Feza Korkusuz (ed.)Musculoskeletal Research and Basic Science10.1007/978-3-319-20777-3_39

39. Chondroprotective Agents

Vasfi Karatosun¹

(1)

Department of Orthopedics and Traumatology, Medical Faculty, Dokuz Eylül University, İzmir, Turkey

Vasfi Karatosun

Abstract

Osteoarthritis is a progressive disorder of the joints, caused by gradual loss of cartilage, and the resulting joint pain and functional limitations. Treatment for osteoarthritis aims to relieve pain and reduce other symptoms. However, there are agents (chondroprotective) suggested to prevent the loss of cartilage. The aim of this chapter is to examine the chondroprotective efficacy of nutritional agents, diacerein, and viscosupplementation, which may change the course of the disease.

Osteoarthritis is a progressive process characterized with pain, deformities, swelling, dysmotility, and loss of functionality in the joints. Loss of the joint cartilage and degeneration are inevitable at the end of the process. The impact of various factors such as age, inherited conditions, obesity, gender, hormonal issues, hypermobility, trauma, joint anomalies, occupation, and sportive activities has been proven to accelerate the onset of osteoarthritis in conjunction with the process. However, the reason underlying such onset is yet unclear.

The pathological process of osteoarthritis does not take place only in the joint cartilage. In addition to the loss of cartilage, other pathological changes also occur. These include baring of the bone surface, deformation of the bone, osteophyte, subchondral cyst formation, synovitis, thickening of the joint capsule, degeneration of the meniscus, and periarticular muscular atrophy. Radiology assists observation of pathologic changes greatly. Numerous classifications have been proposed to grade osteoarthritis radiologically. The Kellgren–Lawrence classification [1] is the most commonly referenced one. According to this classification, 0––No findings; 1––Minimal osteophyte and suspicious clinical findings; 2––Greater osteophyte and intraarticular narrowing; 3––Moderate level of intraarticular narrowing; and 4––Extreme narrowing of the articular surface, sclerosis, and subchondral cyst [1]. Though the pathologic stages can be laid out radiologically, there is no correlation between such staging and scores that determine the articular function [2–5]. This situation may be problematic when it comes to establishing a treatment plan. Treatment of osteoarthritis revolves around the pain, as cartilage degeneration may not always lead to pain; subchondral pain might occur later; and synovial and capsular tissues are the primary sources of pain [6].

The agents that are used to treat osteoarthritis and claimed to possibly reduce cartilage volume and quality are called chondroprotectives. Agents that modify the connective tissue structure (Connective Tissue Structure-Modifying Agents/CTSMAs) directly influence IL-1 synthesis and activate collagenase, proteoglycanase, and matrix metalloproteinases. They also stimulate nitric oxide synthesis and release, as well as expression of prostaglandins E₂, IL-6, and IL-8. Drugs that modify the progression of osteoarthritis are called disease-modifying OA drugs (DMOADs) [7]. The objective of this chapter is to evaluate the chondroprotective activity of DMODs and viscosupplementation.

Nutritional Agents

Nutritional agents are products that are not presented in the form of drugs, but rather as alternative nutritional supplements. Glucosamine and chondroitin sulfate are the most prominent products of this category. The CTSMA (connective tissue structure-modifying agent) and DMOAD (disease-modifying osteoarthritis drugs) impacts of these agents should be discussed. Glucosamine sulfate could not be obtained through in vitro or in vivo processes. So, glucosamine and sulfate were prepared in two different crystallized forms. Being a building block for the cartilage, glucosamine is synthesized by chondrocytes. Experimentation on rats revealed that glucosamine activates NFκB transcription factor, while reducing IL-1 β [8]. Glucosamine was also found to reduce phospholipase A2 activity [9], COX-2 mRNA and protein levels [10–12], and PGE₂ release [11–14] in the articular cartilage. However, it could not be proven in in vivo studies that externally administered glucosamine provides the same effect [15]. Though there are some studies related to chondroitin that claim that cartilage volume is increased through similar mechanisms, there is also serious uncertainty as to its effectiveness in in vivo studies [16].

During experimental studies, the onset of osteoarthritis could not be prevented in rabbits which were given glucosamine and had their anterior cruciate ligaments severed thereafter [17]. In another experiment with rabbits, a chondroprotective effect could not be observed [18].

It is interesting to see that both glucosamine and chondroitin are utilized in nonmedical products in different dosages and obtained through nonstandardized means. Additionally, it is also interesting that studies that yielded positive results were all sponsored by the relevant product brands. Scientific data regarding dosages, half-life, active ingredients, effectiveness, and reliability of those products is insufficient. Furthermore, almost all points as to the side effects and toxic dosages are unknown [19].

