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. 2020 Dec 1;10:20892. doi: 10.1038/s41598-020-78075-x

Table 2.

Summary table of included studies evaluating the effect of nutraceutical supplements in osteoarthritis.

Author (year) Location Inclusion criteria Sample size and treatment (dosage) Sample size at the end of treatment Concomitant treatment Design and study duration Main outcomes
Reginster 200117 Belgium

Knee OA(mild to moderate severity according to KLS)

Age ≥ 50 years

1. GS (n = 106) (1500 mg/day)

2. Placebo (n = 106)

1. GS (n = 68) (1500 mg/day)

2. Placebo (n = 71)

Symptomatic

treatments [Paracetamol 500 mg OR one

NSAIDs

(diclofenac 50 mg OR piroxicam 20 mg OR proglumetacin 150 mg)]

RCT

3 years

JSW, WOMAC index (total, pain, stiffness and physical function)
Appelboom 200118 Belgium

Knee OA (unknown severity)

Age: 45–80 years

VAS ≥ 30 mm

Lequesne index : 4–12

1. ASU (300 mg × 1/day) (n = 86)

2. ASU (600 mg × 1/day) (n = 86)

3.Placebo (n = 88)

1. ASU (300 mg × 1/day) (n = 74)

2. ASU (600 mg × 1/day) (n = 75)

3.Placebo (n = 76)

Symptomatic

treatments (NSAIDs and analgesics)

RCT

3 months

Pain (VAS), LI
Jung 200119 Korea

Knee OA (unknown severity)

Age: 35–75 years

VAS ≥ 35 mm

1. SKI 306X (mixture of Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris) (200 mg × 3/day) (n = 24)

2. SKI 306X (400 mg × 3/day) (n = 24)

3. SKI 306X (600 mg × 3/day) (n = 24)

4. Placebo(n = 24)

1. SKI 306X (200 mg × 3/day) (n = 24)

2. SKI 306X (400 mg × 3/day) (n = 23)

3/ SKI 306X (600 mg × 3/day) (n = 23)

4. Placebo(n = 23)

RCT

4 weeks

Pain (VAS), LI
Schmid 200120 Germany

Hip or knee OA (unknown severity)

Age > 18 years (men) or > 50 years (women)

1. Willow bark extract (240 mg × 1/day) (n = 39)

2. Placebo (n = 39)

1. Willow bark extract (240 mg × 1/day) (n = 39)

2. Placebo (n = 39)

RCT

2 weeks

WOMAC (pain, stiffness

and physical function), Pain (VAS)

Colker 200221 USA

Knee OA (unknown severity)

Age ≥ 35 years

1. Micronutrient-containing beverage (12 oz/day) (n = 20)

2. Placebo (n = 20)

1. Micronutrient-containing beverage (12 oz/day) (n = 16)

2. Placebo (n = 15)

RCT

6 wk

Modified KOOS, WOMAC, Pain (VAS)
Zenk 200222 USA

OA (unknown severity)

Age > 19 years

1. MPC (2000 mg × 2/day)

2. GS (500 mg × 3/day)

3. Placebo

(n = 42)

1. MPC (2000 mg × 2/day) (n = 12)

2. GS (500 mg × 3/day) (n = 13)

3. Placebo (n = 10)

Symptomatic

treatments (Naproxen 220 mg, ibuprofen 200 mg,

acetaminophen 325 mg, and acetylsalicylic acid 325 mg)

RCT

6 weeks

WOMAC (total, pain, stiffness

and physical function)

Lequense 200223 France

Hip OA (mild to moderate severity according to KLS)

Age: 50–80 years

1. ASU (300 mg × 1/day) (n = 85)

2. Placebo (n = 78)

1. ASU (300 mg × 1/day) (n = 45)

2. Placebo (n = 51)

Symptomatic

treatments [NSAIDs

(diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, paroxen, piroxicam, tenoxicam)] AND/OR analgesics

RCT

2 years

JSW, LI, Pain (VAS)
McAlindon 200424 England

Knee OA (mild to severe severity according to KLS)

