Table 5.

GRADE Quality Assessment

A. Treatment vs. Placebo
Quality assessment							№ of events/№ of patients		Effect		Quality	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Treatment	Placebo	Relative (95 %CI)	Absolute (95% CI)
Pain - Curcuminoid vs. Placebo (Lower scores indicate better Pain outcome) (follow up: range 6 weeks to 12 weeks)
5	randomized trials	very seriousa	seriousb	not serious	seriousc	none	N=161	N=170	SMD 0.81 lower (1.25 lower to 0.37 lower)		⊕○○○ VERY LOW	CRITICAL
Function - Curcuminoid vs. Placebo (Lower scores indicate better Functional outcome) (follow up: range 6 weeks to 12 weeks)
3	randomized trials	very seriousa	not serious	not serious	seriousc	none	N=114	N=118	SMD 0.48 lower (0.74 lower to 0.22 lower)		⊕○○○ VERY LOW	CRITICAL
Use of Rescue Medication - Curcuminoid vs. Placebo (Risk ratios less than one favor Curcuminoid) (follow up: range 6 weeks to 8 weeks)
3	randomized trials	very seriousa	seriousd	not serious	seriouse	none	35/67 (52.2%)	60/74 (81.1%)	RR 0.65 (0.40 to 1.05)	284 fewer per 1,000 (from 41 more to 486 fewer)	⊕○○○ VERY LOW	IMPORTANT
Withdrawals due to Adverse Events - Curcuminoid vs. Placebo (Risk ratios less than one favor Curcuminoid) (follow up: range 6 weeks to 12 weeks)
4	randomized trials	very seriousa	not serious	not serious	seriouse	none	4/141 (2.8%)	6/147 (4.1%)	RR 0.90 (0.21 to 3.79)	4 fewer per 1,000 (from 32 fewer to 114 more)	⊕○○○ VERY LOW	CRITICAL
Serious Adverse Events - Curcuminoid vs. Placebo (Risk ratios less than one favor Curcuminoid) (follow up: range 6 weeks to 12 weeks)
3	randomized trials	not serious	not serious	not serious	not serious	none	0/118 (0.0%)	0/119 (0.0%)	Due to zero events, an absolute risk reduction was not estimable.		⊕⊕⊕⊕ HIGH	CRITICAL
Gastrointestinal Adverse Events - Curcuminoid vs. Placebo (Risk ratios less than one favor Curcuminoid) (follow up: range 6 weeks to 12 weeks)
3	randomized trials	very serious a	not serious	not serious	seriouse	none	15/123 (12.2%)	6/124 (4.8%)	RR 2.22 (0.94 to 5.26)	59 more per 1,000 (from 3 fewer to 206 more)	⊕○○○ VERY LOW	CRITICAL
Pain - Boswellia vs. Placebo (Lower scores indicate better Pain outcome) (follow up: range 4 weeks to 12 weeks)
4	randomized trials	very seriousf	very seriousg	not serious	very serioush	none	N=130	N=86	SMD 2.04 lower (2.81 lower to 1.27 lower)		⊕○○○ VERY LOW	CRITICAL
Function - Boswellia vs. Placebo (Lower scores indicate better Functional outcome) (follow up: range 4 weeks to 12 weeks)
4	randomized trials	very serious f	very serious i	not serious	very serioush	none	N=130	N=86	SMD 1.52 lower (2.24 lower to 0.79 lower)		⊕○○○ VERY LOW	CRITICAL
Withdrawals due to Adverse Events - Boswellia vs. Placebo (Risk ratios less than one favor Boswellia) (follow up: range 4 weeks to 12 weeks)
4	randomized trials	not serious	not serious	not serious	seriouse	none	3/150 (2.0%)	2/105 (1.9 %)	RR 0.75 (0.13 to 4.20)	5 fewer per 1,000 (from 17 fewer to 61 more)	⊕⊕⊕○ MODE RATE	CRITICAL
Serious Adverse Events - Boswellia vs. Placebo (Risk ratios less than one favor Boswellia) (follow up: range 4 weeks to 12 weeks)
2	randomized trials	not serious	not serious	not serious	not applicable	none	0/70 (0.0%)	0/50 (0.0%)	Due to zero events, an absolute risk reduction was not estimable.		⊕⊕⊕⊕ HIGH	CRITICAL
Gastrointestinal Adverse Events - Boswellia vs. Placebo (Risk ratios less than one favor Boswellia) (follow up: range 4 weeks to 12 weeks)
3	randomized trials	not serious	not serious	not serious	seriouse	none	3/100 (3.0%)	2/80 (2.5%)	RR 0.93 (0.17 to 5.10)	2 fewer per 1,000 (from 21 fewer to 103 more)	⊕⊕⊕○ MODE RATE	CRITICAL

