PRIMER

Osteoarthritis
Johanne Martel-Pelletier1, Andrew J.Barr2,3, Flavia M.Cicuttini4, Philip G.Conaghan2,3,
Cyrus Cooper5,6, Mary B.Goldring7, Steven R.Goldring7, Graeme Jones8,
AndrewJ.Teichtahl4,9 and Jean-Pierre Pelletier1
Abstract | Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing
socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints.
Primary OA results from a combination of risk factors, with increasing age and obesity being the
mostprominent. The concept of the pathophysiology is still evolving, from being viewed as
cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship
between local and systemic factors modulates its clinical and structural presentations, leading to
acommon final pathway of joint destruction. Pharmacological treatments are mostly related
to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce
symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory
agencies. Identifying phenotypes of patients will enable the detection of the disease in its early
stages as well as distinguish individuals who are at higher risk of progression, which in turn could
beused to guide clinical decision making and allow more effective and specific therapeutic
interventions to be designed. This Primer is an update on the progress made in the field of OA
epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention
anddisease management.

Correspondence to J.-P.P.
and J.M.-P.
Osteoarthritis Research Unit,
University of Montreal
Hospital Research Centre
(CRCHUM), 900 rue
SaintDenis, Suite R11.412,
Montreal, Quebec H2X 0A9,
Canada.
dr@jppelletier.ca;
jm@martelpelletier.ca
Article number: 16072
doi:10.1038/nrdp.2016.72
Published online 13 Oct 2016
Osteoarthritis (OA) is the most common degener
ative joint disorder that affects one or several diarthro
dial joints, including small joints (such as those in the
hand) and large joints (such as the knee and hip joints).
Clinicians did not recognize OA until the late eighteenth
century 1 and further nomenclature confusion delayed
its recognition as it was considered the same entity as
rheumatoid arthritis2. To date, OA remains challenging
to treat and its definitions, risk factors and pathophysio
logy are still evolving 3. Cardinal signs include pain, tran
sient morning stiffness and crepitus on joint motion
(agrating sound or sensation produced in the joint) that
lead to instability and physical disability, thus impairing
quality of life (QOL). OA can be classified as primary
(oridiopathic) and secondary (based on the attribution
to recognized causative factors, such as trauma, surgery
on the joint structures and abnormal joints at birth,
toname a few). Primary OA results from a combin
ation of risk factors, with increasing age and obesity
being the most prominent. Other risk factors include
knee malalignment, increased biomechanical loading
of joints, genetics and, as recently suggested, low-grade
systemic inflammation4.
OA is defined as a group of overlapping distinct
joint disorders with similar biological, morphological
and clinical outcomes 5. The definition of OA was
long centred on the changes in the articular cartilage.
This concept has evolved and OA is now considered
a disease of the whole joint, including alterations in
the articular cartilage, subchondral bone, ligaments,
capsule and synovial membrane, ultimately leadingto
joint failure6 (FIG.1). Among the structural damages
tothe joint (that is, structural OA) are loss of cartilage,
osteophyte formation, subchondral bone changes and
meniscal alterations, some of which can be visualized
using radiography 7, whereas all the above-mentioned
can be seen using MRI8. These alterations could be
accompanied by joint pain (that is, symptomatic OA).
Disease evolution in OA is usually slow and can take
several years to develop. In turn, this disease could also
undergo phases or demonstrate a progressive evolution
over time, leading to a worsening of disease severity
andsymptoms.
Epidemiology
To understand the epidemiology, risk factors and burden
of this disease, the effect of OA on symptoms, structure
and function should be considered3,5. Structural joint
changes are not always accompanied by joint pain and
both pain and structural abnormalities show variable
relationships with physical function (for example, ability
to walk and undertake the activities of daily living).

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Author addresses Americans3,16. By contrast, hip OA is low in South-East

1
Osteoarthritis Research Unit, University of Montreal
Hospital Research Centre (CRCHUM), 900 rue Saint-Denis,
Suite R11.412, Montreal, Quebec H2X 0A9, Canada.
2
Leeds Institute of Rheumatic and Musculoskeletal
Medicine, University of Leeds, Leeds, UK.
3
NIHR Leeds Musculoskeletal Biomedical Research Unit,
Leeds, UK.
4
Department of Epidemiology and Preventive Medicine,
School of Public Health and Preventive Medicine, Monash
University, Alfred Hospital, Melbourne, Victoria, Australia.
5
MRC Lifecourse Epidemiology Unit, University of
Southampton, Southampton, UK.
6
NIHR Musculoskeletal Biomedical Research Unit,
University of Oxford, Oxford, UK.
7
The Hospital for Special Surgery (HSS), HSS Research
Institute; and Weill Cornell Medical College, New York,
New York, USA.
8
Menzies Institute for Medical Research, University of
Tasmania, Hobart, Tasmania, Australia.
9
Baker IDI Heart and Diabetes Institute, Melbourne,
Victoria, Australia.
Prevalence and incidence
Prevalence and incidence estimates for OA differ widely
owing to variation in case definition and joint sites under
consideration3,9. Structural OA of the hands is reported
in ~60%, of the knee in 33% and of the hip in 5% of
adults 65years of age in North America and Europe10,11.
Structural OA is more frequent among women than men
at any given age >50years, with the sex difference most
pronounced for hand and knee OA. Prevalence rates
rise steeply with age in both sexes (FIG.2a). Incidence
studies1214 also suggest high rates for symptomatic
involvement of the hand, knee and hip in European and
NorthAmerican populations (FIG.2b). A recent study
from Spain13 reported these as 6.5 (knee), 2.1 (hip) and
2.4 (hand) per 1,000 person-years.
The frequency of pain varies depending on the
joint sites affected. Among men and women, pain in
structural hand OA is only present in ~15% of cases,
whereas ~50% of patients with structural knee OA and
an even greater proportion of those with structural
hip OA experience pain9. Moreover, about half of the
patients with knee pain and structural changes experi
ence disability. Individuals who develop symptomatic
OA in one joint are more likely to have multiple joint
involvement, and this predisposition manifests clin
ically as a condition known as generalized OA15. This
typically involves the joints of the hand (the distal inter
phalangeal joints, proximal interphalangeal joints and
basal thumbjoints)as well as the cervical and lumbar
spine, hip and knee joints. This variant is most frequent
among older women (>65years of age) and can be
inherited in a polygenicpattern.
Although OA is worldwide in its distribution, geo
graphical and ethnic differences in prevalence are appar
ent. European and American data do not differ markedly
for hand, knee and hip disease. However, hand involve
ment is particularly less frequent in Native American
and African-American populations than in white
Asian and Oriental populations, which is attributable,
inpart, to alterations in pelvic morphology 3.
Risk factors
The risk factors for OA can be divided into those that
act at the level of individual susceptibility and those
that alter the biomechanical stability of individual
joints14,17. Person-level risk factors include increasing
age, female sex, joint biomechanics, genetic factors and
adiposity. The predominant joint-level factors are joint
injury, repetitive joint use through occupation or leisure
and joint malalignment.
Risk factors associated with initiation versus progres-
sion. The distinct difference between initiation and
progression of disease remains controversial and it is
difficult to estimate the extent to which risk factors for
incidence and progression might differ. Index event
bias complicates the search for true risk factors for pro
gression18, and, in addition, progression risk is specific
to the definition of OA used (structural or sympto
matic) as well as the population studied. Some studies
have suggested that certain risk factors selectively
influence progression (that is, obesity, malalignment,
polyarticular diathesis, joint injury, crystal deposition
and high-impact physical activity)14,18,19. Among 50%
of individuals with structural OA who have frequent
joint symptoms, MRI features that distinguished those
with knee symptoms from those without include bone
marrow oedema lesions, meniscal lesions, synovial
hypertrophy andeffusion.
Obesity. Obesity is a well-established risk factor for the
development and progression of OA. The risk ratio for
being overweight (body mass index (BMI): >25kg m2)
and developing hand OA is 1.9 (REF.20). Although the
relationship between OA and obesity risk historically
has been viewed secondary to excessive joint loading 21,
this does not account for the risk of OA in non-weight-
bearing joints. In weight-bearing joints, such as the knee,
body fat has been shown to be a better predictor of cartil
age loss, independent of fat-free mass22. Moreover, the
risk of knee and hip joint replacement for OA was three
fold to fourfold higher in community-based individuals
in the highest quartile of fat mass23. Similarly, the Nurses
Health Study 24 demonstrated a more than fivefold
increased risk for progressing to hip replacement in later
life among 18year-olds in the highest compared with
the lowest BMI categories (35kg m2 and 22kgm2,
respectively).
Physical activity. There has been a misconception that
physical activity may be detrimental to weight-bearing
joints. Increasing evidence suggests that physical activity,
particularly joint loading, is important for developing
and maintaining healthy knee joints. Children who are
physically active accrue greater cartilage volume than
those who are more sedentary 25. Forced immobility in
adults (for example, owing to spinal cord injury) leads
to rapid loss of cartilage volume26.

