State of the Art

Position statement: the epidemiology, pathogenesis

and risk factors of osteoarthritis of the knee
Sherif El-Tawil,1 Elizabeth Arendt,2 David Parker3
1
Department of Orthopaedic ABSTRACT
Surgery, Royal National Osteoarthritis (OA) represents a large burden on
Orthopaedic Hospital,
Box 1 Clinical and radiographic diagnostic
Stanmore, UK
healthcare resources worldwide with continually criteria for osteoarthritis according to the
2
Department of Orthopaedic increasing prevalence. This has led to renewed interest in American College of Rheumatology*2
Surgery, University of the causes and pathogenesis of the condition. In recent
Minnesota, Minneapolis, years, there has been a move away from a simple ‘wear
Minnesota, USA and tear’ model of cartilage to one of a complex 1. Knee pain for most days of previous month
3
Sydney Orthopaedic Research 2. Osteophytes at joint margins on radiographs
Institute, Sydney, New South inflammatory process involving cellular and extracellular
derangements that allow a catabolic state to dominate. 3. Synovial fluid typical of osteoarthritis
Wales, Australia
Ultimately, OA is now seen as pan-joint disease (laboratory)
Correspondence to involving synovium, menisci, ligaments and muscle, in 4. Age≥40 years
Dr David Parker, Sydney
addition to cartilage. There are several classification 5. Crepitus on active joint motion
Orthopaedic Research Institute, 6. Morning stiffness≤30 min duration
445 The Gallery, Chatswood, systems including radiographic, MRI-based, clinical and
Sydney, NSW 2065, Australia; combined classification systems. As radiographs only *Knee osteoarthritis (clinical and radiographic) if 1,
parkeradmin@syndeyortho. detect OA in latter stages, there has been a focus on 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present.
[Link]
early diagnosis using MRI and serum biomarkers. New
Received 22 November 2015 physiological MRI sequences can now measure the
Revised 3 April 2016 proteoglycan content in cartilage and new inflammation, pain and loss of normal joint func-
Accepted 9 April 2016 semiquantitative analyses have been developed to score tion (box 1).
Published Online First total knee joint involvement in the disease process.
10 May 2016
Serum biomarkers can be divided into those that are Prevalence and societal impact
collagen breakdown products and those that are OA is one of the most common causes of disability
inflammatory cytokines; these can be used in early in adults. The prevalence increases with age, with a
detection of OA before radiographic appearances arise. remarkable 13.9% of the population over 25 years
The risk factors for OA include ageing, knee injury, old affected, and 33.6% of the population over
obesity, altered limb alignment, impaired muscle 65 years old affected.3 It has a significant impact on
strength, female gender, heavy physical work and society, compromising quality of life and productiv-
genetic susceptibility. Research continues to identify the ity, and weighs heavily on national healthcare
mechanisms involved that lead to OA development, with resources.4 5
possibly unique processes underpinning each risk factor. Costs of OA care have risen over recent decades
Our understanding of the pathophysiology of OA will accounting for up to 1–2.5% of the gross national
continue to improve in the next few years which should product for countries such as the USA, Canada, the
lead to new intervention strategies that target different UK, France and Australia.6
processes. More informative MRI sequences will continue
to be developed and the optimum combination of Geographical differences
biomarkers to detect early OA will need to be identified. The WHO has developed a tool called the
Genetic studies will continue to identify new disability-adjusted life year to help gauge the burden
susceptibility loci that could be targeted in future of musculoskeletal disease on the world’s popula-
therapies. tion.7 Figure 1 represents international data col-
lected from the WHO regarding the specific burden
of OA worldwide. There is a large and growing
burden in developed and developing nations, which
INTRODUCTION will only increase with growing elderly popula-
Definition tions.8 9 Most of the prevalence statistics originate
The Osteoarthritis Research Society International from Western nations, but the prevalence of symp-
(OARSI) defines osteoarthritis (OA) as ‘a disorder tomatic knee OA in the West appears to be compar-
involving movable joints characterized by cell stress able to rural and urban areas within Asia.10
and extracellular matrix degradation initiated by The Framingham Osteoarthritis Study12 reported
micro- and macro-injury that activates maladaptive prevalence rates of knee OA in a population in
repair responses including pro-inflammatory path- Massachusetts, USA, and a similar population-based
ways of innate immunity’.1 This in turn manifests study using identical methodology and definitions
initially as abnormal joint tissue metabolism, and was performed in the Beijing Osteoarthritis
subsequently by anatomic and physiological Study.13 A similar radiographic and symptomatic
To cite: El-Tawil S, derangements. Clinically, this can manifest as cartil- prevalence of OA was found among Chinese men
Arendt E, Parker D. JISAKOS age degradation, bone remodelling, osteophyte for- and their age-matched American counterparts
2016;1:219–228. mation, with patients presenting with joint (prevalence ratio 0.9 and 1.02, respectively) but
El-Tawil S, et al. JISAKOS 2016;1:219–228. doi:10.1136/jisakos-2015-000002 Copyright © 2016 ISAKOS 219
 State of the Art

