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Osteoarthritis: An update with relevance for clinical practice

Article in The Lancet · June 2011

DOI: 10.1016/S0140-6736(11)60243-2 · Source: PubMed

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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 Lancet 2011; 377: 2115–26
because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features See Comment page 2067
that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians This is the first in a Series of
recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much three papers about arthritis
help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging Department of Rheumatology
procedures and biochemical marker analyses need to be improved and possibly extended with more specific and and Clinical Immunology,
University Medical Centre
sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients Utrecht, Utrecht, Netherlands
according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a (Prof J W J Bijlsma MD,
better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted F P J G Lafeber PhD); and
more specifically at these phenotypes might lead to improved outcomes. Department of Rheumatology,
Pierre and Marie Curie
University, Hospital
Introduction fails and leads to an imbalance in favour of degradation. Saint-Antoine, Paris, France
Epidemiology Increased synthesis of tissue-destructive proteinases (F Berenbaum MD)
The prevalence of osteoarthritis is dependent on the (matrix metalloproteinases and agrecanases),6,7 increased Correspondence to:
precise definition used and on the site of interest. The apoptotic death of chondrocytes, and inadequate Prof Johannes W J Bijlsma,
University Medical Centre
knee, hip, and hand are most affected by the disease synthesis of components of the extracellular matrix, lead Utrecht, Department of
(figure 1). Osteoarthritis becomes more common with to the formation of a matrix that is unable to withstand Rheumatology and Clinical
age, and after age 50 years more women than men are normal mechanical stresses. Consequently, the tissue Immunology, PO Box 85.500,
affected. For example, the Rotterdam study1 of a enters a vicious cycle in which breakdown dominates Utrecht, 3508 GA, Netherlands
[email protected]
population-based cohort of 3906 people 55 years or older synthesis of extracellular matrix. Since articular cartilage
reported that 67% of women and 55% of men had is aneural, these changes do not produce clinical signs
radiographic osteoarthritis of the hand. In people older unless innervated tissues become involved. This is one
than 80 years, 53% of women and 33% of men had reason for the late diagnosis of osteoarthritis.
radiographic osteoarthritis of the knee. The age- Although the pathophysiology of osteoarthritis has
standardised and sex-standardised incidence of osteo- long been thought to be cartilage driven, recent evidence
arthritis of the hand is 100 per 100 000 person-years, for shows an additional and integrated role of bone and
the hip is 88 per 100 000 person-years, and for the knee is synovial tissue, and patchy chronic synovitis is evident in
240 per 100 000 person-years.2 the disease.8 Synovial inflammation corresponds to
Osteoarthritis in general develops progressively over clinical symptoms such as joint swelling and
several years, although symptoms might remain stable inflammatory pain, and it is thought to be secondary to
for long periods within this period. The diagnosis of the cartilage debris and catabolic mediators entering the
disease relies on clinical and radiological features synovial cavity. Synovial macrophages produce catabolic
(panel).3 Nearly half of patients with radiological features and proinflammatory mediators and inflammation starts
of osteoarthritis have no symptoms and vice versa. Risk negatively affecting the balance of cartilage matrix
factors for occurrence and progression of osteoarthritis degradation and repair.9 This process in turn amplifies
have been identified, and differ on the basis of the joints synovial inflammation, creating a vicious cycle. Synovial
involved (table 1).3 inflammation 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 Search strategy and selection criteria
failure of the repair process of damaged cartilage due to The information in our paper is primarily based on PubMed
biomechanical and biochemical changes in the joint. searches with the terms “osteoarthritis” in combination with
Cartilage is non-vascularised, so this restricts the supply “cartilage”, “bone”, “synovitis”, “imaging”, “biomarker”, and
of nutrients and oxygen to the chondrocytes—the cells “treatment”. We mainly included papers from the past
that are responsible for the maintenance of a very large 5 years, with the addition of highly regarded older papers. We
amount of extracellular matrix. At an early stage, in an also included some review articles and book chapters as
attempt to effect a repair, clusters of chondrocytes form comprehensive overviews, the details of which are beyond
in the damaged areas and the concentration of growth the scope of our report.
factors in the matrix rises.4,5 This attempt subsequently

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A B C

Figure 1: Osteoarthritic joints of the hand, hip, and knee

(A) Osteoarthritis is predominantly identified 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.

