OSTEOARTHRITIS

OsteoarthritisTonia L Vincent

Fiona E Watt

Abstract

Osteoarthritis (OA) is the most common form of joint disease, and its

impact is set to grow as the prevalence of obesity rises and our elderly

population increases. Many clinicians regard OA as being simply a disease

of ‘wear and tear’, and by implication one in which disease modification is

not possible. Such prejudices have led to significant academic apathy in

this disease that is reflected not only in our poor understanding of dis-

ease pathogenesis, but also in the failure to classify the disease with

greater precision, and to develop sensitive tools for diagnosis and prog-

nostic assessment. The recent identification of key degradative enzymes

in cartilage and the use of mouse models to study disease pathogenesis

have greatly changed our outlook. The next decade is likely to see

significant advances in our understanding of, and treatment for, this

condition.

Keywords Aggrecanase; articular cartilage; mechanical injury;

osteoarthritis

Pathology

Osteoarthritis (OA) is the most common form of joint disease,

estimated to cost a sum equivalent to 1e1.5% of the gross do-

mestic product of developing countries.1 It is characterized by loss

of the articular cartilage, an avascular and aneural tissue that

overlies the ends of bone at synovial joints, and this likely leads to

changes in the other tissues of the joint that contribute to disease

expression.2 Cartilage is uniquely adapted to perceive and

respond to mechanical stress because of the presence of an

elaborate, organized extracellular matrix made up of the proteo-

glycan, aggrecan, and type II collagen. Chondrocytes, which are

the only cells in cartilage, are responsible for maintaining the

matrix during life. Ultimately, these same cells are probably

responsible for making the degradative enzymes that destroy the

tissue in disease.

Loss of articular cartilage occurs initially at the articulating

surface and then spreads through the matrix down to the sub-

chondral bone (Figure 1). Other changes that occur in the tissue

include patchy loss of aggrecan, and clustering and clonal

expansion of chondrocytes. Within the joint there is also sclerosis

of the subchondral bone, bony expansion with osteophyte for-

mation, and episodic synovitis. Cartilage loss often precedes the

development of pain, which explains why patients often present

Tonia L Vincent FRCP PhD is Professor of Musculoskeletal Biology at

the Kennedy Institute of Rheumatology, and Honorary Consultant

Rheumatologist at the Nuffield Orthopedic Centre, Oxford, UK.

Competing interests: none declared.

Fiona E Watt MRCP PhD is a Senior Lecturer at the Kennedy Institute

of Rheumatology, and Honorary Consultant Rheumatologist at the

Nuffield Orthopedic Centre, Oxford, UK. Competing interests: none

declared.

MEDICINE 42:4 213

with advanced joint degeneration. The source of pain is unclear,

but it may arise from bone or inflamed synovium, or from other

peri-articular structures such as entheses, bursae or tendons.

Chronic pain, resulting from local sensitization of nerve fibres and

central nervous system changes, is common over time.3

Aetiology

Traditionally, OA has been designated as either primary or sec-

ondary, based on the presence or absence of a known predis-

posing factor or factors. In practice, it is usually possible to

identify such factors in all patients with disease even though

these may be multiple low-impact factors such as family history,

obesity and age. We prefer to divide OA into ‘age-related OA’,

where disease is associated with advanced age, and ‘premature

OA’ where there is usually a single strong independent risk factor

that leads to early onset of disease.

Mechanics

Irrespective of how thedisease is classified, the unifying aetiological

factor in OA development is mechanical load e either abnormal

load on a normal joint, or normal load on a joint that has lost its

mechanoprotective mechanisms (Table 1)(reviewed in4). This is

perhaps most clearly illustrated in young individuals who have

sustained destabilizing injuries to the joint (e.g. meniscal and cru-

ciate ligament injuries). They exhibit an OA risk of approximately

50%within 10 years of injury. It is also the case that repetitive low-

impact injuries, often occupational, are strongly associated with

disease. Likewise,malaligned andmisshapen joints are at increased

risk of disease. Conversely, off-loading a diseased joint can halt

disease progression, as seen in those who have sustained a

cerebrovascular accident or polio. Therapeutic approaches to

off-load the diseased joint, for example, by high tibial osteotomy or

joint distraction (where a sprung external fixator is placed across

the joint for a period of 3 months), show good symptomatic re-

sponses and may be disease modifying.5 Other important aetio-

logical factors then contribute to the expression of disease and

presumably explain why disease is highly heterogeneous and the

course unpredictable. Some of these are discussed further below.

