Irrespective of the means of assessment, it is clear that osteoarthritis is a disorder of considerable importance not only to the medical practitioner who is expected to diagnose and treat the patient, but also in terms of its immense socioeconomic consequences. Moreover, with the expected lifespan of most populations increasing, the incidence of osteoarthritis is expected to rise accordingly, placing an additional burden on health resources (Yelin & Callahan, 1995)(Fig.2.)
All connective tissues consist of living cells embedded in a solid substance called an extracellular matrix. This matrix is composed essentially of water, large negatively charged sugar molecules called proteoglycans, fibrous proteins called collagens and some other noncollagenous proteins.(Fig.3)
Inadequate crosslinking and assembly of collagen subunits may therefore render the joint capsule, ligament and tendons more flexible or extensible. Defects in both the primary structure of the collagen molecules (their amino acid sequence) or in their crosslinking have been identified in a number of hereditary collagen diseases, such as Marfans syndrome, X-Linked Cutis Laxa, Homocystinuria and certain types of Ehlers-Danlos syndrome. In the these syndromes, joint laxity and osteoarthritis are frequent clinical observations.
Hyaline cartilage, including articular cartilage, is composed mostly of type II collagen and it has been reported (Knowlton et al., 1990) that members of a family who exhibited early primary osteoarthritis were all found to possess polymorphism in the type II procollagen gene. How this polymorphism was implicated in the early onset of osteoarthritis in the affected family members is presently unknown but the expression of the gene in the form of type II collagen incapable of performing its normal function in the tissues would clearly be implicated.
Prior to such molecular genetic studies, osteoarthritis arising from hypermobile or dysplastic joints was classified as secondary to distinguish it from primary (or idiopathic) osteoarthritis where the cause was unknown. The development of laboratory methods for identifying molecular defects in genes and the proteins they control will undoubtedly lead to the abandonment of this simple means of classification.
While the reasons for getting osteoarthritis are still the subject of intensive research, our understanding of how it develops is more clearly defined.
In diarthrodial joints (joints where two long bones meet), cartilage, together with synovial fluid (the liquid within the joint cavity), provide an almost frictionless bearing surface which, in conjunction with subchondral bone, can absorb and dissipate the wide range of mechanical stresses imposed during normal function. This speciality is made possible by the unique composition and assembly of the components of these tissues. Adult articular cartilage has no nerves (aneural) and no blood vessels (avascular) and covers the long bones at their extremities. Cartilage is composed largely of extracellular matrix, the cells only occupying about 2% by volume (see normal cartilage section Fig. 4A).
The extracellular matrix confers the biomechanical properties of cartilage which allow it to recover after deformation (resilience). This process is made possible by the entrapment of proteoglycans within a collagen network which is anchored in the calcified cartilage above the subchondral bone plate. Proteoglycans (PGs) are very large highly negatively charged sugar and protein molecules which attract and bind water.(Fig.5 & 6)
The strong affinity of proteoglycans for water molecules causes the cartilage to swell up thereby "inflating" the spaces between the restraining collagen network. On compression (loading) of cartilage, water is expelled and the matrix charge density increases because the negatively charged proteoglycans are pushed closer together. However, on removal of the deforming load, the proteoglycan structure opens up (to minimise intermolecular charge interactions) and water molecules and other solutes flow back into the matrix restoring it to its original shape. A sizeable proportion of the applied load is also transmitted through the cartilage to the bone which is elastic and capable of deforming (and recovering) but to a lesser extent than cartilage.
An early, but not exclusive, event in the pathogenesis of osteoarthritis appears to be the loss of proteoglycans from the extracellular matrix of joint cartilage. Since these large molecules provide such a vital role in maintaining the biomechanical properties of cartilage, their depletion from the extracellular matrix leads to a reduction in its ability to recover from deformation in an effective manner. Applied mechanical stresses, even if within the normal range, are then transmitted as high focal stresses through the joint causing damage to chondrocytes, the collagen network and subchondral bone. Remodelling of the subchondral bone occurs, resulting in a "stiffer" (less compliant) substructure to the overlaying cartilage. With time (which may be years in some cases) and the abnormal distribution of loads across the joint cartilage, fibrillation and eventual erosion done to the subchondral bone may occur.
