and connective tissues

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Joints and connective tissues

INTRODUCTION

In order to diagnose and manage the patient presenting with musculoskeletal symptoms, it is important to distinguish whether the pathology is arising primarily in the so-called hard tissues (such as bone) or the soft tissues (such as cartilage, disc, synovium, capsule, muscle, tendon, tendon sheath). It is also important to distinguish between the two most common causes of musculoskeletal symptoms, namely inflammatory and degenerative.

HISTORY AND EXAMINATION

The history and physical examination are the two most important components of the diagnostic process for identifying the cause of musculoskeletal symptoms, and pattern recognition is the key to diagnosis.

• Do the symptoms arise in the musculoskeletal system, or from a disease in another system (e.g. neurological, vascular, endocrine)? In some musculoskeletal conditions, the disease may be multi-system in origin—for example, carpal tunnel syndrome may be due to entrapment of the median nerve by tenosynovitis, or associated with hypothyroidism, diabetes, obesity or pregnancy.

• Is it an articular or non-articular process? Once the doctor has established that the disorder originates in the joints, the history and examination will help to identify a diagnostic pattern (see Box 33.1).

Some arthropathies present with an acute onset of pain, with peak intensity reached within hours or days; in others it occurs gradually over weeks to months. The clinical pattern may be monarticular, oligoarticular or polyarticular. Variations of these patterns may occur within the same disorder. For example, rheumatoid arthritis may present as an acute monarthritis of the knee before spreading to other joints, or as an acute polyarthritis. Although almost any arthropathy may begin as a monarthritis, the initial pattern of certain disorders is characteristically monarticular, with pain, redness and swelling. Certain diagnoses, such as infection or crystal arthritis, should be suspected in this situation (see Box 33.2). Infectious monarthritis is an important diagnosis to make early, as joint damage can occur if untreated.

BOX 33.2 The acute hot joint

• mycobacterial

Crystal-induced

• CPPD (pseudogout)

Chronic monarthritis is the presenting manifestation of a variety of joint disorders, some of which are listed in Box 33.3. Involvement of two to four joints is usually referred to as oligoarthritis. There are a number of conditions in which involvement of two or three joints rather than one may significantly narrow the differential diagnosis, including pseudogout and psoriatic arthritis. The third pattern is the one in which polyarticular involvement dominates the clinical picture. A variety of inflammatory and non-inflammatory disorders, both common and uncommon, may present as polyarthritis (see Table 33.1).

TABLE 33.1 Distribution of common oligo- and polyarthritides

	Symmetric	Asymmetric
Inflammatory	• Rheumatoid arthritis • Systemic lupus erythematosus • Polymyalgia rheumatica

• Ankylosing spondylitis

• Reactive arthritis

• Psoriatic arthropathy

• Colitic arthritis

• Palindromic rheumatism

Degenerative/crystal-induced

• Osteoarthritis (primary generalised, erosive and nodal types)

• CPPD (pseudo-RA type)

• Haemochromatosis arthropathy

• Gout (especially oligoarthritis)

• CPPD (pseudogout)

Infectious

• Viral arthritis

• Bacterial arthritis, esp Neisserial

• Bacterial endocarditis

FIGURE 33.1 Anatomy of knee: A anterior, B medial, C lateral and D posterior views

FIGURE 33.2 Anatomy of hip

FIGURE 33.3 Anatomy of ankle

FIGURE 33.4 Anatomy of shoulder

FIGURE 33.5 Anatomy of right elbow: A, B anterior and posterior views; C posterior view with 90° flexion; D lateral view

FIGURE 33.6 Anatomy of wrist

AETIOLOGY

The accepted aetiology of the common arthropathies is as follows:

• rheumatoid arthritis—genetic, microbial and immunological factors play a role in disease susceptibility; autoimmune disease; inflammation drives pathophysiology

• osteoarthritis—degenerative condition of articular cartilage with secondary bony changes; environmental factors such as obesity, trauma; genetic factors also contribute

• crystal arthropathies:

• gout—inflammatory reaction due to monosodium urate crystals; environmental factors

• calcium pyrophosphate disease—inflammatory reaction to calcium pyrophosphate dihydrate (CPPD) crystal deposition within fibro cartilage or articular cartilage

• systemic lupus erythematosus (SLE)—autoimmune disease with environmental factors such as stress, UV exposure, drugs; genetic factors also contribute

• soft tissue rheumatic syndromes:

• carpal tunnel syndrome—genetic, environmental (occupational), metabolic (hypothyroidism)

• rotator cuff pathology—ageing, environmental, genetic factors, environmental (occupational).