elderly women in Beijing had higher radiographic and symp- through different pathogenic mechanisms, including inflamma-
tomatic prevalence rates compared with their age-matched tion. All tissues within the joint become affected but the loss of
American counterparts ( prevalence ratio of 1.45 and 1.43, articular cartilage and subchondral changes remain the most
respectively); possible reasons given were genetic differences striking features.22 23 There is now a focus on early detection
and higher physical activity in the Chinese population.13 Of with MRI and biochemical markers, thereby allowing earlier,
those with knee OA, lateral compartment OA was much more and possibly even preventative, intervention.24 25
common in the Chinese population (28.5% in Beijing females
vs 11% in Framingham females; 32.3% Chinese males vs 8.8% Reviews and current concept articles
Framingham males) which has been postulated to arise from There has been renewed interest in the biological processes
more valgus distal femoral alignment.14 15 In sharp contrast, hip underpinning OA, which alongside better imaging and biochem-
OA was 80–90% less prevalent in the Beijing population com- ical analysis has furthered our knowledge greatly. The role of
pared with the Framingham cohort, which may be due to mor- inflammation, synovium, genetics and a variety of biochemical
phological advantages in terms of better hip sphericity and less pathways open up the possibilities for more personalised
femora-acetabular impingement.16 17 therapy (tables 1 and 2).
Data from the US’ National Health and Nutrition Examination
Survey (NHANES) as well as a population-based study in Current state of the art
Johnston County, North Carolina, showed that knee OA is up to Classification of OA
twice as common among African-Americans than Plain film radiographs and symptomology have historically been
Caucasians.18 19 The pattern of OA is also different with the mainstay of classifying OA. Recently, MRI assessment of the
African-Americans tending to have more tri-compartmental joint has entered clinical practice, while the use of serum and
disease and more severe radiographic changes in the tibiofemoral urinary biochemical markers is a rapidly developing research area
joint, and lateral joint space narrowing.20 Suggested reasons for early detection. A common factor in radiographic and MRI
include differences in genetics, obesity, bone mineral density, assessments is the changes that occur in the subchondral
occupational physical demands, diet and other lifestyle factors.20 bone.43 44 An emerging concept is that imaging in OA should not
The prevalence of risk factors for OA also differs between only assess cartilage and bone but also the menisci, synovium, fat
developed and developing nations. In developing nations, for and muscle, appreciating OA as a ‘whole-organ’ disease (box 2).22
example, obesity is often less prevalent (though now increasing),
while higher proportions of the population have occupations Radiography
requiring heavy physical labour, squatting, kneeling and climb- Classification strategies for radiographic imaging focus on the
ing; the latter may in part explain why knee OA is more secondary changes of joint space narrowing, subchondral scler-
common in rural communities of China than in urban ones.10 osis and osteophyte formation (tables 3 and 4).
Many Asian countries also currently have rapidly ageing popula- Although plain radiographic imaging classification is the most
tions which will increase the OA burden in the near future.7 commonly quoted, and has endured for many years, the most
limiting aspect of this classification is that it often does not
Historic approach to OA of the knee detect joint degeneration until a more advanced stage.
OA has historically been seen as an age-related degeneration of
articular cartilage, in contrast to the inflammatory destruction of MRI
rheumatoid arthritis, and with little regard for other predispos- A more complete picture of intra-articular disease is revealed by
ing factors.21 The result being detected at a late stage with MRI. Advances in MRI technology have seen better resolution
reduced joint space on traditional plain radiographs and ultim- and new sequences developed that improve its ability to detect
ately joint replacement seen as the only and final solution. bone marrow lesions, cartilage abnormalities, ligamentous and
There has been a shift from the belief that it is a uniform meniscal damage, joint fluid changes and osteophyte formation,
process mainly affecting articular cartilage to a heterogeneous as well as macromolecular changes, which often precede mor-
condition with a plethora of predisposing risk factors working phological changes.29

Figure 1 Age-standardised disability-adjusted life year rates for osteoarthritis by country ( per 100 000 inhabitants) using WHO data.11
220 El-Tawil S, et al. JISAKOS 2016;1:219–228. doi:10.1136/jisakos-2015-000002
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Table 1 Recent reviews