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However, evidence for whether physical activity
isgood or bad for joints in community-based adults is
conflicting. The underlying health of the joint might be a
cause for these conflicting results. For example, vigorous
physical activity levels were associated with an increase
in the risk for knee, but not hip, joint replacement sur
gery in patients with established OA27; however, vigorous
physical activity was associated with a beneficial effect
on knee articular cartilage in healthy adults28. Joints with
structural abnormalities might not be adept at with
standing loads imparted by physical activity. Inpeople
with high baseline cartilage volume, exposure to heavy
occupational and recreational activity slowed the rate
of cartilage loss, whereas the same exposure expedited
cartilage loss among people with lower baseline cartilage
volume29. Similarly, increased number of steps per day
was protective against cartilage volume loss in people
with high baseline cartilage volume, but increased cartil
age loss in those with lower baseline cartilage volume30.
Vigorous physical activity performed on a knee with
bone marrow lesions was also associated with worsen
ing of medial cartilage defects and a trend towards
increased rates of medial tibial cartilage volume loss;
these associations were not observed in the absence of
bone marrowlesions31.
Structural factors. Abnormalities in the shape of
the hip bones are central to OA pathogenesis of this
joint. Broadly, structural abnormalities of the hip can
be grouped into hip dysplasia and femoroacetabular
impingement. Hip dysplasia is defined by insufficient
coverage of the femoral head by the acetabulum (the
concave cavity of the pelvis that forms part of the hip
joint), which results in a concentrated weight-bearing
area of the hip joint. Although overt congenital hip
dysplasia is a well-recognized risk factor for early
(<40years of age) hip OA32,33, more-subtle degrees of
dysplasia are also associated with an increased risk
of hip OA. For instance, when assessed as a continuous
measure, each 1 change towards hip dysplasia increased

a b Articular surface
Cortical bone Chondrocyte Supercial
Trabecular bone zone

Fibrous Middle
layer zone
Articular
capsule Synovial
membrane
Interterritorial
Joint cavity region Deep zone
(containing
synovial uid) Pericellular
matrix
Articular cartilage
Tidemark
Subchondral plate Calcied
cartilage
Subchondral bone
Subchondral bone marrow

c d

Chondrocyte
Articular cartilage

Articular cartilage

Surface brillation and ssuring

Chondrocyte cluster
Chondrocyte hypertrophy
Tidemark duplication
Tidemark
Calcied cartilage
Subchondral Subchondral cortical bone
cortical bone
Vascular invasion
Subchondral
trabecular bone
Figure 1 | Diarthrodial joints in health and OA. a | Diarthrodial joints join two adjacent bonesReviews
Nature that are |covered
Diseaseby
Primers
alayer of specialized articular cartilage and are encased in a connective tissue capsule lined by a synovial membrane,
consisting of a thin cell layer of macrophages and fibroblasts48. b,c | Cross-section of the articular surface of a diathrodial
joint illustrating schematically (part b) and histologically (part c) the main structural elements, including the articular
cartilage (with chondrocytes), tidemark (separating the calcified and articular cartilage), calcified cartilage, and
subchondral cortical and trabecular bone. d | Histopathological cross-section of the articular surface showing advanced
osteoarthritic changes characterized by fissuring and fragmentation of the articular cartilage, chondrocyte proliferation
and hypertrophy, duplication and advancement of the tidemark, expansion of the zone of calcified cartilage,
thickeningofthe subchondral cortical plate and vascular invasion of the bone and calcified cartilage. OA, osteoarthritis.
Images in partc and partd courtesy of E. F. DiCarlo, Hospital for Special Surgery, New York, New York, USA.

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Men Women
a 80

70

60

OA prevalence (%)
50

40

30

20

10

0
b
1,200
OA incidence (per 100,000 person-years)

1,000

800

600

400

200

0
0 20 30 40 50 60 70 80 0 20 30 40 50 60 70 80
Age (years) Age (years)

DIP Knee Hip Hand

Figure 2 | Prevalence and incidence of OA. a | Age-specific and sex-specific prevalenceNature

rates for structural
Reviews osteoarthritis
| Disease Primers
(OA) that affects the distal interphalangeal (DIP), knee and hip joints in a large Dutch population sample11. b|Incidence of
symptomatic OA of the hand, knee and hip. Data from REF.12.

the 20year risk of hip joint replacement by 10.5%33.
Underdevelopment of the acetabulum, which occurs in
pre-term babies, might have long-term implications for
hip joint health32. Indeed, low birth weight and pre-term
birth have recently been shown to be associated with an
increased risk of hip arthroplasty (surgical joint replace
ment) secondary to OA in later life34. Subtle hip dysplasia
might be one mechanism that mediates thisrisk.
Femoroacetabular impingement occurs when anato
mical abnormalities of the femoral head and/or aceta
bulum result in abnormal contact between the two
during hip motion, leading to cartilage damage. The
morphometric abnormalities are described by the cam
deformity of the femoral head (that is, when the femoral
head is not perfectly round) or pincer deformity of the
acetabulum (owing to excessive coverage of the femoral
head by the acetabulum resulting in contact between the
femoral neck and the acetabulum during movement).
The condition is commonly observed in younger adults
(<30years of age) and is a causal pathway to hip OA.
For instance, radiographic evidence of femoroacetabular
impingement in young asymptomatic adults (<30years of
age) precedes hip OA, with even mild deformity associ
ated with a 3.7fold, and severe deformity of 9.7fold,
increased risk for end-stage hip OA in laterlife35.
Modifiable developmental exposures that might
lead to structural joint damage are also gaining interest.
Elite levels of sporting activity during adolescence have
been shown to be a risk factor for femoroacetabular
impingement 3639, particularly when growth plates are
open38,39. The mechanism for this has been speculated to
be secondary to repetitive joint loading on bones under
going rapid growth. Occupations that involve heavy lift
ing, such as farming, are also a risk factor for hip OA40.
However, early occupational exposure is important, with
a study demonstrating that, in those 1830years of age,
heavy lifting was associated with deleterious structural
changes of the hip joint in laterlife41.
Genetics. Although strong evidence for the involvement
of genetic factors in structural OA of the hand and the
spine exists42,43, evidence is inconsistent for knee OA44.
A meta-analysis45 showed that not one out of 199 pub
lished candidate OA genes has a significant association
with knee OA and only two are associated with hip OA.
Genetic and epidemiological studies and genome-
wide association studies (GWAS) have helped to estab
lish the important role of genetic factors in the risk for
the development of OA and the outcomes and evolu
tion of joint pathology and symptoms46,47. Classic twin

