Impact of Supplementation with Curcuminoids on Systemic Inflammation in Patients with Knee Osteoarthritis: Findings from a Randomized Double-Blind Placebo-Controlled Trial

Abstract

Objective:  Osteoarthritis (OA) is a degenerative joint disease associated with inflammation. The present study aimed to determine changes in serum levels of inflammatory biomarkers in OA patients whose clinical symptoms were improved as a result of supplementation with curcuminoids.

Methods:  This study was a randomized double-blind placebo-control parallel-group clinical trial in which 40 subjects with mild-to-moderate degree knee OA were randomly allocated to receive either pure curcuminoids (1 500 mg/day in 3 divided doses; n=19) or matched placebo (n=21) for 6 weeks. In order to enhance the bioavailability of curcuminoids, piperine (15 mg/day) was added to the treatment regimen. Serum levels of interleukins 4 (IL-4) and 6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and high-sensitivity C-reactive protein (hs-CRP), together with erythrocyte sedimentation rate (ESR) were determined at baseline as well as at the end of trial.

Results:  Serum concentrations of IL-4 (p=0.001), IL-6 (p=0.006) and hs-CRP (p=0.004) were significantly reduced in the curcuminoid group whilst serum levels of TNF-α and TGF-β and mean ESR remained unaltered by the end of trial (p>0.05). In the placebo group, serum concentrations of IL-4 (p=0.001), IL-6 (p=0.003), TNF-α (p=0.003) and TGF-β (p=0.005) were significantly reduced but mean hs-CRP and ESR values remained statistically unchanged (p>0.05). Comparison of the magnitude of changes in the evaluated inflammatory biomarkers did not indicate any significant difference between the study groups (p>0.05).

Conclusion:  Significant improvement in clinical symptoms of OA in curcuminoid-treated subjects cannot be attributed to the systemic anti-inflammatory effects of these phytochemicals.

Key words

curcuma longa L. - pro-inflammatory cytokines - acute phase reaction - osteoarthritis

