Initiation of new activities (such as overhead activities
for rotator cuff tendinopathy or jumping for patellar
tendinopathy, or running for Achilles tendinopathy)
• Lack of adequate recovery
• Highly repetitive movement
• Poor workplace ergonomics
• Medications
-- Fluoroquinolones
-- Hormone replacement therapy
• Statins
the microscopic collagen fibrils. Under normal circum-
stances, early tendon matrix injury triggers an effective
healing process; however, poor intrinsic healing ability
of the tendon or lack of adequate recovery might lead
to gradual accumulation of matrix damage over time30.
These initial structural alterations are typically clini-
cally silent and, therefore, asymptomatic. The progres-
sive accumulation of matrix damage and the secreted
cytokines, chemokines, inflammatory mediators and
activated nociceptors eventually lead to symptom man-
ifestation (Fig. 3). Our current understanding of the
pathogenesis of tendinopathy has evolved over the last
decade and is derived from animal models of overuse
tendinopathy and from tissue specimens from patients,
which have provided critical insights into the early cel-
lular and molecular alterations that contribute to the
development of tendinopathy31.
Tendon structure and homeostasis
The fundamental component of tendons is composed
of type I collagen (which forms ~60–85% of its dry
weight), with the remainder consisting of proteogly-
cans, glycosaminoglycans, glycoproteins and other col-
lagen subtypes, such as types III, V and XII collagen1.
Tenocytes, fibroblast-like cells that comprise the basic
cellular component of tendon tissue, uniformly align
along the length of the collagen fibrils32. The main
functions of tenocytes are to control cell metabolism
(that is, formation and degradation of the extracellular
matrix (ECM)) and to respond to mechanical stimuli
experienced by the tendon33. In particular, tenocytes
undergo mechanical transmission; that is, they stretch
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along the collagen fibrils to form longitudinal arrays
upon experiencing tensile load, which acts as a signal
for collagen production34. ECM turnover of a tendon
is influenced by physical activity, blood flow, oxygen
demand and the amount of collagen synthesized and
the extent of matrix metalloproteinases (MMP) increase
with mechanical loading. Gene transcription and espe-
cially post-translational modifications of ECM proteins
are enhanced following exercise. Conversely, inactivity
markedly decreases collagen turnover35. Thus, human
tendon tissue mounts a vigorous acute and chronic
response to mechanical loading involving metabolic and
circulatory changes as well as ECM remodelling 35,
and cumulative total load seems to play a part in the
development of tendinopathy3. Numerous intracellular
and intercellular signalling pathways, including NF-кB,
ERK, MAPK and TGFβ, have been shown to mediate
the adaptive response towards tendon homeostasis36–40.
Matrix changes in tendinopathy are characterized by
a loss of structural organization of collagen and altera-
tions in fibrocartilagenous composition with deposition
of additional matrix protein (for example, glycosamino-
glycans)41,42. Importantly, in the initial phase of tendon
damage, type III collagen is produced43 and acts as a
rapid ‘patch’ to protect the area of damage. Type III col-
lagen is laid down in a haphazard fashion, contributing
to the inferior biomechanical strength and the irregular
alignment seen microscopically in damaged tendon44.
With time, in the normal tendon, type I collagen replaces
type III collagen and resumes the linear structured
arrangement with eventual resolution45. However, in
tendinopathic tissue, this repair mechanism is impaired
with increased accumulation of type III collagen.
Extracellular matrix dysregulation
Several studies have implicated dysregulation of ECM in
the pathogenesis of tendinopathy. Accordingly, research
efforts have concentrated on understanding the inter-
play between mechanical forces and transcription fac-
tors, growth factors and signalling pathways, and their
contribution to the spatial regulation of type I collagen.
Several new studies have highlighted the role of tran-
scription factors, such as MKX, SCX and EGR1, in reg-
ulating type I collagen synthesis through modulation
of COL1A1 or COL1A2 expression46, whereas studies
have implicated TGFβ in regulating the collagen archi-
tecture during tendon development47. In tendinopathy,
collagen degradation exceeds collagen synthesis in the
early phases after loading48. Notably, studies utiliz-
ing the carbon-14 (14C) bomb pulse method to meas-
ure the lifelong replacement rates of collagen in healthy
individuals and patients with Achilles tendinopathy
found a substantial collagen renewal in tendinopathic
samples49,50. However, modelling of the 14C data sug-
gested that 50% of the collagen in diseased matrix had
undergone continuous slow turnover for years before the
presentation of clinical symptoms. This finding implies
that the symptoms of tendinopathy correspond to a late
phase of a prolonged disease or that abnormally high
collagen turnover might be a potential risk factor for
tendinopathy rather than a direct consequence of the
disease. Further work has identified a circadian clock

Interfascicular matrix
mechanism of protein homeostasis, in which a sacrificial
The endotenon that facilitates pool of collagen maintains overall tissue function51. This
sliding between fascicles study indicated that control of the extrinsic secretory
pathway and the circadian clock might be an effective
Fatigue resistance
Resistance to the weakening
tool in regulating collagen homeostasis in the treatment
of a material caused by cyclic of tendinopathy. This regulation might include pro-
loading. moting collagen deposition during wound healing or
impeding the synthesis of certain collagen subtypes, with
type III collagen being an obvious target in tendinopathy.
Another major factor contributing to adverse ECM
remodelling is the upregulation of MMPs and their
endogenous inhibitors (TIMPs). These molecules have a
key role in ECM turnover and remodelling and are often
dysregulated in the setting of tendinopathy52. Tissue
specimens from animal models of overuse tendinopathy
and from patients have demonstrated a dysregulation
in the balance between MMPs and TIMPs, which can
contribute to detrimental changes in the microstructure
and composition of a tendon, with a resultant weakening
of its material properties3.
Interfascicular matrix alterations
In addition to ECM components, studies have indicated
a role for the components of the interfascicular matrix
(also known as the endotenon) (Fig. 1) in tendinopathy
pathogenesis53. Studies performed in equine tendon
have shown that energy storing tendons such as the
Box 2 | Theories on the pathogenesis of tendinopathy
Mechanical theory
As one of the first theories proposed in 1978 (ref.240), this theory led to the classic
definition of ‘tendinosis’ and suggested that impaired healing of tendon lesions leads
to degenerative changes, which results from increased demand on the tendons with
inadequate repair and progressive cell death241,242. This theory proposes that excessive
mechanical stimulation via repetitive tensile strain243 or compression244, or a noxious
trigger of tenocytes, induces tendon degenerative changes. Importantly, this theory
suggests that interactions between tendon cells and their mechanical environment
are crucial for tendinopathy pathogenesis.
Inflammation theory
This model suggests that pathological changes in the tendon arise from inflammatory
processes. Although the results of some studies have led to this hypothesis being
disputed242,245, allowing the mechanical theory of tendon pathology to become widely
accepted, current studies have confirmed the presence of inflammatory mediators,
and that inflammation and overuse are not mutually exclusive246,247.
Apoptosis theory
The apoptosis theory71,72 links high doses of cyclic strain (that is, repetitive load) with
oxidative stress, acquisition of a cartilage phenotype and activation of metalloproteinases
with the development of degenerative injuries.
Vascular or neurogenic theory
A few studies have suggested that increased vascular ingrowth into tendons may
cause tendon weakening and rupture248. Additionally, neurogenic inflammation has also
been suggested to mediate adaptive responses of tendons to mechanical overload249.
Continuum model
The continuum model of tendon pathology was conceptualized to integrate clinical
symptoms and laboratory-based research to guide treatment choices for the
clinical presentations of tendinopathy250,251. The model consists of three stages —
reactive tendinopathy, tendon disrepair (failed tendon healing) and degenerative
tendinopathy. Other studies have tried to amalgamate all of these aspects into a
three-stage process consisting of injury, failed healing and clinical symptoms252.
Overall, although these models are useful in correlating tendon basic science to
clinical findings, any one model is unlikely to fully explain the aetiology of tendon
pathology and the complex interaction between pain and function, which lead to
the development of the disease.
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Achilles have an interfascicular matrix that exhibits
fatigue resistance and low stiffness, suggesting that the
interfascicular matrix might augment the elastic behav-
iour of the tendon, thereby improving its core elastic-
ity efficiency54. Further work is required in humans to
define the cellular subtypes within the interfascicular
matrix and to elucidate whether this seemingly impor-
tant structure regulates human tendon function and
ultimately contributes to tendon pathology.
Non-collagenous matrix alterations
Many studies have also investigated the role of the
non-collagenous matrix in the pathogenesis of tendi-
nopathy 55. Non-collagenous matrix is principally
composed of elastin, proteoglycans and the collagen oli-
gomeric matrix proteins, lubricin and tenascin-C. Small
leucine-rich proteoglycans are the widely expressed
proteoglycan within the tendon, with decorin account-
ing for ~80% of the total proteoglycan content and
lumican, fibromodulin and biglycan comprising the
remainder56. Importantly, in addition to ECM assembly,
non-collagenous matrix components have also been
hypothesized to regulate growth and differentiation of
tenocytes through interactions of small leucine-rich
proteoglycans with resident tenocyte lineages 57.
Additionally, non-collagenous matrix proteins are also
believed to have a crucial role within the mature tendon
in modulating fibre sliding and fascicle sliding, thereby
influencing the viscoelastic properties of a tendon55.
Absence or altered expression of non-collagenous matrix
proteins seems to result in excessive fibre sliding, which
is likely to decrease the mechanical integrity of the
tendon tissue, resulting in increased risk of injury.
Oxidative Injury
Reactive oxygen species (ROS) and oxygen free radicals
are produced in a degenerating tendon58. Oxygen free
radicals have been implicated in stress-induced apop-
totic pathways, whereas mitochondria act as intracellular
mechanotransducers through strain-mediated release of
ROS. During normal cell metabolism, ROS are contin-
ually produced through the mitochondrial respiratory
chain; NADPH-dependent cytochrome P450 enzymes,
lipoxygenase, and cyclooxygenase are also sources of
basal ROS production. ROS are believed to impose
cellular or tissue damage through lipid peroxidation,
protein modification, DNA strand cleavage, and oxida-
tive base modification59. Consequently, ROS and oxy-
gen free radicals are implicated in the pathogenesis of
complex diseases, such as diabetes mellitus, cancer and
Alzheimer disease, and may have a role in tendinopa-
thy development60. For example, BNIP3, a mitochon-
drial protein implicated in pro-apoptotic pathways and
mitochondrial dysfunction, has been reported to be
upregulated in tissue samples obtained from patients
with tendinopathy61.
Following tendon injury, one study showed
increased nitric oxide synthase (NOS) activity, leading
to increased pro­duction of nitric oxide, an important
regulator of inflammation62. In an exercise-induced
overuse model of tendinopathy, NOS mRNA was over­
expressed in the supraspinatus tendon of rats subjected
­ 5
Primer