arthritis, but it might add to the vicious cycle of but also during chronic phases as a persistent feature.
progressive joint degeneration. Restricted passive movement can be the first and sole
The main characteristics of osteoarthritis are changes physical sign of symptomatic disease. Bursitis, tendinitis,
in the subchondral bone. Osteophyte formation, bone muscle spasm, and tissue response to, for instance,
remodelling, subchondral sclerosis, and attrition are damaged meniscus can cause the same pain syndrome
crucial for radiological diagnosis. Several of these bone and must be carefully sought during examination.
changes take place not only during the final stage of the Crepitus, a sensation of crunching or crackling, is
disease, but also at the onset of the disease—possibly commonly felt on passive or active movement of a joint
before cartilage degradation.10,11 This finding led to the with osteoarthritis. Joint deformities relate to advanced
suggestion that subchondral bone could initiate disease with joint damage that involves cartilage,
cartilage damage. periarticular bone, synovium, articular capsule,
ligaments, and muscles (figure 2). A joint can lock if
Clinical features and diagnosis loose bodies or fragments of cartilage (or meniscus) get
Pain is the first and predominant symptom of into the joint space. Caution should be exercised to
osteoarthritis that causes patients to visit their family correctly attribute pain to the correct site—eg, patients
doctor. The pain experienced is intermittent, typically with osteoarthritis of the hip might report knee pain
worst during and after weight-bearing activities. because of referred pain or anserine bursitis. Additional
Inflammatory flares can happen during the course of the neurological and spine examination is often needed.
disease. Patients with osteoarthritis also experience Imaging investigations are seldom needed to confirm
stiffness: in the morning, after a period of inactivity, or the diagnosis; they might be useful to establish the
particularly in the evening. This stiffness generally severity of joint damage and to monitor disease
resolves in minutes, unlike the prolonged (usually progression. However, some sites and clinical scenarios
>30 min) stiffness caused by rheumatoid arthritis. need imaging assessment (including MRI or scintigraphy)
Loss of movement and function is another reason to exclude other diseases, including avascular
patients visit their family doctor. Patients report osteonecrosis, Paget’s disease, complex regional pain
symptoms that limit their day-to-day activities, such as syndrome, inflammatory arthropathies, and stress
stair climbing, walking, and doing household chores. fractures. Also, blood tests are not routinely needed in
Symptomatic osteoarthritis might be associated with cases of uncomplicated chronic pain arising from clearly
depression and disturbed sleep, which additionally defined osteoarthritis. ESR and C-reactive protein are
contribute to disability. The symptoms of osteoarthritis usually within the normal range. Some laboratory tests
diminish the patients’ quality of life.12 might be done to exclude other diseases, such as anti-
Physical examination is needed to confirm and cyclic citrullinated peptide antibodies for rheumatoid
characterise joint involvement, and to exclude pain and arthritis and uric acid for gout. Synovial fluid should be
functional syndromes with other causes—eg, in- assessed if another arthropathy or septic arthritis is
flammatory arthritis.13 Joint enlargement results from suspected. In patients with osteoarthritis, synovial fluid
joint effusion, bony swelling, or both. A synovial effusion is sterile, without crystals, and a white-cell count of less
might not only be identified during osteoarthritis flares, than 1500 cells per μL.

