A REVIEW OF
MEDICAL MANAGEMENT AND THE POTENTIAL APPLICATION OF ORAL SUPPLEMENTS
Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
For the purpose of this review the terms Degenerative Joint Disease and Osteoarthritis are considered synonymous. It is the most common joint disorder of dogs and cats (Bennett and May 1995; Hulse 1998). Johnston (1997) indicates that it may affect as many as 20% of dogs over one year of age and Bennett (1980) reports that it accounts for approximately 37% of all lameness in dogs. The condition may be primary (idiopathic) or secondary to other articular insults. The hallmarks of osteoarthritis are destruction of articular cartilage, synovitis, capsular and periarticular fibrosis and remodelling of subchondral bone. The first recognised sign of articular cartilage degeneration is an imbalance in the normal production and degeneration of articular cartilage macromolecules. Current theories suggest that this is the central and defining feature of the condition and that remaining lesions are secondary to this disruption.
Treatment is aimed at reducing pain, increasing joint mobility and reducing cartilage destruction. These usually require a combination of weight control, exercise management and medication. When degenerative joint disease is secondary to other recognisable lesions, specific treatment of these, such as fragment removal or correction of articular incongruity is also appropriate. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAID) have to date been the cornerstones of degenerative joint disease management. Treatments are usually long term or life long despite the well known adverse side effects of these drugs. More recently these have been joined by the so-called chondroprotective agents such as hyaluronan, polysulphated glycosaminoglycan, chondroitin sulphate and glucosamine. These biological compounds represent safer therapeutic options and may be disease modifying (Ghosh et al 1991; Lequesne et al 1994). It should be the clinician’s aim always to slow the process of cartilage degradation and to promote cartilage matrix synthesis.
NSAID are used widely in the pharmacological management of joint pain and osteoarthritis. Although they are effective in relieving pain and improving mobility, they have significant systemic toxicity. They are indiscriminate inhibitors of cyclo-oxygenase (prostaglandin synthetase) which accounts both for their therapeutic and toxic effects. In man an approximate 35% incidence of adverse effects has been recorded with ibuprofen (Műller–Fassbender et al 1994). In small animal practice, side effects of NSAID are infrequent but potentially devastating. They include nephrotoxicity, reduced platelet aggregation, and gastrointestinal ulceration (Jones et al 1992; Lipowitz 1993; Plumb 1995; McDonald and Langston 1995).
There is also wide spread concern that NSAID may be toxic to articular cartilage (Palmoski and Brandt 1980; Brandt 1987) and therefore accelerate the course of osteoarthritis (Herman et al 1986; Rashad et al 1989; Clark 1991). NSAIDs accelerate cartilage degeneration by suppression of chondrocyte proteoglycan synthesis (Palmoski and Brandt 1979 and 1980; Brandt and Slowman-Kovacs 1986; Slowman-Kovacs et al 1989). This appears to occur in a dose dependant fashion and there is greater inhibition of proteoglycan synthesis in osteoarthritic cartilage than normal cartilage. (Palmoski and Brandt 1983). McKenzie et al (1976) also report that NSAID tend to impair cartilage metabolism further in osteoarthritis including reduced glycosaminoglycan synthesis. NSAIDs increase proteoglycan loss from articular cartilage in experimental animals (Pettipher et al 1986) and have been shown to accelerate degeneration in human hip osteoarthritis proportional to their potency as inhibitors of prostaglandin synthesis (Rashad et al 1989). Many NSAIDs contribute to generation of catabolic cytokines, cause chondrocytes to degrade matrix or prevent expression of anabolic cytokines which results in progression of osteoarthritis (Hulse 1998).
There is no good evidence that NSAIDs are clinically superior to analgesics in the management of joint disease (Bennett and May 1995) and it is generally accepted that their efficacy derives exclusively from their analgesic effect (Ghosh 1990; Booth 1995). The use of NSAIDs therefore requires careful risk benefit analysis including assessment of the stage of articular compromise and the patient’s organic (particularly hepatic, renal and gastrointestinal) situation.
Corticosteroids may be given systemically or by intra-articular injection. They inhibit both cyclo-oxygenase and lipoxygenase inflammatory pathways and are effective in treating acute inflammation. However, chronic parenteral and intra-articular administration cause cartilage matrix degeneration by inhibiting proteoglycan and cartilage biosynthesis by chondrocytes and thus enhance the rate of joint degeneration (Moskowitz et al 1970). Systemic complications of corticosteroid administration include iatrogenic hypoadrenocorticism, pancreatitis and steroidally induced hepatopathy (Mcdonald and Langston 1995; Moskowitz et al 1970). It is therefore generally recommended that corticosteroids should be reserved for end stage osteoarthritis or management of joints which are no longer responsive to NSAIDs (Clark 1991; Lipowitz 1993; Bennett and May 1995).