Epigenetic modification

Environmental factors Altered post-transcriptional Susceptibility genes

• Smoking gene regulation • COL5A1 • TIMP2
• Metabolic disease • MMP3 • TNC
• Drugs
- Fluoroquinolones
Preclinical tendinopathy Adaptive or abnormal
- Prolonged steroids response to load
- Statins

Extracelullar matrix
dysregulation Early tendinopathy Immune cell dysfunction
• Abnormal collagen turnover • Cytokines
• Interfascicular matrix dysfunction • Chemokines
• Small leucine-rich proteoglycans • Alarmins
• Matrix metalloproteinases

Apoptosis

Oxidative stress or
Chronic tendinopathy
mitochondrial dysfunction Stromal cell
• Nitric oxide dysfunction
• BNIP3

Auto-amplicatory loops
• Abnormal collagen
• Interfascicular matrix dysfunction
• Matrix metalloproteinase dysfunction

Fig. 3 | Pathophysiology of tendinopathy. Various risk factors including excess mechanical overuse as well as environmental
factors including smoking, metabolic diseases (for example, diabetes mellitus and hyperlipidaemia) and certain medications
(for example, fluoroquinolones and excessive use of corticosteroids) can trigger the development of tendinopathy.
The concept of preclinical disease, in which clinical symptoms are not apparent, is supported by genetic susceptibility
datasets. Studies have identified single-nucleotide variants in COL5A1, MMP3, TIMP2 and TNC. Human tissue studies analysing
asymptomatic tendons show dysregulation of extracellular matrix, immune responses and stromal responses. Failure of
normal homeostatic responses eventually leads to early tendinopathy with influx of immune cells, stromal cell dysfunction,
apoptosis, oxidative stress and matrix dysfunction. Dysregulation of repair mechanisms (such as auto-amplificatory loops
and matrix–stromal–immune crosstalk dysfunction) leads to established or chronic tendinopathy with the clinical features
of poor function, pain and load capacity.

to treadmill running for 14 days58, and expression of
NOS was elevated in tendon samples from shoulder
surgery in humans63. Additionally, cultured tenocytes
procured from patients during surgery exposed to
exogenous nitric oxide showed increased total collagen
synthesis. Microarray analysis of tendon samples from
patients showed substantial increases in types I, III and
IV collagen, laminin, biglycan and decorin compared
with samples from healthy controls. These findings
clearly indicate an important role for nitric oxide in
regulating the structural integrity of the ECM64.
Altered developmental pathways
Dysregulation of signalling pathways involved in embry-
ological limb development may also play a part in ten-
don response to injury and repetitive overload. Indeed,
a rat model of tendinopathy demonstrated increased
ERK1/2 signalling in tendinopathic tendon compared
with healthy controls65. One study found that ERK1/2
signalling regulates glucocorticoid-mediated inhibi-
tion of collagen synthesis and proliferation in human
tenocytes66. Furthermore, MAPK-dependent pathways
have been shown to be involved in the mechanisms
underlying hypoxia-induced tendon damage67. Another
rodent model of tendinopathy revealed decreased
p38 signalling in affected animals, which resulted in
decreased IL-6 expression, thereby altering the expres-
sion of genes involved in cell proliferation and ECM
regulation68. In addition, one study has also implicated
Wnt signalling in tendinopathy; increased expression
of Wnt3a and β-catenin were found in patients with
tendinopathy69. A new study has identified a role for the
NF-кB pathway in tendinopathy pathogenesis. Tendon
samples from patients with rotator cuff tendinopathy
showed increased activity of the NF-кB pathway, which
was mirrored in mouse tendon cells overexpressing the
regulatory serine kinase subunit, IKKβ38, suggesting a
conserved mechanism across species. Furthermore,
genetic deletion of IKKβ in mouse tendon prevented
ECM remodelling (thereby, preventing tendinopathy
development) in a treadmill running-induced over-
use tendinopathy model and a surgical tendinopathy

