Table 2.

Table showing the review of literature of commonly used nutraceuticals used in the management of knee osteoarthritis.

Nutraceuticals	Author and year	Type of Study	Number of patients	Outcome scoring system used	Results	Conclusion	Remarks
Boswellia
	Krishanu Sengupt,21 et al.	Randomized double-blind placebo controlled study	75	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.
	Belcaro G,22 et al.	Supplement registry	55	Kamofsky scale, WOMAC score, Treadmill test	The effect of supplement is significant higher than only using standard medicine	The difference between standard medicine and suppl. To SM was significant in favor of suppl. For all target measurement used in registry
	Belcaro G,23 et al.	A comparative study	66	WOMAC Score, treadmill test	In supplement plus standard medicine group WOMAC score reduced significantly.	The difference between SM and the flexiqule + SM was in favor of the management with supplement.	Flexiqule: Boswellia extract in capsule: safe and well tolerated.
Aflapin
	Krishanu Sengupt30 et al.	Randomized double-blind placebo controlled trial	60	VAS, Lequesene's Functional Index, WOMAC	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.
	Amar A,31 et al.	Randomized double-blind placebo controlled trail	152	VAS score, Lequesne's functional index, WOMAC score	Significant reduction in all the pain score is observed in aflapin group by day 30. Significne reduction of VAS and LFI observed by day 5	Aflapin is effective and safe in treatment of OA pt. and its effect shows as early as 5th day of starting treatment.
Collagen paptide
	Kumar S55 et al.	Double-blind, placebo-controlled randomized trial		WOMAC, VAS, Quality of life (QOL)	Scores reduced significantly in collagen peptide group compared to placebo group	Collagen peptide found to be effective in reducing pain of OA knee	Collagen paptide was isolated from pork skin and bovine bone
	Lugo JP,56 et al.	Multicenter, randomized, placebo-controlled, double-blind trail	191	WOMAC, VAS, Lequesne Functional Index (LFI)	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
	Figueres Juher T53 et al.	Review study	60 scientific studies		Hydrolyzed collagen reduces collagen damage and loss causing reduction in joint pain	Hydrolyzed collagen found to be effective in OAknee
Curcumin
	Madhu K65et al.	A Randomized placebo-controlled trail		WOMAC subscalesand total score	Improved WOMAC score, joint temderness, crepitation, effusion, limitation of move,ents	Curcumin found effective in treatment of OA knee patients	Single blinded, small sample size, short duration
	Kuptniratsaikul V,67 et al.(2014)	Comparative study between curcuma domestica extract and ibuprofen	345	WOMAC score	Both group showed significant improvement in WOMAC score	Curcuma domestic a extract is an effective in treatment of OA with less side effects	Large sample size, proper blinding and randomization but short duration
	Henrotin Y,68 et al.	Exploratory clinical trail	22	VAS score and blood markers	Significantly reduced circulating markers of collagen degradation, Coll2-1,Fib3-1,Fib3-2, Myeloperoxidase and VAS score reduced significantly	Flexofytol reduce inflation and thus reduce pain in OA patient	Flexofytol: another optimized curcumin formation with emulsifier polysorbate 80, Sample size of this study was small
	Nakagawa Y,71 et al.	Randomized, double-blind, placebo-controlled prospective study		Kellgren and Lawrence scale. Japanese Knee Osteoarthritis Measure	Reduced severity of pain and rate of concomitant celecoxib use. No difference in JKOM	Theracurmin reduces pain significantly.	Large sample and longer duration required.
	Panahi Y,73 et al.	Randomized double-blind placebo-controlled trial		WOMAC,VAS, Lequesne's pain functional index	Significant reduction in all the score compare to placebo	Curcuminoids represent an effective and safe alternative treatment in OA.
