Osteoarthritis, obesity and weight loss: Evidence, hypotheses and horizons - a scoping review

Abstract

Obesity is widely acknowledged as a risk factor for both the incidence and progression of osteoarthritis, and has a negative influence on outcomes. Loss of at least 10% of body weight, coupled with exercise, is recognized as a cornerstone in the management of obese patients with osteoarthritis, and can lead to significant improvement in symptoms, pain relief, physical function and health-related quality of life. However, questions still remain surrounding optimal management. Given the significant health, social and economic burden of osteoarthritis, especially in obese patients, it is imperative to advance our knowledge of osteoarthritis and obesity, and apply this to improving care and outcomes. This paper overviews what is already known about osteoarthritis and obesity, discusses current key challenges and ongoing hypotheses arising from research in these areas, and finally, postulates what the future may hold in terms of new horizons for obese patients with osteoarthritis.

Full text

Obesity Comorbidity
Osteoarthritis, obesity and weight loss: evidence,
hypotheses and horizons – a scoping review
H. Bliddal
1
, A. R. Leeds
2,3,4
and R. Christensen
1
1
The Parker Institute, Department of
Rheumatology, Copenhagen University
Hospital, Bispebjerg and Frederiksberg,
Denmark;
2
Cambridge Weight Plan, Corby,
Northamptonshire, UK;
3
School of Biosciences
and Medicine, University of Surrey, Guildford,
Surrey, UK;
4
Faculty of Science, University of
Copenhagen, Copenhagen, Denmark
Received 20 December 2013; revised 10
January 2014; accepted 14 Januar y 2014
Address for correspondence: Professor H
Bliddal, The Parker Institute, Department of
Rheumatology, Copenhagen University
Hospital, Bispebjerg and Frederiksberg, 2000
Copenhagen F, Denmark.
E-mail: Henning.Bliddal@regionh.dk
Summary
Obesity is widely acknowledged as a risk factor for both the incidence and
progression of osteoarthritis, and has a negative influence on outcomes. Loss of at
least 10% of body weight, coupled with exercise, is recognized as a cornerstone in
the management of obese patients with osteoarthritis, and can lead to significant
improvement in symptoms, pain relief, physical function and health-related
quality of life. However, questions still remain surrounding optimal management.
Given the significant health, social and economic burden of osteoarthritis, espe-
cially in obese patients, it is imperative to advance our knowledge of osteoarthritis
and obesity, and apply this to improving care and outcomes. This paper overviews
what is already known about osteoarthritis and obesity, discusses current key
challenges and ongoing hypotheses arising from research in these areas, and
finally, postulates what the future may hold in terms of new horizons for obese
patients with osteoarthritis.
Keywords: Obesity, osteoarthritis, treatment, weight loss.
Abbreviations: BMI, body mass index; CAROT, Influence of Weight Loss or
Exercise on Cartilage in Obese Knee OA Patients; IL, interleukin; MMP, matrix
metalloproteinase; NIH, National Institutes of Health; OA, osteoarthritis;
WOMAC, Western Ontario and McMaster Universities.
obesity reviews (2014) 15, 578–586
Introduction
The association between osteoarthritis (OA) and obesity is
well established; widely acknowledged as a risk factor for
both the incidence and progression of OA (1), obesity also
has a negative influence on disease outcomes such as the
need for surgery (2). Hence, weight loss, coupled with
exercise, is recognized as an important approach in the
management of obese patients with OA (3).
Despite the high volume of publications on the subject,
there are still gaps in our understanding of the pathogenesis
of OA in the obese patient. Increasing prevalence of these
two interlinked conditions (4,5), and the associated health,
social and economic consequences, make it imperative to
advance our knowledge of OA and obesity, and apply this
to improving care and outcomes for patients.
This paper overviews what is already known about OA
and obesity, discusses current key challenges and ongoing
hypotheses arising from research in these areas and, finally,
postulates what the future may hold in terms of new hori-
zons for obese patients with OA.
Evidence
Osteoarthritis imposes a serious and growing
health burden
The global prevalence of OA continues to escalate, both as
a result of an ageing population (6) and as a result of the
obesity reviews doi: 10.1111/obr.12173
578 © 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
15, 578–586, July 2014

current obesity epidemic, with obesity in the elderly becom-
ing an increasing problem (7).
In 2000, 600 million people worldwide were aged ≥60
years, representing a threefold increase compared with 1950
(6), and the number is expected to triple again to reach 2
billion by 2050 (6). This trend is a cause for concern given
that, as evidenced by data from the United States, the
prevalence of OA rises steeply in older people, with approxi-
mately 34% of those aged ≥65 years estimated to have OA,
compared with 14% of adults aged ≥25 years (8).
Similarly, the global prevalence of obesity has nearly
doubled since 1980 (9), with 475 million adults now esti-
mated to be obese (body mass index [BMI] ≥ 30 kg m
−2
),
and a further 1 billion considered to be overweight (BMI
25–29.9 kg m
−2
) (4). When the Asian-specific definition for
obesity (BMI > 28 kg m
−2
) is taken into account, the number
of adults worldwide considered to be obese rises to in excess
of 600 million (4). Obesity in the elderly is a particular
concern, with a prevalence of 20–30% in Europe, rising to
> 35% in the United States (7). Furthermore, the prevalence
of obesity is continuing to increase, even among older age
groups (7). Again, this is cause for concern given the well-
established association between obesity and OA (1,10).