A number of studies in various species have shown exogenous polysulphated glycosaminoglycans (PSGAG) to be chondroprotective and to produce clinical improvement after intra-articular or intramuscular administration (Trotter 1996). In addition, in vitro studies have demonstrated PSGAG to inhibit degradative enzymes, to have anti-inflammatory properties and to stimulate production of endogenous glycosaminoglycans. Commercial PSGAG is extracted from bovine lung and trachea; and the principal glycosaminoglycan is chondroitin sulphate (Trotter 1996).
The practical and financial limitations of intra-articular and intramuscular PSGAG make use of orally active anti-arthritic agents highly desirable and a number of products have been marketed as such. Unsubstantiated and scientifically spurious claims appear in marketing literature however, only two of the substances that are currently available as oral supplements for the treatment or prevention of joint disease have any scientific justification. These are chondroitin sulphate and glucosamine. Both have been suggested as slow-acting, disease-modifying agents (SADMA), slow acting drugs in osteoarthritis (SADOA) or as chondroprotective (Ghosh et al 1990; Avouac 1993; Lequesne 1993; Lequesne et al 1994; Serni 1993).
Chondroitin sulphate with less sulphation than PSGAG is marketed as a dietary supplement, usually in combination with glucosamine and sometimes with other substances also. In vitro studies have reported a number of potentially beneficial properties of chondroitin sulphate. These include inhibition of degradative enzymes (Paroli et al 1991; Lualdi 1993; Conte et al 1995) and anti-inflammatory activity (Ronca et al 1998) probably by virtue of complement inhibition (Paroli et al 1991). An increased synovial fluid content and molecular weight of hyaluronan has also been reported (Conte et al 1995; Ronca et al 1998).
In clinical trials of intramuscular chondroitin sulphate in man, the course of osteoarthritis was slowed, joint function improved and joint pain/ analgesic usage reduced (Burkhardt and Ghosh 1987). Thereafter a number of reports have described positive responses to oral chondroitin sulphate in the management of human knee osteoarthritis (Morveale et al 1996; Bourgeois et al 1998; Bucsi and Poór 1998; Uebelhart et al 1998a). Positive effects of oral chondroitin sulphate in a rabbit experimental model of osteoarthritis have also been reported (Uebelhart et al 1998b).
At first sight the literature provides apparently conflicting evidence on the bioavailability of orally administered chondroitin sulphate. Basic physiology indicates that a highly negatively charged substance with a molecular weight of > 10,000 daltons cannot cross gastro-intestinal mucosa. Absorption of radiolabelled (tritiated or 35S04) chondroitin sulphate has been reported in man, dogs and rats (Palmieri et al 1990; Conte et al 1991; Ronca and Conte 1993; Ronca et al 1998). However, only 10% (Palmieri et al 1990; Conte et al 1991; Ronca and Conte 1993), 12% (Ronca et al 1998 in man) and 15% (Ronca et al 1998 in rats) were absorbed as high molecular weight fractions and it was concluded that most chondroitin sulphate is absorbed after intestinal degradation and desulphation (Ronca and Conte 1993). No absorption of chondroitin sulphate has been detected using a dimethylmethylene blue assay which detects the presence of sulphated glycosaminoglycans down to the size of hexasaccharides, ie, 3 x disaccharide units. Low molecular weight degradation products such as individual disaccharides or monosaccharide units such as glucosamine are not detected by this technique. Absence of absorption has been reported in man (Baici et al 1992), rabbits (Konador and Kawiak 1977; Andermann and Dietz 1982; Yamanashi et al 1991) and horses (Humphrey 1999; Latino 1999). This divergence of opinions may be explained by enteral degradation of chondroitin sulphate with subsequent incorporation and absorption of radioactive labels with other molecules. Large intestine bacteria, eg, bacteroides spp. use chondroitin sulphate as an energy source and bacterial sulphatase activity is responsible for the appearance of radioactive inorganic sulphate present in the body after oral administration of 35S04 labelled chondroitin sulphate (Salyers 1979; Salyers and O’Brien 1980). This phenomenon has been demonstrated in rats when absorption of 35S04 chondroitin sulphate ceased and all radioactivity was recovered from faeces after administration of antimicrobial drugs (Dohlman 1956).
