Genetic factors are implicated in the pathogenesis of tendinopathy. Identical twin studies have implicated genetic factors in lateral epicondylalgia (Hakim et al. 2003). A number of different genes have been found to be upregulated and downregulated in tendinopathy; however their significance is yet to be determined (September et al. 2007; Jelinsky et al. 2011; Magra and Maffulli 2008). Two variants for COL5A1 gene and the tenascin-C (TNC) gene have been implicated in tendon pathology. COL5A1 encodes for a component of Type V collagen, which aligns and organises Type I collagen (Birk et al. 1990). A specific phenotype results in more tightly packed collagen bundles leading to both better energy storage and also greater vulnerability to tendinopathy. Variations in the COL5A1 gene are linked to an increased risk of Achilles tendinopathy (Chauhan et al. 2015; Mokone et al. 2006; September et al. 2009). Tenascin-C is an anti-adhesive protein, which is important in the regulation of load capacity after tendon loading and compression (Jarvinen et al. 2000). Variants of the TNC gene have also been linked with Achilles tendinopathy, with certain polymorphisms increasing the risk of developing symptoms sixfold (Mokone et al. 2005). Polymorphisms within the TNC or COL5A1 gene have been suggested to be linked to other injuries such as ACL tears (September et al. 2007); however so far results have been conflicting (Stepien-Slodkowska et al. 2015; Posthumus et al. 2010).

Other factors involved in tissue repair in tendons include transforming growth factor β1 (TGF-β1) and growth/differentiation factor 5 (GDF-5) (Hou et al. 2009; Rickert et al. 2005). A genetic association study however showed no difference in TGF-β1 expression between people with tendinopathy and controls. Genes coding for GDF-5 however were significantly associated with Achilles tendinopathy, showing a modest two times elevated risk (Posthumus et al. 2010).

The impact of sex on tendinopathy varies across the population, as well as affecting different tendons. Postmenopausal women exhibit higher rates of tendinopathy (Frizziero et al. 2014) and tendon rupture (Maffulli et al. 2007); however this may be confounded by other factors such as increased blood lipids. There was no impact of gender in Achilles or patellar tendinopathy in masters athletes (Longo et al. 2009, 2011). Peritendon disorders such as De Quervain’s tenosynovitis are more common in women (Wolf et al. 2009), and this may be linked to altered inflammatory responses in women (Hart et al. 1998).

Ageing is thought of as a risk factor for developing degenerative pathology; however ageing alone does not explain tendon pathology. Ageing affects the structure and histology of tendons, with increased stiffness, deformation and cross-sectional area, as well as decreased peak tendon stress and strain (Carroll et al. 2008; Tuite et al. 1997). However, when force is normalised, there is no difference seen between young and old tendons in terms of deformation, strain and stiffness, suggesting change in force-output capacity may be more responsible for the alterations seen during ageing (Carroll et al. 2008). Other studies have shown increase in collagen cross-linking, decrease in water content and collagen concentration (Narici et al. 2008; Couppe et al. 2009), as well as a decrease in blood supply (Tuite et al. 1997). Together it seems that load capacity decreases with age, particularly with reference to energy storage and release loading. Ageing is a risk factor for tendon rupture (Pedowitz and Kirwan 2013), and cumulative loading may also be a factor, as past athletes exhibit higher rates of tendinopathy and rupture (Kujala et al. 2005).

Young athletes exhibit high rates of tendon pathology. In children, tendon pathology may be seen on imaging (Simpson et al. 2016); however pain is commonly attributed to the apophysis (such as Osgood-Schlatters disease). Evidence is however emerging to suggest that tendon pathology may be present in children and adolescents distant to the apophysis (Sailly et al. 2013).

Fluoroquinolones, a class of antibiotic, have been closely associated with the development of tendinopathy and tendon rupture (Lewis and Cook 2014). The Achilles tendon is the site most commonly affected (Lang et al. 2016; Khaliq and Zhanel 2003). Men appear to be at greater risk, with a dose-dependent response seen (Khaliq and Zhanel 2003; Lewis and Cook 2014). Fluoroquinolones are thought to have their effect by decreasing cell numbers and increasing matrix breakdown. Fluoroquinolone-associated tendinopathy may be slower to respond to treatment (Lewis and Cook 2014).