Age

Age is likely to contribute to disease risk by a number of mech-

anisms. Aged joints often exhibit mechanical failure; meniscal

failure is evident in 40% of ‘age-related’ OA in the absence of a

history of acute knee trauma.6 Moreover, loss of muscle strength

and reflexes with age suppresses normal mechanoprotective gait

responses. It is generally accepted that aged cartilage is more

susceptible to degradation, due in part to a reduction in new

matrix synthesis, as well as an increase in activation of degra-

dative pathways. Ageing also leads to a failure to clear damaged

cells that accumulate in tissues, causing release of reactive oxy-

gen species and tissue damage. Such mechanisms have been

observed in joint cells (reviewed in7).

Obesity

Increasedmechanical load on the joint is one obvious consequence

of obesity as is poor muscle tone leading to loss of joint protection.

In addition, adipocytes probably secrete inflammatory cytokines

(adipokines) that drive matrix degradation directly.8 Individuals

with obesity have higher concentrations of circulating

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

a b

(a) Normal and (b) osteoarthritic human cartilage stained forproteoglycan (red). Note patchy loss of proteoglycan, tissuefibrillation and clustering of chondrocytes.

Figure 1

Metabolic causes of osteoarthritis

Acromegaly

Hyperparathyroidism

Hypothyroidism

Diabetes mellitus (may relate to obesity)

Haemochromatosis

Wilson’s disease

Gaucher’s disease

Ochronosis (alkaptonuria)

KashineBeck disease

Haemoglobinopathies/avascular necrosis

Table 2

OSTEOARTHRITIS

inflammatory response proteins and are at increased risk of meta-

bolic syndromes, which are also associated with OA (see below).

Genetics

From twin studies, heritability in OA is calculated to be in the

region of 60%.9 Recent studies have determined that OA is highly

polygenic e in other words, disease is increased by poly-

morphisms in a number of different genes, although the relative

risk of each gene is small. Whole genome-wide analyses have

confirmed this polygenic association and have identified a small

number of weak novel gene candidates.10 Epigenetics, the com-

plex ways in which gene expression is controlled in a given in-

dividual, may be more important and this line of research is

currently being pursued.

Metabolic syndromes

A number of metabolic syndromes have been associated with the

development of OA. These are listed in Table 2. Chondrocalci-

nosis (cartilage calcification) can be present (e.g. in haemo-

chromatosis and hyperparathyroidism) and may indicate a

predisposition to inflammatory episodes precipitated by calcium

pyrophosphate crystal deposition.

Theories of pathogenesis

A number of theories of pathogenesis have been proposed

over the decades, but the discovery in the 1980s of a family of

Evidence for mechanical factors in OA aetiology

Increased disease by increased load Increased disease by loss o

protection

Overuse (e.g. cotton pickers’ (hand), coal

miners’ (back), farmers’ (hip) OA)

Acute destabilizing injuries

meniscal tears)

Obesity Loss of gait reflexes with a

Acute articular cartilage trauma

(e.g. intra-articular fracture)

Chondrodysplasias (weak c

matrix)

Joint malalignment Joint damage due to previo

arthritis

Loss of joint support throu

weakness (e.g. age)

Table 1

MEDICINE 42:4 214

matrix-degrading enzymes, known as matrix metalloproteinases

(MMPs), substantially changed the face of OA research. A new

hypothesis was presented: that osteoarthritis was due to an

imbalance of tissue homeostasis, pushing the scales in favour of

matrix degradation rather than synthesis. This theory was sup-

ported by the identification of fragments of aggrecan in the joint

fluid of patients with OA. However, on close examination, they

did not appear to have been generated by the action of known

MMPs, and it was concluded that another, as yet undiscovered,

class of enzymes was responsible for degradation; these were

termed ‘aggrecanases’.11 The first aggrecanase was purified and

cloned in 1999,12 and in 2000 a second homologous enzyme

(aggrecanase 2) was discovered.13 Despite much industrial in-

terest, strategies for inhibiting aggrecanases in patients with

arthritis have not been forthcoming, possibly due to off-target

effects of inhibitors and partly to a lack of good biomarkers to

monitor disease in clinical trials.

