© Springer International Publishing Switzerland 2016
Piero Volpi (ed.)Arthroscopy and Sport Injuries10.1007/978-3-319-14815-1_5555. Viscosupplementation in Athletes
(1)
Department of Medicine and Science of Aging, University G. d’Annunzio Chieti-Pescara, Via dei Vestini 31, Chieti Scalo, 66013, Italy
Keywords
AthletesHyaluronic acidOsteoarthritisTendinopathyViscosupplementation55.1 Introduction
Besides acute musculoskeletal injuries due to traumatic events, chronic joint and tendon damage, due to overuse or repeated microtraumas, is common in athletes. The prevailing paradigm suggests that osteoarthritis (OA) results from the failure of the damaged cartilage repair process, due to biomechanical and biochemical changes in the joint, which follow, especially in athletes, repeated and stressful exercise and traumas [1]. Namely, OA is considered a disease of the whole joint involving subchondral bone changes with increased metabolism and sclerosis, chondrocyte death, and extracellular matrix catabolism, as well as primary or secondary changes in the synovium, including endothelial cell proliferation, macrophage infiltration, and inflammation with subsequent alterations in the molecular composition of the synovial fluid [1].
As far as tendons are concerned, it is well known that, in physiologic conditions, exercise has beneficial effects on tendon morphology and function [2]. Indeed, when the mechanical load is repeated and intense (as in athletes) but still in the physiologic window, anabolism prevails on catabolism. New extracellular matrix and collagen fibers are formed, so that, in the long run, tendon cross-sectional area increases, and the biomechanical properties are improved. However, when the individual threshold of loading frequency and magnitude is overcome, the tendon response reverses from beneficial toward degenerative [3]. An aberration in the proteoglycan metabolism is likely to drive the pathogenesis of tendon damage, with increased metalloproteinase expression, which favours the formation of degradation products. In addition, inflammatory molecules, such as interleukin1-beta, are released and may be implicated in the disease progression [4]. The chronic tendon damage is epidemiologically prevalent in comparison with acute damage (rupture), which can occur on tendons with evidence of degeneration or even in normal tendon when submitted to very intense exercise.
Quite all joints and tendons may be involved in athletes, some of them more frequently in relation to the peculiar sport activity: the shoulder in swimming, baseball, volleyball, and basketball, the elbow in tennis and golf, and the hip, knee, and ankle in sports requiring running and jumping. While the number of practitioners increases, the rate of sports injuries distressing the musculoskeletal system is growing and becoming a challenging problem. Indeed, these injuries can be the cause of a premature ending or of a long-standing stop of a professional career with ensuing economic damage or a limiting factor of leisure activities with a substantial impact on the quality of life.
The aim of the therapy is twofold: first, to get a physiologic and if possible complete healing process and, second, to shorten the recovery time, especially in professional athletes.
Several conservative treatments, such as oral and topical nonsteroidal anti-inflammatory drugs, glucosamine, chondroitin sulfate, and intra-articular or peritendinous corticosteroids, have been proposed as noninvasive solutions for pain treatment and improvement in function, with varying success rates. However, evidence suggests that they are not able to alter the natural history of the disease and some of them, while efficacious in the short term, may have deleterious local and systemic consequences [5]. With increasing understanding of cell signaling networks, current research is investigating new conservative methods seeking to provide an instructional environment for stimulating joint and tendon repair.
Among the emerging technologies for enhancing and accelerating tissue healing, a biocompatible and cost-effective approach involves the viscosupplementation with hyaluronic acid (HA). “Engineering” the synovial fluid with HA is a safe and effective procedure in the management of OA, as shown by a huge amount of clinical trials [1, 6], but recently, encouraging results have been also reported in the treatment of tendon disorders [7].
The aim of this chapter is to show the current evidence about the use of HA in the treatment of joint and tendon injuries in athletes.
55.2 Rationale
Synovial fluid is essential for the normal joint functioning: it acts both as a lubricant during slow movement (e.g., in walking) and as an elastic shock absorber during rapid movement (e.g., in running). It also serves as a medium for delivering nutrition and transmitting cellular signals to articular cartilage [1]. HA is the major chemical component of synovial fluid. The native HA has a molecular weight of 4–10 million Daltons and is present in articular fluid in a concentration of about 0.35 g/100 ml [8]. It is essential for the viscoelastic properties of the fluid because of high viscosity and has a protective effect on articular cartilage and soft tissue surfaces of joints [9]. Furthermore, due to its abundant negative charges, HA absorbs a large amount of water at equilibrium, and this vast water domain helps to create the spaces through which the cells move and signaling molecules diffuse to reach their targets.
In pathological conditions, the concentration and molecular weight of HA are reduced, resulting in synovial fluid of lower elasticity and viscosity: the factors which contribute to its low concentrations are dilutional effects, reduced hyaluronan synthesis, and free radical degradation [9]. When viscoelasticity of synovial fluid is reduced, the transmission of mechanical force to cartilage may increase its susceptibility to mechanical damage. Therefore, the restoration of the normal articular homeostasis is the rationale for HA administration into OA joints.