Statin medications have also been implicated as a risk factor for developing tendinopathy, though evidence is conflicting (Teichtahl et al. 2016; Kirchgesner et al. 2014). A number of case reports show increased incidence of tendinopathy (Kirchgesner et al. 2014; Marie et al. 2008); however a recent systematic review showed no increased risk (Teichtahl et al. 2016). Conversely simvastatin may actually slightly decrease the risk of tendinopathy (Contractor et al. 2015).

Finally local and systemic use of glucocorticoids has been suggested to negatively affect tendon tissue (Dean et al. 2014; Blanco et al. 2005). Local glucocorticoid injection leads to decreased collagen production, impaired cell proliferation, increased matrix disorganisation and hence lower mechanical load tolerance of the tendon cells (Dean et al. 2014). Long-term clinical outcomes were worse following corticosteroid injection in lateral epicondylalgia (Coombes et al. 2016). An association between local injection and rupture has been proposed (Kirchgesner et al. 2014; Blanco et al. 2005); however little evidence supports this (Scott et al. 2015a).

Obesity is considered a risk factor for a variety of musculoskeletal conditions and has also been shown as a risk factor for developing tendinopathy (Scott et al. 2015b; Gaida et al. 2008, 2009a; Franceschi et al. 2014). Elevated body mass index has been shown in tendinopathy compared to control, though a variety of interactions may be responsible (Scott et al. 2013; Klein et al. 2013; Gaida et al. 2008, 2009a). Increased waist circumference was also linked with asymptomatic tendon pathology. There are differences between fat distributions in men and women; men with tendinopathy have more central adiposity, while women exhibit peripheral distribution of fat (Gaida et al. 2010). This is supported by findings in men showing waist girth over 83 cm was a risk factor for patellar tendinopathy in volleyball players but not in women (Malliaras et al. 2007).

Obesity has both mechanical and systemic effects (Scott et al. 2014). Elevated load on tendons due to excessive weight has been postulated to be behind the elevated risk of tendinopathy. From a systemic viewpoint, obesity increases blood lipids, which have also been shown elevated in Achilles tendinopathy (Gaida et al. 2009b).

Systemic diseases and illnesses associated with obesity can predispose to tendinopathy. People with Type II diabetes mellitus have a 3.6 times greater prevalence of tendinopathy than controls (Ranger et al. 2016). Increased tendon thickness is also reported in diabetes (de Oliveira et al. 2011a). The mechanism may be via hyperglycaemia that reduces proteoglycan content and increased levels of transforming growth factor β1 (TGF-β1) (Burner et al. 2012). Diabetes also leads to increased formation of advanced glycation end products (AGE), which can create more collagen cross-links (Snedeker and Gautieri 2014; Abate et al. 2013; Reddy 2003). Increased AGE content is shown to decrease the viscoelastic properties of tendons, by decreased sliding between fibres (Li et al. 2013; Fessel et al. 2014). Increased cross-linking can increase load to failure (Snedeker and Gautieri 2014) and increase stiffness, while other studies showed greater tissue fragility (Fox et al. 2011; de Oliveira et al. 2011b).

Dyslipidaemia may predispose tendons to pain and pathology by altering tendon structure and increased levels of immune and pro-inflammatory cells (Scott et al. 2014). The dyslipidaemia seen in Achilles tendinopathy is similar to that seen in insulin resistance, and it has been proposed that tendinopathy may be a comorbidity of metabolic syndrome and cardiovascular disease (Gaida et al. 2009b). This may also explain why decreased physical activity is associated with development of tendinopathy (Descatha et al. 2013). Tendon pain then further reduces physical activity.

Hypercholesterolaemia also appears to be associated with tendinopathy (Tilley et al. 2015; Esenkaya and Unay 2011), particularly in familial cases (Abate et al. 2013; Beeharry et al. 2006). Increased blood lipids increase the accumulation of pro-inflammatory cells, mast cells and macrophages, as well as increased deposition of low-density lipoproteins (LDLs) in the tendon matrix (Tilley et al. 2015). Association with lower physical activity levels or other comorbidities may be driving this link (Tilley et al. 2015). A number of other illnesses have been linked with elevated risk for tendinopathy including hyperuricaemia (Abate et al. 2013), systemic lupus, rheumatoid arthritis (Fredberg 1997), psoriatic arthritis (Gutierrez et al. 2010) and hypertension (Holmes and Lin 2006).

