REVIEW

A Perspective on Osteoarthritis Research in Singapore

Ying Ying Leung1, MBChB, FHKAM (MED), Yong Hao Pua2, BSc, PhD, Julian Thumboo1, FRCP (Edin), FAMS (Rheumatology)
Department of Rheumatology and Immunology, Singapore General Hospital
1

Department of Physiotherapy, Singapore General Hospital

2

Abstract

Knee osteoarthritis (OA) is common and is one of the five leading causes of disability in Singapore; it entails
significant cost to society. Singapore is one of the faster ageing populations in Asia and obesity is on the rise.
The public health consequences of OA, particularly knee OA are therefore expected to rise dramatically. There
is thus an urgent need for advancement in research in this area. An accurate estimate of the prevalence of knee
OA would improve the understanding of its impact in different sectors of society, and facilitate public health
decision-making and resource allocation to address this upcoming challenge in public health. Currently there
is no proven drug that slows down the osteoarthritis process and management of knee OA is symptomatic.
Identification of genetic, environmental, inflammatory and biomechanical risk factors will help us to understand
the pathogenesis and find factors for its prevention. There is a need for early diagnosis of knee OA and identifying
subjects who are more likely to benefit from drug treatment. Effort is needed in the discovery of drugs that have
disease modifying effect to treat this disabling disease. Understanding the biomechanical factors underlying
knee OA may also lead to the discovery of new recommendation and treatment strategies.

Keywords: Early diagnosis, Epidemiology, Disease modifying OA drugs, Osteoarthritis

INTRODUCTION residing in high-income countries. These include

Osteoarthritis (OA) is the most common type
of joint disease and its high prevalence entails
significant cost to society. The World Health
Organisation (WHO) estimates that 9.6% of
men and 18% of women aged ≥60 years have
symptomatic OA worldwide1. OA of the knee is
a major cause of impaired mobility, particularly
among women and is one of the five leading
causes of disability among non-institutionalised
adults. More than 80% of patients with knee OA
have some degree of movement limitation, and
25% cannot perform major activities of daily living,
11% need help with personal care and 14% require
help with routine needs2. The cost of OA to society
is impressive, estimated at US$15.5 billion (in 1994
dollars), roughly three times the cost of rheumatoid
arthritis. More than half of the OA costs are due to
work loss3.
THE PERSPECTIVE OF THE OA BURDEN
The burden of OA knee is expected to accelerate in
the coming decades. Risk factors for knee OA have
been studied mostly in Caucasian populations
age, female gender, obesity, a history of knee
surgery or significant trauma, and having an
occupation requiring heavy lifting, kneeling or
squatting4. As the populations of developed
nations age over the coming decades and the
prevalence of obesity grows, the prevalence and
burden of OA is expected to accelerate. Due to
obesity together with symptomatic knee OA,
Americans over the age of 50 will together lose
the equivalent of 86 million healthy years of life as
estimated from census data source5. Singapore is
one of the fastest ageing populations in Asia. The
population above 65 years rose from 7.2% in 2000
to 9% in 2010 and is predicted to be 19% by 2030,
which translates to 235,000 elderly in 2000 and
796,000 elderly in 20306. Obesity is on the rise from
6.9% in 2004 to 10.8% in 2010 and appears to be
related to sedentary lifestyles and eating habits7.
The high prevalence of OA entails significant
costs to society. Costs associated with OA can be
particularly significant for elderly persons, who
face potential loss of independence and who may
need help with daily living activities. Given the low
prevalence of hip OA in Asian countries, knee OA

