Treatment of osteoarthritis: chondroprotectors

Glucosamine sulfate

As a natural component of articular cartilage, glucosamine sulfate (sulfated derivative of natural aminomonosaccharide of glucosamine) was first used as a tool that stimulates reparative processes in patients with osteoarthrosis more than 20 years ago. Glucosamine sulfate has good oral bioavailability and a pharmacokinetic profile favorable for osteoarthritis, including tropism to articular cartilage. In vivo, glucosamine is synthesized by chondrocytes from glucose in the presence of glutamine. Subsequently, glucosamine is used by chondrocytes to synthesize glycosaminoglycans and proteoglycans.

Glucosamine plays an important role in the biochemical processes occurring in articular cartilage, as it forms polysaccharide chains of the main glycosaminoglycans of the synovial fluid and the cartilage matrix.

Pharmacodynamic effects of glucosamine sulfate

Act	Research data
Anabolic	Glucosamine is an essential substrate for the synthesis of glycosaminoglycans and proteoglycans (Vidal in Plana RR et al., 1978) Stimulates the synthesis of proteoglycans by the culture of human chondrocytes (Bassleer C. Et al., 1998) it increases the expression of proteoglycan genes in human chondrocytes (Piperno M. Et al., 2000)
Anticatabolic	Inhibits the action of catabolic enzymes, such as stromelysin. Collagenase, phospholipase A 2, and agglucinase (Jimenez SA et al., 1997; Sandy JD et al., 1998; Dodge GR et al., 1999; Piperno M. Et al., 2000) Promotes the adhesion of chondrocytes to fibronectin (Piperno M. Et al., 1998)
Anti-inflammatory	Oppressing the formation of superoxide radicals (Setnikar I. Et al., 1991) Oppressing the activity of lysosomal enzymes (Setnikar I. Et al., 1991) Inhibits induced synthesis of MO (Shikman AR et al., 1999) Reduces the content of IL-1R in the synovial fluid (Pelletier JP et al., 1999) Do not inhibit the synthesis of prostaglandins (Setnikar I. Et al., 1991)

In a controlled study, W Noack and co-authors (1994) noted that the effectiveness of a four-week treatment with glucosamine sulfate at a dose of 1500 mg / day (n = 126) was significantly higher than that of placebo (n = 126). The effect of treatment became evident after 2 weeks of therapy, then during 2 weeks the symptoms of osteoarthritis continued to weaken. The number of side effects in the main group was not statistically different from that in the placebo group.

N. Muller-Fasbender et al (1994) found in a randomized, double-blind, placebo-controlled study that the efficacy of a four-week therapy with glucosamine sulfate at a dose of 1500 mg / day (n = 100) was equivalent to that of ibuprofen 1200 mg / d (n = 99 ) in patients with OA of knee joints. Glucosamine sulfate was inferior to ibuprofen by the rate of onset of the effect (2 weeks after the start of therapy), but it was significantly superior in safety (6% of side effects in the glucosamine sulfate group and 35% in the ibuprofen group, p <0.001). Premature interruption of treatment was reported in 1% of patients taking glucosamine sulfate, and 7% of patients treated with ibuprofen (p = 0.035).

A six-week treatment of patients with osteoarthritis of the knee by intramuscular injection (n ⁵ = 79, 400 mg 2 times a week) also proved more effective than placebo (n = 76) according to a randomized double-blind study.

The goal of the study by GX Qui and co-authors (1998) was to compare the effects of glucosamine sulfate and ibuprofen on the symptoms of knee OA. Within 4 weeks, 88 patients received glucosamine sulfate at a dose of 1500 mg / day and 90 patients - ibuprofen 1200 mg / day followed by a two-week follow-up period after the end of the course of treatment. The authors found that the effectiveness of glucosamine sulfate is equivalent to that of ibuprofen, the effect was retained for 2 weeks after the end of treatment with glucosamine sulfate.

