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Arthritis 1 Osteoarthritis: an update with relevance for clinical practice


Johannes W J Bijlsma, Francis Berenbaum, Floris P J G Lafeber

Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite eorts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specic and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment eectiveness. In the coming years, a better denition of osteoarthritis is expected by delineating dierent phenotypes of the disease. Treatment targeted more specically at these phenotypes might lead to improved outcomes.

Lancet 2011; 377: 211526 See Comment page 2067 This is the rst in a Series of three papers about arthritis Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, Netherlands (Prof J W J Bijlsma MD, F P J G Lafeber PhD); and Department of Rheumatology, Pierre and Marie Curie University, Hospital Saint-Antoine, Paris, France (F Berenbaum MD) Correspondence to: Prof Johannes W J Bijlsma, University Medical Centre Utrecht, Department of Rheumatology and Clinical Immunology, PO Box 85.500, Utrecht, 3508 GA, Netherlands j.w.j.bijlsma@umcutrecht.nl

Introduction
Epidemiology
The prevalence of osteoarthritis is dependent on the precise denition used and on the site of interest. The knee, hip, and hand are most aected by the disease (gure 1). Osteoarthritis becomes more common with age, and after age 50 years more women than men are aected. For example, the Rotterdam study1 of a population-based cohort of 3906 people 55 years or older reported that 67% of women and 55% of men had radiographic osteoarthritis of the hand. In people older than 80 years, 53% of women and 33% of men had radiographic osteoarthritis of the knee. The agestandardised and sex-standardised incidence of osteoarthritis of the hand is 100 per 100 000 person-years, for the hip is 88 per 100 000 person-years, and for the knee is 240 per 100 000 person-years.2 Osteoarthritis in general develops progressively over several years, although symptoms might remain stable for long periods within this period. The diagnosis of the disease relies on clinical and radiological features (panel).3 Nearly half of patients with radiological features of osteoarthritis have no symptoms and vice versa. Risk factors for occurrence and progression of osteoarthritis have been identied, and dier on the basis of the joints involved (table 1).3

fails and leads to an imbalance in favour of degradation. Increased synthesis of tissue-destructive proteinases (matrix metalloproteinases and agrecanases),6,7 increased apoptotic death of chondrocytes, and inadequate synthesis of components of the extracellular matrix, lead to the formation of a matrix that is unable to withstand normal mechanical stresses. Consequently, the tissue enters a vicious cycle in which breakdown dominates synthesis of extracellular matrix. Since articular cartilage is aneural, these changes do not produce clinical signs unless innervated tissues become involved. This is one reason for the late diagnosis of osteoarthritis. Although the pathophysiology of osteoarthritis has long been thought to be cartilage driven, recent evidence shows an additional and integrated role of bone and synovial tissue, and patchy chronic synovitis is evident in the disease.8 Synovial inammation corresponds to clinical symptoms such as joint swelling and inammatory pain, and it is thought to be secondary to cartilage debris and catabolic mediators entering the synovial cavity. Synovial macrophages produce catabolic and proinammatory mediators and inammation starts negatively aecting the balance of cartilage matrix degradation and repair.9 This process in turn amplies synovial inammation, creating a vicious cycle. Synovial inammation happens in early as well as late phases of osteoarthritis and is seldom as severe as in rheumatoid

Pathology
In addition to the involvement of several joint tissues, osteoarthritis has long been mainly characterised by a failure of the repair process of damaged cartilage due to biomechanical and biochemical changes in the joint. Cartilage is non-vascularised, so this restricts the supply of nutrients and oxygen to the chondrocytesthe cells that are responsible for the maintenance of a very large amount of extracellular matrix. At an early stage, in an attempt to eect a repair, clusters of chondrocytes form in the damaged areas and the concentration of growth factors in the matrix rises.4,5 This attempt subsequently
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Search strategy and selection criteria The information in our paper is primarily based on PubMed searches with the terms osteoarthritis in combination with cartilage, bone, synovitis, imaging, biomarker, and treatment. We mainly included papers from the past 5 years, with the addition of highly regarded older papers. We also included some review articles and book chapters as comprehensive overviews, the details of which are beyond the scope of our report.

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Figure 1: Osteoarthritic joints of the hand, hip, and knee (A) Osteoarthritis is predominantly identied in the distal interphalangeal and proximal interphalangeal jointsdeformations of the distal interphalangeal joints are clearly visible. (B) Plain radiograph of an osteoarthritic hip joint showing the narrowing of the joint space and clearly visible osteophytes. (C) MRI of an osteoarthritic knee with clear medial cartilage loss and osteophyte formation, with minor synovial swelling.

arthritis, but it might add to the vicious cycle of progressive joint degeneration. The main characteristics of osteoarthritis are changes in the subchondral bone. Osteophyte formation, bone remodelling, subchondral sclerosis, and attrition are crucial for radiological diagnosis. Several of these bone changes take place not only during the nal stage of the disease, but also at the onset of the diseasepossibly before cartilage degradation.10,11 This nding led to the suggestion that subchondral bone could initiate cartilage damage.