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model70. Indeed, cultured human tenocytes treated with
an IKKβ inhibitor showed reduced transcription of
NF-кB target genes, suggesting a potential therapeutic
benefit from IKKβ blockade38.
Apoptotic pathways
Another fundamental process hypothesized to contrib-
ute to the underlying pathophysiology of tendinopathy
is apoptosis. The progressive loss of intrinsic tendon cells
owing to apoptosis further compromises the reparative
capacity of the tissue71. In this regard, tendon samples
from patients with degenerative rotator cuff tendinop-
athy as well as tissue samples from a rat model of over-
use tendinopathy demonstrated increased expression of
caspase 3 and caspase 8, which are important mediators
of apoptosis72,73.
Neuronal pathways
Currently, the factors that cause exaggerated pain sensitiv-
ity in patients with tendinopathy are poorly understood.
A mismatch between pain intensity and the under-
lying pathological changes is often observed. Studies
have demonstrated increased sensory neuropeptide
expression74. In addition, studies have shown an upregula-
tion of the glutamatergic system (that is, glutamate and its
peripheral receptors) in patients with rotator cuff tendin-
opathy and Achilles tendinopathy75,76. Another study has
shown localization of glutamate to intrinsic tenocytes in
the tendon and glutamatergic receptors are colocalized
on inflammatory cells (for example, macrophages) within
the tendon tissue77. This study also found increased levels
of other nociceptive mediators including mGluR2, GluK1
and UCH-L1 (also known as PGP 9.5) in tissue samples
from patients with tendinopathy77. Importantly, in addi-
tion to pain modulation, these sensory neuropeptides
may also have a role in the structural remodelling of the
tendons. For example, tenocytes exposed to glutamate
in vitro demonstrated decreased cell viability, decreased
COL1A1 expression and increased ACAN expression,
suggesting that glutamate might directly contribute to
the underlying pathological changes in tendinopathy78.
Molecular inflammation
Early studies indicated that tendinopathy is a degener-
ative process1. However, studies examining the under-
lying cellular and molecular mechanisms over the past
decade have clearly underscored the role of molecular
inflammation in tendinopathy development79. Various
immune cell subtypes and inflammatory mediators have
a key role in the initiation and progression of tendinop-
athy80. Reciprocal interactions between resident or infil-
trating immune cells and resident tenocytes are crucial
in directing a positive resolving inflammatory response
(that is, effective healing in the initial phase of tendon
injury) into a chronic disease process with ultimate
tissue degeneration and symptom production81,82. The
various immune cells and activated tenocytes produce a
number of inflammatory cytokines and chemokines that
initiate and augment the adverse alterations in tendon
microstructure and composition, which are hallmarks
of tendinopathy83,84. For example, animal models have
shown increased accumulation of macrophages and
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mast cells in the damaged tendons compared with ten-
dons from healthy animals85. Additionally, in the setting
of tissue damage, tenocytes in the stromal compart-
ment can be driven towards an activated inflamma-
tory phenotype secreting cytokines and chemokines in
response to signalling from immune cells that are inher-
ent in the tendon (mast cells and macrophages) or that
infiltrate the tendon81.
Inflammatory cytokines
Emerging evidence indicates unequivocal involvement
of an inflammatory component in tendinopathy patho-
genesis, with inflammatory cells and cytokines being
the central regulators of tendon ECM remodelling79.
In response to tissue injury, mechanical stress and
malfunction, tenocytes and immune cells release
pro-inflammatory cytokines such as TNF, IFNγ, IL-1β
and IL-6, as well as growth factors such as TGFβ and
PDGF37,80,86. Indeed, prolonged running causes a signif-
icant increase in the tissue concentration of IL-6, which
exerts both pro-inflammatory and anti-inflammatory
effects in tendon, the net effect being increased total
collagen synthesis87. A separate study showed that
when recombinant human IL-6 is infused locally, col-
lagen synthesis in the peritendinous tissue increases
to a similar degree as with exercise87, suggesting that
IL-6 is a key regulator of collagen synthesis in tendin-
opathy. In addition, cultured human tenocytes treated
with recombinant TNF demonstrate reduced type I
collagen deposition and significantly upregulate other
immunoregulatory cytokines88, which are detrimental
to the tendon ECM. In mouse models of tendinopathy,
mice lacking IL-4 exhibit lower cross-sectional tendon
area and decreased mechanical properties89, implying
a role for IL-4 in the development of tendinopathy.
Furthermore, tissue injury results in the upregulation
of IL21R mRNA90, and its downstream target, STAT3,
has been implicated in tendinopathy (in a human
microarray analysis)91. One study found an increased
expression of another IL-1 family cytokine, IL-33,
which is released following biomechanical overload92
and cellular damage93, in human tendinopathy com-
pared with normal tendon94. Moreover, in mechanistic
studies, addition of recombinant IL-33 to human ten-
ocyte cultures in vitro resulted in increased expression
of type III collagen, with an associated increase in the
inflammatory cytokines, IL-6, IL-8 and CCL2 (ref.94).
Accordingly, addition of recombinant IL-33 in a rodent
model demonstrated downstream deleterious effects on
tendon structure and biomechanical strength.
Another cytokine that seems to be a key regulator
in the development of tendinopathy is IL-17, increased
expression of which has been detected in human sam-
ples of early tendinopathy before the onset of MRI
abnormalities in the tissue95. In the same study, the
addition of IL-17 to human tenocytes in vitro stimu-
lated pro-inflammatory cytokine release and induced
ECM remodelling via type III collagen production.
The involvement of IL-17 is notable owing to the avail-
ability of effective anti-IL-17 monoclonal antibodies
(secukinumab and ixekizumab), which are currently
being evaluated for the treatment of tendinopathy96.
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Resolution pathways
Programmed responses
activated during inflammation
resulting in a switch of lipid
mediators that leads to
resolution of inflammation.
Bursitis
Inflammation or irritation
of a bursa sac.
8 | Article citation ID: (2021) 7:1 www.nature.com/nrdp
Several studies have also highlighted a role for different
alarmins (members of damage-associated mole­cular
patterns) including heat shock proteins and hypoxia-
induced elements in tendon pathology 37,67,86. For
instance, alarmins mobilize and activate innate immune
cells to initiate tissue repair and, therefore, are proba-
bly important in regulating homeostatic inflammatory
mechanisms in tendinopathy84.
MicroRNAs
MicroRNAs, in particular miR-210, a crucial regulator
of angiogenesis97, is implicated in tendon disease. One
study showed that miR-210 accelerated tendon healing
upon injection into diseased tendon in a rodent Achilles
injury model98. Interestingly, miR-210 was also able to
induce superior collagen quality (improved fibre align-
ment) through upregulation of type I collagen, VEGFA
and FGF2 (ref.98). In addition, one study found reduced
expression of miR-29a in biopsy samples of early tendi-
nopathy, suggesting that reduction of this microRNA
contributes to the development of tendinopathy 94.
Decreased miR-29a expression leads to overexpression
of type III collagen, which is a key ECM abnormality in
tendinopathy99.
Resolution pathways
Current evidence has provoked investigation of
resolution pathways in human tendinopathy. One study
discovered enhanced expression of MMR1 (also known
as CD206) and ALOX15, downstream of increased
STAT6 activity, in patients with shoulder tendinopa-
thy after symptom resolution81, indicating that these
genes are involved in symptom resolution. This work
also showed that a stable lipoxin isoform, 15-epi-lipoxin
A4, induced by aspirin, increased the expression of
MMR1, ALOX15 and CCL22 in diseased tenocytes
(obtained from patients), suggesting that low doses of
aspirin and its metabolites may trigger the expression
of pro-resolving mediators. Thus, modulation of reso-
lution pathways might be a potential treatment strategy
in patients to improve tendon structure and reduce pain.
Fibroblast activation. Fibroblast activation is a recog-
nized feature of diseases affecting the joint, whereby fibro-
blasts adopt a pro-inflammatory phenotype. Markers of
activated fibroblasts include Thy1 (also known as CD90),
CD44, CD55, VCAM1 (also known as CD106), uridine
diphosphoglucose dehydrogenase, prolyl-4-hydroxylase,
podoplanin, endosialin (also known as CD248) and pro-
lyl endopeptidase FAP (also known as fibroblast activa-
tion protein). Studies investigating Achilles tendons
and rotator cuff tendons have shown an increase in the
expression levels of fibroblast activation markers in dis-
eased tendons compared with the levels in healthy tendon
tissues and cells100,101, highlighting that functionally dis-
tinct tendons such as the Achilles and rotator cuff share
common cellular and molecular features.
Tendon stem cells
Tendons contain stem cell niches that host tendon stem
or progenitor cells (TSPCs) that are capable of self-
renewal and clonogenicity102. The functions of these
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TSPCs within the tendon ultrastructure is not well
known, but proposed mechanisms include mechanical
loading, alteration of the ECM, vascular changes and
homeostatic metabolic activity103. Current understand-
ing suggests that TSPCs fail to differentiate into tenocytes
but instead differentiate into other cell subtypes such
as adipocytes, osteoblasts and chondrocytes, thereby
altering normal tendon healing processes or promoting
abnormal tendon healing104. Thus, the loss or depletion
of TSPCs during tendon degeneration may be a possible
contributor to the pathogenesis of tendinopathy. Novel
techniques including single-cell RNA sequencing are
being utilized to identify important cell niches within the
tendon tissue105,106, which will help elucidate the mecha-
nisms underlying the transition from health to disease
and to understand whether TSPCs actually functionally
contribute to such a transition.
Diagnosis, screening and prevention
Clinical presentation
In patients with tendinopathy, soreness and stiffness in
the morning or after being still for a longer period of
time are common. A typical complaint in those with
Achilles tendinopathy is having difficulty walking owing
to pain and stiffness after prolonged periods of sitting.
In the early stage of tendinopathy, a person can often
continue their sport or work or activity as they often feel
no symptoms once they are warmed-up. Additionally,
patients often describe a continuum of early initial
symptoms (soreness and stiffness associated only with
initiation of activities), which may then progress to
constant debilitating pain during the activities.
Diagnosis
A new consensus study determined that tendinopathy
is the preferred terminology for persistent tendon pain
and loss of function related to mechanical loading107.
The diagnosis of tendinopathy is based on clinical symp-
toms and patient history of activity-provoked localized
tendon pain and stiffness (Fig. 4).
A detailed clinical examination that confirms a
patient-reported history of load-related tendon pain and
a physical examination are key to diagnosis. For those
tendons that are easily palpable, tenderness to palpation
is often used to confirm the diagnosis. Palpation is also
useful to differentiate between other structures, such
as painful fat pad with patellar tendinopathy or bursitis
in Achilles tendinopathy, which might be involved in
symptom manifestation108. In addition, there might be
localized swelling at the area of the tenderness.
Pain-provoking tests are available to aid in con-
firming a diagnosis depending on the tendon involved
(Table 1). Pain-provoking tests, such as single leg hop-
ping for the Achilles tendinopathy, single leg squats
for patellar tendinopathy and resisted extension of the
wrist, index or middle finger or gripping an object for
elbow tendinopathy, are useful to assist in confirming
the diagnosis109. Clustering of pain-provoking tests has
also been shown to have clinical utility in confirming
the diagnosis of gluteal tendinopathy110. In more deeply
located tendons, such as the rotator cuff tendons, con-
firming the diagnosis with palpation alone becomes
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more difficult. In the case of rotator cuff tendinopathy, a
clinical history of shoulder pain alongside weakness with
external rotation and abduction is common. The rotator
cuff presents a diagnostic challenge, as non-tendinous
structures can contribute to the pain presentation; for
this reason, rotator cuff tendinopathy is one of the pos-
sible sources of rotator-cuff-related shoulder pain107.
The use of different pain-provoking tests (Table 2) can
be helpful in establishing a diagnosis109. However, spe-
cial tests of the shoulder, of which there are many, are
no longer considered useful or valid for establishing
diagnosis of specific structures, as these tests cannot
isolate single structural entities111,112 and their use as
pain-provoking tests is more appropriate112.
Imaging. Imaging is not considered necessary for a clini-
cal diagnosis of tendinopathy107. Ultrasonography is ben-
eficial at point of care for differential diagnosis (Table 2)
and to rule out other causes of pain. Other imaging
modalities, such as plain radiography and MRI, can also
be beneficial to rule in or rule out differential diagnoses.
Findings on ultrasonography associated with tendinop-
athy include tendon thickening, hypoechoic regions,
loss of collagen organization or alignment and possible
neovascularization113. Often the term ‘tendinosis’ is still
used to describe the presence of alterations in micro-
structure seen on imaging. However, tendinosis can
be present in the absence of pain and therefore must be
interpreted in conjunction with a clinical examination;

