Trauma and micro-trauma can produce entheseal changes, among numerous others factors (Resnick and Niwayama, 1983). Clinical literature also reports the presence of entheseal changes in many diseases. The goal is not to present these conditions in detail here (listed in Henderson, 2008; Villotte, 2009), but rather to focus on lesser-known aspects of entheseal changes related to age, hormones, and physical activities. However, it seems necessary to present briefly the two main causes of non-degenerative enthesopathies: seronegative spondyloarthropathies and diffuse idiopathic skeletal hyperostosis (DISH or hyperostotic disease). DISH is characterized by para-articular bridging osteophytes in the anterolateral aspect of the spine (Forestier & Rotes-Querol, 1950; Resnick et al., 1975). Exuberant bone production is seen at extra-spinal fibrocartilaginous and fibrous entheses (Resnick et al., 1975). Very early on, researchers recognized the enthesis as a primary target in ankylosing spondylitis and other seronegative spondyloarthropathies (Ball, 1971; Paolaggi et al., 1984a, 1984b). The inflammation occurs at the level of fibrocartilaginous entheses, leading to erosion of the fibrocartilage (Benjamin & McGonagle, 2001; Fournié, 2004). This erosive process is followed by deposition of reactive bone and the formation of an enthesophyte (Ball, 1971; Resnick & Niwayama, 1983). It is noteworthy that entheseal changes seen in cases of seronegative spondyloarthropathy are characterized, at least for some fibrocartilaginous entheses, by erosive lesions uncommonly seen in other individuals (Villotte & Kacki, 2009).
In studies of entheseal changes in skeletal samples with known age-at-death, age is the main aetiological factor identified (Shaibani et al., 1993; Cunha & Umbelino, 1995; Mariotti et al., 2004, 2007; Villotte, 2009; Alves Cardoso & Henderson, 2010; Villotte et al., 2010a; Niinimäki, 2011; Milella et al., 2012). However, the precise relation between age and entheseal changes remains poorly described (and in some aspects poorly understood). Properties of the entheses during skeletal immaturity are mainly described in studies of animal models and, to a lesser extent, in studies of human cadavers. For adulthood, data derive mainly from sports medicine or that associated with the aged, though the study of identified skeletal collections provides informative results.
Secondary ossification centres
In early development of humans and other mammals, the tendon or ligament attaches to the perichondrium (Hurov, 1986; Gao et al., 1996; Wei & Messner, 1996; Shaw et al., 2008). During growth, entheses seem to act as growth plates; the cartilage is resorbed at the inner side and produced at the outer side, possibly by metaplasia (Gao et al., 1996; Nawata et al., 2002). The classic appearance of a fibrocartilaginous enthesis (i.e. the four histological zones, see supra) appears in non-human mammals when growth slows or stops (Wei & Messner, 1996; Nawata et al., 2002; Wang et al., 2006). For instance, in the attachment zones in the rat anterior cruciate ligament, the boundary between uncalcified and calcified fibrocartilage is not clearly distinguishable before growth slows (Nawata et al., 2002). The process is not described for humans, but this progressive organization of the enthesis during growth and development could explain the lack of a clearly distinguishable area of attachment in juvenile human skeletons (Figure 4, compare with Figure 1). Indeed, in skeletal remains, the classic appearance of a fibrocartilaginous enthesis is seen when epiphyses of short and flat bones (also called apophyses) and long bones are partially or fully fused. The most common activity-related change occurring before the complete fusion of the epiphysis is a total or a partial bony avulsion (e.g. Resnick and Niwayama, 1983; Nakanishi et al., 1996; Stevens et al., 1999; Adirim & Cheng, 2003). Consequences of these avulsions (total or partial) can be observed on the adult skeleton (Villotte et al., 2010b; Knüsel, 2012).
Figure 4. Proximal humeral epiphysis of an immature individual (6–9 years old). The area of attachment of the M. supraspinatus and M.infraspinatus on the greater tubercle (white arrow) is not clearly distinguishable. Scale: 1 cm.
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During adulthood, the degenerative process related to age and mechanical demands affects both the tendon and the fibrocartilaginous enthesis. Within the aging tendons, the amount of denatured collagen and proteolytic cleavage of matrix components increase (Riley, 2004). These changes lead to deterioration in the physical properties of the tendon (Riley, 2004), which, in turn, may favour the occurrence of mechanically induced alterations in the enthesis (Rodineau, 1991; Bard, 2003). From the sixth decade onwards, the fibrocartilaginous enthesis itself is the target of the degenerative process (Durigon & Paolaggi, 1991; Rodineau, 1991; Bard, 2003). Those degenerative changes are well described (Durigon & Paolaggi, 1991; Lagier, 1991; Kumagai et al., 1994; Jiang et al., 2002; Milz et al., 2004; Benjamin et al., 2007, 2009). They are:
- Microtears or microdamage of one of the four histological zones of the enthesis (tendon, uncalcified and calcified fibrocartilage, bone);
- Formation of enthesophytes (bony spurs at the enthesis), induced by the healing process, after microtears;
- Disturbance of collagen fibres and of the organization of cell columns;
- Calcific deposits;
- Increase of the thickness of the calcified fibrocartilage layer;
- Vascularization of the calcified and uncalcified fibrocartilage layers;
- Erosion of the surface and bone resorption beneath the enthesis.
