for the main comparison.

S‐Adenosylmethionine compared with placebo or no intervention for osteoarthritis of the knee or hip
Patient or population: Patients with osteoarthritis of the knee or hip Settings: Outpatient clinic of either rheumatologic, orthopedic or veteran's hospital departments Intervention: S‐Adenosylmethionine Comparison: Placebo or no intervention
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no intervention	S‐Adenosylmethionine
Pain Various validated pain scales Follow‐up: 3 to 12 weeks	‐1.8 cm change on 10 cm VAS1 29% improvement	‐2.2 cm change (Δ ‐0.4 cm, ‐0.9 to 0.0 cm)2 37% improvement (Δ 8%, 0% to 15%)3	SMD ‐0.17 (‐0.35 to 0.01)	533 (2 studies)	+++O moderate4	Little evidence of beneficial effect (NNT: not statistically significant)
Function Various validated function scales Follow‐up: 3 to 12 weeks	‐1.2 units on WOMAC (range 0 to 10)1 21% improvement	‐1.2 units on WOMAC (Δ 0.0, ‐1.4 to +1.5)5 21% improvement (Δ 0%, ‐26% to +26%)6	SMD 0.02 (‐0.68 to 0.71)	542 (3 studies)	++OO low7	Little evidence of beneficial effect (NNT: not statistically significant)
Number of patients experiencing any adverse event Follow‐up: 3 to 12 weeks	150 per 1000 patient‐years1	191 per 1000 (141 to 257)	RR 1.27 (0.94 to 1.71)	632 (4 trials)	+++O moderate8	Little evidence of harmful effect (NNH: not statistically significant)
Number of patients who withdrew because of adverse events Follow‐up: 3 to 12 weeks	17 per 1000 patient‐years1	16 per 1000 (8 to 32)	RR 0.94 (0.48 to 1.86)	656 (4 trials)	+++O moderate9	Little evidence of harmful effect (NNH: not statistically significant)
Number of patients experiencing any serious adverse event Median follow‐up: x weeks	See comment	See comment	Not estimable	0 (0 trials)	See comment	0 trials provided data for this outcome
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; GRADE: GRADE Working Group grades of evidence (see explanations); SMD: standardised mean difference; NNT: number needed to treat; NNH: number needed to harm

GRADE Working Group grades of evidence 
 High quality (++++): Further research is very unlikely to change our confidence in the estimate of effect. 
 Moderate quality (+++O): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. 
 Low quality (++OO): Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. 
 Very low quality (+OOO): We are very uncertain about the estimate.

¹ Median reduction as observed across control groups in large osteoarthritis trials (Nüesch 2009). 
 ² Standardised mean differences (SMDs) were back‐transformed onto a 10 cm visual analogue scale (VAS) on the basis of a typical pooled SD of 2.5 cm in trials that assessed pain using a VAS, and expressed as change based on an assumed standardised reduction of 0.72 standard deviation units in the control group. 
 ³ The median observed pain score at baseline across control groups in large osteoarthritis trials was 6.1 cm on a 10 cm VAS (Nüesch 2009). 
 ⁴ Downgraded (1 level) because analyses was not according to intention‐to‐treat principle, 2 out of 4 trials reported this outcome, potentially leading to selective outcome reporting bias, 1 out of 2 trials used adequate, 1 used unclear concealment of allocation methods, possible indirectness of evidence (indirect population) in 1 out of 2 studies. 
 ⁵ Standardised mean differences (SMDs) were back‐transformed onto a 0 to 10 standardised WOMAC function score on the basis of a typical pooled SD of 2.1 in trials that assessed function on WOMAC function scale and expressed as change based on an assumed standardised reduction of 0.58 standard deviation units in the control group. 
 ⁶ The median observed standardised WOMAC function score at baseline across control groups in large osteoarthritis trials was 5.6 units (Nüesch 2009). 
 ⁷ Downgraded (2 levels) because: analyses was not according to intention‐to‐treat principle, presence of moderate between‐trial heterogeneity, possible indirectness of evidence (indirect population) in 2 out of 3 studies, the confidence interval is wide and crossed no difference, 1 out of 3 trials used adequate, 2 used unclear concealment of 
 allocation methods. 
 ⁸ Downgraded (1 level) because the confidence interval crosses no difference, in 1 out of 4 trials analyses was not according to intention‐to‐treat principle. 
 ⁹ Downgraded (1 level) because the confidence interval is wide and crossed no difference.