ST2L Stromal
IL-33 15-epi-lipoxin A4 dysfunction
IL-1RAcP FPR2 IL-1R1 • Podoplanin
IL-17Ra • Endosialin
Homeostasis IL-13R
IL-6
Collagen IL-6R IL-13
fibres TNF IL-21R
NF-κB
TNFR gp130
JAK1 microRNA
Stromal • miR29a
HMGB1 STAT3 STAT3
compartment MAPK • miR34a/b
STAT6 • miR210
Tenocyte

Chemokines CD163 Cytokines

• CXCL10 Alarmins • IL-17
Immune
• CCL20 • S100A8 • HMGB1 • TNF
T cell compartment
• CCL2 • S100A9 • HSPs • IL-1β
Macrophage Dendritic cell Mast cell • CCL5 • IL-33 • IL-10
MMR

PAR2
Glutamine
Peripheral nerve Histamine
Neural
compartment
NMDAR
NK1 Substance P

Blood vessel Neovascularization

Pericyte
Vascular
VEGF IL-33
compartment
HIF1α

Fig. 4 | Molecular mechanisms of tendinopathy. Molecular mechanisms
of tendinopathy encompass four distinct compartments. The stromal
compartment includes tissue-resident tenocytes and matrix components
(such as collagen, extracellular matrix (ECM) proteins, interfascicular matrix
and small leucine-rich proteoglycans), which are essential for tissue
remodelling and repair. In diseased states, tendons acquire a stromal
‘signature’ with altered surface markers (podoplanin, VCAM1 and
endosialin) and perturbed intracellular signal pathways that have functional
consequences (such as matrix regulation, immune cell recruitment and cell
proliferation) relevant to tendon pathology. For example, activation of the
MAPK pathway by IL-33, IL-6 and IL-17 or the NF-кB pathway by TNF or
15-epi-lipoxin A4, or the JAK–STAT pathway by IL-13 and IL-4 result in
downstream modulation of enhanced cytokine and chemokine production,
ECM remodelling, proliferation and angiogenesis, all of which become
dysregulated in tendon disease. The immune compartment involving T cells,
dendritic cells, mast cells and macrophages (pro-inflammatory versus
pro-resolving) respond to initial tissue insult through damage-associated
molecular patterns or pathogen-associated molecular patterns. Immune
cell recruitment, which in normal circumstances represents a homeostatic
inflammatory response, becomes aberrant in tendon disease. The neural
compartment, which in the homeostatic state plays a role in proprioception,
interacts with mast cells to modulate adaptive responses in the normal
tendon. However, in tendinopathy, excessive stimulation leads to tissue
breakdown, degeneration and neoinnervation involving the glutamatergic
and autonomic systems. The release of neuropeptides, such as substance
P and calcitonin gene-related peptide, stimulates mast cell degranulation,
releasing a variety of agents, which modulate a variety of cellular activities
in the matrix. Although most tendons are poorly vascularized, they respond
to hypoxia by secreting angiogenic factors (VEGF or HIF1α) that induce the
growth of neovessels, which comprise the vascular compartment of
tendinopathy pathogenesis. Fibrin-rich exudates leak from the
neovasculature, resulting in fibrinoid degeneration, a typical feature of
structural alterations in tendinopathy. The complex molecular interactions
among these four compartments comprise a critical balance between tissue
repair and return to homeostasis versus further degeneration within the
tendon. HSPs, heat shock proteins.

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Table 1 | Tests to aid in the diagnosis of tendinopathy

Diagnostic test Description Ref.
Achilles tendinopathy
Palpation Patient complaining of pain on palpation 108

Single leg heel raise Patient complaining of pain on either upward or downward movement 108

Hop test Patient complaining of pain in the mid-Achilles tendon during exercise 108

Royal London Tenderness on palpation decreases substantially or disappears completely with 108

Hospital test maximal ankle dorsiflexion

Arc sign Movement of intratendinous swelling relative to the malleoli with the tendon during 108

ankle movement
Patellar tendinopathy
Palpation Patient complaining of pain on palpation
Single leg decline Whilst standing on the affected leg on a 25° decline board, the patient is asked to 236

squat maintain an upright trunk and squat up to 90°, if possible; diagnostically, the pain
should stay isolated to the tendon or bone junction and not spread during the test
Royal London With the knee extended, local tenderness should be elicited with palpating the tendon; 237

Hospital test the tender portion of the tendon should be palpated again with the knee flexed to
90°; the test is considered positive if the pain is markedly reduced or absent in knee flexion
Gluteal tendinopathy
Palpation Patient complaining of pain on palpation 110

Single leg stance The patient stands side-on to a wall with the affected limb furthest from the wall; 110

(SLS) a finger of the unaffected side can touch the wall at shoulder height for balance;
the foot nearest the wall is then raised so that the hip remains in neutral position with the
knee flexed to 90°; this SLS position is then maintained for up to 30 s; a positive test
is reproduction of the patient’s lateral hip pain within this 30-s period
Hip flexion, With the patient lying supine, the hip is passively flexed to 90°, adducted and externally 110

adduction, external rotated to end of range; this test seeks to increase both tensile and compressive loads
rotation (FADER) on the gluteal tendons at the greater trochanter through positioning of the hip and the
overlying iliotibial band
Hip flexion, The lateral malleolus of the test leg is placed above the patella of the contralateral 110

abduction, external leg; the pelvis is stabilized via the opposite anterior superior iliac spine and the knee
rotation222 is passively lowered so the hip moves into abduction and external rotation; this test is
expected to place the anterior portion of the gluteals on tensile load because of the
muscle’s inherent internal rotation function
Medial or lateral elbow tendinopathy
Palpation Patient complaining of pain on palpation 238

Resisted wrist and/or Pain provocation during wrist or finger extension or flexion is resisted by examiner 238

finger extension or
flexion
Gripping an object Pain provocation on gripping an object 238

Rotator cuff tendinopathy

Palpation Patient complaining of pain on palpation 239

Empty can test The arm of the patient should be elevated to 90° in the scapular plane, with the 239

elbow extended, full internal rotation, and pronation of the forearm; this results in a
thumbs-down position, as if the patient were pouring liquid out of a can; this test is
considered positive if the patient experiences pain or weakness with resistance
Hawkins test The examiner places the arm of the patient in 90° of shoulder flexion with the elbow 239

flexed to 90° and then internally rotates the arm. The test is considered to be positive
if the patient experiences pain with internal rotation
Jobe test The examiner passively elevates the shoulder of the patient to 90° of abduction with 239

internal rotation; the examiner then applies a downward pressure against the arm;
a positive test is the provocation of pain or abnormal weakness

the presence of activity-related tendon pain or loss of
function is required to fulfil the criteria for a diagnosis
of tendinopathy.
Screening
Screening for risk factors is important to understanding
the cause of the injury and to designing the best treat-
ment plan, personalized to each patient. Early detection
of tendinopathy is paramount in achieving full recov-
ery, particularly in the sporting population. Athletes
have reported that early symptoms (that is, stiffness
and pain at initiation of an activity but that disappears
during the activity) still affected their performance.
Notably, there is generally no pain at rest in the initial
stages of tendinopathy and therefore the injury is often
perceived as benign114. Nevertheless, early detection