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Markers of tissue damage

Why there is little relation between clinical characteristics Panel: American College of Rheumatology radiological and
and structural tissue changes in osteoarthritis remains clinical criteria for osteoarthritis of the knee and hip
unclear.14,15 Insensitivity of available monitoring methods Hand (clinical)
for damage to joint tissue combined with slow progression Osteoarthritis if 1, 2, 3, 4 or 1, 2, 3, 5 are present:
of this damage might underlie the discrepancy. Assess- 1 Hand pain, aching, or stiffness for most days of
ment of structural changes is a challenge in studying the previous month
disease and improving treatment modalities. 2 Hard tissue enlargement of two or more of ten selected
Early and minimum tissue damage is difficult to assess joints*
in vivo. Biopsies for detailed histochemical and 3 Swelling in two or more metacarpophalangeal joints
biochemical assessment of cartilage, bone, and synovial 4 Hard tissue enlargement of two or more distal
tissue in osteoarthritis are not feasible and are often interphalangeal joints
contraindicated. Also, tissue changes are often focal and 5 Deformity of two or more of ten selected hand joints*
can be missed by random biopsy procedures.
The exterior of the cartilage can be seen through Hip (clinical and radiographic)
arthroscopic procedures.16 However, these procedures Osteoarthritis if 1, 2, 3 or 1, 2 ,4 or 1, 3, 4 are present:
involve invasive techniques, and there is doubt whether 1 Hip pain for most days of previous month
the various stages of degeneration or regeneration 2 Erythrocyte sedimentation rate of less than 20 mm in the
processes of the cartilage can be reliably detected.17 first hour
Therefore, at present only surrogate markers, as 3 Femoral or acetabular osteophytes on radiographs
indirect measures of the actual destructive process, can 4 Hip joint space narrowing on radiographs
be used for diagnosis and follow-up of tissue damage. Knee (clinical)
There has been much effort to develop new biomarkers, Osteoarthritis if 1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5 are present:
in the hope that they will improve early diagnosis and 1 Knee pain for most days of previous month
treatment of the disease. However, although promising 2 Crepitus on active joint motion
in research settings, there is little use for these markers 3 Morning stiffness lasting 30 min or less
in daily practice. 4 Age 38 years or older
Plain radiography is the gold standard in imaging of 5 Bony enlargement of the knee on examination
osteoarthritic joints, since the technique is inexpensive,
fast, and easily available. Radiography has the advantage Knee (clinical and radiographic)
that high-resolution images can be obtained quickly and Osteoarthritis if 1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present:
routinely under weight-bearing conditions. Restrictions 1 Knee pain for most days of previous month
are radiation exposure and that only calcified bone can be 2 Osteophytes at joint margins on radiographs
visualised, which provides an indirect measure of 3 Synovial fluid typical of osteoarthritis (laboratory)
cartilage thickness without providing information about 4 Age 40 years or older
synovial tissue. Regulatory agencies (US Food and Drug 5 Crepitus on active joint motion
Administration, European Medicines Agency) recom- 6 Morning stiffness lasting 30 min or less
mend joint-space narrowing on radiographs, in addition *Ten selected joints include bilateral second and third interphalangeal proximal joints,
to pain and function, as coprimary endpoints, to establish second and third proximal interphalangeal joints, and first carpometacarpal joint.
the effectiveness of disease-modifying drugs.17
Kellgren and Lawrence classification18 has been x-ray beam is crucial for visualisation of the joint-space
developed as a radiological grading of osteoarthritis for width and for the estimation of bone density and
several joints, including knees, hips, and hands.18 The osteophyte area.25 Standardisation of radiographs is now
classification focuses on a sequence of osteophyte the crucial step in the reproducibility of radiographic
formation, joint-space narrowing, and bone sclerosis, scoring. Reasonably, several radiographic views,
and provides simple and practical ordinal scales for each including the patellofemoral joint for the knee and the
joint. Additional scores have been developed to provide a so-called faux profile image for hip (with backwards
further subcategorisation of individual radiographic rotated pelvis) improve the relation between clinical and
features of knee, hip, and hand joints.19 Interactive radiographic changes.26–29
computerised measurements have improved standard- Generally, clinically significant changes in radiographic
ised assessment of different radiographic features.20–24 As scores take at least 1 or even 2 years.30,31 For the knee, the
expected, the more advanced the measurements, the smallest detectable difference of joint-space width is
more time consuming they are and the more complex about 0·20 mm by an expected average annual decrease
analysis becomes. Improvement of scoring methods by of about 0·15 mm.32 More subtle changes can be detected
making them more objective and reproducible is in a shorter time through the use of advanced
hampered by a lack of standardisation of the image standardisation methods during image acquisition and
acquisition. For instance, the position of the joint in the more complex analyses, preferably of several images.33–35

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Knee Hip Hand

Occurrence Age, sex, physical activity, body-mass index (including Age, physical activity, body-mass index (including Age, grip strength, occupation, intense sport
obesity), intense sport activities, quadriceps strength, bone obesity), previous injury, intense sport activities, genetics activities, genetics
density, previous injury, hormone replacement therapy (including congenital deformities)
(protective), vitamin D, smoking (protective or deleterious),
malalignment (including varus and valgus), genetics
Progression Age, body-mass index (including obesity), vitamin D, Age, symptomatic activity, sex, intense sport activities Unknown
hormone replacement therapy (protective), malalignment
(including varus and valgus), chronic joint effusion, synovitis,
intense sport activities, subchondral bone oedema on MRI