DIAGNOSIS

As noted above, the history and physical examination are the two most important aspects of the diagnostic process in patients complaining of musculoskeletal systems. However, laboratory tests and imaging may help in confirming a suspected diagnosis or excluding certain conditions.

IMAGING PROCEDURES

X-rays

Plain X-rays often provide useful diagnostic information in patients with inflammatory or degenerative arthritis (see Table 33.2).

TABLE 33.2 Typical X-ray findings in osteoarthritis vs rheumatoid arthritis

	Osteoarthritis	Rheumatoid arthritis
Joint space narrowing	Yes	Yes
Erosions	No	Yes
Periarticular osteoporosis	No	Yes
Subchondral sclerosis	Yes	No

CT scanning

Computed tomography (CT) has become widely established as a tool for evaluating bone and soft tissue disorders. In many situations, CT scanning can provide additional information to that provided by plain X-rays because of its increase in dynamic range. It is generally more useful than plain X-rays for imaging of the spine. Subtle cortical and intra-osseous lesions can be visualised by CT. Multiplanar reconstruction helps to better image three-dimensional structures.

FIGURE 33.7 Rheumatoid arthritis

FIGURE 33.8 X-ray of rheumatoid arthritis. A Seen typically is narrowing of the carpal joint with subchondrial cyst formation (dark arrows) and periarticular erosions (white arrow). B Late changes include subluxation and ulnar derivation at the metacarpophalageal joint. C Silicone joint replacements (arrows) in a patient with rapidly progressing disease

Ultrasound

Ultrasound is a more expensive imaging modality used for a wide range of arthritic conditions. Tendon and muscle abnormalities such as rotator cuff tears can be diagnosed using the technique. Synovial effusions, synovial hypertrophy and inflammation can be evaluated using ultrasound. Power Doppler can be used for assessing synovial membrane inflammation. It is important to note that the effectiveness of ultrasound is very much dependent on the experience of the operator.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) offers high-contrast sensitivity for soft tissue and the advantage of a lack of ionising radiation. It can be particularly useful for imaging disc and nerve lesions in the spine as well as soft tissues in sites such as the shoulder and ruptured tendons. However, it is expensive.

LABORATORY TESTS

Acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are often useful for excluding or confirming an inflammatory process or assessing whether there is ongoing disease activity. For many diseases, however, more specific laboratory testing is needed.

Antinuclear antibodies

The presence of high concentrations of antinuclear antibodies (ANA) (titre > 1:160) increases suspicion that an autoimmune disorder is present. However, its positivity alone is not diagnostic of disease. The combination of low titres (< 1:80) and few signs or symptoms of musculoskeletal origin suggest a low likelihood of autoimmune disease. A positive ANA in low titre (e.g. 1:40) is commonly found in the normal population. The tests should be performed in an accredited laboratory.

Extractable nuclear antigens

Extractable nuclear antigens (ENAs) may provide further information about the diagnostic subgroup in patients with a positive ANA (see Table 33.3).

TABLE 33.3 ENA subtypes and associations

Subtype	Associations
Sm	SLE
SS-A	Sjögren’s syndrome, SLE
SS-B	Sjögren’s syndrome, SLE
RNP	Mixed connective tissue disease
Anti-centromere	CREST (limited scleroderma)
Jo-1	Dermatomyositis
Scl-70	Diffuse scleroderma

Rheumatoid factor

Rheumatoid factors are antibodies directed against the Fc portion of immunoglobulin G (IgG). Patients may have detectable serum rheumatoid factor in a variety of rheumatic disorders, including:

• rheumatoid arthritis

• Sjögren’s syndrome

• polymyositis.

Rheumatoid factors may be found in up to 5% of young healthy individuals; the higher the titre, the greater the likelihood that the patient has rheumatic disease. Rheumatoid-factor-positive patients with rheumatoid arthritis generally experience more aggressive and severe erosive joint disease as well as more extraarticular manifestations than those who are rheumatoid factor negative. However, there is wide inter-patient variability.