Clinical features and diagnosis


Pain is the rst and predominant symptom of osteoarthritis that causes patients to visit their family doctor. The pain experienced is intermittent, typically worst during and after weight-bearing activities. Inammatory ares can happen during the course of the disease. Patients with osteoarthritis also experience stiness: in the morning, after a period of inactivity, or particularly in the evening. This stiness generally resolves in minutes, unlike the prolonged (usually >30 min) stiness caused by rheumatoid arthritis. Loss of movement and function is another reason patients visit their family doctor. Patients report symptoms that limit their day-to-day activities, such as stair climbing, walking, and doing household chores. Symptomatic osteoarthritis might be associated with depression and disturbed sleep, which additionally contribute to disability. The symptoms of osteoarthritis diminish the patients quality of life.12 Physical examination is needed to conrm and characterise joint involvement, and to exclude pain and functional syndromes with other causeseg, inammatory arthritis.13 Joint enlargement results from joint eusion, bony swelling, or both. A synovial eusion might not only be identied during osteoarthritis ares,
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but also during chronic phases as a persistent feature. Restricted passive movement can be the rst and sole physical sign of symptomatic disease. Bursitis, tendinitis, muscle spasm, and tissue response to, for instance, damaged meniscus can cause the same pain syndrome and must be carefully sought during examination. Crepitus, a sensation of crunching or crackling, is commonly felt on passive or active movement of a joint with osteoarthritis. Joint deformities relate to advanced disease with joint damage that involves cartilage, periarticular bone, synovium, articular capsule, ligaments, and muscles (gure 2). A joint can lock if loose bodies or fragments of cartilage (or meniscus) get into the joint space. Caution should be exercised to correctly attribute pain to the correct siteeg, patients with osteoarthritis of the hip might report knee pain because of referred pain or anserine bursitis. Additional neurological and spine examination is often needed. Imaging investigations are seldom needed to conrm the diagnosis; they might be useful to establish the severity of joint damage and to monitor disease progression. However, some sites and clinical scenarios need imaging assessment (including MRI or scintigraphy) to exclude other diseases, including avascular osteonecrosis, Pagets disease, complex regional pain syndrome, inammatory arthropathies, and stress fractures. Also, blood tests are not routinely needed in cases of uncomplicated chronic pain arising from clearly dened osteoarthritis. ESR and C-reactive protein are usually within the normal range. Some laboratory tests might be done to exclude other diseases, such as anticyclic citrullinated peptide antibodies for rheumatoid arthritis and uric acid for gout. Synovial uid should be assessed if another arthropathy or septic arthritis is suspected. In patients with osteoarthritis, synovial uid is sterile, without crystals, and a white-cell count of less than 1500 cells per L.
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Markers of tissue damage