Aggrecanase expression can be driven in vitro by inflammatory

cytokines such as interleukin 1, although the role of such cytokines

in driving expression in vivo is controversial. These enzymes can

also be induced by mechanical injury in vivo and in vitro, sug-

gesting that the cellular pathways that drivemechanical responses

could be highly relevant future therapeutic targets.

Clinical features and diagnosis

Osteoarthritis can be considered as a common clinico-

pathological syndrome that is a consequence of diverse

f joint mechano- Reduced disease by mechanical joint off-

loading

(e.g. cruciate/ Polio and CVA patients have reduced disease

on immobilized side

ge Disease arrest following high tibial osteotomy

artilage Disease modification following surgical joint

distraction

us inflammatory Animal are protected from experimental OA

with joint immobilization

gh muscle

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

OSTEOARTHRITIS

aetiological factors in different patients. This syndrome includes

joint pain and functional limitation of the affected joint.14 X-ray

criteria are helpful for the diagnosis of established disease.

Where X-rays are normal, the diagnosis of early disease relies on

careful clinical assessment of the patient, because it is not

practical to sample cartilage histologically.

Symptoms and signs of OA

History: one or more joints are affected, typically in an asym-

metrical manner. Unlike rheumatoid arthritis, non-synovial joints

such as the acromioclavicular joint can also be involved. Not all

affected joints are necessarily symptomatic; the factors controlling

when and how much pain is caused by the osteoarthritic process

are complex. There is typically a lack of the prolonged

early morning stiffness seen in the classical inflammatory ar-

thropathies such as rheumatoid arthritis, although many patients

report short periods (<30 minutes) of this and other inflammatory

symptoms such as swelling during flares. Typically, pain is

worsened by, or follows, activity. A functional history is often

revealing, and needs to be specific to the particular joint and

patient. A family history of OA and relevant diseases, occupa-

tional history, a history of trauma or surgery to joints, and

menstrual history in women should be documented (Tables 1e3).

Secondary causes of OA such as haemochromatosis and hyper-

parathyroidism should be considered, particularly in young

patients.

Examination: affected joints are usually swollen and can be

tender. Swelling or deformity around joints may be caused by

bony expansion (firm, often non-tender) or soft tissue inflam-

mation (often tender, for example synovitis, effusion, enthesitis

or bursitis). Figure 2a and c demonstrate bony expansion or

‘nodes’ of the small joints of the hand. A generalized restriction

in range of movement, and joint crepitus or clunking may be

evident. Joint deformity can also follow or be the cause of

asymmetrical disease in a joint. For example, a varus knee

deformity often occurs in knee OA. Instability symptoms, such as

‘giving way’ usually result from muscle wasting, repeated effu-

sions, remodelling of entheses, and ligament laxity. Entheseal

Surgical interventions for osteoarthritis

Established procedures

Penetration of subchondral bone (‘micro-fracture’)

Cartilage plug/graft (for isolated defects)

Arthroscopy and debridement (only for symptoms of true ‘locking’)

Joint replacement (total joint (arthroplasty)/unicompartmental/hemi-

arthroplasty)

Joint fusion

Osteotomy

Surgical joint distraction

Soft tissue grafts (e.g. in CMC joint disease)

Trapeziectomy (CMC joint disease)

Experimental procedures

Autologous chondrocyte implantation

Mesenchymal stem cell transplantation

CMC, carpometacarpophalangeal.