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

thickness42 enhances its applications. Although the use of

Weakening and
ultrasound to detect osteoarthritic pathological changes43
contracture of (specifically in hand joints44,45) is increasing, its ultimate
ligaments role in osteoarthritis is not certain.
and muscles
MRI provides objective quantitative assessment of
Inflammation of morphology (volume, area, and thickness) and integrity
synovial tissue
(quality) of articular cartilage.46,47 A broad range of
Cartilage damage sequences and scoring systems allow for sensitive
and loss
analyses of periarticular soft tissues in addition to cartilage
Outgrowth of bone and bone. Important limitations are cost, acquisition time
(osteophytes)
and attrition
(on average 45 min), complexity of the more advanced
techniques, and time for whole-organ analyses. These
Changes in subchondral
bone (sclerosis and cysts)
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
Figure 2: Schematic drawing of an osteoarthritic joint sequences produces a high cartilage signal and low signal
The different 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 from adjacent joint fluid, and at present is the standard
synovial tissue involved in osteoarthritis is shown, and the two-way interaction between this interplay and the for quantitative morphological imaging of cartilage.46,49
ligaments and muscles. In the interplay between cartilage, bone, and synovial tissue one of the tissues might The availability of higher field strengths, up to 3 tesla,
dominate the disease, and as such should be targeted for treatment.
makes these measurements even more accurate.32
Several semiquantitative scoring systems (table 2)
Apart from plain radiography, other imaging have been developed that focus on the size and location
techniques have been further developed (table 2): CT, of the lesions, and on subchondral, cartilaginous, bone,
ultrasound, and MRI. Regular CT has similar and other abnormalities. Apart from tissue-specific
disadvantages to plain radiography with clearly higher scores, whole-organ scores have been developed, such
radiation exposure, but the advantage is a three- as the knee osteoarthritis scoring system,50 the whole-
dimensional image and the option of contrast agents organ magnetic resonance imaging score,51 and the
(contrast enhanced CT) to visualise cartilage in addition Boston Leeds osteoarthritis knee score,52 each with their
to bone. Bone is innervated and evidence is accruing own advantages.32
that bone changes might be an important source of More complex acquisition sequences have been
pain in osteoarthritis.36 Assessment of CT has shown a developed that focus on cartilage quality; T2 MRI relaxation
strong relation between the dissolving of cystic bone time is related to collagen orientation and density of
areas and pain relief after treatment of end-stage articular cartilage;53 a possible relation with cartilage
osteoarthritis.37 Techniques are still improving,38,39 but degeneration has been shown.54,55 Also, the T1ρ MRI
are unlikely to become the standard. technique provides information that allows proteoglycan
Ultrasound has the advantages that it also images soft- distribution in articular cartilage to be mapped.53,56 The
tissue structures (such as synovial tissue) in several negatively charged proteoglycans are responsible for the
planes, it does not need contrast agents, and it allows the fixed charged density of the cartilage matrix that makes
visualisation of movement.40 Limitations exist in the sodium MRI57 and delayed gadolinium-enhanced MRI of
depth that the signal can penetrate and the sites (tissues) cartilage useful for visualising proteoglycan content.58
that can be assessed. Most importantly, ultrasound is When given intravenously, gadolinium-diethylenetriamine
very dependent on the experience and skills of the user. penta-acetic acid homes in on regions of cartilage with low
The use of power doppler signal to image vascularisation41 proteoglycan content.59 Some clinical applications have
and specific integrated techniques to assess cartilage shown its value, but variables such as body-mass index,

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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* Inflammation 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
23
Na 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=fixed 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 inflammation, 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, Urine and blood are the most relevant compartments
make use of the technique complex.60–62 Most of the in which to assess biomarkers. There are few studies of
developments in MRI involve the knee, much less research biomarkers reporting on their diagnostic and prognostic
has been done on hips63 and hands.64 properties, their relation to burden of disease, and their
In general, MRI sequences and scoring systems relation to effectiveness of intervention. The relation of
provide good quantitative analyses of several joint biomarkers with structural changes is in general
structures, with more advanced techniques providing better understood than their relation with clinical
information about cartilage quality. Unfortunately, cost, characteristics.68
acquisition, and analytical time restrict developments of Table 3 lists the most reported biomarkers and their
these techniques in research settings and their use in performance. Markers of cartilage degradation, such as
daily clinical practice. In the future, MRI assessments CTXII in urine and COMP in serum, have been assessed
in larger clinical trials might become standard; in extensively and show a moderate to good relation with
today’s practice they have value only for specific clinical and radiographic variables of osteoarthritis.
diagnostic questions. Markers of bone metabolism are less effective,
Biochemical markers of joint metabolism, disease, or presumably because of the size of the bone compartment
both are molecules or molecular fragments that are (mostly outside the joints) and the high turnover of bone.
released into biological fluids (synovial fluid, blood, and Not enough is known about markers of bone metabolism,
urine) from extracellular matrix turnover (synthesis and which might have an important role in osteoarthritis
breakdown), such as collagen or proteoglycan fragments since bone changes might be an important source of
(or neo-epitopes) and cellular metabolism (eg, proteases pain.36,69 Markers of synovial tissue metabolism are the
or cytokines) of articular cartilage, subchondral bone, least studied, but produce positive results, underscoring
and synovial tissue. Biochemical markers seemed to help a role for inflammation in osteoarthritis. Homogeneity
understand the pathophysiology of osteoarthritis and in of the studied population and standardisation of sample
the prediction of structural changes. However, collection might improve the relation between a
breakthroughs have been sparse and there is doubt about biomarker and clinical or radiographic characteristics,
how these markers might be used.65 We lack sufficient since diurnal rhythms and effects of exercise have been
knowledge about molecular validity, systemic origin, described for several markers.70–72
metabolism, and kinetics (absorption, distribution, and None of the presently available biomarkers are
excretion) from many biochemical markers.66,67 The same sufficiently effective to aid diagnosis or prognosis of
marker might increase as well as decrease, dependent on osteoarthritis in individual or small numbers of
the point in the degradation process. patients, nor are any so consistent that they could

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of patients to promote wellbeing and to manage symptoms.

