Is hyaluronic acid systemically absorbed after injection into the knee?

Comment by InpharmD Researcher

Clinical evidence shows that hyaluronic acid (HA) can be systemically absorbed following intra-articular (IA) injection; however, the extent of this systemic absorption is variable, and the true clinical significance of reported systemic adverse effects (AEs) is not clearly defined. Notably, the prescribing information for HA does not mention systemic absorption rates, and most primary literature on IA administration of HA for knee osteoarthritis has not directly evaluated systemic AEs; therefore, evidence on systemic absorption is derived from secondary reporting of AEs in these studies. Available meta-analyses and tertiary literature have suggested a possible association with an increased risk of serious AEs although noting that systemic AEs are rare, but this is based on low-to-moderate certainty of evidence; high-molecular weight HA products may be more likely to produce AEs, but these are predominantly local and not systemic. Additionally, collection and reporting of systemic AEs between studies has varied greatly, further limiting the ability to conclusively state the true extent of HA’s systemic absorption following IA injection.

Please refer to Tables 1-4 for this inquiry.

Background

A 2019 systematic review and meta-analysis evaluated the safety profile of intra-articular hyaluronic acid (IAHA) in the treatment of osteoarthritis (OA), focusing on systemic adverse effects (AEs). Twenty-two studies were included in the qualitative assessment, and 9 studies were included in the meta-analysis. The effect of concomitant use of oral non-steroidal anti-inflammatory drugs (NSAIDs) was evaluated in a separate post-hoc parallel analysis. The primary outcome was System Organ Class (SOC)-related AEs for gastrointestinal, cardiac, vascular, respiratory, thoracic and mediastinal, nervous system, skin and subcutaneous, musculoskeletal and connective tissue, renal and urinary, infections and infestation disorders. Overall AE, serious AE, and hypersensitivity rates were also evaluated. No significant differences between IAHA vs placebo were observed for SOC-related disorders, except for infections and infestations. IAHA was associated with significantly lower odds of infections and infestations, both overall (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.40 to 0.93) and without concomitant anti-OA medication allowed (OR 0.49, 95% CI 0.27 to 0.89). There were significant increased odds of reporting serious AEs with IAHA vs placebo, both overall (OR 1.78, 95% CI 1.21 to 2.63) and with concomitant anti-OA medication use allowed (OR 1.78, 95% CI 1.10 to 2.89), but not in studies without concomitant anti-OA medications (OR 1.78, 95% CI 0.92 to 3.47). The authors concluded that IAHA does not seem to be associated with any safety issue in OA management based on low-to-moderate certainty of evidence; however, a possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation. [1]

A 2016 comprehensive review used real-world evidence and survey data to investigate which OA patient types are most likely to benefit from viscosupplementation with IAHA. The authors comment on a meta-analysis of US-approved HA products for knee OA demonstrating no significant difference between IAHA vs saline control for any safety-related outcome, including a similar incidence of serious AEs between groups (risk difference 0.7%, 95% CI -0.2% to -1.5%, p=0.12). An additional meta-analysis referenced found that high-molecular weight, cross-linked HA formulations (“hylans”) were twice as likely to cause local AEs (risk ratio [RR] 1.91, 95% CI 1.04 to 3.49) and post-injection flares (RR 2.04, 95% CI 1.18 to 3.53) vs intermediate- or low-molecular weight HA formulations. The authors concluded that viscosupplementation with IAHA is safe and effective as part of a multimodal management strategy for knee OA. [2]

A 2004 systematic literature review of 13 randomized controlled trials and 5 case series sought to determine whether viscosupplementation with IAHA injections improves pain and function in patients with knee OA. Included studies focused primarily on high-molecular-weight HA (Synvisc). The review assessed systemic AEs, noting that side effects were minor, with injection site pain and swelling being most common. HA had fewer gastrointestinal side effects vs naproxen comparator. Systemic reactions were rare, with isolated cases of septic arthritis (n=1), cutaneous vasculitis (n=1) within 1 week of injection, skin peeling (n=1), and itching, cramps, or hemorrhoids (n=3) reported. The authors concluded that viscosupplementation with high-molecular-weight HA is an effective treatment for patients with knee OA who have ongoing pain or are unable to tolerate conservative treatment or joint replacement, with a slower onset of action than intra-articular steroids but a potentially longer lasting effect. [3]