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Eccentric training
An eccentric contraction is
the motion of an active muscle
while it is lengthening under
load. Eccentric training is
repetitively doing eccentric
muscle contractions.
Table 2 | Differential diagnosis of tendinopathy
Differential diagnosis
Rotator cuff tendon
Acromioclavicular joint pain
Shoulder instability or glenoid labral tears
Superior labral anterior to posterior
(SLAP) tear
Biceps tendon pain
Lateral elbow tendon
Referred pain from the cervical spine
(common)
Cubital tunnel syndrome
Osteoarthritis
Distal biceps pain
Patellar tendon
Patellofemoral pain
Knee osteoarthritis
Meniscal or ligament injury
Seronegative arthritis
Achilles tendon
Posterior impingement
Bursitis
Referred pain
Seronegative arthritis
Enthesitis
Tibialis posterior tendon (medial ankle)
Flexor hallucis longus (FHL) tendinopathy
Rheumatoid arthritis
Seronegative arthritis
Enthesitis
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is important to prevent an athlete with an injury from
engaging in a sport or activity for an extended period.
Early screening can include evaluation of subtle symp-
toms, such as stiffness or altered performance in athletic
individuals. In the athletic population, the Oslo Sports
Trauma Research Center (OSTRC) overuse injury
questionnaire115 can be useful to detect early symptoms
and progression of symptoms.
Alterations in tendon properties, such as increased
tendon thickness and degenerative changes, seen dur-
ing ultrasonography are also risk factors for developing
symptoms of tendinopathy, whereas alterations in ten-
don properties without clinical symptoms can result in
altered central nervous system control and adapted mus-
cle activation116. Hence, close monitoring of those ath-
letes with changes in tendon structure is recommended
to enable early intervention if there is a change in func-
tion or symptomatic state. Recovery from tendinopa-
thy can take up to 6–12 months or longer, with shorter
recovery times in those with less severe symptoms and
tendon structural changes.
Clinical examination
Examination of the acromioclavicular
joint, assessment for instability and
labral tests
Apprehension test, Sulcus sign
O’Brien’s sign
Speed’s and Yergason’s test
Assess cervical spine
Consider forearm nerve entrapments,
reduced range of motion, pain on biceps
palpation
Palpation
Knee ligament assessment
Knee joint line tenderness, McMurrays test
Palpation
Passive plantarflexion test for posterior
impingement
Palpation (FHL tendinopathy is generally
at the tunnel)
Tibialis posterior tendinopathy is
generally at the navicular insertion
Pain on palpation of enthesis
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Prevention
Very few studies have investigated the effect of preventive
strategies in tendinopathy. However, studies have shown
that shoulder117 and groin118 pain in athletes associated
with tendinopathy can be preventable by introducing
specific exercise regimens aimed at improving strength
and coordination of muscle tendon units in the shoul-
der and hip region. Indeed, exercise regimen have assisted
in reducing the prevalence of shoulder and hip tendin-
opathy by 30–40% during the season in handballers117
and footballers118. However, loading programmes need
to be carefully introduced; for example, the introduction
of heavy loading exercise for athletes including football-
ers and volley ballers with patellar tendinopathy and
Achilles tendinopathy during the season resulted in exac-
erbated tendinopathy symptoms (pain), as high loading
was already ongoing119,253. In workers (for example, indus-
trial technicians), specific strength training programmes
for shoulder, neck and arm reduced forearm symptoms
and work disability, although only by decreasing symp-
toms to a minimal degree122,254. Thus, further research
is required to identify preventive strategies that can be
applied to all anatomical areas.
Management
Multiple rehabilitation strategies have been recom-
mended for use in patients with tendinopathy. Although
these approaches act through divergent mechanisms,
the goal of therapy is to reduce symptoms, in particu-
lar, pain, promote tendon healing and improve patient
function. The therapeutic regimens can be divided
into passive modalities, which include pharmacolog-
ical treatments123, injection therapy, extracorporeal
shockwave therapy (ESWT), therapeutic ultrasonog-
raphy and low-level laser, and active modalities, such
as tendon loading exercise, patient education and load
management124. Different studies have investigated the
efficacy of these different treatment strategies in isola-
tion as well as in combination. In general, the efficacy
of a treatment should be determined by the reversal of
tendinopathy pathology and not just resolution of the
symptomology.
Exercise-based strategies
Currently, exercise regimens, referred to as tendon
loading programmes, remain the most effective con-
servative approach in the treatment of tendinopathy
(Fig. 5). Tendon loading exercises have shown beneficial
effects in patients with chronic Achilles tendinopathy
and patellar tendinopathy120,125. Studies of upper limb
tendinopathies have further supported exercise train-
ing specifically for common extensor and rotator cuff
tendinopathy126,127.
Eccentric training in the treatment of tendinopathy was
explored in the 1980s128 and popularized in the 1990s
based on successful outcomes129. The benefit from
eccentric exercise redirected the treatment of tendin-
opathy away from anti-inflammatory medications and
passive treatment strategies, towards an active rehabili-
tation for tendinopathy in an attempt to restore tendon
capacity. The success of eccentric exercise led to the
presumption that isolated eccentric muscle contractions
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programmes remain a treatment option, the decision as

Diagnosis
• Consider differential diagnosis
• Utilize ICON 2019 consensus guidelines
The patient
• Education
Presentation • Acknowledgement
• Fear mechanisms
Commence load management
• Individualized tailored programme —
precision tendinopathy
Isotonic Energy Energy
Isometrics storage storage
Eccentrics loading release
Re-evaluate
0–12 months
• Consider • Modify
adjuncts if loading
failure to regimen
progress
• Education
• ESWT • Psychosocial
• NSAIDS and/or
injection
• GTN
• Re-evaluate
12 months • Differential, educational, psychosocial
• Surgical opinions
Fig. 5 | Management of tendinopathy. Early diagnosis is
key and should consider a thorough differential diagnosis
and the International Consensus (ICON) 2019 consensus
guidelines107. A patient-centred and personalized approach
should be considered in every case. Education on the
disease process along with acknowledgement of previous
unsuccessful treatments (if appropriate) and potential
prolonged time frames involved in management as well as
appreciation of fear mechanisms involved with commencing
treatment should be undertaken. First-line treatment should
encompass an individualized tailored loading programme,
referred to as the precision tendinopathy management plan.
This approach may include isotonic, isometric, eccentric,
energy storage loading versus energy storage and release.
Importantly, patient engagement and re-evaluation within a
3-month period is crucial to determine loading progression
and consideration of adjunct therapies in combination
with education and psychosocial factors. Throughout the
ensuing months, revisiting this cycle may be required
with further changes in loading programmes or adjunct
therapies. Surgical intervention may be considered in
the recalcitrant non-responders after 12 months of a
personalized loading programme. ESWT, extracorporeal
shockwave therapy; GTN, glyceryl trinitrate.
of the affected musculotendinous unit were needed to
provide clinical benefit to patients with tendinopathy.
This has since been refuted with evidence that mixed
contraction types provide benefit in the treatment of
Achilles121,130, patellar131, gluteal132, lateral elbow133 and
rotator cuff tendinopathy134. Although eccentric exercise
to which is the best tendon loading programme to pre-
scribe should be an individual decision made between
the prescribing health-care professional and the patient.
A dogmatic prescription of eccentric exercise for all
patients with tendinopathy should now be replaced with
options and principles of loading, instead of loading pro-
tocols. Engaging with patients and presenting treatment
options will enhance the clinician–patient working alli-
ance and optimize adherence to the selected programme,
and this practice may play a large role in the success or
failure of the prescribed loading programme135. The opti-
mal programme might simply be the one the patient is
most likely to perform.
Tendons have been shown to respond favourably to
load through improvement in their material, mechan-
ical and morphological properties. However, the
majority of studies that have investigated the effect of
loading on tendon properties were performed in healthy
participants136. There is a relative dearth of data on the
mechanisms underpinning the response to loading in
tendinopathy, and few studies have investigated this
aspect and most of these have focused on the clinical
response. Although evidence has confirmed the benefi-
cial effect of loading programmes in treating tendinopa-
thy, exercise is not a panacea. Thus, several issues linked
to the specifics of tendon loading exercise programmes
are yet to be clarified.
In the past decade, studies have explored the effect of
isometric exercises in the treatment of tendinopathy, in
particular, its acute analgesic role. The pioneering study
that investigated the analgesic effects of isometric exer-
cises revealed a dramatic reduction in pain in patellar
tendinopathy, and spear-headed further research into
isometric contractions137. However, subsequent studies
that investigated the acute response to isometric exer-
cises in patients with patellar tendinopathy138, Achilles
tendinopathy139 and plantar fascia pain140 failed to repro-
duce these results. Thus, further investigation is needed
to understand whether and when to apply isometric
contractions as an essential part of exercise regimens
for tendinopathy141.
One study compared heavy slow resistance (HSR)
training using the Bromsman device with the Alfredson
eccentric exercise protocol in patients with patellar
tendinopathy and analysed improvements in visual
analogue score (to rate pain intensity) and Victorian
Institute of Sport Assessment – Patellar (VISA-P) scores
(a measure of severity of patellar tendinopathy); no sig-
nificant differences in symptom relief were observed
between the two groups142. A further study of HSR131
compared its effect with that of corticosteroid injections
(CSIs) and eccentric decline squat training in patients
with patellar tendinopathy, with similar results found
across groups up to week 12, but by 6 months the two
exercise groups (HSR and eccentric training) maintained
improvements whereas the corticosteroid group deterio-
rated. HSR has also been studied in patients with Achilles
tendinopathy and was shown to produce outcomes sim-
ilar to those following eccentric exercises. Interestingly,
the HSR groups reported higher satisfaction than those
in the eccentric group, suggesting that options may need