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studies and familial aggregation studies indicate that,
after adjustmentfor known risk factors such as age, sex
and BMI, genetic susceptibility for the development of
structural OA ranges from 40% to 65% depending on
the joint site46,47. To date, GWAS have identified several
common variants associated with knee or hip OA46,
although the individual risk alleles exert only moderate-
to-small effects. Loci that are associated with OA include
genes encoding components of the transforming growth
factor and bone morphogenetic protein signalling
pathways: growth/differentiation factor 5 (GDF5);
typeII iodothyronine deiodinase (DIO2), which regu
lates the synthesis of triiodothyronine, the active thyroid
hormone that has a role in cartilage maintenance and
repair; proteins that are involved in apoptosisand mito
chondrial damage; molecules that regulate the synthesis
and remodelling of extracellular matrix components;
WNT signalling pathway components; andproteins
that are associated with inflammation and immune
responses. Despite the modest contributions of the
individual genetic variants to the increased risk of OA,
the identification of these genes has yielded important
insight into the molecular mechanisms involved in
OA pathogenesis. In addition, this information can be
applied to develop biomarkers that can be used to detect
individuals at high risk for the development of OA and
to implement preventive or interventional therapies to
improve patient outcomes.
Mechanisms/pathophysiology
Diarthrodial joints (FIG.1a) join two adjacent bones that
are covered by a layer of specialized articular cartilage
and encased in a synovial capsule48. The bone, articu
lar cartilage and the thin region of calcified cartilage
between form a biocomposite, which is uniquely adapted
to transfer loads during weight bearing and joint motion.
Alteration in the integrity of the individual joint tissues
can occur either acutely associated with traumatic
injury or can evolve over time through cell-derived or
matrix-derived factors that alter the composition, struc
ture and material properties of the joint tissues (BOX1).
Although pathological processes can target a single tissue
(see below), as mentioned earlier, ultimately, all of the
joint tissues are affected because of their intimate phys
ical and functional association. OA is thus considered a
whole-joint disease.
Cartilage and chondrocyte function
The articular cartilage is composed of water (>70%) and
organic extracellular matrix components, mainly typeII
collagen and aggrecan or other proteoglycans, but also
several other collagens and non-collagenous proteins4951.
The collagen network provides tensile strength and the
charged proteoglycans provide compressive resilience
by entrapping large quantities of water through their
hydrophilic glycosaminoglycan (GAG) side chains52,53.
Thecartilage matrix is avascular and aneural and is
populated by a single cell type: the chondrocyte.
Under physiological conditions, the chondrocyte
exhibits no mitotic activity and maintains minimal col
lagen turnover. The chondrocyte is involved mostly in
replacing the GAG constituents on aggrecan and small
proteoglycan core proteins, which undergo turnover in
response to external stimuli, such as mechanical load
ing. However, the ability to perform low-turnover repair
declines with age and in OA. Chondrocytes are encased
in a pericellular matrix consisting of typeVI collagen and
other matrix proteins54 (FIG.1b,c). The pericellular matrix
helps to maintain the chondrocyte in a differentiated
low-turnover state by protecting it from interacting with
extracellular matrix components in the interterritorial
cartilage matrix 55,56. Chondrocytes exist in a low-oxygen-
tension environment, and intracellular survival fac
tors, such as hypoxia-inducible factor 1, are required
for maintenance of homeostasis and adaptation to the
mechanical environment 57. Primary cilia that are located
on the chondrocyte surface and other mechanosensitive
receptors permit the chondrocytes to sense and adapt
their metabolic activity in response to physical forces55,58.
In OA, the cartilage matrix undergoes striking
changes in its composition and structure (FIG.1d). Initially,
surface fibrillations appear and, as the pathological pro
cess continues, deep fissures associated with exfoliation
of cartilage fragments develop, ultimately leading to
delamination and exposure of the underlying calcified
cartilage and bone. These changes are accompanied by
expansion of the zone of calcified cartilage and replace
ment of the overlying articular cartilage5961. This process
is associated with duplication of the tidemark, which is
a histologically defined zone that separates the calcified
articular cartilage from the underlying calcified cartilage.
At sites of microcracks and fissures in the osteochondral
junction, vascular elements from the marrow space
penetrate the subchondral bone and calcified cartilage
accompanied by sensory and sympathetic nerves61. New
bone is formed around these channels, r ecapitulating
aprogramme of endochondral boneformation62,63.
In the early stages of OA, chondrocytes exhibit
increased synthetic activity, reflecting attempts at
repair 64. An early event is the disruption of the chondro
cyte pericellular matrix exposing the cells to compo
nents of the inter-territorial matrix, which deregulates
chondrocyte function through cell surface receptors,
including integrin and discoidin domain receptors56.
As the disease progresses, the proteoglycans become
Box 1 | Factors involved in joint destruction in OA
Cytokines and/or chemokines: IL1, IL6, IL15,
oncostatin M and tumour necrosis factor
Inflammatory mediators: prostaglandin E2, nitric oxide,
reactive oxygen species and complement
Matrix degradation: matrix metalloproteinase 1
(MMP1), MMP3, MMP13, aggrecanase, a disintegrin
and metalloproteinase with thrombospondin motifs 4
(ADAMTS4), ADAMTS5 and cathepsins
Cell-derived and/or matrix-derived products: alarmins
(for example, S100), fibronectin fragments, hyaluronic
acid fragments, collagen fragments, proteoglycan
fragments and high-mobility group box
OA, osteoarthritis.

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depleted followed by the erosion of the collagen net
work, whichmarks irreversible progression. This is
accompanied by the induction of several families of
aggrecanases, which include members of the a dis
integrin and metalloproteinase with thrombospondin
motifs (ADAMTS) family, which cleave the aggrecan
core protein65, and several different matrix metallo
proteinases66 (BOX1). Upregulation of genes encoding
proteins associated with inflammatory and catabolic
responses, primarily through signal transduction
involving nuclear f actor-B (NFB), mitogen-activated
protein kinase, and other inflammation-induced and
stress-induced pathways67,68. There is also evidence of
increased chondrocyte death, which is due, in part, toa
decline in autophagy. Innormal circumstances, auto
phagy serves as a protective mechanism used by cells
under stress69,70. Many of the chondrocytes also assume
a senescence-associated secretory phenotype, which
is characterized by an increased production of reac
tive oxygen species, cytokines, chemokines and other
pro-inflammatoryproducts71.
During the later stages of OA, many of the chondro
cytes show increased expression of genes and production
of proteins associated with hypertrophy 72. Angiogenic
factors, including vascular endothelial growth factor,
are also induced in chondrocytes and contribute to the
vascular invasion and calcified cartilage expansion that
occur at later stages ofOA62,63.
Alterations in the composition of the cartilage
result in marked changes in the material properties
and increase its susceptibility to disruption by physical
forces49,73. Inaddition, the matrix degradation products
OPG
RANK RANKL
Pre-osteoclast Mesenchymal cell
(pre-osteoblast)
Lining cell Osteocyte
Osteoclast
Osteoblast
Sclerostin
RANKL
OPG
Figure 3 | Bone remodelling. Bone remodelling involves Nature Reviews | Disease
the coordinated activityPrimers
of
osteoclasts that resorb the bone and osteoblasts that mediate bone formation59.
Osteocytes regulate bone remodelling in response to mechanical stimuli via direct
cellcell signalling with osteoblasts and osteoclasts and by the release of soluble
mediators197. For example, in response to increased mechanical loading, secretion of
sclerostin, a WNT pathway inhibitor, by osteocytes decreases. Decreased secretion
ofsclerostin results in increased WNT signalling and enhanced osteoblast-mediated
bone formation. Conversely, unloading results in increased secretion of receptor
activator of nuclear factorB (RANK; also known as TNFRSF11A) ligand (RANKL; also
known as TNFSF11), which leads to enhanced osteoclast differentiation and increased
bone resorption. OPG,osteoprotegerin (also known as TNFRSF11B).
and pro-inflammatory mediators that are generated by
chondrocyte catabolic activity act in an autocrine or para
crine manner to further deregulate chondrocyte function,
but, as discussed below, act on the adjacent synovium to
stimulate proliferative and pro-inflammatory responses.
Periarticular bone and cartilage damage
Bone structure and composition is adapted through
out an individuals lifetime via cell-mediated processes
involving osteoblasts, which synthesize new bone, and
osteoclasts, which resorb bone in response to local bio
mechanical factors, systemic hormones and local soluble
mediators (FIG.3). The bone beneath the articular cartil
age is organized into a plate-like layer of cortical bone
and a contiguous region of cancellous bone59,74,75 (FIG.1).
OA is accompanied by increases in the volume, thick
ness and contour of the cortical plate, alterations in the
state of bone mineralization and material properties,
changes in the subchondral trabecular bone architec
ture and bone mass, the formation of bone cysts, and the
appearance of bone marrow lesions and osteophytes74,7678
(FIG.4). These changes are mediated by alterations in the
activity of osteoclasts and osteoblasts59,76,77. Bone may
also undergo direct physical damage that results in the
formation of microcracks or fissures within the cor
tical or trabecular bone, and this process is enhanced
in OA that is related to the adverse effects of increased
mechanicalloading 76,77.
Gradual thickening of the subchondral plate,
acharacteristic feature of advancing OA, reflects the influ
ence of changes in mechanical loading owing to cartilage
damage and changes in properties of the subchondral
bone. Importantly, there is a close anatomical associ
ation between these bone changes and the development
of local OA cartilage pathology 78, indicating that both
tissues are responsive to the adverse effects of mechanical
loading 7981. Radin and Rose82 proposed in the 1980s that
increased bone stiffness in the subchondral bone adversely
affects the overlying cartilage and contributes to the devel
opment of OA cartilage pathology. This hypothesis was
supported by findings of Brown etal.80. However, studies
by Day etal.83,84 in the 2000s challenged the Radin and
Rose concept, as they found that, although the volume of
the subchondral bone was increased, the bone stiffness
was decreased owing to a reduction in bone mineral den
sity. They speculated that the reduction in bone tissue
stiffness might lead to increased cartilage deformation
during loading, contributing directly to the development
of OA cartilage pathology. These studies support the con
cept that alterations in the subchondral bone properties
influence the state of the overlying articular cartilage, but
indicate the complexity of this r elationship, which evolves
over the course of OAprogression.
Bone marrow lesions (FIG.4c) are not just localized
regions of bone marrow oedema, but are characterized
by fat necrosis, localized marrow fibrosis and micro
fractures of the trabecular bone that are associated with
active bone remodelling and repair 85,86. Bone marrow
lesions tend to associate with regions of OA cartilage
damage and are especially common at sites of denuded
subchondralbone87.