Diagnostic Relation to Prognostic Relation to Overall
value burden of value efficacy of positive These programmes in chronic diseases are now thought
disease treatment proportion key elements of good-quality care.79 In long-term disease
Cartilage degradation management these interventions seem to be effective and
CTXII in urine* 12/13 16/25 17/23 4/5 74% necessary for the compliance of patients, although there
COMP in serum* 9/12 15/26 6/17 1/2 54% are few reported benefits.80
Coll 2-1 (NO2)† in urine and serum 7/8 2/6 2/4 ·· 61%
Symptoms can be reduced by providing the patient
KS in serum 1/2 3/8 3/5 1/2 47%
with information about osteoarthritis, its symptoms, the
YKL-40 in serum 1/3 5/12 0/4 1/1 35%
objectives of its treatment, and the importance of
changes in lifestyle—although the effect size of these
C2C in urine and serum 1/1 3/9 0/4 1/3 29%
interventions is small (<0·20).77,78 Pain has many
C1,2C in urine and serum ·· 1/6 0/4 0/2 8%
components, and is also affected by comorbidities, such
Cartilage synthesis
as sleeping problems, loneliness, and mood disorders;81
PIIANP in serum* 2/2 1/4 2/3 0/1 50%
improvement of mental and social wellbeing is therefore
PIICP in serum ·· 3/7 0/4 ·· 27%
also a target in some patients.82
CS846 in serum 0/1 1/7 0/3 ·· 9%
There is evidence for a positive effect of exercise, pacing
Bone degradation
of activities, joint protection, weight reduction, and other
NTX-I in urine and serum* 1/2 1/1 2/5 2/2 60%
measures to unload damaged joints (effect
(D)PYR† in urine 2/3 6/15 0/10 2/2 33%
size 0·20–0·50).76–78 It is unclear if particular exercises are
CTXI in urine and serum 2/4 1/16 1/6 0/1 15%
more beneficial than others for specific joints. Probably
Bone synthesis
the best exercises should be established through
OC in serum* 1/5 2/12 2/6 1/2 24% personalised advice, which takes into account individual
BSP in serum 2/2 1/3 0/2 ·· 43% factors. Exercises that strengthen muscles and improve
PINP in serum 0/1 1/4 0/4 ·· 11% aerobic condition are most effective, at least for
Synovium degradation osteoarthritis of the hip and knee.83
HA in serum* 7/9 7/22 8/11 1/3 51% Weight reduction is not easy, but quite effective,
Glc-Gal-PYR in urine 2/2 3/4 ·· 0/1 71% especially in osteoarthritis of the knee. Randomised
Synovial synthesis controlled trials have shown that weight reduction has
PIIINP in serum 1/1 2/4 0/2 ·· 43% led to lessening of pain and improvement of physical
Data are n/N unless otherwise stated. Biomarkers with less than five reports are not included. Data from van Spil and
function,84 and recent research has also shown structural
colleagues.68 *The most relevant and best performing commercial biomarkers. †Combined biomarkers: Coll 2-1 with improvement of cartilage85 and positive changes in
Coll 2-1 NO2 and PYR with D-PYR. biomarkers of cartilage and bone.86
Table 3: Overview of published work on biomarkers over the past 5 years for knee and hip osteoarthritis
Unpopular measures such as braces, cranes, and other
forms of joint protection might have a slight effect and
are generally cost effective.87,88 These measures should be
function as an outcome in clinical trials. More needs to discussed with the individual patient.
be understood about biochemical markers, and Commonly used treatment modalities are insoles,
combinations thereof, to make these markers of use in lasers,89 transcutaneous electrical nerve stimulation,90
general clinical practice. ultrasound,91 electrotherapy,92 or acupuncture,93 but
evidence is scarce, as is the effect size. However,
Treatment applications of heat and ice are easy to use and
In early osteoarthritis, pain and stiffness dominate the quite effective.94
other symptoms.73 Treatment should therefore focus on Paracetamol is the first-choice oral analgesic for
the reduction of pain and stiffness and on the maintenance osteoarthritis because of its safety and effectiveness,74–76
and improvement of functional capacities. Furthermore, but patients have often used paracetamol with little effect
prevention of progression of joint damage and before they visit their physician. Sometimes a dose
improvement of quality of life are long-term goals. There increase to an optimum regimen for the individual
are three treatment modalities: non-pharmacological, patient is a therapeutic option, but often a non-steroidal
pharmacological, and surgical. In many patients these anti-inflammatory drug (NSAID) is added or substituted.
modalities are combined, tailored to individual needs and The use of stronger analgesics, such as weak opioids and
risk factors. The European League Against Rheumatism narcotic analgesics, is only indicated when other drugs
and the Osteoarthritis Research Society International (such as NSAIDs) have been ineffective or are
have published evidence-based guidelines for the contraindicated.77
treatment of osteoarthritis.74–78 Daily practice is based on NSAIDs can be used in patients with symptomatic
these guidelines and updates from published work. osteoarthritis of the hand, hip, or knee, preferably at the
Self-management interventions can be defined as lowest effective dose and for the shortest duration.76,77 In
patient centred and as designed to foster active participation patients with cardiovascular risk factors all NSAIDs,