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Pain monitoring model
Physiotherapy model showing
that one can safely continue
some activity in a patient with
Achilles tendinopathy by
monitoring patient pain.
NATure RevIewS | DISEASE PRIMERS | Article citation I­D:­ (2021) 7:1
to be tailored to individual needs to ensure compliance
and a beneficial effect of the treatment. An additional
positive finding accompanying the clinical improvement
following HSR has been reported, including its impact
on changing fibril morphology towards a near-normal
appearance131,143.
Performing tendon loading exercise can often induce
pain, and patients report a fear of causing further dam-
age when the exercises cause pain. In turn, this fear
might prevent the patient from sufficiently loading the
tendon, which might be necessary to cause meaningful
clinical changes. Hence, informing the patient about the
importance of proper tendon loading and making them
aware that pain is allowed both during and after per-
forming the exercises are a crucial part of patient educa-
tion. The pain monitoring model can be used to facilitate
patient understanding of the amount of pain allowed
during and after exercise130. The pain monitoring model
is a useful tool for the patient and also the clinician to
determine exercise progression and plan the next steps.
Randomized clinical trials (RCTs) have successfully
employed the pain monitoring model in the treatment
of patients with Achilles tendinopathy130,144 and patellar
tendinopathy142. Discussing the response to exercise and
highlighting potential side effects is a crucial component
to success, and forging a therapeutic alliance and educat-
ing patients on the nature of their condition alongside
realistic time frames may be critical to adherence and
ultimately increasing the success of the intervention
being prescribed.
In clinical trials on the use of exercise for tendi-
nopathy, the length of the interventions tends to be
~12 weeks. In a systematic review of exercise as treat-
ment for Achilles tendinopathy, all 14 RCTs found sig-
nificant improvements in patient-reported outcome
measures (such as pain, everyday activities and return to
sport)145. However, at 12 weeks, the mean VISA-A scores
(Victorian Institute of Sport Assessment–Achilles)
ranged from 69 to 80 (100 being fully recovered), indi-
cating that even with the most effective treatment, after
12 weeks, individuals continue to have symptoms, such
as pain or lack of return to full function. Studies with
longer follow-up periods have also shown continued
improvements up to 1 year146–149. As the recovery and
healing of tendons can take 6–12 months, it should not
be surprising that many patients have not fully recov-
ered at 12 weeks. In addition, one study found that
tendon structural recovery does not occur until after
24 weeks150. The success and the rate of recovery have
also been reported to correlate with the initial degree of
tendon structural abnormality151. The exercise treatment
might, therefore, need to be continued for >12 weeks,
and patience is of great importance for achieving full
recovery in patients with tendinopathy.
At present, clinicians should feel assured to pre-
scribe progressive individualized strengthening that
incorporates the current evidence-based principles of
load and exercise progression for longer than 12 weeks
when treating tendinopathy. However, as not all patients
respond favourably to loading interventions, other
treatment options should be explored as adjuncts or
alternatives to tendon loading programmes.
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Adjuncts to exercise
The treatment of tendinopathy involves different modal-
ities that are usually, but not always, used in conjunction
with exercise. Some adjuvant therapies are used in com-
bination with each other, or sequentially in the course of
treatment. Many adjuvants to exercise do not have strong
evidence for or against their use, but safety is established,
with varying effectiveness. This section provides a brief
review of the known mechanisms and results from trials
investigating these adjunctive treatments.
Corticosteroid injection. CSI has been a mainstay
of treatment for tendon-related disorders for many
years152. Despite this dogma, the effectiveness of CSIs in
the treatment of tendinopathy is controversial. Current
data demonstrate a substantial inflammatory compo-
nent associated with an aberrant healing response in
tendinopathy pathophysiology79. However, studies have
shown that CSIs might impair the physiological heal-
ing response of local tissues, leading to progression of
the disease153–155.
Overall, the usage of CSI for the treatment of tendi-
nopathy has decreased, with conflicting data reported
according to the tendon involved. The use of CSI is per-
haps most prevalent in shoulder disorders. Two investi-
gations have reported short-term reduction in pain and
improvement in function with the use of CSI for rotator
cuff tendinopathy156,157. These beneficial effects, how-
ever, were transient and did not reduce the risk of future
surgical intervention157. Furthermore, evidence shows
that the use of CSI prior to primary rotator cuff repair
surgery is correlated with increased re-tear rates and
revision rotator cuff surgery in a time-dependent
and dose-dependent manner154. This has led to the rec-
ommendation that those undergoing surgical repair
should not receive a CSI in the shoulder prior to surgery.
Lateral elbow tendinopathy (that is, tennis elbow)
also remains a popular indication for the use of CSI.
A study reviewing randomized placebo-controlled tri-
als for the use of CSI in the treatment of lateral elbow
tendinopathy found no difference in pain intensity at
3 or 6 months after CSI versus placebo; no significant
differences were reported in grip strength or functional
outcomes at any time point158. Further work has shown
that CSI may worsen lateral elbow tendinopathy in the
long term (9–12 months after injection) compared
with physiotherapy loading. Despite this finding, many
clinicians still utilize CSI for this condition, as many
patients report short-term (<6 weeks) pain relief from
the injection159.
The use of CSI for patellar tendinopathy and Achilles
tendinopathy is less common. One study compared
different rehabilitation exercises and CSI for patellar
tendinopathy and found inferior pain relief and phys-
ical functioning as well as tendon structure and com-
position at 6 months in the CSI group compared with
the rehabilitation exercise group131. A large systematic
review on the use of CSI for patellar tendinopathy
found no benefit and recommended that it should not
be used160. A double-blind randomized trial compar-
ing high-volume injection of saline and local anaes-
thetic with and without corticosteroids for chronic
Primer
mid-portion Achilles tendinopathy found no differ-
ence in functional outcome or imaging measures at
the final 24-week follow-up examination; however, a
short-term clinical benefit was noted at 6 and 12 weeks
in self-reported function and pain scores, favouring
the corticosteroid group161. Large meta-analyses have
found no long-term benefit for CSI in the treatment
of Achilles tendinopathy162,163. Owing to reports showing
Achilles rupture following CSI164–166, it should be used
cautiously for this condition.
Platelet-rich plasma. Several studies have investigated
the use of platelet-rich plasma (PRP) for managing
tendinopathy involving different anatomical sites and
have found varying results167. PRP is a preparation of
autologous blood centrifuged to contain a high con-
centration of platelets, with or without leukocytes.
Degranulation of platelets releases several factors includ-
ing TGFβ, PDGF, bFGF, VEGF, IGF1 and EGF, all of
which are involved in different phases of tendon healing
and, theoretically, their presence in the tendinopathic
environment will support healing and regeneration of
tendon tissue168.
A randomized study found that leukocyte-rich PRP
(LR-PRP) injections were associated with a significant
improvement in pain at 24 weeks compared with a con-
trol treatment comprising only an anaesthetic169. Other
studies have also shown that LR-PRP provides longer
pain relief than CSIs170–172. Although these studies sup-
port the use of LR-PRP for lateral elbow tendinopathy, it
is not universally established. Importantly, a systematic
review and meta-analysis did not support the use of PRP
for lateral elbow tendinopathy173.
Similar controversy exists within the literature
regarding the use of PRP for patellar tendinopathy, albeit
with less evidence for its use in patellar tendinopathy
than lateral elbow tendinopathy. A systematic review
analysed outcomes following PRP injection for patellar
tendinopathy and found inconsistent results in compar-
ative investigations in demonstrating superiority of PRP
over placebo or other treatments, although PRP showed
promise in non-comparative studies174. Furthermore, an
RCT using LR-PRP and leukocyte-poor PRP for patellar
tendinopathy failed to show any significant differences
in outcome versus a placebo when combined with an
exercise rehabilitation programme175.
In general, PRP has not been demonstrated to
be effective in treating Achilles tendinopathy176,177.
However, results following its use in treating rotator cuff
tendinopathy are mixed, with one study suggesting an
increased rate of apoptosis in cuff tendinopathy treated
with PRP178. Taken together, PRP is clearly not a first-line
treatment for tendinopathy. Although PRP continues to
be utilized as a treatment option, studies providing high
levels evidence have not confirmed a significant efficacy
of PRP in the treatment of tendinopathy168,179.
Glyceryl trinitrate therapy. Topical glyceryl trinitrate
is considered a safe and reliable treatment or adjunct
for the management of tendinopathy. A new system-
atic review of RCTs showed significant improvements
in pain in those receiving topical glyceryl trinitrate
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compared with placebo in the short-term, along with
further significant improvements for up to 6 months180.
However, the use of glyceryl trinitrate can be associated
with an increased incidence of headaches.
Low-energy laser therapy. Low-energy laser therapy
uses light at energy levels low enough to not cause a rise
in skin temperature. Studies have provided evidence
for its ability to reduce inflammation and oedema,
to induce analgesia (pain relief) and promote heal-
ing in a range of musculoskeletal pathologies181. An
umbrella review of seven systematic reviews found no
beneficial effect from the use of low-energy laser ther-
apy for the treatment of lateral elbow tendinopathy182.
By contrast, a systematic review of 13 RCTs found that
low-energy laser therapy, particularly with optimal
doses of 904 nm wavelength light, offered short-term
pain relief (that is, for 2–3 months) in those with lat-
eral elbow tendinopathy183. Another large systematic
review examined the use of non-surgical options in
the treatment of lateral elbow tendinopathy, including
low-energy laser therapy184. At the mid-term follow-up
examination, the investigators found improvement in
pain intensity and in grip strength in those receiving
laser therapy184. Although early experimental data also
demonstrated potential clinical benefits with low-energy
laser therapy for Achilles tendinopathy185,186 and rotator
cuff tendinopathy187, large-scale studies demonstrating
beneficial effects are still lacking.
High-volume injections. High-volume injection is a
treatment involving the injection of a large volume of
saline, usually mixed with corticosteroids and/or local
anaesthetic. Most of the literature is limited to treatment
of Achilles tendinopathy, although a few studies have
analysed high-volume injection in the treatment of patel-
lar tendinopathy as well188. High-volume saline is usu-
ally administered between the Achilles tendon and the
Kager fat pad161. In an investigation of Achilles tendin-
opathy, addition of high-volume injection to an eccentric
training regimen was more effective in reducing pain,
returning patients to prior levels of physical activity and
reducing tendon thickness and intratendinous vascular-
ity than eccentric training alone189. A study investigated
the use of high-volume injection with and without corti-
costeroid in patients with chronic Achilles tendinopathy
in combination with an eccentric training programme.
Both groups demonstrated clinical improvement, with
an increased improvement in self-reported pain and
physical function outcomes in the group receiving
high-volume injection and corticosteroid161. This find-
ing indicates that the corticosteroid was the effective
treatment, and not the high-volume injection proce-
dure in itself. Notably, nearly all studies investigating
high-volume injection have involved relatively small
numbers of patients, limiting the generalizability of this
treatment modality.
Shockwave therapy. First introduced for lithotripsy in
1980, ESWT, which uses high-energy pressure waves, has
been used as a treatment for tendinopathy and soft tissue
disorders of the shoulder, elbow, hip, knee and ankle190.

