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Lancet 2011; 377: 2115–26

See Comment page 2067

This is the fi 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, Netherlandsj.w.j.bijlsma@umcutrecht.nl

Arthritis 1

Osteoarthritis: an update with relevance for clinical practiceJohannes 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 eff orts 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 specifi c 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 eff ectiveness. In the coming years, a better defi nition of osteoarthritis is expected by delineating diff erent phenotypes of the disease. Treatment targeted more specifi cally at these phenotypes might lead to improved outcomes.

IntroductionEpidemiologyThe prevalence of osteoarthritis is dependent on the precise defi nition used and on the site of interest. The knee, hip, and hand are most aff ected by the disease (fi gure 1). Osteoarthritis becomes more common with age, and after age 50 years more women than men are aff ected. 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 age-standardised and sex-standardised incidence of osteo-arthritis 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 identifi ed, and diff er on the basis of the joints involved (table 1).3

PathologyIn 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 chondrocytes—the cells that are responsible for the maintenance of a very large amount of extracellular matrix. At an early stage, in an attempt to eff ect 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

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 infl ammation corresponds to clinical symptoms such as joint swelling and infl ammatory pain, and it is thought to be secondary to cartilage debris and catabolic mediators entering the synovial cavity. Synovial macrophages produce catabolic and proinfl ammatory mediators and infl ammation starts negatively aff ecting the balance of cartilage matrix degradation and repair.9 This process in turn amplifi es synovial infl ammation, creating a vicious cycle. Synovial infl ammation happens in early as well as late phases of osteoarthritis and is seldom as severe as in rheumatoid

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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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 fi nal stage of the disease, but also at the onset of the disease—possibly before cartilage degradation.10,11 This fi nding led to the suggestion that subchondral bone could initiate cartilage damage.

Clinical features and diagnosisPain is the fi 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. Infl ammatory fl ares can happen during the course of the disease. Patients with osteoarthritis also experience stiff ness: in the morning, after a period of inactivity, or particularly in the evening. This stiff ness generally resolves in minutes, unlike the prolonged (usually >30 min) stiff ness 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 confi rm and characterise joint involvement, and to exclude pain and functional syndromes with other causes—eg, in-fl ammatory arthritis.13 Joint enlargement results from joint eff usion, bony swelling, or both. A synovial eff usion might not only be identifi ed during osteoarthritis fl ares,

but also during chronic phases as a persistent feature. Restricted passive movement can be the fi 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 (fi 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 site—eg, 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 confi rm 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, Paget’s disease, complex regional pain syndrome, infl ammatory arthropathies, and stress fractures. Also, blood tests are not routinely needed in cases of uncomplicated chronic pain arising from clearly defi ned osteoarthritis. ESR and C-reactive protein are usually within the normal range. Some laboratory tests might be done to exclude other diseases, such as anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis and uric acid for gout. Synovial fl uid should be assessed if another arthropathy or septic arthritis is suspected. In patients with osteoarthritis, synovial fl uid is sterile, without crystals, and a white-cell count of less than 1500 cells per μL.

Figure 1: Osteoarthritic joints of the hand, hip, and knee(A) Osteoarthritis is predominantly identifi ed in the distal interphalangeal and proximal interphalangeal joints—deformations 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.

A B C

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Markers of tissue damageWhy 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. Assess-ment of structural changes is a challenge in studying the disease and improving treatment modalities.

Early and minimum tissue damage is diffi cult 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 eff ort 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 calcifi ed 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) recom-mend joint-space narrowing on radiographs, in addition to pain and function, as coprimary endpoints, to establish the eff ectiveness of disease-modifying drugs.17

Kellgren and Lawrence classifi cation18 has been developed as a radiological grading of osteoarthritis for several joints, including knees, hips, and hands.18 The classifi cation 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 standard-ised assessment of diff erent radiographic features.20–24 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

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 profi le image for hip (with backwards rotated pelvis) improve the relation between clinical and radiographic changes.26–29

Generally, clinically signifi cant changes in radiographic scores take at least 1 or even 2 years.30,31 For the knee, the smallest detectable diff erence of joint-space width is about 0·20 mm by an expected average annual decrease of about 0·15 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.33–35

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 stiff ness for most days of

previous month2 Hard tissue enlargement of two or more of ten selected

joints*3 Swelling in two or more metacarpophalangeal joints4 Hard tissue enlargement of two or more distal

interphalangeal joints5 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 month2 Erythrocyte sedimentation rate of less than 20 mm in the

fi rst hour3 Femoral or acetabular osteophytes on radiographs4 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 month2 Crepitus on active joint motion3 Morning stiff ness lasting 30 min or less4 Age 38 years or older5 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 month2 Osteophytes at joint margins on radiographs3 Synovial fl uid typical of osteoarthritis (laboratory)4 Age 40 years or older5 Crepitus on active joint motion6 Morning stiff ness lasting 30 min or less

*Ten selected joints include bilateral second and third interphalangeal proximal joints, second and third proximal interphalangeal joints, and fi rst carpometacarpal joint.