B. Treatment vs. NSAID
Quality assessment							№ of events/№ of patients		Effect		Quality	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Treatment	NSAID	Relative (95% CI)	Absolute (95% CI)
Pain - Curcuminoid vs. NSAID (Lower scores indicate better Pain outcome) (follow up: range 4 weeks to 6 weeks)
2	randomized trials	seriousa	seriousb	not serious	seriousc	none	N=216	N=206	SMD 0.05 lower (0.41 lower to 0.31 higher)		⊕○○○ VERY LOW	CRITICAL
Thai WOMAC Function [0–10] - Curcuminoid vs. NSAID (Lower scores indicate better Functional outcome) (follow up: 4 weeks)
1	randomized trials	not serious	not assessable	not serious	seriousc	none	N=171	N=160	SMD 0.02 lower (0.24 lower to 0.19 higher)		⊕⊕⊕○ MODE RATE	CRITICAL
Time to complete 100 m walk [sec] - Curcuminoid vs. NSAID (Lower scores indicate better outcome) (follow up: 6 weeks)
1	randomized trials	seriousa	not assessable	not serious	very seriousd,e	none	N=45	N=46	SMD 0.3 lower (0.71 lower to 0.11 higher)		⊕○○○ VERY LOW	IMPORTANT
Use of Rescue Medication - Curcuminoid vs. NSAID (Risk ratios less than one favor Curcuminoid) (follow up: 4 weeks)
1	randomized trials	seriousa	not assessable	not serious	seriousf	none	5/185 (2.7%)	2/182 (1.1%)	RR 2.46 (0.48 to 12.5 2)	16 more per 1,000 (from 6 fewer to 127 more)	⊕⊕○○ LOW	IMPORTANT
Withdrawals due to Adverse Events - Curcuminoid vs. NSAID (Risk ratios less than one favor Curcuminoid) (follow up: range 4 weeks to 6 weeks)
2	randomized trials	seriousa	not serious	not serious	not serious	none	2/237 (0.8%)	10/2 37 (4.2 %)	RR 0.22 (0.05 to 0.99)	33 fewer per 1,000 (from 0 fewer to 40 fewer)	⊕⊕⊕○ MODE RATE	CRITICAL
Serious Adverse Events - Curcuminoid vs. NSAID (Risk ratios less than one favor Curcuminoid) (follow up: 6 weeks)
1	randomized trials	not serious	not assessable	not serious	not applicablee	none	0/48 (0.0%)	0/52 (0.0 %)	Due to zero events, an absolute risk reduction was not estimable.		⊕⊕⊕○ MODE RATE	CRITICAL
Gastrointestinal Adverse Events - Curcuminoid vs. NSAID (Risk ratios less than one favor Curcuminoid) (follow up: range 4 weeks to 6 weeks)
2	randomized trials	seriousa	not serious	not serious	not serious	none	87/233 (37.3%)	118/234 (50.4%)	RR 0.74 (0.60 to 0.91)	131 fewer per 1,000 (from 45 fewer to 202 fewer)	⊕⊕⊕○ MODE RATE	CRITICAL

CI: Confidence interval; SMD: Standardized mean difference; RR: Risk ratio

^aAll trials received at least one High Risk of Bias rating, and >50% of trials received ≥3 Unclear Risk of Bias ratings outside of the “Other” dimension. With particular reference to Use of Rescue Medication and Withdrawal due to Adverse Events outcomes, two studies were marked down for potential attrition bias, and one study provided no data on study discontinuation.

^bI²= 71%; moderate heterogeneity.

^c95% Confidence Interval of an SMD extends between >0.2-≤0.5 points in either direction (Cohen 1988*)

^dI²= 74%; moderate heterogeneity

^e95% Confidence Interval of a Risk Ratio crosses null.

^fThree of four studies received at least one High risk of bias rating due to very small sample size and/or potential reporting bias.

^gI²= 79%

^h95% Confidence Interval of an SMD extends between >0.5 points in either direction (Cohen 1988*)

ⁱI²= 80%

^aOne study received a High risk of bias rating due to potentially inadequate blinding.

^bI²= 60%; moderate heterogeneity.

^c95% Confidence Interval of an SMD extends between >0.2-≤0.5 points in either direction (Cohen 1988*)

^d95% Confidence Interval of an SMD extends between >0.5 points in either direction (Cohen 1988*)

^eSample size in each study arm <50.

^f95% Confidence Interval of a Risk Ratio crosses null.

^eSample size in one study arm <50.