Title Date Journal
26
Osteoarthritis year in review 2015 January 2016 Osteoarthritis and Cartilage
Chondropenia: current concept review27 December 2015 Musculoskeletal Surgery
Cytokines as biochemical markers for knee osteoarthritis28 January 2015 World Journal of Orthopaedics
Early knee osteoarthritis29 August 2015 Rheumatic & Musculoskeletal Diseases
MRI-based semi-quantitative methods for knee osteoarthritis30 December 2015 Magnetic Resonance in Medical Sciences
Osteoarthritis—a case for personalised healthcare31 January 2014 Osteoarthritis and Cartilage
Advances and challenges in gene-based approaches for osteoarthritis32 October 2013 Journal of Gene Medicine
Osteoarthritis: an update with relevance for clinical practice33 June 2011 The Lancet

Two broad types of MRIs can now be performed: ‘morpho- includes the degradation products of bone and cartilage such as
logical’ which is the conventional technique visualising C-terminal telopeptide of type II collagen, cartilage oligomeric
intra-articular structures, and ‘physiological’ which comprise matrix protein, collagen type II-specific neoepitope, an aggrecan
state-of-the-art MRI sequences that are able to detect and measure neoepitope, a number of matrix metalloproteinases and procol-
proteoglycan content within cartilage, the concentration of which lagen type I amino-terminal properties.54–59 The second group
is altered early in the disease process (table 5). Physiological includes proinflammatory and anti-inflammatory cytokines that
sequences currently remain research tools (figure 2). can be further divided according to those that aid diagnosis
In MRI, the most common features that indicate OA are car- such as interleukin (IL)-6 and IL-15,24 60–62 those that reflect
tilage thinning and subchondral bone oedema48; however, as the burden of disease such as IL-1β, tumour necrosis factor
knee OA is increasingly being seen as a pan-joint disease, this (TNF)-α and vascular endothelial growth factor,63–67 and those
had led to semiquantitative MRI-based scoring systems that that may be prognostic such as IL-6 and IL-10.68 69 There is yet
grade the involvement of several other intra-articular structures to be any large-scale study to determine their validity but it is
in addition (table 6). These use conventional MRI sequences likely that a combination of markers from both groups will be
with a knee coil, but are time consuming and largely used in needed to improve the sensitivity and specificity of such a tool
research. in OA (figure 3).
MRI can not only be used to grade the severity of OA but
may be able to help predict its onset. Non-contrast-enhanced Pathogenesis of OA
T2-weighted MRI has been used to detect synovitis in non-OA There is a clear association between OA and the ageing
patients who then go on to develop the disease indicating it may process12 70 71 and also mechanical injury.72 73 Initially, there is
be a useful predictor in the very early stages.25 51 This supports a loss of glycosaminoglycans from cartilage which lowers the
the notion that synovial inflammation has a pivotal role to play osmotic pressure, leaving it softer and with diminished resist-
in the pathogenesis of OA, and highlights the importance of ance to compressive forces.74 A repair response then leads to
MRI assessment of extracartilaginous structures. increased production of proteoglycans and collagen type II, and
chondrocyte proliferation and clustering.75
Biochemical markers However, increased expression of inflammatory cytokines and
The final stages of OA can take decades to develop, but there proteases means catabolic activity dominates, and cartilage is
are changes in the biochemical environment within the affected degraded; initially fibrillation occurs in the superficial zone, fol-
joint and subsequently blood that can be used to detect path- lowed by deep fissures and full chondral loss. Implicated cyto-
ology early on in the disease process. In addition to advanced kines include IL-6, IL-1β, TNF-α, IL-10, IL-13 and IL-4.76–81
imaging, serum and urinary markers have been used to detect They act through proinflammatory and anti-inflammatory path-
OA in its early stages, looking for bone, cartilage and/or syn- ways, and are also involved in angiogenesis and chemotaxis.82–84
ovial degradation products.52 53 A recent laboratory study showed OA-affected chondrocytes
Research has focused on two main groups of biomarkers, exhibit higher levels of the zinc importer ZIP8 leading to an
with studies in animal models and humans. The first group increased level of intracellular zinc that triggers a catabolic

Table 2 Ten most cited articles on osteoarthritis epidemiology and pathophysiology

Title Date Journal
Osteoarthritis: new insights. Part 1: the disease and its risk factors34 2000 Annals of Internal Medicine
The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip35 1991 Arthritis and Rheumatism
The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study12 1987 Arthritis and Rheumatism
An update on the epidemiology of knee and hip osteoarthritis with a view to prevention36 1998 Arthritis and Rheumatism
Obesity and knee osteoarthritis: the Framingham Study37 1988 Annals of Internal Medicine
Weight loss reduced the risk for symptomatic knee osteoarthritis in women: the Framingham Study38 1992 Annals of Internal Medicine
Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets39 2001 Arthritis and Rheumatism
The role of cytokines in osteoarthritis pathophysiology40 2002 Biorheology
Whole-organ magnetic resonance imaging score (WORMS) of the knee in osteoarthritis41 2004 Osteoarthritis and Cartilage
Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis42 2001 Arthritis Research

El-Tawil S, et al. JISAKOS 2016;1:219–228. doi:10.1136/jisakos-2015-000002 221

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Table 4 Osteoarthritis Research Society International Grading