Why there is little relation between clinical characteristics and structural tissue changes in osteoarthritis remains unclear.14,15 Insensitivity of available monitoring methods for damage to joint tissue combined with slow progression of this damage might underlie the discrepancy. Assessment of structural changes is a challenge in studying the disease and improving treatment modalities. Early and minimum tissue damage is dicult to assess in vivo. Biopsies for detailed histochemical and biochemical assessment of cartilage, bone, and synovial tissue in osteoarthritis are not feasible and are often contraindicated. Also, tissue changes are often focal and can be missed by random biopsy procedures. The exterior of the cartilage can be seen through arthroscopic procedures.16 However, these procedures involve invasive techniques, and there is doubt whether the various stages of degeneration or regeneration processes of the cartilage can be reliably detected.17 Therefore, at present only surrogate markers, as indirect measures of the actual destructive process, can be used for diagnosis and follow-up of tissue damage. There has been much eort to develop new biomarkers, in the hope that they will improve early diagnosis and treatment of the disease. However, although promising in research settings, there is little use for these markers in daily practice. Plain radiography is the gold standard in imaging of osteoarthritic joints, since the technique is inexpensive, fast, and easily available. Radiography has the advantage that high-resolution images can be obtained quickly and routinely under weight-bearing conditions. Restrictions are radiation exposure and that only calcied bone can be visualised, which provides an indirect measure of cartilage thickness without providing information about synovial tissue. Regulatory agencies (US Food and Drug Administration, European Medicines Agency) recommend joint-space narrowing on radiographs, in addition to pain and function, as coprimary endpoints, to establish the eectiveness of disease-modifying drugs.17 Kellgren and Lawrence classication18 has been developed as a radiological grading of osteoarthritis for several joints, including knees, hips, and hands.18 The classication focuses on a sequence of osteophyte formation, joint-space narrowing, and bone sclerosis, and provides simple and practical ordinal scales for each joint. Additional scores have been developed to provide a further subcategorisation of individual radiographic features of knee, hip, and hand joints.19 Interactive computerised measurements have improved standardised assessment of dierent radiographic features.2024 As expected, the more advanced the measurements, the more time consuming they are and the more complex analysis becomes. Improvement of scoring methods by making them more objective and reproducible is hampered by a lack of standardisation of the image acquisition. For instance, the position of the joint in the
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Panel: American College of Rheumatology radiological and clinical criteria for osteoarthritis of the knee and hip Hand (clinical) Osteoarthritis if 1, 2, 3, 4 or 1, 2, 3, 5 are present: 1 Hand pain, aching, or stiness for most days of previous month 2 Hard tissue enlargement of two or more of ten selected joints* 3 Swelling in two or more metacarpophalangeal joints 4 Hard tissue enlargement of two or more distal interphalangeal joints 5 Deformity of two or more of ten selected hand joints* Hip (clinical and radiographic) Osteoarthritis if 1, 2, 3 or 1, 2 ,4 or 1, 3, 4 are present: 1 Hip pain for most days of previous month 2 Erythrocyte sedimentation rate of less than 20 mm in the rst hour 3 Femoral or acetabular osteophytes on radiographs 4 Hip joint space narrowing on radiographs Knee (clinical) Osteoarthritis if 1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5 are present: 1 Knee pain for most days of previous month 2 Crepitus on active joint motion 3 Morning stiness lasting 30 min or less 4 Age 38 years or older 5 Bony enlargement of the knee on examination Knee (clinical and radiographic) Osteoarthritis if 1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present: 1 Knee pain for most days of previous month 2 Osteophytes at joint margins on radiographs 3 Synovial uid typical of osteoarthritis (laboratory) 4 Age 40 years or older 5 Crepitus on active joint motion 6 Morning stiness lasting 30 min or less
*Ten selected joints include bilateral second and third interphalangeal proximal joints, second and third proximal interphalangeal joints, and rst carpometacarpal joint.

x-ray beam is crucial for visualisation of the joint-space width and for the estimation of bone density and osteophyte area.25 Standardisation of radiographs is now the crucial step in the reproducibility of radiographic scoring. Reasonably, several radiographic views, including the patellofemoral joint for the knee and the so-called faux prole image for hip (with backwards rotated pelvis) improve the relation between clinical and radiographic changes.2629 Generally, clinically signicant changes in radiographic scores take at least 1 or even 2 years.30,31 For the knee, the smallest detectable dierence of joint-space width is about 020 mm by an expected average annual decrease of about 015 mm.32 More subtle changes can be detected in a shorter time through the use of advanced standardisation methods during image acquisition and more complex analyses, preferably of several images.3335
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Knee Occurrence Age, sex, physical activity, body-mass index (including obesity), intense sport activities, quadriceps strength, bone density, previous injury, hormone replacement therapy (protective), vitamin D, smoking (protective or deleterious), malalignment (including varus and valgus), genetics Age, body-mass index (including obesity), vitamin D, hormone replacement therapy (protective), malalignment (including varus and valgus), chronic joint eusion, synovitis, intense sport activities, subchondral bone oedema on MRI

Hip Age, physical activity, body-mass index (including obesity), previous injury, intense sport activities, genetics (including congenital deformities)

Hand Age, grip strength, occupation, intense sport activities, genetics

Progression

Age, symptomatic activity, sex, intense sport activities

Unknown

Table 1: Selected risk factors for the occurrence and progression of osteoarthritis in knees, hips, and hands

Weakening and contracture of ligaments and muscles Inammation of synovial tissue Cartilage damage and loss Outgrowth of bone (osteophytes) and attrition Changes in subchondral bone (sclerosis and cysts)

Figure 2: Schematic drawing of an osteoarthritic joint The dierent tissues involved in clinical and structural changes of the disease are shown on the left. Note that cartilage is the only tissue not innervated. On the right the bidirectional interplay between cartilage, bone, and synovial tissue involved in osteoarthritis is shown, and the two-way interaction between this interplay and the ligaments and muscles. In the interplay between cartilage, bone, and synovial tissue one of the tissues might dominate the disease, and as such should be targeted for treatment.