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a b c Suprapatellar
eusion
Cartilage defect
in the patella
Large
Bone marrow osteophyte
lesion

Hoa Anterior horn

synovitis meniscal tear

Figure 4 | Characteristic periarticular bone abnormalities in OA. a | Radiography of the hand showing
Nature Reviews characteristic
| Disease Primers
narrowing of the joint space (arrow). b | Radiography of the knee showing narrowing of the joint space (white arrow) and
chondrocalcinosis (black arrow), which is a rheumatic disorder associated with calcium pyrophosphate dehydrate
crystalaccumulation in the soft tissues that is often associated with osteoarthritis (OA). c | Knee MRI showing all the
characteristic features of OA, including effusion of the suprapatellar pouch and inflammation of the infrapatellar fat pad
(the Hoffa pad). Bone marrow lesions are regions of increased signal intensity in the subchondral bone. Part c adapted
withpermission from REF.122, Wiley, 2016 Royal Australasian College of Physicians.

Subchondral bone cysts (fluid-filled holes) are a
common feature of advanced OA (FIG.4c). The obser
vations that cysts tend to develop at sites of pre-existing
bone marrow lesions have led to the concept that they
are generated directly within the subchondral bone,
and that bone damage and necrosis initiate the process
of osteoclast-mediated bone resorption that leads to
cystformation88.
Osteophytes are bony outgrowths that are localized
on the joint margins (FIG.4c). Bone cysts are formed
by endochondral ossification, which is a process of
bone formation that starts with cartilage formation89.
Osteophytes might serve to stabilize the joint rather than
contribute to the progression of joint pathology. Indeed,
the removal of osteophytes increases joint instability
in animal models of OA90, and a relationship between
structural progression of knee OA and osteophyte size
in humans with OA is absent 91.
Synovium and inflammation
The synovium includes the synovial membrane and the
fluid. The synovial membrane is a thin cellular layer
that lines the joint cavity, which acts as a semipermeable
membrane to regulate the transfer of molecules in and
out of the joint (FIG.1a). It is a major source of the syno
vial fluid components, including nutrients and lubricant
factors, such as lubricin and hyaluronic acid (a GAG).
Lubricant factors contribute to the unique low-friction
properties of the articular surface.
Synovitis (inflammation of the synovium), which
is characterized by hyperplasia of the synovium and
diffuse or perivascular infiltrates of T lymphocytes and
Blymphocytes, is a common feature of OA92 (FIG.5).
Imaging studies using MRI and ultrasonography
have established a positive correlation between syno
vitis and the risk for structural progression of OA and
jointsymptoms9396.
Dysfunctional chondrocytes and cartilage damage
have a key role in the development of synovial inflamma
tion (FIG.6). Proteinases that are released by chondrocytes
lead to the generation of pro-inflammatory cartilage
degradation products, which act as damage-associated
molecular patterns (DAMPs) that interact with Toll-like
receptors (TLRs), integrins and receptor for advanced
glycation end-products (RAGE) expressed on chondro
cytes to further increase the expression of inflammatory
and catabolic products50,70,92,97 (BOX1). DAMPs are also
released into the synovial fluid where they act on the
adjacent synovium to induce inflammation that in turn
generates additional pro-inflammatory and catabolic
products that feedback on the chondrocytes to further
deregulate their function.
Gene and protein analysis of synovium derived from
patients with OA identified enhanced expression of
molecules involved in angiogenesis, tissue catabolism,
inflammation and innate immunity in inflamed versus
non-inflamed synovium. The role of immune system
activation in OA is further demonstrated by the finding
that cartilage matrix degradation products can activate
TLRs. Proteins that are involved in the complement,
acute-phase response and coagulation pathways are
differentially expressed in synovial fluids from patients
with OA versus controls98. In addition, mice that are
deficient in several complement proteins are partially
protected from the development of OA99. Finally, sev
eral pro-inflammatory cytokines can be detected in
synovial fluid, cartilage and the synovium derived from
patients with OA, whereas they are absent in healthy
controls92,100 (BOX1). IL1 and tumour necrosis factor
(TNF) are potent regulators of catabolic processes in
chondrocytes and synovial cells, but their exact roles
inOA pathogenesis still need to be established. The
levels of IL15, and to a lesser extent IL6, are also
increased in synovial fluids and tissues from patients
with OA compared with controls101. IL15 is involved in
the recruitment and activation of lymphocytes and thus
could be a contributing factor to the lymphocytic reac
tion that is associated with synovial inflammation in
OA. Many chemokines, including IL8, CC-chemokine
ligand5 (CCL5) and CCL19, have been detected in
synovial fluids and the synovial membrane of patients
with OA. Their receptors are widely expressed on

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a b Chondrocytes in the articular cartilage and osteo

cytes in bone sense these local biomechanical forces via
cellular structures, such as primary cilia and a complex
system of cell surface receptors that act as mechano
sensors to modulate and adapt the cells to their local
biomechanical environment 51,55,58,59. Compressive forces
and tensile strains, as well as osmotic stresses and fluid
flow, act on these cell surface sensors to modulate
cellular responses via multiple mechanisms, including
activation of intracellular calcium signalling pathways
and modulation of osmolyte channels such as transient
* receptor potential cation channel subfamily V member4
(TRPV4)111. These mechanosensors and their down
stream signalling pathways represent potential thera
peutic targets to modulate the responses of resident cells
Figure 5 | Histopathology of the synovial membrane. Nature a | Normal
Reviews | Disease
synovial Primers
membrane to mechanical forces to prevent the activation of path
with a thin lining layer on top of a subintimal layer that consists of loose connective ways that are involved in deregulating remodelling and
tissue. b | Characteristic abnormalities of the synovial membrane in osteoarthritis are repair of joint tissues. Many of the mechanotransduction
synovial lining hyperplasia (arrow), villous hyperplasia (arrowhead), fibrosis (asterisk) events overlap with those involved in inflammatory
andperivascular mononuclear cell infiltrates (squares). Reproduced with permission stress. Metabolic stress associated with obesity and the
from REF.92, Elsevier.
metabolic syndrome adds another level of complexity 114.