	Kok-Yong Chin,62 et al.	Review study			Reduction in pain and improvement in physical function	Patients has better quality of life after taking curcumin	More well planned randomized control trails and enhanced curcumin formulation required
	Daily JW74et al.	Systematic review	8 RCTs	Pain Visual Analog score, WOMAC score	Reduction of PVAS compared to placebo (p < .00001) in 3 RCTs, Reduction of WOMAC score in 4 RCTs, No significant difference in PVAS in 5 RCTs	1000 mg/day is effective for treatment of arthritis. It is difficult to draw definitive conclusion due to total sample size, quality of primary study	More rigorous and larger studies are needed to confirm therapeutic efficacy of turmeric for arthritis
Fish Oil
	Nuria Caturla,77 et al.	Randomized, double-blinded, placebo-controlled study	45	WOMAC, Lequesne's score	WOMAC, Lequesne's total score reduced 53% and 78% respectively	Standardized lemon verbena extract and Fish oil omega-3 fatty acid reduced pain and stiffness significantly	May be considered for further investigation as a alternative treatment.
	Peanpadungrat P,78 et al.	Comparative study	75	VAS score, 100 m walking velocity, three steps walking time	Average score of patient satisfaction was 9.06 of 10. all parameters improved significantly	Safe and effective in mild to moderate OA knee pts.
	Hill CL,79 et al.	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.	Fish oil is an effective treatment in OAknee
	Boe C,75 et al.	Review study				In vitro studies: anti-inflammatory action, Canine trial: reduction in symptoms Human clinical trial: Not consistently sigmificant	Long-term, well-designed studies required, and standardization of fish oil industry required
	Senftleber NK,80 et al.	Systematic review	42	Grading of Recommendation Assessment, Development, and Evaluation (GRADE)	The standardized mean difference suggested unfavorable effect in OA patients	Evidence of marine oil using in alleviate pain arthritis patients was over all of the low quality
Ginger
	Naderi Z81 et al.	double-blind randomized placebo-controlled clinical trial	120	Serum concentration of nitric oxide (NO) and hs-C reactive protein (hs-CRP	concentration of these markers declined more in the Ginger containing group	Ginger powder supplementation can reduce inflammatory markers
	Mozafarri – Khosravi82 et al.	randomized double-blind clinical trial	120	serum TNF-α and IL-1β level	both cytokines decreased in the Ginger containing group relative to the Placebo group	benefit in reducing inflammatory biomarkers
	Bartels EM83 et al.	Meta analysis of randomised placebo controlled trials	593	Hedges' standardized mean difference (SMD), and safety by risk ratio (RR)	Statistically significant pain reduction and a statistically significant reduction in disability were seen, both in favor of ginger.	modestly efficacious and reasonably safe but moderate quality evidence
	Paramdeep G84et al.	randomized open label study	60	VAS SCORE, WOMAC SCORE	statistically significant improvement with time in all groups with patients who received both ginger and diclofenac treatments	Ginger powder has add-on effect with acceptable safety profile.
	Amorndoljai P85 et al.	comparative study comparing paired t score before and after treatment	60	KOOS, ISOA, PGA	statistically significant improved patient's global assessment, knee joint pain, symptoms, daily activities, sports activities, and quality of life	Application of Ginger extract nanoparticles relieves joint pain with symptomatic and improved quality of life
	Rondanelli M,86 et al.	A pilot study		Tegner Lysholm Knee Scoring,VAS,SF-36), anthropometric parameters,hydration	significant improvement of pain by Lysholm scale score, SF-36	This study shows feasibility and safety data for the use of highly standardized ginger.
Green tea
	Hashempur MH,93 et al.	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.	Duration and sample size of this study is small.
Rose Hip Extract
	Winther99 K et al.	Randomized, double-blind, placebo-controlled trail		WOMAC pain, stiffness, global assessment of severity of the disease	Significant reduction in WOMAC pain, and global assessment of severity of the disease	Reduces symptom of osteoarthritis
	Rossnagel K,100 et al.	Meta-analysis of RCT	2 RCTs revied		1st RCT:no improvement in knee flexion 2nd RCT: reduction of pain in RHP group	In both studies RHP has moderate effect in OA patients	1st RCT: parallel design 2nd RCT: crossover design In both studies sample size was small
	Christensen R,101 et al.	Meta analysis of RCT	3 RCT reviewed		Reduction of pain score in RHP compared to placebo	Although sparse amount of data available, RHP reduces pain in OA pt.	In future, large-scale/long term trail require