Background References: [1] Honvo G, Reginster JY, Rannou F, et al. Safety of Intra-articular Hyaluronic Acid Injections in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. 2019 Apr;36(Suppl 1):101-127. doi:10.1007/s40266-019-00657-w
[2] Maheu E, Rannou F, Reginster JY. Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45(4 Suppl):S28-S33. doi:10.1016/j.semarthrit.2015.11.008
[3] Aggarwal A, Sempowski IP. Hyaluronic acid injections for knee osteoarthritis. Systematic review of the literature. Can Fam Physician. 2004 Feb;50:249-56.
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is hyaluronic acid systemically absorbed after injection into the knee?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

 

Safety and clinical performance of intra-articular high-purity sodium hyaluronate injection in patients with knee osteoarthritis: a 28-week post-market clinical follow-up study
Design

Prospective, single-arm, open-label post-market follow-up study

N= 65
Objective To evaluate the safety and clinical performance of a high-purity sodium hyaluronate formulation in a real-world population with symptomatic knee OA
Study Groups All patients (N= 65)
Inclusion Criteria Age > 40 years; radiographic diagnosis of Kellgren-Lawrence grade II–III knee OA; inadequate symptom control despite conservative, non-pharmacologic interventions; negative pregnancy test in women of childbearing potential; clinically stable condition
Exclusion Criteria Hypersensitivity to hyaluronate or its excipients; active local infection or skin disease at the injection site; pregnancy or lactation; history of alcohol or substance abuse; participation in other clinical trials within 3 months prior to enrollment; recent overseas travel (within 3 months before screening)
Methods Participants received three weekly intra-articular injections of high-purity sodium hyaluronate (1.5%, 15 mg/mL; 2 mL per injection). No corticosteroids or local anesthetics were co-administered. Concomitant use of systemic analgesics or other intra-articular treatments was not permitted. 
Duration August 2, 2021, to November 21, 2022
Outcome Measures

Change in VAS pain scale
Baseline Characteristics   All patients (n= 65)
Age, years 62.7 ± 9.04
Female 53 (81.5%)
BMI, kg/m2 25.1 ± 4.41
Kellgren-Lawrence grade II (mild) 41 (63.08%)
Kellgren-Lawrence grade III (moderate) 24 (36.92%)
Bilateral knee involvement 48 (73.85%)
Right knee involvement 11 (16.92%)
Left knee involvement 6 (9.23%)
Pain, mean ± SD, mm 41.53 ± 23.08
Results Timepoint by visit number (V1-7) Knee N Change in VAS (mean ± SD) Paired t-test vs. baseline (p-value)
V1 Left 54 41.41 ± 23.72 –
V5 Left 50 23.58 ± 19.12 < 0.001
V7 Left 50 14.10 ± 18.11 < 0.001
V1 Right 59 41.64 ± 22.69 –
V5 Right 55 25.87 ± 20.28 < 0.001
V7 Right 54 18.89 ± 21.78 < 0.001
V1 All knees 113 41.53 ± 23.08 –
V5 All knees 105 24.78 ± 19.68 < 0.001
V7 All knees 104 16.59 ± 20.15 < 0.001
Adverse Events

No serious treatment-related adverse events reported. Mild, transient joint pain and swelling in two participants (3.1%), resolved without intervention.