Apart from plain radiography, other imaging techniques have been further developed (table 2): CT, ultrasound, and MRI. Regular CT has similar disadvantages to plain radiography with clearly higher radiation exposure, but the advantage is a threedimensional image and the option of contrast agents (contrast enhanced CT) to visualise cartilage in addition to bone. Bone is innervated and evidence is accruing that bone changes might be an important source of pain in osteoarthritis.36 Assessment of CT has shown a strong relation between the dissolving of cystic bone areas and pain relief after treatment of end-stage osteoarthritis.37 Techniques are still improving,38,39 but are unlikely to become the standard. Ultrasound has the advantages that it also images softtissue structures (such as synovial tissue) in several planes, it does not need contrast agents, and it allows the visualisation of movement.40 Limitations exist in the depth that the signal can penetrate and the sites (tissues) that can be assessed. Most importantly, ultrasound is very dependent on the experience and skills of the user. The use of power doppler signal to image vascularisation41 and specic integrated techniques to assess cartilage
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thickness42 enhances its applications. Although the use of ultrasound to detect osteoarthritic pathological changes43 (specically in hand joints44,45) is increasing, its ultimate role in osteoarthritis is not certain. MRI provides objective quantitative assessment of morphology (volume, area, and thickness) and integrity (quality) of articular cartilage.46,47 A broad range of sequences and scoring systems allow for sensitive analyses of periarticular soft tissues in addition to cartilage and bone. Important limitations are cost, acquisition time (on average 45 min), complexity of the more advanced techniques, and time for whole-organ analyses. These limitations hamper the use of MRI for the imaging of osteoarthritis, although its value in identifying bonemarrow and meniscal lesions is well established.48 The use of fat-suppressed spoiled gradient echo sequences produces a high cartilage signal and low signal from adjacent joint uid, and at present is the standard for quantitative morphological imaging of cartilage.46,49 The availability of higher eld strengths, up to 3 tesla, makes these measurements even more accurate.32 Several semiquantitative scoring systems (table 2) have been developed that focus on the size and location of the lesions, and on subchondral, cartilaginous, bone, and other abnormalities. Apart from tissue-specic scores, whole-organ scores have been developed, such as the knee osteoarthritis scoring system,50 the wholeorgan magnetic resonance imaging score,51 and the Boston Leeds osteoarthritis knee score,52 each with their own advantages.32 More complex acquisition sequences have been developed that focus on cartilage quality; T2 MRI relaxation time is related to collagen orientation and density of articular cartilage;53 a possible relation with cartilage degeneration has been shown.54,55 Also, the T1 MRI technique provides information that allows proteoglycan distribution in articular cartilage to be mapped.53,56 The negatively charged proteoglycans are responsible for the xed charged density of the cartilage matrix that makes sodium MRI57 and delayed gadolinium-enhanced MRI of cartilage useful for visualising proteoglycan content.58 When given intravenously, gadolinium-diethylenetriamine penta-acetic acid homes in on regions of cartilage with low proteoglycan content.59 Some clinical applications have shown its value, but variables such as body-mass index,
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Primary use Plain radiograph* CT Standard* CECT Ultrasound Standard* Power doppler MRI Standard SPGR* T2 MRI relaxation T1
23

Analyses (Semi)quantitative

Advantages Low cost, easy applicable

Disadvantages Indirect, two-dimensional image of a three-dimensional problem Radiation exposure, only bone As standard plus contrast agent needed User dependent Relative importance for osteoarthritis Time-consuming analyses Complex interpretation Complex interpretation Field strength 3T Contrast agent needed Time consuming, observer variance Time consuming, observer variance Time consuming, observer variance

Cartilage thickness

Bone characteristics As standard plus cartilage volume Inammation Vascularisation Cartilage morphology Collagen distribution Proteoglycan distribution FCD/proteoglycan content FCD/proteoglycan content

Semiquantitative Semiquantitative Impression Semiquantitative Quantitative Semiquantitative Semiquantitative Semiquantitative Semiquantitative Semiquantitative Semiquantitative Semiquantitative

Three dimensional Three dimensional, information on cartilage Cheap Direct measure Three dimensional, quantitative Information on cartilage quality Information on cartilage quality Information on cartilage quality Information on cartilage quality, early changes Whole-organ score Whole-organ score Whole-organ score

Na MRI

dGEMRIC MRI whole-organ scoring KOSS WORMS BLOKS

CECT=contrast-enhanced CT. SPGR=spoiled gradient echo. FCD=xed charge density. dGEMRIC=delayed gadolinium-enhanced MRI of cartilage. KOSS=knee osteoarthritis scoring system. WORMS=whole-organ magnetic resonance imaging score. BLOKS=Boston Leeds osteoarthritis knee score. *Techniques that have a more common clinical and research applications for the assessment of cartilage (and bone), bone, and synovial inammation, as well as quantitative cartilage morphology (at present the most used MRI modality in clinical trials).