OA is a leading cause of disability and has a significant
impact on health-related quality of life (1,8). Approxi-
mately, 80% of affected individuals have some degree of
movement limitation, while 25% are unable to perform
major activities of daily living (8). Knee OA is of particular
importance, as the knee is a key factor in ambulation and
therefore social involvement (10). In a survey looking at the
changing profile of joint disorders with age, knee and back
problems were most frequently reported (approximately
10%), with knee problems having the greatest increase in
prevalence with age compared with other joints (11). Knee
pain is present in a large proportion of the elderly, with
25% of people aged > 55 years experiencing a persistent
episode of knee pain and around 10% experiencing painful
disabling knee OA (12). OA is also costly, accounting for a
> $10 billion per year health care spend in the United States
(13), much of this attributable to loss of working days and
the cost of knee and hip replacements (14).
In the efforts to reduce the health, social and economic
burden of OA, obesity seems an obvious target, given its
role as a key and modifiable risk factor for OA. Early
diagnosis of OA is also imperative; and, as obese patients
have a greater risk of developing OA, they should be moni-
tored for signs of the disease.
Obesity is a risk factor for incidence and
progression of osteoarthritis, and negatively
influences disease outcomes
Obesity is widely acknowledged as a risk factor for OA,
with every 5 kg of weight gain conferring a 36% increase in
the risk of knee OA (1). There is evidence that the risk
accumulates with increased exposure to high BMI through-
out adulthood, with an association between BMI and later
knee OA starting as early as 20 years in men and 11 years
in women (15). In addition, body weight influences the
severity of OA; obese individuals have significantly more
severe joint degeneration in the knees compared with
normal weight or underweight individuals (16). Data from
a case–control study have also indicated a strong associa-
tion between increasing BMI and surgical replacement of
hip and knee joints (2).
Of note, obesity and OA collectively reduce mobility.
This can initiate a vicious cycle of events: reduced activity,
further weight gain and decreased muscle strength, leading
to increased joint problems and disease progression (10).
Hence, weight loss is a primary goal in obese individuals
with OA.
Weight loss can prevent onset of osteoarthritis,
relieve symptoms, improve function and increase
quality of life
Results from the Framingham study have demonstrated
that weight loss reduces the risk for OA in women. In this
study, a 5.1-kg reduction in weight over a 10-year period
decreased the likelihood of women developing sympto-
matic knee OA by 50% (17). In a subgroup analysis,
weight loss was associated with a significant reduction in
OA risk in individuals with high baseline BMI
(25 ≥ kg m
−2
), but not in those with BMI < 25 kg m
−2
(17).
One major reason for this is that weight loss reduces
joint loads. For example, a study of overweight and obese
older adults with knee OA estimated that every pound of
weight lost resulted in a fourfold reduction in the load
exerted on the knee per step during daily activities, which
appears to be clinically meaningful (18). Similar findings
have been reported in other studies (19,20).
Weight loss can also relieve symptoms in obese patients
with OA including, importantly, pain. Of note, decreasing
body fat and increasing physical activity are particularly
important in producing symptomatic relief of knee OA
(21). Recent data from a cohort study of 1,410 individuals
with symptomatic knee OA suggest that a significant dose–
response relationship exists between changes in body
weight and corresponding changes in self-reported Western
Ontario and McMaster Universities’ (WOMAC) pain, as
well as physical function scores (Fig. 1) (22). While loss of
approximately 5% of body weight has been shown to
provide some relief in obese patients with OA (23), several
studies have indicated that the ultimate goal should be an
initial decrease in body weight of at least 10%, in order to
provide significant reductions in pain (22,24). This is sup-
ported by clinical guidelines on the identification, evalu-
ation and treatment of overweight and obesity in adults
obesity reviews Osteoarthritis, obesity and weight loss H. Bliddal et al. 579
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity 15, 578–586, July 2014

from the Obesity Education Initiative of the National Insti-
tutes of Health (NIH), which recommend an initial goal for
weight loss of 10% from baseline in obese individuals (25).
If successful, further weight loss may be attempted if
required. Importantly, concomitant with OA pain reduc-
tion comes increased mobility and physical function
(3,22,24). Quality of life is also improved following weight
loss in patients with OA, as evidenced by improvements in
the composite physical health score of the Short Form-36
Health Survey, as well as improvements in satisfaction with
body function and appearance (26).
Further insight comes from the Influence of Weight Loss
or Exercise on Cartilage in Obese Knee OA Patients
(CAROT) study, which evaluated the effects of an intensive
weight-loss programme over 16 weeks in obese patients
with knee OA. This low-energy, formula-diet, weight-loss
programme was shown to reduce OA symptoms (27),
although no changes were demonstrated in bone marrow
lesions in response to weight loss (28). The impact of
increased knee joint loading because of improved ambula-
tory function and walking speed following weight loss was
also investigated; no acceleration of symptomatic and
structural disease progression was observed in patients
with increased joint loads relative to those with reduced
joint loads (29).
Weight loss and exercise is the optimal approach
to managing obese patients with osteoarthritis
Guidelines from the American College of Rheumatology
(30) and European League Against Rheumatism (31) rec-
ommend the need for weight loss as well as exercise in the
management of overweight or obese patients with OA.
