Platelet-Rich Plasma Injections Show No Benefit in Knee OA in Placebo-Controlled Trial

Bianca Nogrady

November 23, 2021

A large randomized, placebo-controlled trial of platelet-rich plasma injections for knee osteoarthritis has found almost no symptomatic or structural benefit from the treatment, giving some clarity to an evidence base that has seen both positive and negative trials for the treatment modality.

Dr Kim Bennell

Given the need for better disease-modifying treatments for osteoarthritis, there has been a lot of interest in biological therapies such as platelet-rich plasma and stem cells, the lead author of the study, Kim Bennell, PhD, told Medscape Medical News. "People have started to use it to treat osteoarthritis, but the evidence to support it was limited in terms of its quality, and there's been very little work looking at effects on structure," said Bennell, a research physiotherapist and chair of physiotherapy at the the University of Melbourne, Melbourne, Australia.

Platelet-rich plasma contains a range of growth factors and cytokines that are thought to be beneficial in building cartilage and reducing inflammation. There have been several clinical trials of the treatment in knee osteoarthritis, but the current study's authors said these were limited by factors such as a lack of blinding and were at high risk of bias. "That was the impetus to do a large, high-quality study and to look at joint structure," Bennell said.

Study Details

For the study, which was published November 23 in JAMA, the researchers enrolled 288 adults older than 50 with knee osteoarthritis who had experienced knee pain on most days of the past month and had radiographic evidence of mild to moderate osteoarthritis of the tibiofemoral joint.

After having stopped all nonsteroidal anti-inflammatory and pain-relief drugs 2 weeks prior ― except acetaminophen ― participants were randomly assigned to receive three weekly intra-articular knee injections of either a commercially available leukocyte-poor platelet-rich plasma or saline placebo. They were then followed for 12 months.

Among the 288 participants in the study, researchers saw no statistically significant difference in the change in pain scores between the treatment and placebo groups at 12 months, although there was a nonsignificantly greater reduction in pain scores among those given platelet-rich plasma. The study also found no statistically significant difference between the two groups in the change in medial tibial cartilage volume.

The researchers also looked at a large number of secondary outcomes, including the effects of treatment on pain and function at 2 months, change in Knee Injury and Osteoarthritis Outcome (KOOS) scores, and change in quality-of-life scores. There were no indications of any benefits from the treatment at the 2-month follow-up, and at 12 months, the study showed no significant improvements in knee pain while walking or in pain scores, KOOS scores, or quality-of-life measures.

However, significantly more participants in the treatment group than in the placebo group reported overall improvement at the 2-month point ― 48.2% of those in the treatment arm compared with 36.2% of the placebo group (risk ratio, 1.37; 95% CI, 1.05 – 1.80; P = .02). At 12 months, 42.8% of those who received platelet-rich plasma reported improved function, compared with 32.1% of those in the placebo group (risk ratio, 1.36; 95% CI, 1.00 – 1.86, P = .05).

The study also found that significantly more people in the platelet-rich plasma group had three or more areas of cartilage thinning at 12 months (17.1% vs 6.8%; risk ratio, 2.71; 95% CI, 1.16 – 6.34; P = .02).

Even when researchers looked for treatment effects in subgroups ― for example, based on disease severity, body mass index, or knee alignment ― they found no significant differences from placebo.

Bennell said the results were disappointing but not surprising. "Anecdotally, people do report that they get better, but we know that there is a very large placebo effect with treatment of pain," she said.

Results Emphasize Importance of Placebo Controls

In an accompanying editorial by Jeffrey N. Katz, MD, director of the Orthopaedic and Arthritis Center for Outcomes Research at Brigham and Women's Hospital, professor of medicine and orthopedic surgery at Harvard Medical School, and professor of epidemiology and environmental health at the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, draws parallels between this study and two earlier studies of platelet-rich plasma for ankle osteoarthritis and Achilles tendinopathy, both published in JAMA in 2021. None of the three studies showed any significant improvements over and above placebo.

"These findings emphasize the importance of comparing interventions with placebos in trials of injection therapies," Katz writes. However, he notes that these studies do suggest possible benefits in secondary outcomes, such as self-reported pain and function, and that earlier studies of the treatment had had more positive outcomes.

Katz said it was premature to dismiss platelet-rich plasma as a treatment for knee osteoarthritis, but "until a new generation of trials using standardized approaches to PRP [platelet-rich plasma] therapy provides evidence of efficacy, it would be prudent to pause the use of PRP for OA and Achilles tendinitis."

Not Ready to Stop Using Platelet-Rich Plasma?

When asked for comment, sports medicine physician Maarten Moen, MD, from the Bergman Clinics Naarden, the Netherlands, said the study was the largest yet of the use of platelet-rich plasma for knee osteoarthritis and that it was a well-designed, double-blind, placebo-controlled trial.

Dr Maarten Moen

However, he also pointed out that at least six earlier randomized, placebo-controlled studies of this treatment approach have been conducted, and of those six, all but two found positive benefits for patients. "It's a very well-performed study, but for me, it would be a bridge too far to say, 'Now we have this study, let's stop doing it,' " Moen said.

Moen said he would like to see what effect this study had on meta-analyses and systematic reviews of the treatment, as that would give the clearest indication of the overall picture of its effectiveness.

Moen's own experience of treating patients with platelet-rich plasma also suggested that among those who do benefit from the treatment, that benefit would most likely show between 2 and 12 months afterward. He said it would have been useful to see outcomes at 3- and 6-month intervals.

"What I tell people is that on average, around 9 months' effect is to be expected," he said.

Bennell said the research group chose the 12-month follow-up because they wanted to see if there were long-term improvements in joint structure which they hoped for, given the cost of treatment.

The study was funded by the Australian National Health and Medical Research Council, and Regen Lab SA provided platelet-rich plasma kits free of charge. Two authors reported using platelet-rich plasma injections in clinical practice, one reported scientific advisory board fees from Biobone, Novartis, Tissuegene, Pfizer, and Lilly; two reported fees for contributing to UpToDate clinical guidelines, and two reported grants from the National Health and Medical Research Council outside the submitted work. No other conflicts of interest were declared.

JAMA. Published online November 23, 2021. Full text

Bianca Nogrady is a freelance journalist based in Sydney, Australia.

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