It therefore appears that chondroitin sulphate is not absorbed following oral administration but that low molecular weight desulphated degradation products of the dissaccharide polymer probably are absorbed. Unfortunately, the existence of a polymer chain and the presence of sulphate groups are necessary for the biological activity of chondroitin sulphate (Németh-Csóka et al 1977; Paroli et al 1991). It should also be noted that glycosaminoglycans of cartilage matrix are synthesised in the endoplasmic reticulum and Golgi apparatus of chondrocytes and there is no known mechanism for their absorption into cartilage matrix. Positive clinical responses to oral supplementation with chondroitin sulphate may be explained either by biological activity of its low molecular weight degradation products such as individual glycosamine units or from the activity of other substances such as glucosamine.
Glucosamine has been marketed as a constituent of a number of supplements for several years and has more recently been made available in a pure form. No research exists to quantify its levels in food and there is little published on its clinical effects in animals. Glucosamine is an amino-monosaccharide and a precursor of the disaccharide units of articular cartilage glycosaminoglycans. Chondrocytes normally manufacture glucosamine from glucose but when glucosamine is available it is preferentially taken up by cartilage where it is the preferred substrate for (Rodén 1956) and stimulates the synthesis of glycosaminoglycans (Vidal-y-Plana et al 1978).
Glucosamine is a small molecule (mol. wt = 179) and is soluble in water. At 37° C it has a pKa of 6.91 which is very favourable for absorption from the small intestine and for crossing biological barriers in the body. It is not protein bound in plasma and therefore interactions with other drugs are unlikely (Setnikar et al 1986). Glucosamine is also devoid of antigenic properties. Following oral administration of glucosamine hydrochloride or glucosamine sulphate there is gastric dissociation of the salts liberating non-ionised glucosamine (Setnikar et al 1986). The hydrochloride salt yields a greater amount of active glucosamine than the sulphate. The ability of glucosamine to exist in a non-ionised form contributes directly to its bioavailability.
Almost complete bioavailability of uniformly [14C] labelled glucosamine has been demonstrated following oral administration to dogs (Setnikar et al 1986). Only 5% faecal loss was recorded confirming excellent enteral absorption. Similar results have been reported with this technique in rats and in man (Setnikar et al 1984; Setnikar et al 1993) and confirmed by use of a specific ion-exchange chromatographic technique (Setnikar et al 1986). Enteral absorption without any metabolic breakdown of the molecule has been quantified in man at 90% (Setnikar et al 1993). Absorption of intact glucosamine has also been reported from isolated rat small intestine (Tesoriere et al 1972). All authors have also demonstrated tropism for articular cartilage which has been quantified as 30% (Setnikar et al 1984).
The availability of glucosamine is a rate limiting step in glycosaminoglycan synthesis (Karsel and Domenjoz 1971; Kim and Conrad 1974; Vidal y Plana et al 1978). Exogenous glucosamine stimulated synthesis of cartilage glycosaminoglycans and proteoglycans in vitro (Rodén 1956; Karzel and Domenjoz 1971; Vidal y Plana and Karzel 1980; Clark et al 1991; Setnikar et al 1991a and 1991b) in a dose responsive manner (Karzel and Domenjoz 1971; Kim and Conrad 1974; Vidal-y-Plana et al 1978; Bassleer et al 1992 and 1993). Proteoglycan biosynthesis is enhanced by two mechanisms: the availability of substrate for the macromolecules and a stimulating effect on the incorporation of other essential substrates (Rodén 1956). Incorporation of exogenous glucosamine into newly synthesised glycosaminoglycans has been confirmed (Bassleer et al 1992). Specific stimulation of hyaluronan synthesis has also been demonstrated (Rodén 1956; Karzel and Domenjoz 1971; Setnikar et al 1991b). In contrast, one study has reported catabolic effects of glucosamine on canine chondrocyte cultures (Anderson et al 1999).
