Sage Journals: Discover world-class research

Abstract

Background:

Hip osteoarthritis is a debilitating condition that leads to progressive joint pain and stiffness. While total hip arthroplasty provides definitive treatment, intra-articular injections offer a less invasive alternative for patients. Several injection options are available, including corticosteroids (CS), hyaluronic acid (HA), and platelet-rich plasma (PRP). Previous reviews and network meta-analyses have compared the short-term efficacy of these injections, but it remains unclear if a particular injection provides superior symptom relief for up to 12 months.

Purpose:

To provide an updated summary of the current hip intra-articular injection literature and compare the efficacy of all injection types at 3 months, 6 months, and 12 months.

Study Design:

Systematic review; Level of evidence, 1.

Methods:

Four databases were queried: Web of Science, Embase, MEDLINE, and Cochrane Central Register of Controlled Trials. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index Total Score (WOMAC–Total) and the visual analog scale (VAS) at 3, 6, and 12 months. The Cochrane risk-of-bias tool was used to assess study quality. Treatment effects were expressed as mean differences for the WOMAC–Total and standardized mean differences for the VAS.

Results:

A total of 14 studies were included in the final analysis with 1254 participants. Eight unique intra-articular injection types were identified: CS, HA of varying molecular weights (low, high, and ultra-high), PRP, CS + high molecular weight HA, PRP + HA, and standard of care/placebo (SOC/PBO) group. When compared with SOC/PBO, no statistically significant differences in WOMAC–Total and VAS outcomes were observed between any injections at 3, 6, or 12 months.

Conclusion:

There were no statistically significant differences in WOMAC–Total and VAS outcomes at any time point between all injection types to baseline. Future studies should compare the long-term efficacy of various intra-articular injections with a control and examine the efficacy of combined injections.

Registration:

CRD42024574937 (PROSPERO identifier).

Keywords

hip osteoarthritis intra-articular injection network meta-analysis

Hip osteoarthritis (OA) is a debilitating condition that causes pain and stiffness, which can substantially affect patients’ physical function, mental health, and overall quality of life.^29,46 Many patients suffer from hip OA, as it is estimated to affect 7.95% of the adult population in North America and 12.59% in Europe.¹⁸ While severe hip OA can be definitively treated with total hip arthroplasty, the procedure may not be suitable for all patients based on the associated risks of the surgery and patients’ own preferences. An alternative to total hip arthroplasty is intra-articular injections, which provide temporary symptom alleviation for patients. Several injection options are available on the market, including corticosteroids (CS), hyaluronic acid (HA), and platelet-rich plasma (PRP).^19,21 Different types of intra-articular injections act in different ways to relieve hip OA symptoms. For example, CS inhibits the activity of proinflammatory cytokines and helps reduce inflammation by attenuating the immune system.³¹ PRP is derived from autologous blood and contains a high concentration of platelets, growth factors (eg, vascular endothelial growth factor and platelet-derived growth factor), and immunomodulatory cytokines (eg, interleukin 1–beta, IL-1Ra).⁵² It has been suggested that immunomodulatory cytokines reduce inflammation in the joint space, ultimately alleviating hip OA symptoms.¹ Last, HA alleviates OA by providing chondroprotective, anti-inflammatory, and lubrication effects in the joint space.^17,23 Given the diverse intra-articular injection options, it can be challenging for clinicians and patients to choose the best option. Hence, it is clinically important to determine the relative efficacy of injections. Elucidating the relative efficacy of these injections will improve outcomes, guide protocols, and optimize the use of health care resources.

Prior reviews and network meta-analyses (NMAs) offer important contributions to the field, but existing results have been based on short-term follow-up durations (eg, up to 6 months for Gazendam et al²¹) or outdated database searches (eg, Zhao et al⁵¹). Zhao et al also did not differentiate between different formulations of HA, such as high molecular weight (HMW-HA) versus low molecular weight (LMW-HA), and some evidence suggests they may vary in efficacy.^7,37,49,50 Results from existing NMAs are also inconsistent. Gazendam et al²¹ is the most recent synthesis of the literature and compared the efficacy of HA, CS, and PRP with up to 6 months of follow-up. The authors reported no difference in symptom alleviation between HA, CS, PRP, and PRP + HA compared with controls. Zhao et al compared HA, PRP, CS, and PRP + HA with controls. They reported significant advantages of HA and CS in reducing pain at 3 months compared with controls (saline or local anesthetic injections). The conflicting results in the literature leave the comparative efficacy of available injections unclear.

The current study updates prior work by extending follow-up to 12 months, incorporating new randomized controlled trials (RCTs) published since 2021, and differentiating molecular weight formulations of HA. Compared with a conventional meta-analysis, which only synthesizes outcomes from direct comparisons, NMA facilitates indirect comparisons among treatments within the same network.²⁰ These indirect comparisons are advantageous in the presence of literature gaps or limited sample sizes.¹¹ The current NMA will evaluate the efficacy of intra-articular injections for managing hip OA at 3, 6, and 12 months.

Methods

This systematic review and NMA was prospectively registered on PROSPERO. We adhered to The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (see complete checklist in Appendix Table A1).²⁵

Study Identification

Four databases were systematically searched for relevant studies from inception to November 20, 2023: Web of Science (Core Collection), Embase, MEDLINE, and Cochrane Central Register of Controlled Trials (CENTRAL). No language or date limits were applied. The search strategy included key terms covering hip OA, injection options, and delivery routes. The complete search strategy is available in Supplemental Material Tables S2 to S5 (available separately). The reference section of previous reviews was also searched for relevant articles.