Proceedings of Singapore Healthcare  Volume 22  Number 1  2013 31

Review
would be the main problem8,9. The objective of this
article is to review the current research of knee OA
in Singapore. Several research gaps are identified
and possible research directions are proposed.
METHODS AND SEARCH RESULTS
We performed a literature search on Ovid Medline
and Pubmed from January 1992 to October 2012,
using keywords “knee osteoarthritis”and “Singapore
or Asia”. We included original articles of all study
designs including epidemiology studies, cohort
studies, observational studies, and controlled trials.
We excluded non-human and in-vitro studies, case
reports, review articles, articles with main focuses
on outcome of “knee replacement surgeries”,
“surgical techniques” and “evaluation or validation
of outcome instruments”. Of 57 articles retrieved
that were from Singapore or Asia, we included six
articles10–15. A further two articles were identified
from references of included articles16,17 and one
from the Singapore National Health Survey18. These
articles were discussed under the research gaps
identified. There were six, three, two, and seven
articles excluded due to non-human studies, case
reports, reviews, and irrelevance. Twenty-one and
12 articles were excluded for their main focuses
being surgical outcomes or surgical techniques
and evaluation of outcome instruments.
WHAT IS KNOWN ABOUT THE BURDEN OF OA
KNEE IN SINGAPORE?
Prevalence estimates are essential for the evaluation
of the costs of knee OA and the healthcare needs
generated. This knowledge is crucial to plan and
optimise health resource allocation. There is a
paucity of epidemiological research in OA knee
in the Asian region. The prevalence of OA or knee
OA in Singapore is unknown. A population survey
in Singapore in 1991 revealed that arthritis and
rheumatism was very common, in up to 25%
in different ethnic groups. A sizable proportion
of this may be related to OA16. From the 2007
National Health Survey, the crude prevalence of
self-reported arthritis was 10%. Prevalence of joint
symptoms was higher among females, Indians and
those of advancing age. The prevalence was up to
19.8% among the 60–69 age groups18. In the 2004
Singapore Burden of Disease Study, OA was the
fifth highest cause of disability-adjusted life years
(DALY) in the older age group17. The data on OA in
this study was based on the best available data, as
accurate information on the prevalence of OA in
Singapore is not available.
32 Proceedings of Singapore Healthcare  Volume 22  Number 1  2013
While it is reasonable to extrapolate some of the
prevalence data and risk factor findings from
Caucasian countries, there are also likely to be
significant demographic and environmental
differences that influence the onset and
progression of OA in these regions. In the 1990s,
the WHO initiated the Community Oriented
Program for Control Of Rheumatic Disorders
(COPCORD) in developing countries. From the
COPCORD studies, the prevalence of knee pain
is high among Asian countries. However in most
studies, plain radiography (X-ray) was used as
case definition and this limits the application in
epidemiology studies. The cause of knee pain is not
evaluated and prevalence estimates for OA knee is
rarely available8,9,19. These limit the evaluation of
the impact of knee OA in the population.
In Singapore, there is no prevalence data on knee
OA. However in hospital settings, the direct and
indirect costs for patients with advanced hip and
knee OA are as high as that in Western countries20.
Direct costs of OA include clinician visits,
medications, and surgical interventions. Indirect
cost refers to the productivity loss incurred due to
the illness, such as time lost from work or time lost
from work from the patient’s caregiver. Intangible
costs are defined as pain and suffering of patients
because of a disease, which are usually measured
using the reduction in quality of life. The direct cost
to patients (calculated as mean costs per patient
per annum in 2003) ranged from SGD 1,320 to SGD
12,140; direct cost to society ranged from SGD
2,939 to SGD 17,879. There was a threefold increase
in economic burden of OA to society and patients
for those with end-stage disease who required
joint replacement surgery10. This direct cost is
even higher than that of most Western countries20
and similar to that in Hong Kong14. Indirect cost
for OA was substantial and accounted for 2.8% of
average household income as calculated with the
average earnings per capita per day in Singapore
between 1993 and 200321. In the same study, the
intangible cost incurred by OA was also high,
accounting for 3.3% of the average household
income. It is well known that costs of illness may
vary from country to country, given their different
health systems and the methodology in cost
evaluation22. The burden of illness of knee and hip
OA in terms of pain and disability could also be
influenced by ethnicities, socioeconomic status and
psychosocial factors23. Despite these differences,