Table 3

MEDICINE 42:4 215

tenderness or bursitis may be present, and a cause of focal pain.

Patients should be examined for leg length discrepancy as well as

foot biomechanics on walking.

Joint involvement in osteoarthritis

Osteoarthritis can affect any joint, but those frequently affected

include the small joints of the hands and feet, the hip and the

knee (Figure 3). Osteoarthritis at these different joint sites is

associated with discrete genetic and environmental risk factors

(see earlier discussion). However, OA at a single site increases an

individual’s risk of OA elsewhere, and some patients have

‘generalized osteoarthritis’ (i.e. OA affecting three or more sites).

Hand: OA commonly occurs in women and often presents at the

time of the menopause. Bony swellings of the distal interpha-

langeal (DIP) joints are referred to as Heberden’s nodes

(Figure 2a and c), whereas bony swellings of proximal inter-

phalangeal (PIP) joints are known as Bouchard’s nodes. These

terms are only ever used in the context of osteoarthritis. Such

nodal OA may represent a subset of patients with hand osteo-

arthritis. Inflammatory OA affecting the DIP and PIP joints can

resemble seronegative spondyloarthropathies such as psoriatic

arthritis, which may be difficult clinically to differentiate. The

first carpometacarpophalangeal (CMC) joint is also frequently

affected by osteoarthritis, signified by ‘squaring’ and often pain

at the base of the thumb (Figure 2a). Some hypothesize that this

joint is susceptible to OA because of its relatively recent evolu-

tion. OA does not typically affect the metacarpophalangeal

(MCP) joints, but this can occur in haemochromatosis.

Foot: OA commonly affects the first metatarsophalangeal joint.

Flares of arthritis here can be confused with gout. Involvement of

the small joints of the foot can give rise to deformities such as

hallux valgus, hallux rigidus (which can affect ‘toeing off’ and

therefore gait) and hammer toe.

Knee: typically, the medial compartment is affected first in

osteoarthritis of the knee (Figure 3c and d). If this is severe, and

other compartments are spared, unicompartmental joint

replacement can be considered. The lateral and patello-femoral

compartments can also be affected, either alone, or as part of

‘tri-compartmental’ knee osteoarthritis.

Hip: obesity and congenital femoro-acetabular deformities (pin-

cer or cam deformities) predispose to hip OA, which is a

frequently affected joint. Like knee OA, it is costly in terms of

joint replacement and socioeconomic impact. It typically pre-

sents with pain or aching in the groin, or more unusually in the

back or as pain referred to the knee on the affected side.

Spine: in contrast to RA, where axial disease is unusual, the

spine and sacroiliac joints are frequently affected by osteoar-

thritis. Facet joints, vertebral endplates and ligamentous in-

sertions may all be involved. Sometimes, spinal OA is referred to

as ‘spondylosis’. Spinal OA is often associated with degenerative

disc disease. Diffuse idiopathic skeletal hyperostosis (DISH) (also

known as Forestier’s disease) causes florid ligamentous calcifi-

cation and bony hypertrophy, which leads to spinal stiffness

(usually non-inflammatory) and fusion of vertebrae; it can mimic

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

a b

dc

(a) Osteoarthritis of the hand affecting DIP joints and first carpometacarpophalangeal (CMC) joint. Note Heberden’s nodes at DIP joints andsquaring at the base of thumb. (b) Bone scan showing increased uptake at DIP joints and first CMC joint. (c) Erosive nodal osteoarthritis with marked joint swelling and deformity. (d) Note classical features of joint space narrowing, sclerosis and bone cysts on X-ray. Erosions are also present.

Figure 2

OSTEOARTHRITIS

ankylosing spondylitis clinically, but can usually be distin-

guished radiologically (Figure 3b). Thoracic DISH may be evident

on a patient’s chest X-ray.

Investigations

Blood tests

Blood tests such as erythrocyte sedimentation rate tend to be

normal in osteoarthritis. A modestly elevated serum C-reactive

protein can be associated with progressive ‘erosive’ osteoarthritis

in some patients. A number of matrix degradation products such

as CTX-II and COMP have been investigated as experimental

biomarkers for OA. However, none have yet proved useful in a

clinical setting to aid diagnosis, assess prognosis, or monitor

disease or response to treatment.

