Table 3 The characteristics of the included studies

Vishal 2011 [33]

1. Participants must understand risks and benefits of the protocol and able to give informed consent

2. Male and female subjects of 40–80 years of age

3. Females of child bearing potential must agree to use an approved form of birth control and have a negative pregnancy test result

4. Unilateral or bilateral OA of the knee for more than 3 months

5. Visual Analogue Scale (VAS) score during the most painful knee movement between 40 and 70 mm after 7 day withdrawal of usual medication

6. Lequesne’s Functional Index (LFI) score greater than 7 points after 7 days of withdrawal of usual medication

7. Ability to walk

8. Availability for the duration of the entire study period

1. History of underlying inflammatory arthropathy or severe rheumatoid arthritis (RA)

2. Hyperuricemia (greater than 440 umol/L) and/or past history of gout

3. Recent injury in the area affected by OA of the knee (past 4 months) and expectation of surgery in the next 4 months

4. Intra-articular corticosteroid injections within the last 3 months

5. Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), abnormal liver or kidney function tests, history of peptic ulceration and upper gastrointestinal (GI) haemorrhage, congestive heart failure, hypertension, hyperkalemia

6. Major abnormal findings on complete blood count, history of coagulopathies, haematological or neurological disorders

7. High alcohol intake (greater than 2 standard drinks per day)

8. Pregnant, breastfeeding or planning to become pregnant during the study

9. Use of concomitant prohibited medication other than ibuprofen

10. Obesity: body mass index (BMI) more than 30 kg/m^2

VAS, WOMAC pain subscale, WOMAC stiffness subscale, WOMAC function subscale, Lequesne Index, adverse events

4 weeks

Sengupta 2008 [26]

VAS, WOMAC pain subscale, WOMAC stiffness subscale, WOMAC function subscale, Lequesne Index, MMP-3, adverse events

12 weeks

Sengupta 2010 [24]

VAS, WOMAC pain subscale, WOMAC stiffness subscale, WOMAC function subscale, Lequesne Index, adverse events

12 weeks

Haroyan 2018 [34]

Patients with a diagnosis of degenerative hypertrophic osteoarthritis of the knee (M17, according to International Classification of Diseases (ICD-10) of bone joints, verified by radiography (Grade 1–3 by Kellgren-Lawrence radiographic grades).

1. subjects with inflammatory and any secondary arthritis

2. moderate and severe synovitis (grades 2 and 3) tear of meniscus

3. chronic diseases of the kidneys, liver, gastrointestinal, cardiovascular, endocrine and nervous systems

4. allergic anamnesis and drug intolerance

5. pregnant or nursing

6. history of substance abuse

7. subjects taking non-steroidal anti-inflammatory drugs and analgesics within 2 weeks prior to the study

8. subjects taking glucosamine sulfate, chondroitin sulfate, intra-articular hyaluronate, systemic or intra-articular glucocorticoids within 3 months prior to the study

WOMAC pain subscale, WOMAC stiffness subscale, WOMAC function subscale, adverse events

12 weeks

Karimifar 2017 [35]

1. age of 40 to 80 years

2. knee osteoarthritis in at least one knee for at least 6 months based on ACR (American College of Rheumatology) diagnostic criteria

3. pain score > 4 based on VAS (visual analog scale)

4. LPFI (Lequesne Pain and Function Index) > 7

5. serum CRP (C-reactive protein) < 10 mg/dl and ESR (erythrocyte sedimentation rate) < 20 mg/dL, (6) grade 2 or 3 of KellgrenLawrence scale in knee radiography obtained within the last 6 months

7. free of liver, renal, or cardiac dysfunction

8. no use of intra-articular glucocorticoids or hyaluronic acid preparations within the last 3 months

9. no use of systemic glucocorticoids within the last 3 months

10. free of all other bone and joint disorders including rheumatoid arthritis and gout

11. free of peptic ulcer disease

12. no knee arthroscopic procedure within the last 3 months

13. not being pregnant or lactating (for women).