The histological sections shown illustrate normal cartilage on the left and early cartilage failure on the right. The surface of the cartilage (at the top) is smooth in normal cartilage and rough and pitted in osteoarthritic cartilage. The slides have been stained with Alcain Blue, a dye which binds to the proteoglycans. The normal cartilage has deep staining around the cells (chondrocytes) which are fairly evenly dispersed throughout the matrix. In the early osteoarthritic cartilage the staining is much less, indicating loss of the proteoglycans from the matrix. The chondrocytes in the osteoarthritic cartilage are dividing (nesting, cloning) and producing new matrix (note the deeper staining around the cells), ie. they are metabolically hyperactive. This early metabolic response by osteoarthritic cartilage is one of attempted repair by the chondrocytes and dispels previous ideas that cartilage cells were debilitated and were incapable of mounting any kind of healing response.
Even though the chondrocytes and bone cells react to the abnormal loads and attempt to make a mechanically more efficient matrix, their biosynthetic efforts may not be sufficient to outweigh the excessive catabolic activities which are also ensuing. This critical imbalance between anabolic processes on the one hand and catabolic on the other in osteoarthritic cartilage will , if not arrested, eventually lead to joint failure.
The initiation of cartilage breakdown in osteoarthritis is still not totally resolved but can arise from mechanical damage or disturbance to the phospholipid bilayer which constitutes the outer membrane of chondrocytes and indeed of all cells. Experimentally, sublethal mechanical damage to chondrocytes, fibroblasts or osteoblasts (bone cells) can stimulate the release of arachidonic acid from the disturbed cell membranes (Chrisman et al., 1981; Ngan et al., 1990). Arachidonic acid is a metabolic precursor of prostaglandins and leukotrienes which are well known mediators of inflammation. However it has also been shown (Fulkerson et al., 1979) that prostaglandin E2 can stimulate normal chondrocytes to release enzymes known as proteinases, which are capable of degrading the PGs and collagens of the cartilage matrix.
Once this mechanically driven catabolic cascade, (see figure) is initiated, it may be controlled by endogenous inhibitors present within cartilage. The ineffectual production of such inhibitors by chondrocytes, particularly those which block proteolytic activity (the breakdown of proteins), may explain why some individuals with early OA lesions (chondromalacia) progress to clinically active OA while others, whose chondrocytes may be capable of producing adequate amounts of these inhibitory proteins, do not. The level of production by chondrocytes of these endogenous inhibitors in response to trauma would be expected to be influenced by genetic and hormonal factors as well as the ageing of the cell, again illustrating the difficulty of identifying the causes of osteoarthritis.
In principle, the cycle could be broken by altering the level of mechanical stresses acting across the joint, which might diminish chondrocyte and bone cell catabolic activity (eg. by osteotomy) or by using therapeutic agents which block a particular element of the cycle (eg. the synthesis and release of prostaglandins and/or cytokines)(Fig. 8). The effectiveness of both these approaches is discussed in the section entitled ‘How can my osteoarthritis be treated?’.
Apart from the pathological changes described above for cartilage and synovium, it is also evident that the subchondral bone is undergoing extensive modification in the osteoarthritic joint. This is seen pathologically as the resorption (disappearance), sclerosis (hardening), necrosis (death of bone cells) and remodelling (changing shape) of subchondral bone, much of which has been attributed to an impairment of the intraosseous (within bone) blood supply in the osteoarthritic joint (Kiaer et al., 1988). While abnormal mechanical loading can provoke such a response, it would appear that the deposition of blood clots, cholesterol and lipid (fat) complexes in the subchondral blood vessels is also contributory. The situation is considered to be analogous to atherosclerosis and the pain arising from the blockages and loss of the blood supply in the subchondral tissues has been referred to as bone angina (Altman, 1987).