Age ≥ 45 years

1. GS (1.5 g/d) (n = 101)

2. Placebo (n = 104)

1. GS (1.5 g/d) (n = 93)

2. Placebo (n = 93)

Symptomatic

treatments (Acetaminophen)

RCT

12-week,

WOMAC (total, pain, stiffness

and physical function)

Miller 200525 India

Knee OA(mild to moderate severity according to KLS)

Age ≥ 20

years

VAS ≥ 50 mm

1. Sierrasil (containing silicate minerals of calcium, magnesium, potassium, sodium and aluminum, among others) (n = 25) (3 g/day)

2. Sierrasil (n = 24) (2 g/day)

3. sierrasil (2 g/day) + cat's claw extract (100 mg/

day) (n = 29)

4. Placebo (n = 29)

1. Sierrasil (n = 20) (3 g/day)

2. Sierrasil (n = 22) (2 g/day)

3. sierrasil (2 g/day) + cat's claw extract (100 mg/

day) (n = 26)

4. Placebo (n = 23)

Symptomatic

treatments (Acetaminophen up to 2 g/day)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function)

Kim 200626 USA

Knee OA (mild to moderate severity according to KLS)

Age > 40 years

VAS > 40 mm

global assessment (GA) > 2

1. MSM

(1 g × 2/day for 3 days, 2 g × 2/day for 4 days, then 3 × 2 g/day) (n = 25)

2. Placebo (n = 25)

1. MSM

(1 g × 2/day for 3 days, 2 g × 2/day for 4 days, then 3 × 2 g/day) (n = 21)

2. Placebo (n = 19)

Symptomatic

treatments (Acetaminophen up to 2.6 g/day)

RCT

12-week

Pain (VAS), WOMAC (total, pain, stiffness

and physical function)

Pavelka 200727 Czech Republic and Slovak Republic

Knee OA (mild to moderate severity according to KLS)

Age: 40–75 years

VAS ≥ 40 mm WOMAC pain ≥ 2

1.Diacerein (50 mg × 1/day) (n = 84)

2. Placebo (n = 84)

1.Diacerein (50 mg × 1/day) (n = 76)

2. Placebo (n = 76)

Symptomatic

treatments (Acetaminophen up to 1500 mg/day)

RCT

3 months

WOMAC (total, pain, stiffness

and physical function)

Farid 200728 Iran

Knee OA (mild severity according to ACR)

Age: 25- 65 years

WOMAC ≥ 40

Pain ≥ 50% of the time in last 3 months

1. Pycnogenol (n = 19) (150 mg × 1/day)

2. Placebo (n = 18)

1. Pycnogenol (n = 18) (150 mg × 1/day)

2. Placebo (n = 17)

Symptomatic

treatments (NSAIDs and COX-2

inhibitors)

RCT

90 days

WOMAC (total, pain, stiffness

and physical function)

Mehta 200729 India

Knee OA (mild to moderate severity according to KLS)

VAS: ≥ 40 mm and ≤ 80 mm

Age ≥ 20 years

1. GS (750 mg × 2/day) (n = 47)

2.Reparagen (blend of vincaria: an extract of Uncaria guianensis (300 mg) and RNI 249: an extract of Lepidium meyenii (1500 mg)) (900 mg × 2/day) (n = 48)

1. GS (750 mg × 2/day) (n = 41)

2.Reparagen (900 mg × 2/day) (n = 38)

Symptomatic

treatments (Acetaminophen up to 1500 mg/day for the first 4 weeks and 1000 mg/day

for the last 4 weeks)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function), Pain (VAS)

Alishiri GH.H.200730 Iran

Knee OA (mild severity according to KLS)

Age: 50–80 years

VAS: ≥ 40 mm

1. Elaeagnus Angustifolia extract (100 mg × 2/day) (n = 40)

2.Acetaminophen (500 mg × 2/day) (n = 40)

3. Placebo(n = 40)

1. Elaeagnus Angustifolia extract (100 mg × 2/day) (n = 38)

2.Acetaminophen (500 mg × 2/day) (n = 37)

3. Placebo(n = 40)

RCT

7 weeks

Pain (VAS), LI
Sengupta 20088 India

Knee OA (mild to moderate symptoms)