 No systemic reactions reported. 
Study Author Conclusions Intra-articular injection of high-purity sodium hyaluronate was well tolerated and associated with significant pain reduction and high patient satisfaction, with no radiographic signs of acute or unexpected structural deterioration. These findings support the use of this high-purity HA formulation as a safe and effective option for symptomatic management of knee OA in real-world clinical practice.
Critique The study provides valuable real-world data on the safety and efficacy of high-purity sodium hyaluronate for knee OA, with a robust follow-up period of 28 weeks. However, the single-arm design limits direct comparisons with placebo or active comparators. The sample size, while adequate for safety and clinical trends, may not detect subtle radiographic changes. The exclusion of systemic analgesics may limit generalizability to broader OA populations. Future studies with larger cohorts and advanced imaging modalities are warranted to explore potential disease-modifying effects.
Table 1 References:
[4] Chen CF, Chen CT, Lin YH, Chiang CF, Mao YW. Safety and clinical performance of intra-articular high-purity sodium hyaluronate injection in patients with knee osteoarthritis: a 28-week post-market clinical follow-up study. Clin Rheumatol. 2026;45(3):1835-1844. doi:10.1007/s10067-025-07891-1

 

Elimination of Stabilised Hyaluronan from the Knee Joint in Healthy Men
Design

Single-centre, single-dose study

N= 6
Objective To investigate the elimination of stabilised hyaluronan following intra-articular injection into the knee joint
Study Groups All participants (N= 6)
Inclusion Criteria Healthy men aged 28 to 47 years, free of osteoarthrosis, rheumatoid arthritis, cardiovascular, hepatic, renal, gastrointestinal and haematological disease
Exclusion Criteria N/A
Methods Subjects received a single intra-articular injection (3ml; 20 mg/ml) of 131I-labelled non-animal stabilised hyaluronic acid (NASHA). Radioactivity in the knee, blood, urine and over the liver was measured with gamma counters for 3 weeks post-injection.
Duration 3 weeks post-injection
Outcome Measures

Radioactivity distribution within the knee joint, hepatic radioactivity uptake
Baseline Characteristics   All participants (n= 6)
Age, mean years 38
Age range, years 28 to 47
Results   Radioactivity in knee (%) Radioactivity in blood (%) Radioactivity in urine (%)
Day 0 100 0.48 -
Day 1 - 0.11 -
Day 2 - 0.00 -
Day 3 - - -
3 weeks - - -
Liver uptake (first 2 days) Low but above background - -
Adverse Events Two volunteers reported local pain in the injected knee during the first 24 hours following injection. No clinical signs of septic arthritis, hydrops, or inflammation were observed.
Study Author Conclusions The elimination kinetics of 131I-labelled NASHA from the human knee joint were described by three distinct phases, with half-times of 1.5 hours, 1.5 days and 4 weeks. Most likely, the last value reflects the true half-life of NASHA following intra-articular injection since the labelling method used causes minimal modification of hyaluronan.
Critique The study was limited by a small sample size and the lack of a control group. The use of radiolabelled hyaluronan may not fully represent the behavior of the non-labelled product. The study provides valuable insights into the elimination kinetics of stabilised hyaluronan in healthy individuals, but further research is needed to confirm these findings in patients with joint diseases.
Table 2 References:
[5] Lindqvist U, Tolmachev V, Kairemo K, Aström G, Jonsson E, Lundqvist H. Elimination of stabilised hyaluronan from the knee joint in healthy men. Clin Pharmacokinet. 2002;41(8):603-613. doi:10.2165/00003088-200241080-00004

Clearance kinetics of a hylan-based viscosupplement after intra-articular and intravenous administration in animal models
Design Animal study using rabbit and rat models
Objective To evaluate the clearance kinetics of hylan G-F 20 components after intra-articular and intravenous administration in animal models
Study Groups

Rabbits (n=12)

Rats (n=25)
Inclusion Criteria

Normal, healthy New Zealand White rabbits weighing between 2.5-3.5 kg

Normal, healthy female Sprague-Dawley rats
Exclusion Criteria Not specified
Methods