|
|
|||
| Tissue | Osteoarthritis | Normal Ageing | |
| Cartilage | |||
| Thickness | Marked decrease | Gradual decrease | |
| Colour (pigmentation) | No | Yes | |
| Surface roughening | Progressive | Nonprogressive | |
| Cells divide into groups (mitosis/cloning) |
Yes | No | |
| Cell activity | Elevated | Normal or decreased | |
| Water content | Increased | Decreased | |
| Proteoglycan content | Marked decline | Slow decline | |
| Proteoglycan size | Marked decrease | Gradual decrease | |
| Proteoglycan size | Marked decrease | Gradual decrease | |
| Invasion by blood vessels | Yes | No | |
| Bone | |||
| Cell activity | Increased | Normal | |
| Bone thickening | Increased | Normal | |
| Bony spur formation | Yes | No | |
| Joint congruency | Decreased | Increased | |
| Increased blood content (hyperaemai) |
Yes | No | |
| Hardening (sclerosis) | Yes | No | |
| Loss of blood supply (ischaemia) | Yes | No | |
| Pressure inside bone marrow |
Increased | Normal | |
| Synovium | |||
| Infiltration by inflammatory cells |
Yes | No | |
| Shrinking (hypertrophy) | Yes | No | |
| Synthesis of lubricating substance (hyaluronan) |
Increased | Normal |
There is also evidence that osteoarthritis may be passed on from one generation to another. Thus genetic influences would appear to contribute to the development of this disorder, although researchers are only just beginning to understand how this influence may occur at the molecular level.
There is not a single cause of osteoarthritis. It is a disorder which arises due to many different factors (multifactorial aetiology) in which ageing, mechanical, genetic, hormonal and cultural factors may all be involved, leading to a final common pathway of joint failure.
The contributions made by these factors may vary and they may be interrelated. For example, osteoarthritis commonly arises in individuals with hypermobile joints, a finding which has been attributed to the high shearing stresses introduced across the joint by its instability. But the mechanical properties of all tissues are determined by their composition and the manner in which their components are assembled, and both of these are products of our genes and the environment.
The pain described by the patient with osteoarthritis is normally that of a dull ache which persists at rest but which is intensified with physical exercise. Morning stiffness is also common but of shorter duration (5 minutes to 1 hour) than in the rheumatoid patient. The limited range of joint movement invariably observed is due to the pain produced on flexion but also by the fibrosis (increase in fibrous tissue) in the joint capsule, synovial effusion (increased fluid volume) and sometimes by the bony proliferations (osteophytes) at the joint margins.
The origin of pain in osteoarthritis is still poorly understood but it would appear to arise from a number of causes, including mechanical excitation of pain receptors (nociceptors) in the joint capsule, synovium and where the ligaments insert into the bone. As already mentioned, small blockages in subchondral blood vessels would also be contributory to osteoarthritic pain, particularly at rest. All these pain receptors would be stimulated by the mechanical instability of the osteoarthritic joint, as well as the synovitis which gives rise to a host of molecules during the inflammatory process (histamine, serotonin, kinins, prostaglandins, leukotrienes, etc.) which sensitise nerve fibres.
There is at present no specific seriological markers for osteoarthritis. However, as cartilage and bone are actively remodelling in osteoarthritis, research is in progress to identify and quantitate extracellular matrix breakdown products from these tissues in blood and/or joint synovial fluid which could be used to assess the progress of the disease, or the patient's response to treatment. Good correlations, at least in the early stages of osteoarthritis, have been found by monitoring the levels of keratan sulphate in sera (Thonar et al., 1985) and proteoglycan fragments in synovial fluid (Lohmander et al., 1989). A biochemical marker for joint tissue degeneration would be particularly useful for examining the effectiveness of new anti-arthritic drugs to determine if they are only relief-giving (palliative) or whether they actually stop the disease progressing (disease modifying). A recent study (Anderson et al., 1997) of certain blood clotting parameters (monocyte procoagulant activity) in osteoarthrtis patients has indicated that these could provide a useful means of monitoring disease progression and patients response to disease modifying treatments in osteoarthritis. Anti-arthritic drugs are currently evaluated using clinical methods of assessment, which for the most part are subjective and difficult to quantitate.