chondrocytes and synovial cells, implicating a poten
tial role in synovial inflammation in OA102104. Further
studies are needed to establish the role of chemokines
in OA pathogenesis and to identify them as relevant
targets for OA therapy.
Obesity and adipokines
It is speculated that adiposity triggers metabolic inflam
mation, in which various adipokines released from
adipose tissues induce pro-inflammatory cytokines in
the synovium and chondrocytes, ultimately leading to
cartilage matrix damage and subchondral bone remodel
ling 105.This hypothesis is supported by invivo studies,
in which increased serum levels of adipokines, such as
leptinand adipsin, are associated with greater cartilage
loss anda higher incidence of knee joint replacement106,107.
Inaddition to these systemic effects of adiposity, local
effects have also been observed. Forexample, increased
intramuscular quadriceps fat content was found to be a
strong predictor ofknee cartilage loss108,109. In patients
with symptomatic kneeOA, maintaining muscle size
is associated with benef icial structural changes and
a reduced risk of knee jointreplacement 110.
Mechanical factors
As mentioned, both physiological and pathological
overload forces can affect the biological activity and
viability of the cell types that populate the individual
joint tissues. At a macro-scale level, several factors affect
the local forces that are experienced by cells and their
extracellular matrices, including joint alignment, kine
matics and aspects of gait that can considerably affect the
distribution of load transfer across the joint 111,112. Joint
injuries such as anterior cruciate ligament rupture or loss
of integrity of the menisci are examples of conditions
that markedly affect the distribution of forces within
the joint, but, importantly, they result in sustained alter
ations in joint mechanics that produce long-term effects
on cell activity and function113.
Diagnosis, screening and prevention
Diagnosis
When patients with OA seek clinical help, it is gener
ally because of symptoms. Despite the fact that OA is an
extremely common illness, it can be difficult to diagnose.
Diagnostic criteria were developed for the knee115,116,
hand117 and hip118. No diagnostic criteria for other com
monly affected sites, such as the spine or big toe, have
been developed, but these are usually diagnosed based
on symptoms and/or imaging. The primary aimof
these criteria was to differentiate OA from other forms
of arthritis, such as rheumatoid arthritis and ankylosing
spondylitis. How these criteria perform to differentiate
patients with OA from healthy elderly patients is unclear,
as this was not the aim for which they were developed.
In clinical practice, patients would often have blood tests
(to determine, for example, rheumatoid factor, erythro
cyte sedimentation rate (ESR) and Creactive protein)
to rule out other conditions. However, these tests are not
essential as a diagnosis can be made in their absence.
It is easier to diagnose OA when it is well established
but can be difficult in early disease. Imaging can be
helpful when there is diagnostic uncertainty. MRI might
besuperior to radiography in early disease. It should be
noted that population screening programmes show that
many structural abnormalities seen on imaging are very
common in older populations119, thus should be placed
in the appropriate clinical context.
Knee OA. The diagnostic criteria for either clinical
or structural knee OA (BOX2) are highly sensitive and
specific to differentiate knee OA from other forms of
arthritis115 and correlate well with cartilage damage on
arthroscopy (a minimally invasive procedure in which
the joint is examined with an endoscope). Patients with
structural OA show more cartilage and bone damage
than those diagnosed only clinically 116, presumably
reflecting more longstanding disease as radiographic
changes can take years to appear. Positioning of the knee

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during radiography is crucial to avoid a spurious diagno
sis of structural OA; ways to achieve correct positioning
include fluoroscopic and semi-flexed radiography.
Crepitus on active motion is a diagnostic parameter,
which is most common in OA, but whether it is useful
to identify all types of knee OA is debated. One study
showed that crepitus is specific to patellofemoral OA and
not tibiofemoral disease diagnosed on MRI120, whereas
another arthroscopy-based study reported an associ
ation between crepitus and cartilage pathology in both
compartments of the knee121.
There are some limitations to both clinical and
radiographic criteria. First, although osteophytes are
included in the criteria for structural OA, they may
be an epiphenomenon rather than a key player in the
pathophysiology 122. Joint space narrowing and other
radiographic features are not part of the criteria despite
being considered a key part of the disease in radio
graphic atlases. Indeed, joint space narrowing is usually
more common than osteophytes123. Selection of patients
for trials using the clinical criteria may lead to greater
potential for response than choosing only patients with
radiographic changes because, as mentioned above,
the clinical criteria select patients with less cartilage
damage than the radiographic criteria. Second, many
studies have shown a poor correlation between radio
graphs andsymptoms124, suggesting that this construct
of combining pain and other clinical parameters with
radiographic information is artificial. This has led to
the development of MRI criteria125. The diagnostic per
formance of MRI abnormalities was greatest for osteo
phytes, cartilage loss, bone marrow lesions and meniscal
tear in any region125. As a consequence, the MRI criteria
resulted in good specificity for the diagnosis of knee
OA, but sensitivity was less optimal, probably owing to
abnormalities being more common on MRI. Although
the individual components of the MRI abnormalities
described above are relevant for pain and structural
change124, the specific combination mentioned is dif
ferent for the tibiofemoral and patellofemoral compart
ments of the knee and does not consider pain. Thus,
these MRI criteria require validation before widespread
acceptance. In addition, pain can come from inside or
outside the joint. Hence, an alternative way of d efining
this could be: pain in combination with any feature
within the joint known to lead to cartilage damage
(symptomatic OA) or any feature outside the joint
known to lead to cartilage damage (OA syndrome); for
example, obesity can lead to knee pain and structural
change122. This additional subgrouping may lead to
specific therapies based on the source ofpain.

Joint cavity Synovial Hand OA. Criteria for OA of the hand were alsodevel
Cytokines membrane
Chemokines oped to differentiate hand OA from other forms of arthri
TLR and/or RAGE ligands tis117 and have similar issues as the knee. The criteria for
Adipokines
hand OA include the presence of hand pain in addition
Cartilage to three or more of the following characteristics: bony
Mechanical stress degradation enlargements of two or more of the ten selected joints
Adipokines products (DAMPs)
of the hand, bony enlargements of two or more distal
Cartilage interphalangeal joints, less than three s wollen meta
carpophalangeal joints, or deformity of one or more of
the ten selected joints. These criteria alone are sufficient
MMPs to diagnose OA of the hand, and laboratory tests and
ADAMTS radiographs are unnecessary. In fact, radiography was
Chondrocyte
of less value than clinical examination to classify symp
Cytokines NOS2 tomatic OA of the hands117. Data are less well developed
Chemokines COX2 for MRI of the hand than of the knee, but it is clear that
NO some of the features (such as bone marrow lesions and
PGE2
Adipokines
synovitis) that are commonly seen in the knee are also
seen in the hand126.

Hip OA. Criteria to diagnose clinical and structural

Subchondral bone Joint
Figure 6 | Crosstalk between cartilage and the synovium in the
Nature pathogenesis
Reviews Diseaseof OA.
Primers
Nature Reviews | |Disease Primers
Products that are released from the cartilage matrix and/or the chondrocytes in
responseto adverse mechanical forces and other factors induce the release of products
that deregulate chondrocyte function via paracrine and autocrine mechanisms.
Catabolicenzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and
metalloproteinase with thrombospondin motifs (ADAMTS), released by chondrocytes
degrade the cartilage matrix, releasing cartilage degradation products that, along with
the other pro-inflammatory chondrocyte derived-products, act on the synovium to
induceinflammation and the release of pro-inflammatory products that feedback on
chondrocytes to further deregulate their function (see http://primer.oarsi.org).
COX2,cyclooxygenase2; DAMP, damage-associated molecular pattern; NO, nitric oxide;
NOS2, nitric oxide synthase 2; OA, osteoarthritis; PGE2, prostaglandin E2; RAGE,receptor
for advanced glycation end-products; TLR, Toll-like receptor.
hip OA are shown in BOX3 (REF.118). In contrast to the
hand, the radiographic presence of osteophytes best
distinguishes patients with OA and controls. Owing to
the difficulty in detecting synovitis in the hip, a normal
ESR is also required. Data on the use of MRI to diag
nose hip OA are limited, but preliminary studies indicate
that bone marrow lesions are much less common than
at other sites, suggesting different pathological processes
such as hip shape may be more important 127.
Prevention
Weight management is the most well-established pri
mary (that is, prevention before clinical symptoms or
structural disease develops) and secondary (that is, after