FIGURE 33.9 Osteoarthritis X-ray of A fingers and B the carpus, showing cartilage loss deviations, sclerosis and spur formation

FIGURE 33.10 Osteoarthritis of the finger

FIGURE 33.11 No rotator cuff tendons A—there are few restraints to anterosuperior sublaxation when attempt is made to raise the arm. The pull of the deltoid muscle worsens this by pulling superiorly and medially (arrow). B With reverse arthroplasty, the deltoid muscle lever is restored, allowing it to pull the humerous upward and outward (arrow)

FIGURE 33.12 Rotator cuff tear: A superior view showing involvement of supraspinatus (SS) and infraspinatus (IS) tendons; B repaired tear

FIGURE 33.13 Rotator cuff calcific tendonitis

Antineutrophil cytoplasmic antibody

The antineutrophil cytoplasmic antibody (ANCA) test is useful in diagnosing certain connective tissue disorders and vasculitis. Two different immunofluorescent patterns can be seen. The cANCA is usually directed against a serum protease called proteinase 3 and found primarily in patients with Wegener’s granulomatosis. The pANCA is usually directed again myeloperoxidase and more commonly associated with microscopic polyarteritis, Churg-Strauss syndrome and idiopathic necrotising glomerulonephritis.

Serum uric acid

Measurement of serum uric acid may be helpful in certain clinic situations, particularly in suspected gout or when monitoring urate-lowering therapy. Most patients with asymptomatic hyperuricaemia will never develop gout, so screening patients for hyperuricaemia is not generally recommended. Measurement of 24-hour uric acid may be useful in the evaluation of nephrolithiasis or to classify the patient as an over-producer or under-excreter of uric acid.

FIGURE 33.14 Hyperostosis X-rays: A lateral and B anteroposterior views showing bridging osteophytes at multiple levels, out of proportion to the degree of underlying degenerative change

FIGURE 33.15 Infrahyoid neck X-ray: A sagittal and B coronal images. cc: cricoid cartilage; e: epiglottis; *: false vocal cord; small arrows: pharyngeal mucosal space; pe: pre-epiglottic fat; pl: paralaryngeal fat; arrowheads: retropharyngeal space; s: strap muscle; SC: superficial cervical space; smg: submandibular gland; tr: trachea; tvc: true vocal cord

FIGURE 33.16 Alkaptonuria X-ray: spinal abnormalities include widespread disc narrowing, disc calcification and osteoporosis

Synovial fluid analysis

Synovial fluid analysis is very useful in diagnosing bacterial infections, crystal-induced arthritis and haemarthrosis. Its other main value is in allowing classification into inflammatory, non-inflammatory or haemorrhagic categories. It is a safe bedside procedure when using a ‘sterile non-touch’ technique. The white cell count, culture and polarised light microscopy to determine the presence of crystals are the most valuable studies on synovial fluid.

MANAGEMENT OF DISORDERS

The general practitioner is most often where the initial diagnosis and investigations occur, and plays a central role in coordinating care with other healthcare professionals—this requires good communication between all professionals involved. Other healthcare professionals who may be involved include:

• rheumatologist

• physiotherapist

• occupational therapist

• appropriate complementary practitioner

• orthopaedic surgeon.

EDUCATION

With an acute self-limiting form of musculoskeletal problem or arthritis, treatment can be self-limiting and education is not required. With chronic forms of musculoskeletal disease, such as rheumatoid arthritis, education is important and the healthcare professional acts as informed adviser to the patient. Management plans must be mutually agreed.

The primary aim of treatment of rheumatoid arthritis is to prevent joint damage. This helps to improve quality of life and minimise effects on mobility and the need for surgery. When devising a management plan, consideration needs to be given to the patient’s level of education, preferences and financial resources.

PHYSIOTHERAPY AND EXERCISE

Exercise and weight loss may be useful for osteoarthritis of the knee. Exercise therapy may also be useful in rheumatoid arthritis, to limit the adverse effects of the disease on muscle strength, endurance and aerobic capacity. An exercise physiologist may be a useful referral for an individualised and supervised exercise program in a person with joint disease.

