Table 2 Summary table of included studies evaluating the effect of nutraceutical supplements in osteoarthritis.

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)