Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials

Figures & data

Figure 1 PRISMA flow diagram.

Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Table 1 Baseline patient characteristics

Characteristics	Viscosupplementation	Saline
Patients, n	2,673	2,193
Age, yr, mean (min–max)	65 (53–72)	62 (53–73)
Female, %, median (min–max)	64 (27–92)	65 (22–100)
Body mass index, kg/m^2, mean (min–max)	28 (25–32)	29 (25–33)
Symptom duration, yr, mean (min–max)	4.9 (1.0–9.1)	4.3 (0.8–8.5)
Kellgren–Lawrence grade, mean (min–max)	2.5 (1.9–3.0)	2.5 (1.8–3.5)

Abbreviations: max, maximum; min, minimum; yr, years.

Table 2 Characteristics of studies included in meta-analysis

Study	Blindinga				Viscosupplementation details
	Patient	Injectors	Outcome assessors	Tradeb name	Total no injections	Total no cycles	Industry-funded study?
Altman and Moskowitz, 1998^Citation21	1	0	1	Hyalgan	5	1	Yes
Altman et al, 2009^Citation22	1	0	1	EUFLEXXA	3	1	Yes
Bragantini et al, 1987^Citation23	0 1	0 0	0 0	Hyalgan Hyalgan	3 3	1 1	Unclear
Brandt et al, 2001^Citation24	1	0	1	Orthovisc	3	1	Yes
Bunyaratavej et al, 2001^Citation25	1	0	1	Hyalgan	4	1	Unclear
Carrabba et al, 1995^Citation26	1	0	1	Hyalgan	5 3 1	1	Unclear
Cubukçu et al, 2005^Citation27	0	0	0	Synvisc	3	1	Unclear
Day et al, 2004^Citation28	1	0	1	Artzal	5	1	Yes
DeCaria et al, 2012^Citation29	1	0	0	Hyalgan	3	1	No
Diracoglu et al, 2009^Citation30	1	0	1	Synvisc	4	1	Unclear
Grecomoro et al, 1987^Citation31	0	0	0	Hyalgan	3	1	Unclear
Henderson et al, 1994^Citation32	1	0	1	Hyalgan	5	1	Unclear
Huang et al, 2011^Citation33	1	0	1	Hyalgan	5	1	Yes
Huskisson and Donnelly, 1999^Citation34	1	0	1	Hyalgan	5	1	Unclear
Jørgensen et al, 2010^Citation35	1	0	1	Hyalgan	5	1	Yes
Jubb et al, 2003^Citation36	1	0	1	Hyalgan	3 (9)c	1 (3)c	Yes
Karlsson et al, 2002^Citation37	1	0	1	Artzal Synvisc	3 3	1 1	Yes
Kotevoglu et al, 2006^Citation38	1	0	1	Orthovisc Synvisc	3	1	Unclear
Kul-Panza and Berker, 2010^Citation39	1	0	1	Orthovisc	3	1	Unclear
Lohmander et al, 1996^Citation40	1	0	1	Artzal	5	1	Yes
Lundsgaard et al, 2008^Citation41	1	0	1	Hyalgan	4	1	No
Petrella et al, 2008^Citation42	1	0	0	Synvisc Hyalgan	3	1	Unclear
Puhl et al, 1993^Citation43	1	0	1	Artzal	5	1	Yes
Rolf et al, 2005^Citation44	1 1	0 0	1 1	Synvisc Artzal	3 3	1 1	Yes Yes
Sala and Miguel, 1995^Citation49	1	0	0	Hyalgan	5	1	Unclear
Scale et al, 1994^Citation45	1 1	0 0	1 1	Synvisc Synvisc	2 3	1 1	Yes
Strand et al, 2012^Citation46	1	0	1	Gel-One	1	1	Yes
Wobig et al, 1998^Citation47	1	1	1	Synvisc	3	1	Yes
Wu et al, 1997^Citation48	1	0	0	Artzal	5	1	Unclear

Notes:

a Assessment of blinding adequacy was independent of text description;

b Artzal is categorized as a US marketed product; Although Artzal is not marketed in the US, the formulation is identical to Supartz, which is marketed in the US;

c one cycle of three injections each for safety evaluation.

Table 3 Assessment of study quality using Jadad scale

Study	Randomization	Blinding	Accountablility	Total score
Altman and Moskowitz, 1998^Citation21	1	1	1	3
Altman et al, 2009^Citation22	1	1	1	3
Bragantini et al, 1987^Citation23	1	1	1	3
Brandt et al, 2001^Citation24	1	2	1	4
Bunyaratavej et al, 2001^Citation25	1	1	0	2
Carrabba et al, 1995^Citation26	1	1	1	3
Cubukçu et al, 2005^Citation27	1	0	1	2
Day et al, 2004^Citation28	1	1	1	3
DeCaria et al, 2012^Citation29	1	1	1	3
Diracoglu et al, 2009^Citation30	1	1	1	3
Grecomoro et al, 1987^Citation31	1	1	1	3
Henderson et al, 1994^Citation32	1	1	1	3
Huang et al, 2011^Citation33	1	1	1	3
Huskisson and Donnelly, 1999^Citation34	1	1	1	3
Jørgensen et al, 2010^Citation35	1	1	1	3
Jubb et al, 2003^Citation36	1	1	1	3
Karlsson et al, 2002^Citation37	1	1	1	3
Kotevoglu et al, 2006^Citation38	1	1	1	3
Kul-Panza and Berker, 2010^Citation39	1	1	1	3
Lohmander et al, 1996^Citation40	1	1	1	3
Lundsgaard et al, 2008^Citation41	2	2	1	5
Petrella et al, 2008^Citation42	1	1	1	3
Puhl et al, 1993^Citation43	2	2	1	5
Rolf et al, 2005^Citation44	1	1	1	3
Sala and Miguel, 1995^Citation49	1	1	1	3
Scale et al, 1994^Citation45	1	1	0	2
Strand et al, 2012^Citation46	2	2	1	5
Wobig et al, 1998^Citation47	1	1	1	3
Wu et al, 1997^Citation48	1	1	1	3

Figure 2 Forest plot of viscosupplementation versus saline controls on knee pain at 14 to 26 weeks.

