December 12, 2012
Natural compounds can help manage joint health and arthritis via several different approaches with varying time frames for realizing benefits. Addressing inflammation and pain can be a quicker pursuit, as the mechanisms for inflammation are more easily reached than the inner components of joints, where there is no blood supply. Among the natural inflammatory compounds are omega-3 fatty acids, curcumin, boswellia and a handful of other botanicals.
The long-chain omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have roles in the inflammatory cascade. These fatty acids compete with arachadonic acid (AA) for conversion enzymes that can produce cytokines, which regulate inflammation. AA tends to result in pro-inflammatory compounds, while EPA and DHA tend to result in anti-inflammatory benefits. Recent research has even implicated a similar role for docosapentaenoic acid (DPA).1,2
Resolving inflammation has been another area of study, as researchers noticed pro-resolution compounds such as lioxins, resolvins and protectins help keep beneficial inflammation in check, but can be depleted during autoimmune disease progression.3 These resolution molecules may also be reduced during the aging process, which can alter AA metabolism and limit the stop signals needed for resolution.4
Much of the work on resolution molecules has been headed by Charles Serhan, Ph.D., Harvard Medical School. Serhan and his team have noted lipoxin is derived from AA, but requires the presence of EPA and DHA; resolvins are derived from both EPA and DHA, while protectins are from DHA. Protectins are more active in brain inflammation.5 He has also published work showing resovlins RvE1 and RvD1 may quell pain hypersensitivity by normalizing spinal synaptic plasticity, suggesting these resolution compounds are good analgesic options for treating inflammatory pain such as in arthritis.6
DHA and EPA have commonly been supplemented as fish oil, so many studies have focused on the effect of oil on inflammation, especially in rheumatoid arthritis (RA). A 12-week, double blind, randomized study on a high-EPA fish oil formula (as EPAX 4510 TG, from EPAX) revealed treatment in patients with RA significantly reduced plasma Interleukin-1 (IL-1) beta, an inflammatory biomarker.7 Ritchie's articular index scores indicated the EPA-rich oil improved clinical status, a benefit not experienced in the placebo group. In another multicenter, double blind, randomized trial of 512 Danish RA patients, 12 weeks of 3.6 g/d EPAX fish oil, compared to placebo, modestly, but significantly reduced morning stiffness, joint tenderness and CRP.8
Research on ankylosing spondylitis, a chronic disease marked by inflammation between spinal bones and the joint between the spine and pelvis, can offer some further insight on the roles of AA and omega-3s on inflammation. In a 2006 trial, patients randomized to a high-dose fish oil protocol (4.55 g/d omega-3) experienced a significant decrease in disease activityBath Ankylosing Spondylitis Disease Activity Index (BASDAI)compared to those on low-dose fish oil (1.95 g/d omega-3).9 Then in 2012, Swedish researchers published research results showing a positive correlation between plasma phsopholipid AA levels and disease activity (BASDAI), while long-chain omega-3s showed a negative correlation.10
Fish oil is not the only source of DHA and EPA. Krill oil contains phospholipid forms of these omega-3s and has been studied for similar anti-inflammatory benefits. An animal study involving krill oil powder (as Superba, from Aker Biomarine) discovered six weeks of krill supplementation in high-fat animals with persistent inflammation was able to reduced inflammatory markers.11
In other research, 300 mg/d krill oil (as Neptune Krill Oil, NKO, from Neptune Technologies & Bioressources) in patients with various combinations of cardiovascular disease (CVD), RA, osteoarthritis (OA) and high C-reactive protein (CRP), an indicator of inflammation, inhibited inflammation and reduced arthritis symptoms after seven and 14 days of treatment.12 The randomized, double blind, placebo-controlled study looked at CRP levels, stiffness, functional impairment and Western Ontario and McMaster Universities (WOMAC) OA index scoresall which improved from krill supplementation.
While fish and krill oils contain both EPA and DHA, as well as DPA, scientists have found EPA produces anti-inflammatory cytokines, in addition to conversion competition with AA; DHA does not produce such cytokines, but does produce more resolution molecules. Thus, some inflammation research has focused on EPA content and associated cytokines.
Other fatty acids also have made their mark on arthritis. A combination of esterfied fatty acid carbons and creatine (as Kre-Celazine®, from All American Pharmaceuticals) may reduce pain and inflammation by enhancing the lipid structure of the cell membrane and enabling the cells to repair and regenerate. The combo may also inhibit AA and decrease pro-inflammatory actions by other fatty acids. According to research, Kre-Celazine works best on inflammation and pain in the extremities, as well as the neck and shoulder joints.13 Compared to placebo, 30 days of Kre-Celazine supplementation was effective at eliminating pain as prescription drugs, as reported by subjects. Ankle and foot pain saw the greatest benefit (100 percent), followed closely by neck, shoulder, elbow, wrist and hand pain (80 to 85 percent), and knee pain (71 percent). Hip and back pain scores were not significantly different between the treatment and placebo groups.