Table 2: Imaging techniques for assessment of tissue-structure changes in osteoarthritis

severity of synovitis, and subchondral bone alterations, make use of the technique complex.6062 Most of the developments in MRI involve the knee, much less research has been done on hips63 and hands.64 In general, MRI sequences and scoring systems provide good quantitative analyses of several joint structures, with more advanced techniques providing information about cartilage quality. Unfortunately, cost, acquisition, and analytical time restrict developments of these techniques in research settings and their use in daily clinical practice. In the future, MRI assessments in larger clinical trials might become standard; in todays practice they have value only for specic diagnostic questions. Biochemical markers of joint metabolism, disease, or both are molecules or molecular fragments that are released into biological uids (synovial uid, blood, and urine) from extracellular matrix turnover (synthesis and breakdown), such as collagen or proteoglycan fragments (or neo-epitopes) and cellular metabolism (eg, proteases or cytokines) of articular cartilage, subchondral bone, and synovial tissue. Biochemical markers seemed to help understand the pathophysiology of osteoarthritis and in the prediction of structural changes. However, breakthroughs have been sparse and there is doubt about how these markers might be used.65 We lack sucient knowledge about molecular validity, systemic origin, metabolism, and kinetics (absorption, distribution, and excretion) from many biochemical markers.66,67 The same marker might increase as well as decrease, dependent on the point in the degradation process.
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Urine and blood are the most relevant compartments in which to assess biomarkers. There are few studies of biomarkers reporting on their diagnostic and prognostic properties, their relation to burden of disease, and their relation to eectiveness of intervention. The relation of biomarkers with structural changes is in general better understood than their relation with clinical characteristics.68 Table 3 lists the most reported biomarkers and their performance. Markers of cartilage degradation, such as CTXII in urine and COMP in serum, have been assessed extensively and show a moderate to good relation with clinical and radiographic variables of osteoarthritis. Markers of bone metabolism are less eective, presumably because of the size of the bone compartment (mostly outside the joints) and the high turnover of bone. Not enough is known about markers of bone metabolism, which might have an important role in osteoarthritis since bone changes might be an important source of pain.36,69 Markers of synovial tissue metabolism are the least studied, but produce positive results, underscoring a role for inammation in osteoarthritis. Homogeneity of the studied population and standardisation of sample collection might improve the relation between a biomarker and clinical or radiographic characteristics, since diurnal rhythms and eects of exercise have been described for several markers.7072 None of the presently available biomarkers are suciently eective to aid diagnosis or prognosis of osteoarthritis in individual or small numbers of patients, nor are any so consistent that they could
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Diagnostic Relation to value burden of disease Cartilage degradation CTXII in urine* COMP in serum* Coll 2-1 (NO2) in urine and serum KS in serum YKL-40 in serum C2C in urine and serum C1,2C in urine and serum Cartilage synthesis PIIANP in serum* PIICP in serum CS846 in serum Bone degradation NTX-I in urine and serum* (D)PYR in urine CTXI in urine and serum Bone synthesis OC in serum* BSP in serum PINP in serum Synovium degradation HA in serum* Glc-Gal-PYR in urine Synovial synthesis PIIINP in serum 1/1 2/4 7/9 2/2 7/22 3/4 1/5 2/2 0/1 2/12 1/3 1/4 1/2 2/3 2/4 1/1 6/15 1/16 2/2 0/1 1/4 3/7 1/7 12/13 9/12 7/8 1/2 1/3 1/1 16/25 15/26 2/6 3/8 5/12 3/9 1/6

Prognostic value

Relation to ecacy of treatment

Overall positive proportion

17/23 6/17 2/4 3/5 0/4 0/4 0/4 2/3 0/4 0/3 2/5 0/10 1/6 2/6 0/2 0/4 8/11 0/2

4/5 1/2 1/2 1/1 1/3 0/2 0/1 2/2 2/2 0/1 1/2 1/3 0/1

74% 54% 61% 47% 35% 29% 8% 50% 27% 9% 60% 33% 15% 24% 43% 11% 51% 71% 43%

Data are n/N unless otherwise stated. Biomarkers with less than ve reports are not included. Data from van Spil and colleagues.68 *The most relevant and best performing commercial biomarkers. Combined biomarkers: Coll 2-1 with Coll 2-1 NO2 and PYR with D-PYR.