Hydrotherapy and occupational therapy may improve strength and physical functioning, and help relieve symptoms. Site-specific physiotherapy may be useful in a number of soft-tissue rheumatic disorders (e.g. rotator cuff pathology) and in helping to improve the recovery rate from acute low back pain.

THERAPEUTIC STRATEGIES

Therapeutic strategies in musculoskeletal conditions can be considered non-pharmacological, pharmacological or surgical (see Box 33.4).

BOX 33.4 Therapeutic approaches in joint disease

Non-pharmacological

• rehabilitation

• behaviour modification

• relaxation techniques

• stress management

• physiotherapy

• general preventive

• specific therapeutic

• hydrotherapy

• transcutaneous nerve stimulation

• mobilisation/manipulation

• household modifications

• home/work/walking devices

• complementary medicine

• glucosamine/chondroitin

• acupuncture

Pharmacological

• non-steroidal anti-inflammatory drugs

• antirheumatic drugs

• corticosteroids (systemic, intraarticular)

• immunosuppressive agents

• biological agents

• specific anti-gout therapies

• viscosupplementation

• reconstruction

• arthroplasty

• arthrodesis

• synovectomy

INTEGRATIVE APPROACH TO THERAPY

Acupuncture

A large body of evidence exists for the underlying physiological basis of acupuncture in the treatment of pain. Evidence for the efficacy of acupuncture in the treatment of rheumatic and musculoskeletal disorders varies, but its safety is well documented.

Osteopathy

Osteopathy consists of a range of soft tissue stretching, massaging and relaxation techniques, as well as manipulative therapy for specific spinal and soft tissue disorders. Its efficacy remains unproven.

Chiropractic

Beneficial results are reported in some patients from experienced chiropractors. Manipulation is a commonly used technique for the treatment of mechanical and degenerative spinal disorders.

Herbal

A number of herbal mixtures have been used for arthritis, including devil’s claw, St John’s wort, evening primrose oil, Ayurvedic medicines and green-lipped mussel.

• Devil’s claw (Harpagophytum procumbens) is a plant widely used in South African traditional medicine. Extracts of devil’s claw roots are widely used in Europe for rheumatic pain. Two of the active components of devil’s claw are harpagoside and harpagide. The potential mechanism of action of devil’s claw is still unclear.

• St John’s wort (Hypericum perforatum) is an aromatic perennial herb that produces golden-yellow flowers that seem to be particularly abundant on 24 June (in the northern hemisphere), the day traditionally celebrated as the birthday of John the Baptist—hence its common name, St John’s wort. It has been used to treat arthritis and gout as well as numerous other complaints. In general, the clinical evidence supporting its benefit in inflammatory arthritis is considered weak, and a Cochrane review of its use in depression was inconsistent.¹ There continues to be a need for more high-quality research into, and properly designed randomised trials of, the efficacy and safety of complementary therapies in rheumatoid arthritis.

• Green-lipped mussel (Perna canaliculus) is a New Zealand shellfish, of which an extract containing omega-3 polyunsaturated fatty acids has been shown to have anti-inflammatory properties. Commercially this is available as Liprinol®, which has been shown to have anti-inflammatory activity in vitro in inhibiting leukotriene synthesis.

Supplements

Fish oil

Traditional NSAIDs provide symptomatic relief of arthritis by inhibiting the COX enzyme but have significant side effects, particularly in the elderly. Fish oils contain a natural inhibitor of COX, and can reduce reliance on NSAIDs, and reduce cardiovascular risk.

The dietary essential fatty acids are polyunsaturated fatty acids (PUFA) that contain the omega-6 with or without the omega-3 double bond, neither of which can be synthesised endogenously. This is important because the ratios of these fatty acids in the tissues are largely determined by their ratios in the diet. In seeking to alter the balance of omega-3 and omega-6 PUFAs for therapeutic purposes, it is necessary to understand which foods are rich in these fatty acids.