the economic burden incurred by OA in Singapore
is substantial.
There are ways to reduce the burden of this disabling
disease by early diagnosis and implementation
of effective evidence-based strategies such as
large-scale community based self-management
education, advocating weight management and
exercise programmes, preventing joint injuries
and more focused research in this area24,25. All of
these involve relocation of health care resources,
which is based on an accurate prevalence
estimation followed by careful evaluation of the
impact of knee OA in larger groups of subjects in
the population.
THE PREVALENCE OF OA IN SINGAPORE
Careful estimates of OA prevalence would improve
the understanding of healthcare needs and
would facilitate public health decision-making
and resources allocation. Self-administered
questionnaires on OA symptoms alone have
shown inadequate sensitivity and specificity for OA
screening26. Newer studies using questionnaires
that combine symptoms, disability, and self-
reported diagnosis have proven validity in
screening symptomatic OA27–29. A study to evaluate
and validate instruments that may be suitable
for purpose of screening symptomatic OA knee
in the population against the American College
of Rheumatology (ACR) classification criteria for
OA knee is currently underway in the Singapore
General Hospital (SGH). If successful, it will provide
an accurate prevalence estimate of symptomatic
OA knee in Singapore when applied in
epidemiological studies. It could also be a valuable
instrument to reveal the impact of symptomatic
OA knee in the general population. The next step
would be to determine the prevalence and impact
of OA in different sectors of society such as among
the elderly and in the work place.
RISK FACTOR IDENTIFICATION
Currently, there is no cure for OA. A balanced
diet with supplementing ‘nutraceuticals’ has
therefore been proposed for the prevention
of OA development and progression30. On the
molecular level, catabolism and oxidative stress
within the chondrocytes, cartilage matrix,
synovium and synovial fluid can promote cartilage
degradation31–33. However, prospective data from
observational studies conducting a comprehensive
evaluation, including diet, lifestyle and genetic
Proceedings of Singapore Healthcare  Volume 22  Number 1  2013
Osteoarthritis Research in Singapore
factors, as well as gene-environment interaction,
on the etiologic association with severe knee OA
are scarce31,34. Asian populations have different
dietary and lifestyle factors, and are rarely studied
compared to Western populations. A collaborative
team from SGH and Duke-National University of
Singapore has initiated a cohort study in 2012
based on the database from the Singapore Chinese
Health study (SCHS). The SCHS is a NIH supported
large-scale research study on 63,257 Chinese
subjects since 1993. A link has been established
with the Ministry of Health database to identify
cases that had undergone knee joint replacement
surgery (TKR) for OA. These cases should represent
those who had the most severe form of knee OA.
Dietary, lifestyle, inflammatory and genetic factors
will be analysed and compared with controls
who reported no knee problem repeatedly.
This will be the first longitudinal study on the
etiology of severe OA of the knee from an Asian
population, which will provide additional, novel
and informative data to the current literature on
knee OA.
THE CHALLENGES OF DMOAD DEVELOPMENT
Given the limited effective and safe therapeutic
options, current treatment of OA is palliative.
An appreciable percentage of patients with OA
knees are refractory to existing analgesics35,36;
and a significant proportion of patients still
experience pain, functional disability, poor quality
of life and dissatisfaction even after the definitive
treatment — TKR37. Advances in tissue engineering
techniques have taken various types of stem cells and
chondrocytes implantation to early phase clinical
trials in human and may benefit a younger group
of selected subjects with knee OA. The National
University of Singapore has been pioneering
research in this area38; however cost-effectiveness
has yet to be evaluated39–41. Another strategy is to
modify the progression of structural damage. Given
the large patient population and unmet medical
need, the discovery and development of disease-
modifying OA drugs (DMOADs) have become a
focus of drug development in the past decade.
A variety of target agents are in mature phases
of development. Some agents like glucosamine
sulphate, chondriotin sulphate, diacerin, doxycycline,
licofelone, strontium and intra-articular hyaluronans
have demonstrated structural modifying ability
in isolated clinical trials42, although none have
convincingly demonstrated disease-modifying
efficacy with concurrent clinically meaningful
33
Review
effects; and none was approved by the regulatory