Radiography

The classical features of radiographic osteoarthritis are shown

in Figures 2d and 3c. Joint space narrowing (JSN) on an X-ray

reflects the progressive loss of volume of articular cartilage

seen in the disease. Bone density is maintained, and often

increased subchondrally. Not all radiographic features need be

present for diagnosis. It is recommended that weight-bearing X-

rays are taken of load-bearing joints such as the knee, as this

increases sensitivity for detection of JSN. In contrast, the

presence of osteophytes (bony spurs around the joint) is quite

specific to osteoarthritis. Radiographic severity of OA can be

MEDICINE 42:4 216

graded using the KellgreneLawrence scale. Chondrocalcinosis

resulting from secondary calcium pyrophosphate deposition in

cartilage may be visible on X-rays (the knee and wrist are

frequently affected areas). Calcium crystals are seen in 12% to

60% of synovial fluids in OA patients with effusions, and may

be responsible for episodic inflammatory symptoms in some

OA patients.15

Plain X-rays can be normal in early disease. Radioisotope

bone scans frequently show modestly increased uptake in

affected joints, although are rarely justifiable clinically

(Figure 2b). Increasingly sophisticated imaging techniques allow

us to visualize joint tissues with increasing resolution. Magnetic

resonance imaging (MRI) has been increasingly used as a

research tool in OA to demonstrate change over time. However,

although musculoskeletal ultrasound and MRI can be suggestive

of OA processes in advance of established radiographic change

(such as early osteophytes on ultrasound, or change in

morphology or volume of articular cartilage on MRI), there are

no widely agreed, validated diagnostic criteria for these modal-

ities. SPECT-CT (single photon emission computed tomography

operating with a conventional CT scanner) and MRI are useful in

the assessment of those considering surgical intervention for

isolated cartilage defects (generally younger, history of sports

injuries), and MRI is indicated for those with symptoms and

signs suggesting meniscal or ligamentous disruption. However,

its place in other routine clinical assessment is far less clear.16,17

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

a

b

d

c

Radiographic osteoarthritis. (a) Osteoarthritis causing arthrodesis atthird PIP joint. (b) Asymmetrical diffuse idiopathic skeletalhyperostosis with associated sacroiliac disease. Note bridgingosteophytes. (c) Antero-posterior standing knee X-ray with joint spaceloss especially in the medial compartment and osteophytes bilaterally.(d) ‘Skyline’ view of patello-femoral joint demonstrating goodpreservation of the joint space except in the most medial aspect.

Figure 3

LifestyleEducation, advice, information access

Strengthening exercisesAerobic fitness

Weight loss if applicable

Surgery

Second-line analgesiaNSAIDs (with PPI)COX-2 selective

OpioidsTopical capsaicin

Supportive therapyAssistive devicesFoot orthotics

Supports and bracesManual therapy

(manipulation and stretching)

First-line analgesiaParacetamol

Topical NSAID gel

Treatment of osteoarthritis

NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor

Adapted from NICE guidelines, February 2014;

http://guidance.nice.org.uk/CG177/NICEGuidance/pdf/English

Figure 4

OSTEOARTHRITIS

Management

The current management of patients falls into four broad areas:

education and supportive/lifestylemeasures, non-pharmacological,

pharmacological and surgical interventions. A summary of the

clinical guideline for the care and management of osteoarthritis in

adults by the National Institute for Health and Care Excellence

(NICE) is shown in Figure 4.18 Other guidelines have been produced

by the European League against Rheumatism (EULAR) and the

Osteoarthritis Research Society International (OARSI), with broadly

similar guidance. Despite its much greater prevalence, the medical

treatment of osteoarthritis lags behind diseases such as rheumatoid

arthritis. No disease-modifying OA drugs (DMOADs) are currently

in routine clinical use.