1. irregular use of capsules (less than 80% of total capsules)

2. no use of capsules for at least 3 days

VAS, Lequesne Index, adverse events

4 weeks

Notarnicola 2016 [36]

1. a diagnosis of OA of the knee according to the criteria of the American College of Rheumatology

2. grade 3 Kellgren and Lawrence radiographic staging,16 in which the severity of the arthritis is assessed on a scale in the range of 0–4, hypothesizing a sequential evolution from the manifestation of osteophytes through a reduction in the width of the joint space, to subchondral sclerosis and finally the formation of cysts

3. frequent joint pain (several days a week) for at least 6 months before recruitment

4. pain in the knee, scored at least 4 cm on a 10 centimetric visual analogic scale (VAS) (from moderate to severe pain), where 0 means no pain and 10 is the worst pain possible

5. a score of > 2 on the Lequesne pain-function index (LI).18 The LI is an OA-specific validated questionnaire that poses a series of questions about pain in the knee (five questions on a scale from 0 to 2, where 0 indicates no pain and 2 intense pain), functional limitation (four questions, using the same scale), and maximum walking distance (one question, with a score from 0 to 6, where 0 indicates the ability to walk for an unlimited distance and 6, the inability to cover 100 m). The maximum worst final score is 24

1. previous surgery of the affected knee

2. disease processes such as rheumatoid arthritis, autoimmune diseases, systemic diseases, and tumors

3. severe obesity (BMI > 40 kg/m2)

4. meniscal or ligament injuries

5. allergy to shellfish

6. altered blood chemistry and kidney, liver, and metabolic (diabetes mellitus) function

7. intra-articular hyaluronic acid/cortisone infiltrations to the affected knee within 3 months before the start of the study

8. systemic cortisone treatment taken within 3 months before the start of the study;

9.supplements (glucosamine, chondroitin sulfate, bromeline, etc.) taken within 3 months before the start of the study (patients were also informed that they were not to be taken for the following 6 months)

VAS, Lequesne Index

24 weeks

Notarnicola 2011 [37]

1. men and women > 45 and < 85 years of age;

2. a diagnosis of OA of the knee according to the criteria of the American College of Rheumatology

3. grade 3 Kellgren and Lawrence radiographic staging,13 in which the severity of the arthritis is assessed on a scale from 0 to 4, hypothesizing a sequential evolution from the manifestation of osteophytes through a reduction in the width of the joint space, to subchondral sclerosis and fnally the formation of cysts;

4. frequent joint pain (several days a week) for at least 6 months before recruitment;

5. pain in the knee, scored at least 2 cm on a 10 centimetric visual analogic scale (VAS), where 0 means no pain and 10 is the worst pain possible;

6. a score of > 2 on the Lequesne pain-function index (LI).14 The LI is a disease-specific validated questionnaire that poses a series of questions about pain in the knee (five questions on a scale from 0 to 2, where 0 indicates no pain and 2 intense pain), functional limitation (four questions, using the same scale) and maximum walking distance (one question, with a score from 0 to 6, where 0 indicates the ability to walk for an unlimited distance and 6, the inability to cover 100 m). The maximim worst fnal score was 24.

1. previous surgery of the affected knee;

2. disease processes such as rheumatoid arthritis, autoimmune diseases, systemic diseases, and tumors;

3. obesity (BMI > 30 kg/m2);

4. altered blood chemistry and kidney, liver, and metabolic (diabetes mellitus) function;

5. intra-articular hyaluronic acid/cortisone infiltrations to the affected knee within 3 months before the start of the study;

6. systemic cortisone treatment taken within 3 months before the start of the study;

7. supplements (glucosamine, chondroitin sulfate, bromeline, etc) taken within 3 months before the start of the study (patients were also informed that they were not to be taken for the following 6 months).

VAS, Lequesne Index, adverse events

24 weeks