The efficacy of multiple versus single Hyaluronic Acid injections: A systematic review and meta-analysis

Intra-articular injections of hyaluronic acid (HA) used in a 2–4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee osteoarthritis (OA), and was generally deemed safe with few or no treatment-related  adverse events (AEs) reported across studies.

Knee OA is a chronic inflammatory joint disorder with an estimated prevalence of 250 million people worldwide. It is characterized by joint pain, cartilage degeneration, and inflammation at the joints. Various treatments such as physical regimens, non-operative therapy (non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen) and intra-articular (IA) medicines such as corticosteroids and hyaluronic acid (HA) are available for the treatment of knee OA. Intra-articular HA is approved by Food and Drug Administration (FDA) and is being used since 1997 in the United States for knee OA.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) recommended against the use of IA-HA for knee OA. However, physician-specialty societies have recommended the IA-HA for the treatment of knee OA. For the patients who had the inadequate response to initial therapy, the American College of Rheumatology (ACR) recommended IA-HA for knee OA. The American Medical Society for Sports Medicine (AMSSM) also recommended HA for knee OA treatment. The OA Research Society International (OARSI) has an uncertain recommendation for the use of IA-HA in treating knee OA. Despite the availability of the number of evidence recommending the use of IA-HA in treating knee OA, the optimal treatment regimen and patient selection criteria is yet to be determined.

Therefore, Andrew Concof et al. conducted this systematic to evaluate the efficacy of IA-HA vs IA-Saline in patients with knee OA.

Rationale behind the research:

Although the number of clinical considerations recommended the use of IA-HA in treating knee OA, the optimal treatment regimen and patient selection criteria is yet to be determined.

Therefore, the present study was conducted to determine the efficacy of IA-HA vs. IA-Saline in patients with knee OA.

Objective:

To determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens.

Study outcome measures:

• Primary endpoint: The mean knee pain score at the reported follow-up nearest to 13 Weeks (3 months) or 26 weeks (6 months)
• Secondary endpoint: The number of treatment-related AEs and treatment-related serious adverse events (SAEs). Differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline were evaluated.

Time period: 13 weeks and 26 weeks 

Study Outcomes:

• Study characteristics and demographics:

Most of the included studies were conducted in Europe (63.3%), followed by North America (23.3%), Asia (10.0%) and Australia (3.3%). we included 26 double-blinded RCTs (86.7%) and four single-blinded RCTs (13.3%). A total of 5848 patients were included in this analysis. Of which four studies consisted 1196 patients who had single injections of IA-HA and sixteen studies consist of 2865 patients who had 2–4 injections, and about 1847 patients from eleven studies took ≥5 injections. One study (N = 63) reported administering 1–11 injections of IA-HA and was included in both the 2–4 injections subgroup and ≥5 injections subgroup. Mostly the low molecular weight HA was used (47%), followed by high molecular weight HA (43%) and moderate weight HA (10%).

• IA-HA versus IA-saline: Follow-up closest to 3 months (13 weeks):

Single injection was comprised of only one estimable study (Standard mean difference [SMD] = −0.03; −0.29 to 0.23). 2–4 injections of IA-HA vs. IA-Saline produced the largest effect size of the subgroups (SMD = −0.76; −0.98 to −0.53, 95% CI, p<0.00001). IA-HA injections ≥5 vs. IA-Saline produced a non-significant effect size estimate of −0.20 (−0.43 to 0.03, 95% CI, P=0.09). Test for subgroup differences were significant (p<0.00001). Heterogeneity was only observed for studies in the 2–4 injections subgroup (I2=19%) (Figure 1).

Figure 1: Efficacy of IA-HA injections closest to 3-months

• IA-HA versus IA-saline: Follow-up closest to 6 months (26 weeks):

Single injection studies yielded a non-significant treatment effect (SMD=−0.04; −0.20 to 0.13, 95% CI, P=0.67). IA-HA injections (2–4) vs. IA-Saline produced the largest significant effect size (SMD=−0.36; −0.63 to −0.09 95% CI, P=<0.00001). Studies with ≥5 injections of IA-HA vs. IA-Saline produced a significant effect size estimate of −0.18 (−0.35 to 0.01, 95% CI, P=0.04). Heterogeneity was observed for studies in the 2–4 injections subgroup (I2 = 82%) and ≥5 injections subgroup (I2 = 74%) (Figure 2).