Omega-3 PUFA are found in the flesh of all marine fish, including crustaceans and shellfish. In fish and fish oils, omega-3 PUFA are present as long-chain PUFA. In certain vegetable oils, such as flaxseed, perilla and canola oil, omega-3 PUFA are present as the C18 PUFA, linolenic acid. In sunflower, cottonseed, safflower and soy oils, and the spreads manufactured from them, the main fatty acid is the omega-6 C18 PUFA. Olive oil and canola oil are rich sources of oleic acid, which is a monounsaturated fatty acid containing a single double bond.

Because Western diets are typically low in long-chain omega-3 PUFA, substantial increases in tissue long-chain omega-3 can be achieved by taking a fish oil supplement without additional dietary modification. However, a choice of spreads that are rich in omega-3 PUFA or rich in monounsaturated fatty acids and low in omega-6 PUFA allow higher tissue omega-3 levels to be reached with a given dose of fish oil. To achieve anti-inflammatory doses of long-chain omega-3 PUFA by simply eating fish, a substantial dietary intake is required—greater than would be practical for most people. A daily intake of 2.7 g of long-chain omega-3 fatty acids is the threshold amount that has been shown consistently to deliver an anti-inflammatory effect in groups of patients in randomised trials ² and is found in 10 mL of standard fish oil (from a bottle of fish oil) daily or nine standard 1000 mg capsules daily. People taking one or two capsules daily will generally have an insufficient dose for any anti-inflammatory effect in conditions like rheumatoid arthritis.

Recommendation: 15 mL fish oil daily to get well within the anti-inflammatory range or 10 capsules per day. A meal of oily fish is equivalent to only one or two capsules. In practice it is better to regard fish eaten as a desirable bonus rather than as a basis for achieving an anti-inflammatory action or making adjustments to capsules or oil.

Glucosamine and chondroitin

Numerous studies indicate that glucosamine alone or combined with chondroitin provides symptomatic benefit for the treatment of osteoarthritis of the knee. However, a lack of standardisation in glucosamine preparations has contributed to inconsistency in study results across trials. A recent updated Cochrane review of glucosamine therapy in osteoarthritis found that pain and function improved by 28% and 21% respectively, compared with placebo.³ A large NIH-sponsored study found that the combination of glucosamine hydrochloride and chondroitin sulfate was more effective than placebo only in the subgroup with moderate to severe osteoarthritis.⁴

There may also be some effect on ‘disease modification’—that is, not just symptoms. In a landmark trial assessing the disease modifying potential of glucosamine sulfate, patients were randomly assigned 1500 mg daily of glucosamine with placebo for 3 years. Patients on placebo had progressive joint space narrowing, whereas no significant joint space loss was seen in patients taking glucosamine.⁵ The results have since been questioned because of the radiographic technique used to measure joint space width,⁶ and further studies using MRI are needed.

Recommended dose: glucosamine 1500 mg per day; chondroitin 1200 mg per day.

PHARMACOLOGICAL

Simple analgesics

Analgesics, including paracetamol/acetaminophen, have no anti-inflammatory effects. They can be used every 4–6 hours for pain relief if necessary. They seldom produce side effects and are well tolerated.

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) enzyme. Two classes of COX enzymes are described: COX-1 and COX-2. Traditional NSAIDs inhibit both COX-1 and COX-2 enzymes. However, selective COX-2 inhibitors have minimal effects on the COX-1 enzyme. As a class of drugs, their use has been limited by adverse effects, mainly upper gastrointestinal. COX-2 specific agents appear to provide anti-inflammatory effects with lesser upper gastrointestinal toxicity but an increase in cardiac events.

NSAIDs act quickly (within hours to a few days) and reduce joint inflammation by inhibiting the production of inflammatory cyclo-oxygenase products, particularly the prostaglandins—small lipid molecules with potent effects on many steps in the inflammatory process. These drugs, of which there are a large number, are potent anti-inflammatory agents. Commonly used agents include diclofenac, naproxen, ketoprofen, sulindac, piroxicam, indomethacin, ibuprofen. Examples with COX-2-specific actions include celecoxib and meloxicam. NSAIDs are usually administered by the oral route, usually in conjunction with food.

In susceptible individuals, NSAIDs are nephrotoxic, by inhibiting prostaglandin-dependent compensatory renal blood flow. Recent studies have also identified an increased risk of cardiovascular events with these agents,⁷ suggesting that natural inhibition of COX by fish oils may have certain advantages (see below).