Table 3: Overview of published work on biomarkers over the past 5 years for knee and hip osteoarthritis

function as an outcome in clinical trials. More needs to be understood about biochemical markers, and combinations thereof, to make these markers of use in general clinical practice.

Treatment
In early osteoarthritis, pain and stiness dominate the other symptoms.73 Treatment should therefore focus on the reduction of pain and stiness and on the maintenance and improvement of functional capacities. Furthermore, prevention of progression of joint damage and improvement of quality of life are long-term goals. There are three treatment modalities: non-pharmacological, pharmacological, and surgical. In many patients these modalities are combined, tailored to individual needs and risk factors. The European League Against Rheumatism and the Osteoarthritis Research Society International have published evidence-based guidelines for the treatment of osteoarthritis.7478 Daily practice is based on these guidelines and updates from published work. Self-management interventions can be dened as patient centred and as designed to foster active participation
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of patients to promote wellbeing and to manage symptoms. These programmes in chronic diseases are now thought key elements of good-quality care.79 In long-term disease management these interventions seem to be eective and necessary for the compliance of patients, although there are few reported benets.80 Symptoms can be reduced by providing the patient with information about osteoarthritis, its symptoms, the objectives of its treatment, and the importance of changes in lifestylealthough the eect size of these interventions is small (<020).77,78 Pain has many components, and is also aected by comorbidities, such as sleeping problems, loneliness, and mood disorders;81 improvement of mental and social wellbeing is therefore also a target in some patients.82 There is evidence for a positive eect of exercise, pacing of activities, joint protection, weight reduction, and other measures to unload damaged joints (eect size 020050).7678 It is unclear if particular exercises are more benecial than others for specic joints. Probably the best exercises should be established through personalised advice, which takes into account individual factors. Exercises that strengthen muscles and improve aerobic condition are most eective, at least for osteoarthritis of the hip and knee.83 Weight reduction is not easy, but quite eective, especially in osteoarthritis of the knee. Randomised controlled trials have shown that weight reduction has led to lessening of pain and improvement of physical function,84 and recent research has also shown structural improvement of cartilage85 and positive changes in biomarkers of cartilage and bone.86 Unpopular measures such as braces, cranes, and other forms of joint protection might have a slight eect and are generally cost eective.87,88 These measures should be discussed with the individual patient. Commonly used treatment modalities are insoles, lasers,89 transcutaneous electrical nerve stimulation,90 ultrasound,91 electrotherapy,92 or acupuncture,93 but evidence is scarce, as is the eect size. However, applications of heat and ice are easy to use and quite eective.94 Paracetamol is the rst-choice oral analgesic for osteoarthritis because of its safety and eectiveness,7476 but patients have often used paracetamol with little eect before they visit their physician. Sometimes a dose increase to an optimum regimen for the individual patient is a therapeutic option, but often a non-steroidal anti-inammatory drug (NSAID) is added or substituted. The use of stronger analgesics, such as weak opioids and narcotic analgesics, is only indicated when other drugs (such as NSAIDs) have been ineective or are contraindicated.77 NSAIDs can be used in patients with symptomatic osteoarthritis of the hand, hip, or knee, preferably at the lowest eective dose and for the shortest duration.76,77 In patients with cardiovascular risk factors all NSAIDs,
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including both non-selective and cyclo-oxygenase-2 selective drugs should be used with caution and are sometimes contraindicated; the individual drug characteristics seem to be more relevant than the class of drug.78 In patients with high gastrointestinal risk, either a cyclo-oxygenase-2 selective drug or a non-selective NSAID with co-prescription of a proton pump inhibitor for gastroprotection, might be considered. A possible additional argument for the use of selective cyclooxygenase-2 drugs was reported in a trial comparing celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis.95 Both drugs were equally eective for the treatment of upper gastrointestinal problems, but celecoxib was better than diclofenac and omeprazole in the reduction of all gastrointestinal events (especially clinically signicant anaemia of presumed gastrointestinal origin). Another attempt to reduce the gastrointestinal and cardiovascular side-eects of NSAIDs is the linking of an NSAID with a nitric-oxide-donating group, which creates a cyclooxygenase-inhibiting nitric-oxide donor. Nitric oxide thus might help to maintain gastric integrity and cardiovascular homoeostasis.96,97 Topical NSAIDs are recommended as alternative or adjunctive treatment and have been reported to be as eective as and possibly safer than oral NSAIDs.98 The use of opioid analgesics for the treatment of osteoarthritis has risen, but a real improvement in osteoarthritic pain that has not responded to NSAIDs has been noted only with strong opioids (oxymorphone, oxycodone, oxytrex, fentanyl, morphine sulphate).99 This use is reserved for exceptional circumstances, such as patients awaiting planned surgery; there is a high (over 30%) withdrawal rate of patients treated, because of nausea, constipation, dizziness, somnolence, and vomiting.99 The ecacy of weaker opioids (tramadol or codeine) has not been assessed in long-term trials. Paracetamol codeine combinations provide a small (5%), but statistically signicant (p<005), benet over paracetamol alone, but are associated with more adverse events.100 In the absence of convincing evidence for their safe and eective use, concerns about risks of dependence or addiction to opiates aects the prescription of these drugs.77 Patients sometimes use a group of symptomatic slowacting drugs for osteoarthritisie, glucosamine sulphate, chondroitin sulphate, hyaluronic acidand, less commonly, avocado soybean unsaponiable, and diacerhein. Randomised trials with glucosamine sulphate have been debated heavilythere is concern about bias, heterogeneity of outcomes, and eect size.78 Most published studies show that glucosamine sulphate has a benecial eect on pain, with eect size ranging between 030 and 087,78 but no eect on function and controversial eects on structure modication.101,102 Whether glucosamine sulphate is eective in osteoarthritis remains undetermined.103 In the USA,
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glucosamine hydrochloride has been assessed thoroughly, but no benecial eect has been reported. There is less, but still conicting, evidence for the eectiveness of chondroitin sulphate on pain and function.104 Avocado soybean unsaponiables have been assessed for the treatment of osteoarthritis of the knee and hip, but not of the hand. This treatment was eective in relieving pain and improving function in hip more than in knee, osteoarthritis (eect size 001076).105 Avocado soybean unsaponiables are used in some regions of the world, but are unknown in others. Diacerein is reported to have slow-acting, but persistent, symptomatic relief in patients with osteoarthritis (eect size for pain 024; 95% CI 008039).78 Intra-articular injection of long-acting glucocorticoids is an eective treatment of inammatory ares of osteoarthritis (eect size for pain relief 058); the eect is greatest after 1 week, and diminishes thereafter.106 After injection of the weight-bearing large joints (ankle, knee, hip) the eectiveness of the injection can be enhanced by complete bed rest of the treated joint for 72 h.107 Hyaluronic acid has varying eectiveness when used for intra-articular injections for the treatment of osteoarthritis of the knee. Dierent products with dierent injection regimens (up to ve consecutive weekly injections) have been used (eect size up to 039).108 Investigators have suggested that the high molecular-weight products (even cross-linked components, such as Hylan G-F 20) need to be injected less often and improve eectiveness.78,109,110 A Cochrane review of surgical lavage and debridement in osteoarthritis of the knee111 showed no benet in the short or long term compared with placebo; in general this procedure is not advised. Other surgical interventions include osteotomy, joint fusion, joint distraction, and joint replacement. Joint replacement is very cost eective in patients with severe symptoms or functional limitations associated with a reduced quality of life, despite conservative treatment.77

