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Knee Osteoarthritis (OA) is a progressive degenerative joint disease affecting the quality of life of the elderly population. There is considerable evidence that nutraceuticals from natural herbs may play a significant role in inflammation and joint destruction in OA. We review the current status of some of the commonly used nutraceuticals in Indian market – Boswellia, Aflapin, Chondroitin sulphate, Glucosamine sulphate, Collagen peptide, Curcumin, Fish Oil, Ginger, Green tea, and Rosehip extract. We have summarized their mechanism of action, biological effects, toxicities and efficacy in the management of Knee OA. These supplements have been found to be effective in knee OA in various studies. No serious side effects have been reported for any of these supplements. Overall, our study identifies and support the use of these nutraceuticals to provide symptomatic relief to patients with knee OA and justify their use as an adjunct therapy for the management. More good quality trials are needed to provide definitive answers to questions related to their efficacy and safety for OA prevention and treatment.
Co-expression and co-localization of cartilage glycoproteins CH13L1 and lubricin in osteoarthritic cartilage: morphological, immunohistochemical and gene expression profile.
Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in african american caucasians: the johnston county osteoarthritis project.
and are associated with serious adverse events on gastrointestinal, renal and cardiovascular systems.
The ideal treatment should modify the natural history of OA and alter the articular cartilage destructive process. Such substances which protect the articular cartilage during OA are termed as ‘chondroprotective agents,’ and when these modify the course of the disease, these are called as ‘disease-modifying OA drugs’.
OARSI-OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease-modifying osteoarthritis drug (DMOAD) clinical trial.
In the recent times, Nutraceuticals are used commonly in the management of OA knee in India and abroad. The term ‘nutraceutical’ was coined from ‘nutrition’ and ‘pharmaceuticals’ in 1989 by DeFelicen
and was described as food that provides medical or health benefits.
In the current study, we have investigated the role of 10 commonly used nutraceuticals in the management of knee OA in India, to evaluate their role and efficacy, based on the available literature. In this review article, extensive pubmed search has been done in each category and studies have been selected based on the level of the study and clinical relevance but the list may not be complete. The agents discussed herewith in the text and tables (Table 1) are in alphabetical order and they neither show the preference of our usage nor do these depict their popularity in the market.
Table 1Table showing the Nutraceuticals used in the management of knee osteoarthritis, their source, active ingredient, mechanism of action and side effects.
GlcN penetrates into cells by means of glucose transporters. GlcN associate to O-GlcNAcylate proteins and modulates their activity, e.g. decrease nuclear factor-κB nuclear translocation. GlcN may also affect the transcription of pro-inflammatory cytokines by epigenetic mechanisms.
CS do not penetrate into chondrocytes, synoviocytes, and elicit the anti-inflammatory effect by engaging membrane receptors, e.g. CD44, TLR4, and ICAM1, with a resulting dual effect: impede the fragments of extracellular matrix engaging these receptors, cause of inflammatory reaction, and block the signal transduction pathways activated by the fragments and so diminish the nuclear translocation of pro-inflammatory transcription factors.
Derived from gelatinization and subsequent enzymatic hydrolysis of native collagen and it contains small peptide with a molecular weight lower than 5000 Da53
Curcumin is derived from turmeric, a popular spice used in India, South Asia, and Japan, which is the grounded root and rhizome of the plant Curcuma Longa
Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclooxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
Effect of ginger powder supplementation on nitric oxide and C-reactive protein in elderly knee osteoarthritis patients: a 12-week double-blind, randomized placebo-controlled clinical trial.
Effect of ginger supplementation on proinflammatory cytokines in older patients with osteoarthritis: outcomes of a randomized controlled clinical trial.
Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
Epigallocatechin-3-O-gallate modulates global micro RNA expression in interleukin-1β-stimulated human osteoarthritis chondrocytes: potential role of EGCG on negative co-regulation of microRNA-140-3p and ADAMTS5.