Box 2 Methods to classify osteoarthritis System (OARSI) for medial and lateral tibiofemoral joint space
narrowing47
1. Radiographic imaging45 Grade 0 Normal
2. MRI; including whole-organ scoring46 Grade 1 Mild (1–33% narrowed)
3. Clinical symptoms, including stiffness, swelling, knee range
Grade 2 Moderate (34–66% narrowed)
of motion and knee crepitus2
Grade 3 Severe (67–100% narrowed)
4. Combination of symptoms and imaging2

cascade through increased expression of matrix metalloprotei- Knee injury

nases (MMP3, MMP9, MMP12, MMP13).85 Interestingly, in a A 22-year prospective study of Finnish participants98 researched
mouse model, this also led to subchondral sclerosis in addition the association of new cases of OA over time, diagnosed by phy-
to cartilage damage, but no synovitis or osteophytes.85 sicians using information on disease histories, symptoms and
State-of-the-art microarray analysis of OA chondrocytes sug- standardised clinical examinations. The risk of developing knee
gests that there is faster messenger RNA (mRNA) decay with OA was strongly associated with the heaviest category of phys-
short-lived transcripts of genes involved in the regulation of ical stress at work (compared with the lightest category), and
transcription and programmed cell death.86 Affected chondro- past knee injury.
cytes also exhibited more short-lived transcripts of genes A recent meta-analysis pooling 24 observational studies
involved in extracellular matrix turnover, contributing to pheno- (20 997 participants) concluded that knee injury is a major risk
typical instability in these chondrocytes.86 factor for the development of knee OA irrespective of study
design and definition of knee injury.99 It identified knee injury
as one of the few modifiable risk factors for OA, advocating its
prevention in future public health programmes.99
The role of synovium
In a separate study, follow-up of 44 surgically treated knee
The role of synovial inflammation in the pathophysiology of
dislocations showed that at a mean of 10 years follow-up, the
cartilage degradation has been a controversial issue, but
incidence of OA was 23%,100 again indicating the significant
recently has won favour with studies showing lymphocytic
association between major knee trauma and the subsequent
infiltration and perivascular lymphoid aggregates with release
development of OA.
of inflammatory mediators that directly promote cartilage deg-
Anterior cruciate ligament (ACL) rupture and meniscal tear
radation.87–89 Recent research shows that the procatabolic med-
are major independent risk factors for OA.72 A study of 205
iators alarmins S100A8 and S100A9 are increased in OA joints
soccer players with ACL injuries showed that 41% developed
and appear to be closely associated with synovial inflammation,
advanced degenerative changes at 14 years follow-up, compared
allowing a potential target for treatment.90 91 Similarly
with 4% of uninjured knees.101 In a similar study of female
proteinase-activated receptor-2 is elevated in human OA cartil-
soccer players, 51% had radiographic OA 12 years after ACL
age and synovium, and in vitro studies have shown that its
injury.102 There is also a high predisposition to OA with menis-
ablation can modulate synovial macrophage activation and
cal injury; a multicentre study showed that at 30-month
thereby confer chondroprotection.92
follow-up, untreated meniscal injuries had an OR of 5.7 greater
There is evidence that the pain associated with OA originates
risk of OA.103 A fourfold risk was seen after partial meniscec-
from inflamed synovium, with increased levels of the proalgesic
tomy at 16-year follow-up.104
nerve growth factor (NGF) found in synovial fibroblasts and
Although it is conventionally believed that OA arises in such
macrophages.93 Chondrocytes also appear to have the capacity
injured joints due to the abnormal biomechanical forces acting
to produce NGF,94 95 and this has successfully been exploited in
in the destabilised knee, studies suggest an alternative or
a study using anti-NGF antibodies to modulate pain in a rat
model.96
Table 5 Advanced MRI sequences for imaging knee OA
MRI sequence Advantage Disadvantage
Risk factors
SPGR Quantitative assessment of Time-consuming
OA is a heterogeneous disease with differing phenotypes which (morphological) cartilage morphology ‘segmentation’
could be due to different risk factors working through distinct analysis
processes.97 Some of the main risk factors are discussed below, T2 relaxation Assesses collagen distribution; Complex interpretation
with specific studies to illustrate the evidence for each (box 3). mapping semiquantitative information on
(physiological) cartilage quality
Table 3 Radiographic imaging classification for osteoarthritis of the T1ρ-weighted MRI Assesses proteoglycan content; Complex interpretation
(physiological) semiquantitative information on
knee; the Kellgren-Lawrence Grading System45
cartilage quality
Grade 0 No feature of osteoarthritis 23Na MRI FCD Assesses proteoglycan content; Requires MRI field
Grade 1 Doubtful narrowing of joint space and possible osteophytic lipping (physiological) semiquantitative information on strength≥3 T
cartilage quality
Grade 2 Definite osteophytes and possible narrowing of joint space
dGEMRIC FCD Assesses proteoglycan content ; Contrast agent needed
Grade 3 Moderate multiple osteophytes, definite narrowing of joint space, and
(physiological) semiquantitative information on
some sclerosis and possible deformity of bone ends
cartilage quality
Grade 4 Large osteophytes, marked joint space narrowing, severe sclerosis and
definite deformity of bone ends dGEMRIC, delayed gadolinium-enhanced MRI of cartilage; FCD, fixed charge density;
Na, sodium; SPGR, spoiled gradient recalled.

