Randomised, double-blind comparison of a fixed co-formulation of intra-articular polynucleotides and hyaluronic acid versus hyaluronic acid alone in the treatment of knee osteoarthritis: Two-year follow-up
Open accessAbstract
Background: A first-year interim analysis of this two-year study suggested that intra-articular injections of highly purified, natural-origin polynucleotides and hyaluronic acid (HA) as a fixed combination (PNHA) might improve knee function and joint pain more effectively than HA alone in patients with knee osteoarthritis (OA). The purpose of the second-year analysis herein described was to verify whether the first-year interim outcomes persist over the whole two-year period. Methods: Randomised, double-blind, HA-controlled clinical trial in 100 knee OA patients (98 randomised, 79 completing the study) in a high-specialisation tertiary care setting. The hypothesised difference of efficacy between PNHA and HA for the original sample size estimate is 20%. Treatment cycle: three intra-articular knee injections of either PNHA or HA, at baseline and weekly for two weeks. Evaluations: Western Ontario and McMaster Universities (WOMAC) score and Knee Society Score (KSS) as, respectively, primary and secondary endpoints, evaluated at baseline and after 2, 6, 12, and 24 months; synovial fluid levels of mediators (at baseline and the end of the treatment cycle). Adverse effects investigated at each control visit. Statistical analysis: Kruskal-Wallis test for independent samples (nonparametric one-way analysis of variance) after correction of means for age, Body Mass Index and Kellgren-Lawrence grade. If significant, pairwise post-hoc Sidak multiple comparisons. Results: KSS total score and KSS pain item: significant improvement in both groups, with significantly more pain improvement in patients treated with PNHA (2-point reduction) than HA (1-point reduction). Both groups experienced significant long-term reductions in WOMAC total scores: significantly stronger in PNHA-treated patients after 24 months with a steady difference of 16% favouring PNHA in WOMAC pain subscore. No clinically significant adverse events in either group. Conclusions: The outcomes of the 2-year study confirmed that a short cycle of intra-articular treatment (3 weekly double-blind injections) with polynucleotides (long-acting viscosupplementation properties, chondrocyte activation, pain-relieving properties) in fixed combination with high molecular weight hyaluronic acid is more effective in improving knee function and pain in knee OA patients than HA alone. PNHA may be elective for viscosupplementation in knee OA patients with fastidious and resistant pain and worsening disease. Trial registration: NCT02417610. Registration, 15/04/2015. ClinicalTrials.gov database link:
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A combination of HA and PN injections in a joint area was more effective than either agent alone.
“Dallari et al. and Stagni et al. also reported that a combination of HA and PN injections in a joint area was more effective than either agent alone [36,39].”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [39]
The Abstract Methods describe a trial comparing intra-articular PNHA with HA alone in patients with knee osteoarthritis; there was no PN-only group. The Abstract Results report greater pain improvement with PNHA than with HA, but this paper cannot establish that the combination was more effective than PN alone. (LLM, conf=0.91)
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Research works printed but not linked: 17
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Sorted by citations
Kim, T. W., Chang, M. J., Shin, C. Y., Chang, C. B., & Kang, S.-B. (2023) · Scientific Reports · doi:10.1038/s41598-023-35982-z · Cited by 24 · see citing works
Kim, S. T. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17081024 · Cited by 18 · see citing works
- Authors
- Stagni, C., Rocchi, M., Mazzotta, A., Del Piccolo, N., Rani, N., Govoni, M., Vivarelli, L., Veronesi, F., Fini, M., & Dallari, D.
- Affiliations
- Istituto Ortopedico Rizzoli (IT)
- Corresponding author
- Rocchi, Martina
- Venue
- BMC Musculoskeletal Disorders
- Published
- 2021-09-12
- Volume
- 22
- Issue
- 1
- Pages
- 773-773
- ISSN
- 1471-2474 (ISSN-L)
- PMC
- PMC8436495
- OpenAlex
- W3133573753
- Cited by
- 34
- References
- 0
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 1
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Musculoskeletal Disorders (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Urology › Periodontal Regeneration and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- knee osteoarthritis, polynucleotides, hyaluronic acid, intra-articular injection, viscosupplementation, knee pain, knee function, WOMAC, Knee Society Score, synovial fluid biomarkers, chondrocyte activation, long-term efficacy, adverse events, Kellgren-Lawrence grade, body mass index
- MeSH terms
- Follow-Up Studies, Humans, Hyaluronic Acid, Polynucleotides, Treatment Outcome, Osteoarthritis, Knee
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