Age: 40–80 years

VAS: 40–70 mm

LF Index score > 7

Ability to walk

1.5-Loxin (Boswellia serrata extract contain at least 30 percent 3-O-Acetyl-11-keto-β-boswellic acid) (250 mg × 1/day) (n = 25)

2. 5-Loxin (100 mg × 1/day) (n = 25)

3.Placebo (n = 25)

1.5-Loxin (250 mg × 1/day) (n = 23)

2.5- Loxin (100 mg × 1/day) (n = 24)

3.Placebo (n = 23)

Symptomatic

treatments (ibuprophen up to 1,200 mg/day)

RCT

90-day

Pain (VAS), LI, WOMAC (pain, stiffness and physical function)
Kalman 200831

United

States

Knee OA (mild to severe severity according to KLS)

Age ≥ 40 years

1. Chicken comb extract (80 mg × 1/day) (n = 11)

2. Placebo (n = 9)

1. Chicken comb extract (80 mg × 1/day) (n = 8)

2. Placebo (n = 8)

Symptomatic

treatments (paracetamol up to 2000 mg/daY)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function), QOL (SF-36)

Frestedt 2008 32 USA

Knee OA (moderate to severe severity according to ACR)

Age: 25–75 years

WOMAC total ≤ 75

1. Aquamin

(2400 mg × 1/day) (n = 20)

2.Glucosamine sulfate (1500 mg × 1/d) (n = 19)

3. Glucosamine sulfate (1500 mg × 1/day) + Aquamin

(2400 mg × 1/day) (n = 15)

4.Placebo (n = 16)

1. Aquamin

(2400 mg × 1/day) (n = 15)

2.Glucosamine sulfate (1500 mg × 1/d) (n = 14)

3. Glucosamine sulfate (1500 mg × 1/day) + Aquamin

(2400 mg × 1/day) (n = 12)

4.Placebo (n = 9)

Symptomatic

treatments (Acetaminophen, 325 mg, 1–2 tablets every 4–6 h)

RCT

12 weeks

WOMAC (total, pain, stiffness

and physical function), 6 MWD

Jacquet 200933 France

Knee or hip (unknown severity)

Age: 40–80 years

1. Phytalgic (fish-oil, vitamin E, Urtica dioica) (n = 41)

2. Placebo (n = 40)

1. Phytalgic (fish-oil, vitamin E, Urtica dioica) (n = 40)

2. Placebo (n = 36)

Symptomatic

treatments (analgesics and/or NSAIDs)

RCT

3 months

WOMAC (total, pain, stiffness

and physical function)

Frestedt 200934 USA

Knee OA (moderate to severe severity according to ACR)

Age: 35–75 years

WOMAC total ≤ 75

1.Aquamin (A calcium and magnesium-rich seaweed-derived multi-mineral supplement)

(801 mg × 3/day) (n = 8)

2.Placebo (n = 14)

1 .Aquamin

(801 mg × 3/day) (n = 5)

2.Placebo (n = 9)

Symptomatic

treatments (NSAIDs)

Pilot RCT

12 weeks

6 MWD, ROM

WOMAC (total, pain, stiffness

and physical function)

Ruff 200935 USA

Knee OA (mild to severe severity according to ACR)

Age ≥ 18 years

VAS ≥ 30 mm

1. NEM (500 mg × 1/d) (n = 29)

2. Placebo (n = 31)

1. NEM (500 mg × 1/d) (n = 20)

2. Placebo (n = 18)

Symptomatic

treatments (Acetaminophen)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function)

Pain (VAS)

Farid 201036 Iran

Knee OA (mild to severe severity according to ACR)

Age: 25–65 years

WOMAC pain subscale index ≥ 40

1. PFP (150 mg × 1/d) (n = 20)

2. Placebo (n = 20)

1. PFP (150 mg × 1/d) (n = 17)

2. Placebo (n = 16)

Symptomatic

treatments (NSAIDs and COX-2 inhibitor)

RCT

2 months

WOMAC (total, pain, stiffness

and physical function)

Sengupta 201037 India

Knee OA(unknown severity)

Age: 40–80 years

VAS: 40–70 mm LF Index > 7 Ability to walk

1. 5-Loxin (100 mg × 1/day) (n = 20)