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Figure 2 Example of physiological MRI: delayed gadolinium-enhanced MRI of cartilage fixed charge density sagittal images where proteoglycan
content is represented by a colour scale (blue/green=high content; yellow/red=low content). The lateral compartment (left side image) demonstrates
healthier articular cartilage (green) than the medial compartment (right side image; yellow/red).

additional mechanism. Studies in ACL-deficient knees,105 106 knee extensors shock absorb and stabilise the knee during
and recently those researching meniscal tears,89 107 have shown loading, so that their deficiency can lead to excessive mechanical
proteases and inflammatory cytokines are released into the joint stress on articular cartilage.109 113
following injury that may directly degrade cartilage.
Consequently, intra-articular inhibition of IL-1 in a mouse
model significantly reduced cartilage degradation and synovitis Gender
following tibial plateau fracture.108 Knee OA has a strong female sex preponderance.114 In a pro-
spective 12-year study of 315 495 Norwegians, the rate of knee
Impairments in muscle function replacement was double for women (0.55%) than men
Muscle weakness, altered muscle activation patterns and pro- (0.28%).115 Obesity is a stronger risk factor for knee OA in
prioceptive deficits are commonly found in association with women than in men. Women also appear to be affected more
knee OA.109 Improvement of muscle strength ( particularly than men if categorised in the moderate OA group with weaker
quadriceps) is a key component of conservative management of performance scores and greater impairment to activities of daily
knee OA and has not only been found to be effective in improv- living.116
ing pain, physical function and quality of life110 but also to Some of the reasons for this are speculated to be: women lose
reduce the risk of developing symptomatic OA in the first knee articular cartilage at a faster rate than men, female human
instance.111 This effect does not appear to result from any articular chondrocytes may function better when oestrogen is
detectable structural changes on knee MRI.112 The underlying available, male human articular chondrocytes are more respon-
mechanism is not fully understood, but one theory is that the sive to vitamin D metabolites than female cells, vitamin D recep-
tors and mRNA for inflammatory cytokines are differentially
expressed in degenerated cartilage in a sex-specific fashion, and
subchondral bone osteoblasts exhibit sex-specific responses to
Table 6 MRI-based scores for osteoarthritis of the knee
oestrogen.117 One case–control study suggests that low intake of
Scoring vitamins D C are possible risk factors for OA, especially in
system Items scored Reported reliability
females.118
KOSS49 Cartilaginous lesions—osteophytes— Interobserver ICC:
subchondral cysts—bone marrow oedema 0.77
—meniscal abnormalities—size of Intraobserver ICC:
effusion—synovitis—presence of Baker’s 0.83 Heavy physical work
cyst (N=25) The relationship of heavy physical work to OA has been the
WORMS22 Cartilage integrity—subarticular bone Interobserver ICC: subject of considerable interest and investigation.119 Of particu-
marrow abnormality—subarticular cysts— 0.98 lar note, vibration, repetitive movement, long hours of kneeling,
subarticular bone attrition—marginal Intraobserver ICC: not squatting and standing have been shown to be associated with
osteophytes—medial and lateral meniscal reported an increased risk of development of OA.120 121 Frequent knee
integrity—anterior and posterior cruciate (N=19)
ligament integrity—medial and lateral bending while loading is another activity that has been related
collateral ligament integrity—synovitis/ to cartilage degeneration.122
effusion—intra-articular loose bodies— A case–control study in Germany involving 1310 patients
periarticular cysts/bursitis with and without symptomatic knee OA suggested a dose–
BLOKS50 Cartilage integrity—bone marrow lesions Interobserver response relationship between kneeling/squatting and symptom-
—cysts—osteophytes—ligaments— weighted κ=0.51– atic knee OA.123 Occupational risks such as jumping or climbing
synovitis—effusion—meniscal extrusion/ 0.79
tear/signal—periarticular features (N=10) stairs/ladders, however, did not correlate with symptomatic knee
OA.123 There are particularly deleterious interactions of high
BLOKS, Boston Leeds Osteoarthritis Knee Score; ICC, intraclass correlation coefficient,
KOSS, Knee Osteoarthritis Scoring System; N, sample size; WORMS, Whole-Organ MRI body mass index (BMI) with kneeling/squatting and heavy
Score. lifting.124
El-Tawil S, et al. JISAKOS 2016;1:219–228. doi:10.1136/jisakos-2015-000002 223
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Figure 3 Summary of some of the pathways involved in the pathogenesis of osteoarthritis. GAGs, glycosaminoglycans; mRNA, messenger RNA;
TNF-α, tumour necrosis factor α; PAR2, proteinase-activated receptor 2.

