Intraarticular Injection of Hyaluronic Acid for Osteoarthritis of the Knee: A Review

By Philip Rouchotas, MSc, ND, Siobhan Egan, BSc, Rachael O’Connell, ND, Jordan Morton, ND, MJ Atkins, ND, Alex Del Duca, ND

Abstract

Hyaluronic acid (HA) represents a safe, minimally invasive intervention known to provide significant symptomatic relief for individuals suffering with osteoarthritis. Naturopathic doctors (NDs) practicing in several jurisdictions across North America are provided scope of practice that allows for clinical application of this important tool. The goal of this review is two-fold; to familiarize ND’s with this intervention in regions where its use is permitted, and to encourage ND’s in regions currently excluded from this medicine to pursue its inclusion as an allowed substance for administration by injection. There are several hundred human intervention trials of injectable HA. To establish an evidence base manageable for the scope of this review, authors Rouchotas and Egan reached out to a team of NDs actively using the substance in British Columbia, Canada. We chose to cover the specific agent Durolane, also known as NASHA (Non-Animal Stabilized Hyaluronic Acid), due to our colleagues’ familiarity with the agent. We acknowledge the existence of several other specific forms of the substance and suggest future reviewers endeavour to systematically assimilate all available evidence of this important agent. Other available forms of injectable HA include Euflexxa, Orthovisc, Synvisc-One, Synvisc, Supartz, Monovisc, Gelsyn-3, Hyalgan, Hymovis, and Supartz FX. Hyaluronic acid proves safe and effective for knee OA. Use across a broader range of applications is reasonable and should be further explored.

Introduction

Osteoarthritis (OA) is the most prevalent form of arthritis, characterized by the degeneration of the joint lining, ligaments, cartilage, bone within the affected joint, as well as the presence of osteophytes (Menkes 1991). OA targets joints of the hands and spine, as well as weight-bearing joints such as the knee and hip. Impacting an estimated 4% of the global population, OA is classified as one of the 50 most common diseases and injuries, with OA of the knee contributing to 83% of reported cases (Vos et al 2012). The number of individuals impacted is expected to rise to 78.4 million by the year 2040 as a result of the aging populace born between the 1940s- 1960s, combined with the current obesity epidemic (Osteoarthritis Action Alliance 2021). In 2010, Canada saw an OA prevalence of 13.8% with an average cost of $2.9 billion, which is projected to increase to 18.6% with a cost of $7.6 billion in 2031 (Sharif et al 2015). Signs and symptoms include pain, stiffness, a decrease in joint range of motion (ROM), and swelling. OA proves to significantly reduce the overall quality of life in those impacted (Centre for Disease Control and Prevention 2021). Fifty-four percent of individuals diagnosed with knee OA will undergo total knee arthroplasty (TKA) at some point in their life with a direct $140,300 discounted per person lifetime cost (Losina et al 2015).

Hyaluronic acid (HA) belongs to a family of molecules known as glycosaminoglycans. Glycosaminoglycans are complex polysaccharides containing amino groups principally occurring as components of connective tissue. Molecules belonging to the glycosaminoglycan class include HA, chondroitin, keratin, and heparin. HA is a linear chain of repeating disaccharide units. Each disaccharide unit contains N-acetyl-D-glucosamine and D-glucuronic acid. At physiological pH, HA is negatively charged and attracts a variety of positively charged cations. The resulting hydrophilic salts are referred to as hyaluronan or hyaluronate and result in a hydration shell (Fallacara et al 2018). These complex long chains of hydrophilic polysaccharides possess qualities ideal for increasing viscosity in situations of compromised joint integrity, providing joint lubrication and shock absorbency, as well as restoring the rheological properties of synovial fluid (Filardo et al 2012, Maia et al 2019).

The use of HA as treatment for knee OA results in substantial cost savings. Out of 2,030,497 knee OA patients, only 15.9% of those treated with HA required TKA within two years, however, the HA treatment then contributed to 1.7% of total OA related costs, saving an average of $20,740 per patient (Ong et al 2019).

Human Intervention Trials of NASHA (Non-Animal Stabilized Hyaluronic Acid)

A superficial PubMed search of “intraarticular injection hyaluronic acid” with “clinical trial” as limits produced over 400 results in April of 2021. Similar to subcutaneous injection of mistletoe for patients with cancer, intraarticular injection of HA has expanded to the level of requirement for evaluation of each individual preparation available, as opposed to a scoping review of all evidence. As such, the decision was made to focus on evidence relating to the use of Durolane, manufactured by Bioventus, headquartered in North Carolina, USA. The basis for covering this specific preparation stemmed from colleagues in British Columbia choosing to use this material in their private practices and the goal of partnering with these colleagues to include accurate and concise guidance on administration of the substance within this review.