Several studies support the combination of exercise and
weight loss, together with appropriate analgesia, as a
cornerstone for these patients (3,32). These studies have
highlighted important benefits of combined exercise and
diet therapy compared with either exercise or diet alone,
including greater improvements in gait, knee pain and
physical function (32). Although long-term weight loss can
be achieved through calorie restriction alone, the addition
of exercise is also required in order to significantly improve
mobility (an important determinant of disability), self-
reported function and pain (3). In addition, the CAROT
study indicated a decrease in lower extremity muscle mass
and muscle strength following weight loss in obese patients
with knee OA, suggesting that significant weight loss
should be followed by an exercise regimen to restore or
increase muscle mass in this patient population (33).
In contrast to weight loss among the general population,
where rapid initial weight loss can indicate a poorer long-
term prognosis in terms of regaining weight (25), greater
initial weight loss in obese people with OA is associated
with better long-term prognoses, and can be associated
with better compliance with treatment (34). However, this
is in contrast with clinical opinion recommending a slower
rate of weight loss (34).
The NIH guidelines recommend that, in order to achieve
10% weight loss over 6 months, overweight patients
(BMI 27–35 kg m
−2
) should aim for a decrease of 300–
500 kcal day
−1
(1,300–2,100 kJ day
−1
), resulting in weight
loss of about 250–500 g week
−1
. For more severely
obese patients (BMI > 35 kg m
−2
), deficits of up to 500–
1,000 kcal day
−1
(2,100–4,200 kJ day
−1
) are required for
10.00
5.00
-5.00
≥10% loss
5.0 to 9.9 %
loss
-4.9 to 4.9 %
change
.00
5.0 to 9.9 %
gain
≥10% gain
Mean change in WOMAC physical function
scores (95% CI)
4.00
3.00
2.00
1.00
-1.00
-2.00
≥10% loss
5.0 to 9.9 %
loss
-4.9 to 4.9 %
change
.00
5.0 to 9.9 %
gain
≥10% gain
Mean change in WOMAC pain scores (95% CI)
% weight loss or gain categories% weight loss or gain categories
(b)(a)
Figure 1 Dose–response relationship for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function (a) and
pain (b) scales. Point estimates and 95% confidence interval (95% CI) bars were derived from unadjusted estimates. Reproduced with permission
from Riddle DL, Stratford PW. Arthritis Care Res (Hoboken) 2013; 65: 15–22 (22)
580 Osteoarthritis, obesity and weight loss H. Bliddal et al. obesity reviews
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity15, 578–586, July 2014

weight loss of about 500–1,000 g week
−1
(25). For obese
people with established OA, who may have relatively low
activity levels and inactivity-induced lean mass atrophy
(35), weight loss tends to be less than expected (36) and the
energy deficit of an effective diet has to be greater to com-
pensate for this (AR Leeds, personal communication).
Opinions on the optimal method for weight loss are
varied. While evidence supports a calorie-restricted diet,
the evidence to support differences in diet composition is
limited and inconclusive. Although it is critical – especially
in elderly OA patients – to introduce a low-calorie diet that
still provides all the essential nutrients, maintenance of
recommended daily calcium intake is particularly impor-
tant for women who may be at risk of osteoporosis (25).
For some obese patients, compliance with long-term life-
style changes is low and other approaches, such as bariatric
surgery (e.g. laparoscopic adjustable gastric banding or
sleeve gastrectomy) (37,38) or pharmacotherapy, may be
the best way to achieve weight loss.
While exercise can aid weight loss, there is also evidence of
other benefits that exercise can have in patients with OA,
even in those with severe OA (39,40). For example, exercise
has been shown to strengthen muscles that support
the joints, reduce pain and improve physical function
(32,40,41). Both aerobic walking and quadriceps’ strength-
ening exercises have been shown to reduce pain and disabil-
ity in subjects with knee OA, but in a systematic review of 13
randomized clinical trials, it was not possible to identify the
superiority of one approach over the other (40). Although
the optimal exercise regimen for OA patients is not currently
known, it is important – especially in elderly OA patients –
to tailor the exercise programme according to patient mobil-
ity, comorbidities and patient preferences (42).
Hypotheses
In addition to what is already known, there exists a number
of intriguing questions surrounding the treatment of
obese individuals with OA, which are worthy of further
exploration.
Should exercise be postponed until weight loss
has been achieved?
It has been postulated that exercise may cause further joint
damage in obese patients with OA because of the increased
strain and load on the joints. This leads to the hypothesis
that weight loss should be achieved prior to commencing
exercise. This theory is supported by evidence from an
8-week study assessing the effect of rapid diet-induced
weight loss on physical function in 80 obese, knee OA
patients (24). In this study, implementation of a low-energy
diet (3.4 MJ day
−1
) led to a weight loss of 11.1%, com-
pared with 4.3% in individuals on a control diet
(5 MJ day
−1
). In the group on the low-energy diet, physical
function – as assessed by WOMAC function score – was
significantly improved versus baseline; there was no signifi-
cant change in the control group (24). This finding suggests
that rapid weight loss enabled obese OA patients to subse-
quently obtain a higher degree of physical activity com-
pared with the control group.
However, initial findings indicate that patients who exer-
cise following dietary weight loss actually gain weight (H
Bliddal, personal communication), but this requires further
investigation.
Can weight loss be maintained?