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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 three-dimensional 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 soft-tissue 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 specifi c integrated techniques to assess cartilage

thickness42 enhances its applications. Although the use of ultrasound to detect osteoarthritic pathological changes43 (specifi cally 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 bone-marrow 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 fl uid, and at present is the standard for quantitative morphological imaging of cartilage.46,49 The availability of higher fi 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-specifi c scores, whole-organ scores have been developed, such as the knee osteoarthritis scoring system,50 the whole-organ 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 T1ρ MRI technique provides information that allows proteoglycan distribution in articular cartilage to be mapped.53,56 The negatively charged proteoglycans are responsible for the fi 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,

Knee Hip Hand

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

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

Progression Age, body-mass index (including obesity), vitamin D, hormone replacement therapy (protective), malalignment (including varus and valgus), chronic joint eff usion, synovitis, intense sport activities, subchondral bone oedema on MRI

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

Figure 2: Schematic drawing of an osteoarthritic jointThe diff erent 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.

Weakening and contracture of ligaments and muscles

Inflammation ofsynovial tissue

Cartilage damageand loss

Outgrowth of bone(osteophytes)and attrition

Changes in subchondralbone (sclerosis and cysts)

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severity of synovitis, and subchondral bone alterations, make use of the technique complex.60–62 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 today’s practice they have value only for specifi c diagnostic questions.

Biochemical markers of joint metabolism, disease, or both are molecules or molecular fragments that are released into biological fl uids (synovial fl 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 suffi cient 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.

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 eff ectiveness 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 eff ective, 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 infl ammation 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 eff ects of exercise have been described for several markers.70–72

None of the presently available biomarkers are suffi ciently eff ective to aid diagnosis or prognosis of osteoarthritis in individual or small numbers of patients, nor are any so consistent that they could

Primary use Analyses Advantages Disadvantages

Plain radiograph* Cartilage thickness (Semi)quantitative Low cost, easy applicable Indirect, two-dimensional image of a three-dimensional problem

CT

Standard* Bone characteristics Semiquantitative Three dimensional Radiation exposure, only bone

CECT As standard plus cartilage volume Semiquantitative Three dimensional, information on cartilage As standard plus contrast agent needed

Ultrasound

Standard* Infl ammation Impression Cheap User dependent

Power doppler Vascularisation Semiquantitative Direct measure Relative importance for osteoarthritis

MRI

Standard SPGR* Cartilage morphology Quantitative Three dimensional, quantitative Time-consuming analyses

T2 MRI relaxation Collagen distribution Semiquantitative Information on cartilage quality Complex interpretation

T1ρ Proteoglycan distribution Semiquantitative Information on cartilage quality Complex interpretation

23Na MRI FCD/proteoglycan content Semiquantitative Information on cartilage quality Field strength ≥3T

dGEMRIC FCD/proteoglycan content Semiquantitative Information on cartilage quality, early changes Contrast agent needed

MRI whole-organ scoring

KOSS ·· Semiquantitative Whole-organ score Time consuming, observer variance

WORMS ·· Semiquantitative Whole-organ score Time consuming, observer variance

BLOKS ·· Semiquantitative Whole-organ score Time consuming, observer variance

CECT=contrast-enhanced CT. SPGR=spoiled gradient echo. FCD=fi 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 infl ammation, 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

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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.

TreatmentIn early osteoarthritis, pain and stiff ness dominate the other symptoms.73 Treatment should therefore focus on the reduction of pain and stiff ness 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.74–78 Daily practice is based on these guidelines and updates from published work.