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the diagnosis of OA to slow down progression) preven
tive strategy for OA. For instance, women who lost an
average of 11 pounds (~5kg) decreased their risk for
knee OA by 50% in the Framingham Study 128. In obese
adults, as little as a 1% change in body weight modified
the rate of knee cartilage loss129, such that avoidance of
weight gain could also be an important clinical target
in the prevention of knee OA. As mentioned earlier,
preferential loss of fat, rather than fat-free mass, will
probably offer the most effective means of preventing
OA130. Thus, weight management remains central to
the prevention of OA at various anatomical sites, with
a particular focus on maintaining muscle mass while
reducing adiposity.
Advice for physical activity for primary and second
ary prevention of knee OA might differ, although fur
ther work is needed to better inform clinical guidelines.
Indeed, the effect of physical activity on protecting or
accelerating cartilage loss in the knee joint depends on
the health of the knee joint. Maintaining physical activity
could be important for preventing the development of
knee OA, but may need to be modified once substantial
structural damage has developed.
Early developmental factors that influence bone
shape might be central to the prevention of hip OA.
For example, the increased risk of low-birth-weight and
pre-term babies to develop OA could be due to subtle
hipdysplasia34.
Although requiring further examination, early inter
vention may mitigate abnormal hip development in
high-risk neonates, although there has been a paucity
of literature examining such concepts thus far. Efforts to
elucidate preventive strategies in OA continue, with new
approaches being identified as we gain a greater under
standing of the complexity of the pathogenesis of OA
across differentjoints.
Management
Individuals with OA require a comprehensive assess
ment of the severity and functional impact of OA along
with their personal perception of their health to ensure
Box 2 | Diagnostic criteria for knee OA
Clinical OA*
Presence of knee pain and three or more of the following
characteristics:
>50years of age
Morning stiffness that lasts for <30minutes
Crepitus on active motion
Bony tenderness of the knee
Bony enlargement
No detectable warmth
Structural OA*
Knee pain and one of the following characteristics:
>50years of age
Morning stiffness that lasts for <30minutes
Crepitus on active motion and osteophytes
OA, osteoarthritis. *See REFS115,116.
that a personalized management strategy is tailored to
their needs. Indeed, a patient-centred multidisciplinary
approach involving a combination of interventions,
including self-management strategies, is associated with
better pain management and functional outcomes131.
Abaseline assessment should include the assessment
of BMI along with the distribution of joints affected by
OA. The involvement of multiple joints and comorbid
obesity is a poor prognostic phenotype132,133.
Management guidelines
The management of OA has been described in
evidence-based guidelines from important musculo
skeletal organizations. There is a general consensus on
recommended therapy across these guidelines, although
discordance exists on particular therapies (TABLE1).
The efficacy of therapies may vary according to the
anatomical location and number of joints affected by
OA (FIG.7). However, the majority of the evidence base
used in writing these guidelines originates from clin
ical trials of knee OA. The medical management of OA
includes pharmacological and non-pharmacological
therapies, and clinicians and people with OA often use
multipletherapies.
Non-pharmacological interventions
A multidisciplinary, patient-centred combination of
education, self-management, exercise, weight loss with
realistic goals, encouragement and regular reassess
ment is recommended for individuals with OA 131.
Allmanagement guidelines recommend health educa
tion and promotion of self-management. Individuals
with OA should understand their own risk factors
(forexample, obesity), their prognosis and that OA rep
resents failure of joint repair, commonly following one
or more joint insults. This insight should be reinforced
during serial consultations along with electronic and
writteninformation.
Individuals with OA should be encouraged to par
take in exercise and be informed of the benefits of this,
irrespective of the functional status and structural or
pain severity of the OA with which they suffer. Cochrane
reviews report that land-based exercise programmes
for the hip and knee can improve physical function and
pain134,135, although there is less evidence to indicate that
hand exercises reduce pain in hand OA. Exercise pro
grammes should first aim to improve muscle strength
around the affected joints, followed by general aerobic
exercise. Indeed, muscle weakness plays a major part
in the development of disability, and muscle strength
ening is effective at reducing pain and disability 136.
Patient adherence to exercise for OA declines over
time, so programmes should be tailored to the sever
ity of the OA and involve shared decision making to
ensure tolerability and optimize long-term adherence.
For example, individuals with substantial sarcopaenia
will benefit from initial low-impact exercises (such as
walking laps in a swimming pool or cycling on exer
cise bikes) to strengthen the muscles, in which inten
sity can be increased after according to the capability
of theindividual.

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Individuals who are overweight or obese should be
provided with dietary advice because weight loss (usu
ally ~10% of body weight) is associated with improved
pain and function, and might be associated with reduced
progression of structural damage 128,129,137,138. Obese
individuals who are attempting weight loss should be
encouraged by explaining that improvement in knee OA
symptoms follows a doseresponse relationship with
percentage weight loss139. The combination of weight
loss and exercise in obese and overweight individuals
offers an additive reduction in pain138.
Aids for OA include adaptation devices, splints and
braces. Specific aids are recommended for specific indi
cations by all of the guidelines; these include splints for
base-of-thumb OA140,141, devices for opening jars and
walking canes142. These can facilitate activities of daily
living and reduce OA symptoms. Knee braces can also
reduce knee pain and the size of bone marrow lesions in
patellofemoral knee OA143. Individuals with OA of the
lower limbs are recommended to use footwear with thick
shock-absorbing soles, no heel elevation and adequate
plantar arch support 131. Transcutaneous electrical nerve
stimulation144, acupuncture and thermotherapy 145 may
be adjuncts for treating OA but are not universally
recommended owing to the limited evidence supporting
their efficacy.
Pharmacological inventions
Topical, oral and injectable pharmacological treatments
are available for individuals with OA. Age, concurrent
medications, comorbid conditions (in particular, cardio
vascular and gastrointestinal problems) and predicted
adherence should be considered for each individual
before prescribing a pharmacological intervention.
Current therapies are at best moderately effective pain
relievers, and it is worth noting that studies report that
most people with OA have persistent pain despite t aking
all their prescribed therapies. The effect size of these
therapies is summarized in TABLE2.
First-line therapies include topical NSAIDs and oral
paracetamol146. Topical NSAIDs have better safety pro
files than oral NSAIDs as systemic drug levels are much
lower. However, they are limited by joint penetration
and multiple daily applications. Paracetamol is prob
ably a less effective analgesic in OA than NSAIDs147149.
Topical capsaicin is a chilli pepper extract that depletes
neurotransmitters in sensory terminals and attenuates
the central transmission of peripheral pain impulses
from the joint. It is generally recommended as a sup
plementary analgesic for hand and knee OA and avoids
systemic toxicity 146.
Oral NSAIDs and selective cyclooxygenase 2 (COX2)
inhibitors are the most common oral pharmacological
agents used for the treatment of OA. They are associ
ated with considerable toxicities (in particular, gastro
intestinal and cardiovascular complications), especially
with increasing age and comorbidities. Opioids are vari
ably used across countries, although they often remain
the only option for people who cannot tolerate or should
not be exposed to NSAIDs. However, opioids have their
own considerable toxicity profile (including dizziness,
Box 3 | Diagnostic criteria for hip osteoarthritis
Clinical hip OA*
Hip pain in combination with either:
Hip internal rotation of 15, pain present on internal
rotation of the hip, morning stiffness of the hip for
60minutes and >50years of age
Hip internal rotation of <15 and an erythrocyte
sedimentation rate (ESR) of 45mm per hour; if no ESR
was obtained, hip flexion of 115 can be used instead
with a sensitivity of 86% and specificity of 75%
Clinical plus radiographic criteria for hip OA*
All of the above combined with pain and two or more
ofthe following three criteria:
Osteophytes (femoral or acetabular)
Joint space narrowing (superior, axial and/or medial)
ESR of <20mm per hour
OA, osteoarthritis. *See REF.118.
nausea, constipation and falls). Evidence for the use of
duloxetine, a serotoninnoradrenaline reuptake inhib
itor, in knee OA is limited; the Osteoarthritis Research
Society International (OARSI) and the American College
of Rheumatology (ACR) guidelines recommend its use in
multi-joint OA and knee OA, respectively. Inthe United
States (but not in Europe), duloxetine is licensed for
musculoskeletalpain.
Systemic treatment with nutraceuticals includ
ing glucosamine and chondroitin sulfate products,
which are natural compounds that consist of GAG unit
components and GAGs, respectively is not recom
mended by the UK National Institute for Health and
Care Excellence (NICE) or guidelines150152 owing to the
lack of certainty of clinically important analgesic benefit.
Conversely, Cochrane reviews and the European Society
for Clinicaland Economic Aspects of Osteoporosis,
Osteoarthritis and Musculoskeletal Diseases (ESCEO)
guidelines conclude that these therapies may have analge
sic effects beyond the placebo effect 153155. However,
more-recent observational and trial evidence indicates
their potential as an effective analgesic156 and for the
attenuation of structural progression157,158. Controversy
remains regarding the e fficacy of nutraceuticals inOA.
Intra-articular corticosteroids might be recom
mended in patients in whom pain is preventing
appropriate muscle strengthening exercise or, more
uncommonly, in which large effusions are painful or
limit joint movement 159,160. They provide short-term
analgesic benefits typically for 34weeks in individuals
with moderate-tosevere OA pain presumably due to
their anti-inflammatory actions160,161.
Hyaluronic acid (also known as hyaluronan) is a
high-molecular-weight GAG and a naturally occurring
component of synovial fluid and cartilage. It provides
the viscoelastic properties of synovial fluid that might
provide lubricating and shock-absorbing properties.
Hyaluronic acid use in knee OA is conditionally recom
mended by the 2012 ACR guidelines150 in individuals
with knee OA who are >74years of age, with symptoms
refractory to standard pharmacological treatments.