Proposed M/A: Rose hip extract inhibited the chemotaxis and chemiluminescence of peripheral blood polymorphonuclear leucocytes and also reduces the level of serum creatinine and acute phase protein CRP
The role of Boswellia in various health conditions like inflammatory diseases, cancers, wound healing and antimicrobial activity is well known. The gum resin is extracted from the ancient herb, Boswellia serrata (Fig. 1a). It has been found to be a potent anti-inflammatory, anti-arthritic and analgesic agent.
also reviewed literature for the side effect of Boswellia and concluded that the number and severity of side effects are meager. The most active component of Boswellia extract is 3-O-Acetyl-11-keto-beta-boswellic acid (AKBA), which inhibits 5-lipoxygenase (5-LOX) and complement system involved in cellular inflammatory cascade.
Boswellia frereana (frankincense) suppresses cytokine-induced matrix metalloproteinase expression and production of pro-inflammatory molecules in articular cartilage.
concluded that Boswellia decreases MMP-9 and MMP-13 mRNA levels; inhibit MMP9 expression and activation. It also decreases the production of nitrite (the stable end product of nitric oxide), prostaglandin E2 and cyclooxygenase-2. Sengupta et al.
found that 5-Loxin which is a novel Boswellia Serrata extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) is efficient and safe in OA patients. It was also observed that the MMP-3 of synovial fluid was also reduced significantly.
also found that at the end of 4 weeks, the Karnofski Scale was improved more in the Boswellia group compared to control group. The WOMAC Score considering pain, stiffness and physical functions were decreased significantly more in the treatment group in comparison with controls. Belcaro G et al.
Comparative efficacy and tolerability of 5-loxin® and Aflapin® against osteoarthritis of the knee: a double-blind, randomized, placebo-controlled clinical study.
Aflapin contains B. serrata extract enriched in AKBA and non-volatile oil portion of B. Serrata gum resin. The bioavailability of AKBA increased when given in the form of Aflapin.
Table 2Table showing the review of literature of commonly used nutraceuticals used in the management of knee osteoarthritis.
VAS, Lequesne's Functional Index, WOMAC, Cartilage degrading enzyme from synovial fluid
Statistically and clinically significant improvement in pain score and physical function score, and reduction of cartilage degradation enzyme in synovial fluid
5-Loxin® reduces pain and improves physical functioning significantly in OA patients; and it is safe for human consumption. 5-Loxin® may exert its beneficial effects by controlling inflammatory responses through reducing proinflammatory modulators, and it may improve joint health by reducing the enzymatic degradation of cartilage in OA patients.
5-Loxin is Boswellia serrata extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid.
Comparative efficacy and tolerability of 5-loxin® and Aflapin® against osteoarthritis of the knee: a double-blind, randomized, placebo-controlled clinical study.
Significant improvement in pain score and physical function score. Significant improvement in pain score and functional ability were recorded at the 7th day of treatment.
Aflapin and 5-Loxin reduce pain and improve physical functions significantly in OA subjects. Aflapin exhibited better efficacy compared to 5-Loxin. Both were safe.
Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study.
Significant improvement in UC II group compared to other GS and placebo group
UC=II improved symptoms in OA patients and well tolerated
Undenatured type II collagen obtained from chiken sternum cartilage However, further studies required for establishing its effect and mechanism of action
Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial.
A randomized, double-blinded, placebo-controlled study of the effect of a combination of lemon verbena extract and fish oil Omega-3 fatty acid on joint management.
Randomized clinical trial of low dose versus high dose of fish oil
WOMAC pain and function score
Improvement in both the group, greater improvement in pain and functions score at 2 years in low-dose patients. No difference in cartilage volume loss.
Effect of ginger powder supplementation on nitric oxide and C-reactive protein in elderly knee osteoarthritis patients: a 12-week double-blind, randomized placebo-controlled clinical trial.
Effect of ginger supplementation on proinflammatory cytokines in older patients with osteoarthritis: outcomes of a randomized controlled clinical trial.
The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea Angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis.
Randomized open-label active-controlled clinical trial, Intervention group: green tea extract + diclofenac Control group: diclofenac
VAS, total WOMAC
Mean difference of VAS pain, total WOMAC, and WOMAC physical functional score shows significant reduction compared with the control group. No significant difference between two groups in mean differences of WOMAC pain and stiffness scores.
Green tea extract can be considered as an adjunctive treatment for control of pain and betterment of knee joint physical function in OA knee pt.