Nineteen human trials of intraarticular injection of HA were identified for this review. Thirteen of them focused on knee osteoarthritis, as summarized in Table 1. Six of them evaluated HA use for sites other than the knee and are included for completeness, as found in Table 2.

Knee Osteoarthritis

Two of the 13 studies examining knee OA focused on determining impact of NASHA relative to control (saline) (Altman et al 2004, Arden et al 2014). Both were robust, well-controlled, and long-term. Altman and colleagues (2004) conducted their trial across 18 centres from the USA, Canada, and Sweden, and appears to be the most well-controlled of the trials reviewed. While the outcomes for NASHA-treated patients were impressive, saline-treated patients achieved significant benefit, and therefore between group comparisons for several outcomes were non-significant. The study was confounded by including participants with OA of multiple sites as opposed to focusing on knee OA. Sub-analysis did reveal statistically significant superiority for NASHA across several important parameters, notably among patients with specifically knee OA, and even stronger outcomes among individuals with unilateral knee OA.

Several studies compared NASHA to other treatments, notably platelet-rich plasma (PRP) (Buendia-Lopez et al 2018, Louis et al 2018), platelet-rich growth factor (PRGF) (Vaquerizo et al 2013), allogeneic bone marrow mesenchymal stem cells (Vega et al 2015), umbilical cord-derived mesenchymal stromal cells (Matas et al 2019), and various steroids (Leighton et al 2014, Skwara et al 2009). These papers appeared to be set up in a manner focused on establishing superiority of the comparator treatment, yet NASHA was reproducibly found to deliver meaningful clinical outcomes.

Lastly, several studies compared NASHA to other available HA preparations (Estades-Rubio et al 2017, McGrath et al 2013, Zhang et al 2015). All three papers demonstrate significant superiority of NASHA relative to other forms of HA. Of note, Estades-Rubio and colleagues (2017), as well as McGrath and colleagues (2013) declare no conflicts of interest, while Zhang and colleagues (2015) disclose funding and manuscript review from Bioventus, the manufacturer of Durolane (NASHA).

Jurado and colleagues (2013) conducted a retrospective case analysis of 224 patients referred for knee prosthesis to evaluate factors that delay requirement for surgery. The paper has been omitted from Table 1 based on the lack of intervention trial design. The authors represent the Specialty Clinic of Knee Osteoarthritis (SCKO) of the Rheumatology department of the Hospital of Jaen, Spain. The team relies heavily on the use of NASHA, as 90.2% of cases reviewed received the treatment. The mean time to surgery for patients not receiving NASHA was 694 days, compared to 1093 days for patients receiving the therapy.

Osteoarthritis of Sites Other than the Knee

Six studies have evaluated intraarticular injection of NASHA for sites other than the knee (see Table 2). Shoulder (McKee et al 2019), ankle (Younger et al 2019), and thumb (Velasco et al 2017) have each been evaluated by one human trial. All three of these studies are open-label in design. Hip OA has been evaluated by two open-label trials (Berg and Olsson 2004, Conrozier et al 2009) and one controlled study (Atchia et al 2011). The controlled trial by Atchia and colleagues has concerns, notably that it was presented as a symposium supplement, and differences appear in outcomes as presented in the supplement versus its presentation in PubMed. While this preliminary body of evidence of NASHA administration for sites other than the knee is encouraging, it would be desirable to see the evidence in the area further developed.

Pharmacokinetics

Lindqvist and colleagues (2002) undertook an investigation of single administration of ¹³¹I-labeled NASHA to the knee of six healthy participants with the goal of evaluating elimination of the substance from the knee following injection. Elimination is described as conforming to a “three-exponential-function model”, suggesting a rapid elimination immediately following injection (1.5-hour half-life), followed by a period of delayed elimination (1.5-day half-life), then followed by a period of very slow elimination (four-week half-life).

Administration

Successful HA therapy is accomplished when the substance is safely and accurately injected into the joint capsule. It is for this reason that providers must undergo adequate training in orthopedic injections to ensure the success of this therapy. When delivering intraarticular joint injections, aseptic technique is recommended to decrease the risk of in-office infection and post-injection complications (Suvikas-Peltonen et al 2017).