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including both non-selective and cyclo-oxygenase-2 glucosamine hydrochloride has been assessed thoroughly,
selective drugs should be used with caution and are but no beneficial effect has been reported.
sometimes contraindicated; the individual drug There is less, but still conflicting, evidence for the
characteristics seem to be more relevant than the class of effectiveness of chondroitin sulphate on pain and
drug.78 In patients with high gastrointestinal risk, either function.104 Avocado soybean unsaponifiables have been
a cyclo-oxygenase-2 selective drug or a non-selective assessed for the treatment of osteoarthritis of the knee
NSAID with co-prescription of a proton pump inhibitor and hip, but not of the hand. This treatment was effective
for gastroprotection, might be considered. A possible in relieving pain and improving function in hip more
additional argument for the use of selective cyclo- than in knee, osteoarthritis (effect size 0·01–0·76).105
oxygenase-2 drugs was reported in a trial comparing Avocado soybean unsaponifiables are used in some
celecoxib versus omeprazole and diclofenac in patients regions of the world, but are unknown in others.
with osteoarthritis and rheumatoid arthritis.95 Both drugs Diacerein is reported to have slow-acting, but persistent,
were equally effective for the treatment of upper symptomatic relief in patients with osteoarthritis (effect
gastrointestinal problems, but celecoxib was better than size for pain 0·24; 95% CI 0·08–0·39).78
diclofenac and omeprazole in the reduction of all Intra-articular injection of long-acting glucocorticoids
gastrointestinal events (especially clinically significant is an effective treatment of inflammatory flares of
anaemia of presumed gastrointestinal origin). Another osteoarthritis (effect size for pain relief 0·58); the effect is
attempt to reduce the gastrointestinal and cardiovascular greatest after 1 week, and diminishes thereafter.106 After
side-effects of NSAIDs is the linking of an NSAID with a injection of the weight-bearing large joints (ankle, knee,
nitric-oxide-donating group, which creates a cyclo- hip) the effectiveness of the injection can be enhanced by
oxygenase-inhibiting nitric-oxide donor. Nitric oxide complete bed rest of the treated joint for 72 h.107
thus might help to maintain gastric integrity and Hyaluronic acid has varying effectiveness when used
cardiovascular homoeostasis.96,97 Topical NSAIDs are for intra-articular injections for the treatment of
recommended as alternative or adjunctive treatment and osteoarthritis of the knee. Different products with
have been reported to be as effective as and possibly different injection regimens (up to five consecutive
safer than oral NSAIDs.98 weekly injections) have been used (effect size up
The use of opioid analgesics for the treatment of to 0·39).108 Investigators have suggested that the high
osteoarthritis has risen, but a real improvement in molecular-weight products (even cross-linked
osteoarthritic pain that has not responded to NSAIDs components, such as Hylan G-F 20) need to be injected
has been noted only with strong opioids (oxymorphone, less often and improve effectiveness.78,109,110
oxycodone, oxytrex, fentanyl, morphine sulphate).99 This A Cochrane review of surgical lavage and debridement
use is reserved for exceptional circumstances, such as in osteoarthritis of the knee111 showed no benefit in the
patients awaiting planned surgery; there is a high (over short or long term compared with placebo; in general
30%) withdrawal rate of patients treated, because of this procedure is not advised. Other surgical interventions
nausea, constipation, dizziness, somnolence, and include osteotomy, joint fusion, joint distraction, and
vomiting.99 joint replacement. Joint replacement is very cost effective
The efficacy of weaker opioids (tramadol or codeine) has in patients with severe symptoms or functional
not been assessed in long-term trials. Paracetamol– limitations associated with a reduced quality of life,
codeine combinations provide a small (5%), but statistically despite conservative treatment.77
significant (p<0·05), benefit over paracetamol alone, but
are associated with more adverse events.100 In the absence New developments
of convincing evidence for their safe and effective use, New discoveries about the pathophysiology of
concerns about risks of dependence or addiction to opiates osteoarthritis prompt the division of the disease into
affects the prescription of these drugs.77 distinguishable phenotypes. Delineating the different
Patients sometimes use a group of symptomatic slow- clinical and structural phenotypes of the disease will
acting drugs for osteoarthritis—ie, glucosamine sulphate, improve understanding—of disease in patients with
chondroitin sulphate, hyaluronic acid—and, less pain, trauma, or obese-dominated clinical phenotypes
commonly, avocado soybean unsaponifiable, and (table 4 lists our attempt)—and will also allow specific
diacerhein. Randomised trials with glucosamine sulphate targeted treatment in those in whom structural changes
have been debated heavily—there is concern about bias, in either cartilage, bone, or synovial tissue dominate the
heterogeneity of outcomes, and effect size.78 Most disease. Although these phenotypes are not yet fully
published studies show that glucosamine sulphate has a characterised, distinguishing different phenotypes could
beneficial effect on pain, with effect size ranging herald the start of further discussions. Lack of in-depth
between 0·30 and 0·87,78 but no effect on function and understanding of disease pathogenesis and the
controversial effects on structure modification.101,102 misconception that all forms of osteoarthritis are the
Whether glucosamine sulphate is effective in same and have the same clinical and structural
osteoarthritis remains undetermined.103 In the USA, characteristics might restrict further development of