arbitrators. Challenges are faced in the process of
DMOADs development and there are numerous
negative reports in the literature42,43. Overall,
these trials mostly reported significant side-effect
profile, no concomitant symptomatic relief and
the radiographic methodology was criticised
for deficient standardisation and inadequate
positioning of the joint. Studies using joint-space
narrowing (JSN) on X-ray as a structural modifying
end-point were thought to be insensitive and
inadequate to show up the changes in structure.
EARLY DIAGNOSIS OF OA
Traditionally structural assessment and diagnosis
of OA has relied upon plain X-rays, which identify
patients with late stage disease when structural
damage may be irreversible. There is a need for new
tools that foster early diagnosis of OA, particularly
in the pre-radiological phase. Modern imaging
technology like MRI has great potential in bridging
this gap, once the validation and qualification
process is optimised44,45. However MRI is costly
to perform and the scoring is labour intensive.
Biomarkers are thus a promising modality to
address this need, as they are relatively inexpensive
and easy to perform in comparison with MRI. A
combination of multiple biomarkers have been
shown to improve the detection and prediction
of radiographic changes in OA45–47. A study on the
predictive values of a combination of biomarkers
of cartilage metabolism, inflammation and genes
to predict MRI outcomes in 120 subjects with knee
pain is initiating in SGH. The project will inform
on the possibility of using biomarkers, which is
more cost-effective in the early diagnosis of OA. It
would be a paradigm shifting discovery that paves
the way for clinical trial in patients with early (pre-
radiographic) OA where they would have a higher
chance of responding to treatment.
THE ROLE OF INFLAMMATION, INNATE
IMMUNITY AND DMOAD DISCOVERY
There is cumulative evidence that inflammation
play a major role in the pathogenesis of OA.
Agents targeting specific inflammatory pathways
potentially can reduce the inflammatory load
and may slow down the structural damage.
Colchicine, an agent used for the treatment of
gout has the potential as a DMOAD. In a knee OA
cohort with no clinical evidence or self-report of
gout, a significant correlation of synovial fluid
uric acid with radiographic and scintigraphic
34 Proceedings of Singapore Healthcare  Volume 22  Number 1  2013
measures of OA severity was found48. There were
also strong correlations between radiographic and
scintigraphic severity and synovial fluid uric acid
with synovial fluid IL-18 and IL-1β, two cytokines
classically produced by uric acid-activated
inflammasomes in gout. These results strongly
support the potential involvement of the innate
immune system in OA pathology and progression,
just as for gout. The pain and symptom relieving
effects of colchicine for knee OA have been
demonstrated in three small but well-performed
human randomised double-blinded placebo-
controlled clinical trials (RCT)s49–51. One study in
36 subjects with knee OA demonstrated greater
symptomatic improvement at 20 weeks with
colchicine than placebo despite background
therapy with nimesulide (30% WOMAC response
rate 57.9% versus 23.5%)50. Another study of 61
knee OA subjects exhibited greater improvement
in patient and physician global assessment at the
end of three months treatment of colchicine versus
placebo in addition to usual treatment (analgesics,
NSAIDs and physiotherapy) (11.14 +/- 4.06 vs 3.14
+/- 2.18, P <0.001; and 9.83 +/- 3.799 vs 3.72 +/-
3.35, P <0.001, respectively)51.
In collaboration with Duke University Durham, we
have proposed a randomised placebo-controlled
trial (RCT) in Singapore to determine whether oral
colchicine at standard clinical doses (0.5 mg, two
times daily), compared to placebo, may decrease the
pain of symptomatic OA knee and improve function
when used as adjunctive daily therapy in addition
to background therapy with the patient’s current
stable analgesic regimen. We will also evaluate the
mechanism of action of colchicine for reducing
knee OA signs and symptoms through analyses of
synovial fluid, serum, and urine biomarker profiles
– these will interrogate and characterise the state
of activation of joint metabolism (joint degradation
and synthesis markers), inflammatory mediators
and the innate immune system specifically both
before and after 16 weeks of therapy. The structure
modifying effect will be evaluated in a proportion
of subjects with knee MRI. This study is well
grounded in a strong biological rationale; and
with the several small preceding human studies
of colchicine for knee OA provide a strong clinical
rationale. This study will break new ground by
exploring the mechanism of action of colchicine
in knee OA through stringent testing of the ability
of colchicine to inhibit inflammasome activation
in OA. This trial can serve as a valuable paradigm