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The2014 NICE151 and 2014 OARSI152 guidelines do not
recommend hyaluronic acid and were informed by a
larger literature review and health economic evaluation.
This conclusion is supported by a meta-analysis of the
therapeutic benefit of hyaluronic acid in knee OA, which
states that the benefit is small and clinically irrelevant162.
Joint surgery
Arthroscopic lavage and debridement (flushing debris
out of the joint space or resecting cartilage and/or
meniscus) are not recommended for the treatment of
knee OA without a clear history of true mechanical
locking, as the clinical outcomes are not improved132.
Ifmedical interventions fail to sufficiently improve per
sistent debilitating symptoms of OA, joint replacement
surgery should be considered. Joint replacement sur
gery has been highly effective for the hip and increas
ingly so for the knee joint; the evidence for other joints
lags behind. The patient should be adequately informed
about the relative benefits of surgery, the risks of contin
ued medical treatment and surgical options along with a
realistic understanding of the postsurgical rehabilitation.
Individuals who consider knee replacement should be
reviewed for independent risk factors for persistent pain
that occurs after total knee replacement. The strongest
preoperative predictors of this complication include
mental health disorders, catastrophizing, pain at multi
ple sites and preoperative knee pain163. Surgical referral
should occur before a functional limitation or severe
pain occurs. As a general rule, joint replacement surgery
in younger patients (<60years of age) might be delayed
because joint prostheses have a finite life expectancy and
revision surgery offers less-favourable outcomes164,165.
Structure modification
Therapies that confer a cessation or inhibition of
structural deterioration of knee pathologies are highly
desirable. However, conclusive evidence of a structure-
modifying therapy of oral pharmacological thera
pies is lacking. Although some randomized, placebo-
controlled trials have reported achieving reduction in
cartilage loss, the results are not consistent. These used

Table 1 | Evidence-based guidelines for OA treatments

Guideline NICE 2014* ESCEO 2014 OARSI 2014 EULAR 2013|| ACR 2012
All sites Knee Knee Multi-joint Knee and hip Hand Knee Hip
Education or self-management + + + + + (+) (+) (+)
Exercise and/or physiotherapy + + + + + NE + +
(water-based and land-based)
Weight loss in obesity + + + + + NE + +
Aids, adaptations, braces and footwear (site-specific) + (+) (+) (+) + (+) (+) (+)
Transcutaneous electrical nerve stimulation + + NR NE NE (+) NE
Acupuncture + NR NR NE NE (+) NE
Thermotherapy (for example, hot packs or spas) + + NR (+) NE (+) (+) (+)
Topical NSAIDs + + + NR NE (+) (+) NR
Oral NSAIDs (lowest possible dose) + + (+) (+) NE (+) (+) (+)
Paracetamol + + (+) + NE NE (+) (+)
Cyclooxygenase 2 inhibitors + (+) (+) (+) NE (+) (+) NR
Topical capsaicin +# (+) (+) NR NE (+) NE
Opioids (for refractory pain) (+) + NR NR NE (+) NR
Serotoninnoradrenaline reuptake inhibitor NE (+) (+) + NE NR (+) NR
Nutraceuticals (for example, glucosamine + NR NR NE NE
andchondroitin sulfate)
Intra-articular corticosteroids + (+) (+) + NE (+) (+)
Intra-articular hyaluronic acid (+) NR NE (+) NR
Duloxetine NE (+) NR + NE NE (+) NR
Risedronate NE NE NE NE NE NE
Strontium ranelate NE NE NE NE NE NE NE
Surgery (lavage or debridement) ** NE NE NE NE NE NE
Surgery (total joint replacement or arthroplasty) (+) (+) + NE NE NE NE NE
(site-specific)
This is not a headtohead comparison of the guidelines but a summary of the recommendations. Each guideline addresses different anatomical sites. +, treatment
is unconditionally recommended; (+), treatment is conditionally recommended; , treatment is not recommended; ACR, American College of Rheumatology;
ESCEO, European Society for Clinical and Economical Aspects of Osteoporosis and Osteoarthritis; EULAR, European League Against Rheumatism; NE, treatment
isnot evaluated; NICE, UK National Institute for Health and Care Excellence; NR, no recommendation for treatment despite reviewing the evidence;
OA,osteoarthritis; OARSI, Osteoarthritis Research Society International. *See REF.151. See REF.155. See REF.152. ||See REFS131,198,199. See REF.150.
#
Excluding hip osteoarthritis. **Unless there is a clear history of mechanical knee locking. Data from REF.200.

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 PRIMER

Core treatments (appropriate for all individuals)

Land-based exercise Water-based exercise
Weight management Self-management
Strength training and education

Knee-only OA without comorbidities Knee-only Multi-joint OA without Multi-joint OA with

Biomechanical interventions OA with comorbidities comorbidities
Intra-articular corticosteroids comorbidities Oral COX2 inhibitors Balneotherapy
Topical NSAIDs Biomechanical (selective NSAIDs) Biomechanical
Walking cane interventions Intra-articular interventions
Oral COX2 inhibitors Walking cane corticosteroids Intra-articular
(selective NSAIDs) Intra-articular Oral non-selective NSAIDs corticosteroids
Capsaicin corticosteroids Duloxetine Oral COX2
Oral non-selective NSAIDs Topical NSAIDs Biomechanical interventions inhibitors
Duloxetine Acetaminophen (selective NSAIDs)
Acetaminophen (paracetamol) (paracetamol) Duloxetine

Recommended treatments for specic OA types*

Figure 7 | Osteoarthritis Research Society International guidelines for the non-surgical management
Nature of kneePrimers
Reviews | Disease OA.
*Osteoarthritis Research Society International also recommends referral for consideration of open orthopaedic surgery
ifmore-conservative treatments are found ineffective. COX2, cyclooxygenase2; OA, osteoarthritis. Adapted with
permission from REF.152, Elsevier.

agents, including chondroitin sulfate and glucosamine
sulfate157,158,166168, that have not demonstrated significant
structural modification in meta-analysis151. They are
considered to act primarily by slowing the net catabolic
changes within the cartilage. A single randomized con
trolled trial reports structure modification with strontium
ranelate169, which primarily targets bone remodelling.
However, the generation of further evidence of structure
modification and routine clinical use of strontium ranel
ate is now limited by its association with greater risk of
cardiovascular morbidity 170; there is currently no licensed
structuremodifying therapy.
Monitoring
The guidelines do not generally comment on followup.
However, the NICE guidance recommended regular
reviews, especially when refractory and disturbing joint
pain exists, when there is more than one symptomatic
joint or comorbidity and when regular oral medications
require monitoring (full blood count and renal func
tion)151. The frequency of followup should be agreed
on between the patient and the practitioner in conjunc
tion with sensible goal-setting, and should be used as an
opportunity to reassess and reinforce important educa
tion and self-management messages, titrate therapies and
monitor for efficacy and toxicity.
Quality of life
QOL questionnaires
Measurements of structural changes and pain need to
be supplemented by indices of activity limitation and
participation restriction. Standardized questionnaires are
available that are targeted at generic parameters, such as
general health, vitality and mental health (for example,
the physical function scale of the 36Item Short-Form
Health Survey (SF36)) or at disease-specific disabilities.
The most widely used disease-specific questionnaires
developed to assess OA of the knee and hip are the
Western Ontario and McMaster Universities Arthritis
Index (WOMAC)171, the Hip Disability and Osteoarthritis
Outcome Score (HOOS)172 and the Knee Injury and
Osteoarthritis Outcome Score (KOOS)173. These ques
tionnaires obtain self-report information on disabilities,
such as pain, stiffness and QOL; activity limitations, such
as activities of daily living, sports participation and recre
ational activities; and participation restriction as part of
the general assessment of QOL.
Morbidity
According to the WHO Global Burden of Disease Study
in 2010, OA was the 11th highest cause of years lived
with disability worldwide; this represented a rise from
15th position in the 1990 study 174,175. The lifetime risk of
morbidity associated with hip OA is approximately 25%,
which increases to 45% for knee OA. A large proportion
(>70%) of the 57,000 knee and 55,000 hip arthroplasties
in the United Kingdom alone are due to OA176178. The
disorder is associated with major activity limitations179,
especially walking (22% of patients), but also affects daily
living activities, such as dressing (12.8% of patients) and
carrying heavy objects (18.6% of patients). In Europe180,
around 11.8% of affected individuals require assistance
in care from health professionals, 9.2% require assistance
from immediate family and 8.9% of health service deliv
ery is directly attributable to the disorder. The pain and
loss of function account for a substantial economic bur
den, with estimates typically ranging from ~1% to 2.5%
of gross domestic product in western nations177.
Mortality
Patients with OA are at greater risk of premature death
than matched controls from the general population181.
In a large population-based sample of British men and
women182 with symptomatic, radiographicallyevident

