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com

Benefits of massive weight loss on symptoms,

systemic inflammation and cartilage turnover in
obese patients with knee osteoarthritis
Pascal Richette, Christine Poitou, Patrick Garnero, et al.
Ann Rheum Dis 2011 70: 139-144 originally published online October 26,
2010

doi: 10.1136/ard.2010.134015

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Extended report

Benefits of massive weight loss on symptoms,

systemic inflammation and cartilage turnover in
obese patients with knee osteoarthritis
Pascal Richette,1 Christine Poitou,25 Patrick Garnero,6,7 Eric Vicaut,8
Jean-Luc Bouillot,9 Jean-Marc Lacorte,10 Arnaud Basdevant,25 Karine Clment,25
Thomas Bardin,1 Xavier Chevalier11
1Universit

Paris 7, UFR
mdicale, Assistance PubliqueHpitaux de Paris, Hpital
Lariboisire, Fdration de
Rhumatologie, Paris Cedex,
France
2Assistance Publique-Hpitaux
de Paris, Piti-Salptrire
Hospital, Nutrition and
Endocrinology Department,
Paris, France
3Center of Research on Human
Nutrition Ile de France, Paris,
France
4INSERM, U872, Nutriomique
Team 7, Paris, France
5Universit Pierre et Marie
Curie-Paris 6, Centre de
Recherche des Cordeliers,
UMRS 872, Paris, France
6INSERM Research Unit 664
and Cisbio Bioassays, Lyon,
France
7Synarc, Lyon, France (past
affiliation)
8Universit Paris 7, UFR
mdicale, Assistance Publique
Hpitaux de Paris, Hpital
Fernand Widal, Unit de
Recherche Clinique, Paris
Cedex, France
9Assistance Publique-Hopitaux
de Paris, Htel-Dieu Hospital,
Surgery Department, Paris,
France
10Assistance Publique-Hpitaux
de Paris, Piti-Salptrire
Hospital, Endocrinology
and Oncology Biochemistry
Department, Paris, France
11Assistance Publique-Hpitaux
de Paris, Hpital Henri-Mondor,
Crteil, France
Correspondence to
Dr Pascal Richette, Fdration
de Rhumatologie, Hpital
Lariboisire, 2 Rue Ambroise
Par, 75475 Paris cedex 10,
France;
pascal.richette@lrb.aphp.fr
The first two authors
contributed equally to this work.
Accepted 11 August 2010
Published Online First
26 October 2010

ABSTRACT
Objective To investigate the effect of massive
weight loss on (1) knee pain and disability, (2) lowgrade inflammation and metabolic status and (3) joint
biomarkers in obese patients with knee osteoarthritis
(OA).
Methods 140 patients involved in a gastric surgery
programme were screened for painful knee OA, and 44
were included (age 44 10.3 years, body mass index
(BMI) 50.7 7.2 kg/m2). Clinical data and biological
samples were collected before and 6 months after
surgery.
Results Before surgery, interleukin 6 (IL-6) levels were
correlated with levels of high-sensitivity C reactive protein
(hsCRP) (p=0.006) and Helix-II (p=0.01), a biomarker
of cartilage turnover, and the Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC)
function score (p=0.03). Surgery resulted in substantial
decrease in BMI (20%). Levels of insulin and insulin
resistance were decreased at 6 months. Knee pain
decreased after surgery (24.5 21 mm vs 50 26.6
mm; p<0.001), and scores on all WOMAC subscales
were improved. Levels of IL-6 (p<0.0001), hsCRP
(p<0.0001), orosomucoid (p<0.0001) and fibrinogen
(p=0.04) were decreased after surgery. Weight loss
resulted in a significant increase in N-terminal propeptide
of type IIA collagen levels (+32%; p=0.002), a biomarker
of cartilage synthesis, and a significant decrease in
cartilage oligomeric matrix protein (COMP) (36%;
p<0.001), a biomarker of cartilage degradation. Changes
in COMP concentration were correlated with changes in
insulin levels (p=0.02) and insulin resistance (p=0.05).
Conclusion Massive weight loss improves pain and
function and decreases low-grade inflammation. Change
in levels of joint biomarkers with weight loss suggests a
structural effect on cartilage.
INTRODUCTION
Obesity is the main modiable risk factor for the
onset of knee osteoarthritis (OA).13 The strong
association between body mass index (BMI) and
OA of the knee is thought to be mainly due to an
increase in mechanical loads to the tibiofemoral
cartilage.4
The observation that obesity is also a risk factor for OA of non-weightbearing joints such as
the hand5 has suggested that the link between
overweight and OA might also occur through systemic inammation. Adipose tissue may act as
an endocrine organ, releasing several proinammatory mediators and adipokines in blood that