Inclusion criteria for this review included RCTs investigating adult patients (≥18 years of age) with a diagnosis of hip OA. To be eligible, studies were required to assess the use of intra-articular injections, have a minimum follow-up period of ≥3 months, and report the mean and standard deviation of the Western Ontario and McMaster Universities Osteoarthritis Index Total Score (WOMAC–Total) and the visual analog scale (VAS). The exclusion criteria included studies not available in English, unpublished studies, and cadaveric studies. Additionally, we excluded crossover RCTs, pseudo-randomized RCTs, case studies, case series, retrospective observational studies, and any trial that did not report the mean and standard deviation for WOMAC–Total and VAS.

Two reviewers (C.L. and J.D.) independently screened the articles in duplicate. Eligible studies compared any intra-articular injection therapy with another injection. Studies deemed eligible by both reviewers then underwent subsequent independent full-text screening. Disagreements between the 2 reviewers were resolved through discussion, with 2 authors (D.L.L. and A.A.) providing additional consultation if needed.

Data Extraction

Two reviewers (C.L. and J.D.) performed data extraction independently and in duplicate using a standardized data extraction form established a priori. Discrepancies during extraction were resolved through discussions between the 2 reviewers. From each included article, the following information was extracted: publication year, number of participants, number of hip joints, mean age, mean body mass index, adverse events (AEs), severe adverse events (SAE), and the Kellgren-Lawrence (KL) grade. We extracted the WOMAC–Total score and the VAS score at baseline, 3 months, 6 months, and 12 months.

Risk of Bias

The revised Cochrane risk-of-bias tool for randomized trials (RoB2) was used to evaluate the risk of bias for all articles.⁴⁵ The 2 reviewers independently assessed the risk of bias for all articles, and conflicts were resolved with consultation with 2 other authors of the team (D.L.L. and A.A.).

Statistical Analysis

All statistical analyses were completed on R Statistical Software (Version 1.4.1717) using the netmeta package.^3,36 For direct comparisons, pairwise meta-analyses were conducted to estimate pooled mean differences and 95% CIs for WOMAC–Total outcomes. For VAS, we calculated the standardized mean differences because of heterogeneity in scale formats across studies. For example, some studies used a 0 to 10 scale (eg, Di Sante et al¹⁶), while others used a 0 to 100 scale (eg, Rezende et al³⁸).

Statistical significance was determined based on the 95% CIs. A comparison was considered statistically significant if the confidence interval did not include the null value. A random-effects model was used to account for potential heterogeneity across studies, with between-study variance (τ²) estimated using the DerSimonian-Laird method.¹⁵ Heterogeneity was further quantified using the I² statistic. An I² value of 0% indicated no observed heterogeneity, while higher values reflected increasing inconsistency among study results.²⁴ In contrast to traditional direct comparisons, NMA evaluated both direct and indirect evidence across a network of treatments. Probability scores (P-scores) were derived from networks and were used to compare the relative efficacy between injections. P-scores are frequentist analogs to the Surface Under the Cumulative Ranking (SUCRA) scores in Bayesian NMAs.⁴⁰ P-scores are derived from point estimates and standard errors of treatment effects. Similar to SUCRA scores, P-scores measure the mean extent of certainty that one injection type is better than another. Unlike SUCRA, P-scores do not reflect Bayesian probability-based ranking and do not require resampling methods.⁴⁰ P-scores range from 0 to 1. A P-score close to 1 indicates that a particular injection is likely the most effective compared with all other injections. In contrast, a P-score of 0 indicates that the treatment is likely the least effective.

A network plot was created to illustrate the relationship between injections among included studies. The size of the nodes was proportional to the number of studies evaluating each injection, and the thickness of the edges represented the relative number of direct connections between the connected nodes. Isolated nodes indicated a lack of direct comparison, which could limit the precision of indirect estimates.

Results

After removing duplicates, a total of 1909 studies were identified. After title and abstract review, 63 studies progressed to full-text review and were assessed for eligibility. Ultimately, 14 studies met the inclusion criteria and were included in the final analysis (Figure 1).

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. The PRISMA flow diagram is adapted from the template outlined in Page et al.³⁴

Study Characteristics

Across all injections, the 14 included studies covered a total of 1254 participants. Table 1 summarizes all included articles. Eight different intra-articular injections were included in the current NMA: (1) CS, (2) ultra–high molecular weight hyaluronic acid (UHMW-HA), (3) HMW-HA, (4) LMW-HA, and (5) PRP. Additionally, combination therapies including (6) CS plus HMW-HA (CS + HMW-HA), (7) PRP plus HMW-HA (PRP + HMW-HA) and standard of care/placebo (SOC/PBO) were included. The (SOC/PBO) group served as a comparator when possible, and included participants who received saline or local anesthetic injections (eg, Migliore et al³² used mepivacaine, Richette et al³⁹ used saline water). Some studies included a noninjection arm. For example, Paskins et al³⁵ had a noninjection arm, which educated patients on noninjection ways to alleviate symptoms, such as exercise and weight loss. These noninjection groups were excluded from the final analysis. The network diagram for WOMAC–Total and VAS at 3 months, 6 months, and 12 months can be found in the Supplemental Material (Figures S1 and S2, available separately).