It was observed as a result of the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) study that was performed in 16 centers around the United States to prove the effectiveness of glucosamine and chondroitin sulfate on osteoarthritis that the use of those agents was no superior than the placebo drugs [20]. Also, as the result of an evaluation made at Western Ontario and McMaster Universities, within the scope of the Osteoarthritis Index (WOMAC), no clinically significant difference was observed [21]. Radiologically, the use of glucosamine and chondroitin sulfate was not found to have any positive or significant impact on osteoarthritis. According to the American College of Rheumatology (ACR) Guidelines for Hand, Hip, and Knee (2012), the use of glucosamine and chondroitin is not recommended in the case of knee and hip osteoarthritis [22].

Diacetylrhein/Diacerein

DMOAD is a product with proven effectiveness. It offers anti-inflammatory, analgesic, and chondroprotective effect; yet, its analgesic effectiveness is far lower than NSAIDs [15]. While its pharmacodynamic interference is disputed, it inhibits IL-1β and NO synthesis and stimulates PGE2 synthesis [23, 24]. Whereas the number of studies is not adequate, there are publications that provide results indicating recovery in osteoarthritis symptoms and radiological parameters [25, 26]. Its side effects on the gastrointestinal system [25] and genotoxic effects [27] prevent widespread use of the drug. Diacerein is not listed in the treatment guidelines.

Viscosupplementation

Discovery of the Hyaluronan molecule dates back to 1934. It is present within all living beings that share the same chemical structure [28]. The initial clinical trials were run in the early 1970s, and the first-gen hyaluronic acid (HA) was created in the form of a complete product in the 1980s. Initially, it was utilized to halt the process of degeneration in the articular cartilage of race horses.

In its ordinary course, HA manifests its protective effect on the synovia by repressing and barring nociceptors. In the cartilage, it functions in the form of a barrier and proteoglycan aggregate in the bone tissue. During the course of osteoarthritis, viscosity of the synovial fluid and lubrication decrease, leading to reduced shock absorption. The cartilage and synovium are separated from the articular surface covered with HA, causing mechanical and inflammatory damage. This, in turn, starts an inflammatory process in the synovium, and damage occurs on the articular cartilage. The lack of HA in the synovial liquid causes proinflammatory and IL-1 damage on pain mediators. HA ensures viscosity of the synovial liquid, shock absorption, and filtration [28]. When orally administered, the HA acid is completely metabolized. Therefore, it should be exogenously administered. Upon being administered exogenously, the mechanical and barrier functions of HA establish the primary effect, and the pharmacologic activity provides the secondary effect.

Currently, HA treatment is practiced in various areas of medicine in addition to articular atrophies. However, disputes on the number and location of injections (active substances and molecular weight), storage (active substance formulation), indications, effectiveness, reliability, and cost–benefit relation are still going on.

A study by Jackson et al. [29], on the location of injection, makes comparisons among suprapatellar, anterolateral, anteromedial, and central injections, and concludes that the lateral midpatellar area is the most convenient area for injection with 93 % articular reach.

In addition to being used for articular motile difficulty and pain, HA was administered for rheumatoid arthritis, hemophilic arthropathy, and crystal arthropathy. While it is most commonly applied on the knee joint, HA is also applied on the temporomandibular and primary metatarsophalangeal joints, and on the joints of the hip, shoulder, ankle, and elbow [28, 30]. As for the treatment cycle, recommended application frequency is at least three injections in a fortnight. While not superior to placebo drugs, some synthetic products of nonanimal origin are suitable for single injections [31]. The treatment may be reiterated with at least a period of 4 weeks allowed in between each treatment course and no more than two treatment cycles within every 6 months. Administering different products during the same cycle or during consecutive cycles should be a topic of discussion. It is not convenient to apply anesthetic agents on the knee joint or other drugs during treatment, as such products might dilute HA and pose the risk of disrupting its reliability.

HA may be administered throughout all radiological stages [32, 33]. The flexibility of application stems from the facts that there is no correlation between knee degeneration and pain and that the effect of HA on knees with varying degrees of degeneration is not yet known.

Though the exact term of relief is not known, the use of HA was found to offer relief, improved mobility, and better living quality for up to a year as well as good cost–benefit performance [34]. Karatosun et al. [35] were able to find a more prolonged period of activity in their study on comparison of administering HA and physiotherapy for knee osteoarthritis. Published studies concluding that administration of HA reduces intraarticular narrowing are present [36]. On the other hand, there are other published studies indicating that it does not have any impact on the process [37, 38].

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