Ann Rheum Dis 2011;70:139144. doi:10.1136/ard.2010.134015

may participate in cartilage alteration in obese

patients.69 With mass enlargement of fat, adipose
tissue accumulates inammatory cells, particularly
macrophages, and secretes inammatory cytokines
such as interleukin 6 (IL-6), tumour necrosis factor
, serum amyloid A; high levels of leptin, resistin
and visfatin; and low levels of adiponectin.10 11 In
vitro and in vivo studies have shown that all these
adipokines could affect cartilage homoeostasis.1215
Additionally, some studies have suggested that
metabolic risk factors such as diabetes mellitus,
increased levels of triglycerides and/or cholesterol
might also be associated with OA.16 17
Randomised controlled trials have evaluated the
effects of diet weight loss on pain and function in
overweight patients with knee OA.1822 In those
studies, the magnitude of the weight loss was mild
to moderate, ranging from 5% to 11%. A recent
meta-analysis of pooled data from four of these randomised controlled trials demonstrated that a moderate weight loss of about 5% in obese patients reduces
functional disability and, to a lesser extent, pain.23
Few studies have explored the effects of moderate
diet weight loss on systemic inammation, knee OA
structural progression and joint biomarkers.19 24 25 A
5% weight loss over 18 months, alone or in combination with exercise, reduced the serum concentrations
of C reactive protein (CRP), IL-6 and tumour necrosis
factor soluble receptor 125 but did not attenuate OA
progression, as assessed by sequential measurements
of joint space width of the knee.19 The effect of exercise and a weight-loss intervention on the serum levels of joint biomarkers yielded inconclusive results.24
One explanation for these somewhat disappointing
results might be that the magnitude of weight loss in
these studies (510%) was not enough to sufciently
reduce systemic inammation, knee joint loads and
metabolic status impairment to demonstrate a benet on cartilage turnover.
We aimed to investigate the effect of weight loss
>10% in obese patients with knee OA on pain, disability, cartilage turnover and systemic inammation.
We chose the model of gastric surgery, which results
in drastic weight loss, leading to signicant metabolic
changes with improvement in insulin sensitivity and
lipid parameters and systemic inammation.26 27

PATIENTS AND METHODS

Ethics statement
The ethics committee of the Htel-Dieu Hospital
approved the clinical investigations. All subjects
139

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Extended report
gave their written informed consent before their inclusion in the
study.

Subjects and study design

We screened 140 patients involved in a gastric surgery programme, who were prospectively recruited between 2006
and 2007 in the Department of Nutrition, Center of Reference
for Medical and Surgical Care of Obesity, Piti Salptrire
Hospital (Paris, France). Patients met the criteria for obesity surgery: BMI 40 kg/m2, or 35 kg/m2 with at least one
comorbidity (hypertension, diabetes mellitus, dyslipidaemia,
obstructive sleep apnoea syndrome). Preoperative evaluation
included medical history and physical, nutritional, metabolic,
cardiopulmonary and psychological assessments. Subjects did
not demonstrate acute or chronic inammatory disease, infectious diseases, viral infection, cancer and/or known alcohol
consumption (>20 g/day).
To be included, patients had to have radiographically conrmed knee OA (Kellgren/Lawrence (K/L) grade 24) with
symptoms for at least 1 month, dened by a knee pain score
of at least 30 mm on a 0100 mm visual analogue scale (VAS).
Exclusion criteria were a K/L grade of 1, inammatory joint disease, chondrocalcinosis of the knee, current use of symptomatic slow-acting drugs, viscosupplementation within the past
6 months and oral corticosteroid treatment or intra-articular
corticosteroid injection into any joint within the last month
before the bariatric surgery. For all patients, the radiographic
evidence of knee OA and eligibility criteria were veried by the
same investigator (PR).
Of the 140 screened patients, 44 met the inclusion criteria
and were enrolled. Patients weight had to be stable (ie, variation within 2 kg) for at least 3 months before surgery. The
surgical procedure was laparoscopic Roux-en-Y gastric bypass
(RYGB) (n=38) or laparoscopic adjustable gastric banding (n=6)
and was performed in the department of surgery of Htel-Dieu
Hospital.