Table 1

Summary of Participant Demographics ^a

Study	Injections	Total Participants	Total Hip Joints	KL 1Hips	KL 2 Hips	KL 3 Hips	KL 4 Hips	Age, Mean (SD)	BMI, Mean (SD)
Battaglia 2013⁴	HMW-HA	50	50	NR	23	23	4	56 (12)	27 (4)
	PRP	50	50	NR	16	21	13	51(12)	26(5)
Clementi 2018¹⁰	UHMW-HA	23	23	NR	NR	23	NR	65.9(10.02)	27.2(2.38)
	HMW-HA	27	27	NR	NR	27	NR	67.4(10.3)	26.2(5.15)
Dallari 2016¹³	HMW-HA	36	37	10	5	12	10	NR	NR
	PRP	44	47	14	10	10	13	NR	NR
	PRP+HMW-HA	31	33	8	8	14	3	NR	NR
Rezende 2020³⁸	CS	19	28	NR	18	12	NR	60.1(12.8)	29.6(4.6)
	CS+HMW-HA	63	104	NR	65	39	NR	62.5(12.34)	28.52(5.89)
Di Sante 2016¹⁶	HMW-HA	22	22	NR	7	15	NR	73.62(7.87)	NR
	PRP	21	21	NR	5	16	NR	71.37(6.03)	NR
Kraeutler 2021²⁷	LMW-HA	13	14	NR	2	12	NR	53.6(7.6)	23.5(2.0)
	PRP	18	19	NR	7	12	NR	53.3(8.4)	23.7(2.1)
Migliore 2009³²	Local anesthetic	20	27	NR	3	15	2	67(7.2)	24.8(4.1)
	HMW-HA	22	34	NR	1	21	NR	68(10.3)	25.6(2.2)
Nouri 2022³³	HMW-HA	29	29	NR	16	13	NR	60.93(4.54)	27.62(2.25)
	PRP	32	32	NR	16	15	NR	58.22(5.1)	27.72(2.11)
	PRP+HMW-HA	31	31	NR	17	14	NR	60.29(4.83)	27.94(2.8)
Paskins 2022³⁵	Local anesthetic	66	85	NR	NR	NR	NR	62.3(9.8)	28.4(4.9)
	Local anesthetic+ CS	66	80	NR	NR	NR	NR	62.5(9.3)	29.5(5.6)
Richette 2009³⁹	Saline	43	43	NR	4	39	NR	59.5(12.6)	26.4(4.2)
	HMW-HA	42	42	NR	7	35	NR	60.8(10.2)	26.7(4.2)
Setaro 2020⁴¹	HMW-HA	32	32	NR	NR	32	NR	62.5(11.4)	26.2(3.7)
	LMW-HA	32	32	NR	NR	32	NR	65.4(10.7)	27.9(2.8)
Spitzer 2010⁴⁴	HMW-HA	156	174	NR	57	99	NR	59(12)	29.3(5.5)
	CS	156	169	NR	66	90	NR	59(11)	29.4(6.0)
Tikiz 2005⁴⁷	HMW-HA	18	24	1	7	16	NR	60.4(9.6)	29.8(3.9)
	LMW-HA	25	32	2	10	29	NR	58.8(9.8)	28.7(4.3)
Villanova-Lopez 2020⁴⁸	HMW-HA	36	36	13	19	4		61.1(12.3)	28.4(4.5)
	PRP	38	38	14	18	6		61.2(9.72)	28.6(4.2)

Levels of hip osteoarthritis severity are reported as KL grade. Overall, HA was the most studied treatment. Note that in Rezende et al,³⁸ the 4-mL hylan G-F20 arm showed an inconsistency in the KL grade reported: 36 hips were included, but only 24 KL 2 and 10 KL 3 hips were accounted for. Villanova-Lopez⁴⁸ combined KL 3 and 4. We reported the data the authors presented. BMI, body mass index; CS, corticosteroids; HA, hyaluronic acid; HMW, high molecular weight; KL, Kellgren-Lawrence; LMW, low molecular weight; NR, not reported by the authors or not applicable to the study; PRP, platelet-rich plasma; UHMW, ultra–high molecular weight.

Risk of Bias

Based on the RoB2 assessment, 8 studies were rated as having a low risk of bias, and 6 studies were rated as having some concerns regarding risk of bias (Figure 2). Most of the bias arose from the randomization process, missing data, and reported results.

Figure 2.

Summary plot for risk of bias. Six studies had some concerns for risk of bias. Bias arose from domain 1 (bias arising from the randomization process), domain 3 (bias due to missing outcome data), and domain 5 (bias in selection of the reported result).

WOMAC–Total

At 3 months, 6 articles reported the WOMAC–Total score for 5 injections involving 305 participants.^{10,27,38,39,41,47} Results from these 6 articles showed no difference in WOMAC–Total between all injections and SOC/PBO (Figure 3) (τ² = 0.0; I² = 0.0%). At 6 months, 9 articles reported 8 injections, covering 941 participants.^** These 9 studies also indicated no difference in WOMAC–Total score between all injection types and placebo (Figure 4) (τ² = 24.42; I² = 59% [95% CI, 0.0%-83.4%]). At 12 months, 5 articles reported the WOMAC–Total score for 4 injections involving 301 participants.^{10,27,38,41,48} Since no articles reported WOMAC–Total outcomes with SOC/PBO, PRP was set as the baseline, and there was no significant difference between other injections with PRP (Figure 5) (τ² = 0.0; I² = 0.0%).

Figure 3.

In WOMAC–Total at 3 months, there was no statistically significant difference between all injections and SOC/PBO. HMW-HA ranked highest on the P score. HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; MD, mean difference; PRP, platelet-rich plasma; UHMW, ultra–high molecular weight; SOC/PBO, standard of care/placebo; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 4.

In WOMAC–Total at 6 months, there was no statistically significant difference between all injections and SOC/PBO. PRP+HMW-HA ranked highest on the P score. CS, corticosteroids; HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; MD, mean difference; PRP, platelet-rich plasma; UHMW, ultra–high molecular weight; SOC/PBO, standard of care/placebo; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 5.