Further in vitro studies have shown that glucosamine inhibits superoxide radical generation and lysosomal enzyme production (Setnikar et al 1991a). Glucosamine also inhibits nitric oxide production, proteoglycan loss, gelatinase and collagenase activity in equine cartilage explants exposed to lipopolysaccharide and recombinant interleukin 1b (Fenton et al 1999a and 1999b). The anti-inflammatory activity of glucosamine is achieved through a cyclo-oxygenase (prostaglandin) independent mechanism (Karzel and Domenjos 1971; Setnikar et al 1991b; Müller-Fassbender et al 1994) which not only contributes to cartilage preservation but also provides protection against the metabolic impairment induced by nonsteroidal anti-inflammatory drugs (Vidal y Plana et al 1978; Burkhardt and Ghosh 1987; Setnikar et al 1991a and 1991b; Basleer et al 1992). It is therefore logical that glucosamine might be beneficial in the treatment and/or prevention of osteoarthritis (Fenton et al 1999a and 1999b).
In vivo studies have shown selective incorporation of uniformly [14C] labelled glucosamine into articular cartilage (Setnikar et al 1984 and 1986) and specifically into newly synthesised proteoglycans (Murnane and Belt 1972) in experimental animals. Animal models have confirmed its anti-inflammatory activity, produced without inhibiting the synthesis of prostaglandins (Setnikar et al 1991a and b) and have shown that glucosamine improves the morphological damage to cartilage produced in experimental models of osteoarthritis (Eichler and Nöh 1970). Similarly, electron microscopic examination of cartilage samples taken before and after treatment of human osteoarthritis with glucosamine or a placebo demonstrated reversal of cartilage degradation in people receiving glucosamine and not in those receiving the placebo (Drovanti et al 1980). Glucosamine also counteracted metabolic and morphological damage to chondroytes produced by intra-articular dexamethasone in rats. Depleted Golgi apparatus, reduced mitochondria, increased lipid deposition and intensified microfilament intercalation were reversed by glucosamine (Raiss 1985).
Ten randomised trials involving oral (6) and intramuscular (4) glucosamine in the treatment of human arthrosis/osteoarthritis have been reported. In each case the oral dose of glucosamine was 1.5 grams per day. In 7 trials glucosamine was compared with a placebo (Drovanti et al 1980; Pujalte et al 1980; Crolle and D’Este 1980; D’Ambrosio et al 1981; Rovati et al 1993; Noack et al 1994; Reichelt et al 1994) and all showed statistical superiority of glucosamine. Two trials compared glucosamine to ibuprofen in the treatment of human knee osteoarthritis. The first reported ibuprofen to produce superior symptomatic improvement after 2 weeks treatment but glucosamine to result in better clinical features after 8 weeks treatment (Vaz 1982). The second reported a similar difference in response at 2 weeks but from 3 weeks onwards there was no significant difference in response between ibuprofen and glucosamine (Müller-Fazzbender et al 1994). However, the adverse side-effects were significantly lower with glucosamine than ibuprofen. Other authors have also noted that the beneficial effects of glucosamine take an average of 2 to 3 weeks before clinical improvement is reported (Noack et al 1994). In a large uncontrolled clinical study of osteoarthritis, response to glucosamine was significantly greater than any previous treatments (Tapadinhas et al 1982). Glucosamine has also proved superior to phenylbutazone in the management of back pain (Mund-Hoyn 1980) and to a placebo in the treatment of spinal osteoarthritis (Giocovelli and Rovati 1993). Positive responses to intra-articular glucosamine in the treatment of gonarthrosis have been reported either as the sole treatment (Vetter 1969) and in comparison to a placebo (Vajardul 1981). Most authors report also a tail off in response following cessation of glucosamine administration. This is in contrast to the response recorded with nonsteroidal anti-inflammatory drugs and suggests that glucosamine genuinely modifies the disease process rather than acting in an analgesic only manner.
Toxicity with oral glucosamine in man is practically absent which makes is suitable for longterm treatment regimes (Setnikar et al 1991a and 1991b). In placebo controlled studies the incidence of reported adverse effects with glucosamine have not differed from administration of the placebo (Crolle and D’Est 1980; Drovanti et al 1980; Pujalte et al 1980; Giocovelli and Rovati 1993; Rovati et al 1993; Noack et al 1994; Reichelt et al 1994). Safety in conjunction with other medicaments has also been documented in man (Tapadinhas et al 1982).
In all species studies, the literature indicates that glucosamine is efficiently absorbed following oral administration. It is safe, has tropism for articular cartilage and is a physiologic substrate for and stimulator of glycosaminoglycan synthesis. Glucosamine has anti-inflammatory properties and currently is the oral supplement of choice for the management of osteoarthritis in man. There is a dearth of studies in animals but it appears also to be the most logical choice for the treatment and prevention of joint disease in the veterinary field also.