Exercise The literature is less optimistic with regard to higher level ath-
A cross-sectional study of 2439 participants with OA showed letic activity with some low-level evidence that it may be asso-
that exposure to non-elite running at any time in life was not ciated with later development of hip and knee OA.128
associated with higher odds of prevalent knee pain, symptomatic
OA or radiographic OA.125 Indeed, sporting activities may even
Obesity
have a protective effect if not associated with traumatic
In a prospective 12-year study of 315 495 Norwegians,
injury.125 126 A separate literature review concluded that low-
increased BMI was directly correlated with increased risk of
distance and moderate-distance running is not associated with
requiring knee replacement.115 Men with a BMI>27 had a
OA, with long-distance running, barefoot and minimalist shoes
sixfold increased incidence of knee replacement compared with
being inconclusive.127
men with a BMI<23. Women with a BMI>26 had an 11-fold
increase compared with women with a BMI<21. Combining
heavy labour with high BMI was particularly hazardous, with
the risk increasing to 12-fold in men and 16-fold in women.
Box 3 Salient risk factors for osteoarthritis Increased awareness of the relationship between obesity and
metabolic and inflammatory activities has made researchers
1. Advancing age rethink the role of obesity and OA. The relationship of obesity
2. Body mass index>30 kg/m2 to the development of knee OA is not necessarily proportional
3. Female gender to the severity of obesity. Development of OA appears to be
4. Limb malalignment strongly related to the coexistence of disordered glucose and
5. Poor muscle strength and control lipid metabolism.129 130 Cytokines associated with adipose
6. Previous knee injury tissue, including leptin, adiponectin and resistin, may influence
7. Heavy physical labour including kneeling and squatting OA through direct joint degradation or control of local inflam-
8. Genetic predisposition matory processes.129 131
9. High-level athletic activity Metabolic risk factors including obesity, hypertension, dyslipi-
daemia and impaired glucose tolerance (collectively known as
224 El-Tawil S, et al. JISAKOS 2016;1:219–228. doi:10.1136/jisakos-2015-000002
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the ‘metabolic syndrome’) raise not only the risk of occurrence being a disease that has affected generations from antiquity, we
of OA, but also its progression.132 This risk rises with the are only starting to comprehend the complex processes
increasing number of metabolic risk factors present, illustrating involved.21 As we acknowledge the role of synovial inflamma-
the significant relationship between these risk factors and tion and other intra-articular structures in OA, new pathways
OA.133 Obesity is a particular issue in Western countries and is will continue to be discovered and with every discovery, there is
one of the few modifiable risk factors that can be a powerful the potential for targeted therapy.26 90 91 The next 3–5 years
tool in the reduction of OA prevalence in these countries.134 will reveal if indeed different risk factors work towards OA
through ‘signature pathways’ that can then be targeted in perso-
Genetics nalised therapies.92 108
A meta-analysis of four genome-wide association studies with a Technological advances will continue to be made in MRI,
cumulative sample size of 6709 cases and 44 439 controls in further enhancing our understanding of the pathophysiological
Caucasian populations identified a significant susceptibility locus processes and also allowing earlier diagnosis.25 51 The role of
for knee OA on chromosome 7q22.135 Other studies have physiological MRI in the knee will assume a bigger role in the
uncovered a likely role in OA for the genes encoding structural years to come and the complex and time-consuming analysis
extracellular matrix components (such as DVWA) and molecules currently involved in semiquantitative measurements will
involved in prostaglandin metabolism (such as DQB1 and become streamlined.26
BTNL2).136 A powerful association study showed that the In the next 5 years, biomarkers have the potential to make a
genetic polymorphisms predisposing to knee OA differed from great difference in the way we diagnose and treat patients. From
those for hip OA.137 Recently, the genes encoding NCOA3, detecting the disease process at such an early stage, treatments
SULF2, ALDH1A2 have all been associated with hip and hand can be developed to tackle the pathophysiology in its most early
OA, but not necessarily knee OA (table 7).138 stages, when it may be possible to abort or delay progression.24
Research in the next few years should focus on elucidating the
Future perspectives best combination of biomarkers to most sensitively and specific-
With an ageing population globally, OA is a growing problem ally detect early OA, for different risk factor profiles. Indeed,
with an increasing burden on the health of populations and the the OARSI has made recommendations that future OA clinical
economies of nations worldwide.8 9 Future health strategies will trials should collect biospecimens to allow measurement of bio-
thus need to focus on earlier diagnosis and preventative inter- markers for a number of reasons, including the early detection
vention in order to cope with such demand. This will be aided of disease, the assessment of treatment efficacy and to identify
by advances in our understanding of OA pathophysiology that patient subgroups that may respond better to certain types of
will continue to be made through laboratory-based studies, intervention.141
which have recently flourished in recent years with Valuable recommendations have also been made to ensure
goal-orientated and clinically relevant research. Despite OA future trials use standardised nomenclature that will aid