Blood sampling and clinical evaluation

For all patients, clinical data and biological samples were collected just before surgery (ie, baseline) and at 6 months after
surgery. Venous blood was collected in the morning (between
08:00 and 10:00) after a 12 h overnight fast. Serum samples were
stored at 80C for biological assays.

Outcomes for knee OA

The severity of the knee OA pain was evaluated using a continuous 100 mm VAS assessing the global level of pain in the target knee, regardless of the circumstances over the previous 48 h.
Other outcomes included the Western Ontario and McMaster
Universities Osteoarthritis Index (WOMAC) subscores for pain,
stiffness and disability, and the patient global assessment of the
severity of knee OA measured on a 100 mm VAS. When both
knees were painful, only the most painful knee was selected for
the evaluation.

the euglycaemic-hyperinsulinaemic clamp values.28 Therefore,

the HOMA represents a useful index for study of morbidly
obese individuals in whom the evaluation of insulin sensitivity
with the clamp technique has understandable technical limitations because of extreme BMI.

Measurements of body composition

Fat-free body mass and adiposity were determined by dual
energy x-ray absorptiometry (GE Lunar Prodigy, Madison,
Wisconsin, USA) before and 6 months after surgery.

Immunoassays for adipokines and inflammatory markers

Serum leptin and adiponectin were determined with a radioimmunoassay kit from Linco Research (St Louis, Missouri, USA),
according to the manufacturers recommendations. The sensitivity is 0.5 ng/ml and 0.8 g/ml for leptin and adiponectin,
respectively. Intra- and interassay coefcients of variation (CVs)
are <4% and 9% for leptin and adiponectin, respectively. Serum
levels of IL-6 were measured by a high-sensitivity ELISA system (Quantikine US; R&D Systems Europe, Lille, France). The
sensitivity of this assay is <0.04 pg/ml, and intra- and interassay
CVs are <8%. High-sensitivity CRP (hsCRP) and orosomucoid
levels were measured with an IMMAGE automatic immunoassay system (BeckmanCoulter, Fullerton, California, USA).
The sensitivity is 0.02 and 35 mg/dl, respectively; intra- and
interassay CVs are <5% and 7.5%, respectively, for hsCRP and
4% and 6% for orosomucoid. Serum levels of brinogen were
measured with use of a Star Diagnostica Stago system by FibriPrest (Parsippany, New Jersey, USA).

Immunoassays for joint biomarkers

Serum cartilage oligomeric matrix protein (COMP) is a biomarker
of cartilage degradation and a potential prognostic indicator of
joint OA damage.16 29 It was measured by ELISA (COMP ELISA
Kit; AnaMar Medical, Lund, Sweden) with two monoclonal
antibodies raised against different antigenic determinants of the
COMP molecule. Intra- and interassay CVs are <10% and 12%,
respectively. Serum hyaluronic acid (HA), a marker of synovial
metabolism,30 was measured by ELISA (Corgenix, Broomeld,
Colorado, USA) with a specic HA binding protein isolated
from bovine cartilage. Intra- and interassay CVs are <7% and
9%, respectively.
Serum N-terminal propeptide of type IIA collagen (PIIANP), a
marker of type II collagen synthesis,31 was measured by competitive ELISA (human PIIANP ELISA; Linco, El Paso, Texas, USA)
with a polyclonal antibody raised against recombinant human
type II procollagen exon 2 fusion protein. Intra- and interassay CVs are <8% and 14%, respectively. Serum collagen helical peptide (Helix-II), a marker of cartilage collagen turnover,32
was measured by competitive ELISA (SYNCART; Synarc, Lyon,
France). Intra- and interassay CVs are both <15%. Assays for
joint biomarkers were performed in a central specialised laboratory (Synarc) in batches, with the two samples for the same
subject in the same run to reduce analytical variation.