Supportive/lifestyle interventions

Management should be focused on the individual, and should

include an assessment of the effect of OA on their work, leisure

activities, function and quality of life. Patients should be

MEDICINE 42:4 217

educated and given constructive messages about their disease

(see the Arthritis and Musculoskeletal Alliance [ARMA] stan-

dards of care for people with OA). All patients with OA should be

encouraged to remain in work and to exercise. Delivery of care

for osteoarthritis is typically in primary care. If there is persistent

pain or poor response to multiple oral agents, doubt as to the

cause of the pain, or progressive loss of function, it is reasonable

to consider a referral to a specialist.

Non-pharmacological interventions

General aerobic fitness is important for all types of osteoarthritis;

in addition a physiotherapist’s involvement may be appropriate.

Isometric quadriceps strengthening improves pain and prognosis

in knee OA.19 In the case of hand OA, hand exercises and

splinting by a hand therapist is helpful: splinting of the first CMC

joint improves pain in hand OA.20 If the patient is overweight or

obese, weight loss should be a priority, as there is good evidence

that this will improve pain and slow disease progression in all

types of OA, even in patients of relatively normal weight. Some

patients may benefit, in addition, from supports and braces

(particularly in the presence of deformity), specialist shoe ware,

such as arch supports or wedges, and walking aids. Trans-

cutaneous nerve stimulation (TENS) and acupuncture may be

helpful for the management of chronic pain in certain patients.

Pharmacological interventions

Not all those with OA will need regular oral analgesia. For those

who do, paracetamol and topical non-steroidal anti-inflamma-

tory drugs (NSAIDs; applied as gel) are the first-line treatments.

Both have been shown to be effective for the treatment of the

pain of OA and, importantly, have a preferable adverse-event

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

OSTEOARTHRITIS

profile compared with oral NSAIDs. Some caution should be

exercised when prescribing paracetamol; since the OARSI

guidelines were published, further evidence has suggested an

increase in gastrointestinal events and a probable over-

estimation in the magnitude of pain relief.21

For those whose pain fails to respond to regular dosing with

paracetamol and NSAID gel in combination, second-line agents

include oral NSAIDs, COX-2 inhibitors and opioid drugs. When

considering the choice of agent, individual patient risk factors

including age and other co-morbidities should be taken into ac-

count. For example, if a patient needs to take low-dose aspirin, or

has ischaemic heart disease (or significant risk for this) or peptic

ulcer disease, alternative analgesics to NSAIDs or COX-2 in-

hibitors should be considered. All NSAIDs or COX-2 inhibitors

are effective (although an individual’s response may vary, so

switching between agents should be considered). All can cause

gastrointestinal, hepatic, cardiac and renal adverse effects,

although toxicity profiles vary between agents. Adverse effects

are more likely in older patients and with longer duration of use.

If prescribed, these drugs should be used at the lowest effective

dose, for the shortest time possible, and co-prescribed with a

proton pump inhibitor (for gastroprotection).18 Ongoing assess-

ment of response and, in the event of longer-term use, moni-

toring (e.g. of blood pressure, renal function and any

gastrointestinal adverse effects) should be arranged.

Topical capsaicin (an extract from chilli pepper) may aid in

pain relief when rubbed onto an affected joint, although some

patients do not tolerate its irritant qualities. Intra-articular

corticosteroid injections do not appear to have long-term ef-

fects on disease progression in osteoarthritis.22 However, such

injections can improve symptoms for an average of 6 weeks in

single joint flares and have a place in management for some

patients. Nutraceuticals, such as glucosamine sulphate and

chondroitin sulphate, rosehip extract and avocado bean unsa-

ponifiables have not to date been included in guidelines, as their

cost-benefit ratio has been too high to support widespread use.

