Treatment of osteoarthritis: chondroprotectors

Glucosamine sulfate

As a natural component of articular cartilage, glucosamine sulfate (a sulfated derivative of the natural amino monosaccharide glucosamine) was first used as a means of stimulating reparative processes in patients with osteoarthritis more than 20 years ago. Glucosamine sulfate has good bioavailability when taken orally and a pharmacokinetic profile favorable for osteoarthritis, including affinity for articular cartilage. Under in vivo conditions, glucosamine is synthesized by chondrocytes from glucose in the presence of glutamine. Glucosamine is then used by chondrocytes to synthesize glycosaminoglycans and proteoglycans.

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

Pharmacodynamic effects of glucosamine sulfate

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

In a controlled study, W Noack et al. (1994) noted that the effectiveness of four-week treatment with glucosamine sulfate at a dose of 1500 mg/day (n=126) significantly exceeded that of placebo (n=126). The effect of treatment became apparent after 2 weeks of therapy, and subsequently, for 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.

H. Muller-Fasbender et al. (1994) in a randomized double-blind placebo-controlled study found 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 at a dose of 1200 mg/day (n=99) in patients with knee OA. Glucosamine sulfate was inferior to ibuprofen in the speed of onset of effect (2 weeks after the start of therapy), but was significantly superior in safety (6% of side effects in the glucosamine sulfate group and 35% in the ibuprofen group; p<0.001). Premature discontinuation of treatment was recorded in 1% of patients taking glucosamine sulfate and in 7% of patients treated with ibuprofen (p=0.035).

Six-week treatment of patients with osteoarthritis of the knee joints by intramuscular administration of the drug (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 aim of the study by GX Qui et al. (1998) was to compare the effects of glucosamine sulfate and ibuprofen on the symptoms of knee OA. For 4 weeks, 88 patients received glucosamine sulfate at a dose of 1500 mg/day and 90 patients received ibuprofen at a dose of 1200 mg/day, followed by a 2-week observation period after the end of the course of treatment. The authors found that the efficacy of glucosamine sulfate was equivalent to that of ibuprofen, and the effect was maintained for 2 weeks after the end of treatment with glucosamine sulfate.

JY Reginster et al. (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 placebo group, progression of joint space narrowing was observed at an average rate of 0.1 mm per year, whereas in patients treated with glucosamine sulfate, progression of joint space narrowing was not noted. Thus, by the end of 3 years of therapy, the average and minimum joint space height in patients receiving glucosamine sulfate was significantly greater than in the placebo group (p=0.043 and p=0.003, respectively).

On average, in short-term controlled clinical trials, side effects during treatment with glucosamine sulfate were observed in 15% of cases; side effects were recorded in placebo groups with approximately the same frequency. Side effects of glucosamine sulfate therapy were usually transient, mild, and manifested themselves as a feeling of discomfort and pain in the stomach, constipation, diarrhea, flatulence, nausea, hypersensitivity reactions (itchy skin rash, erythema) were rare, and very rare - headache, visual disturbances, hair loss.

Chondroitin sulfate

Chondroitin sulfate is a glycosaminoglycan localized in the extracellular matrix of articular cartilage. Pharmacokinetic studies have shown that when taken orally, it is well absorbed and is found 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) in a randomized placebo-controlled double-blind study studied the efficacy and tolerability of chondroitin sulfate in 120 patients with osteoarthritis of the knee and hip joints. Patients took chondroitin sulfate or placebo for 3 months, 4 capsules per day, followed by a 2-month observation phase, during which remote results were assessed. The primary criterion of efficacy was the need for NSAIDs, expressed in diclofenac equivalent (mg). Upon completion of the 3-month treatment, patients taking chondroitin sulfate needed significantly fewer NSAIDs than patients receiving placebo, and during the observation period the average daily dose of NSAIDs continued to decrease. Analysis of secondary efficacy criteria (VAS, Lequesne index, overall assessment of efficacy by physician and patients) also demonstrated a statistically significant advantage of the studied drug over placebo. Tolerability of chondroitin sulfate was comparable to that of placebo - side effects were recorded in 7 patients of the control group (gastralgia, constipation, diarrhea, eyelid edema) and in 10 patients of the control group (gastralgia, nausea, diarrhea, drowsiness, dryness of the oral mucosa).

Another multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and tolerability of two chondroitin sulfate dosing regimens (1200 mg/day once or in 3 doses) in patients with knee osteoarthritis (Kellgren and Lawrence stages I-III). Patients receiving chondroitin sulfate showed a significant decrease in the Lequesne index and VAS (p<0.01), while in the placebo group there was only a significant positive change in VAS (p<0.05) and an insignificant tendency to decrease the Lequesne index (p>0.05). Tolerability of chondroitin sulfate was satisfactory and comparable to tolerability of placebo (side effects were observed in 16 of 83 patients treated with chondroitin sulfate and in 12 of 44 patients receiving placebo).