Radiolabeled hylan G-F 20 (a mixture of 80% v/v hylan fluid solution at 8-10 mg/mL and 20% v/v hylan gel at 3.5-5.5 mg/mL) was injected intra-articularly into rabbit knee joints at a volume of 0.3 mL. Solubilized 3H-hylan gel was administered intravenously to rats via a tail vein at a dose of 22 mg/kg. Radioactivity was measured in synovial fluid, joint tissues, blood, popliteal lymph nodes, liver, spleen, kidney, and lung tissues at specified timepoints.
Duration Not specified
Outcome Measures

Primary: Clearance kinetics of hylan G-F 20 components

Secondary: Distribution of radioactivity in tissues and fluids
Baseline Characteristics  

Rabbits

(n=12)

Rats

(n=25)
Weight, kg 2.5 to 3.5 Not specified
Results  

Rabbits

(n=12)

Rats

(n=25)
Half-life of hylan fluid 1.5 ± 0.2 days Not applicable
Half-life of hylan gel 8.8 ± 0.9 days 22 min
Radioactivity recovery in urine (24h) Not applicable 82.3% ± 5.1%
Adverse Events

No significant radioactivity was detected in blood or major organs following intra-articular injection in the rabbit model.

No accumulation of hylan gel degradation products in major organs following intravenous administration was observed in the rat model.
Study Author Conclusions Clearance of hylan G-F 20 after intra-articular injection in rabbits and intravenous administration in rats exhibits elimination kinetics similar to HA, supporting the safety and effectiveness of a single 6 mL injection in humans.
Critique The study provides valuable insights into the clearance kinetics of hylan G-F 20, showing lack of systemic absorption into several tissues and organs following both intra-articular and intravenous injection, but the use of animal models may limit the direct applicability of results to humans. The study does not specify the duration of follow-up, which could impact the understanding of long-term clearance dynamics. 
Table 3 References:
[6] Larsen NE, Dursema HD, Pollak CT, Skrabut EM. Clearance kinetics of a hylan-based viscosupplement after intra-articular and intravenous administration in animal models. J Biomed Mater Res B Appl Biomater. 2012;100(2):457-462. doi:10.1002/jbm.b.31971

 

Distribution of biologically labelled radioactive hyaluronic acid injected into joints
Design

Experimental study using animal model (rabbits)

N= not specified
Objective To study the fate of hyaluronic acid within synovial joints using radioactive labelling
Study Groups N/A
Inclusion Criteria Adult albino New Zealand rabbits weighing about 2 kg
Exclusion Criteria N/A
Methods Radioactive hyaluronic acid was synthesized using synovial cell cultures with 14C-labelled glucose. The solution was sterilized and injected into the right knee joint of rabbits. Control saline solution was injected into the left knee joint. Autoradiography and scintillation counting were used to trace the distribution of radioactivity in tissues and blood.
Duration N/A
Outcome Measures Detection of radioactivity in synovial layer, articular cartilage, regional lymph nodes, and blood plasma
Baseline Characteristics   All rabbits
Weight, kg 2
Results   Right knee Left knee (control)
Synovium + 0
Meniscus + 0
Articular cartilage + 0
Popliteal lymph node + 0
Muscle 0 0
***Radioactivity was detected in bloodstream, but was cleared rapidly. 
Adverse Events No microscopic evidence of inflammation was found in the excised tissues of the joints.
Study Author Conclusions Radioactive hyaluronic acid penetrates synovial and cartilage tissues rapidly, indicating potential degradation before absorption. The study demonstrates the feasibility of using radioactive labelling to trace hyaluronic acid distribution in joints.
Critique The study provides valuable insights into the distribution of hyaluronic acid in joint tissues. However, the lack of detailed participant numbers and potential variability in rabbit physiology may limit the generalizability of the findings. Additionally, the study does not specify the exact number of animals used, which is crucial for understanding the robustness of the results.
Table 4 References:
[7] Antonas KN, Fraser JR, Muirden KD. Distribution of biologically labelled radioactive hyaluronic acid injected into joints. Ann Rheum Dis. 1973 Mar;32(2):103-11. doi:10.1136/ard.32.2.103