The conceptual basis for the use of HA in the treatment of tendon disorders comes from physiopathologic considerations [4, 7]: first, because HA is an essential component of the tendon itself and, second, because sound experimental data show that an intense HA synthesis occurs during the healing phase after damage.
55.3 Therapeutic Activities of HA
The beneficial effects of HA are due to complex mechanisms [1]. Besides the restoration of the viscoelastic properties of the synovial fluid, basic research has shown that HA has several pleiotropic signaling properties [1, 10].
Actually, HA binds to a number of cell membrane receptors termed hyaladherins. The predominant and more widely expressed is CD44, which is provided of protective effects on tissue remodeling and damage progression [11]. Moreover, HA is provided of anti-inflammatory and antinociceptive activities and contributes to the normalization of endogenous HA synthesis. The analgesic properties of HA are attributed to a specific activity on opiod receptors [12]. In particular, it has stimulatory effects on the k receptors in a concentration-dependent manner, thus increasing the pain threshold by a direct action on synovial nerve endings.
In OA, the efficacy in the short term is mainly due to a substitution effect (viscosupplementation), i.e., to the restoration of the viscoelastic properties of the synovial fluid, such as cushioning, lubrication, and elasticity. On the contrary, the long-term effects are mainly dependent on the restoration of joint rheology (biosupplementation), i.e., the anti-inflammatory and antinociceptive activities, the normalization of endogenous HA synthesis, and chondroprotection [1]. The efficacy on tendon disorders can be ascribed to the improvement of the healing process and to the lubricating effect on the tendon sheaths, which has been clearly shown on hand flexors [7].
55.4 HA Preparations
At present, preparations with different molecular weight are commercially available. The enhanced penetration of low molecular weight (LMW) preparations (0.5–1.5 million Daltons) through the extracellular matrix of the synovium is thought to facilitate the interaction with target synovial cells, thus reducing the synovial inflammation [13]. HA preparations with high molecular weight (HMW) (6–7 million Daltons) [14], by means of their hydrophilic properties, retain higher amounts of fluid in the articular space and are also provided by anti-inflammatory activity, as shown by studies on migration of inflammatory cells in the joint and on reduced prostaglandin E2 and bradykinin concentration [15].
Recently, new preparations have been proposed, aiming to ameliorate the therapeutic efficacy of HA. New types of particulate carriers have been investigated for increasing the retention time of therapeutic agents within the joint cavity, among them, cationic polymeric nanoparticles that form diffuse ionically associated filamentous structures (“ionically cross-linked hydrogels”) with resident hyaluronate in the synovial cavity after intra-articular injection [16]. Moreover, a preparation of celecoxib-loaded liposomes embedded in HA gel has been formulated [17]. The combination of these drugs, both efficient in the treatment of OA but with different mechanisms, injected into the joints, is expected to have synergistic effect, as preliminarily shown in animal models [18]. However, despite these promising results, high-quality clinical studies proving the superiority of new formulations toward the available preparations of HA are still lacking.
55.5 Clinical Trials
Information about the efficacy of HA in the treatment of joint and tendon pathologies in athletes comes in part from studies specifically performed in subjects, both professional and amateurs, practicing sport activities and largely from trials, where young subjects with overuse and/or post-traumatic joint and tendon damage were included.
55.5.1 Knee
Viscosupplementation with HA in knee OA has been approved by the Food and Drugs Administration [19] and is recommended by OARSI for non-severe OA [20]. Guidelines are based on a meta-analysis of randomized saline-controlled trials, including a total of 29 studies representing 4.866 subjects (intra-articular HA, 2,673; saline, 2,193) [21, 22]. These trials were performed, single or double blind, with different types of HA (LMW and HMW). The number of injections ranged from 3 to 5 weekly, the doses from 15 to 60 mg, and the trials’ length from 4 weeks to 18 months. HA injection resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values. The percentages of improvement from baseline were similar in the trials where LMW or HMW HA was used [21, 23]. However, the number of injections needed was in general lower for HMW preparation, and this is an advantage for patients and doctors [21].
The benefit of intra-articular HA injection has been also demonstrated in younger patients with acute knee damage, including symptomatic meniscal tears and isolated ACL injury with chondral injury [1, 24].
In athletic patients with patellar tendinopathy (stage 2 or 3 according to Blazina’s classification), a mixture of 25 mg HA and 1 ml of 1 % lidocaine was injected blindly at the proximal interface between the posterior surface of the patellar tendon and the infrapatellar fat pad or into the region of maximum tenderness [25]. One week after the first injection, other injections were done on the patient’s request; conservative treatments (exercises and instrumental therapies) were also prescribed. After treatment, 54 % of patients were rated in excellent conditions (return to previous athletic activities), while 40 % in good conditions complained some degree of limitation. The open design and the subjective evaluation methods used (no imaging) are important limitations of this study.
55.5.2 Hip
The experience about viscosupplementation of hip OA in athletes is scanty, because the modest epidemiological relevance of the disease in these subjects and in young patients in general. Therefore, the efficacy of the treatment cannot be definitely proved. Some trials have shown a reduction of pain, which, in general, becomes evident within 3 months and persists in the following months. However, it must be underlined that only few studies report longer follow-up periods (at 12 and 18 months) [26].
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