Disturbance of enthesis organization and subsequent healing processes are visible on skeletal remains: vascularization, enthesophytes, calcific deposits, cysts, and irregularity of the surface are common in the skeletons of old individuals (Shaibani et al., 1993; Cunha & Umbelino, 1995; Mariotti et al., 2004, 2007; Villotte, 2009; Alves Cardoso & Henderson, 2010; Villotte et al., 2010a; Milella et al., 2012). Bony spur formation typically occurs in the most fibrous part of an enthesis (Villotte, 2006; Benjamin et al., 2009). It should be noted that, contrary to other fibrocartilaginous entheses, there is no correlation between frequency and size of enthesophytes at the ligamenta flava attachment sites and age-at-death (Cunha & Umbelino, 1995; Villotte, 2009).
Excessive mechanical stress in terms of frequency, speed, and/or intensity can cause a series of micro-traumatic insults that tend to disturb the tissue structure of the fibrocartilaginous enthesis (Husson et al., 1991; Khan et al., 1999; Benjamin et al., 2006). In young adults, these mechanical stresses are the main factor in the occurrence of an activity-related enthesopathy (Rodineau, 1991). In the older individual, on the contrary, it is the gradual depletion of tendon vascularity close to the insertion that favours the occurrence of lesions (Rodineau, 1991). Biomechanical parameters are, in this case, a secondary factor. Other factors may increase the risk of developing enthesopathy, for instance cold temperatures, the use of unsuitable equipment, very heavy muscular stresses endured without training or appropriate warm-up, and abnormal structures disrupting joint biomechanics (Commandré, 1977; Rodineau, 1991; Bard, 2003). The work of several authors, including Khan et al. (1999) and Milz et al. (2004), clearly indicate that overuse enthesopathies are similar to degenerative ones described in older individuals. Thus, micro- and macro-bony avulsions, tidemark irregularity (disorganization of the layer of calcified fibrocartilage), vascularization of the fibrocartilage, calcification, and ossification of soft tissues can be observed in cases of overuse enthesopathy (Dupont et al., 1983; Husson et al., 1991; Saillant et al., 1991; Potter et al., 1995; Selvanetti et al., 1997). It is noteworthy that in these sports medicine reports, skeletal alterations are, in most cases, inconspicuous.
Sports and occupational injuries at tendons and entheses seem, at present, more common in women (Punnett & Herbert, 2000; Bard, 2003). However, these differences are not observed for all anatomical sites and many sex-related parameters (e.g. muscle mass, fat mass, size, morphology), may interact (e.g. Punnett & Herbert, 2000; Bard, 2003). Among the factors involved, ovarian hormones, including estradiol and relaxin, could play an important role. The contribution of these hormones in reducing the amount of glycosaminoglycans and collagen has been demonstrated for fibrocartilaginous joints (Naqvi et al., 2005; Hashem et al., 2006). Moreover, these hormones promote hyper-laxity and increase the risk of intrinsic mechanical lesions (Punnett & Herbert, 2000; Bard, 2003). At the menopause, blood levels of estrogen drop significantly (Sowers, 2000). This decrease causes a change in the composition of collagen connective tissue, including ligaments, associated with loss of elasticity (Falconer et al., 1996; Ewies et al., 2003).
As for fibrocartilaginous entheses, the following discussion on properties of fibrous entheses during skeletal immaturity is based on animal models. These models are of two kinds: those focusing on gross anatomy and those studying the histological properties of these entheses. The first type indicates that during growth, there is a relationship between muscle activity/properties and the morphology of attachment sites. For instance, Dysart et al. (1989) demonstrated that denervation of the rat forelimb is followed by an abnormally formed humerus, notably a smaller and less curved deltoid tuberosity. Based on these findings, they postulated ‘that muscle pull affects periosteal tension and consequently bone form and growth in length’ (Dysart et al., 1989: 158). In a study of mutant strains of mice, Montgomery et al. (2005: 819) reached a slightly different conclusion: ‘These findings suggest that muscle attachment sites expand during growth in order to accommodate increases in muscle size and mass, but that expansion of these bony regions is not necessarily dependent on increases in muscle contractile strength […]’.
