Tendinopathy: Update on Pathophysiology

“Tendinitis,” “Tendinosis,” or “Tendinopathy”? The Challenges of Terminology

In the late 1990s, Maffulli et al⁶⁵ advocated a shift in clinical terminology from tendinitis to tendinopathy. Both terms are typically used as generic descriptors for pain/swelling of injured tendon, without distinguishing involvement of tendon versus paratendon or presence/absence of inflammation.⁶⁵Tendinopathy is an umbrella term that indicates a nonrupture injury in the tendon or paratendon that is exacerbated by mechanical loading. The term is typically used to describe the same conditions previously identified with the term tendinitis. Newer evidence^{4,10,11,15,35,40,54,56,72,101,102} does indicate that inflammation accompanies, and can cause, the development of tendon overuse injury.

The terminology in relation to the description of tendinopathies has further broadened since the early 1990s, though inconsistencies in the use of nomenclature remain. Tendinosis is a term that has been used to describe chronic mid-portion tendon pathology as described above; however, specific definitions vary (compare the Oxford Medical Dictionary, 8th edition to The Oxford Dictionary of Sports Science and Medicine, 3rd edition). The term tendinosis is used by some in preference to tendinitis to shift the focus away from inflammation. The term tenosynovitis refers specifically to pathology of a fully developed synovial sheath (eg, finger flexors/extensors), which typically presents with acute swelling with or without crepitus and triggering. Paratendonitis or peritendinitis describes involvement of the paratendon, alone or in combination with tendinosis. The clinical presentation of paratendonitis can be very similar to that of tendinosis (insidious onset of load-related tendon pain and thickening, with or without morning stiffness), and the two often occur together.

Tendon Pathomechanics

In 1992, Gross⁴² extensively summarized the current state of knowledge about tendon pathomechanics and healing. The model presented by Gross⁴² held that when tendons are chronically exposed to volumes or magnitudes of loading (tension, compression, friction) that are beyond their physiological capacity, they experience cumulative cycles of injury, inflammation, and repair, leading to pain and swelling (tendinopathy). The resulting accumulation of poor-quality repair tissue in tendons is analogous to the healing after acute injury (eg, laceration or rupture), except that with overuse tendinopathy, the injury-repair response evolves gradually over time. The onset is typically insidious, and the prognosis for a patient presenting with chronic symptoms is either a frustratingly slow resolution or failure to resolve and inability to return to full activity. Without proper rehabilitation guidance to address potentially related pathomechanics, many individuals with tendinopathy are caught in a cycle of chronic and acute-on-chronic pain as they attempt to return to activity with a poorly healed and deconditioned tendon, leaving risk factors and root causes, including factors related to the kinetic chain, unaddressed.⁵⁸

Characteristic Structural Changes in Tendinopathic Tendon

The general composition and organization of normal, healthy tendons have been well described previously and are only briefly summarized here (FIGURE 1).⁴² The classic description of the tensile load-bearing region of tendon includes 3 main components: (1) type I collagen fibers, which are predominantly longitudinally oriented; (2) a well-hydrated, noncollagenous extracellular matrix (rich in glycosaminoglycans); and (3) cells. The predominant cell population in healthy tendon is traditionally categorized as collagen-producing fibroblasts, responsible for the synthesis of the collagen fibers and extracellular matrix.⁴² In addition to the primary load-bearing part of the tendon, there is an extensive network of septae (endotendon), where the nerves and vessels are mainly located. Throughout the body, there are also structures closely associated with tendons (bursae, sheaths, reflection pulleys, underlying joint capsules, etc). These other structures should be assessed if possible, as they may contribute to symptoms—particularly when they impinge on the tendon or inhibit its gliding action through the development of adhesions.

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Patients with tendinopathy display tendons that are thicker, but with reduced energy-storing capacity, meaning that for the same load, their tendons exhibit higher strains than those of healthy individuals (FIGURE 2).^8,45 This represents a decline in both the structural and material properties of the tendon tissue. Indeed, abnormal tendon histology is correlated with reduced load-bearing capacity.⁸⁸

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It may be worth noting that although the stiffness (deformation in response to tensile load) of the tissue is, on average, lower in tendinopathic tendon, this phenomenon is unrelated to the sensation of increased “stiffness” often mentioned by individuals with tendinopathy, which is likely related to sensory and motor changes. These are separate phenomena with different definitions, but they happen to have the same term in the English language.