As already discussed, the radiographic assessment of osteoarthritis may give a false impression of the prevalence of this disorder. Furthermore, as cartilage is translucent to X-rays, a decrease in joint space only becomes apparent when 50% or more of the cartilage is lost. Traditional radiographic methodology thus has limited diagnostic value in the early stages of the disease when focal cartilage changes predominate. However for more established osteoarthritis, a radiological system for grading osteoarthritis and its progression has been developed by the American College of Rheumatology. High sensitivity was reported (Altman et al., 1987) using radiographs and blinded assessment and in Table 2 the criteria considered the most useful for monitoring the progression of the disease over 12-60 months has been summarised for various joints.
|
Table 2. |
|||
| Most important |
Second most important |
Third most important |
|
| Hand | |||
| Spurs | 46 | 52 | 4 |
| Erosions | 33 | 38 | 21 |
| Narrowing | 33 | 33 | 17 |
| Alignment | 0 | 13 | 8 |
| MC widening | 0 | 0 | 4 |
| Hip | |||
| Narrowing | 95 | 5 | 0 |
| Cysts | 15 | 48 | 5 |
| Spurs | 0 | 15 | 15 |
| Sclerosis | 3 | 13 | 13 |
| Buttressing | 0 | 0 | 0 |
| Buttressing | 0 | 0 | 0 |
| Knee (taken from behind the knee while bearing weight) | |||
| Narrowing | 97 | 3 | 0 |
| Spurs | 6 | 59 | 6 |
| Alignment | 3 | 19 | 28 |
| Attrition | 3 | 6 | 3 |
| Sclerosis | 3 | 16 | 6 |
| *Percentage of films in which a radiographic variable was judged most frequently, second most frequently, or third most frequently among the 8 readers. MC widening = distance between the bases of the first and second. (Modified from Altman et al., 1987). | |||
Notwithstanding the enormous potential of MRI, its high capital investment and running cost presently preclude its routine use. Hopefully, future advances in microcircuitry and low temperature physics will progress to a sufficient level within the next few decades to allow the manufacture of cheaper instruments which could be made available for widespread use.
A quantitative microfocal radiographic technique has been reported (Buckland-Wright et al., 1990) which provides a 5 X magnification of the observation area. This higher resolution of joint and subchondral bone changes has allowed a more precise picture of the changes which take place in progressive osteoarthritis to be determined. Osteoarthritis of the hand when followed over 18 months and examined at 6 monthly intervals showed, using the microfocal technique, progressive changes in subchondral bone, as well as an increase in the numbers of osteophytes. Significantly no correlation was found between the extent of subchondral sclerosis, osteophytes or joint space narrowing. This study (Buckland-Wright et al., 1990) thus confirmed that during progression of osteoarthritis, evidence of joint space narrowing, i.e. a decrease in cartilage thickness, becomes radiographically apparent only after significant changes have already occurred in subchondral bone.
Magnetic resonance imaging (MRI) is a technique which offers considerable potential for detecting early cartilage, bone and soft tissue changes in osteoarthritic joints. Positive correlations were reported (Sabiston et al., 1987) between gross pathological changes determined at autopsy and serial MRI images. Abnormalities were evident on MRI as early as 4 weeks after the onset of the disease which was half the time for lesions to be detected radiographically. Since MRI visualises the distribution of water in tissues and this is bound to proteoglycans this technique offers a useful means of detecting degenerative changes in cartilage before lesions become evident. Such a relationship has been demonstrated for degeneration of the intervertebral disc (Thompson et al., 1988).
For the most part present systems of management of the osteoarthritis patient are either that of providing symptomatic relief or are reconstructive (surgical). Symptomatic relief is generally directed at reducing pain, increasing mobility and improving the patient's quality of life.
Physical methods of treatment include the use of walking aids, sticks, braces, etc., but counselling on food intake to reduce obesity, the nature at daily activities undertaken or even wearing rubber heeled shoes can be of some benefit. Traditional physiotherapy and hydrotherapy to strengthen and improve muscle tone may be necessary in cases where muscle wastage is evident. However, regular non-intensive activities such as moderate walking, bicycle riding or swimming should be encouraged where possible to maintain joint mobility and muscular fitness.