Considerations for injection technique regarding in-office HA are broadly divided into two main categories: Use of image-guided injections and blind injections. Current literature supports the use of image-guidance for intraarticular knee injections (Bum Park et al 2012) when compared to blind injection success rate. When examining skilled injectors, blind approach to intraarticular needle placement resulted in an 83.7% success rate, while ultrasound-guided intraarticular injection resulted in a 96% success rate (Hashemi et al 2016).

While competency to deliver both Point Of Care Ultrasound and ultrasound guided injections will take a physician years to master, current Canadian courses exist for physicians to learn injection techniques via ultrasound guidance that can be completed in a series of weekend courses. Physicians may seek a formal designation from the Alliance for Physician Certification & Advancement (APCA) under the Musculoskeletal Sonography Certification (RMSK). Currently, British Columbia is the only legislated provincial jurisdiction in Canada where Naturopathic Physicians can use ultrasound for both attaining information towards a diagnosis and injection procedure in a clinical setting.

When performing a sterile tray setup for aseptic ultrasound-guided knee injections, the following tools are needed to successfully complete the in-office procedure.

Sterile drape sheet plain 18”x26”

Aquasonic ultrasound gel, sterile, 20g packets

OR towel, huck 17”x26” sterile

Sterile sauze 4”x4” 4-ply non-woven

NitriDerm nitrile sterile exam gloves

IV extension set 6″

Sterile ultrasound probe cover

ChloraPrep clear, 1mL Appl, CA

2-inch 22G Luer lock needle

When performing an ultrasound-guided intraarticular knee injection, the recommended injection site is superolateral to the patella, with the knee in 30° of flexion, in order to access the joint capsule. For those with limited amounts of synovium, aka “dry knee,” the medial mid-patellar approach may be utilized. Blind anterolateral patella injections can be completed with the patient in a seated position with the knee in 90° of flexion.

Upon entering the capsule, a distinctive “popping” can be felt in the form of needle reverberation. After ensuring against vascular placement, little to no resistance should be felt upon injecting the substance. Clinicians would benefit from repeated procedural experience to understand the resistance feedback of non-articular placement of HA.

Discussion

Associations establishing guidelines for OA management present mixed opinions on use of HA, yet it is not difficult to find reputable authorities showcasing robust recommendations for HA administration. The Osteoarthritis Research Society International (OARSI) showcases intraarticular HA as a Level 1B/2 recommendation (Bannuru et al 2019). To achieve a Level 1A recommendation, 75-100% of the advisory panel must vote in favour of the intervention’s inclusion. A Level 2 recommendation requires 60-74% of the advisory panel to approve the intervention.

Similarly, the OARSI recognizes intraarticular corticosteroids (IACS) as a Level 1B/2 recommendation. Yet, when comparing IACS with HA, the team showcases that while IACS provides short-term relief, HA delivers relief at and beyond week 12, and also delivers a more favorable long-term safety profile (Bannuru et al 2019).

All intervention trials reviewed objectively documented adverse events. In 10-15% of patients, a worsening of pain is reported following HA treatment, yet this worsening is short-lived, transient, and resolves quickly on its own or with the assistance of basic analgesics. Beyond this acute treatment-related event, the intervention appears devoid of adverse effects.

Given this impressive safety profile, and important magnitude of efficacy reproducibly delivered, it is not surprising that clinicians utilizing this intervention push beyond the peer-reviewed applications of the intervention. It is not unreasonable to consider administering more than a single treatment, nor is it unreasonable to consider the treatment for sites other than the knee. Furthermore, it is also not unreasonable to consider the treatment for situations of chronic pain not defined by OA, notably sport-related injuries or joint pain from other chronic inflammatory diseases.

Table 1: Human Intervention Trials of NASHA Injection for Osteoarthritis of the Knee