This is also true of intra-articular synthetic hyaluronans. Identi-

fying individuals with features of neuropathic pain is helpful as

they may respond to agents such as gabapentin and

amitriptyline.3

Surgical interventions

For those patients who fail to respond to escalating supportive

and medical therapy, surgical options should be considered

(Table 3). A recent study suggests that there is no place for the

routine use of joint arthroscopy in OA.23 Surgical options range

from microfracture (full-thickness localized drilling into the

subchondral bone, which allows secondary repair of the defect)

and transplantation of articular cartilage or chondrocyte sus-

pensions in younger patients with small cartilage defects, to

hemiarthroplasty or total-joint arthroplasty. Repair strategies

tend to result in an area of fibrocartilage, which might improve

the patient’s symptoms but is prone to further degeneration over

time. Where the individual has significant joint deformity or

abnormalities of joint shape, there is increasing evidence that

surgical correction of these abnormal joint mechanics might be

disease modifying. For example, high tibial osteotomy to correct

alignment of valgus knees in knee OA or surgical intervention for

femoro-acetabular impingement in hip OA are widely used, and

MEDICINE 42:4 218

clinical trials to assess their place in management are under way.

Mechanical off-loading of the joint can also be achieved by joint

distraction, where a rigid external frame is placed across the OA

joint for a period of 3 months. Although joint distraction is not

routinely available, clinical trials show clinical benefit as well as

evidence of cartilage repair.5 Meniscal failure is common in knee

OA, but the effects of new procedures such as meniscal trans-

plantation on OA outcome are not yet understood.

Joint replacement should be considered for patients with

moderate or severe OA who have significant pain and loss of

function impairing their quality of life, which are poorly

responsive to other measures. In younger patients who are likely

to outlive the life of their prosthesis, the decision to operate is

complex.24 Where unicompartmental knee disease exists, a uni-

compartmental replacement is a smaller, cheaper procedure with

comparable or better outcomes than total joint replacement.

New therapies

Ensuring that a patient is vitamin D-replete is good practice for

both muscle and joint health, and trials are underway to assess

whether vitamin D might slow progression of OA. There is

limited evidence that hydroxychloroquine, an antimalarial ther-

apy used for the treatment of other rheumatic diseases, has

beneficial effects, particularly in hand OA: its role is currently

under assessment. The place of other injectables such as plasma

rich in growth factors (PRGF) or stem cell therapies remain un-

proven. Many OA trials show a strong placebo response

(w40%), complicating the assessment of these and novel ther-

apies. Recently a drug blocking nerve growth factor (NGF) was

found to significantly improve OA pain, but potentially accelerate

progression to joint replacement. Trials of drugs inhibiting

degradative pathways in OA (such as metalloproteinase or

aggrecanase enzymes) have to date been hampered by the un-

desirable off-target effects of these drugs. An alternative strategy

is to identify, and augment intrinsic repair pathways, or inter-

vene in the mechano-sensing pathways that drive degradation:

improving our understanding of these mechanisms will improve

our ability to identify novel targets for intervention in OA. A

REFERENCES

1 Reginster JY. The prevalence and burden of arthritis. Rheumatology

(Oxford) 2002 Apr; 41(suppl 1): 3e6.

2 Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and

osteoarthritis, repair, regeneration, and transplantation. Instr Course

Lect 1998; 47: 487e504.

3 Kidd BL. Osteoarthritis and joint pain. Pain 2006 Jul; 123: 6e9.

4 Brandt KD, Dieppe P, Radin EL. Commentary: is it useful to subset

“primary” osteoarthritis? A critique based on evidence regarding the

etiopathogenesis of osteoarthritis. Semin Arthritis Rheum 2009 Oct;

39: 81e95.

5 Wiegant K, van Roermund PM, Intema F, et al. Sustained clinical

and structural benefit after joint distraction in the treatment of

severe knee osteoarthritis. Osteoarthr Cartil 2013 Aug 13; 21:

1660e7.

6 Englund M, Guermazi A, Roemer FW, et al. Meniscal tear in knees

without surgery and the development of radiographic osteoarthritis

among middle-aged and elderly persons: the Multicenter Osteoar-

thritis Study. Arthritis Rheum 2009 Mar; 60: 831e9.

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.