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Table 2 | Effect size for pain relief in OA Translational approach

Treatments All trials High-quality
(ES(95%CI)) trials (Jadad=5)
(ES (95%CI))
Acupuncture 0.35 (0.15, 0.55) 0.22 (0.01, 0.44)
Acetaminophen 0.14 (0.05, 0.23) 0.10 (0.03, 0.23)
NSAIDs 0.29 (0.22, 0.35) 0.39 (0.24, 0.55)
Topical NSAIDs 0.44 (0.27, 0.62) 0.42 (0.19, 0.65)
IAHA 0.60 (0.37, 0.83) 0.22 (0.11, 0.54)
GS 0.58 (0.30, 0.87) 0.29 (0.003, 0.57)
CS 0.75 (0.50, 1.01) 0.005 (0.11, 0.12)
ASU 0.38 (0.01, 0.76) 0.22 (0.06, 0.51)
Lavage or 0.21 (0.12, 0.54) 0.11 (0.30, 0.08)
debridement
The relationship between effect size (ES) for pain relief and
quality of randomized controlled trials (RCTs) is depicted.
Effect size is calculated between treatment and placebo.
Jadad=5 refers to the selection of RCTs scoring five out of
fivepoints for study quality. ASU, avocado soybean
unsaponifiables; CS, chondroitin sulfate; GS, glucosamine;
IAHA, intra-articular hyaluronic acid; OA, osteoarthritis.
Reproduced with permission from REF.146, Elsevier.
OA of the knee and hip, all-cause mortality was signifi
cantly increased (standard mortality ratio: 1.55; 95%CI:
1.411.70). Cause-specific mortality was particularly
high for cardiovascular disease and dementia, possibly
through low-grade systemic inflammation, long-term
use of NSAIDs or physical inactivity. These findings
were replicated in a Canadian cohort study, in which
increased all-cause mortality was associated with base
line functional limitation183, as well as in the US Study of
Osteoporotic Fractures184, which detected an excess risk
of all-cause mortality (hazard ratio (HR): 1.14; 95%CI:
1.051.24) and cardiovascular mortality (HR:1.24;
95%CI: 1.091.41). Although associations with cardio
vascular risk factors, most notably obesity, insulin resist
ance and hypertension, might explain part of the effect
of OA on premature death, novel pathways that lead to
accelerated biological senescence present an intriguing
additional possibility. However, those with functional
loss in some of these studies seem to have a selective
increase in mortality and it remains possible that the
finding may not be disease-specific.
Outlook
OA is among the diseases with the fastest growing
incidence, which is mainly owing to the ageing world
population185. The burden of this chronic, crippling
and debilitating disease is an enormous challenge for
the health care system and society in general, related
tothe direct cost of the disease and all the indirect
costs that are generated by it, and, as mentioned, OA
is now recognized as an independent risk factor for
increased mortality 181,186. Much has been accomplished
in OA research and management, but much remains to
be done. This is particularly true with regard to devel
oping new drugs and agents that can improve disease
symptoms at the same time as reduce the progression
of jointdestruction.
Considerable investment in basic and clinical research
over the past few decades has provided important clues
about the risk factors that are associated with disease
development and progression. New findings with regard
to the disease pathophysiology have enabled a better
understanding of the disease process and identified
potential therapeutic targets6. The recent advances in
understanding the origin of pain in OA from a mech
anistic and structural point of view will help in the
development of more targeted therapy with improved
benefit-torisk balance that can also improve the QOL
of patients.
However, much work remains to be done to under
stand how we can integrate these findings into a final
and comprehensive concept that can explain the chrono
logical steps of the development of OA. The basic
research findings need to be comprehensively integrated
with those from clinical research to provide a global and
clearer picture of the disease process. Hence, results from
epidemiological, observational, genetic, epigenetic and
clinical studies, including those that have explored struc
tural changes using imaging technologies such as MRI,
have provided a large body of new information about
risk factors that are associated with OA progression,
which complement those generated from basic science
research8,187. This integrated translational approach to
OA research makes it possible to move the research focus
from observational to interventional, which is the main
challenge of the next decade in this field of research.
Patient stratification
OA is a more complex disease than previously assumed
and it is believed to include multiple phenotypes and
subgroups. Identification of phenotypes will also
probably help the development of approaches to non-
pharmacological management of OA as well as other
treatment modalities. It is now of the utmost impor
tance to move this therapeutic field forward; we need to
look closely at past experience with disease-modifying
OA drugs (DMOADs) and personalized medicine and
take steps to improve on what we have learned8,187.
Selectively targeting some phenotypes of patients with
OA may enable the development of DMOADs based on
personalized medicine188191. New tools are needed that
can help to predict which patients are best suited for a
given DMOAD, and should allow for a better response
to a specific treatment 192.
Management
Prevention should remain an important dimension
ofthe management of OA. Observational studies suchas
the Osteoarthritis Initiative (OAI)193, the Tasmanian
older adult cohort (TASOAC)194 and others have helped
provide valuable information in that respect and hope
fully more will come from ongoing and future observa
tional studies. The therapeutic options for OA treatment,
such as NSAIDs, analgesics and corticosteroids, are still
for the most part symptomatic and no DMOAD has
yet received regulatory approval. The development of
safe and effective new treatments for OA is the main

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 PRIMER

challenge of the future. The cardiovascular and renal
safety issues surrounding NSAIDs and paracetamol have
unfortunately left clinicians with even fewer options for
the treatment of patients with OA148,195. Symptomatic
slow-acting drugs for OA, local and topical, could be
helpful155. Moreover, the requirement of DMOADs to
act on both the symptoms and the structures should be
reconsidered and inclusive of an improvement in QOL
and in the w ell-being of patients, rather than focusing
primarily onpain.
Clinical trial design
Clinical trial protocols would benefit from being
better standardized and more uniform 187. Several
important issues need to be addressed, including the
heterogeneity between studies and regulatory guidelines.
Studyoutcome measures as defined today by regulatory
bodies are not optimal in view of the recent advances in
OA research196. These should be updated, taking into
account recommendations from different groups of
experts looking at defining response. Much emphasis
has been placed on studying the weight-bearing joints.
As OA is very often a generalized disease, the question
as to what should be the primary outcome of DMOAD
studies, as well as which patient subgroups with OA to
include, should be revisited. Reducing study duration
and the number of patients needed in DMOAD trials
can probably be achieved with the use of advanced imag
ing technologies such as MRI rather than Xrays8. As in
many other fields of medical research, this should allow
for substantial savings, making DMOAD development
programmes more accessible.

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Acknowledgements
J.M.-P. and J.-P.P. acknowledge the Chair in Osteoarthritis of
the University of Montreal and the Groupe de recherche des
maladies rhumatismales du Qubec for their support in
osteoarthritis research. The authors thank V. Wallis for her
assistance with the manuscript preparation.
Author contributions
Introduction (J.M.-P. and J.-P.P.); Epidemiology (C.C.); Mech
anisms/pathophysiology (M.B.G. and S.R.G.); Diagnosis,
screening and prevention (F.M.C., G.J. and A.J.T.); Manage
ment (A.J.B. and P.G.C.); Quality of life (C.C.); Outlook (J.M.-P.
and J.P.P.); Overview of Primer (J.M.-P. and J.-P.P.).
Competing interests
J.M.-P. is a shareholder of ArthroLab Inc. and consultant for
AbbVie, Bioibrica, Ferring, Medapharma, Pierre-Fabre and
TRB Chemedica. P.G.C. is a member of the speakers bureau
and/or is a consultant for AbbVie, Flexion, Janssen, Lilly,
Novartis, Pfizer, Regeneron and Roche. C.C. has received
consultancy fees and honoraria from Alliance for Better Bone
Health, Amgen, Eli Lilly, GlasoSmithKline, Medtronic, Merck,
Novartis, Pfizer, Roche, Servier, Takeda and UCB. J.-P.P. is a
shareholder of ArthroLab Inc. and is a consultant for AbbVie,
Bioibrica, Centrexion, Ferring, Medapharma, Pfizer, Pierre-
Fabre, Teva Pharmaceuticals and TRB Chemedica. All other
authors declare no competing interests.

18 | 2016 | VOLUME 2 www.nature.com/nrdp

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