Figure 2: Efficacy of IA-HA injections closest to 6-months

• Efficacy of IA-HA vs IA-saline: Dosage comparison:

No significant subgroup difference was observed when studies were analyzed by total dose of IA-HA administered (P=0.90) (Figure 3).

Figure 3: Total number of participants experiencing a treatment-related serious adverse event

• Treatment-related adverse events and serious adverse events for IA-HA vs. IA-saline:

There were no statistically significant differences in the total number of treatment-related AEs compared to saline injection for single injection of IA-HA vs IA-Saline (Risk ratio [RR] = 1.11; 0.93 to 1.32 95% CI, p = 0.26) or 2–4 injections of IA-HA vs IA-Saline (RR = 0.98; 0.87 to 1.09 95% CI, p = 0.67 (Figure 4).

Figure 4: Subgroup analysis of the efficacy of IA-HA by total dose administered

• Studies with ≥5 injections of IA-HA had statistically more treatment related AEs compared to IA-Saline (RR=1.70; 1.12 to 2.59 95% CI, p=0.01). Significant subgroup differences were observed between number of injections and treatment-related AEs (P=0.03), but not for treatment-related SAEs (Figure 5).

 Figure 5: Total number of participants experiencing a treatment-related adverse event

• Sensitivity analysis:

Four single-blinded studies were removed from the sensitivity analysis. The pooled effect size remained statistically significant with little change in total effect size when these single-blind studies were removed from the analysis (SMD=−0.19 [−0.25, −0.13], p<0.001). In studies with a follow-up closest to 6 months (26 weeks), removing one study in the ≥5 injections subgroup changed the subgroup results from significant to non-significant.

• Risk of bias:

Included studies demonstrated minimal bias with respect to categories of selection bias, detection bias, performance bias, attrition bias and reporting bias. Few studies failed to report methods of randomization and methods of blinding (Figure 6).

Figure 6: Risk of bias summary 

At both 3 and 6 months follow-up, it was demonstrated that the IA-HA was more useful in the treatment of knee OA pain compared to IA-Saline. Single injections of IA-HA were not significantly effective than saline at 3-month or 6- month follow-ups. The subgroup with ≥5 injections showed significant improvement in pain at 6 months only. The group with 2-4 injection demonstrated consistent results at both 3 and 6 months follow-up when compared to IA-Saline. The overall results showed most significant improvement at 3 months, as compared to 6 months follow-up. Bannuru and colleagues also showed the similar type of results. The present analysis demonstrated not only the overall pooled estimate for HA as a class benefitial for pain relief, but there also seem to be differences in effect as a result of the injection regimen provided.

The results of this study for evaluating the efficacy for 1 injection, 2–4 injections and ≥5 injections of IA-HA matched with a recently published RCT suggesting that the dosing regimen of IA-HA should help for the development of future guidelines on knee OA management. Zoboli et al. issued a RCT assessing whether a single 6 mL administration of HA has the same effectiveness as the three-weekly 2 mL dose. Recent evidence suggests products with a higher molecular weight (HMW) approximately ≥3000 kDa to provide more effictive outcomes than the lower molecular weight (LMW) products. This may be attributed to HMWs increased residency time off within the synovial fluid causing prolonged anti-inflammatory response within the joint. This study revealed that while molecular weight is an essential factor in the efficacy of HA products, the number of injections provided also plays a significant role in optimizing the efficacy in knee OA patients. This is particularly clear given that, although all single injection HA products were of a HMW, they did not demonstrate a reduction in pain comparable to the 2–4 injections subgroup, which included several studies of LMW HA products.

This study showed that administration of 3 injection regimen of a HA might be more effective than a single injection HMW product. Significantly more treatment-related AEs were observed in participants receiving ≥5 injections vs IA-Saline.

This study meta-analysis detected very few treatment-related severe AEs, with little or no events reported for all injection regimens. A study conducted by Miller and Block also showed the similar type of results as that of our research. A search of the grey literature or unpublished literature was not performed; however, authors scanned references in articles that met the inclusion criteria for literature not captured in the search. This report showed the differences between injection regimens of IA-HA for knee pain in OA. Future studies should directly compare different injection regimens of IA-HA in head-to-head RCTs.

In conclusion, the patients administered with 2–4 and ≥5 IA-HA injection regimens provided more pain relief over IA-Saline. More research is needed to investigate the effects of other parameters, such as product molecular weight, in the comparison of IA-HA injection treatment regimens.