A systematic review analysed the effectiveness of ESWT
in the treatment of Achilles tendinopathy, patellar
tendinopathy and proximal hamstring tendinopathy190.
ESWT was superior to anti-inflammatory medication
and physical therapy for patellar tendinopathy and
proximal hamstring tendinopathy, and was similar to
eccentric training for Achilles tendinopathy. A review
evaluating the effectiveness of ESWT found that it is an
effective intervention for alleviating pain and improving
physical performance, and should be considered for the
treatment of patellar tendinopathy and Achilles tendin-
opathy, particularly when other non-surgical treatments
have failed191. ESWT for the treatment of tendinopathy
in the upper extremity, particularly for lateral elbow
tendinopathy, has also been studied extensively, and has
been shown to lead to pain relief and improved upper
extremity function with minimal treatment risks192,193.
Cellular therapy. The use of cellular therapy, in the
form of progenitor cells or stem cells as well as autol-
ogous tenocytes, in the treatment of tendon disorders
is increasing. Progenitor cells are typically acquired
from bone marrow (in the form of bone marrow aspi-
rate concentrate or bone marrow mononuclear cells) or
from adipose tissue (adipose-derived stem cells, ASCs).
They have been used to treat a wide range of tendon
disorders, including rotator cuff tendinopathy, lateral
elbow tendinopathy, patellar tendinopathy and Achilles
tendinopathy194. Many investigations in this area have
provided only level IV evidence of the value of cellu-
lar therapy. In one RCT, patients with Achilles tendin-
opathy received either intratendinous PRP or ASCs195.
At 6 months, both treatment groups showed reduced
pain and improved physical function scores, with the
ASC group demonstrating superiority at 15 days and
30 days. In addition, studies have investigated the use
of autologous tenocyte injection for the treatment of
shoulder, elbow and gluteal tendinopathy. All of these
investigations were pilot studies or small case series and,
therefore, drawing conclusions on the effectiveness of
this treatment option is difficult.
Surgical management
In theory, surgery for tendinopathy aims to promote a
regenerative healing response by triggering a reparative
response in the matrix environment. Surgical procedures
for tendinopathy involve excision of the degenera-
tive tendon, removal of adhesions around the tendon,
decompression of the tendon and/or multiple longi-
tudinal tenotomies124. The surgical procedures have
advanced from open techniques to minimally invasive
approaches using arthroscopy or through percutaneous
incisions under image guidance. Recently, several RCTs
have evaluated the outcomes of these procedures, which
are summarized in the sections below.
Achilles tendinopathy. In patients with Achilles tendi-
nopathy, surgery usually consists of tenotomy and/or
debridement of degenerative tissue, with or without
paratenon stripping. Augmentation of the repair with
the flexor hallucis longus tendon may be done, but one
RCT showed no difference in results196. One study found
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radiofrequency microdebridement to be non-inferior
to surgical decompression197. However, no RCTs com-
paring surgery with a non-operative form of treatment
are available.
Patellar tendinopathy. Tenotomy with excision of tendi-
nopathic tissue remains the most common form of sur-
gery for patellar tendinopathy with results similar to and
no better than those following eccentric loading alone198.
A study found that ultrasonography-guided arthro-
scopic debridement of the surrounding neovasculariza-
tion was more effective at relieving pain at 12 months
than injection of sclerosing agents199. In addition, stud-
ies have investigated procedures to address the adjacent
structures, including partial resection or drilling of the
inferior patellar pole, synovectomy and debridement of
the retropatellar fat pad. However, no RCTs examining
these techniques are available.
Lateral elbow tendinopathy. The most common surgi-
cal management remains debridement and excision of
the diseased portion of the extensor carpi radialis brevis
in patients with lateral elbow tendinopathy. Posterior
interosseous nerve200 decompression may be done con-
comitantly, but studies have suggested no additional
benefit201,202. Outcomes are favourable and comparable for
either open surgery or arthroscopic techniques203. One
study found that surgical treatment may provide better
long-term pain relief than PRP injections204. However, a
randomized double-blind study found that open excision
of the degenerative portion of the extensor carpi radialis
brevis was not more effective than placebo surgery205.
Rotator cuff tendinopathy. Arthroscopic subacromial
decompression (ASAD) or acromioplasty has been
a popular and mainstay surgical treatment for rota-
tor cuff tendinopathy or rotator cuff impingement206.
Several RCTs have compared this procedure with PRP
injection178 and radiofrequency microtenotomy207 but
failed to show any significant difference in clinical out-
comes. Indeed, a study found that the outcomes follow-
ing ASAD were equivalent to those following supervised
physiotherapy regimen208–210. Two new multicentre, pla-
cebo surgery-controlled randomized trials failed to show
any benefit of ASAD over arthroscopy alone, exercise
alone or no treatment at all200,211.
In summary, surgical excision of degenerative tendi-
nopathy in the elbow and subacromial surgery for
rotator cuff impingement or rotator cuff tendinopathy
have been found to be no better than sham surgery212.
Currently, no placebo surgery-controlled (level I or II)
evidence for surgical management of tendinopathies in
other parts of the body is available.
Quality of life
Tendinopathy, as do all musculoskeletal diseases, causes
pain and can negatively impact mental health, quality
of life, work, and sport and social participation213,214.
The majority of research regarding tendinopathy has
focused on ameliorating the physical impairments of
the disease215; however, there is a paucity of research
investigating quality of life and the psychosocial impact
Primer
of tendinopathy. This scarcity lies contrary to the grow-
ing awareness of the importance of these factors in opti-
mal management of musculoskeletal conditions135,216.
In addition to being associated with pain, tendinopa-
thies have been shown to negatively affect quality of life,
participation in sports and recreation and work, and
to be associated with psychological stress, depression
and anxiety in patients. The wide-reaching impact of
reduced physical activity as a consequence of tendinop-
athy, and its impact on general health may be substantial.
As depression and anxiety have been shown to correlate
with pain217,218, failure to address these issues might neg-
atively affect recovery and result in suboptimal outcomes
in patients with tendinopathy135.
Current reports have highlighted the impact of
Achilles tendinopathy on physical, emotional and social
well-being and on quality of life215. In those with patellar
tendinopathy, which is typically associated with sports
involving repetitive jumping, the effect of patellar tendi-
nopathy reaches beyond sports and negatively affects
ability to work and productivity, particularly in those
who have a physically demanding occupation219.
Studies investigating gluteal tendinopathy have
revealed that patients experience severe pain intensity
and disability, and moderate to poor quality of life.
Patients with gluteal tendinopathy are also less likely
to be engaged in work compared with their healthy
counterparts213. Indeed, Dutch studies have echoed this
finding, showing that only 40% of patients with greater
trochanteric pain syndrome were engaged in work
activities220.
Similar findings of pain and impaired function, in
addition to depression and anxiety, have been found
in patients with lateral elbow tendinopathy221. Approx­
imately 25% of patients with lateral elbow tendinopathy
reported difficulty with simple daily activities such as
dressing, carrying objects, driving and sleeping, with
absenteeism from work also linked to lateral elbow
tendinopathy. One study also highlighted reduced men-
tal health and physical quality of life in patients with
rotator cuff tendinopathy222.
Outlook
Despite several advances in tendinopathy research, both
clinically and in the laboratory, much remains to be elu-
cidated. This gap is particularly true pertaining to the
development of new drugs and agents that can improve
disease in those patients who are non-responders to
loading programmes or exercise regimens. Given the
complex pathogenesis of tendinopathy, detailed insights
into the molecular regulation, structural adaptation and
subsequent mechanical properties of the tendon are of
paramount importance to understanding the disparity
among patients. Loading programmes improve symp-
toms in certain patients, whereas in up to 30% of patients
loading programmes alone without adjuvant therapies
fail to resolve symptoms. It is incumbent on those
involved in the management of tendinopathy — physio­
therapists, sports clinicians and surgeons alike — to
work together to identify how these patients can be best
treated in the modern molecular era that medicine has
entered. Indeed, a deeper understanding of how various
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loading programmes translate to symptom improvement
or resolution is required.
Translational potential
Research over the last decades has provided crucial
clues about risk factors associated with disease onset
and progression, and has enabled a more comprehen-
sive understanding of the disease processes and poten-
tial therapeutic targets. However, the integration of
these findings into a potential reproducible treatment
strategy that can be applied across the whole spectrum
of tendon disease remains elusive. The findings from
basic research need to be comprehensively integrated
into clinical research to provide an overarching picture
of the pathophysiological process involved in tendinop-
athy. Thus, results from epidemiological, observational,
genetic, epigenetic, in vitro, in vivo and clinical stud-
ies need to be integrated into logical pathways to treat
the disease. Importantly, studies exploring structural
changes using conventional imaging techniques, such
as MRI and traditional ultrasonography, as well as novel
imaging methods such as shear wave elastography and
ultrasonography tissue characterization61, must comple-
ment the data generated from basic science and clinical
research to facilitate translation of research into clin-
ical practice. Future potential treatments are likely to
encompass pharmacological, regenerative and novel
nanotechnology strategies.
Pharmacological therapies. An ideal drug for tendi-
nopathy should help reduce the chronic inflamma-
tory response and promote tendon tissue resolution
by limiting inflammation-induced tissue damage and by
stimulating robust and rapid matrix repair. In several
musculoskeletal diseases, rationalizing immunobiology
and interactions with matrix biology at the mechanis-
tic level has demonstrated clear translational benefit in
patients79. Given the inflammatory component involved
in tendinopathy pathogenesis, emerging studies have
highlighted cytokine manipulation, targeting of resolu-
tion molecules (lipoxins), epigenetic modification (for
example, of microRNAs) and modulation of various
signalling pathways (Wnt, NF-кB and nitric oxide) as
potential therapeutic avenues79. Importantly, treatment
approaches based on these discoveries are now in early
phase clinical trials223,224, which will be informative in
realizing the translational potential of pharmacological
manipulation of tendon regenerative biology.
Regenerative medicine. The ultimate aim of tissue engi-
neering is to regenerate tendon tissue with the same
biomechanical properties as native undamaged tendon
by harnessing the regenerative process of in vivo tis-
sue or producing a functional tissue in vitro that can
be implanted into areas of damaged tendon. One such
approach is the delivery of cells that are capable of syn-
thesizing ECM molecules to promote tendon healing.
In this regard, studies have investigated different cellular
sources, including tenocytes, TSPCs and ‘non-specific’
mesenchymal cells derived from multiple sources
(for example, bone marrow and adipose tissue)225.
However, the use of cells for the restoration of damaged
 Primer