Table 7 Important studies evaluating risk factors for osteoarthritis

Study Topic Study type Results
130
Jungmann et al Metabolic factors contributing to NIH multicentre, longitudinal, observational Participants: no symptomatic radiographic knee OA at baseline but
cartilage pathology on MRI cohort (n=403) ≥1 risk factor for developing knee OA, and follow-up MRIs with
T2 relaxation data. The following metabolic risk factors were
associated with higher baseline T2 relaxation times: high
abdominal circumference, hypertension, high-fat consumption and
diabetes mellitus, all with cumulative effect.
Martin et al139 Obesity, occupation, activity level British 1946 birth cohort; snapshots at age OA association with BMI is strong, while manual with labour
and OA 36, 43, 53 years (n=2597) occupation is moderate. High BMI levels more risky for active vs
sedentary participants. In low BMI women, high activity levels had
a protective effect for OA.
Prieto-Alhambra Incidence and risk factors of Spanish cohort, retrospective, 2006–2010, OA incidence in knee only=2.95%, knee+hand 0.43%, knee
et al70 OA—age, gender, cross-over sites age≥40, n=3 266 826 +hip=0.45%, all three=0.04%. Total knee incidence 3.87%.
(knee-hip-hand) Knee-only were highly female (64.4%), BMI 25–30 (37.86%)/
BMI≥30 (51.59%) and comorbid for hypertension (55.47%).
Yoshimura et al133 MS (overweight, hypertension, 3-year follow-up of the ROAD (Research on OR for OA incidence significantly increased according to the
dyslipidaemia, impaired glucose Osteoarthritis/Osteoporosis Against number of MS components present (1=2.33, 2=2.82, 3=9.83).
tolerance) and OA Disability) study (n=1690) OA progression risk also significantly increased (1=1.38, 2=2.29,
3=2.80). MS prevention may be useful in reducing future knee
OA risk.
Muthuri et al134 Obesity and OA Meta-analysis of 47 studies (n=446 219) Obesity is a risk factor for many conditions, including knee OA.
The benefit of modifying this risk factor may cause significant risk
reduction of knee OA.
Toivanen et al140 Obesity, physically demanding work, Prospective survey study of 8000 Obesity, heavy work load and knee injury were strongly associated
and knee injury and OA participants (Finland, age>30) with the aetiology of knee OA.
Blagojevic et al71 Risk factors for OA in elderly adults Systematic review and meta-analysis; 85 The main factors consistently associated with knee OA were
studies obesity (pooled OR=2.63), previous knee trauma (pooled
OR=3.86), hand OA (pooled OR=1.49), female gender (pooled
OR=1.84) and older age. Physical occupation and physical activity
needs more and better quality studies.
BMI, body mass index; MS, metabolic syndrome; NIH, National Institute for Health; OA, osteoarthritis; ROAD, risks of OA development.