Prominent features of chronic tendinopathy histopathology (FIGURE 1) include the following: a disorganization of collagen fibers, an increase in the number of vessels and sensory nerves,^5,26,27,90 an increase in the hydrated components of the extracellular matrix,⁹¹ a breakdown of tissue (tendon/endotendon/paratendon) organization,⁴⁸ and haphazardly arranged proliferation of smaller, type III collagen fibers.^81,84 There are frequently areas of cell death (eg, hypocellularity)⁶⁹ or, alternatively, of fibroblast reaction (eg, hypercellularity and adhesions).⁵⁷ Indeed, it is typical to find both degenerative and reactive changes within the same biopsy, even in very severe, long-standing cases. It is also postulated that there is a resident population of fibroblast-like cells within tendons that, after injury, can differentiate into several lineages (osteoblast, chondrocyte, adipocyte, tenocyte), leading to metaplasia (eg, bony, cartilaginous, or adipocyte transformation).⁸⁶ Metaplasia is not usually discernible on imaging, unless the ossification is advanced, but is frequently encountered in biopsy specimens (reviewed in Lui⁶²). The implication is that patients with chronic symptoms and evidence of structural change on imaging typically have profound underlying abnormalities that will not be quickly resolved, and that are associated with the loss of tendon function.

At the cellular level, several authors have reported increased numbers of leukocytes (especially macrophages and mast cells) in chronically painful tendons (rotator cuff, patellar and Achilles tendons),^26,56,72,90 as well as increased numbers of vascular cells (endothelial and smooth muscle).⁹³ However, compared to the more immune-driven pathologies, such as rheumatoid arthritis, with measurable systemic inflammation, the number of leukocytes is small. In other words, there is indeed an inflammatory reaction within chronically painful tendinopathy, but to a lesser extent than that of immune-driven rheumatological disorders. Macrophages with accumulations of hemosiderin in their cytoplasm are more prevalent in tendinopathic than in normal tendon⁷⁴; hemosiderin is an indicator of prior injury that resulted in an activation of the innate immune response. At a biochemical level, the cells in painful tendons produce increased levels of glycosaminoglycan and inflammatory mediators such as substance P and prostaglandin E2 (PGE₂).^34,37,41 Substance P is released by peripheral sensory nerves⁸⁷ and repetitively stretched tendon fibroblasts,^11,13 and activates local mast cells that may contribute to pain and fibrosis.⁵⁹ Tendon cells derived from tendinopathic tendon produce more PGE₂ than cells from healthy individuals, indicating a chronic upregulation.³⁷ Taken together, the evidence suggests that during the rehabilitation process, any worsening of edema, morning stiffness, or delayed-onset pain should be closely monitored and controlled, as inflammation could drive the tendon further down the pathological path. An early return to sport before adequate tendon load-bearing capacity is a significant risk factor for recurrence of Achilles tendinopathy.³⁹

As a general rule, therapy should promote repair/remodelng rather than further injury/inflammation.³³ However, it should be pointed out that there is often a discrepancy between clinical improvement and structural improvement as measured with clinical imaging; that is, we do not yet have a good clinical outcome measure for tendon remodeling. At the microscopic level, as a tendon heals, vessels and nerves regress¹; collagen fibers become stronger; and the tendon becomes less thickened, more resistant to load, and less prone to reinjury (ie, recovering a more normal stress-strain curve).⁸⁹ Longer-term ultrasound follow-up of resolved tendinopathies does indicate a reduction in tendon thickening and improved collagen alignment.⁷⁶ This is an important point, as some authors have advocated reinjuring the tendon through treatments such as intratendinous needling and injections, aggressive soft tissue therapy, etc. These approaches may improve the patient's symptoms in the short term, but could result in long-term damage to the tendon. In addition to clinical trials that show a lack of effect of this type of approach (eg, de Vos et al²⁹), the rationale is not well supported by current knowledge of pathology as outlined above.