A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
Comparative efficacy and tolerability of 5-loxin® and Aflapin® against osteoarthritis of the knee: a double-blind, randomized, placebo-controlled clinical study.
did 90-days, randomized, double-blind, placebo-controlled study to evaluate the efficacy of 5-Loxin and Aflapin in osteoarthritis (OA) of the knee. Both 5-Loxin and Aflapin showed significant improvements in pain scores and physical function scores in patients with knee OA. Vishal et al.
Glucosamine sulfate (GS), and Chondroitin sulfate (CS) are glycosaminoglycans (GAGs) synthesized by chondrocytes and synoviocytes. These are essential components of the extracellular matrix and synovial fluid. GS is extracted from the chitosan and chitin exoskeleton of crustaceans such as shellfish and is stabilized by a salt.
The proposed mechanism of GlcN is by penetration into cells by glucose transporters. GS associated with O-GlcNAcylate proteins are responsible for modulating the inflammatory process like decreasing nuclear factor-κB nuclear translocation. GlcN also affects the transcription of pro-inflammatory cytokines by epigenetic mechanisms. The mechanism of action of CS differs from that of GlcN. Being large molecules; CS does not penetrate into cells,e.g., chondrocytes and activates the anti-inflammatory effect by associating membrane receptors, e.g., CD44, TLR4, and ICAM1. It obstructs the fragments of extracellular matrix engaging these receptors, and blocks the signal transduction pathways activated by the fragments to reduce the nuclear translocation of proinflammatory transcription factors.
noted that GS can affect glucose metabolism and may induce insulin resistance. GlcN may also cause shellfish allergy (Table 3). The GS is administered as salt and may affect the hypertensive and renal patients.
Long-term effects of chondroitin 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized,double-blind, placebo-controlled trial.
GL and CS showed anti-inflammatory action in in vitro study on human chondrocyte, Beneficial effect of CS and GL on pain and function. Small but significant reduction in rate of joint space narrowing.
This review clarifies the role of these compounds in the therapeutic arsenal for OA knee pt.
Long-term effects of chondroitin 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized,double-blind, placebo-controlled trial.
Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo:a six-month multicenter, randomized, double-blind, placebo-controlled clinical trial.
All trials have found the safety of these compounds to be equal to placebo. Inconsistent efficacy in reducing OA pain and improving joint function.
Because of many studies confirmed OA pain relief with GL + GS and their excellent safety, these supplements may serve a role as an initial treatment modality for OA knee pt.
Long-term effects of glucosamine and chondroitin sulfate on the progression of structural changes in knee osteoarthritis: six-year follow-up data from the osteoarthritis initiative.
Significantly reduced the cartilage volume loss in the global knee. The protective effect at 6 years being significant in participants exposed to 2 or more years of treatment.
These findings provide future support for the long-term protective structure-modifying effects of GL/CS treatment in OA knee pt.
1)trial should to methodological standard (CONSORT) 2)systematic review should follow similar standards (MECIR)
The best dosage, duration of dosage that provide symptom relief is still unknown. More advanced tools (e.g. MRI) should be used to assess the joint. The quality and quantity of cartilage should also be more accurately defined. (DGRMRIC) Group of pt. who get benefit should be clearly defined.
Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo:a six-month multicenter, randomized, double-blind, placebo-controlled clinical trial.
found that any of the combinations provide clinically significant pain relief in knee OA irrespective of dose fractionation and capsule or sachet formulations. Vangsness CT Jr et al.
reviewed literature for the same and found that both the drugs were found safe compared to placebo. As an individual drug, there are inconsistent results, but in combination, they found to be effective.
Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique.
also reviewed the literature and concluded that there is an evidence of a reduction in the rate of joint space narrowing.
There are several reasons for these inconsistent results which include that current treatment dose of GlcNbarely reaches the required therapeutic concentration in plasma and tissue. There is no standard formulation available in the market for these supplements. Bruyère et al.
examined patented crystalline GS (PCG) formulation and found it to be superior to other GS formulations. PCGs also showed a delay in joint structural changes in various studies, indicating potential benefit in altering disease course of OA knee. Raynauld JP et al.