A sizeable cache of botanicals also possess the ability to influence inflammation pathways, and relieve pain and associated symptoms. Ayurveda offers a number of such botanicals. RA-11, an Ayurvedic combination product containing boswellia (Boswellia serrata), curcumin (Curcuma longa), ashwagandha (Withania somnifera) and ginger(Zingiber officinale), given to RA patients significantly reduced pain and improved WOMAC scores after 16 and 32 weeks of supplementation.14
Boswellia inhibits the 5-lipoxygenase (5-LOX) enzyme and associated inflammatory pathway, in addition to limiting the activities of tumor necrosis facto-alpha (TNF-alpha) and interleukin (IL).15 Research linked boswellia extract to reduced lameness and joint pain.16 In vitro investigation on standardized boswellia extract (as 5-Loxin®, from PL Thomas) revealed an inhibiting effect on inhibit TNF-alpha-induced expression of matrix metalloproteinase-3 (MMP-3) tied to RA tissue damage, including the synoviumand inducible expression of apoptosis mediators.17 Looking deeper, scientists discovered a extract with 30-percent acetyl-11-keto-beta-boswellic acid (AKBA) was significantly more effective against inflammatory markers, both in vitro and in vivo, than was a 3-percent AKBA extract.18
Curcumin, a curcuminoid found in turmeric, has been used traditionally to treat inflammation, and research has supported this use with results indicating the compound modulates several important molecular targets relevant to OA treatment, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2) and cell-surface adhesion molecules.19
A variant (C. domestica) at 2 g/d was reported to equal the effectiveness of 800 mg/d of ibuprofen in addressing knee OA inflammation and pain.20 In 2012, a pilot clinical study published in Phytotherapy Research discussed the safety and effectiveness of curcumin (500 mg) and the inflammation and pain drug diclofenac (50 mg) alone and in combination in RA patients.21 While all treatments had a positive effect, the curcumin alone group had the highest improvements to disease activity score (DAS) and American College of Rheumatology (ACR) criteria.
An extract from hops (as Perluxan®, from Pharmachem) in softgel form (from Soft Gel Technologies) also improved OA pain. In a double blind, randomized trial, patients took 1 g/d for 14 days, which resulted in a rapid effect on mean pain relief, showing improvement over placebo within two hours of ingestion. A follow-up double-blind, randomized, parallel study on healthy subjects showed Perluxan, in softgel or powder form, was as effective against cyclooxygenase-2 (COX-2) inflammatory enzyme pathway, and also exhibited significant COX-1 sparing activity over a nine-hour period. The softgel form appeared to act more quickly on pain-related enzymes.
A mixture of plant flavonoids from Scutellaria baicalensis and Acacai catechu (as Unvestin, from Unigen) also inhibited COX and LOX enzymes and reduced production of pro-inflammatory compounds.22 Researchers noted Univestin reduced associated swelling of tissues in a dose-dependent manner, in addition to decreasing gene and protein expressions of pro-inflammatory cytokines, IL and TNF-alpha. A 2012 report in Nutrition Journal noted Univestin bioflavonoids addressed OA pain as well as did NSAID treatment.23 The randomized, double blind, placebo- and active-controlled pilot study included 60 subjects (age 40 to 75) with symptomatic OA of the hip or knee given either 250 mg/d or 500 mg/d of Univestin, or 200 mg/d the NSAID celecoxib or a placebo. WOMAC pain scores decreased in both Univestin groups at 90 days, but not in either placebo or celecoxib groups; WOMAC stiffness scores decreased in Univestin groups at 30 and 60 days, but not in the placebo or the NSAID group.
Standardized extract of French maritime pine (as Pycnogenol®, from Horphag Research Ltd.) addresses inflammation in a number of ways. It can inhibit pro-inflammatory gene expression, including MMP-9 release and NFkappaB activation.24 It may also inhibit COX-2, as research has shown Pycnogenol alleviates OA symptoms and the need for patients to take cox-2 inhibitors.25 In one double blind, placebo-controlled study, 100 mg/d of Pycnogenol for three months decreased WOMAC scores by 56 percent in the treatment group of OA patients, compared to only 9.6 percent in the placebo group.26 Those taking Pycnogenol were more likely (56 percent) to stop taking pain/inflammation drugs than were those taking placebo (1 percent), and were far less likely to experience gastrointestinal problems. OA patients taking Pycnogenol in another double blind, placebo-controlled, randomized trial had improved WOMAC scores and less pain, compared to those taking placebo.27 The treatment groups also reduced their use of NSAIDs more than did the placebo group.