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Post-traumatic Metabolic Ageing Genetic Pain

(acute or repetitive)
Age Young (<45 years) Middle-aged (45–65 years) Old (>65 years) Variable Variable
Main causative feature Mechanical stress Mechanical stress, adipokines, AGE, chondrocyte Gene related Inflammation, bony changes,
hyperglycaemia, oestrogen/ senescence aberrant pain perception
progesterone imbalance
Main site Knee, thumb, ankle, shoulder Knee, hand, generalised Hip, knee, hand Hand, hip, spine Hip, knee, hand
Intervention Joint protection, joint Weight loss, glycaemia control, lipid No specific intervention, No specific intervention, Pain medication,
stabilisation, prevention of falls, control, hormone replacement sRAGE/AGE breakers gene therapy anti-inflammatory drugs
surgical interventions therapy

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

Table 4: Proposal for differentiation of clinical phenotypes of osteoarthritis

diagnosis, treatment, and monitoring of the many forms RAGE) expressed on chondrocytes, increasing their
of the disease. A consensus on subgrouping osteoarthritis catabolic activity.128,129 AGE induces alteration of bio-
into such phenotypes will take time. mechanical properties by stiffening the cartilage, which
In the structure phenotype, after entering a point of no makes it brittle and more prone to damage. There is no
return in which damage of the cartilage matrix over-rides clear clinical evidence of how AGE contributes to the
synthesis, a vicious cycle of progressive damage ensues development and progression of osteoarthritis.130
in which impaired biomechanical properties result in Development of soluble AGE receptors, sRAGE, that
further damage.5–7 Autocrine loops of soluble factors bind to AGEs and thereby inhibit the activation of cell-
released by the triggered chondrocytes112–115 trigger an surface RAGE, showed efficacy in the treatment of
inflammatory response that accelerates the breakdown vascular complications in animal models of diabetes.
process.8,9 This inflammatory activity is enhanced by the Also, prevention or reversal of AGE formation by diet or
accelerated release of catabolic cartilage constituents that specific cleavage of AGE-crosslinks is subject to study
provide an additional vicious cycle in the process of tissue and might become feasible.
destruction. The stiffening of the subchondral bone In the obesity phenotype, the overload effect on joint
(sclerosis) reported in the more advanced stages of the cartilage might, in part, explain the greater risk of
disease increases stresses in the overlying cartilage and osteoarthritis in overweight people. Advances in the
adds to the damage. Also, in the early phase, subchondral physiology of adipose tissue provide further information
bone changes might cause cartilage damage and might about the relation between obesity and osteoarthritis.131
even precede it.10,11 Soluble factors produced locally in Indeed, a positive association between obesity and
subchondral bone are potential candidates to act on deep- osteoarthritis has been reported for non-weight-bearing
zone articular chondrocytes to promote abnormal joints, such as those of the hands, and not only knee
remodelling and metabolism of deep cartilage, leading to joints.132 These reports suggest that joint damage might
its breakdown.116–118 This breakdown is facilitated by the be caused by systemic factors such as adipose factors, the
interaction between bone and cartilage that was originally so-called adipokines, which might provide a metabolic
thought to be a tight interface, but is now recognised as link between obesity and osteoarhtritis,133 and which, in
allowing soluble factors to migrate between bone and addition to weight loss, could become a specific
cartilage.119–121 Moreover, angiogenesis has been identified therapeutic target.
at the junction of articular hyaline cartilage and adjacent Growing knowledge of the pathogenetic mechanisms
subchondral bone;122,123 and therefore tissue damage involved in osteoarthritis will lead to the development of
of the whole joint is also biochemical and not new classes of drugs for targeted treatment; many new
merely mechanical.124 pharmacological approaches in the management of
In the age phenotype, chondrocytes sense alterations osteoarthritis are under development.134 Calcitonin, a
in mechanical stresses and, dependent on the context, hormone of calcium homoeostasis, inhibits osteoclast
respond with anabolic or catabolic biochemical activity and also has a direct effect on cartilage by the
processes.125,126 This cartilage degeneration is not merely inhibition of matrix metalloproteinase activity. In a pilot
mechanically induced wear and tear, but a complex of study in patients with osetoathritis,135 CTXII, a degradation
biochemical interactions. marker, decreased after patients were given oral
Ageing alters the response of chondrocytes: aged calcitonin. At present, calcitonin is under investigation in
chondrocytes produce more inflammatory cytokines, a long-term randomised controlled trial.
tissue degrading enzymes, and growth factors.127 Nitric oxide is one of the catabolic mediators in cartilage
Moreover, advanced glycation endproducts (AGEs), and synovium. Inducible nitric oxide synthase is
which accumulate in cartilage, can bind to specific upregulated in osteoarthritis and in various pain states.
receptors (receptor of advanced glycation endproducts; At present, a study is assessing a specific inducible nitric