2. 100 mg of Aflapin (Boswellia serrata extract) (100 mg × 1/day) (n = 20)

3. Placebo (n = 20)

1. 5 -Loxin (100 mg × 1/day) (n = 19)

2. 100 mg of Aflapin (100 mg × 1/day) (n = 19)

3. Placebo (n = 19)

Symptomatic

treatments (ibuprofen up to 1200 mg/day)

RCT

90-day

Pain (VAS), LI, WOMAC (pain, stiffness

and physical function)

Debbi 201138 Israel

Knee OA (unknown severity)

Age: 45–90 years

1. MSM (1.125 g × 3/day) (n = 25)

2. Placebo (n = 25)

1. MSM (1.125 g × 3/day) (n = 25)

2. Placebo (n = 25)

Unknown

RCT

12 weeks

WOMAC (total, pain, stiffness, physical function), Pain (VAS), QOL (SF-36), KSKS, KSFS
Notarnicola 201139 Italy

Knee OA (moderate severity according to KLS)

Age: > 45 and < 85 years

VAS ≥ 2 cm on a

10 cm

LI > 2

1. MSM 5 gr and 7.2 mg of titred Boswellic Acids (n = 30)

2. Placebo (n = 30)

1. MSM 5 gr and 7.2 mg of titred Boswellic Acids (n = 30)

2. Placebo (n = 30)

Symptomatic

treatments (paracetamol 500 mg) OR

NSAIDs (pyroxicam 20 mg, diclofenac 50 mg)/day

RCT

60 days

Pain (VAS), LI
Schauss 201240 United States

Knee and/or hip OA (unknown severity)

Age: 40–70 years

VAS ≥ 4

1. BioCell Collagen (500 mg × 4/day) (n = 40)

2. Placebo (n = 40)

1. BioCell Collagen (500 mg × 4/day) (n = 35)

2. Placebo (n = 33)

Symptomatic

treatments (

Paracetamol up to 4 gr/day)

RCT

70 days

Pain (VAS), WOMAC (total, pain, stiffness

and physical function)

McAlindon 201341 United States

Age ≥ 45 years (mild to severe severity according to KLS)

Knee OA

1.Cholecalciferol (initial dose 2000 IU/day)(n = 73)

2. Placebo (n = 73)

1.Cholecalciferol (initial dose 2000 IU/day)(n = 64)

2.Placebo (n = 60)

Conventional treatments ( Acetaminophen &

NSAIDs

RCT

2 years

WOMAC (pain and function )
Ebrahimi 201442 Iran

Knee OA (mild to moderate severity according to KLS)

Sex: female

Age: 40–70 years

BMI: 25–34.9 kg/m2

1. Whole fruit powder of Elaeagnus angustifolia L. (n = 30) (15 g × 1/day)

2. Medulla powder of Elaeagnus angustifolia L. (n = 30) (15 g × 1/day)

3. Placebo (n = 30)

1. Whole fruit powder of Elaeagnus angustifolia L. (n = 26) (15 g × 1/day)

2. Medulla powder of Elaeagnus angustifolia L. (n = 27) (15 g × 1/day)

3. Placebo (n = 25)

Conventional treatments ( Acetaminophen &

NSAIDs (Celecoxib, Ibuprofen,

Naproxen)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function)

Kolahi 201543 Iran

Knee OA (mild to moderate severity according to KLS)

Age: 40 to 60 years

Sex: female

BMI: 25–34.9 kg/m2

1. L-carnitine ( 250 mg × 3/day) (n = 36)

2. Placebo (n = 36)

1. L-carnitine (250 mg × 3/day) (n = 33)

2. Placebo (n = 36)

Symptomatic

treatments (Acetaminophen)

RCT

8 weeks

WOMAC (total, pain, stiffness

and physical function)

Kumar 201544 India

Knee OA (mild to severe severity according to KLS)

Age: 30–65 years

1. PCP daily twice (5 g dissolved in 250 mL of milk or water) (n = 20)

2. Placebo (n = 10)

1. PCP daily twice (5 g dissolved in 250 mL of milk or water) (n = 19)

2. Placebo (n = 11)

Symptomatic

treatments (Aceclofenac

sodium 100 mg/day)