Therapeutic agents are widely used in the treatment of osteoarthritis patients. Non-steroidal anti-inflammatory drugs (NSAIDs) represent the mainstay of treatment. The rationale for using anti-inflammatory drugs for a disorder in which inflammation is considered to be secondary to a primary event which arises in cartilage and bone has been questioned. However, as already discussed the synovitis arising from cartilage breakdown can, via prostaglandins and cytokines, stimulate chondrocyte resorption of the extracellular matrix.
Furthermore, chondrocytes subjected to mechanical and chemical injury release arachidonic acid, the metabolic precursor of prostaglandins and leukotrienes. NSAIDs are potent inhibitors of the enzymes (cyclooxygenase) responsible for the conversion of arachidonic acid to prostaglandins. By this pathway they could therefore positively influence both the initiation and perpetuation of osteoarthritis as well as modulate the symptoms of pain, joint swelling and stiffness. Against these useful activities must be weighed, the possible deleterious effects that NSAIDs may exhibit on gastric mucosa and other tissues. Within recent years concern has also been expressed on the inhibitory effects that certain NSAIDs may have on the biosynthesis of proteoglycans in osteoarthritic cartilage. While such inhibitory activity has been demonstrated in vitro and in vivo for aspirin, phenylbutazone and indomethacin many of the currently used NSAIDs including diclofenac, piroxicam, tiaprofenic acid
and ketoprofen appear from several independent experimental studies to be innocuous to cartilage repair processes (Ghosh, 1988).
It may be concluded therefore that the usage of NSAIDs, particularly those which have become available within the last 15 years can be justified on scientific grounds but individual patient tolerance and preference for a particular drug still emerges as the primary means of selection. While NSAID are effective in controlling pain in mild to moderate osteoarthritis , they are associated with significant toxicity (most frequently gastrointestinal) and may even cause complications that result in death. Patients who experience the pain associated with arthritis would benefit from agents that are devoid of significant toxicities. Cyclooxygenase-2 (COX-2) inhibitors are being evaluated in clinical trials or are in development. These agents appear to inhibit only the enzyme which is produced largely during inflammation and is responsible for the biosynthesis of prostaglandins and other mediators of inflammation as well as sensitizers to pain and not the enzyme (COX-1) which protects the gut wall in normal conditions. Because COX-2 inhibitors do not inhibit COX-1 isoenzyme activity at pharmacologic concentrations, they are devoid of many of the toxicities that are typical side effects of NSAIDs. Short term studies found that COX-2 inhibitors were an effective analgesic but did not cause gastroduodenal erosions (Lane, 1997). Further studies are required to substantiate these findings.
Systemic corticosteroids, which are more potent anti-inflammatory/immunosuppressive agents than NSAIDs, are not recommended for the management of the osteoarthritis patient, however, a limited number of local injections may provide a useful adjunct to treatment. There exists a large number of laboratory studies to show that corticosteroids can profoundly downregulate connective tissue cell metabolism thereby shutting-off cellular repair activities. In addition, chronic use of these drugs is associated with a number of other side-effects, such as osteoporosis, which can have disastrous consequences in the elderly patient.
Notwithstanding the useful role that NSAIDs may offer in the management of the osteoarthritis patient, none of these compounds, as yet, have been shown to actually improve the underlying pathology. A rational approach to the therapeutic management of the OA requires that the drug used should fulfill a number of criteria besides reducing synovitis and joint pain. A candidate drug should:
- Support, or at least not suppress, chondrocyte macromolecular (proteoglycan, collagen and DNA) biosynthetic activities.
- Stimulate, or not suppress, synovial lining cell synthesis of synovial fluid components (especially hyaluronan) which keep the fluid functioning optimally as a lubricant and protector of the cartilage surfaces.
- Inhibit those enzymes and/or mediators implicated in the degradation of cartilage extracellular matrix and synovial components (proteoglycans, hyaluronan and collagen).
- Mobilise blood clots (thrombi), fibrin lipids and cholesterol deposits in the synovial compartment as well as subchondral blood vessels.
Of the drugs currently available, very few could fulfil all of the above criteria. However, from both laboratory and clinical studies conducted on pentosan polysulphate, many of the listed postulates may be satisfied. Although pentosan polysulphate has been used clinically for over 25 years for the treatment of a variety of conditions including thrombosis and hyperlipidaemia, its application as a second-line antiarthritic agent has only been studied closely during the last ten years.