Read the first article in this series, "When Bones Collide."
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References listed on the next page.
1. Norris PC and Dennis EA. "Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling." Proc Natl Acad Sci U S A. 2012 May 29;109(22):8517-22.
2. Akiba S et al. Involvement of lipoxygenase pathway in docosapentaenoic acid-induced inhibition of platelet aggregation." Biol Pharmaceutical Bull. 2000;23(11):1293-1297.
3. Levy BD et al. "Diminished lipoxin biosynthesis in severe asthma." Am J Respir Crit Care Med. 2005 Oct 1;172(7):824-30.
4. Gangemi S et al. "Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels." Exp Gerontol. 2005 Jul;40(7):612-4.
5. Recchiuti A and Serhan CN. "Pro-Resolving Lipid Mediators (SPMs) and Their Actions in Regulating miRNA in Novel Resolution Circuits in Inflammation." Front Immunol. 2012;3:298.
6. Serhan CN et al. "Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions." Nat Med. 2010 May;16(5):592-7, 1p following 597.
7. Espersen GT et al. Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids." Clin Rheumatol. 1992 Sep;11(3):393-5.
8. Faarvang KL et al. [Fish oils and rheumatoid arthritis. A randomized and double-blind study]."[Article in Danish] Ugeskr Laeger. 1994 Jun 6;156(23):3495-8.
9. Sundström B et al. "Supplementation of omega-3 fatty acids in patients with ankylosing spondylitis." Scand J Rheumatol. 2006 Sep-Oct;35(5):359-62.
10. Sundström B et al. " Plasma phospholipid fatty acid content is related to disease activity in ankylosing spondylitis." J Rheumatol. 2012 Feb;39(2):327-33.
11. Bjørndal B et al. "Krill powder increases liver lipid catabolism and reduces glucose mobilization in tumor necrosis factor-alpha transgenic mice fed a high-fat diet." Metabolism. 2012 Oct;61(10):1461-72.
12. Deutsch L. Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms." J Am Coll Nutr. 2007 Feb;26(1):39-48.
13. Golini J et al. A single-center, double-blind placebo-controlled study to evaluate the efficacy of Kre-Celazine®, an oral buffered creatine-cetylated fatty acid compound, in its ability to reduce site-specific inflammation and pain." JANA. 2009;12(1):20-25.
14. Chopra A et al. A 32-Week Randomized, Placebo-Controlled Clinical Evaluation of RA-11, an Ayurvedic Drug, on Osteoarthritis of the Knees." J Clin Rheumatol. 2004 Oct;10(5):236-245.
15. Ammon HP. Boswellic acids in chronic inflammatory diseases." Planta Med. 2006 Oct;72(12):1100-16.
16. Kimmatkar N et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial." Phytomedicine. 2003 Jan;10(1):3-7.
17. Roy S et al. Human Genome Screen to Identify the Genetic Basis of the Anti-inflammatory Effects of Boswellia in Microvascular Endothelial Cells." DNA Cell Biol. 2005;24(4):244-55.
18. Roy S et al. Regulation of Vascular Responses to Inflammation: Inducible Matrix Metalloproteinase-3 Expression in Human Microvascular Endothelial Cells Is Sensitive to Anti-Inflammatory Boswellia." Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):653-60.
19. Shishodia S, Sethi G, Aggarwal BB. "Curcumin: getting back to the roots." Ann N Y Acad Sci. 2005 Nov;1056:206-17.
20. Kuptniratsaikul V et al. "Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis." J Altern Complement Med. 2009 Aug;15(8):891-7.
21. Chandran B and Goel A. "A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis." Phytother Res. 2012 Nov;26(11):1719-25. doi: 10.1002/ptr.4639.
22. Burnett, B et al. A Medicinal Extract of Scutellaria baicalensis and Acacai catechu Acts as a Duel Inhibitor of coclooxygenase and 5-Lipoxyygenase to Reduce Inflammation" J Med Food 2007;10(3)
23. Sampalis JS and Brownell LA. "A randomized, double blind, placebo and active comparator controlled pilot study of UP446, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin." Nutr J. 2012 Apr 5;11:21.
24. Grimm, T et al. Inhibition of NF-κB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol)" Journal of Inflammation 2006;3:1
25. Reza Farida, R et al. Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis" Nutrition Research 2007;27(692697).
26. Belcaro, G. et al. Treatment of Osteoarthritis with Pycnogenol®.The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of Signs, Symptoms, Physical Performance and Vascular Aspects." Phytother. Res. 2008;(22)518523
27. Cisar P et al. Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis." Phytother Res. 2008 Aug;22(8)1087-92.
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