for a subsequent larger longer-term multi-centred
RCT to evaluate colchicine as a DMOAD for knee OA
with long-term radiographic and MRI end-points to
evaluate the ability of colchicine to slow or halt the
progression of OA structural deterioration. With
the increased understanding of the pathogenesis
of OA at the molecular and cellular level, it is hoped
that disease-modifying rather than just symptom-
modifying therapies will become a reality for this
devastating condition.
BIOMECHANICAL FACTORS IN OA
Knee OA is not merely a condition characterised by
cartilage degradation and inflammation, but it is
also a mechanical joint failure driven by abnormal
joint loading52–56. Hence, it is important to prevent
or to reduce the abnormal intra-articular forces
that are causing joint damage in the first place.
Biomechanical factors that cause excessive knee
loading and may influence the onset of knee OA
are obesity57,58, knee malalignment59,60, knee joint
laxity61, knee range-of-motion limitations62,63, hip
and knee muscle weakness64–68, and proprioceptive
and postural control (balance) impairments12,69–71.
These factors are also closely associated with
pain and functional disabilities12,13,60,69,72,73. Among
them, muscle and balance impairment are
potentially modifiable.
As regards muscle impairments, the hip and knee
musculature play an important role in minimising
knee joint loading64–67 and protect the knee joint
from micro-damage via an active absorbing
mechanism74. For this reason, novel interventions
that can safely and effectively overload both the
hip and knee musculature are needed to slow
disease progression and better yet, to improve pain
relief and physical function. Eccentric resistance
training — via eccentric ergometry — is one such
intervention that is currently under-explored in knee
OA research but worthy of consideration given its
potential ability to induce muscle hypertrophy and
strength gains at a lower metabolic cost than does
concentric training in both older adults and clinical
populations23,75–77. A randomised study on the
effectiveness of eccentric ergometry in improving
muscle performance and physical function in
patients with mild-to-moderate symptomatic knee
OA is currently underway in SGH.
As regards balance impairments, compared with
people without knee OA, those with knee OA have
impaired standing balance78–81 — commonly defined
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Osteoarthritis Research in Singapore
as greater postural body sway or centre of pressure
(CoP) displacement — and more important, balance
impairments were associated with increased fall
risk82,83. The estimated prevalence of falls in older
adults was 22% for radiographic knee OA84, 48%
for knee pain84 and 48% in symptomatic end-stage
knee OA85. Fall prevalence remained high at 24–
40% even after TKR85. In prospective population
studies, patients with TKR or clinically-diagnosed
knee OA were found to have a paradoxical high risk
of hip fracture86,87. What factors perpetuate — or
reciprocally relate to — balance impairments and
disability in knee OA? Apart from the biomechanical
factors described earlier, psychological factors – for
example, fear of falling88,96, pain catastrophising89,
depression89,90 and fear-induced activity
limitation 13,92
— are also important correlates. Of
interest, fear induced activity limitation (FIAL), which
is the avoidance or curtailment of daily activities due
to an excessive fear of falling, may lead to a vicious
cycle of physical deconditioning, which in turn,
perpetuates or increases the fear of falling and the
fall risk. The SGH physiotherapy team found that in
a sample of 72 patients one-year post-TKR, FIAL is
common with a frequency of two of five patients
(41% [31 patients]; 95% CI, 31% to 55%)13. These
data highlight that FIAL is a common, but under-
reported problem in knee OA and suggest that
early, preventive interventions are needed to
improve physical function and to reduce fall risk
in patients with FIAL. Due to the complex and
multi-dimensional nature of falls and disability in
knee OA, there is a paucity of well-accepted and
validated falls screening tools available in the
community setting93. Although CoP-based balance
measures have prognostic and predictive relevance
for fall82 and fear of falling96, they are not commonly
measured. The existing measuring equipment and
methods are expensive, difficult to set-up, and thus
not practicable to be used in large patient cohorts.
To overcome the logistical and technical difficulties
of assessing postural control in large patient
samples, the SGH physiotherapists, together
with sports biomechanists from the University of
Melbourne, has created a programme to interface