Development of Tendon Pathologies Due to Overuse: Insights From Animal Models

Animal studies over the past 2 decades have demonstrated that tendons respond to overuse with a limited cellular and biochemical inflammatory response involving macrophages, mast cells, and resident fibroblasts. After 6 weeks of intensive concentric/eccentric kicking exercise, a paratendonitis with accompanying structural changes in the rabbit Achilles tendon is observed¹⁰; the recruitment of inflammatory cells to the paratendon appears gradually over the course of 6 weeks, and macrophages (rather than neutrophils or lymphocytes) predominate in the infiltrate.⁴ After 3 or 4 weeks of repetitive reaching and grasping, a widespread inflammatory cell infiltrate is observed throughout overused rat forelimb and tendons, as well as a low-grade upregulation of inflammatory cytokines in the flexor tendons.^15,40 This inflammatory activity increases with more prolonged exposure to overuse.³² Within the endotendon, an intrinsic inflammatory response develops in response to repetitive tensile loading⁹¹—intrinsic because inflammatory cytokines, which are known to trigger collagen degradative activity, are produced by a subpopulation of tendon cells that reside in the endotendon. At the rabbit elbow, repetitive muscle stimulation upregulates intrinsic inflammatory and angiogenic pathways within local tendon cells.⁷⁵ The origin of increased vascularity in tendinopathy may result from local vascular hyperplasia as a result of angiogenic factors like vascular endothelial growth factor, expressed by repetitively stressed tendon fibroblasts.⁶

One of the main proinflammatory substances involved in tendon injuries, prostaglandin E2 (PGE₂), is produced both intrinsically (by repetitively strained tendon fibroblasts)³ and by leukocytes.⁹² PGE₂ depresses collagen synthesis in tendon cells and upregulates their degradative enzyme activity.¹⁶ Chronic inflammation in the paratendon that is experimentally induced (eg, by injections of substance P or prostaglandins) causes or exacerbates tendinopathy.¹⁰² Taken together, the animal studies have taught us that the end result of overuse—tendinopathy—can develop as a result of repeated release of inflammatory and reparative mediators.

Low-grade inflammation may come and go in short bursts following a period of intensive mechanical loading, making it difficult to detect clinically. For example, in response to repetitive loading of tenocytes, many inflammatory genes are upregulated after 4 hours, but return to baseline levels within 24 hours.⁷³ However, the extent of inflammatory and fibrotic activity can also gradually increase over a period of several weeks with prolonged exposure to repetitive loading³⁵; the tendency of inflammatory activity to increase over time is more marked in older, compared to younger, tendons.⁵⁴ Nevertheless, transient bursts of inflammatory activity in a tendon, if repeated and prolonged, can lead to the progressive accumulation of damage, even if these episodes are not registered as symptomatic by the patient.

The mechanism of tendinopathy pain relief in response to nonsteroidal anti-inflammatory drugs (NSAIDs)^19,80 is not known, but NSAIDs are known to influence sensory nerves,³² tenocytes,⁸⁵ and mast cells,¹¹¹ in addition to their well-known effect on macrophages and neutrophils. The majority of animal studies that have examined the impact of NSAIDs on tendon healing (Achilles, plantaris, or flexor digitorum) after acute injury have found improved tendon healing (fewer adhesions, improved recovery of biomechanical properties),^{22,31,36,104,105} which supports the concept that ongoing tendon inflammation may be considered pathological. In contrast to the above studies of tendon injury, NSAIDs appear to be detrimental to bone-to-tendon (enthesis) healing after acute injury in rats^21,23,25 (similar to their inhibitory effect on fracture healing) and may also be detrimental to muscle repair when used long term.⁶⁴ Further research is necessary to understand whether NSAIDs influence the long-term outcomes of recovery from tendinopathy.