RCT

13 weeks

WOMAC, Pain (VAS), QOL
Dehghan 201545 Iran

Knee OA (mild to moderate severity according to the Ahlback classification)

VAS ≥ 4 cm

Age: 30–60 years

1. Vitamin B Complex (× 2/day) (n = 40)

2. Placebo (n = 40)

1. Vitamin B Complex (× 2/day) (n = 38)

2. Placebo (n = 35)

Symptomatic

treatments (Diclofenac 100 mg /day)

RCT

21 days

Pain (VAS), WOMAC (pain, stiffness

and physical function)

Jin 201646 Australia

Knee OA (mild to moderate severity according to the Altman and Gold atlas)

Age: 50–79 years old

VAS ≥ 20 mm

Serum vitamin D level: > 12.5 and < 60 nmol/L

1. Vitamin D3

(50,000 IU × 1/month)(n = 209)

2. Placebo (n = 204)

1. Vitamin D3

(50,000 IU × 1/month)(n = 209)

2. Placebo (n = 204)

Unknown

RCT

24 months

WOMAC (total, pain, stiffness

and physical function), Pain (VAS)

Stebbings 201647 New Zealand

Knee or hip OA (unknown severity)

Age: 35–75 years

BMI < 40 kg/m2

VAS ≥ 30 mm on a 100-mm

1. ART (150 mg × 1/day) (n = 14)

2

ART high dose (300 mg × 1/day) (n = 14)

3. Placebo (n = 14)

1. ART (150 mg × 1/day) (n = 12)

2

ART high dose (300 mg × 1/day) (n = 9)

3. Placebo (n = 13)

Symptomatic

treatments (NSAIDs and analgesics)

RCT

12 weeks

WOMAC (total, pain, stiffness

and physical function), Pain (VAS)

Lugo 201648 India

Knee OA (mild severity according to KLS)

Age: 40–75 years

BMI: 18–30 kg/m2

LI score: 6–10 VAS score: 40–70 mm

1. UC- II (40 mg × 1/day) (n = 63)

2. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) (n = 65)

3. Placebo(n = 58)

1. UC- II (40 mg × 1/day) (n = 54)

2. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) (n = 57)

3. Placebo(n = 53)

Symptomatic

treatments (Acetaminophen 1000 mg

daily)

RCT

180-day

WOMAC (total, pain, stiffness

and physical function), LI, Pain (VAS), ROM

Lubis 201749 Indonesia Knee OA (mild severity according to KLS)

1. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) + saccharumlactis (500 mg × 1/day) (n = 49)

2. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) + MSM (500 mg × 1/day) (n = 50)

3. Placebo (n = 48)

1. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) + saccharumlactis (500 mg × 1/day) (n = 49)

2. GS (1500 mg × 1/day) + CS (1200 mg × 1/day) + MSM (500 mg × 1/day) (n = 50)

3. Placebo (n = 48)

Unknown

RCT

3 months

WOMAC, Pain (VAS)
Rafarf 201750 Iran

Knee OA (mild severity according to KLS)

Age: 38–60 years old

Sex: female

BMI: between 30–35 kg/m2

1. Pomegranate peel extract (PPE) (1000 mg/day) (n = 33)

2. Placebo (n = 33)

1. Pomegranate peel extract (PPE) (1000 mg/day) (n = 30)

2. Placebo (n = 30)

Symptomatic

treatments (Acetaminophen 1000 mg + Glucosamine 500 mg per day)

RCT

8 weeks

KOOS

(Total and subscales), Pain (VAS)

Lei 201751 China

Knee OA (mild severity according to KLS)

Age < 80 years

1. Skimmed milk containing probiotic LcS (n = 230)

2. Placebo (plain skimmed milk) (n = 231)

1. Skimmed milk containing probiotic LcS (n = 215)

2. Placebo (plain skimmed milk) (n = 218)

Unknown

RCT

6 months

WOMAC (total, pain, stiffness

and physical function), Pain (VAS)

Shin 201852 New Zealand

Knee OA (moderate to severe severity according to KLS)