with the Wii Balance Board (WBB) (Nintendo, Kyoto,
Japan). This is a portable (~3.5kg) low-cost (~130
SGD) gaming device that could be repurposed to
measure CoP-based standing balance. These WBB-
derived standing CoP measures have demonstrated
good concurrent validity with data obtained from
a laboratory-grade forceplate97. The predictive
validity has also been demonstrated in two
35
Review
prospective studies98. These served as a proof-of-
concept for this balance protocol to be developed
as a valuable tool in balance assessments in
different clinical settings.
FUTURE PERSPECTIVE
Osteoarthritis is a growing public health issue.
Collaborative efforts from primary healthcare
providers, secondary healthcare services, allied
health and varies sector of the communities are
necessary to help reduce the burden in the next
few decades. The American Centre of Disease
Control and Prevention (CDD) and the Arthritis
Foundation have published their agenda to
combat osteoarthritis24. No such initiative has
been established in Singapore. An important
consideration is to ensure current evidence-based
intervention strategies, including self-management
education, physical activity, injury prevention, and
weight management and healthy nutrition are
delivered to those who have OA. This also involves
establishing supportive policies, communication
initiatives and strategic alliances for OA prevention
and management. Low impact, moderate intensity
aerobic physical activity, muscle strengthening
exercise and weight management should be
promoted widely as a public health intervention
and prevention for OA. National nutrition and
dietary guidelines for the general population and
even legislation to prevent over-consumption
of fat and unhealthy ingredients in the public
could be considered. Research and evaluation
should be pursued to enhance surveillance, better
understand risk factors, refine recommended
intervention strategies, evaluate workplace
interventions, and examine emerging evidence
on additional promising pharmacological or non-
pharmacological interventions. It is sad to note
that less than 1% of the total expenditure on OA is
presently spent on research.
In Singapore, there is an urgent need for more
accurate prevalence estimation of OA in society
and to determine the impact on the level of the
individual and society. This will help policy makers
plan and optimise health resource allocation.
Prospective or population-based studies are
required to improve our knowledge of risk factors
for the development and progression of knee OA.
The clinical and biological predictors of response
to both pharmacological and non-pharmacological
treatment for OA knee need to be determined.
The efficiency and cost-effectiveness of various
36 Proceedings of Singapore Healthcare  Volume 22  Number 1  2013
exercise programmes and how to implement at the
public level need to be evaluated. There is growing
knowledge about the cell biology and biochemistry
of the cartilage that could give rise to new treatment
possibilities in the future. Biochemical markers and
new imaging techniques may identify people at risk
or in earlier stages of the disease and allow for an
early intervention in the near future and hasten up
the discovery of DMARDs. Besides, understanding
of the biomechanical factors that are associated
with OA, like joint alignment, posture and balance,
may lead to new treatment development.
CONCLUSION
Knee OA is prevalent, disabling, incurring high cost
to affected individuals and society. The prevalence
is expected to rise due to the ageing population
and the increasing prevalence of obesity. There
has been a paradigm shift in the concept of OA
from a purely degenerative process to a dynamic
process involving inflammation, proper healing
associated with joint loading before the end-stage
process of cartilage degradation and eventually
joint failure. The concept and understanding of the
pathophysiology of OA is still evolving. Given the
burden of disease from knee OA, there is a dearth
of research in this area, particularly in Asia. Many
areas of OA are ripe for research, for instance, to
determine the burden of knee OA, to identify risk
factors for progression, to identifying a model that
diagnoses OA early when it is relatively treatable,
the discovery of DMOADs, and the evaluation of
biomechanical factors and their assessment in knee
OA. Very few investigators are actively researching
OA, because the old concept of it being a boring
age-related, degenerative disease persists. We hope
to encourage the next generation of clinicians and
scientists to take up this exciting challenge of OA.
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