Methods	Outcomes	Reference
Multicentre trial across USA, Canada, and Sweden. Patients with osteoarthritis (OA) at various sites (346) assigned to receive a single injection of NASHA vs saline placebo, with 26-week follow-up. WOMAC served as the primary endpoint measure, with at least a 40% improvement or 5-point reduction in WOMAC considered a “responder”. ITT outcomes reported.	WOMAC scores improved significantly in both groups with no significant differences between groups. Among responders at week two, most remained responders at week 26. Among a subset of individuals only presenting with knee OA (216), NASHA was significantly superior to saline. NASHA demonstrated superior efficacy for individuals with OA isolated to one knee vs individuals with bilateral OA.	Altman et al 2004
RCT of intraarticular NASHA vs saline, single injection, in 218 patients with six-week follow-up. WOMAC absolute reduction of >/= five points, or >/= 40% improvement from baseline criteria for “response”. ITT outcomes reported.	No difference in responder rate at six weeks (NASHA 30.6% vs saline 26.4%). Subgroup analysis among individuals without clinical effusion showed superiority of NASHA (responder rate 40.6% vs 19.7%). The team notes image guidance for injection was intended to be used but was not.	Arden et al 2014
Patients were randomized to a single injection of PRP (N=33), NASHA (N=32), or daily NSAID (N=33). Follow-up at 26 and 52 weeks. Primary outcome: 20% decrease in WOMAC pain subscale. Secondary outcomes: 20% decrease in WOMAC physical function scale and VAS.	PRP outperformed NASHA and NSAID significantly by 30% at 26 and 52 weeks in primary and secondary outcomes. NASHA outperformed NSAID at 26 and 52 weeks, yet the differences were not significant.	Buendia-Lopez et al 2018
Comparative investigation of two different HA preparations; single injection of NASHA vs five injections of Go-ON. Fifty-four patients were randomized and followed for 26 weeks. WOMAC and analgesic use served as endpoint measures.	NASHA significantly outperformed Go-ON by week four, and continued to outperform through week 26. NASHA-treated patients consumed significantly less analgesic medication relative to Go-ON treated patients over the 26-week treatment period.	Estades-Rubio et al 2017
Knee OA patients (N=442) were randomly assigned to single injection of NASHA vs methylprednisolone acetate (MPA) for 26 weeks. WOMAC responder rate as endpoint measure. In open-label fashion, NASHA was offered to all participants after week 26.	No difference between WOMAC responder rate at week 26 (44.6% NASHA, 46.2% MPA). WOMAC subscales of pain, physical function, and stiffness favoured NASHA vs MPA from weeks 12-26. Further improvement among participants who received a NASHA after week 26, regardless of initial treatment received.	Leighton et al 2014
Fifty-four patients with knee OA were randomized to receive one-time injections of PRP or NASHA, and were followed for six months. Forty-eight patients (24 in each group) were available for final analysis. WOMAC responder rate served as a primary endpoint measure.	PRP achieved a higher percentage of WOMAC responders relative to NASHA, yet the difference was not significant. The satisfaction rate was 82% in the PRP group and 79% in the NASHA group.	Louis et al 2018
Twenty-nine patients were randomized to two-time injection of NASHA, single injection of UC-MSCs, or repeat injection of UC-MCSs for knee OA and followed for 12 months. WOMAC and VAS as endpoint measures.	NASHA reduced total WOMAC 13.7 points (28.9 to 15.2) and total VAS 10.7 points (38.7 to 28.0) at six months, with further improvement through 12 months. Multiple UC-MCSs achieved superior outcomes to NASHA at both the six-month and 12-month assessments.	Matas et al 2019
A comparative investigation of patients receiving a single injection of NASHA vs Synvisc for knee OA, followed for 12 months. One hundred sixty-eight patients participated in the final assessment. VAS, SF-36, and the Oxford knee scores served as endpoint measures.	Both groups achieved significant reductions in joint pain by three months, with the impact of NASHA superior to Synvisc. Reduction in pain remained significant at six months in the NASHA group, yet was no longer significant in the Synvisc group.	McGrath et al 2013
Sixty patients were randomly assigned to single injection of NASHA or triamcinolone for treatment of knee OA, with 50 patients available for final analysis. Follow-up was conducted 12 weeks following treatment. Gait was assessed using the Helen-Heyes marker set. VAS and KSS also served as endpoint measures.	NASHA led to significant improvements in gait, notably for stride strength, walking speed, and range of motion. Likewise, VAS significantly improved, as did total knee and function scores of the KSS. Triamcinolone treatment achieved similar outcomes, with no differences between groups.	Skwara et al 2009
Ninety-six patients with knee OA were randomly assigned to a single injection of NASHA vs three injections per two weeks of PRGF for 48 weeks. WOMAC, OMERACT-OARSI, and Lequesne scores served as endpoint measures.	The study focused on comparing NASHA to PRGF. PRGF outperformed NASHA on all evaluated endpoint measures. Three treatments per two weeks with PRGF vs a single treatment with NASHA is relevant. NASHA appeared to deliver benefit across assessed endpoints, yet statistical analysis was not performed comparing NASHA to baseline.	Vaquerizo et al 2013
Thirty patients were randomly assigned to receive single injection of NASHA or allogeneic bone marrow mesenchymal stem cells and followed for 12 months. VAS, WOMAC, and Lequesne scales served as endpoint measures.	VAS and pain subscale of WOMAC were significantly reduced in both groups at 12 months, and not significantly different from each other. Allogeneic bone marrow mesenchymal stem cells outperformed NASHA regarding the Lequesne scale and general subscales of WOMAC.	Vega et al 2015
Patients with knee OA (N=349) were randomized to a single injection of NASHA or five (once weekly) injections of sodium hyaluronate (Artz). WOMAC and global self-assessment served as endpoint measures. Patients were followed for 26 weeks.	Single injection of NASHA and five injections of Artz significantly improved endpoint measures over the 26-week observation period. There were no significant differences between the two treatment arms.	Zhang et al 2015
In open-label fashion, fifty patients with knee pain received a single injection of NASHA. Patients were followed for 26 weeks. VAS served as the primary endpoint measure.	At 26 weeks of follow-up, significant improvements were observed for pain, range of motion, and quality of life and activity.	Krocker et al 2006. Abstract.