Long-term effects of glucosamine and chondroitin sulfate on the progression of structural changes in knee osteoarthritis: six-year follow-up data from the osteoarthritis initiative.
observed that despite a significant number of available RCTs, the question of the effectiveness of GS and CS is still not answered. They also noted that which group of patients with the specific grading of OA gets the most benefit of this supplement is not clear.
2.3 Collagen peptide
Hydrolysate Collagen (HC) is derived from gelatinization and enzymatic hydrolysis of native collagen derived from collagenic animal tissue and contained small peptide with a molecular weight lower than 5000 Da.
In preclinical studies, it is found that HC stimulates collagenic tissue regeneration by increasing collagen synthesis and also by increasing glycosaminoglycans and hyaluronic acids.
Ability of a urine assay of type II collagen cleavage by collagenases to detect early onset and progression of articular cartilage degeneration: results from a population-based cohort study.
used collagen peptides in their study and results were evaluated by WOMAC, VAS and Quality of Life (QOL) score from starting of study to 13 weeks of the study. These scores reduced significantly in collagen peptide group compared to placebo group. Lugo et al.
Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study.
carried out a study to evaluate the Undenatured type II collagen (UC II) derived from chicken sternum cartilage in modulating knee OA symptoms. UC II was found to be effective in patients with OA knee and was well tolerated. Figueres Juher T et al.
did a review of the effect of hydrolyzed collagen on the joint in 60 scientific studies and found that HC intake reduces collagen damage and loss causing a reduction in joint pain. Schadow et al.
found that the pharmacological effect of the various compositions is different on human chondrocytes. So, standardization of CHs formulation is required.
2.4 Curcumin
The grounded root and rhizome of the plant Curcuma longa provides Turmeric which is used to treat the biliary digestive disorder, healing wounds and in rheumatic diseases (Fig. 1b). Curcumin (77%) is the main constituent of Turmeric but also contains bisdemethoxycurcumin (17%), and bisdemethoxycurcumin (3%). All these together are called “curcuminoids”.
Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclooxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
Curcumin acts as a chondroprotective agent by inhibiting apoptosis of chondrocytes; proteoglycans and metal metalloproteases release inhibition and inhibition of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines expression in chondrocytes.
Marsetyawan Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cyclooxygenase-2 enzyme by synovial fluid's monocytes of patients with osteoarthritis.
compared curcumin with Diclofenac Sodium, and they found curcumin to be equally efficient in suppressing the synthesis of COX-2. Kuptniratsaikul et al.
did a randomized multicentric study and observed similar results. Adverse effect profile observed include dyspepsia, abdominal pain, nausea, loose stool, and edema. Henrotin et al.
Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial.
In a study, it was found that the peak plasma Curcumin concentration of Theracurmin (Curcumin formulation dispensed with colloidal submicron-particles) was higher compared to other formulations in the market.
Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized clinical trials.
systematically reviewed all RCTs and found that three RCTs showed a reduction of PVAS with curcumin in comparison with placebo.
2.5 Fish oil
The effect of fish oil in knee OA patients is still not well understood. It is postulated that the fatty acids present in fish oil alter metabolic pathways by reducing the inflammatory process (Fig. 1c). Various studies showed the reduction in inflammatory destruction of cartilage tissue.
The anti-inflammatory actions of n-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) from fish oil were observed on human cartilage cells. Some adverse effect like intolerance, diarrhea, and gastroesophageal reflux have reported
A randomized, double-blinded, placebo-controlled study of the effect of a combination of lemon verbena extract and fish oil Omega-3 fatty acid on joint management.
also concluded that the fish oil is efficient and safe in mild to moderate stages of knee OA patients, however, the higher dose of 2000 mg did not show greater efficacy than 1000 mg of fish oil. Hill et al. and March et al.
also concluded that the low-dose fish oil group showed better pain and functional score improvement. Standardization of the fish oil formulations is required for consistency of therapy. Senftleberet al.
searched database systematically and suggested unfavorable effect in knee OA patients. They concluded that the evidence for using marine oil to alleviate pain in arthritis patients was over all of the low quality.
2.6 Ginger
Ginger is one of the ancient herbs used in India for cooking and for the treatment of different diseases. Ginger has anti-inflammatory action which helps in treating knee OA (Fig. 1d). Naderi et al.
