Omega-3 fatty acid for inflammatory control in osteoarthritis
Osteoarthritis (OA) is a common joint condition that often affects the knees, leading to pain, stiffness and dysfunction. At a webinar organized by the Hong Kong College of Family Physicians (HKCFP), Dr Changhai Ding of Zhujiang Hospital of Southern Medical University, Guangzhou, China, discussed the role of inflammation in OA, highlighting clinical evidence on anti-inflammatory omega-3 fatty acid (FA) supplementation in improving knee OA–related symptoms.
Symptomatic knee OA common in Chinese elderly
Knee OA and its related symptoms are commonly found in Chinese patients. “In China, the prevalence of symptomatic knee OA in older individuals [mean age, 59.8 years] is 8.1 percent,” said Ding. “In a survey assessing musculoskeletal pain rates among 4,000 community-dwelling elderly individuals in Hong Kong, nearly one-third [31 percent] reported knee pain in the past 12 months.” [Arthritis Rheumatol 2016;68:648-653; Public Health 2009;123:549-556]
Inflammation in OA
OA is now recognized as a complex disease with heterogeneous aetiology and pathogenesis beyond degeneration. “OA can be classified into six types according to pathogenesis, including the inflammation-based and metabolic-based types,” explained Ding. “[For example,] obesity is an OA risk factor that induces chronic systemic low-grade inflammation.” [Lancet 2019;393:1745-1759; Ann Transl Med 2020;8:1068; Curr Rheumatol Rep 2016;18:57]
Low-grade inflammation contributes to OA development by increasing the levels of proinflammatory cytokines in joints. Subsequently, the affected joints release inflammatory cytokines into the circulation, leading to amplification of systemic low-grade inflammation and development of OA symptoms over time. [Osteoarthritis Cartilage 2013;21:16-21] “Control of inflammation is one of the key aspects of OA treatment,” Ding commented.
According to Osteoarthritis Research Society International (OARSI) guidelines, Level 1A recommendation for most patients with knee OA is treatment with topical NSAIDs, which are inhibitors of the cyclooxygenase (COX) enzyme in the prostaglandin synthesis pathway. [Osteoarthritis Cartilage 2019;27:1578-1589; Front Cardiovasc Med 2018;5:146]
“However, topical NSAIDs only exert their effects at inflamed local sites. Systemic NSAIDs and corticosteroids should be used only for a limited duration due to their risks of adverse events,” Ding pointed out. [Ann Rheum Dis 2017;76:948-959]
Possible role of omega-3 FA in controlling inflammation in OA
“Dietary supplementation may help control inflammation in OA,” Ding suggested.
In the prostaglandin synthesis pathway, COX catalyzes arachidonic acid (AA) into proinflammatory mediators, which induce inflammatory responses. The inflammatory activities can be suppressed by eicosapentaenoic acid (EPA), an omega-3 FA that competes with AA for COX. [Front Cardiovasc Med 2018;5:146]
“Both EPA and docosahexaenoic acid [DHA] help promote the biosynthesis of anti-inflammatory mediators,” Ding explained. “Omega-3 FA is considered as a preventive therapy, and an alternative to NSAIDs for resolving long-term inflammation. However, it is essential to investigate the safety of long-term use of omega-3 FA.” [Front Cardiovasc Med 2018;5:146]
Clinical benefits of omega-3 FA–based supplementation
Omega-3 FA has shown beneficial effects in OA. In a post hoc analysis of a randomized controlled trial (RCT) in overweight or obese adults aged 50–80 years at high risk of OA, daily fish oil supplementation containing EPA 400 mg and DHA 2,000 mg (n=39) significantly decreased OA-specific pain at 16 weeks vs placebo (n=36) (p=0.002). These findings indicate potential OA pain relief with omega-3 FA in patients at high risk of OA, and the next step would be to target those with clinically diagnosed OA. [Rheumatol Adv Pract 2020;23:4:rkaa036]
“Both low-dose and high-dose omega-3 FA were found to reduce OA-related symptoms in an RCT involving 202 patients with knee OA. However, high-dose supplementation provided no additional benefits over low-dose supplementation,” Ding stated. In the RCT, 24 months of low-dose fish oil (EPA and DHA in total 450 mg daily; n=101) supplementation significantly improved Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and function scores (p=0.009 and p=0.032, respectively) vs high-dose (EPA and DHA in total 4,500 mg daily; n=101) supplementation. [Ann Rheum Dis 2016;75:23-29] “Only an appropriate dose of omega-3 FA may exert effects on knee pain,” Ding added.
Another RCT further proved that using combination supplementation containing omega-3 FA and glucosamine provided incremental clinical benefits for moderate-to-severe OA compared with glucosamine alone. In this study, OA patients 45–75 years of age were randomized to receive daily supplementation with omega-3 FA plus glucosamine sulfate or glucosamine sulfate alone. After 26 weeks, the percentage of patients who achieved ≥80 percent reduction in WOMAC pain score was significantly higher with the combination of omega-3 FA plus glucosamine sulfate (n=80) vs glucosamine sulfate alone (n=84) (p=0.044). (Figure) “This result suggests a probable synergistic effect when omega-3 FA and glucosamine sulfate are used in combination,” Ding commented. [Adv Ther 2009;26:858-871]
In addition to symptom control, omega-3 FA supplementation is associated with other clinical benefits, including reduction in NSAID use. In an RCT in 81 OA patients with regular use of NSAIDs, 3 months of omega-3 FA–based supplementation led to a significantly reduced defined daily doses of NSAIDs used per day vs placebo (p=0.02). “The mean dose difference between the two groups was equivalent to diclofenac 67 mg/day or celecoxib 134 mg/day,” Ding noted. [Arthritis Res Ther 2009;11:R192]
Adequate vitamin D for OA
Vitamin D deficiency is associated with knee cartilage loss and knee pain in older adults. [Arthritis Rheum 2009;60:1381-1389; Ann Rheum Dis 2014;73:697-703] “Our studies showed that taking vitamin D supplementation for 2 years significantly relieved OA-related inflammation and symptoms, such as effusion synovitis, physical dysfunction, foot pain, and depressive symptoms. Furthermore, maintaining a sufficient level of vitamin D is associated with significantly decreased cartilage loss and improved knee function in knee OA patients,” said Ding. [Osteoarthritis Cartilage 2017;25:1304-1312; J Am Med Dir Assoc 2019;20:1634-1640.e1; Arthritis Care Res (Hoboken) 2021;73:781-787]
A network meta-analysis of 79 clinical trials further confirmed vitamin D as one of the effective treatment options for improving pain and function over the long term (>6 months) among patients with knee OA. However, no significant long-term improvement was found with NSAIDs, including celecoxib and etoricoxib. [Drugs 2020;80:1947-1959] “Vitamin D could have some [long-term] effects on OA,” Ding suggested.
Systemic inflammation may play a key role in the aetiology and pathogenesis of OA. Dietary supplementation, such as with omega-3 FA and vitamin D, may help control inflammation and relieve OA-related symptoms in patients.