In WOMAC–Total at 12 months, no studies reported results for a standard of care/placebo, so different injection options were compared against PRP. There was no statistically significant difference between all injections against PRP, and PRP ranked highest on the P score. HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; MD, mean difference; PRP, platelet-rich plasma; UHMW, ultra–high molecular weight; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Based on P-score rankings, HMW-HA was the highest-ranking injection at 3 months (P-score, .65). At 6 months, PRP + HMW-HA was the highest-ranking injection (P-score, .86). At 12 months, PRP was the highest-ranking injection (P-score, .71).

Visual Analog Scale

At 3 months, 6 articles reported pain outcomes covering 381 participants.^{4,10,32,38,41,47} There was no difference between 4 different types of injection treatments against SOC/PBO (Figure 6) (τ² = 0.24; I² = 74.2% [95% CI, 28.0%-90.8%]). At 6 months, 7 articles reported 7 injections, involving 497 participants, with no difference across all injection types to SOC/PBO (Figure 7) (τ² = 0.18; I² = 74.1% [95% CI, 44.7%-87.9%]).^{4,32,33,38,41,47,48} Finally, at 12 months, 6 articles reported VAS, comparing 5 different injections and including 481 participants.^{4,10,13,38,41,48} However, no article reported outcomes for SOC/PBO at 12 months, so PRP was used as the baseline. All injections had no significant difference compared with PRP at 12 months (Figure 8) (τ² = 0.16; I² = 73.6% [95% CI, 26.1%-90.6%]).

Figure 6.

In the visual analog scale at 3 months, there was no statistically significant difference between all injections and SOC/PBO. LMW-HA ranked highest on the P score. HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; SMD, standardized mean difference; PRP, platelet-rich plasma; SOC/PBO, standard of care/placebo; UHMW, ultra–high molecular weight.

Figure 7.

In the visual analog scale at 6 months, there was no statistically significant difference between all injections and SOC/PBO. PRP ranked highest on the P score. HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; SMD, standardized mean difference; PRP, platelet-rich plasma; SOC/PBO, standard of care/placebo; UHMW, ultra–high molecular weight.

Figure 8.

In the visual analog scale at 12 months, no studies reported results for SOC/PBO, so different injection options were compared against PRP. There was no statistically significant difference between all treatments against PRP, and LMW-HA ranked highest on the P score. HA, hyaluronic acid; HMW, high molecular weight; LMW, low molecular weight; SMD, standardized mean difference; PRP, platelet-rich plasma; SOC/PBO, standard of care/placebo; UHMW, ultra–high molecular weight.

At 6 months, PRP was likely the highest-ranking injection (P-score, .77). At 12 months, LMW-HA was the highest-ranking injection (P-score, .84)

Safety Profile

Nine studies reported AEs related to the injection (Table 2).^†† The most commonly reported AE was injection-site pain, which was reported across 7 studies affecting 38 participants.^{4,13,32,35,39,44,47} Three studies reported 4 SAEs.^35,39,44 The SAEs included 1 case of rapidly destructive OA requiring hip replacement, 1 case of subacute bacterial endocarditis, 1 case of spontaneous abortion, and 1 case of choroidal dystrophy (Table 3).

Table 2

Adverse Reactions ^a

Study	Treatment Arm	AE Reported	n/N (%)
Battaglia 2013⁴	HMA-HA	Injection-site pain	10/50 (20.0)
	PRP	Injection-site pain	6/50 (12.0)
Dallari 2016¹³	PRP + HMW-HA	Injection-site pain	13/31 (41.9)
Rezende 2020³⁸	CS	Rapid progression to KL grade 4	1/19 (5.3)
	CS+HMW-HA	Rapid progression to KL grade 4	4/63 (6.5)
Migliore 2009³²	Local anesthetic	Injection-site pain	1/20 (5.0)
	HMW-HA	Hip pain	1/22 (4.5)
Paskins 2022³⁵	Local anesthetic	Whitening of skin	2/66 (3.0)
		Thinning of skin	2/66 (3.0)
		Bruising	16/66 (24.2)
		Injection-site pain	7/66 (10.6)
		Other skin problems	2/66 (3.0)
		Infection	1/66 (1.5)
		Anxiety	1/66 (1.5)
	Local anesthetic + CS	Whitening of skin	4/66 (6.1)
		Thinning of skin	2/66 (3.0)
		Bruising	15/66 (25.7)
		Injection-site pain	1/66 (1.5)
		Flushing	4/66 (6.1)
		Menorrhagia	1/66 (1.5)
		Infection	1/66 (1.5)
		Anxiety	1/66 (1.5)
Richette 2009³⁹	Saline	Injection-site pain	1/43 (2.3)
		Exacerbation of hip pain	1/43 (2.3)
	HMW-HA	Injection-site pain	3/42 (7.1)
		Pruritus	1/42 (2.4)
		Hematoma	1/42 (2.4)
Spitzer 2010⁴⁴	HMW-HA	Arthralgia	10/156 (6.4)
		Stiffness	3/156 (1.9)
		Asthenia	1/156 (0.6)
		Groin pain	1/156 (0.6)
		Injection-site pain	1/156 (0.6)
	CS	Arthralgia	7/156 (4.5)
		Groin pain	1/156 (0.6)
		Dizziness	1/156 (0.6)
		Feeling hot	1/156 (0.6)
		Hypoesthesia	1/156 (0.6)
		Injection-site pain	1/156 (0.6)
		Muscle spasms	1/156 (0.6)
		Pain in extremity	2/156 (1.2)
		Paraesthesia	1/156 (0.6)
Tikiz 2005^{† 47}	LMW-HA	Injection-site pain/swelling	3/32 (9.4)
	HMW-HA	Injection-site pain/swelling	3/24 (12.5)

AE, adverse event; n, number of participants who reported the specified AE; N, total number of participants in that arm; CS, corticosteroids; HA, hyaluronic acid; HMW, high molecular weight; KL, Kellgren-Lawrence; LMW, low molecular weight; PRP, platelet-rich plasma.