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Figure 3 Forest plot of viscosupplementation versus saline controls on knee function at 14 to 26 weeks.

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Figure 4 Forest plot of viscosupplementation versus saline controls on risk of serious adverse events.

Abbreviation: CI, confidence interval.

Figure 5 Forest plot of viscosupplementation versus saline controls on risk of adverse event-related patient withdrawals.

Abbreviation: CI, confidence interval.

Table 4 Subgroup analysis of study- and patient-related factors on saline-corrected knee pain

Factor	SMD	95% CI	P-value
Age
≥65 years (n=11)	0.27	0.03 to 0.51	0.20
<65 years (n=23)	0.46	0.29 to 0.64
Body mass index
≥30 kg/m^2 (n=5)	0.28	0.00 to 0.56	0.72
<30 kg/m^2 (n=18)	0.34	0.17 to 0.51
Female proportion
≥67% (n=15)	0.54	0.30 to 0.77	0.15
<67% (n=19)	0.32	0.14 to 0.49
Symptom duration
≥5 years (n=9)	0.35	0.10 to 0.60	0.07
<5 years (n=15)	0.66	0.43 to 0.89
Kellgren–Lawrence grade
≥3 (n=6)	0.07	−0.28 to 0.42	0.06
<3 (n=12)	0.47	0.24 to 0.70
Kellgren–Lawrence grade IV
≥ any (n=6)	0.11	−0.24 to 0.46	0.25
<none (n=11)	0.35	0.14 to 0.57
Total sample size
≥100 (n=14)	0.17	0.01 to 0.33	<0.001
<100 (n=20)	0.67	0.47 to 0.86
Jadad score
≥3 (n=30)	0.34	0.20 to 0.48	0.03
<3 (n=4)	0.87	0.42 to 1.33
Industry funding
Yes or unclear (n=32)	0.41	0.27 to 0.56	0.21
No (n=2)	0.04	−0.52 to 0.61

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Table 5 Subgroup analysis of study- and patient-related factors on saline-corrected knee function

Factor	SMD	95% CI	P-value
Age
≥65 years (n=7)	0.17	−0.07 to 0.40	0.07
<65 years (n=17)	0.42	0.26 to 0.59
Body mass index
≥30 kg/m^2 (n=4)	0.28	−0.01 to 0.56	0.91
<30 kg/m^2 (n=15)	0.30	0.13 to 0.46
Female proportion
≥67% (n=9)	0.63	0.36 to 0.89	0.01
<67% (n=15)	0.25	0.10 to 0.39
Symptom duration
≥5 years (n=6)	0.30	0.02 to 0.59	0.15
<5 years (n=11)	0.58	0.33 to 0.83
Kellgren–Lawrence grade
≥3 (n=4)	0.45	0.09 to 0.81	0.86
<3 (n=8)	0.41	0.16 to 0.66
Kellgren–Lawrence grade IV
≥ any (n=2)	0.25	−0.17 to 0.67	0.78
< none (n=9)	0.31	0.13 to 0.50
Total sample size
≥100 (n=13)	0.22	0.08 to 0.35	0.001
<100 (n=11)	0.69	0.44 to 0.93
Jadad score
≥3 (n=21)	0.28	0.15 to 0.40	0.002
<3 (n=3)	1.05	0.57 to 1.52
Industry funding
Yes or unclear (n=22)	0.35	0.21 to 0.49	0.86
No (n=2)	0.30	−0.18 to 0.78

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Table 6 Subgroup analysis of study- and patient-related factors on serious adverse events

Factor	RD (%)	95% CI (%)	P-value
Age
≥65 years (n=10)	0.1	−1.4 to 1.6	0.39
<65 years (n=18)	0.9	−0.1 to 1.9
Body mass index
≥30 kg/m^2 (n=5)	1.0	−1.0 to 3.1	0.75
<30 kg/m^2 (n=15)	0.7	−0.3 to 1.7
Female proportion
≥67% (n=12)	1.5	−1.0 to 4.1	0.48
<67% (n=16)	0.6	−0.3 to 1.5
Symptom duration
≥5 years (n=7)	0.5	−1.1 to 2.1	0.26
<5 years (n=13)	1.7	0.2 to 3.3
Kellgren–Lawrence grade
≥3 (n=5)	0.0	−1.7 to 1.7	0.053
<3 (n=9)	2.4	0.7 to 4.2
Kellgren–Lawrence grade IV
≥ any (n=4)	0.0	−2.2 to 2.2	0.15
< none (n=7)	2.0	0.4 to 3.6
Total sample size
≥100 (n=12)	0.8	−0.1 to 1.7	0.57
<100 (n=16)	0.0	−2.4 to 2.4
Jadad score
≥3 (n=25)	0.7	−2.0 to 1.5	0.83
<3 (n=3)	0.0	−0.6 to 0.6
Industry funding
Yes or unclear (n=26)	0.8	−0.1 to 1.7	0.53
No (n=2)	0.0	−2.3 to 2.3

Abbreviations: CI, confidence interval; RD, risk difference.

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