Weight loss is clearly important in managing obese OA
patients, but once it has been achieved, how difficult is it to
maintain this weight loss? In a prospective study assessing
the effects of physical activity on weight maintenance in 32
women who had recently (within 3 months) achieved their
target for weight loss, the amount of physical activity
required to minimize weight gain for 1 year after weight
loss was determined (43). It was apparent that active
women maintained their weight loss better than inactive
women, although the relationship was found to be non-
linear. Instead, a threshold-like relationship was observed
between physical activity and weight control, with the
threshold corresponding to a physical activity level of
80 min of moderate exercise or 35 min of vigorous exercise
per day in order to prevent weight regain following weight
loss (43).
Despite evidence of its benefits, weight loss through diet
and exercise is notoriously difficult to achieve and sustain
in the long term, with patient non-compliance being a key
problem. Factors that appear to pose a particular risk for
weight regain include a history of weight cycling,
disinhibited eating, binge eating, more hunger, eating in
response to negative emotions and stress, and more passive
reactions to problems (34). In the Look Action for Health
in Diabetes trial, which evaluated the cardiovascular effects
of intensive lifestyle intervention in patients with type 2
diabetes, initial mean weight loss was 8.6%, declining to an
average weight loss of 6.0% after 10 years (44). Although
modest weight loss was sustained over the length of the
trial, patients were specifically recruited if they were moti-
vated to lose weight through lifestyle intervention and were
only included in the study if they could complete a
maximal-fitness test at baseline (44). Maintenance of
weight loss in non-motivated individuals is likely to be even
more difficult over time, with particular difficulties encoun-
tered in maintaining standard diet and exercise pro-
grammes in previously sedentary, overweight adults with
OA and its associated mobility disability (3). Of note, while
the general advice is to exercise to maintain weight loss,
this may not be possible in obese knee OA patients because
obesity reviews Osteoarthritis, obesity and weight loss H. Bliddal et al. 581
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity 15, 578–586, July 2014

of the potential adverse effects of exercise on the joints
during training (10). This highlights the need for strategies
to improve patient adherence to diet and exercise pro-
grammes (3), as well as additional ways to support patients
in achieving sustainable weight loss.
In fact, there are a number of approaches aimed at
improving compliance and supporting long-term weight
control. A review of factors associated with weight loss
maintenance by Elfhag and Rössner proposes that con-
tributors to successful long-term weight loss include achiev-
ing initial weight loss, reaching a self-determined goal
weight, having a physically active lifestyle, maintaining a
regular meal rhythm including breakfast and healthier
eating, exerting control of overeating and instigating self-
monitoring of behaviours (34). In addition to an internal
motivation to lose weight, other important factors include
social support, better coping strategies and ability to handle
life stress, self-efficacy, autonomy, assuming responsibility
in life, and overall more psychological strength and stabil-
ity (34).
Patient–therapist contact appears to be a key factor in
achieving weight loss of approximately 10% over a period
of 16–26 weeks (45). Continued contact appears to be
effective whether it occurs in person (e.g. by attending
weight maintenance classes) or through telephone, post or
email-based communications (45).
Does weight loss need to be a key focus both
before and after surgery in osteoarthritis patients?
End-stage OA is treated with surgery, in particular, knee
and hip replacements. Obese individuals with OA are more
likely to require surgery, as shown by a case–control study
involving > 7,000 individuals, which demonstrated a
strong association between increasing BMI and total hip
and knee replacements (2). It has been postulated that
outcomes from surgery are negatively influenced by weight
and that weight loss should therefore be a key focus both
before and after surgery in OA patients.
Given these considerations, a case could be made for
bariatric surgery prior to knee or hip replacement in obese
patients with OA. A study of 20 total hip and knee
arthroplasties performed in patients with morbid obesity
who were treated with bariatric surgery before arthroplasty
showed a reduction in BMI prior to arthoplasty, improve-
ments in Knee Society/Harris hip scores and a high level of
patient satisfaction at follow-up, and minimal complica-
tions (46). However, while these findings support the use of
bariatric surgery in morbidly obese patients with OA, in
whom arthroplasty may otherwise be considered too risky,
there are limited data in the literature assessing the effec-
tiveness of bariatric surgery in overweight/obese patients
with OA. Indeed, a recent systematic review highlighted the
paucity of data in this area and called for further research
(47).
One assumption that may be made is that post-surgery
patients lose weight because they are able to be more active.
However, data show that almost a third of patients gain
≥5% of their baseline body weight after surgery (48).
Somewhat surprisingly, a significant association was not
found between increasing BMI and the risk of knee or hip
revisions of previous joint replacement surgeries (2).
Further evidence comes from a study assessing the effect of
body weight on outcomes after total knee arthroplasty,
using the Nottingham Health Profile to assess health status
and the Knee Society score to assess clinical outcome at
baseline and 12 months after surgery (49). Over this
period, the study demonstrated that body weight did not
adversely influence the outcome of total knee arthroplasty
(49). Further studies are needed to inform optimal pre- and
post-surgical management.
Does weight loss have an impact on the
progression of osteoarthritis?
While the short-term benefits of weight loss in obese
patients with OA are undisputed, the effect of weight loss
on the progression of OA remains a topic for debate. Some
results have suggested a positive effect of weight loss on
cartilage in non-OA subjects. For example, in a prospective
study of obese adults recruited from gastric banding or diet
and exercise programmes, weight loss was found to be
associated with improvements in both the quality and
quantity of medial articular cartilage (50).