Lipid profile and insulin sensitivity calculation

Statistical analysis

Plasma glucose and insulin were measured on a Modular Hitachi

system (Roche Diagnostics, Meylan, France) by the glucose
oxidase method and an IMMULITE 2000 system (Siemens, La
Garenne Colombe, France). Homoeostasis model assessment
(HOMA) of insulin resistance (IR) was determined using the
HOMA Calculator v2.2.2 (http://www.dtu.ox.ac.uk). This index
has been validated in different populations in comparison with

Data are reported as mean (SD) or median (range) depending

on distribution. The Wilcoxon test was used for comparisons
between clinical outcomes and biological marker levels before
and after weight loss. Correlations between relative changes in
joint biomarker levels, clinical outcomes or changes in metabolic status and systemic inammation were tested with the
non-parametric Spearman correlation test. Multiple regression

140

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Extended report
analysis was used to assess the independent association and
contributions of changes in BMI, insulin and HOMA-IR with the
dependant variable COMP. A two-sided signicance level was
xed at 5%. All analyses involved use of SAS v9.2 (SAS Institute,
Cary, North Carolina, USA). A two-tailed p value <0.05 was
considered statistically signicant.

subscales were improved: pain (50%; p<0.001), stiffness

(47%; p<0.001) and function (57%; p<0.001). Patient global
assessment of the severity of the target knee OA was signicantly decreased (50%; p<0.001) (table 2).

RESULTS
Demographic characteristics of patients and effects of
weight loss on metabolic status

The changes in levels of inammation biomarkers after gastric

surgery are shown in table 3. As expected, the serum levels of
IL-6 (26%; p<0.0001), hsCRP (46%; p<0.0001), orosomucoid
(20%; p<0.0001) and brinogen (5%; p=0.04) were all signicantly decreased after surgery. Moreover, weight loss was
associated with changes in adipokine levels: mean serum leptin concentration was decreased by 48% (63.2 24.4 ng/ml vs
3316.7 ng/ml; p<0.0001), and serum level of adiponectin was
increased by 21% (7.94.6 g/ml vs 9.97.7 g/ml; p=0.03).

Our study population consisted of 44 obese patients (mean age

44 10.3 years, 36 women) with moderate to severe knee OA
(K/L grade 2, 50%; grade 3, 35%; grade 4, 15%). Duration of
knee OA symptoms was 5.2 4.6 years. Mean BMI at age 20 was
31.1 10.2 kg/m2 and was 50.7 7.2 kg/m2 just before surgery
(table 1). Bariatric surgery resulted in a substantial decrease in
BMI (20% of baseline values; p<0.0001), body weight (20%;
p<0.0001), fat mass (21%; p<0.0001) and fat free mass (9%;
p<0.0001) at 6 months. Additionally, levels of circulating total
cholesterol, triglycerides and insulin were signicantly decreased
after surgery (all p<0.01). Level of high-density lipoprotein cholesterol did not change (p=0.1). Finally, glycaemic status and
insulin resistance, as evaluated by HOMA-IR, were signicantly
decreased 6 months after surgery (p<0.0001; table 1).

Effect of weight loss on adipokine levels and systemic

inflammation

Changes in joint biomarkers with massive weight loss

Weight loss resulted in a signicant increase (+32%) in serum
level of PIIANP (443.6257.5 ng/ml vs 586.4239.4 ng/ml;
p=0.002), whereas serum levels of Helix-II and HA were
unchanged (p=0.98 and p=0.41, respectively). By contrast, the
serum level of COMP was signicantly decreased (36%) after
surgery: 10.53.5 UI/l vs 6.7 2.2 UI/l (p<0.001) (table 4 and
gure 1).