Self-management interventions can be defi ned as patient centred and as designed to foster active participation

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 eff ective and necessary for the compliance of patients, although there are few reported benefi ts.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 lifestyle—although the eff ect size of these interventions is small (<0·20).77,78 Pain has many components, and is also aff ected 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 eff ect of exercise, pacing of activities, joint protection, weight reduction, and other measures to unload damaged joints (eff ect size 0·20–0·50).76–78 It is unclear if particular exercises are more benefi cial than others for specifi c 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 eff ective, at least for osteoarthritis of the hip and knee.83

Weight reduction is not easy, but quite eff ective, 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 eff ect and are generally cost eff ective.87,88 These measures should be discussed with the individual patient.

Commonly used treatment modalities are insoles, lasers,89 transcutaneous electrical nerve stimulation,90 ultra sound,91 electrotherapy,92 or acupuncture,93 but evidence is scarce, as is the eff ect size. However, applications of heat and ice are easy to use and quite eff ective.94

Paracetamol is the fi rst-choice oral analgesic for osteoarthritis because of its safety and eff ectiveness,74–76 but patients have often used paracetamol with little eff ect 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-infl ammatory 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 ineff ective or are contraindicated.77

NSAIDs can be used in patients with symptomatic osteoarthritis of the hand, hip, or knee, preferably at the lowest eff ective dose and for the shortest duration.76,77 In patients with cardiovascular risk factors all NSAIDs,

Diagnostic value

Relation to burden of disease

Prognostic value

Relation to effi cacy of treatment

Overall positive proportion

Cartilage degradation

CTXII in urine* 12/13 16/25 17/23 4/5 74%

COMP in serum* 9/12 15/26 6/17 1/2 54%

Coll 2-1 (NO2)† in urine and serum 7/8 2/6 2/4 ·· 61%

KS in serum 1/2 3/8 3/5 1/2 47%

YKL-40 in serum 1/3 5/12 0/4 1/1 35%

C2C in urine and serum 1/1 3/9 0/4 1/3 29%

C1,2C in urine and serum ·· 1/6 0/4 0/2 8%

Cartilage synthesis

PIIANP in serum* 2/2 1/4 2/3 0/1 50%

PIICP in serum ·· 3/7 0/4 ·· 27%

CS846 in serum 0/1 1/7 0/3 ·· 9%

Bone degradation

NTX-I in urine and serum* 1/2 1/1 2/5 2/2 60%

(D)PYR† in urine 2/3 6/15 0/10 2/2 33%

CTXI in urine and serum 2/4 1/16 1/6 0/1 15%

Bone synthesis

OC in serum* 1/5 2/12 2/6 1/2 24%

BSP in serum 2/2 1/3 0/2 ·· 43%

PINP in serum 0/1 1/4 0/4 ·· 11%

Synovium degradation

HA in serum* 7/9 7/22 8/11 1/3 51%

Glc-Gal-PYR in urine 2/2 3/4 ·· 0/1 71%

Synovial synthesis

PIIINP in serum 1/1 2/4 0/2 ·· 43%

Data are n/N unless otherwise stated. Biomarkers with less than fi 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

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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 cyclo-oxygenase-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 eff ective for the treatment of upper gastrointestinal problems, but celecoxib was better than diclofenac and omeprazole in the reduction of all gastrointestinal events (especially clinically signifi cant anaemia of presumed gastrointestinal origin). Another attempt to reduce the gastrointestinal and cardiovascular side-eff ects of NSAIDs is the linking of an NSAID with a nitric-oxide-donating group, which creates a cyclo-oxygenase-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 eff ective 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 circum stances, 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 effi cacy of weaker opioids (tramadol or codeine) has not been assessed in long-term trials. Paracetamol–codeine combinations provide a small (5%), but statistically signifi cant (p<0·05), benefi t over paracetamol alone, but are associated with more adverse events.100 In the absence of convincing evidence for their safe and eff ective use, concerns about risks of dependence or addiction to opiates aff ects the prescription of these drugs.77

Patients sometimes use a group of symptomatic slow-acting drugs for osteoarthritis—ie, glucosamine sulphate, chondroitin sulphate, hyaluronic acid—and, less commonly, avocado soybean unsaponifi able, and diacerhein. Randomised trials with glucosamine sulphate have been debated heavily—there is concern about bias, heterogeneity of outcomes, and eff ect size.78 Most published studies show that glucosamine sulphate has a benefi cial eff ect on pain, with eff ect size ranging between 0·30 and 0·87,78 but no eff ect on function and controversial eff ects on structure modifi cation.101,102 Whether glucosamine sulphate is eff ective in osteoarthritis remains undetermined.103 In the USA,

glucosamine hydrochloride has been assessed thoroughly, but no benefi cial eff ect has been reported.