Effect of ginger powder supplementation on nitric oxide and C-reactive protein in elderly knee osteoarthritis patients: a 12-week double-blind, randomized placebo-controlled clinical trial.
in their study found that inflammatory markers like nitric oxide and C- reactive protein were reduced significantly in the serum of patients who were given ginger as a treatment compared to placebo. The similar study was done by Mozaffari-Khosravi et al.
Effect of ginger supplementation on proinflammatory cytokines in older patients with osteoarthritis: outcomes of a randomized controlled clinical trial.
assessing the levels of proinflammatory after ginger supplementation and suggested that Cytokines were decreased in the Ginger Group relative to the Placebo Group. The efficacy and safety of ginger are evaluated in various studies. Meta-analyses of randomized placebo-controlled trials by Bartels EM et al.
did randomized, open-label study and found that the group which received both ginger and diclofenac showed better improvement than the individual treatments. The exact dosage and the duration of treatment with Ginger extract still need to be validated. Local application of ginger is also found to be effective in reducing symptoms of OA knee. Amorndoljai P et al.
The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea Angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis.
also found significant improvement in pain relief in patients with Ginger with knee OA who have a poor response with NSAIDs.
2.7 Green tea
The tea is one of the most commonly consumed beverage worldwide. Green tea is 'non-fermented,' and contains more Catechins which are potent antioxidants as compared to black tea (Fig. 1e). There is an increasing interest to evaluate the role of green tea in various diseases including knee OA. “Polyphenols” present in green tea inhibits the inflammatory response at cellular levels. Epigallocatechin-3-gallate (EGCG), is the most important type of polyphenol which inhibits enzyme activities and signal transduction pathways.
Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes.
have done in vitro study on human chondrocytes. EGCG significantly reduces advanced glycation end products (AGEs) which induce pro-inflammatory substances in chondrocytes through various mechanisms. EGCG inhibits expression of TNF alpha, MMP-13 and NF-kappaB and also IL-1beta-induced glycosaminoglycan (GAG) release from human cartilage explants.
Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
Newer studies have shown that the role of EGCG in OA might be related to its ability to inhibit inflammatory response by modulating micro RNAs expressions.
Epigallocatechin-3-O-gallate modulates global micro RNA expression in interleukin-1β-stimulated human osteoarthritis chondrocytes: potential role of EGCG on negative co-regulation of microRNA-140-3p and ADAMTS5.
found that rose hip extract inhibits the peripheral blood polymorphonuclear leucocytes (PMNs) and also reduce the level of acute phase protein CRP and serum creatinine. It was observed that the gene expression of CCL5/RANTES, CCL20/MIP-3α, CXCL2/MIP-2 and CXCL10/IP-10 on target cells like chondrocytes, was reduced by Rosehip. The expression of genes that degrade ECM was also reduced, and thus RHP showed a chondroprotective effect on the cartilage tissue. Jäger AK et al.
reported from an in vitro study that component of rose hip powder: (Linoleic acid and alpha-linolenic acid) inhibit COX-1 and COX-2 and contribute anti-inflammatory property. Saaby Let al
evaluated the immunomodulatory effect of Rosehip powder and found that it inhibits the lipopolysaccharide-induced interleukin-6 release. Winther K et al.
A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
also conducted a comprehensive review, according to which anti-oxidative and anti-inflammatory properties of various preparations of the Rosehip have been demonstrated. Chrubasik-Hausmann S et al.
performed a 3-month investigation and found the rose hip shell powder to be as effective as pseudo-fruit powder Litozin (®). However, future research is required to elaborate the importance of the reported promising experimental effects in clinical use.
3. Conclusion
Knee OA is one of the most prevalent diseases in the elderly population. Lifestyle modification and physical therapy forms the first line of management follows by Analgesics and NSAIDs, but these agents only give symptomatic relief and do not affect the natural history of the disease. Nutraceuticals are dietary compounds that are considered to alter inflammatory process and change the natural course of the disease process of OA. However, the term nutraceuticals is not recognized by the US Food and Drug Administration (FDA), which uses the term ‘dietary supplements’ instead. The responsibility of framing and regulating standards for nutraceuticals rests with the Food Safety and Standards Authority of India (FSSAI) as outlined in the Food Safety Act 2006.