†

For Tikiz 2005, n is the number of hips, and N is the total number of hips.

Table 3

Severe Adverse Reactions ^a

Study	Treatment Arm	AE Reported	n/N (%)
Richette 2009³⁹	HMW-HA	Rapidly destructive OA requiring hip replacement	1/42 (2.4)
Paskins 2022³⁵	Local anesthetic + CS	Subacute bacterial endocarditis	1/66 (1.5)
Spitzer 2010⁴⁴	HMW-HA	Spontaneous abortion	1/156 (2.4)
	CS	Choroidal dystrophy	1/156 (0.6)

AE, adverse effect; CS, corticosteroids; HA, hyaluronic acide; HMW, high molecular weight; OA, osteoarthritis.

Discussion

This study provides an updated review and comparison of intra-articular injections for hip OA. The current NMA included 8 different types of intra-articular injections for hip OA: CS, PRP, LMW-HA, HMW-HA, UHMW-HA, PRP + HMW-HA, CS + HMW-HA, and SOC/PBO. The efficacy of these injections was assessed on WOMAC–Total and VAS. We found no statistically significant differences between all injections at 3 months, 6 months, and 12 months on WOMAC–Total and VAS.

The NMA-derived P-scores suggest that some injections may be superior at specific time points, even though direct comparisons revealed no statistically significant differences between them. It is important to acknowledge that P-scores do not directly provide a measure of statistical significance. Instead, P-scores rank injections based on their probability of being superior, considering the point estimates and standard errors across the network.⁴⁰ P-scores should always be interpreted in the context of confidence intervals. While an injection with the highest P-score may appear superior, a confidence interval that includes zero indicates that the difference compared with SOC/PBO is statistically insignificant and the evidence may be inconclusive.⁸

The current NMA shows no statistically significant difference between UHMW-HA, HMW-HA, and LMW-HA. The current evidence adds to the existing literature, which has been inconsistent regarding whether molecular weights affect efficacy. Some evidence suggests that HMW-HA is better than LMW-HA for managing OA symptoms.^37,49,50 Others have argued that they are comparable.^{2,12,22,28,42} While we report variations in P-score rankings between UHMW-HA, HMW-HA, and LMW-HA, the P-scores alone are insufficient to conclude if one HA formulation is better than another. The rapid degradation of materials in the joint space could account for the lack of significant long-term differences between HA formulations and across all studied injections. For instance, the terminal half-life of corticosteroids in the joint space is less than a week.¹⁴ Their relatively short half-life could contribute to their short period of efficacy. It has been suggested that HA with a higher molecular weight is better at resisting degradation in the joint space, but results of our NMA do not support this theory.^7,17,30 The lack of significant long-term differences across all injections reflects the complex pathophysiology of hip OA, and no single treatment can address all aspects of the disease process.

Results from the current NMA have important implications for both clinical practice and future research. Our results show that no injection is superior. Practically, this means clinicians do not need to favor one type over another based solely on efficacy. Instead, factors such as patient preference, cost, and availability can play a larger role in the shared decision-making process. For patients, knowing that all injections perform similarly could have important implications for the cost of care, as some health care systems or insurance plans may only cover certain injections but not others.⁵ Our review of the literature also reveals a gap: no studies have compared an injection with a SOC/PBO group at 12 months of follow-up. This gap makes it difficult to infer if any injection provides benefits beyond SOC/PBO in the long term.

Another gap in the literature is the limited evidence on combination therapies, such as PRP + HMW-HA and CS + HMW-HA. Only 3 studies in our review used a combination therapy. Theoretically, combination therapies provide better symptom alleviation by combining the complementary benefits of different injections. For example, PRP offers regenerative and immunomodulatory effects, while HA contributes mechanical and anti-inflammatory benefits.^9,26 Although our findings indicate no statistically significant advantage for combination therapies, the lack of significant differences may be due to the limited evidence in the literature and the small sample sizes of the 3 included studies. Meta-analyses in knee OA suggest that combination therapy is more advantageous than single therapy.^26,43 However, these findings should be interpreted with caution since current evidence relies on a limited number of primary studies.

Limitations

This study is not without its limitations. We were unable to stratify outcomes by KL grade because the included studies did not report results stratified by KL grade. None of the included studies had an SOC/PBO group at 12 months, which limited our ability to compare the efficacy of injections against a baseline. Finally, heterogeneity is an inherent limitation of NMAs, as variability across included studies introduces bias.¹¹ The P value does not adjust for the uncertainty or heterogeneity in the network. Injections with wide confidence intervals or high variability may still receive high P values.¹¹ Given that the current NMA only included 14 trials, we acknowledge that the P value should be interpreted with caution, as the P value ranking may fluctuate with the addition of future studies.

Conclusion

This systematic review and NMA evaluated the efficacy of intra-articular injections for reducing hip OA symptoms. We compared 8 types of injections at 3, 6, and 12 months and found no significant differences among all injection types at any time point. There is a lack of placebo-controlled trials with longer-term follow-up, which reflects a gap in the literature. Further research on biologic treatments and combination therapies is needed to clarify their comparative efficacy for hip OA.