In the publication by L. Bucsi and G. Poor (1998) the results of a 6-month randomized double-blind placebo-controlled study of the efficacy and tolerability of chondroitin sulfate at a dose of 800 mg/day in 80 patients with osteoarthritis of the knee joints (stages I-III according to Kellgren and Lawrence) were summarized, conducted in two centers. According to the VAS data, a slow decrease in pain severity was observed in the chondroitin sulfate group throughout the study (by 23% after 1 month, by 36% after 3 months, by 43% by the end of treatment), whereas an insignificant decrease in the indicator was noted against the background of placebo (by 12% after 1 month, by 7% after 3 months and by 3% by the end of the study). Similar dynamics were observed for the Lequesne index. The tolerability of chondroitin sulfate and placebo was the same.

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

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

Structum restores the mechanical integrity and elasticity of the cartilaginous matrix and acts as a kind of lubricant for the articular surfaces. Clinically, this is manifested in a significant improvement in joint mobility, an effective reduction in the severity of 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 to achieve a stable therapeutic effect should be 6 months, the duration of the aftereffect is from 3 to 5 months.

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Hyaluronic acid and sodium hyaluronate preparations

Hyaluronic acid and sodium hyaluronate preparations are slow-acting antiarthrosis agents that contain hyaluronic acid or its sodium salt - a polysaccharide, a natural component of articular cartilage. Hyaluronic acid is a natural factor that participates in the trophism of articular cartilage.

Hyaluronic acid and its sodium salt have been the subject of many studies in patients with osteoarthritis, where NSAIDs or GCS for intra-articular administration served as the reference drug.

When comparing intra-articular injections of hyaluronic acid and methylprednisolone in patients with osteoarthritis, equally high efficiency in controlling the symptoms of osteoarthritis was revealed. A longer remission of OA symptoms was noted after treatment with hyaluronic acid than after the use of GCS. G. Leardini et al. (1987) recommended hyaluronic acid as an alternative to GCS for intra-articular injections.

At present, there is an ambiguous attitude towards hyaluronic acid preparations. There is data indicating that the effect of its intra-articular injections is made up of the sum of the effects of placebo and arthrocentesis, which is always carried out before the injection. Moreover, JR Kirwan, E. Rankin (1997) and GN Smith et al. (1998) discovered the damaging effect of hyaluronic acid on the condition of articular cartilage in animals.

According to KD Brandt (2002), the contradictory results of clinical studies of hyaluronic acid to some extent depend on the imprecise introduction of the drug into the joint cavity. Thus, according to A. Johns et al. (1997), only in 66% of cases was depot methylprednisolone introduced accurately into the knee joint cavity, while the effectiveness of the treatment correlated with the accuracy of getting into the joint cavity. The accuracy of the introduction of the drug into the joint cavity increases with preliminary aspiration of the fluid. In addition, the contradictory results of clinical studies of the use of hyaluronic acid preparations may be due to the fact that polysaccharides of different molecular weights and different origins are used for their manufacture.

The use of intra-articular injections of hyaluronic acid is recommended for patients in whom other types of treatment are ineffective or cause side effects that require discontinuation of treatment.

Diacerein

Diacerein is an anthraquinone derivative capable of inhibiting the production of IL-1, IL-6, TNF-a and LIF in vitro, reducing the number of plasminogen activator receptors on synovocytes 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 collagenase and stromelysin and inhibits the release of lysosomal enzymes such as beta-glucuronidase, elastase and myeloperoxidase. At the same time, the drug stimulates the synthesis of proteoglycans, glycosaminoglycans and 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 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, diacerein therapy can be combined with NSAIDs or so-called simple analgesics. The following side effects are observed against the background of diacerein treatment:

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

As established in a prospective randomized double-blind placebo-controlled study in patients with osteoarthritis of the hip joints, diacerein at a dose of 100 mg/day was not inferior in effectiveness to 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 onset of the analgesic effect of diacerein was noted by the end of the 1st week of treatment, while the effectiveness of tenoxicam was registered already in the first days of therapy. In patients treated with diacerein, mild diarrhea was noted in 37% of cases.

According to R. Marcolongo et al. (1988), diacerein had a symptomatic effect equivalent to that of naproxen, the effect obtained persisted for 2 months after the end of diacerein therapy, while in the group of patients taking naproxen, such a phenomenon was not observed.

M. Lesquesne et al. (1998) found that the need for NSAIDs in patients with osteoarthritis of the knee and hip joints during treatment with diacerein was statistically significantly less than during treatment with placebo.

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

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Avocado and Soybean Unsaponifiables

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

Other treatments for osteoarthritis

BV Christensen et al. (1992) in a controlled study found a significant reduction in pain and a decrease in the daily dose of analgesics against the background of acupuncture in patients with osteoarthritis preparing for arthroplasty (7 of 42 patients refused the operation). In a number of countries, homeopathic and naturopathic remedies are used in the treatment of osteoarthritis. In recent years, so-called complex biological preparations have appeared on the Ukrainian pharmaceutical market, containing extracts of hyaline cartilage, intervertebral discs, umbilical cord, embryos, pig placenta, plant extracts, vitamins, microelements, the production of some of which is based on the principles of homeopathy (homviorevman, revmagel, traumeel C, discus compositum, cel T.

Alflutop

Alflutop is a sterile extract of marine organisms and consists of amino acids, peptides, glucides and microelements - 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.

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