JY Reginster and co-authors (2001) studied the effect of glucosamine sulfate at a dose of 1500 mg / day (n = 106) on the progression of structural changes in joints and symptoms of osteoarthritis in patients with gonarthrosis compared with placebo (n = 106) after three years of treatment. In the group of patients receiving placebo, progression of the narrowing of the joint gap was observed with an average rate of 0.1 mm per year, whereas in patients treated with glucosamine sulfate, there was no progression of narrowing of the joint space. Thus, by the end of the 3-year therapy, the mean and minimum height of the joint gap in patients receiving glucosamine sulfate was significantly higher than in the placebo group (p = 0.043 and p = 0.003, respectively).

On an average, short-term controlled clinical trials were reported, side effects were observed in 15% of cases with glucosamine sulfate treatment; About the same frequency, side effects were recorded in placebo groups. Side effects of glucosamine sulphate therapy were usually transient, mild and expressed by a feeling of discomfort and pain in the stomach, constipation, diarrhea, flatulence, nausea, occasionally there were reactions of hypersensitivity (an itchy skin rash, erythema), very rarely - headache, hair loss.

Chondroitin sulfate

Chondroitin sulfate is a glycosaminoglycan localized in the extracellular matrix of articular cartilage. Pharmacokinetic studies have shown that when ingested, it is well absorbed and detected in high concentrations in the synovial fluid. In vitro studies have shown that chondroitin sulfate has anti-inflammatory activity, mainly on the cellular component of inflammation, stimulates the synthesis of hyaluronic acid and proteoglycans and inhibits the action of proteolytic enzymes.

V. Mazieres et al. (1996) studied the efficacy and tolerability of chondroitin sulfate in 120 patients with knee and hip osteoarthritis in a randomized, placebo-controlled, double-blind study. Patients received chondroitin sulfate or placebo for 4 capsules per day for 3 months, followed by a two-month observation phase, during which long-term results were evaluated. The primary efficacy criterion was the need for NSAIDs, expressed in diclofenac equivalent (mg). At the end of the three-month treatment, patients taking chondroitin sulfate needed significantly fewer NSAIDs than patients who received placebo, and during the observation period the average daily dose of NSAIDs continued to decrease. Analysis of secondary efficacy criteria (VAS, Leken index, overall assessment of efficacy by the physician and patients) also demonstrated a statistically significant advantage of the study drug over placebo. The tolerability of chondroitin sulfate was comparable to that of placebo - side effects were registered in 7 patients of the control group (gastralgia, constipation, diarrhea, edema of the eyelids) and in 10 patients of the control group (gastralgia, nausea, diarrhea, drowsiness, dryness of the oral mucosa).

In another multicenter, randomized, double-blind, placebo-controlled study, the efficacy and tolerability of two dosing regimens of chondroitin sulfate (1200 mg / day once or in 3 doses) were compared in patients with osteoarthrosis of the knee joints (stages I-III according to Kellgren and Lawrence). In patients receiving chondroitin sulfate, a significant decrease in the Leken index and VAS (p <0.01) was observed, while in the placebo group there was only a significant positive dynamics of VAS (p <0.05) and an unreliable tendency to decrease the Leken index ( p> 0.05). The tolerability of chondroitin sulfate was satisfactory and comparable to that of placebo (side effects were observed in 16 of 83 patients treated with chondroitin sulfate and 12 of 44 patients receiving placebo).

The publication of L. Bucsi and G. Poor (1998) summarizes the results of a six-month, randomized, double-blind, placebo-controlled study of the efficacy and tolerability of chondroitin sulfate 800 mg / day in 80 patients with knee osteoarthritis (Kellgren I-III stage and Lawrence), held in two centers. According to the VAS data, a slow decrease in pain throughout the study (23% at 1 month, 36% at 3 months, 43% at the end of the treatment) was observed in the chondroitin sulfate group, whereas in the placebo group, there was a slight decrease (12% at 1 month, 7% at 3 months, and 3% at the end of the study). A similar dynamics was observed from the side of the Leken index. The tolerability of chondroitin sulfate and placebo was the same.