New developments
New discoveries about the pathophysiology of osteoarthritis prompt the division of the disease into distinguishable phenotypes. Delineating the dierent clinical and structural phenotypes of the disease will improve understandingof disease in patients with pain, trauma, or obese-dominated clinical phenotypes (table 4 lists our attempt)and will also allow specic targeted treatment in those in whom structural changes in either cartilage, bone, or synovial tissue dominate the disease. Although these phenotypes are not yet fully characterised, distinguishing dierent phenotypes could herald the start of further discussions. Lack of in-depth understanding of disease pathogenesis and the misconception that all forms of osteoarthritis are the same and have the same clinical and structural characteristics might restrict further development of
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Post-traumatic (acute or repetitive) Age Main causative feature Young (<45 years) Mechanical stress

Metabolic Middle-aged (4565 years) Mechanical stress, adipokines, hyperglycaemia, oestrogen/ progesterone imbalance Knee, hand, generalised

Ageing Old (>65 years) AGE, chondrocyte senescence Hip, knee, hand

Genetic Variable Gene related

Pain Variable Inammation, bony changes, aberrant pain perception Hip, knee, hand Pain medication, anti-inammatory drugs

Main site Intervention

Knee, thumb, ankle, shoulder Joint protection, joint stabilisation, prevention of falls, surgical interventions

Hand, hip, spine No specic intervention, gene therapy

Weight loss, glycaemia control, lipid No specic intervention, sRAGE/AGE breakers control, hormone replacement therapy

Osteoarthritis is not one disease, and might benet from the recognition of its dierent phenotypes. AGE=advanced glycation endproducts. sRAGE=soluble receptor for advanced glycation endproducts.