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5 Bindawas SM, Vennu V, Auais M. Health-related quality of life in older adults with
bilateral knee pain and back pain: data from the Osteoarthritis Initiative.
Box 4 Future perspectives Rheumatol Int 2015;35:2095–101.
6 March LM, Bachmeier CJ. Economics of osteoarthritis: a global perspective.
Baillieres Clin Rheumatol 1997;11:817–34.
1. Continued research into the pathogenesis of osteoarthritis
7 Reginster JY, Khaltaev NG. Introduction and WHO perspective on the global burden
(OA) including the role of synovium and other intra-articular of musculoskeletal conditions. Rheumatology (Oxford) 2002;41(Supp 1):1–2.
structures, with targeted therapy for implicated pathways 8 Brooks PM. The burden of musculoskeletal disease—a global perspective. Clin
(such as those in inflammation). Rheumatol 2006;25:778–81.
2. Further research into the risk factors of OA and the unique 9 Reginster JY. The prevalence and burden of arthritis. Rheumatology (Oxford)
2002;41(Supp 1):3–6.
pathophysiological processes that may underpin each one. 10 Fransen M, Bridgett L, March L, et al. The epidemiology of osteoarthritis in Asia.
3. Risk factor scoring for predicting total OA risk. Int J Rheum Dis 2011;14:113–21.
4. Public health campaigns to address modifiable risk factors 11 WHO. Death and DALY estimates for 2004 by cause for WHO Member States
such as obesity and knee injury in an attempt to reduce the (Persons, all ages) World Health Organisation: Lokal_Profil CC-BY-SA-2.5. 2009
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impact of dramatic increases in OA prevalence globally.
estimates_country/en/
5. Further advanced MRI sequences to detect cartilage 12 Felson DT, Naimark A, Anderson J, et al. The prevalence of knee osteoarthritis in the
degeneration early by measuring proteoglycan content, with elderly. The Framingham Osteoarthritis Study. Arthritis Rheum. 1987;30:914–18.
faster analysis of results. 13 Zhang Y, Xu L, Nevitt MC, et al. Comparison of the prevalence of knee
6. Use of serum biomarkers to detect OA in early stages, with osteoarthritis between the elderly Chinese population in Beijing and whites in
the United States: the Beijing Osteoarthritis Study. Arthritis Rheum
identification of the best combinations for optimum 2001;44:2065–71.
sensitivity and specificity. 14 Felson DT, Nevitt MC, Zhang Y, et al. High prevalence of lateral knee osteoarthritis
7. Using consensus nomenclature in future trials to unify in Beijing Chinese compared with Framingham Caucasian subjects. Arthritis
disease concepts to allow identification of specific OA Rheum 2002;46:1217–22.
15 Harvey WF, Niu J, Zhang Y, et al. Knee alignment differences between Chinese
phenotypes.
and Caucasian subjects without osteoarthritis. Ann Rheum Dis 2008;67:1524–8.
8. Further identification of genetic susceptibility loci with 16 Dudda M, Kim YJ, Zhang Y, et al. Morphologic differences between the hips of
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17 Nevitt MC, Xu L, Zhang Y, et al. Very low prevalence of hip osteoarthritis among
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risk scores in osteoporosis. Risk stratification can be divided 19 Jordan JM, Helmick CG, Renner JB, et al. Prevalence of knee symptoms and
radiographic and symptomatic knee osteoarthritis in African Americans and
into risks of OA development and risks of OA progression.142 Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol 2007;34:172–80.
Earlier diagnosis of OA will be the first major step in better 20 Braga L, Renner JB, Schwartz TA, et al. Differences in radiographic features of
treatment strategies and there are sensible calls for consensus knee osteoarthritis in African-Americans and Caucasians: the Johnston county
around more sensitive and specific diagnostic criteria for OA, osteoarthritis project. Osteoarthritis Cartilage 2009;17:1554–61.
21 Dequeker J, Luyten FP. The history of osteoarthritis-osteoarthrosis. Ann Rheum Dis
including biomarkers, to allow formulation of tools for identify-
2008;67:5–10.
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—Reliable Early Disease Identification (REDI).142 Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage
The various risk factors for OA will continue to be researched 2004;12:177–90.
with specific attention to the pathological mechanisms that may be 23 Maas O, Joseph GB, Sommer G, et al. Association between cartilage degeneration
and subchondral bone remodeling in patients with knee osteoarthritis comparing
unique to each risk factor.129 130 Public health education should MRI and (99m)Tc-DPD-SPECT/CT. Osteoarthritis Cartilage 2015;23:1713–20.
focus on the two main modifiable risk factors of obesity and knee 24 Ling SM, Patel DD, Garnero P, et al. Serum protein signatures detect early
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bally.8 9 In the field of genetics, we will see further mapping and 25 Atukorala I, Kwoh CK, Guermazi A, et al. Synovitis in knee osteoarthritis: a
precursor of disease? Ann Rheum Dis 2016;75:390–5.
identification of risk loci, additional functional studies, and further
26 Wang Y, Teichtahl AJ, Cicuttini FM. Osteoarthritis year in review 2015: imaging.
integration with other genome-wide approaches, with the new- Osteoarthritis Cartilage 2016;24:49–57.
found realisation that different polymorphisms may exist for dif- 27 Speziali A, Delcogliano M, Tei M, et al. Chondropenia: current concept review.
ferent sites of OA in the skeleton (box 4).138 Musculoskelet Surg 2015;99:189–200.
28 Mabey T, Honsawek S. Cytokines as biochemical markers for knee osteoarthritis.
Contributors SE-T prepared the manuscript and EA and DP revised and World J Orthop 2015;6:95–105.
co-authored the final manuscript. 29 Favero M, Ramonda R, Goldring MB, et al. Early knee osteoarthritis. RMD Open
2015;1(Suppl 1):e000062.
Competing interests None declared.
30 Jarraya M, Hayashi D, Roemer FW, et al. MR imaging-based semi-quantitative
Provenance and peer review Commissioned; externally peer reviewed. methods for knee osteoarthritis. Magn Reson Med Sci 2016;15:153–64.
31 Karsdal MA, Christiansen C, Ladel C, et al. Osteoarthritis—a case for personalized
health care? Osteoarthritis Cartilage 2014;22:7–16.
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