If these experiments provide interesting insights into the effects of muscle properties and activity on bone morphology, the study of histological properties of attachment sites appears more informative for a better understanding of the ‘normal’ appearance of fibrous entheses in the immature human skeleton. In dog, rabbit and rat studies on diaphyseal entheses, tendons, and ligaments attach via periosteum during growth (Laros et al., 1971; Dörfl, 1980a, 1980b; Hurov, 1986; Matyas et al., 1990; Gao et al., 1996; Wei & Messner, 1996). Both osteoclastic and osteoblastic activity are seen at fibrous attachment sites during this period and appear to be mainly related to the migration of the attachments of tendons and ligaments during the growth in length of long bones (Hoyte & Enlow, 1966; Dörfl, 1980a, 1980b; Hurov, 1986). It is noteworthy that muscular traction plays no role in this migration (Dörfl, 1980a, 1980b; Grant et al., 1981). All these animal model studies included the tibial insertion of the medial collateral ligament. This ligament attaches to the tibia of growing individuals in an area called the ‘metaphyseal depression’, where growth-related osteoclastic resorption is more predominant than osteoblastic activity (Dörfl, 1980a; Matyas et al., 1990; Wei & Messner, 1996). Osteoclasts are most obvious at the periosteal side of the bone, but they are also seen at the endosteal or marrow side (Wei & Messner, 1996). It is noteworthy that the ‘metaphyseal depression’ disappears in mature rabbits (Matyas et al., 1990), but a shallow depression persists in rats up to 120 days of age, which was interpreted by Wei & Messner (1996) as a sign of continuing growth. Many biological anthropologists (e.g. Saunders, 1978; Castex, 1990; Stirland, 1996; Mariotti et al., 2004) reported high frequencies of a ‘fossa’ in juveniles and young adults for several metaphyseal attachment sites (e.g. humeral insertions of the Mm. pectoralis major and teres major and the femoral insertion of the M. gluteus maximus). Actually, these grooves or ‘fossae’ are very common in immature human skeletons, in frequency but also in their distribution in the body (Figure 5), and it may be tentatively suggested that they are related to a process similar to that described for the tibial ‘metaphyseal depression’ in rats and rabbits. These changes, especially for the humeral insertion of the M. pectoralis major, seem to be more dramatic in males during late adolescence and early adulthood, before the complete fusion of the epiphysis (Mariotti et al., 2004). Consequently, linking these erosions in young adult males solely to mechanical stresses (e.g. Hawkey & Merbs, 1995) appears, at least, highly hazardous (see Villotte, 2008b for a review of the possible causes of a ‘fossa’ at the humeral insertion of the M. pectoralis major in adults). Moreover, the bottom of these grooves is usually not smooth in juvenile human skeletons: marked porosity, short striae, and small asperities are often present (Villotte, 2006). One could speculate that those changes are related to the irregularity of the mineralization front (i.e. the superficial cortex) before skeletal maturity in other mammals (Matyas et al., 1990; Wei & Messner, 1996).
Figure 5. Proximal tibial shaft of an immature individual (6–9 years old). The area of attachment of the M. soleus displays the classic appearance of immature metaphyseal entheses, a ‘fossa’ with porosity, short striae, and small asperities/irregularities at its bottom. Scale: 1 cm.
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In mature animals, the periosteal layer may or may not disappear, depending on the species and the enthesis. In adult humans, periosteal fibrous entheses are seen where muscles attach to a large area by short fibrous ends (Kenesi & Tallineau, 1991), and for some masticatory muscles (Hems & Tillmann, 2000). As the mediating layer of periosteum often disappears with age and leaves the soft tissue attaching directly to bone (Benjamin et al., 2002), it has been hypothesized that the physiological transition from a periosteal to a bony attachment in early adulthood may explain the high frequency of skeletal changes (i.e. irregularity) seen in young/middle-aged adults (Villotte 2009).
Benjamin et al. (2002: 934) note that ‘relatively little attention has been paid to fibrous entheses, even though they are associated with some of the largest and most powerful muscles in the body […]. This partly reflects a clinical bias toward fibrocartilaginous entheses – which are more vulnerable to overuse injuries, but also the attraction of working with a richer variety of tissues that such entheses can offer.’ In a study that focuses mainly on fibrocartilaginous entheses, Benjamin et al. (2007) briefly describe two modifications observed in elderly subjects at the fibrous insertion of M. pronator teres: a bony production and a vascular invasion of the fibrous tissue. Micro-trauma at fibrous entheses is described mainly for periosteal attachment sites (e.g. Condouret & Pujol, 1985); they lead to a periostitis. Only a few cases were reported for bony ones: enthesopathy at the M. deltoideus insertion on the humerus in golfers and ‘pala’ players (Commandré, 1977: 67) and small resorptive areas at the humeral insertion of the M. pectoralis major in gymnasts (Fulton et al., 1979).
To conclude this section, it seems important to report an interesting study on the effect of inactivity for several entheses in dogs (Laros et al., 1971). In active immature dogs, normal metaphyseal remodelling was seen with a marked bone resorption at the tibial insertion of the medial collateral ligament (i.e. a normal appearance, cf. supra). In inactive adolescent dogs, the reaction was more generalized. Contrary to the other entheses under study, simple caging for six weeks produced resorption at the tibial insertion of the medial collateral ligament in adult dogs. Moreover, after several weeks of immobilization in a plaster cast, resorptive changes at this enthesis were seen for the immobilized limb of adult dogs, but also in a lesser extent for the non-immobilized limb, free for activity, and weight-bearing! With continued caging (over a period of six months or more) and in dogs sacrificed 12 weeks after removal of plaster immobilization, bone resorption healed as fibrous tissue replaced resorbed bone and then became mineralized.