There is less, but still confl icting, evidence for the eff ectiveness of chondroitin sulphate on pain and function.104 Avocado soybean unsaponifi ables have been assessed for the treatment of osteoarthritis of the knee and hip, but not of the hand. This treatment was eff ective in relieving pain and improving function in hip more than in knee, osteoarthritis (eff ect size 0·01–0·76).105 Avocado soybean unsaponifi ables 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 (eff ect size for pain 0·24; 95% CI 0·08–0·39).78

Intra-articular injection of long-acting glucocorticoids is an eff ective treatment of infl ammatory fl ares of osteoarthritis (eff ect size for pain relief 0·58); the eff ect is greatest after 1 week, and diminishes thereafter.106 After injection of the weight-bearing large joints (ankle, knee, hip) the eff ectiveness of the injection can be enhanced by complete bed rest of the treated joint for 72 h.107

Hyaluronic acid has varying eff ectiveness when used for intra-articular injections for the treatment of osteoarthritis of the knee. Diff erent products with diff erent injection regimens (up to fi ve consecutive weekly injections) have been used (eff ect size up to 0·39).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 eff ectiveness.78,109,110

A Cochrane review of surgical lavage and debridement in osteoarthritis of the knee111 showed no benefi t 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 eff ective in patients with severe symptoms or functional limitations associated with a reduced quality of life, despite conservative treatment.77

New developmentsNew discoveries about the pathophysiology of osteoarthritis prompt the division of the disease into distinguishable phenotypes. Delineating the diff erent clinical and structural phenotypes of the disease will improve understanding—of disease in patients with pain, trauma, or obese-dominated clinical phenotypes (table 4 lists our attempt)—and will also allow specifi c 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 diff erent 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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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.5–7 Autocrine loops of soluble factors released by the triggered chondrocytes112–115 trigger an infl ammatory response that accelerates the breakdown process.8,9 This infl ammatory activity is enhanced by the accelerated release of catabolic cartilage constituents that provide an additional vicious cycle in the process of tissue destruction. The stiff ening 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 deep-zone articular chondrocytes to promote abnormal remodelling and metabolism of deep cartilage, leading to its breakdown.116–118 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.119–121 Moreover, angiogenesis has been identifi ed 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 infl ammatory cytokines, tissue degrading enzymes, and growth factors.127 Moreover, advanced glycation endproducts (AGEs), which accumulate in cartilage, can bind to specifi c receptors (receptor of advanced glycation endproducts;

RAGE) expressed on chondrocytes, increasing their catabolic activity.128,129 AGE induces alteration of bio-mechanical properties by stiff ening 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 cell-surface RAGE, showed effi cacy in the treatment of vascular complications in animal models of diabetes. Also, prevention or reversal of AGE formation by diet or specifi c cleavage of AGE-crosslinks is subject to study and might become feasible.

In the obesity phenotype, the overload eff ect 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 specifi c 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 eff ect 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 specifi c inducible nitric

Post-traumatic (acute or repetitive)

Metabolic Ageing Genetic Pain

Age Young (<45 years) Middle-aged (45–65 years) Old (>65 years) Variable Variable

Main causative feature Mechanical stress Mechanical stress, adipokines, hyperglycaemia, oestrogen/progesterone imbalance

AGE, chondrocyte senescence

Gene related Infl ammation, bony changes, aberrant pain perception

Main site Knee, thumb, ankle, shoulder Knee, hand, generalised Hip, knee, hand Hand, hip, spine Hip, knee, hand

Intervention Joint protection, joint stabilisation, prevention of falls, surgical interventions

Weight loss, glycaemia control, lipid control, hormone replacement therapy

No specifi c intervention, sRAGE/AGE breakers

No specifi c intervention, gene therapy

Pain medication, anti-infl ammatory drugs

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

Table 4: Proposal for diff erentiation of clinical phenotypes of osteoarthritis

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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 neuro trans-mitters and eff ectors in chronic pain. Antibodies to nerve growth factor have been developed by several companies. The benefi t-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 benefi t of the centrally acting compound duloxetine in patients with chronic painful osteoathritis.138 Duloxetine is a serotonin–norepinephrine reuptake inhibitor used in the treatment of depression, and also assessed in fi bromyalgia and diabetic peripheral neuropathy.

ContributorsAll authors contributed equally to the search of published work, the

discussions, and writing. All authors gave their fi nal approval for the

decision to submit for publication.

Confl icts of interestWe declare that we have no confl icts of interest.

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