However, other studies have indicated that weight loss
does not alter the course of OA, and an association
between symptom relief and altered course of structural
damage remains to be shown. In the Arthritis, Diet and
Activity Promotion Trial, no difference in joint space width
(a measure of disease progression) was seen between
patients treated with diet, exercise, diet plus exercise or
healthy lifestyle (the control group) (3). However, the
authors noted that the relatively short duration of the inter-
vention (18 months) coupled with the number of subjects
per group (approximately 80) probably prevented the
detection of meaningful differences in radiographic disease
progression. Hence, more research is required in order to
answer this interesting question.
What are the mechanisms linking obesity
and osteoarthritis?
Understanding of the mechanisms by which obesity predis-
poses the onset and progression of OA has evolved over
time. Initially, the link between OA and obesity was con-
sidered purely biomechanical (18–20). In fact, on closer
inspection, the mechanisms linking obesity and OA appear
582 Osteoarthritis, obesity and weight loss H. Bliddal et al. obesity reviews
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity15, 578–586, July 2014

to be more complex and multifactorial (Fig. 2) (37). Rela-
tive loss of muscle mass and strength over time also con-
tributes to the onset of OA in obese individuals. Although
muscle as well as fat mass increases with weight gain,
overall, the volume of muscle mass remains relatively low
and inadequate to match the loads placed upon it (37).
There is also evidence that mechanical stress may lead to
the release of a range of pro-inflammatory mediators
from joint tissues, including interleukin (IL)-1beta,
cyclooxygenase-2, prostaglandin E
2
, matrix metallo-
proteinase (MMP)-2, MMP-3, IL-6, MMP-9, MMP-13,
receptor activator of nuclear factor-kappaB ligand, fibro-
blast growth factor-2 and IL-8 (51–55). Of note, pro-
inflammatory cytokines such as IL-6 and C-reactive protein
have been shown to predict both the incidence (56) and
progression (57,58) of arthritis. Furthermore, recent
evidence from the Intensive Diet and Exercise for
Arthritis study suggests that weight loss may have anti-
inflammatory, as well as biomechanical, benefits in obese
subjects with concomitant knee OA, as evidenced by
reduced levels of IL-6 (59).
Intriguingly, although a definite association exists
between obesity and OA in weight-bearing joints such as the
knee and hip, obesity is also associated with the develop-
ment of OA in non–weight-bearing joints, such as those in
the hand (60). This suggests that non-mechanical risk
factors must also play a part. In particular, there is interest in
the potential role of adipokines (cytokines secreted by
adipose tissue). For example, leptin has long been implicated
in the pathogenesis of OA, independent of the mechanical
effect of obesity (61). However, recent evidence indicates
that serum leptin concentration does not correlate with hand
OA (62). Adiponectin has been implicated as a predictor of
disease progression in early rheumatoid arthritis (63),
although its precise role in OA is less clear. There is also
interest in the potential role of chemerin in the development
and progression of OA, with recent data indicating that
chemerin levels may predict the severity of OA (64). Other
adipokines with a potential role in the pathogenesis of OA
include visfatin, resistin, lipocalin–2, serum amyloid 3,
vaspin and omentin (61). Of note, the infrapatellar fat pad,
an adipose tissue depot located in the knee joint, may
contribute to the pathophysiological changes that occur in
the OA joint via local production of cytokines and
adipokines (65). Studies are now exploring the potential for
adipokines as biomarkers for diagnosing OA at an early
stage, which remains a key challenge (66–68).
Also worthy of note is the association of obesity and OA
with metabolic abnormalities, such as hyperinsulinaemia
and other cardiometabolic defects. OA of the knee is asso-
ciated with hyperinsulinaemia, which may play a role in
OA in overweight patients, possibly via changes in insulin-
like growth factor-1 (69). Furthermore, an increased risk
of OA has been observed in obese women with
cardiometabolic clustering versus those without (70).
Notably, obesity was only found to be significantly associ-
ated with pain measures or many of the physical function-
ing performance measures when it was accompanied by
cardiometabolic clustering (70). This observation may have
significance in terms of optimizing treatment for knee OA.
Horizons
OA imposes a serious and growing health burden and
commands increased attention in terms of patho-
physiological understanding in order to optimize manage-
ment of affected patients.
A key question that arises in terms of what the future
may hold for obese patients with OA is whether a better
understanding of obesity and OA can lead to more effective
therapeutic approaches. The ideal treatment would be an
intervention that tackles both obesity and OA, providing
Figure 2 Potential obesity-related pathways that contribute to
osteoarthritis.
CRP, C-reactive protein; IL, interleukin; TNF, tumour necrosis factor.
Reproduced with permission from Vincent HK, Heywood K, Connelly J,
Hurley RW. PM R 2012; 4(5 Suppl): S59–67 (37).
obesity reviews Osteoarthritis, obesity and weight loss H. Bliddal et al. 583
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity 15, 578–586, July 2014

weight loss, but also addressing the underlying mechanisms
that link the two conditions. It would need to be acceptable
to this patient population for long-term use, as the typical
subject with concomitant obesity and OA has lifelong
problems with overweight.
Conclusion
It is imperative to diagnose OA as early as possible; as
obese patients have a greater risk of developing OA, they
should be monitored for signs of the disease. In the future,
earlier diagnosis of OA may be aided by the identification
of effective biomarkers.
For all obese patients with OA, weight loss should be
advocated as a first-line management approach, with a goal
of rapid initial weight loss of approximately 10% of body
weight. The challenge of how to maintain weight loss, and
the question of whether or not weight loss can alter pro-
gression of OA, remain key areas of ongoing research.