Footnotes

Appendix

Appendix Table A5

Cochrane Central Register of Controlled Trials (CENTRAL) Search Strategy ^a

Line #	Search statement	Results
#1	(platelet-rich or platelet-derived or (platelet NEAR/3 (concentrate or plasma or gel or fibrin or growth factor or lysate)) or "PRP" or "PRGF" or "PRF" or (autologous NEAR/3 (plasma or protein)) or "APS" or "ACP"):ti,ab	10,120
#2	MeSH descriptor: [Platelet-Rich Plasma] explode all trees	967
#3	(steroid* or cortico* or glucocortico* or dexamethason* or methylprednisolon* or betamethason* or triamcinolon* or hydroxycortico* or hydrocort* or cortison* or prednison* or prednisolon*):ti,ab	81,282
#4	MeSH descriptor: [Steroids] explode all trees	68,923
#5	MeSH descriptor: [Dexamethasone] explode all trees	5687
#6	MeSH descriptor: [Methylprednisolone] explode all trees	3109
#7	MeSH descriptor: [Prednisolone] explode all trees	5586
#8	MeSH descriptor: [Prednisone] explode all trees	4497
#9	MeSH descriptor: [Hydrocortisone] explode all trees	6812
#10	MeSH descriptor: [Cortisone] explode all trees	178
#11	MeSH descriptor: [Betamethasone] explode all trees	1655
#12	MeSH descriptor: [Triamcinolone] explode all trees	1648
#13	(orthobiolog* or prolotherap* or ((proliferat* or regenerat* or biolog) NEAR/5 (therap or inject)) or "MSC" or "MSCs" or allogen or stem cell* or mesenchymal or stromal or progenitor or (marrow NEAR/3 (concentrat* or aspirat)) or "BMAC" or (adipo NEAR/3 (microfrag* or micro-frag)) or lipoaspirat or "SVF" or "ASA" or placent* or umbilic* or amnio*):ti,ab	68,957
#14	MeSH descriptor: [Prolotherapy] explode all trees	42
#15	MeSH descriptor: [Cell- and Tissue-Based Therapy] explode all trees	8748
#16	MeSH descriptor: [Stem Cells] explode all trees	1152
#17	MeSH descriptor: [Biological Products] explode all trees	34,103
#18	(hyaluron* or hylan* or viscosup* or synvisc* or orthovisc* or monovisc* or durolane):ti,ab	5451
#19	MeSH descriptor: [Hyaluronic Acid] explode all trees	2139
#20	MeSH descriptor: [Viscosupplementation] explode all trees	62
#21	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20	238,487
#22	(intra-articular or inject* or intraarticular):ti,ab	109,409
#23	MeSH descriptor: [Injections] explode all trees	25,077
#24	#22 or #23	121,597
#25	(osteoarthr* or arthr* or degenerat*):ti,ab	68,198
#26	hip:ti,ab,kw	29,415
#27	#25 and #26	8684
#28	MeSH descriptor: [Osteoarthritis, Hip] explode all trees	1235
#29	#27 or #28	8833
#30	#21 and #24 and #29	407
#31	#30 in Trials	402

MeSH, Medical Subject Headings.

Final revision submitted November 17, 2025; accepted December 22, 2025.

The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

ORCID iDs

Chunlin Liu

Jiawen Deng

Darius Luke Lameire

**

References 10, 13, 27, 33, 35, 38, 41, 44, .

††

References 4, 6, 13, 32, 33, 35, 38, 39, .

References

Anitua

Sánchez

Orive

Padilla

A biological therapy to osteoarthritis treatment using platelet-rich plasma. Expert Opin Biol Ther. 2013;13(8):1161-1172. doi:10.1517/14712598.2013.801450

Bahrami

Raeissadat

Cheraghi

Rahimi-Dehgolan

Ebrahimpour

Efficacy of single high-molecular-weight versus triple low-molecular-weight hyaluronic acid intra-articular injection among knee osteoarthritis patients. BMC Musculoskelet Disord. 2020;21(1):550. doi:10.1186/S12891-020-03577-8

Balduzzi

Rücker

Nikolakopoulou

, et al. Netmeta: an R package for network meta-analysis using frequentist methods. J Stat Softw. 2023;106(2):1-40. doi:10.18637/jss.v106.i02

Battaglia

Guaraldi

Vannini

, et al. Efficacy of ultrasound-guided intra-articular injections of platelet-rich plasma versus hyaluronic acid for hip osteoarthritis. Orthopedics. 2013;36(12):e1501-e1508. doi:10.3928/01477447-20131120-13

Berlinberg

Swindell

Patel

, et al. The epidemiology of platelet-rich plasma injections from 2010 to 2020 in a large US commercial insurance claims database: a recent update. J Am Acad Orthop Surg. 2023;31(3):e135-e147. doi:10.5435/JAAOS-D-22-00397

Brander

Skrepnik

Petrella

Jiang

Accomando

Vardanyan

Evaluating the use of intra-articular injections as a treatment for painful hip osteoarthritis: a randomized, double-blind, multicenter, parallel-group study comparing a single 6-mL injection of hylan G-F 20 with saline. Osteoarthritis Cartilage. 2019;27(1):59-70. doi:10.1016/j.joca.2018.08.018

Brandt

Smith

Simon

LS.

Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: what is the evidence?