D. Uebelhart et al. (1998) studied the effect of chondroitin sulfate (800 mg / day for 1 year) on the progression of knee osteoarthritis in 42 patients in a pilot randomized, double-blind, placebo-controlled study. A digital automatic analysis of the radiographs of knee joints performed before and after the treatment showed that the patients with chondroitin sulfate stabilized the height of the joint gap in the medial TFO region of the knee joint, whereas in the placebo group there was a significant narrowing of the joint gap.

In Ukraine, a drug of this group called Structum (Pierre Fabre Medicament, France), containing chondroitin sulfate, obtained from cartilage tissue of birds (two isomers of chondroitin-4, and 6-sulfate) was registered. Numerous studies have shown that Structum suppresses catabolic processes in the cartilage: it inhibits the synthesis of matrix metalloproteases of collagenase and agglucenase, inhibits chondrocyte apoptosis, inhibits the synthesis of antibodies to collagen and activates anabolic processes: increases the synthesis of proteoglycans and collagen in vitro, stimulates the synthesis of hyaluronic acid. All these data indicate a potential "chondro-modifying" effect of chondroitin sulfate.

Structum restores the mechanical integrity and elasticity of the cartilaginous matrix and plays the role of a kind of lubrication of articular surfaces. Clinically, this manifests itself in a significant improvement in joint mobility, an effective reduction in the severity of the pain syndrome, and a reduction in the need for NSAIDs.

The daily dose is 1 g (1 capsule 2 times a day). The recommended initial course for achieving a stable therapeutic effect should be 6 months, the duration of the aftereffect is 3 to 5 months.

[1], [2], [3], [4], [5], [6], [7]

Preparations of hyaluronic acid and sodium hyaluronate

Preparations of hyaluronic acid and sodium hyaluronate are slow acting anti-arthrosis agents, which contain hyaluronic acid or its sodium salt - a polysaccharide, a natural component of articular cartilage. Hyaluronic acid is a natural factor that takes part in the trophic of articular cartilage.

Hyaluronic acid and its sodium salt have been the subject of many studies in patients with osteoarthritis, where NSAIDs or GCS were used as a comparative drug for intra-articular injection.

When comparing intraarticular injections of hyaluronic acid and methylprednisolone in patients with osteoarthritis, an equally high efficacy in controlling the symptoms of osteoarthritis was observed. Longer remission of symptoms of OA after treatment with hyaluronic acid was noted than after application of GCS. G. Leardini and co-authors (1987) recommended hyaluronic acid as an alternative to GCS for intraarticular injections.

By now, there is an ambiguous attitude towards the preparations of hyaluronic acid. There is evidence that the effect of her intra-articular injection is made up of the sum of the placebo and arthrocentesis effects that must be performed before the injection. Moreover, JR Kirwan, E. Rankin (1997) and GN Smith and co-authors (1998) found the damaging effect of hyaluronic acid on the articular cartilage in animals.

According to KD Brandt (2002), the inconsistency of the results of clinical studies of hyaluronic acid depends to some extent on the inaccurate introduction of the drug into the joint cavity. So, according to A. Johns and co-authors (1997), only in 66% of cases depot-methylprednisolone was injected exactly into the cavity of the knee joint, while the effectiveness of the treatment correlated with the accuracy of falling into the joint cavity. The accuracy of the introduction of the drug into the joint cavity increases with the preliminary aspiration of the fluid. In addition, the inconsistency of the results of clinical trials of the use of hyaluronic acid preparations may be due to the fact that polysaccharides of different molecular weight, as well as of different origin, are used for their manufacture.

The appointment of intra-articular hyaluronic acid injections is recommended for patients in whom other treatments are ineffective or cause side effects requiring discontinuation of treatment.

Diacerein

Diacerein is an anthraquinone derivative that can inhibit the production of IL-1, IL-6, TNF-a and LIF in vitro, reduce the number of receptors of the plasminogen activator on synovitis and chondrocytes, thereby inhibiting the conversion of plasminogen to plasmin, and reducing the formation of nitric oxide. Due to these effects, diacerein reduces the production of metalloproteases of collagenase and stromelysin and inhibits the release of lysosomal enzymes, such as beta-glucuronidase, elastase and myeloperoxidase. At the same time, the preparation stimulates the synthesis of proteoglycans, glycosaminoglycans, hyaluronic acid. In experimental modeling of osteoarthrosis in animals in vivo, diacerein effectively reduces inflammation and damage to articular cartilage, without affecting the synthesis of PG.