Effect of weight loss on knee OA symptoms

Massive weight loss greatly improved both pain and function in
these obese patients with knee OA. After surgery, at 6 months,
knee OA pain scores on the VAS decreased from 50 26.6 to
24.5 21 mm (51%; p<0.001), and scores on all WOMAC

Table 1 Demographic characteristics of obese patients with knee

osteoarthritis and variation in metabolic marker levels before and after
bariatric surgery
Age, years
Sex, male/female, n
BMI, kg/m2
Weight, kg
Fat mass (kg)
Free fat mass (kg)
Total cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Triglycerides (mmol/l)
Glucose (mmol/l)
Insulin (IU/l)
HOMA-IR

Baseline

6 Months

p Value

44 10.3
8/36
50.7 7.2
138.8 23.5
59.6 10.0
64.0 9.9
4.8 1.2
1.2 0.3
1.2 0.6
6.7 3.3
15.4 9.6
2.2 1.6

NA
NA
40.4 6.8
110.2 20.6
47.2 11.5
58.3 10.9
4.1 0.7
1.2 0.3
1.0 0.4
4.8 0.8
8.7 6.6
1.1 0.9

NA
NA
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.1
0.001
<0.0001
<0.0001
<0.0001

Unless otherwise indicated, values are mean SD.

BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homoeostasis model
assessment estimate of insulin resistance; NA, not applicable.

Table 2 Effect of massive weight loss on knee osteoarthritis

symptoms
Pain score (100 mm VAS)
Patient global assessment of the
severity of knee OA (100 mm VAS)
WOMAC pain score
WOMAC stiffness score
WOMAC function score

Baseline

6 Months

p Value

5026.6
51.626.5

24.521
25.320.9

<0.0001
<0.0001

187.3124.4
68.253.8
643.9424.2

94.193.9
36.441.9
272.6289

<0.0001
<0.0001
<0.0001

Values are the mean SD.

OA, osteoarthritis; VAS, visual analogue scale; WOMAC, Western Ontario and
McMaster Universities Osteoarthritis Index.

Ann Rheum Dis 2011;70:139144. doi:10.1136/ard.2010.134015

Correlation between biochemical markers and clinical

outcomes at baseline
We searched for correlations between markers of systemic
inammation or joint biomarkers and symptoms (pain or disability) at baseline. We found a signicant correlation between
level of IL-6 and WOMAC function score (r=0.33; p=0.03). IL-6
level was also correlated with levels of hsCRP (r=0.42; p=0.006)
and Helix-II (r=0.37; p=0.01). Levels of leptin or adiponectin
were not correlated with clinical outcomes or joint biomarker
levels. We also found a signicant correlation between Helix II
and hsCRP (r=0.63; p<0.0001) and orosomucoid (r=0.33; p=0.03).
None of the other joint biomarkers correlated with inammatory biomarkers or with outcomes for knee OA at baseline.

Correlation between changes in COMP or PIIANP levels and

changes in clinical outcomes, systemic inflammation and
metabolic status
Variation in COMP concentration was signicantly correlated
with changes in pain (VAS) (r=0.05; p=0.03) and WOMAC stiffness score (r=0.33; p=0.04). Change in COMP concentration
was also correlated with change in BMI (r=0.48; p=0.001), insulin level (r=0.36; p=0.02) and HOMA-IR score (r=0.31; p=0.05)
(table 5). However, the relationship between changes in COMP
levels and changes in insulin levels or HOMA-IR score was not

Table 3 Serum levels of adipokines and inflammatory biomarkers at

baseline and 6 months
Leptin, ng/ml
Adiponectin, g/ml
IL-6, pg/ml
hsCRP, mg/dl
Orosomucoid (g/l)
Fibrinogen (g/l)

Baseline

6 Months

p Value

63.224.4
7.94.6
5.02.5
1.10.8
1.00.2
4.10.8

3316.7
9.97.7
3.72.0
0.60.5
0.80.2
3.90.9

<0.0001
0.03
<0.0001
<0.0001
0.0001
0.04

Values are the mean SD.

hsCRP, high-sensitivity C reactive protein; IL-6, interleukin 6.

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Extended report
Table 4

Serum levels of joint biomarkers at baseline and 6 months after bariatric surgery
Baseline

PIIANP, ng/ml
Helix-II, ng/ml
COMP, UI/l
HA, ng/ml

6 Months

MeanSD

MedianIQR

MeanSD

MedianIQR

p Value

443.6257.5
5.94.6
10.53.5
31.326.8

377.4220.2
3.95.0
10.44.9
20.438.0

586.4239.4
6.36.5
6.72.2
36.234.0

538.4242.6
3.85.5
6.12.9
27.735.3

0.002
0.98
<0.001
0.41

Values are mean SD or median IQR.