Arthritis Rheum. 2000;43(6):1192-1203. doi:10.1002/1529-0131(200006)43:6%3C1192::AID-ANR2%3E3.0.CO;2-L

Brignardello-Petersen

Florez

Izcovich

, et al; GRADE Working Group. GRADE approach to drawing conclusions from a network meta-analysis using a minimally contextualised framework. BMJ. 2020;371:M3900. doi:10.1136/bmj.m3900

Ciapini

Simonettii

Giuntoli

, et al. Is the combination of platelet-rich plasma and hyaluronic acid the best injective treatment for grade II-III knee osteoarthritis? A prospective study. Adv Orthop. 2023;2023:1868943. doi:10.1155/2023/1868943

10.

Clementi

D’Ambrosi

Bertocco

, et al. Efficacy of a single intra-articular injection of ultra-high molecular weight hyaluronic acid for hip osteoarthritis: a randomized controlled study. Eur J Orthop Surg Traumatol. 2018;28(5):915-922. doi:10.1007/S00590-017-2083-9

11.

Cote

Lubowitz

Brand

Rossi

MJ.

Understanding network meta-analysis (NMA) conclusions requires scrutiny of methods and results: introduction to NMA and the geometry of evidence. Arthroscopy. 2021;37(7):2013-2016. doi:10.1016/j.arthro.2021.04.070

12.

Dai

Lin

Guo

Shi

Wang

Efficacy and safety of hylan versus hyaluronic acid in the treatment of knee osteoarthritis. J Knee Surg. 2019;32(3):259-268. doi:10.1055/S-0038-1641142/ID/JR170258OA-30/BIB

13.

Dallari

Stagni

Rani

, et al. Ultrasound-guided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis. 2016;44(3):664-671. doi:10.1177/0363546515620383

14.

Derendorf

Möllmann

Grüner

Haack

Gyselby

Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration. Clin Pharmacol Ther. 1986;39(3):313-317. doi:10.1038/clpt.1986.45

15.

DerSimonian

Laird

Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188. doi:10.1016/0197-2456(86)90046-2

16.

Di Sante

Villani

Santilli

, et al. Intra-articular hyaluronic acid vs platelet-rich plasma in the treatment of hip osteoarthritis. Med Ultrason. 2016;18(4):463-468. doi:10.11152/MU-874

17.

Elmorsy

Funakoshi

Sasazawa

Todoh

Tadano

Iwasaki

Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model. Osteoarthritis Cartilage. 2014;22(1):121-127. doi:10.1016/j.joca.2013.10.005

18.

Fan

Yan

Liu

, et al. The prevalence of hip osteoarthritis: a systematic review and meta-analysis. Arthritis Res Ther. 2023;25(1):51. doi:10.1186/S13075-023-03033-7

19.

Ferrara

Codazza

Coraci

Malerba

Ferriero

Ronconi

State of art in intra-articular hip injections of different medications for osteoarthritis: a systematic review. BMC Musculoskelet Disord. 2021;22(2):997. doi:10.1186/s12891-021-04866-6

20.

Florez

De La Cruz-Mena

Veroniki

AA.

Network meta-analysis: a powerful tool for clinicians, decision-makers, and methodologists. J Clin Epidemiol. 2024;176:111537. doi:10.1016/j.jclinepi.2024.111537

21.

Gazendam

Ekhtiari

Bozzo

Phillips

Bhandari

Intra-articular saline injection is as effective as corticosteroids, platelet-rich plasma and hyaluronic acid for hip osteoarthritis pain: a systematic review and network meta-analysis of randomised controlled trials. Br J Sports Med. 2021;55(5):256-261. doi:10.1136/BJSPORTS-2020-102179

22.

Gigis

Fotiadis

Nenopoulos

Tsitas

Hatzokos

Comparison of two different molecular weight intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis. Hippokratia. 2016;20(1):26.

23.

Gupta

Lall

Srivastava

Sinha

Hyaluronic acid: molecular mechanisms and therapeutic trajectory. Front Vet Sci. 2019;6:192. doi:10.3389/FVETS.2019.00192

24.

Higgins

JPT

Thompson

SG.

Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558. doi:10.1002/SIM.1186

25.

Hutton

Salanti

Caldwell

, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784. doi:10.7326/M14-2385

26.

Karasavvidis

Totlis

Gilat

Cole

BJ.

Platelet-rich plasma combined with hyaluronic acid improves pain and function compared with hyaluronic acid alone in knee osteoarthritis: a systematic review and meta-analysis. Arthroscopy. 2021;37(4):1277-1287.e1. doi:10.1016/j.arthro.2020.11.052

27.

Kraeutler

Houck

Garabekyan

Miller

Dragoo

Mei-Dan

Comparing intra-articular injections of leukocyte-poor platelet-rich plasma versus low–molecular weight hyaluronic acid for the treatment of symptomatic osteoarthritis of the hip: a double-blind, randomized pilot study. Orthop J Sports Med. 2021;9(1):2325967120969210. doi:10.1177/2325967120969210

28.

Lee

Kim

Lim

, et al. Comparison between high and low molecular weight hyaluronates in knee osteoarthritis patients: open-label, randomized, multicentre clinical trial. J Int Med Res. 2006;34(1):77-87. doi:10.1177/147323000603400110

29.

Lespasio

Sultan

Piuzzi

, et al. Hip osteoarthritis: a primer. Perm J. 2018;22:17-84. doi:10.7812/TPP/17-084

30.

Lindqvist

Tolmachev

Kairemo

Åström

Jonsson

Lundqvist

Elimination of stabilised hyaluronan from the knee joint in healthy men. Clin Pharmacokinet. 2002;41(8):603-613. doi:10.2165/00003088-200241080-00004

31.

Malemud

CJ.

Cytokines as therapeutic targets for osteoarthritis. BioDrugs. 2004;18(1):23-35. doi:10.2165/00063030-200418010-00003

32.