Gross⁴² also alerted us to the fact that clinically, a single subfailure overload injury can develop into a chronic tendinopathy—this observation is supported by animal studies using partial failure models⁹⁴ in that tendon disruption with histology very similar to that reported in humans¹⁰³ can persist 12 months after an acute injury. Clinically, it can be very difficult to distinguish partial tears (ie, macroscopic partial defect of acute onset and marked functional deficit) from tendinopathies (which typically demonstrate a more insidious onset of pain and loss of function).⁵⁰ Histologically, partial tears and tendinopathies have the same appearance,⁹ but the extent of tissue affected in a partial tear may necessitate a different approach to finding the optimal load to allow healing and remodeling (eg, extensive partial Achilles ruptures may benefit from a period of immobilization to prevent disruption of the healing area, much as one would protect a conservatively managed complete Achilles rupture).⁹⁹

Mechanisms of Injury

The mechanism of injury for a given tendinopathy can vary from region to region, and from patient to patient. Tendons and their insertions are rarely loaded purely in tension; although tensile overload may be the dominant mechanism for many tendinopathies, there is often compression of the tendon as well, either internally (eg, one fascicle or bundle of fibers against another) or against external structures (paratendon, retinacula, bone). The combination of tension and compression results in shearing and friction. For example, the rotator cuff may experience substantial shearing forces when coming in contact with the acromion and subacromial bursa, particularly if the tendon and/or bursa are thickened, or against the glenoid labrum in positions of extreme external rotation.⁹⁷ The common extensor tendons of the wrist and fingers at the elbow may be injured not only by repetitive tensile loading, but also by shearing forces against the capitellum with rotation.²⁰ In the Achilles region, shearing and torsional forces could result from the differential displacement of gastrocnemius and soleus tendon components, the “whipping/wringing” effect of excessive pronation, or friction against the adjacent plantaris tendon.^2,18,24

Another aspect of pathomechanics that may be clinically relevant is that of tendon “stress shielding,” as well as de-adaptation (“use it or lose it”). Stress shielding refers to the existence of a zone within a tissue that receives less load compared to surrounding areas due to the microinjury of collagen fibers⁷ or to the uneven distribution of forces (eg, it has been proposed that there may be differential force distribution through the patellar tendon³⁰). Reduction of load through tendons (eg, bed rest or relative inactivity) can lead to a large and rapid loss of structural organization and mechanical properties.⁸² Thus, a period of relative inactivity followed by a sudden increase in loading may precipitate a tendon injury.

Once symptoms and pain develop, ensuing movement dysfunction may contribute to the chronicity of symptoms. Tendon pain causes widespread motor inhibition in the affected region, evidenced by decreased muscular activity as assessed with electromyography.⁴⁶ Individuals with tendinopathy also tend to use movement patterns that place excessive or abnormal load on their tendons: the faulty movement may represent either a root cause or a reason for chronicity or slow resolution. For example, the results of several studies focusing on the relationship between jump biomechanics and patellar tendinopathy suggest that individuals with patellar tendinopathy have a less upright position (more hip and knee flexion) at initial contact in landing.¹⁰⁷ In individuals with rotator cuff tendinopathy or tear, scapular dyskinesia is a common finding.^43,52 More prospective studies are needed, but normalizing movement patterns with the goal of optimizing the loading environment of the tendon seems to be a reasonable approach.⁵³

Classification of Tendinopathies According to Relevant Pathophysiological Features

The pathophysiology features described above lead to the following classification and staging system for tendinopathy (TABLE 1). The classification is meant to alert clinicians to the fact that not all tendinopathies are the same and to facilitate clinical reasoning and communication. This system has not been extensively validated (level 5 evidence) but is rooted in the research evidence presented above, and we hope that readers will find it clinically useful.

As an example of how this classification system may be helpful in considering different treatment options, compare and contrast the implications of a case labeled “chronic, grade 3 insertional Achilles tendinopathy with underlying type 2 diabetes mellitus” with those of a case labeled “acute, grade 1 Achilles midportion tendinopathy with paratendonitis and increased pronation during weight bearing.” Therapy in the first clinical scenario should proceed cautiously and patiently, with an exercise-based approach to stimulate adaptation and repair, perhaps in combination with techniques to offload the tendon insertion (eg, heel lifts) and avoiding positions of extreme dorsiflexion, which could further exacerbate the injured enthesis. In the second clinical scenario, the individual may be able to return to full activity rapidly if the biomechanical fault can be adequately addressed with a trial of taping,¹⁰⁰ for example, followed by the potential use of orthoses and strengthening of the intrinsic foot musculature. Each patient can present with a unique cluster of features that precludes a “recipe book” approach to physical therapy management. Based on clinical experience and knowledge of underlying pathophysiology, certain features may require more caution (eg, diabetes, advanced age), a different type of load management (eg, relative rest for more acute presentation, heavy controlled loading for more chronic presentation), a balancing of rehabilitation loading with sport or work requirements, and biomechanical considerations (eg, offloading insertion and addressing individual impairments of strength, range of motion, and motor control).