• References

• 1 Suri P, Morgenroth DC, Hunter DJ. Epidemiology of osteoarthritis and associated comorbidities. PMR 012 4: S10-S19
• 2 Ahmed S, Anuntiyo J, Malemud CJ et al. Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: a review. Evid Based Complement Alternat Med 2005; 2: 301-308
• 3 Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011; 23: 471-478
• 4 Goldring MB. Osteoarthritis and cartilage: the role of cytokines. Curr Rheumatol Rep 2000; 2: 459-465
• 5 Spector TD, Hart DJ, Nandra D et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997; 40: 723-727
• 6 Wolfe F. The C-reactive protein but not erythrocyte sedimentation rate is associated with clinical severity in patients with osteoarthritis of the knee or hip. J Rheumatol 1997; 24: 1486-1488
• 7 Baraf HS, Fuentealba C, Greenwald M et al. Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial. J Rheumatol 2007; 34: 408-420
• 8 Towheed TE, Judd MJ, Hochberg MC et al. Acetaminophen for osteoarthritis. The Cochrane database of systematic reviews 2003; CD004257
• 9 Sahebkar A. Molecular mechanisms for curcumin benefits against ischemic injury. Fertil Steril 2010; 94: e75-e76
• 10 Sahebkar A. Why it is necessary to translate curcumin into clinical practice for the prevention and treatment of metabolic syndrome?. Biofactors 2013; 39: 197-208
• 11 Sahebkar A. Are Curcuminoids effective c-reactive protein-lowering agents in Clinical practice? Evidence from a Meta-Analysis. Phytother Res 2014; 28: 633-642
• 12 Sahebkar A. Curcuminoids for the management of hypertriglyceridaemia. Nat Rev Cardiol 2014; 11: 123
• 13 Panahi Y, Saadat A, Beiraghdar F et al. Adjuvant Therapy with Bioavailability-Boosted Curcuminoids Suppresses Systemic Inflammation and Improves Quality of Life in Patients with Solid Tumors: A Randomized Double-Blind Placebo-Controlled Trial. Phytother Res 2014;
• 14 Panahi Y, Saadat A, Beiraghdar F et al. Antioxidant effects of bioavailability-enhanced curcuminoids in patients with solid tumors: A randomized double-blind placebo-controlled trial. J Funct Foods 2014; 6: 615-622
• 15 Gupta SC, Kismali G, Aggarwal BB. Curcumin, a component of turmeric: from farm to pharmacy. BioFactors 2013; 39: 2-13
• 16 Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J 2013; 15: 195-218
• 17 Shehzad A, Lee J, Lee YS. Curcumin in various cancers. BioFactors 2013; 39: 56-68
• 18 Shehzad A, Rehman G, Lee YS. Curcumin in inflammatory diseases. BioFactors 2013; 39: 69-77
• 19 Henrotin Y, Priem F, Mobasheri A. Curcumin: a new paradigm and therapeutic opportunity for the treatment of osteoarthritis: curcumin for osteoarthritis management. Springerplus 2013; 2: 56
• 20 Belcaro G, Cesarone MR, Dugall M et al. Product-evaluation registry of Meriva(R), a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med 2010; 52: 55-62
• 21 Belcaro G, Hosoi M, Pellegrini L et al. A controlled study of a lecithinized delivery system of curcumin (meriva^®) to alleviate the adverse effects of cancer treatment. Phytother Res 2014; 28: 444-450
• 22 Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res 2012; 26: 1719-1725
• 23 Panahi Y, Sahebkar A, Amiri M et al. Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: results of a randomised, double-blind, placebo-controlled trial. Br J Nutr 2012; 108: 1272-1279
• 24 Sahebkar A, Mohammadi A, Atabati A et al. Curcuminoids Modulate Pro-Oxidant-Antioxidant Balance but not the Immune Response to Heat Shock Protein 27 and Oxidized LDL in Obese Individuals. Phytother Res 2013; 27: 1883-1888
• 25 Buhrmann C, Mobasheri A, Busch F et al. Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem 2011; 286: 28556-28566
• 26 Buhrmann C, Mobasheri A, Matis U et al. Curcumin mediated suppression of nuclear factor-kappaB promotes chondrogenic differentiation of mesenchymal stem cells in a high-density co-culture microenvironment. Arthritis Res Ther 2010; 12: R127
• 27 Csaki C, Mobasheri A, Shakibaei M. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis. Arthritis Res Ther 2009; 11: R165
• 28 Panahi Y, Rahimnia AR, Sharafi M et al. Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial. Phytother Res 2014;
• 29 Kawasaki T, Inoue K, Ushiyama T et al. Assessment of the American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Ryumachi 1998; 38: 2-5
• 30 Wu CW, Morrell MR, Heinze E et al. Validation of American College of Rheumatology classification criteria for knee osteoarthritis using arthroscopically defined cartilage damage scores. Semin Arthritis Rheum 2005; 35: 197-201
• 31 Shoba G, Joy D, Joseph T et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356
• 32 Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis 2013; 5: 77-794
• 33 Scanzello CR, McKeon B, Swaim BH et al. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. Arthritis Rheum 2011; 63: 391-400
• 34 Goldring MB. Clinical cytokine therapy for OA. Expert Opin Biol Ther 2001; 1: 817-829
• 35 Vlad SC, Neogi T, Aliabadi P et al. No association between markers of inflammation and osteoarthritis of the hands and knees. J Rheumatol 2011; 38: 1665-1670
• 36 Kertia N, Asdie AH, Rochmah W. Marsetyawan. Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cycloxygenase-2 enzyme by synovial fluid’s monocytes of patients with osteoarthritis. Acta Med Indones 2012; 44: 105-113
• 37 Shakibaei M, John T, Schulze-Tanzil G et al. Suppression of NF-κB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis. Biochem Pharmacol 2007; 73: 1434-1445
• 38 Shrivastava AK, Pandey A. Inflammation and rheumatoid arthritis. J Physiol Biochem 2013; 69: 335-347
• 39 Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol 2007; 595: 453-470
• 40 Anand P, Kunnumakkara AB, Newman RA et al. Bioavailability of curcumin: Problems and promises. Mol Pharm 2007; 4: 807-818
• 41 Shoba G, Joy D, Joseph T et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356
• 42 Khajuria A, Thusu N, Zutshi U. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine 2002; 9: 224-231
• 43 Atal CK, Dubey RK, Singh J. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther 1985; 232: 258-262
• 44 Chearwae W, Anuchapreeda S, Nandigama K et al. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochem Pharmacol 2004; 68: 2043-2052
• 45 Mohammadi A, Sahebkar A, Iranshahi M et al. Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial. Phytother Res 2013; 27: 374-379
• 46 Panahi Y, Sahebkar A, Parvin S et al. A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 2012; 49: 580-588