Knee osteoarthritis: Should your patient opt for hyaluronic acid injection?

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Applied Evidence

Knee osteoarthritis: Should your patient opt for hyaluronic acid injection?

J Fam Pract. 2006 August;55(8):669-674

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References

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Homogeneity

All groups across all included studies were similar at baseline. All patients had mild to severe osteoarthritis of the knee. Mean ages of the groups were similar (treatment groups=67.1 years, placebo=66.7 years). Not all patients received treatment as per manufacturer’s recommendations ( TABLES 1 AND 2 ). A saline placebo was used for control groups in all studies. The volume of saline placebo for each study was equal to volume of hyaluronic acid injection plus saline vehicle used for that study. All studies used either the WOMAC scale or the Lequesne Functional Index as an outcome measurement tool. All studies included a follow-up outcome measurement; however, the range of follow-up time periods was wide (4 to 52 weeks).

Meta-analysis

The analysis for the outcome measurements on the WOMAC scale revealed no significant difference between groups in regards to pain or disability (95% confidence interval [CI] for pain, –0.6043 to 5.4755; for disability, –0.8282 to 4.8619). The outcome measurement for stiffness demonstrated a significant difference between treatment and control (95% CI for stiffness, 2.1780 to 8.7955).

The analysis for the outcome measurement on the Lequesne index revealed a significant difference between groups for measurements taken up to 6 months post-treatment (95% CI, 1.2315 to 2.6268). However, these differences were not seen in the 6+ month outcomes analysis (95% CI, –.8489 to .04787]. Confidence intervals are presented in FIGURE 1 . Mean differences for each outcome at baseline and post-treatment between the active treatment and placebo are presented in TABLE 3 .

TABLE 1
Hyaluronic acid: Manufacturer’s recommendations

HA BRAND	ARTZAL	SYNVISC	HYALGAN	DUROLANE	SUPLASYN	NRD101
Number of injections (given 1 week apart)	5	3	5	1	3	N/A
Concomitant local anesthetic injection recommended	Yes	No*	Yes	NR	N/A	N/A
Aspiration recommended prior to injection	Yes	Yes	Yes	Yes	No	N/A
Dosage per injection (mg)	25.0	32.0	40.0	60.0	20.0	25.0
Molecular weight (kDa)	620–1170	6000	500–730	N/A	N/A	1900
Cross-linked	No	Yes	No	Yes	No	N/A
HA, hyaluronic acid; NR, not reported; N/A, not available.
* Purported to alter the efficacy of Synvisc.

TABLE 2
Details of included studies

STUDY	KARLSSON ET AL⁷		DOUGADOS ET AL⁸	HUSKISSON⁹	DAY ET AL¹⁶	ALTMAN ET AL¹⁷	PETRELLA ET AL¹⁸	PHAM ET AL¹⁹
Brand	Artzal	Synvisc	Hyalgan	Hyalgan	Artzal	Durolane	Suplasyn	NRD101
Number of injections
given 1 wk apart	3	3	4	5	5	1	3	3*
Mfr’s recommendations	5	3	5	5	5	1	3	NA
Concomitant local anaesthetic injection	NR	NR	NR	NR	Yes	NR	NR	Yes
Aspiration prior to injection	NR	NR	Yes	NR	Yes	NR	NR	Yes
Dosage per injection (mg) + vehicle†	25/2.5 mL saline	32/2.5 mL saline	20/2.0 mL saline	20/2.0 mL saline	25/2.5 mL saline	60/3.0 mL saline	20/2.0 mL saline	25/2.5 mL saline
Cross-linked	No	Yes	No	No	No	Yes	NR	NR
NR=not reported
* Given as 3 courses every 3 months of 3 weekly injections
† Volume of saline placebo for each study equal to volume of hyaluronic acid injection plus saline vehicle used for that study

FIGURE 1
Hyaluronic acid vs control: 95% confidence intervals

Confidence intervals that cross the 0-value represent a nonsignificant difference between active treatment and control. Also included is a result from the Wang et al meta-analysis¹⁵ for comparison.

TABLE 3
Mean improvements: treatment vs. control

	BASELINE		POST-TREATMENT
	HA	PLACEBO	HA	PLACEBO
LEQUESNE	12.7 (3.0)	12.44 (2.7)	8.7 (4.4)	8.91 (4.4)
% Lequesne*	53.0 (12.8)	51.83 (11.2)	36.3 (18.5)	37.1 (18.1)
WOMAC
Pain*	40.5 (17.0)	43.9 (19.0)	26.8 (18.3)	30.9 (21.6)
Stiffness*	47.0 (17.6)	50.9 (21.1)	33.0 (21.4)	42.8 (24.0)
Disability*	42.5 (18.6)	46.8 (22.2)	27.9 (19.0)	33.3 (21.8)
The mean (standard deviation) change among included studies in outcomes scores between baseline and post-treatment at the final collection point for hyaluronic acid and placebo. An increase in outcome score represents improvement.
* Normalized to a maximal score of 100 possible points

FIGURE 2
Comparing effect sizes of hyaluronic acid therapy and saline placebo

Across studies, effect sizes were similar for hyaluronic acid therapy and placebo.

Discussion: Benefits are limited

Based on this meta-analysis, we cannot conclude that hyaluronic acid performs better than saline placebo for a reduction of pain or disability on the WOMAC. Some indication may be warranted for reduction in stiffness. It is notable that hyaluronic acid injection and saline placebo groups both experienced an improvement in pain, stiffness, and disability scores on the WOMAC.

We also cannot conclude that hyaluronic acid enhances functionality as evaluated on the Lequesne Index past 6 months post-treatment. In 2 studies,^7,19 patients with placebo actually showed reduced disability compared with patients in the hyaluronic acid group. While a short-term improvement in functionality was observed in other studies, this effect was not seen in follow-up reports greater than 6 months.

Comparisons with other meta-analyses

A recently published meta-analysis by Modawal et al²⁰ also pooled data to compare hyaluronic acid treatment to saline placebo. That meta-analysis was similar to ours in that it had relatively small sample size (n=11) and examined self-reported patient outcomes as the item of interest. The difference between this meta-analysis and ours is that the length of the evaluation periods for the other analysis was fairly short; the longest follow-up was 26 weeks. Our study examined the pooled effects of hyaluronic acid carried out to at least 24 weeks and up to 52 weeks. Their results for the short-term outcomes demonstrated significant decrease in pain in the active treatment group; however, these results diminished considerably when controlled for study quality.