Another area for focus is advancing our knowledge of
the pathophysiology that underpins both OA and obesity.
This, in turn, may facilitate the identification of alternative
therapeutic approaches. In particular, any approach that
tackles both OA and obesity would be a major step
forward in stemming the global epidemic of these two
interlinked conditions.
Conflict of interest statement
ARL is the salaried medical director of Cambridge Weight
Plan, but holds no company shares or share options. HB
and RC have received research grants from this company,
but no personal benefits.
Acknowledgements
The authors are grateful to Dr Emma Kenny of AXON
Communications for writing assistance in the development
of this paper. This assistance was funded by Novo Nordisk.
Novo Nordisk was also provided with the opportunity to
perform a medical accuracy review.
References
1. Lementowski PW, Zelicof SB. Obesity and osteoarthritis. Am J
Orthop (Belle Mead NJ) 2008; 37: 148–151.
2. Wendelboe AM, Hegmann KT, Biggs JJ et al. Relationships
between body mass indices and surgical replacements of knee and
hip joints. Am J Prev Med 2003; 25: 290–295.
3. Messier SP, Loeser RF, Miller GD et al. Exercise and dietary
weight loss in overweight and obese older adults with knee osteo-
arthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis
Rheum 2004; 50: 1501–1510.
4. International Association for the Study of Obesity.
(2013). Obesity the Global Epidemic. [WWW document].
URL http://www.iaso.org/iotf/obesity/obesitytheglobalepidemic/
(accessed 4 April 2014).
5. Hiligsmann M, Cooper C, Arden N et al. Health economics in
the field of osteoarthritis: an expert’s consensus paper from the
European Society for Clinical and Economic Aspects of Osteopo-
rosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum 2013;
43: 303–313.
6. United Nations. (2009). World Population Ageing. [WWW
document]. URL http://www.un.org/esa/population/publications/
WPA2009/WPA2009_WorkingPaper.pdf (accessed 4 April 2014).
7. Mathus-Vliegen EM. Prevalence, pathophysiology, health con-
sequences and treatment options of obesity in the elderly: a guide-
line. Obes Facts 2012; 5: 460–483.
8. Centers for Disease Control and Prevention. (2011). Osteoar-
thritis. [WWW document]. URL http://www.cdc.gov/arthritis/
basics/osteoarthritis.htm (accessed 4 April 2014).
9. World Health Organization. (2013). Obesity and overweight.
[WWW document]. URL http://www.who.int/mediacentre/
factsheets/fs311/en/index.html (accessed 4 April 2014).
10. Bliddal H, Christensen R. The management of osteoarthritis in
the obese patient: practical considerations and guidelines for
therapy. Obes Rev 2006; 7: 323–331.
11. Badley EM, Tennant A, United Kingdom. Changing profile of
joint disorders with age: findings from a postal survey of the
population of Calderdale, West Yorkshire. Ann Rheum Dis 1992;
51: 366–371.
12. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in
older adults: a review of community burden and current use of
primary health care. Ann Rheum Dis 2001; 60: 91–97.
13. Bliddal H. Guidelines for the use of nonsurgical interventions
in osteoarthritis management. Expert Rev Clin Immunol 2008; 4:
583–590.
14. Lethbridge-Cejku M, Helmick CG, Popovic JR. Hospitaliza-
tions for arthritis and other rheumatic conditions: data from the
1997 National Hospital Discharge Survey. Med Care 2003; 41:
1367–1373.
15. Wills AK, Black S, Cooper R et al. Life course body mass
index and risk of knee osteoarthritis at the age of 53 years: evi-
dence from the 1946 British birth cohort study. Ann Rheum Dis
2012; 71: 655–660.
16. Muehleman C, Margulis A, Bae WC, Masuda K. Relationship
between knee and ankle degeneration in a population of organ
donors. BMC Med 2010; 8: 48.
17. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ.
Weight loss reduces the risk for symptomatic knee osteoarthritis in
women. The Framingham Study. Ann Intern Med 1992; 116:
535–539.
18. Messier SP, Gutekunst DJ, Davis C, DeVita P. Weight loss
reduces knee-joint loads in overweight and obese older adults with
knee osteoarthritis. Arthritis Rheum 2005; 52: 2026–
2032.
19. Aaboe J, Bliddal H, Messier SP, Alkjaer T, Henriksen M.
Effects of an intensive weight loss program on knee joint loading in
obese adults with knee osteoarthritis. Osteoarthritis Cartilage
2011; 19: 822–828.
20. Messier SP, Legault C, Loeser RF et al. Does high weight loss
in older adults with knee osteoarthritis affect bone-on-bone joint
loads and muscle forces during walking? Osteoarthritis Cartilage
2011; 19: 272–280.
21. Toda Y, Toda T, Takemura S, Wada T, Morimoto T, Ogawa
R. Change in body fat, but not body weight or metabolic correlates
of obesity, is related to symptomatic relief of obese patients with
knee osteoarthritis after a weight control program. J Rheumatol
1998; 25: 2181–2186.
584 Osteoarthritis, obesity and weight loss H. Bliddal et al.
obesity reviews
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity15, 578–586, July 2014

22. Riddle DL, Stratford PW. Body weight changes and corre-
sponding changes in pain and function in persons
withsymptomatic knee osteoarthritis: a cohort study. Arthritis
Care Res (Hoboken) 2013; 65: 15–22.
23. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of
weight reduction in obese patients diagnosed with knee osteoar-
thritis: a systematic review and meta-analysis. Ann Rheum Dis
2007; 66: 433–439.
24. Christensen R, Astrup A, Bliddal H. Weight loss: the treatment
of choice for knee osteoarthritis? A randomized trial. Osteoarthri-
tis Cartilage 2005; 13: 20–27.
25. National Institutes of Health. (1998). Clinical guidelines on
the identification, evaluation, and treatment of overweight and
obesity in adults. [WWW document]. URL http://www.nhlbi.nih
.gov/guidelines/obesity/ob_gdlns.pdf (accessed 4 April 2014).
26. Rejeski WJ, Focht BC, Messier SP, Morgan T, Pahor M,
Penninx B. Obese, older adults with knee osteoarthritis: weight
loss, exercise, and quality of life. Health Psychol 2002; 21: 419–
426.
27. Riecke BF, Christensen R, Christensen P et al. Comparing two
low-energy diets for the treatment of knee osteoarthritis symptoms
in obese patients: a pragmatic randomized clinical trial. Osteoar-
thritis Cartilage 2010; 18: 746–754.
28. Gudbergsen H, Boesen M, Christensen R et al. Changes in
bone marrow lesions in response to weight-loss in obese knee
osteoarthritis patients: a prospective cohort study. BMC
Musculoskelet Disord 2013; 14: 106.
29. Henriksen M, Hunter DJ, Dam EB et al. Is increased joint
loading detrimental to obese patients with knee osteoarthritis? A
secondary data analysis from a randomized trial. Osteoarthritis
Cartilage 2013; 64: 438–442.
30. Hochberg MC, Altman RD, April KT et al. American College
of Rheumatology 2012 recommendations for the use of
nonpharmacologic and pharmacologic therapies in osteoarthritis
of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;
64: 465–474.
31. Fernandes L, Hagen KB, Bijlsma JW et al. EULAR recommen-
dations for the non-pharmacological core management of hip and
knee osteoarthritis. Ann Rheum Dis 2013; 72: 1125–1135.
32. Messier SP, Loeser RF, Mitchell MN et al. Exercise and
weight loss in obese older adults with knee osteoarthritis: a pre-
liminary study. J Am Geriatr Soc 2000; 48: 1062–1072.
33. Henriksen M, Christensen R, Danneskiold-Samsoe B, Bliddal
H. Changes in lower extremity muscle mass and muscle strength
after weight loss in obese patients with knee osteoarthritis: a
prospective cohort study. Arthritis Rheum 2012; 64: 438–442.
34. Elfhag K, Rössner S. Who succeeds in maintaining weight
loss? A conceptual review of factors associated with weight loss
maintenance and weight regain. Obes Rev 2005; 6: 67–85.
35. Segal NA, Toda Y. Absolute reduction in lower limb lean body
mass in Japanese women with knee osteoarthritis. J Clin
Rheumatol 2005; 11: 245–249.
36. Christensen P, Bartels EM, Riecke BF et al. Improved nutri-
tional status and bone health after diet-induced weight loss in
sedentary osteoarthritis patients: a prospective cohort study. Eur J
Clin Nutr 2012; 66: 504–509.
37. Vincent HK, Heywood K, Connelly J, Hurley RW. Obesity
and weight loss in the treatment and prevention of osteoarthritis.
PM R 2012;
4: S59–S67.
38. Edwards C, Rogers A, Lynch S et al. The effects of bariatric
surgery weight loss on knee pain in patients with osteoarthritis of
the knee. Arthritis 2012; 2012: 504189.
39. Rogind H, Bibow-Nielsen B, Jensen B, Moller HC,
Frimodt-Moller H, Bliddal H. The effects of a physical training
program on patients with osteoarthritis of the knees. Arch Phys
Med Rehabil 1998; 79: 1421–1427.
40. Roddy E, Zhang W, Doherty M. Aerobic walking or strength-
ening exercise for osteoarthritis of the knee? A systematic review.
Ann Rheum Dis 2005; 64: 544–548.
41. Toda Y. The effect of energy restriction, walking, and exercise
on lower extremity lean body mass in obese women with osteoar-
thritis of the knee. J Orthop Sci 2001; 6: 148–154.
42. Bennell KL, Hinman RS. A review of the clinical evidence for
exercise in osteoarthritis of the hip and knee. J Sci Med Sport 2011;
14: 4–9.
43. Schoeller DA, Shay K, Kushner RF. How much physical activ-
ity is needed to minimize weight gain in previously obese women?
Am J Clin Nutr 1997; 66: 551–556.
44. Group TLAR. Cardiovascular effects of intensive lifestyle
intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–
154.
45. Wadden TA, Butryn ML, Byrne KJ. Efficacy of lifestyle modi-
fication for long-term weight control. Obes Res 2004; 12(Suppl.):
151S–62S.
46. Parvizi J, Trousdale RT, Sarr MG. Total joint arthroplasty in
patients surgically treated for morbid obesity. J Arthroplasty 2000;
15: 1003–1008.
47. Gill RS, Al-Adra DP, Shi X, Sharma AM, Birch DW, Karmali
S. The benefits of bariatric surgery in obese patients with hip and
knee osteoarthritis: a systematic review. Obes Rev 2011; 12:
1083–1089.
