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. 2023 May 26;24(11):9340. doi: 10.3390/ijms24119340

Table 3.

Human studies and clinical trials of n-3 PUFAs in OA patients. Up arrows refer to increase and down arrows to decrease.

Molecule Tested Study Types Patient Data Treatments/
Follow-Up (F.up)		 Main Effects Ref.
FA intake Prospective study. N = 2092 participants
with radiographic knee OA.		 Followed at yearly intervals up to 48 months.
Questionnaire for food intake.		 Significant positive relationships between total fat and SFA with
joint space width loss were observed.
MUFA, PUFA and a higher ratio of PUFA to SFA were associated with a reduced joint space width loss.		 [182]
Fasting plasma phospholipid
n-6 (AA) and
n-3 PUFAs
(EPA
and DHA)
with synovitis		 Multicenter Osteoarthritis Study (MOST). N = 472 patients with knee OA (50% women).
Mean age = 60 year.
BMI = 30
(1° grade of Ob).		 n-3 PUFAs.
n-6 PUFAs.		 Multivariable logistic regression showed the following:
  • ▪

    Positive effects of plasma levels of n-3 PUFAs with patellofemoral cartilage;

  • ▪

    Negative effects of n-6 PUFAs in mediating synovitis.

 [165]
Fish oil (FO) (DHA + EPA) Randomized, double-blind clinical study. N = 152 older adults between
50 and 80 years.
BMI 25–40 kg/m2 		Group 1—FO 2000 mg/day DHA + 400 mg/day EPA).
Group 2—CUR
curcumin (160 mg/day).
Group 3—FO + CUR.
  • ▪

    FO reduced OA-specific pain and burden;

  • ▪

    FO improved microvascular functions;

  • ▪

    CUR alone and in combination with FO did not reduce pain measures.

 [164]
Cod liver oil
(EPA) 		A double-blind, placebo- RCT. N = 26;
Female, n = 21;
Age range = 52–85 years.		 Group 1—EPA oil (10 mL/d EPA) and ibuprofen (1200 mg/d).
Group 2—placebo (oil of undescribed content) and ibuprofen.
F.up = 6 months.
  • ▪

    No significant differences in pain and daily activities.

 [166]
Cod liver oil
(EPA + DHA)
+ NSAIDs 		A double-blind, placebo- RCT. N = 86;
female, n = 60;
Age range = 49–87 years.		 Group 1—cod liver oil (10 mL of oil containing 786 mg EPA) + NSAIDs.
Group 2—Placebo (10 mL olive oil) + NSAIDs.
F.up = 24 weeks.
  • ▪

    No significant benefit was observed for patients taking cod liver oil compared with the placebo group.

 [167]
GLM
(high proportion of EPA and DHA + low presence of several minor lipid components)		 A double-blind, placebo- RCT. N = 80;
Female, n = 44;
age = 66.4 ± 10 years.
Pain rated > 30 mm in the last week on 100 mm VAS.		 Group 1—GLM extract (600 mg/d).
Group 2—Placebo (600 mg/d corn oil).
F.-up = 0, 6, 12 and 15 wks.
  • ▪

    No pain improvement;

  • ▪

    Beneficial effects on stiffness;

  • ▪

    Reduction in acetaminophen treatment in the post-intervention period.

[168]
Lyprinol®
(a lipid extract of GLM rich in EPA and DHA)		 A double-blind, placebo- RCT. N = 80 patients with knee OA
female, n = 69
knee pain,
radiographic evidence of osteophytes.		 GLM group—four capsules of Lyprinol®/day.
Placebo group—olive oil in the same number of capsules.
F.up = 6 months.
Revision at week 0, 2, 4, 8, 12, 18 and 24.
  • ▪

    Safe and well tolerated;

  • ▪

    ↓ Knee pain in the GLM group;

  • ▪

    Improvement in the patient’s global assessment of arthritis.

 [169]
GLM extract Non-blinded randomized clinical trial. N = 38 patients with knee OA. Group 1—GLM extract (3000 mg/day).
Group 2—glucosamine (3000 mg/day).
Treatment for 12 weeks.
  • ▪

    ↓ Clostridium and Staphylococcus species in both groups;

  • ▪

    ↑ Lactobacillus, Streptococcus and Eubacterium species;

  • ▪

    Improvement in the GI tract;

  • ▪

    ↓ Joint pain.