Table 4: Proposal for dierentiation of clinical phenotypes of osteoarthritis

diagnosis, treatment, and monitoring of the many forms of the disease. A consensus on subgrouping osteoarthritis into such phenotypes will take time. In the structure phenotype, after entering a point of no return in which damage of the cartilage matrix over-rides synthesis, a vicious cycle of progressive damage ensues in which impaired biomechanical properties result in further damage.57 Autocrine loops of soluble factors released by the triggered chondrocytes112115 trigger an inammatory response that accelerates the breakdown process.8,9 This inammatory activity is enhanced by the accelerated release of catabolic cartilage constituents that provide an additional vicious cycle in the process of tissue destruction. The stiening of the subchondral bone (sclerosis) reported in the more advanced stages of the disease increases stresses in the overlying cartilage and adds to the damage. Also, in the early phase, subchondral bone changes might cause cartilage damage and might even precede it.10,11 Soluble factors produced locally in subchondral bone are potential candidates to act on deepzone articular chondrocytes to promote abnormal remodelling and metabolism of deep cartilage, leading to its breakdown.116118 This breakdown is facilitated by the interaction between bone and cartilage that was originally thought to be a tight interface, but is now recognised as allowing soluble factors to migrate between bone and cartilage.119121 Moreover, angiogenesis has been identied at the junction of articular hyaline cartilage and adjacent subchondral bone;122,123 and therefore tissue damage of the whole joint is also biochemical and not merely mechanical.124 In the age phenotype, chondrocytes sense alterations in mechanical stresses and, dependent on the context, respond with anabolic or catabolic biochemical processes.125,126 This cartilage degeneration is not merely mechanically induced wear and tear, but a complex of biochemical interactions. Ageing alters the response of chondrocytes: aged chondrocytes produce more inammatory cytokines, tissue degrading enzymes, and growth factors.127 Moreover, advanced glycation endproducts (AGEs), which accumulate in cartilage, can bind to specic receptors (receptor of advanced glycation endproducts;
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RAGE) expressed on chondrocytes, increasing their catabolic activity.128,129 AGE induces alteration of biomechanical properties by stiening the cartilage, which makes it brittle and more prone to damage. There is no clear clinical evidence of how AGE contributes to the development and progression of osteoarthritis.130 Development of soluble AGE receptors, sRAGE, that bind to AGEs and thereby inhibit the activation of cellsurface RAGE, showed ecacy in the treatment of vascular complications in animal models of diabetes. Also, prevention or reversal of AGE formation by diet or specic cleavage of AGE-crosslinks is subject to study and might become feasible. In the obesity phenotype, the overload eect on joint cartilage might, in part, explain the greater risk of osteoarthritis in overweight people. Advances in the physiology of adipose tissue provide further information about the relation between obesity and osteoarthritis.131 Indeed, a positive association between obesity and osteoarthritis has been reported for non-weight-bearing joints, such as those of the hands, and not only knee joints.132 These reports suggest that joint damage might be caused by systemic factors such as adipose factors, the so-called adipokines, which might provide a metabolic link between obesity and osteoarhtritis,133 and which, in addition to weight loss, could become a specic therapeutic target. Growing knowledge of the pathogenetic mechanisms involved in osteoarthritis will lead to the development of new classes of drugs for targeted treatment; many new pharmacological approaches in the management of osteoarthritis are under development.134 Calcitonin, a hormone of calcium homoeostasis, inhibits osteoclast activity and also has a direct eect on cartilage by the inhibition of matrix metalloproteinase activity. In a pilot study in patients with osetoathritis,135 CTXII, a degradation marker, decreased after patients were given oral calcitonin. At present, calcitonin is under investigation in a long-term randomised controlled trial. Nitric oxide is one of the catabolic mediators in cartilage and synovium. Inducible nitric oxide synthase is upregulated in osteoarthritis and in various pain states. At present, a study is assessing a specic inducible nitric
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oxide synthase inhibitor (SD-6010) in patients with knee osteoarthritis. Studies with bisphosphonates were done with the aim of inhibiting increased bone turnover in osteoarthritis; however, they were negative with regard to symptoms and radiological progression, although biochemical markers of cartilage turnover decreased.136 Advances in pain neurobiology have shown the role of supraspinal pathways and downstream neurotransmitters and eectors in chronic pain. Antibodies to nerve growth factor have been developed by several companies. The benet-to-risk ratio of these compounds is not yet clear and needs to be assessed further.137 Initial studies in patients with osteoarthritis have shown a slight clinical benet of the centrally acting compound duloxetine in patients with chronic painful osteoathritis.138 Duloxetine is a serotoninnorepinephrine reuptake inhibitor used in the treatment of depression, and also assessed in bromyalgia and diabetic peripheral neuropathy.
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