Anti-inflammatory, anti-arthritic and analgesic action of Boswellia has been observed in many studies, but the bio-availability is found to be low. Aflapin have shown better bio-availability than Boswellia. The effect of Aflapin was observed as early as the 5th day of starting treatment. Ginger and green tea extract are also found to be effective and safe for OA knee patients. However, further studies required confirming these results. Collagen peptide is also found to be effective in the treatment of OA but different formulations are available in the market, and each formulation has a different pharmacological effect, so standardization of collagen peptide formulation required before using it in the treatment of OA knee.
GS and CH supplements are found to be safe, but results of their effects were inconsistent. However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis has recommended them as first-line therapy in the treatment algorithm for knee OA. In future, more specific studies are required to evaluate the exact dosage of these drugs, which formulation is most effective, which group and stage of patients get most benefited, duration of treatment required, when to stop medicine if no response and the exact role of GS/CH in modifying disease process.
Rosehip powder is an effective nutraceutical for treatment of OA patients because of its anti-inflammatory, chondroprotective and immune-modulatory action but the only sparse amount of data is available. In future, more extensive studies are required for establishing its efficacy. Curcumin also has shown positive results but the bio-availability of curcumin found to be low. In future, well-planned RCTs required with enhanced Curcumin formulation to overcome low bio-availability. The low dose of fish oil (1000 mg) is found to be more efficacious than the higher dose. Overall, it is found to be safe, but some side effects like diarrhea, intolerance and gastro-esophageal reflux also have been observed.
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Osteoarthritis in the XXIst century: risk factors and behaviors that influence disease onset and progression.
Co-expression and co-localization of cartilage glycoproteins CH13L1 and lubricin in osteoarthritic cartilage: morphological, immunohistochemical and gene expression profile.
Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in african american caucasians: the johnston county osteoarthritis project.
OARSI-OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease-modifying osteoarthritis drug (DMOAD) clinical trial.
Boswellia frereana (frankincense) suppresses cytokine-induced matrix metalloproteinase expression and production of pro-inflammatory molecules in articular cartilage.
Comparative efficacy and tolerability of 5-loxin® and Aflapin® against osteoarthritis of the knee: a double-blind, randomized, placebo-controlled clinical study.
Comparative efficacy and tolerability of 5-loxin® and Aflapin® against osteoarthritis of the knee: a double-blind, randomized, placebo-controlled clinical study.
Long-term effects of chondroitin 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized,double-blind, placebo-controlled trial.
Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo:a six-month multicenter, randomized, double-blind, placebo-controlled clinical trial.
Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique.
Long-term effects of glucosamine and chondroitin sulfate on the progression of structural changes in knee osteoarthritis: six-year follow-up data from the osteoarthritis initiative.
Ability of a urine assay of type II collagen cleavage by collagenases to detect early onset and progression of articular cartilage degeneration: results from a population-based cohort study.
Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study.
Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclooxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
Marsetyawan Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cyclooxygenase-2 enzyme by synovial fluid's monocytes of patients with osteoarthritis.
Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial.
Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized clinical trials.
A randomized, double-blinded, placebo-controlled study of the effect of a combination of lemon verbena extract and fish oil Omega-3 fatty acid on joint management.
Effect of ginger powder supplementation on nitric oxide and C-reactive protein in elderly knee osteoarthritis patients: a 12-week double-blind, randomized placebo-controlled clinical trial.
Effect of ginger supplementation on proinflammatory cytokines in older patients with osteoarthritis: outcomes of a randomized controlled clinical trial.
The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea Angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis.
Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes.
Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
Epigallocatechin-3-O-gallate modulates global micro RNA expression in interleukin-1β-stimulated human osteoarthritis chondrocytes: potential role of EGCG on negative co-regulation of microRNA-140-3p and ADAMTS5.
A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
Declaration of Competing Interest statements were not included in published version of the articles that appeared in previous volumes of Journal of Clinical Orthopaedics and Trauma. Hence, the authors of the below articles were contacted after publication to request a Declaration of Interest statement:
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