COMP, cartilage oligomeric matrix protein; HA, hyaluronan; Helix-II, type II collagen helical peptide; PIIANP, N-terminal propeptide of
type IIA collagen.

Figure 1 Serum levels of N-terminal propeptide of type IIA collagen

(PIIANP), type II collagen helical peptide (Helix-II), cartilage-oligomeric
matrix protein (COMP) and hyaluronan (HA) in obese patients with
knee osteoarthritis (OA) before (M0) and 6 months after (M6) bariatric
surgery. Boxes represent the interquartile range, lines inside boxes
represent the median, and lines outside boxes indicate 95% CI.
independent of changes in BMI because BMI was the only signicant regressor found on multivariate regression analysis (=0.42,
p=0.04). Finally, change in the PIIANP level was not correlated
with changes in clinical outcomes or biological marker levels.

DISCUSSION
Our study shows that a surgically induced mean weight loss of
20% in patients with severe obesity and knee OA can improve
pain and function, decrease levels of metabolic parameters and
low-grade inammation, and result in a change in cartilage turnover as assessed by systemic biochemical markers.
Behavioural and pharmacological treatments of obesity usually result in short-term weight loss of approximately 510%
body weight.33 According to a recent meta-analysis, the pooled
effect sizes for improvement in pain and physical disability in
patients with knee OA who lost an average of 6.1 kg were 0.2
(95% CI 0 to 0.39) and 0.23 (95% CI 0.04 to 0.42), respectively.
Weight loss alone of <5% seems ineffective or poorly effective in alleviating OA knee pain in obese patients.34 Trials that
have assessed the efcacy of surgically induced massive weight
loss on knee OA symptoms are scarce and have not specically
included patients with well-dened radiographic evidence of
knee OA, as in our study.35 36 Hooper et al, using a single-arm
open study design, found that obese patients with knee OA
who lost 29% of body weight between 6 and 12 months after
bariatric surgery showed improved WOMAC pain, function
and stiffness scores, by 51%, 74% and 64%, respectively.36 In
142

our study, a 20% weight loss over 6 months decreased scores

for pain by 50%, as assessed by a VAS or the WOMAC subscore and for function by 57%. The reductions in WOMAC
pain, stiffness and function were signicantly correlated among
themselves and the WOMAC function correlated best with the
patient global assessment of the severity of knee OA (data not
shown). Although these data should be cautiously compared,
they suggest that the greater the weight loss, the greater the
benet for pain and function.
Obesity is now recognised as a low-grade inammatory disease. Elevated inammatory protein levels in obese individuals suggest that inammation may have a determinant role in
connecting obesity to metabolic, hepatic and cardiovascular
diseases.10 11 Whether this systemic inammatory state has a
role in the genesis of OA in obese patients is a subject of growing interest.37 Among a myriad of inammatory mediators, IL-6
has been shown to be secreted substantially by adipose tissue
and its level correlates with metabolic complications in some
studies.10 Interestingly, here we found a signicant correlation at
baseline between circulating levels of IL-6 and WOMAC function score. We also observed that the level of IL-6, which mainly
originates from adipose tissue in obese patients but which is
also produced by infrapatellar fat pad within the joint,38 was
correlated with Helix-II, a biomarker of cartilage turnover. By
contrast, no other inammatory protein or adipokine level or
BMI were correlated with clinical outcomes before surgery. Our
ndings extend the results of recent work showing a signicant
association of IL-6 circulating levels and the prevalence and incidence of knee OA.39
As expected, bariatric surgery resulted in a signicant increase
in the serum level of adiponectin and a signicant decrease in
that of leptin, IL-6, hsCRP, orosomucoid and brinogen.27 40
However, none of the changes in these inammatory biomarkers was correlated with changes in clinical outcomes, which
suggests that the decrease in low-grade inammation has no
role or is of little importance in clinical improvement related to
weight loss.
Because the morphology of our patients precluded carrying
out repeated MRI or standard x-ray examinations for structural
evaluation, we used biochemical markers of joints as surrogate
markers to assess cartilage turnover.41 Massive weight loss
resulted in a signicant increase in the level of PIIANP (+32%),
a marker of type II collagen synthesis, and a decrease in that of
COMP (36%), a marker of cartilage degradation, according to
the BIPED classication.30 These results are the rst to suggest
a benet of weight loss on both cartilage anabolism and catabolism. Of note, one recent study also found a positive correlation
between moderate weight loss and changes in COMP levels.24
The mechanism by which weight loss decreases COMP levels is
unknown. A decrease in knee joint load with weight loss42 may
modulate the release of COMP, because this protein has been
shown to be mechanosensitive.43 44
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Extended report
Table 5 Correlation between change in biochemical parameters and
change in COMP and PIIANP levels
Change in