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 Series

oxide synthase inhibitor (SD-6010) in patients with knee 14 Dieppe PA, Cushnaghan J, Shepstone L. The Bristol ‘OA500’ study:
osteoarthritis. progression of osteoarthritis (OA) over 3 years and the relationship
between clinical and radiographic changes at the knee joint.
Studies with bisphosphonates were done with the aim Osteoarthritis Cartilage 1997; 5: 87–97.
of inhibiting increased bone turnover in osteoarthritis; 15 Hochberg MC, Lawrence RC, Everett DF, Cornoni-Huntley J.
however, they were negative with regard to symptoms Epidemiologic associations of pain in osteoarthritis of the knee:
data from the National Health and Nutrition Examination Survey
and radiological progression, although biochemical and the National Health and Nutrition Examination-I Epidemiologic
markers of cartilage turnover decreased.136 Follow-up Survey. Semin Arthritis Rheum 1989; 18: 4–9.
Advances in pain neurobiology have shown the role of 16 Oakley SP, Portek I, Szomor Z, et al. Arthroscopy—a potential
“gold standard” for the diagnosis of the chondropathy of early
supraspinal pathways and downstream neurotrans- osteoarthritis. Osteoarthritis Cartilage 2005; 13: 368–78.
mitters and effectors in chronic pain. Antibodies to nerve 17 Bekkers JE, Creemers L, Dhert WJ, Saris DB. Diagnostic modalities
growth factor have been developed by several companies. for diseased articular cartilage—from defect to degeneration:
a review. Cartilage 2010; 1: 157–64.
The benefit-to-risk ratio of these compounds is not yet
18 Kellgren JH, Lawrence JS. Radiological assessment of
clear and needs to be assessed further.137 Initial studies in osteo-arthrosis. Ann Rheum Dis 1957; 16: 494–502.
patients with osteoarthritis have shown a slight clinical 19 Altman RD, Gold GE. Atlas of individual radiographic features in
benefit of the centrally acting compound duloxetine in osteoarthritis, revised. Osteoarthritis Cartilage 2007;
15 (suppl A): A1–56.
patients with chronic painful osteoathritis.138 Duloxetine 20 Conrozier T, Tron AM, Mathieu P, Vignon E. Quantitative
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21 Marijnissen AC, Vincken KL, Vos PA, et al. Knee Images Digital
fibromyalgia and diabetic peripheral neuropathy. Analysis (KIDA): a novel method to quantify individual
Contributors radiographic features of knee osteoarthritis in detail.
All authors contributed equally to the search of published work, the Osteoarthritis Cartilage 2008; 16: 234–43.
discussions, and writing. All authors gave their final approval for the 22 Oka H, Muraki S, Akune T, et al. Fully automatic quantification of
decision to submit for publication. knee osteoarthritis severity on plain radiographs.
Osteoarthritis Cartilage 2008; 16: 1300–06.
Conflicts of interest 23 Sharp JT, Angwin J, Boers M, et al. Computer based methods for
We declare that we have no conflicts of interest. measurement of joint space width: update of an ongoing
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