Corticosteroids

Corticosteroids (or glucocorticoids) are hormones produced by the adrenal glands. They have potent anti-inflammatory and immunosuppressive properties. By far the most commonly used compound is prednisone, which is 4–5 times as potent as cortisol and has less mineralocorticoid activity, resulting in less fluid retention. Prednisone is administered orally and acts rapidly to reduce inflammation, resulting in a lessening of joint swelling, pain and stiffness in inflammatory arthritis.

Despite their clinical efficacy, corticosteroids are toxic if used at high doses for prolonged periods. Corticosteroids have important effects on bone metabolism, resulting in osteoporosis and eventual non-traumatic fractures. They interfere with glucose metabolism and are diabetogenic. Corticosteroids cause salt and water retention and may precipitate or exacerbate hypertension. They interfere with ocular lens metabolism, resulting in cataract formation.

Disease-modifying antirheumatic drugs

Disease-modifying antirheumatic drugs (DMARDs) are a group of disparate compounds that share one important feature—they retard the development of bony erosions in rheumatoid arthritis. Drugs in this category include gold compounds, d-penicillamine, sulfasalazine and the antimalarial drug hydroxychloroquine. Immunosuppressive drugs are also sometimes considered in this group. These include the folic acid antagonist methotrexate, the antimetabolite azathioprine, the alkylating agent cyclophosphamide, cyclosporin, which inhibits the production of interleukin-2 by T-lymphocytes, and recently the pyrimidine antagonist leflunomide. Methotrexate is the most widely prescribed drug in this group.

A new era has emerged with the use of biological agents in the treatment of rheumatoid arthritis. These include monoclonal antibodies directed against T-cells (such as infliximab and adalimumab), or proteins (such as etanercept) that block receptors for inflammatory cytokines such as tumour necrosis factor (TNF).

In osteoarthritis, structure-modifying drugs that prevent cartilage degradation remain an area of active research, although claims have been made in this regard for glucosamine and chondroitin via enhancement of proteoglycan synthesis by chondrocytes. (This is discussed in more detail below.)

Opioid analgesia

Opioids have an important role in the management of patients with chronic, intractable pain for whom surgery is not an option and where other modalities have failed. Both oxycodone and tramadol, a weak opioid antagonist, have been used. Their side-effect profile is well described and there are important drug interactions to watch for, notably serotonergic syndrome with tramadol.

Intraarticular and local injection therapy

Pain and inflammation can be effectively relieved by intraarticular corticosteroid injections. Soft-tissue rheumatic syndromes also respond well in many cases to local corticosteroid therapy. Injection techniques that selectively and specifically target the lumbar zygapophyseal joints may be useful in some patients with low back pain.

Viscosupplementation with hyaluronic acid injections has also been used in osteoarthritis. Although no direct comparison between specific products has been performed, viscosupplementation was more efficacious from 5 to 13 weeks with regard to pain, range of motion and Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) and Lesquene scores, than placebo.⁸ In Australia, the only compound available is hylan G-F 20 (SYNVISC®). It does not attract PBS reimbursement and is only approved for knee osteoarthritis.

Arthritis Australia. http://www.arthritisaustralia.com.au.

Cleland LG, James MJ, Proudman SM. Fish oil: what the prescriber needs to know. Arthritis Res Ther. 2006;8:202.

Hochberg M, Silman A, Smolen J, et al. Rheumatology. 3rd edn. London: Mosby, 2003.

March L, Ananda A. Management of osteoarthritis: part 2. Medical Observer. 2007;20 April:27-30.

Sambrook P, Schrieber L, Taylor T, et al. The musculoskeletal system. London: Churchill Livingstone, 2001.

1 Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008;3:CD000448.

2 Proudman SM, Cleland LG, James MJ. Dietary omega-3 fats for treatment of inflammatory joint disease: efficacy and utility. Rheum Dis Clin North Am. 2008;34(2):469-479.

3 Towheed T, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2008;4:CD002946.

4 Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808. 858–860.

5 Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:247-248.

6 McAlindon T. Glucosamine for osteoarthritis: dawn of a new era? Lancet. 2001;357:247-248.

7 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8):954-959.

8 Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2005;2:CD005321.

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