tendinopathic tissue remains cost-intensive, and current
clinical trials show only minimal benefits226.
Another approach is to employ gene delivery, which
is designed to supply exogenous genetic material into
cells with the aim of subsequently altering the DNA
and inducing, silencing, upregulating or downregulat-
ing the expression profile and secretion of proteins227.
Several preclinical studies have focused on establishing
gene delivery systems for the regeneration of tendon
tissue by regulating the expression of BMP2, BMP14,
TGFβ1 and LacZ, with initial promising results relat-
ing to tendon strength and accelerated healing227,228.
However, concerns remain regarding the safety profile
of these genetic materials, such as potential extratendon
mutagenicity associated with the use of plasmids. Hence,
further laboratory investigations are required before this
treatment can be used in clinical practice.
Scaffolds. Scaffolds can be utilized to provide mechani-
cal support or as carriers of deliverable factors with the
aim of providing a suitable environment for the attach-
ment, proliferation and subsequent migration of resident
cells to provide a base for ECM remodelling and eventu-
ally native tissue regeneration229. The ideal biomaterial
should mimic the native tendon ECM architecture and
biomechanical properties concomitantly attempting to
effectively mirror the spatiotemporal signalling profile
of a healing tendon tissue. Biomaterials are required
to act as a delivery prototype for the prolonged release
of genes, proteins and cells, and to provide a suitable
environment for cells infiltrating into the site of dam-
age. The ideal formulation should be easily delivered
to the site of repair or damage, should degrade at a
rate concurrent with normal tissue formation, whilst
additionally modulating normal homeostatic func-
tions including cell proliferation and gene expression
for the synthesis of normal tendon tissue components.
Further investigation is required to determine the
ideal biomaterial that will be reproducible, scalable,
non-toxic, non-immunogenic, and bioresorbable for
the regeneration of tendon tissue230.
Nanotechnology. Lastly, as tendons and their ECM
are composed of nanostructured materials, interest in
developing novel nanomaterials for tendon restoration
is growing. Nanotechnology is the precise placement,
measurement, manipulation and modelling of matter
that consists of 4–400 atoms. Current work has high-
lighted that nanoparticles could play a part in labelling
TSPCs and could therefore serve as carriers for gene
therapy and drug delivery, thereby permitting modula-
tion of the cellular and the ECM response231 compliant
with a bioactive scaffold. As with scaffold technology,
before the translation of nanomaterials to the clinic,
assessing the safety of these nanoparticles in the human
body is vital.
Disease stratification
Owing to the multiple anatomical sites and different
phenotypes of tendinopathy, translation of findings
from clinical studies is challenging. Interpretation of
clinical trials in elite athletes versus recreational athletes
or non-athletic individuals is rarely undertaken and
therefore whether certain loading programmes or ther-
apeutic strategies are beneficial in different subgroups
of patients is difficult to determine. For example, one
study suggested that early identification of patients
with intratendinous structural changes (seen on MRI)
and tenderness at the insertion who should be directed
towards surgical treatment and may lead to earlier return
to function232. Surgical RCTs (that is, RCTs randomiz-
ing patients who have failed all other treatments) in
which patients are stratified according to disease sever-
ity to identify those who may respond to surgery are
superior to pragmatic ‘all-comer’ surgical RCTs233. This
shift in trial design and patient stratification may also
be useful in loading programmes and early phase thera-
peutic trials in patients with tendinopathy and should be
considered by investigators moving forwards.
Clinical trials in patients with tendinopathy remain
fraught with inconsistences in outcome measures.
Whilst we welcome the newly published key reporting
domains and standards for trials in tendinopathy107,234,235,
several important issues need to be addressed, which
include heterogeneity of studies, accurate reporting of
patient subgroups, comparisons with imaging findings
and classifying response to treatments, specifically those
altering specific loading programmes. Consequently, the
community still relies on a trial and error approach and
future research to link the genetic, epigenetic, environ-
mental and therapeutic factors together is warranted.
With such knowledge, we may succeed in the quest for
preventive or curative therapies for tendon diseases.
Bridging this knowledge gap remains the pivotal topic
on the agenda of basic and clinical scientists and, hope-
fully, will be achieved within the coming decade. These
findings might drive the development of new diagnos-
tic techniques, evidence-based screening methods and
more targeted personalized interventions, underscoring
the need for a multidisciplinary approach to the man-
agement of tendinopathy that integrates biological,
psychological and social aspects of the disease.
Published online xx xx xxxx

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Author contributions
Introduction (N.L.M., G.A.C.M. and I.B.M.); Epidemiology
(N.L.M., K.G.S. and K.T.); Mechanisms/pathophysiology
(N.L.M., G.D.A., P.D.K., S.A.R. and L.M.G.); Diagnosis,
screening and prevention (N.L.M., P.D.K., S.A.R., K.G.S. and
K.T.); Management (N.L.M., G.D.A., P.D.K., G.A.C.M., K.G.S.,
K.T. and L.M.G.); Quality of life (N.L.M. and P.D.K.); Outlook
(N.L.M., G.D.A. and I.B.M.); Overview of Primer (N.L.M.).
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks M. Kjaer, N. Maffulli
and the other, anonymous, reviewer(s) for their contribution
to the peer review of this work.
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