Practice points

C OA is a highly prevalent condition that affects the axial skeleton

and peripheral joints

C Diagnosis is clinical e X-ray features may be absent in early

disease

C Education, exercise and weight loss are important first-line steps

in management

C Oral NSAIDs are not recommended as first-line analgesics

C Future research directions will include better understanding of the

role of surgical procedures, and development of therapeutic tar-

gets aimed at mechanosensing pathways in joint tissues, pro-

motion of intrinsic tissue repair, and identification of prognostic

and diagnostic biomarkers

OSTEOARTHRITIS

7 Lotz M. Osteoarthritis year 2011 in review: biology. Osteoarthr Cartil

2012 Dec 1; 20: 192e6.

8 Griffin TM, Guilak F. Why is obesity associated with osteoarthritis?

Insights from mouse models of obesity. Biorheology 2008; 45:

387e98.

9 Valdes AM, Spector TD. The contribution of genes to osteoarthritis.

Med Clin North Am 2009 Jan; 93: 45e66.

10 Zeggini E, Panoutsopoulou K, Southam L, et al. Identification of new

susceptibility loci for osteoarthritis (arcOGEN): a genome wide

association study. Lancet 2012; 380: 815e23.

11 Lohmander LS, Neame PJ, Sandy JD. The structure of aggrecan frag-

ments in human synovial fluid. Evidence that aggrecanase mediates

cartilage degradation in inflammatory joint disease, joint injury, and

osteoarthritis. Arthritis Rheum 1993 Sep; 36: 1214e22.

12 Tortorella MD, Burn TC, Pratta MA, et al. Purification and cloning of

aggrecanase-1: a member of the ADAMTS family of proteins. Science

1999 Jun 4; 284: 1664e6.

13 Abbaszade I, Liu RQ, Yang F, et al. Cloning and characterization of

ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem

1999 Aug 13; 274: 23443e50.

14 Altman R, Asch E, Bloch D, et al. Development of criteria for the

classification and reporting of osteoarthritis. Classification of oste-

oarthritis of the knee. Diagnostic and Therapeutic Criteria Committee

of the American Rheumatism Association. Arthritis Rheum 1986; 29:

1039e49.

15 Olmez N, Schumacher HR. Crystal deposition and osteoarthritis. Curr

Rheumatol Rep 1999 Dec; 1: 107e11.

16 Menashe L, Hirko K, Losina E, et al. The diagnostic performance of

MRI in osteoarthritis: a systematic review and meta-analysis.

Osteoarthr Cartil 2012 Jan; 20: 13e21.

17 Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis

on MRI: results of a Delphi exercise. Osteoarthr Cartil 2011 Aug; 19:

963e9.

18 Conaghan PG, Dickson J, Grant RL. Guideline Development Group.

Care and management of osteoarthritis in adults: summary of NICE

guidance. BMJ 2008; 336: 502e3.

MEDICINE 42:4 219

19 Sharma L, Cahue S, Song J, Hayes K, Pai Y-C, Dunlop D. Physical

functioning over three years in knee osteoarthritis: role of psycho-

social, local mechanical, and neuromuscular factors. Arthritis Rheum

2003 Dec; 48: 3359e70.

20 Rannou F, Dimet J, Boutron I, et al. Splint for base-of-thumb oste-

oarthritis: a randomized trial. Ann Intern Med 2009 May 19; 150:

661e9.

21 ZhangW, Nuki G, Moskowitz RW, et al. OARSI recommendations for the

management of hip and knee osteoarthritis: part III: changes in evi-

dence following systematic cumulative update of research published

through January 2009. Osteoarthr Cartil 2010 Apr; 18: 476e99.

22 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intra-

articular corticosteroid for treatment of osteoarthritis of the knee.

Cochrane Database Syst Rev 2006. Issue 2. Art. No.:CD005328.

23 Kirkley A, Birmingham TB, Litchfield RB, et al. A randomized trial of

arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2008

Sep 11; 359: 1097e107.

24 Carr AJ, Robertsson O, Graves S, et al. Knee replacement. Lancet

2012 Apr 7; 379: 1331e40.

Crown Copyright � 2014 Published by Elsevier Ltd. All rights reserved.