Pentosan polysulphate is a semisynthetic molecule made from beechwood which shows some similarity in structure and charge to the endogenous glycosaminoglycans of connective tissues, including those present in cartilage (Burkhardt and Ghosh, 1987). It has some similarities to heparin, though it is smaller, more highly charged and not as potent as an anticoagulant. These properties allow pentosan polysulphate to localise within the extracellular matrix and directly influence enzymatic and cellular events over a longer period than most other drugs. This reduces considerably the frequency of treatment and thus side-effects.
A double-bind trial using pentosan polysulfate was undertaken in 43 patients with knee arthrosis of Severity I and II (Engel & Juhran, 1982). After a washout period of three days the drug (100mg) was administered intramuscularly to half the group according to the following protocol: days 1 - 3, one injection (100mg) daily; day 4, no drug treatment; Days 5 - 27, one injection (100mg) every second day. This represented a total of 15 injections or 1500mg of pentosan polysulfate or the placebo solution. The patient response was assessed using a 1 - 5 pain scale of both subjective and objective criteria which included pain at rest, pain during movement, activity limitation of movement, passive limitation of movement and pain caused by fatigue. The results obtained in this study showed that for the drug treated group a significant (p < 0.05) improvement in pain score was obtained during joint movement or passive limitation of movement or with the pain associated with fatigue. Overall assessment by the physician and patients on a weekly basis showed an improvement in all clinical criteria measured over the four week study period in the drug-treated group relative to the placebo group.
A doubleblind, placebo-controlled clinical study in 105 patients with osteoarthritis of the knee has been performed in Perth, Australia (Edelman et al., 1994) where patients either received a salt solution or pentosan polysulphate at 3mg/kg as an intramuscular injection once weekly for 4 weeks. In the pentosan polysulphate-treated patients, stiffness significantly improved after the first week and pain on walking or at rest, time to walk upstairs and overall pain significantly improved after the first month. Pain at rest and step time were still significantly better than the placebo group after 2 months.
Pentosan polysulphate is currently undergoing double-blind clinical trials for the management of the osteoarthritis patient in a number of countries.
A preliminary report has been published (Rasaratnam et al., 1996) of a double-blind placebo controlled study of intra-articular pentosan polysulphate (0 or 50mg per joint once weekly for 4 weeks) in 50 patients suffering osteoarthritis of the knee. Even with 31 of the 50 patients evaluated, there were significant improvements in pain and mobility for up to 2 months after completing the treatment.
Extensive veterinary application of this drug over the last ten years for the treatment of traumatic and geriatric osteoarthritis in dogs has demonstrated clinical effectiveness in this species.
In most cases reconstructive surgery for osteoarthritis represents the end point of many years unsuccessful medical treatment which has left the patient with intractable pain and unacceptable disability. While it is not at all clear (but see earlier discussion) why some patients progress to this status while others do not, total joint replacement, particularly for the hip, generally provides rapid pain relief and improved mobility for many years post-operatively. Prosthesis failure and infection are now relatively rare in well established surgical units but the high cost and long waiting lists in some public hospitals for such procedures can be a deterrent for the elderly patient. Joint realignment by means of osteotomy can successfully redistribute mechanical loading to a joint compartment in which intact cartilage is present. Such surgery is reported to be beneficial and provides effective pain relief by the improving subchondral blood flow. An excellent review (Harris and Sledge, 1990) of the indications, complications and outcomes of total joint knee and hip replacement should be consulted for up-date information on these procedures.
For many years osteoarthrtis was considered by most as a wearing out of joints due to ageing and over use and patients were advised that apart from surgery there was little that could be done to halt the progression of their condition. Today, through extensive world-wide research this view is changing and osteoarthritis is now appreciated as a disorder of considerable complexity which we are only now beginning to understand. With this enlightenment new avenues for therapeutic intervention become open including opportunities to capitalise on the hypermetabolic status of the chondrocyte in the early stages of the disease. These changing attitudes auger well for the future.
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