Abbreviations

ITT = Intention To Treat

KSS = Knee Society Score

N = Number of participants

NASHA = Non-Animal Stabilized Hyaluronic Acid

NSAID = Non-Steroidal Anti-inflammatory Drug

OMERACT-OARSI = Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative

PRGF = Platelet Rich Growth Factor

PRP = Platelet Rich Plasma

RCT = Randomized Controlled Trial

SF-36 = Short Form Survey-36

UC-MSC’s = Umbilical Cord-Derived Mesenchymal Stromal Cells

VAS = Visual Analogue Scale

WOMAC = Western Ontario McMaster Universities osteoarthritis index

Table 2: Human Intervention Trials of NASHA Injection for Sites Other than the Knee

Methods	Outcomes	Reference
Forty consecutive patients referred for single injection of NASHA therapy for hip OA. Six-month follow-up. Investigators administered the following endpoint measures: OMERACT-OARSI, PASS, MCII. Patients were asked to complete the VAS walking pain subscale, WOMAC, and the PGA.	VAS walking pain, PGA, and WOMAC were reduced 40%, 36%, and 25% respectively. Mean reduction in NSAID use was 32%, ranging from 0-97%. 76% of patients achieved PASS. 71% were OMERACT-OARSI responders. 61% achieved MCII.	Conrozier et al 2009
Open-label trial in 31 patients with hip OA administered single injection of NASHA, followed for three months. WOMAC response rate and patient global assessment served as endpoint measures.	WOMAC response rate was 50% at two weeks and 54% at three months. 68% of patients reported improved global assessment of pain.	Berg and Olsson 2004
Seventy-seven patients with hip OA were randomized to one of four groups: standard care (no injection), saline, NASHA, and methylprednisolone acetate. WOMAC, “worst pain” (rated 0-10), and OMERACT-OARSI served as endpoint measures.  Follow-up spanned eight weeks.	Methylprednisolone acetate outperformed all other interventions. At week one, responders based on the OMERACT-OARSI scale were 74% in the methylprednisolone group, 21% in the NASHA group, 11% in the saline group, and 10% in the no injection group. Data was not provided for the eight- week assessment.	Atchia et al 2011
Open-label trial in 41 patients administered a single injection of NASHA for shoulder OA, followed for 26 weeks. VAS as primary endpoint measure.	Intervention significantly reduced total VAS score 20.1mm, for a mean VAS reduction of 29.5%.  Patient global assessment scores also improved significantly.	McKee et al 2019
Open-label study in 35 patients with thumb OA. Patients received a single injection of NASHA and were followed for six months. VAS served as the main endpoint measure.	Over the six-month treatment period, a significant 2.0-point reduction in VAS was observed, corresponding to a mean 27.8% improvement.	Velasco et al 2017
Open-label study in 37 patients with ankle OA received a single injection of NASHA and were followed for 26 weeks. VAS served as the main endpoint measure.	VAS pain score improved a significant 40%, and the VAS disability score improved a significant 34% over the 26-week observation period.	Younger et al 2019

Abbreviations

MCII = Minimal Clinically Important Improvement

NASHA = Non-Animal Stabilized Hyaluronic Acid

OMERACT-OARSI = Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative

PASS = Patient Acceptable Symptom State

PGA = Patient’s Global Assessment

VAS = Visual Analogue Scale

WOMAC = Western Ontario McMaster Universities osteoarthritis index

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