Age ≥ 50 years

WOMAC pain score ≥ 5.0

1. DBE (550 mg/day) (n = 30)

2. Placebo (n = 30)

1. DBE (550 mg/day) (n = 26)

2. Placebo (n = 24)

Symptomatic

treatments (Acetaminophen 2000 mg daily not

more than twice per week)

RCT

12 weeks

WOMAC (total, pain, stiffness

and physical function), Pain (VAS)

Dehghani 201853 Iran

Knee OA (mild severity according to KLS)

Age: 50–75 years

Sex: female

BMI: 25–40 kg/m2)

1. Garlic tablets (1000 mg × 1/day) (n = 40)

2. Placebo (n = 40)

1. Garlic tablets (1000 mg × 1/day) (n = 39)

2. Placebo (n = 37)

RCT

12-week

Pain (VAS)
Salimzadeh 201854 Iran

Knee OA (unknown severity)

Age: 50–75 years

Sex: female

BMI: 25–40 kg/m2)

1. Garlic tablet (1000 mg × 1/day) (n = 39)

2. Placebo (n = 37)

1. Garlic tablet (1000 mg × 1/day) (n = 38)

2. Placebo (n = 34)

RCT

12 weeks

WOMAC (total, pain, stiffness

and physical function), body composition (weight, WC, BMI, FFM, FM, VAT)

Hancke 201955 India

Knee OA(mild severity according to KLS)

Age: 40–70 BMI ≥ 25

and ≤ 29.9 kg/m2

WOMAC pain score: 10–16

1. ParActin (300 mg × 1/day) (n = 37)

2. ParActin (600 mg × 1/day) (n = 35)

3. Placebo (n = 36)

1. ParActin (300 mg × 1/day) (n = 35)

2. ParActin (600 mg × 1/day) (n = 33)

3. Placebo (n = 35)

RCT

12 week

WOMAC (total, pain, stiffness

and physical function), QOL (SF-36), FACIT score

Majeed 201956 India

Knee OA (mild to moderate severity according to KLS)

Age: 35–75 years

VAS score > 4 cm

1. Boswellin: (β‐boswellic acids 87.3 mg × 2/day) (n = 24)

2. Placebo (n = 24)

1. Boswellin: (β‐boswellic acids 87.3 mg × 2/day) (n = 22)

2. Placebo (n = 20)

RCT

120 days

WOMAC, 6 MW, Pain (VAS), QOL(European Quality of life‐5 Dimension, JSW
Rondanelli 201957 Italy

Knee OA (mild to moderate according to KLS)

Aged ≥ 55 years

BMI: 25–30 kg/m2

VAS: 40–70 mm

1. CS (600 × 1/mg) (n = 30)

2. Placebo (n = 30)

1. CS (600 × 1/mg) (n = 30)

2. Placebo (n = 30)

Pilot RCT

12 weeks

WOMAC, Pain (VAS), TLKS scale, QOL (SF-36), Body Composition (Weight, BMI, FFM, FM, VAT)

6 MW 6 min walking test, ACR American College of Rheumatology Classification Criteria for Knee Osteoarthritis, ART Artemisia annua extract, ASU Avocado soybean unsaponifiable, BMI body mass index, CS chondroitin sulfate, DBE Deer bone extract, FACIT Functional Assessment of Chronic Illness Therapy, FFM free fat mass, FM fat mass, GS Glucosamine sulphate, JSW joint space width, KLS Kellgren and Lawrence scoring system for classification of knee OA, KOOS Knee Injury and Osteoarthritis Outcome Score, KSFS Function Score, LcS Lactobacillus casei Shirota, KSKS, Knee Society Clinical Rating System for Knee Score, LI Lequesne's Index, MPC milk protein concentrate, MSM Methylsulfonylmethane, NEM natural egg membrane, NSAIDs Non-steroidal anti-inflammatory drugs, ParActin A. paniculata purified extract, PFP extract of the skin of the passion fruit, PCP Collagen peptides isolated from pork skin, QOL quality of life, ROM range of motion, TLKS Tegner Lysholm Knee Scoring, VAS Visual analogue scale, VAT visceral adipose tissue, WOMAC Western Ontario and McMaster Universities Arthritis.