BMI, kg/m2
Total cholesterol (mmol/l)
Triglycerides (mmol/l)
Glucose (mmol/l)
Insulin (IU/l)
HOMA-IR
Leptin, ng/ml
Adiponectin, g/ml
IL-6, pg/ml
hsCRP, mg/dl
Orosomucoid (g/l)
Fibrinogen (g/l)

R
0.48
0.14
0.09
0.2
0.36
0.31
0.17
0.04
0.19
0.09
0.24
0.006

Ethics approval The ethics committee of the Htel-Dieu Hospital approved the
clinical investigations.
Provenance and peer review Not commissioned; externally peer reviewed.

COMP
Change in

Patient consent Obtained.

PIIANP
p Value
0.001
0.35
0.58
0.20
0.02
0.05
0.27
0.79
0.22
0.54
0.16
0.97

r
0.13
0.12
0.10
0.03
0.04
0.01
0.10
0.17
0.21
0.14
0.20
0.04

p Value
0.390
0.44
0.53
0.81
0.79
0.90
0.53
0.29
0.20
0.36
0.25
0.81

BMI, body mass index; COMP, cartilage oligomeric matrix protein; HOMA-IR,
homoeostasis model assessment estimate of insulin resistance; hsCRP, high-sensitivity
C reactive protein; IL-6, interleukin 6; PIIANP, N-terminal propeptide of type IIA collagen;
r, Spearman rank correlation coefficient.

Changes in adipokine levels were not correlated with

changes in joint biomarkers, suggesting that variation in leptin
or adiponectin concentrations had little or no effect on cartilage homoeostasis in our patients. Bariatric surgery resulted
in a sharp decrease in levels of cholesterol and triglycerides
and insulin resistance. Interestingly, change in COMP level
was correlated with changes in insulin resistance, but this
correlation was not independent of change in BMI, probably
because insulin resistance and BMI are closely related biologically. Although there is no formal clinical evidence for a
link between diabetes mellitus and OA, several experimental data suggest a detrimental effect of insulin resistance on
cartilage.4548
Our study has some limitations that deserve attention. Our
trial was conducted as an open exploratory study, and bias in
evaluation of clinical outcomes may have occurred. Thus, our
ndings need to be replicated in conrmatory studies. The relatively small sample size may have missed some weak associations. Moreover, our ndings on correlations do not imply
causality between assessed variables, and thus should be carefully interpreted. The strengths of this study include the assessment of severely obese patients recruited from a centre of
reference for medical and surgical care of obesity, which allows
for a well-standardised biological and clinical evaluation of such
patients before and after bariatric surgery.
In conclusion, our data show that massive weight loss (20%)
in patients with symptomatic knee OA improves pain and
function, decreases the low-grade inammatory state and may
modied cartilage turnover, which suggests a structural effect
of substantial weight loss. The effect of changes in insulin resistance related to weight loss on cartilage homoeostasis needs further investigation.
Acknowledgements The authors thank all the patients for their participation in this
study. The authors also thank Mme Christine Baudouin, Dr Florence Marchelli and
Mme Patricia Ancel involved in patients recruitment, data collection and sampling at
the Center of Research on Human Nutrition, Paris Piti-Salptrire Hospital.
Funding Assistance Publique-Hpitaux de Paris (APHP) and Direction of Clinical
Research (PHRC N0702 and CRC N P050318), which promoted and supported the
clinical investigation, and a grant from the European community (Collaborative Project
ADAPT, contract number HEALTH-F262008-201100). This work was also supported by
the Association Rhumatisme et Travail (Hpital Lariboisire, Paris, France).
Competing interests None.
Ann Rheum Dis 2011;70:139144. doi:10.1136/ard.2010.134015

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Ann Rheum Dis 2011;70:139144. doi:10.1136/ard.2010.134015