Reduced flexibility of muscles attaching to the at-risk tendon as well as antagonist muscle groups has been shown to increase the risk of developing tendinopathy. Both quadriceps and hamstring inflexibility have been shown as a risk factor for development of patellar tendinopathy (Witvrouw et al. 2001; Silva et al. 2016; Crossley et al. 2007; Cook et al. 2002). Too much or too little ankle dorsiflexion range is a risk factor for developing Achilles and patellar tendinopathy (Backman and Danielson 2011; Malliaras et al. 2006; Crossley et al. 2007; Kaufman et al. 1999; Rabin et al. 2014; Mahieu et al. 2006).

There is little evidence that foot posture and mechanics are associated with tendinopathy nor that altering them with orthotics is effective despite widespread clinical use (Munteanu et al. 2015). Static foot posture has not been shown as a risk factor for patellar tendinopathy (de Groot et al. 2012; Crossley et al. 2007). Increased ankle inversion moments during landing and jumping tasks have been associated with patellar tendinopathy (Richards et al. 2002). Excessive foot pronation is often suggested as a risk factor for Achilles tendinopathy (Munteanu and Barton 2011); however quality research beyond anecdotal evidence is lacking (Dowling et al. 2014).

Clinically, poor strength is often associated with tendinopathy, likely mediated by pain. Decreased eccentric strength has been found in the quadriceps in people with patellar tendinopathy (Gaida et al. 2004) and gastrocnemius in those with Achilles tendinopathy (Silbernagel et al. 2006; Haglund-Akerlind and Eriksson 1993). Functional deficits such as decreased vertical jump and hopping ability (Silbernagel et al. 2006) have also been shown.

However a strength deficit has not been shown prospectively, with no relationship shown between quadriceps and hamstring strength and the development of patellar tendinopathy (Witvrouw et al. 2001). Consideration of kinetic chain deficits is important, as reduced strength in other regions may predispose a tendon to overload, and should be assessed on an individual basis when managing tendinopathy (Malliaras et al. 2015; Kountouris and Cook 2007).

Excessive loading above a tendon’s capacity is a cause of tendinopathy. Clinically, activities requiring energy storage loads (such as running for the Achilles tendon) are associated with onset of tendon pain. While previous terminology has referred to tendinopathy as ‘repetitive strain injuries’, sports with high-frequency cyclical load such as cycling and rowing with low-energy storage components do not have high rates of tendinopathy. The clinician must understand load and use it as part of their differential diagnosis and decision making; the cyclist and rower are vulnerable to paratendinitis due to the repetitive friction in these activities and require different management.

The amount of loading may be critical; female basketball players with patellar tendon pathology trained 2.14 h more each week on average than their pain-free colleagues (Gaida et al. 2004). The number of hours trained significantly correlated with supraspinatus tendinopathy in swimmers (Sein et al. 2010). Training volume, as well as increased game exposure, was also a risk factor for patellar tendinopathy in volleyball players (Visnes and Bahr 2013). These findings are similar to other sports-related injuries, such as in those seen in throwers in baseball (Olsen et al. 2006) and bowlers in cricket (Hulin et al. 2014).

While total load is important, change in loading and training errors are key factors in a number of musculoskeletal pathologies, including tendinopathy. Consideration of the acute versus chronic workloads may be a factor to decrease risk of injury (Gabbett 2016). An optimum amount of loading appears to be protective while excess or insufficient loading precipitating greater risk. Orchard et al. (2015) found that medium-term workload (3 months) was protective for the development of tendon injuries in cricket bowlers. Clinically, tendinopathy presentations are very often seen after changes in training loads (Ferretti 1986). This may be change of training cycle, onset of intensive competitions, and even change in equipment or footwear. It is often common to see increased cases of tendinopathy in the beginning of a season after resumption of training, and this may also relate to underloading in the off-season and a relative increase in load with resumption of training.

While the majority of research concerns tendon overload, offloading or unloading may predispose a tendon to pain and symptoms as it may lower the load capacity, placing an individual at risk of tendinopathy (Kannus et al. 1997). Sedentary individuals are also at risk of developing tendinopathy, when they perform abusive loading or unaccustomed activity (as it exceeds their load capacity). This has been proposed in rotator cuff tendinopathy, often seen in older less active patients (Lewis 2010). Underload may also be seen when an athlete resumes training after a long layoff (such as the off-season) or injury. The importance of load is reinforced by the fact that complete rest of a symptomatic tendon will not cure a patient’s presentation and often leads to a worsening tendinopathy once load is resumed.