Diacerein is considered as a symptomatic slow-acting drug for the treatment of osteoarthritis (SYSADOA), since the analgesic effect occurs after 2-4 weeks of treatment, reaches a maximum after 4-6 weeks and persists for several months after the end of therapy. In the first 2-3 weeks of treatment, if necessary, you can combine diacerein therapy with NSAIDs or so-called simple analgesics. On the background of diacerein treatment, the following side effects are observed:

• Relaxation of the stool (in 7% of cases) during the first few days of therapy, in most cases disappears spontaneously,
• diarrhea, pain in the epigastric region (in 3-5% of cases),
• nausea, vomiting (in <1% of cases).

As was established in a prospective, randomized, double-blind, placebo-controlled trial in patients with osteoarthrosis of the hip joints, 100 mg daily diacerein was as effective as tenoxicam (80 mg / day) and significantly superior to placebo. At the same time, the combination of diacerein and tenoxicam was significantly more effective than monotherapy with diacerein or tenoxicam. The beginning of the analgesic effect of diacerein was noted towards the end of the first week of treatment, whereas the effectiveness of tenoxicam was registered already in the first days of therapy. In patients treated with diacerein, a slight diarrhea was noted in 37% of cases.

According to R. Marcolongo and co-authors (1988), diacerein had a symptomatic effect equivalent to that of naproxen, the effect persisted for 2 months after the end of diacerein therapy, while in the group of patients taking naproxen, no such phenomenon was observed.

M. Lesquesne et al (1998) found that the need for patients with knee and hip joint osteoarthrosis in NSAIDs with diacerein was statistically significantly lower than with placebo.

G. Bianchi-Porro et al. (1991) observed lesions of the gastric and / or duodenal mucosa in 50% of patients treated with naproxen (750 mg / day) and 10% of patients receiving diacerein (100 mg / day). The drug is not registered in Ukraine.

[8], [9], [10], [11]

Unsaponified compounds of avocado and soya

Unsaponified avocado and soya compounds are extracted from avocado and soybean fruits in a 1: 2 ratio, respectively. Given to in vitro studies, they are able to inhibit IL-1 and stimulate the synthesis of collagen by human chondrocyte culture, inhibit IL-1-induced stromelysin production, IL-6, IL-8, PGE ₂ and collagenase. The clinical efficacy of unsaponifiable avocado and soy compounds in patients with knee and hip osteoarthritis was demonstrated in two randomized, placebo-controlled studies. After 6 months of treatment, the patients had statistically significant positive dynamics from the VAS, the Leken index and a decrease in the need for NSAIDs. In Ukraine, these drugs are not currently registered.

Other methods of treatment of osteoarthritis

BV Christensen et al. (1992) found a significant reduction in pain and a reduction in the daily dose of analgesics in acupuncture in patients with osteoarthritis who were preparing for arthroplasty (7 of 42 patients refused surgery) in a controlled study. In a number of countries, homeopathic and naturopathic agents are used in the therapy of osteoarthritis. In recent years, the so-called complex biological preparations containing extracts of hyaline cartilages, intervertebral disks, umbilical cord, embryos, placenta of pigs, plant extracts, vitamins, microelements have appeared on the Ukrainian pharmaceutical market, the principles of homeopathy (homovioreman, rheumagel, traume C , discus compositum, goalT.

Alflutop

Alflutop is a sterile extract of marine organisms and consists of amino acids, peptides, glucides and trace elements - sodium, potassium, magnesium, iron, copper and zinc ions. According to experimental data, the drug has a unique ability to simultaneously stimulate the synthesis of hyaluronic acid and block the activity of hyaluronidase.

[12], [13], [14], [15], [16]