Migliore

Massafra

Bizzi

, et al. Comparative, double-blind, controlled study of intra-articular hyaluronic acid (Hyalubrix) injections versus local anesthetic in osteoarthritis of the hip. Arthritis Res Ther. 2009;11(6):R183. doi:10.1186/ar2875

33.

Nouri

Babaee

Peydayesh

Esmaily

Raeissadat

SA.

Comparison between the effects of ultrasound guided intra-articular injections of platelet-rich plasma (PRP), high molecular weight hyaluronic acid, and their combination in hip osteoarthritis: a randomized clinical trial. BMC Musculoskelet Disord. 2022;23(1):1-12. doi:10.1186/s12891-022-05787-8

34.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71

35.

Paskins

Bromley

Lewis

, et al. Clinical effectiveness of one ultrasound guided intra-articular corticosteroid and local anaesthetic injection in addition to advice and education for hip osteoarthritis (HIT trial): single blind, parallel group, three arm, randomised controlled trial. BMJ. 2022;377:e068446. doi:10.1136/bmj-2021-068446

36.

R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Published 2020. Accessed June 27, 2024. https://www.r-project.org/

37.

Raman

Dutta

Day

Sharma

Shaw

Johnson

GV.

Efficacy of hylan G-F 20 and sodium hyaluronate in the treatment of osteoarthritis of the knee—a prospective randomized clinical trial. Knee. 2008;15(4):318-324. doi:10.1016/j.knee.2008.02.012

38.

Rezende

MUD

Gurgel

HMC

Ocampos

, et al. Improvements in hip osteoarthritis with lavage, triamcinolone, and hylan G-F 20. Acta Ortopédica Bras. 2020;28(6):280-286. doi:10.1590/1413-785220202806240075

39.

Richette

Ravaud

Conrozier

, et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum. 2009;60(3):824-830. doi:10.1002/ART.24301

40.

Rücker

Schwarzer

Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol. 2015;15(1):58. doi:10.1186/s12874-015-0060-8

41.

Setaro

Luciani

Farinelli

Gigante

Conservative treatment of hip osteoarthritis; comparison between three medium/high molecular weight hyaluronic acid injections and two injections of HYADD4: a randomized controlled double-blind study. J Biol Regul Homeost Agents. 2020;34(6):2401-2405. doi:10.23812/20-575-L

42.

Shewale

Barnes

Fischbach

Ounpraseuth

Painter

Martin

BC.

Comparison of low-, moderate-, and high-molecular-weight hyaluronic acid injections in delaying time to knee surgery. J Arthroplasty. 2017;32(10):2952-2957.e21. doi:10.1016/j.arth.2017.04.041

43.

Smith

Patel

Vannabouathong

, et al. Combined intra-articular injection of corticosteroid and hyaluronic acid reduces pain compared to hyaluronic acid alone in the treatment of knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2019;27(6):1974-1983. doi:10.1007/s00167-018-5071-7

44.

Spitzer

Bockow

Brander

, et al. Hylan G-F 20 improves hip osteoarthritis: a prospective, randomized study. Phys Sportsmed. 2010;38(2):35-47. doi:10.3810/PSM.2010.06.1781

45.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898

46.

Stubbs

Aluko

Myint

Smith

TO.

Prevalence of depressive symptoms and anxiety in osteoarthritis: a systematic review and meta-analysis. Age Ageing. 2016;45(2):228-235. doi:10.1093/ageing/afw001

47.

Tikiz

Ünlü

Şener

Efe

Tüzün

Ç.

Comparison of the efficacy of lower and higher molecular weight viscosupplementation in the treatment of hip osteoarthritis. Clin Rheumatol. 2005;24(3):244-250. doi:10.1007/S10067-004-1013-5

48.

Villanova-López

Núñez-Núñez

Fernández-Prieto

, et al. Ensayo clínico fase III para evaluar la eficacia y seguridad del uso de plasma rico en plaquetas frente a ácido hialurónico en coxartrosis. Rev Esp Cir Ortopédica Traumatol. 2020;64(2):134-142. doi:10.1016/J.RECOT.2019.09.008

49.

Wobig

Bach

Beks

, et al. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clin Ther. 1999;21(9):1549-1562. doi:10.1016/s0149-2918(00)80010-7

50.

Huang

, et al. Molecular weight of hyaluronic acid has major influence on its efficacy and safety for viscosupplementation in hip osteoarthritis: a systematic review and meta-analysis. Cartilage. 2021;13(1)(suppl):169S-184S. doi:10.1177/19476035211021903

51.

Zhao

J-X

X-L.

Different intra-articular injections as therapy for hip osteoarthritis: a systematic review and network meta-analysis. Arthroscopy. 2020;36(5):1452-1464.e2. doi:10.1016/j.arthro.2019.09.043

52.

Ziegler

Van Sloun

Gonzalez

, et al. Characterization of growth factors, cytokines, and chemokines in bone marrow concentrate and platelet-rich plasma: a prospective analysis. Am J Sports Med. 2019;47(9):2174-2187. doi:10.1177/0363546519832003

Comparing the Efficacy and Safety of Intra-articular Injection Treatments for Hip Osteoarthritis: A Systematic Review and Network Meta-analysis

Abstract

Background:

Purpose:

Study Design:

Methods:

Results:

Conclusion:

Registration:

Keywords

Methods

Study Identification

Data Extraction

Risk of Bias

Statistical Analysis

Results

Study Characteristics

Risk of Bias

WOMAC–Total

Visual Analog Scale

Safety Profile

Discussion

Limitations

Conclusion

Footnotes

Appendix

ORCID iDs

**

††

References