 [172]
Phytalgic®
(fish oil rich in
n-3 PUFA+ n-6 PUFAs+ vitamin E, Urtica dioica)		 Randomized double-blind parallel-groups clinical trial. N = 81 patients with OA of the knee or hip using NSAIDs and/or analgesics regularly.
Female, n = 55;
Mean age = 57.5;
Age range = 28–84 years)
F.up = 3 months.		 Group 1—Phytalgic® (n = 41).
Group 2—placebo (n = 40).
  • ▪

    ↓ WOMAC score for pain stiffness;

  • ▪

    ↓NSAID use.

 [173]
EPA+ DHA A randomized, double-blind, multicenter trial.
Trial registration number ACTRN 12607000415404.		 N = 202 patients with knee OA.
Female, n = 100;
Mean age = 61 ± 10 years,
Participants were >40 years with clinical knee and VAS > 20 mm,
No indication of BMI.		 Group 1—hHigh-dose fish oil
(4.5 g EPA + DHA per day) (59% women) 15 mL/day.
Group 2—low-dose fish oil (0.45 g EPA + DHA
per day)
(40% women).
  • ▪

    The low dose had a greater improvement in WOMAC pain and function scores at 2 years;

  • ▪

    No difference between the two groups in cartilage volume loss.

[174]
Neptune Krill Oil (NKOTM)
EPA (20:5 n-3) + DHA (22:6 n-3) + antioxidants (e.g., astaxanthin, etc.) 		A randomized, double-blind, placebo-controlled study. N = 90 patients with
cardiovascular disease and/or rheumatoid arthritis and/or OA and high levels of CRP (>1.0 mg/dL).		 Group 1—treatment with NKO™ (300 mg daily).
Group 2—placebo
30 days of treatment.
  • ▪

    ↓ CRP;

  • ▪

    ↓ WOMAC pain score;

  • ▪

    ↓ Pain;

  • ▪

    ↓ Functional impairment.

 [175]
Krill oil
(EPA (20:5 n-3) + DHA (22:6 n-3))		 Randomized, double-blind, parallel-group, placebo-controlled trial. N = 50 patients with mild knee pain (no severe pain). Group 1—treatment with 2 g/day.
Group 2—placebo.
F.up = 30 days.
  • ▪

    ↓ Knee pain;

  • ▪

    ↑ Plasma EPA and EPA/AA ratio.

 [176]
Krill oil
(EPA (20:5 n-3) + DHA (22:6 n-3))		 Multicenter, randomized, double-blind, placebo-controlled
clinical trial.		 N = 260 patients with clinical knee OA, significant knee pain and effusion-synovitis. Group 1—treatment of 2 g/day.
Group 2—placebo.
F.up = 6 months.
  • ▪

    Safe

  • ▪

    ↓ Knee pain

  • ▪

    Reduced sizes of knee-effusion synovitis.

 [177]
Krill oil
(EPA (20:5 n-3) + DHA (22:6 n-3))]		 Multicenter, randomized, double-blind, placebo-controlled trial N = 235;
Female, n = 129;
Mean age = 55.9 ± 6.8 yrs;
BMI > 18.5 to <35 kg/m2;
Mild-to-moderate knee OA.		 Group 1—4 g/d of a commercially available krill oil supplement daily (0.60 g EPA/d, 0.28 DHA/d, 0.45 mg astaxanthin/d).
Group 2—placebo (4 g/d mixed vegetable oil).
F.up = 6 months.
  • ▪

    ↓ Knee pain

  • ▪

    Improved stiffness and physical functions;

  • ▪

    No changes in NSAID use.

 [178]
Combination of glucosamine sulfate + EPA DHA RCT, a double-blind study. N = 177 patients with moderate-to-severe hip or knee OA.
Mean age 62 y; mean BMI = 29; 63% women.		 Group 1—glucosamine sulfate + EPA DHA.
Group 2—glucosamine sulfate alone.
  • ▪

    ↓ WOMAC pain score superior in group 1;

  • ▪

    ↓ OA symptoms (morning stiffness, pain in hips and knees) were superior in group 1.

 [179]
EPA + l-serine Randomized, double-blind, placebo-controlled, parallel-group study. N = 120 participants aged ≥ 20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 year. Group 1—oral administration of
549 mg l-serine+ 149 mg/daily EPA.
Group 2—placebo group.
8 wk dosing and
4 wk post-treatment observation.
  • ▪

    ↓ Pain score.

 [180]
Resolvins D1, D2 and 17-HDHA, DHA OA case-control cohort. N = 62 individuals affected with radiographic knee OA (Kellgren–Lawrence grade of 2 or higher).
52 individuals without radiographic or clinical symptoms of OA.		 No treatment
gas chromatography
  • ▪

    17-HDHA was associated with pain: ↑ thermal pain sensitivity and intensity of chronic pain;

  • ▪

    No evidence of pain-related features for other studied resolvins.

[181]