48. Riddle DL, Singh JA, Harmsen WS, Schleck CD, Lewallen
DG. Clinically important body weight gain following knee
arthroplasty: a five-year comparative cohort study. Arthritis Care
Res (Hoboken) 2013; 65: 669–677.
49. Deshmukh RG, Hayes JH, Pinder IM. Does body weight
influence outcome after total knee arthroplasty? A 1-year analysis.
J Arthroplasty 2002; 17: 315–319.
50. Anandacoomarasamy A, Leibman S, Smith G et al. Weight
loss in obese people has structure-modifying effects on medial but
not on lateral knee articular cartilage. Ann Rheum Dis 2012; 71:
26–32.
51. Chauffier K, Laiguillon MC, Bougault C et al. Induction of the
chemokine IL-8/Kc by the articular cartilage: possible influence on
osteoarthritis. Joint Bone Spine 2012; 79: 604–609.
52. Sanchez C, Gabay O, Salvat C, Henrotin YE, Berenbaum F.
Mechanical loading highly increases IL-6 production and decreases
OPG expression by osteoblasts. Osteoarthritis Cartilage 2009; 17:
473–481.
53. Sanchez C, Pesesse L, Gabay O et al. Regulation of
subchondral bone osteoblast metabolism by cyclic compression.
Arthritis Rheum 2012; 64: 1193–1203.
54. Takao M, Okinaga T, Ariyoshi W et al. Role of heme
oxygenase-1 in inflammatory response induced by mechanical
stretch in synovial cells. Inflamm Res 2011; 60: 861–867.
55. Wang Y, Tang Z, Xue R et al. Combined effects of TNF-alpha,
IL-1beta, and HIF-1alpha on MMP-2 production in ACL fibro-
blasts under mechanical stretch: an in vitro study. J Orthop Res
2011; 29: 1008–1014.
56. Livshits G, Zhai G, Hart DJ et al. Interleukin-6 is a significant
predictor of radiographic knee osteoarthritis: the Chingford study.
Arthritis Rheum 2009; 60: 2037–2045.
57. Sharif M, Shepstone L, Elson CJ, Dieppe PA, Kirwan JR.
Increased serum C reactive protein may reflect events that precede
radiographic progression in osteoarthritis of the knee. Ann Rheum
Dis 2000; 59: 71–74.
58. Spector TD, Hart DJ, Nandra D et al. Low-level increases in
serum C-reactive protein are present in early osteoarthritis of the
obesity reviews Osteoarthritis, obesity and weight loss H. Bliddal et al. 585
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity 15, 578–586, July 2014

knee and predict progressive disease. Arthritis Rheum 1997; 40:
723–727.
59. Messier SP, Mihalko SL, Legault C et al. Effects of intensive
diet and exercise on knee joint loads, inflammation, and clinical
outcomes among overweight and obese adults with knee osteoar-
thritis: the IDEA randomized clinical trial. JAMA 2013; 310:
1263–1273.
60. Yusuf E, Nelissen RG, Ioan-Facsinay A et al. Association
between weight or body mass index and hand osteoarthritis: a
systematic review. Ann Rheum Dis 2010; 69: 761–765.
61. Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ,
Gualillo O. Adipokines and osteoarthritis: novel molecules
involved in the pathogenesis and progression of disease. Arthritis
2011; 2011: 203901.
62. Massengale M, Reichmann WM, Losina E, Solomon DH,
Katz JN. The relationship between hand osteoarthritis and serum
leptin concentration in participants of the Third National Health
and Nutrition Examination Survey. Arthritis Res Ther 2012; 14:
R132.
63. Klein-Wieringa IR, van der Linden MP, Knevel R et al. Base-
line serum adipokine levels predict radiographic progression in
early rheumatoid arthritis. Arthritis Rheum 2011; 63: 2567–2574.
64. Huang K, Du G, Li L, Liang H, Zhang B. Association of
chemerin levels in synovial fluid with the severity of knee osteoar-
thritis. Biomarkers 2012; 17: 16–20.
65. Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens
YM et al. The infrapatellar fat pad of patients with osteoarthritis
has an inflammatory phenotype. Ann Rheum Dis 2011; 70: 851–
857.
66. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an
update with relevance for clinical practice. Lancet 2011; 377:
2115–2126.
67. Staikos C, Ververidis A, Drosos G, Manolopoulos VG,
Verettas DA, Tavridou A. The association of adipokine levels in
plasma and synovial fluid with the severity of knee osteoarthritis.
Rheumatology (Oxford) 2013; 52: 1077–1083.
68. van Spil WE, Jansen NW, Bijlsma JW et al. Clusters within a
wide spectrum of biochemical markers for osteoarthritis: data
from CHECK, a large cohort of individuals with very early symp-
tomatic osteoarthritis. Osteoarthritis Cartilage 2012; 20: 745–
754.
69. Silveri F, Brecciaroli D, Argentati F, Cervini C. Serum levels of
insulin in overweight patients with osteoarthritis of the knee. J
Rheumatol 1994; 21: 1899–1902.
70. Sowers M, Karvonen-Gutierrez CA, Palmieri-Smith R,
Jacobson JA, Jiang Y, Ashton-Miller JA. Knee osteoarthritis in
obese women with cardiometabolic clustering. Arthritis Rheum
2009; 61: 1328–1336.
586 Osteoarthritis, obesity and weight loss H. Bliddal et al.
obesity reviews
© 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity15, 578–586, July 2014