Extrinsic and Intrinsic Factors Associated With Tendinopathy

Józsa and Kannus' classic 1997 text⁴⁸ summarizes a number of clinical features that place tendons at risk of overuse injury. As each patient may present with a unique cluster of relevant risk factors,⁶⁶ the clinician must decide which of these to emphasize in assessment and treatment. Extrinsic factors include excessive volume, magnitude, or speed of loading; training errors such as the use of poor-quality equipment and abrupt or acute changes in amount or type of load (eg, sudden change to a different shoe type); and environmental conditions such as temperature (eg, cold weather, which makes the tendon stiffer and reduces its circulation) and running surface. Intrinsic factors include individual biomechanics (malalignments, muscle weakness or imbalance, decreased flexibility), age, and adiposity. Some of these risk factors have now been observed in controlled prospective or retrospective studies.^{12,44,60,61,67,70,71,77–79,83,107,108,110} At the highest level of activity, tendinopathy is nearly universally prevalent in some sports (eg, radiologically diagnosed rotator cuff tendinopathy in elite swimmers).⁹⁶ Rehabilitation programs emphasizing individualized biomechanics and overall movement/function have recently been validated in large randomized controlled trials,^47,109 underlining the potential importance of biomechanics in the etiology of tendinopathy.

With regard to adiposity as a risk factor for tendinopathy, an association between elevated body mass index and increased risk of tendinopathy appears to hold true both for lower extremity tendons (Achilles, patellar) and upper extremity tendons (rotator cuff, common wrist extensor tendon at the elbow).³⁸ The biological mechanisms have not yet been established, but excessive dietary intake of cholesterol does result in the accumulation of oxidized low-density lipoprotein in the load-bearing region of tendon, where it impairs type I collagen production and reduces tendon strength and energy-storage capacity.⁹⁵ Individuals with tendinopathy who have a body mass index or waist girth above healthy reference values could be informed that their diet or their weight may be contributing to their tendon condition, and an appropriate exercise prescription made (and perhaps a lipid profile should be suggested if it has not been done recently). Generalized exercise targeted at weight loss, for example, for the overweight individual with rotator cuff tendinopathy or golfer's elbow, may also address concomitant features of chronic musculoskeletal pain syndromes, such as decreased pain threshold and emotional depression.

Smoking is also associated with worse tendon histology than that seen in nonsmokers.⁶³

Medications

In the following section, we provide an update on the role certain medications are now known to play in causing or exacerbating tendinopathy.⁵⁵ A complete history of any patient will always include the list of their medications, but patients with tendinopathy should specifically be asked about the medications listed below. Tendon pathology caused by medications may present similarly to an overuse condition (eg, gradual onset and pain and swelling aggravated by activity, features typical of statin-induced tendinopathy), or the onset may be sudden, at times characterized by a spontaneous rupture (as characteristic of many fluoroquinolone-induced tendinopathies).

Other Causative or Contributing Medical Conditions

A number of medical conditions are associated with tendinopathies and ought to be considered relevant when conducting the history and clinical examination. These are described in TABLE 2. Some patients present with multiple tendon injuries, with or without a family history. Despite the fact that a number of gene variants associated with increased risk of tendon injury or tendinopathy have been identified,⁹⁸ there is no clinically useful genetic test for these; however, a positive family history or tendinopathies at multiple locations could signal elevated risk.

Conclusion

Although tendons are anatomically designed to withstand extensive mechanical loading, they are prone to injury through a variety of biomechanical and biological mechanisms. The healing response may be slow or incomplete in many individuals, resulting in long-term structural and functional deficits that predispose them to ongoing irritation and pain. However, the clinical presentation and prognosis of tendinopathy can be very individualized (acute or chronic, focal or generalized, paratendon versus tendon, etc), and a detailed assessment of the extent or nature of pathology and risk factors can assist in clinical reasoning.