Common injections don’t help knee osteoarthritis more than placebo, large data review finds

A commonly used treatment for people with knee osteoarthritis is barely more effective than the placebo effect in reducing pain and improving function, a new review of 50 years of data found. Yet despite decades of mounting evidence showing hyaluronic acid injections don’t help most osteoarthritis patients, the shots have become more widely used, costing the American health care system over $300 million each year in Medicare claims alone.

Osteoarthritis is an incurable, chronic condition that occurs as cartilage breaks down in the knees, hips, hands, or other joints, resulting in pain, limited range of motion, and swelling. More than 32 million adults in the United States have osteoarthritis, according to estimates from the Centers for Disease Control and Prevention. Since there is no cure, people with osteoarthritis often manage their condition with exercise, physical therapy, medications, and injected therapies. Since the 1970s, hyaluronic acid has been one of those injectables.

Originally sourced from cartilage in the fleshy, flamboyant-red crown atop a rooster’s head, the treatment has been dubbed the “rooster comb injection,” and thought to offer a gelatinous cushion for worn-down joints. In 2018, it was administered as the first treatment to an estimated one in seven patients with osteoarthritic knee pain, according to a paper published in The BMJ medical journal on Wednesday.

That broad look at the scientific literature concluded that injecting hyaluronic acid — called viscosupplementation — offers such a small reduction in knee osteoarthritis pain and stiffness when compared to placebo shots that it makes no meaningful difference in the lives of patients. Moreover, the shots were also linked to a greater risk of experiencing a wide range of negative side effects, the paper reported.

Senior author Bruno da Costa, a physical therapist, has been following the trajectory of hyaluronic acid injections for more than a decade. In 2012, he and a team of researchers published a similar review in the Annals of Internal Medicine showing viscosupplementation had a very small effect, if any, on knee osteoarthritis when compared to placebo. The therapy is the most investigated joint injection in the field, and yet no rigorous studies have shown a significant benefit to patients, he said. “We have enough trials already to come to a conclusion. We don’t need more.”

Yet even after that 2012 paper was published, the rate of new trials per year doubled, to eight per year. Between 2009 and 2021, “more than 12,000 patients were subjected to intra-articular injections in viscosupplementation trials, which raises ethical concerns,” the BMJ paper says.

Those trends pushed da Costa to conduct an updated, wider-reaching systematic review of hyaluronic acid studies. His team at the Li Ka Shing Knowledge Institute at St Michael’s Hospital in Toronto scoured international research databases to find 169 randomized trials that met their criteria. In total, 21,163 participants were involved. The researchers then focused on a few dozen large, placebo-controlled trials, with over 6,000 participants in total, to analyze reported changes in pain intensity, function levels, and risk of adverse events.

The results further support what da Costa and others have asserted for years: hyaluronic acid injections offer negligible improvements while possibly increasing people’s risk of serious side effects. Some studies reported gastrointestinal inflammation and infections, cardiovascular problems, blurred vision and dizziness, among other issues, in patients receiving hyaluronic acid, though the authors dismissed those as unrelated to the injections. In 2018, more than a quarter of Medicare expenditures for viscosupplementation were incurred for treating subsequent joint infections, the paper says. Since people who participate in trials tend to be healthier than the general population, those risks could be even more pronounced in real-life settings.

Chronic illness can be a voyage of desperation, making floating debris resemble a life raft. When faced with gradually worsening osteoarthritis, patients and physicians alike often go searching for tools that might help avoid surgery. Along the way, many encounter by word-of-mouth, seemingly legitimate health websites, or heavy marketing, a slew of supplements and therapies backed by little-to-no unbiased scientific evidence.

Paul von Hippel, a statistician, waded through research on collagen supplements when he started developing knee osteoarthritis in his early 50s. A professor at the Center for Health and Social Policy at the University of Texas, Austin, von Hippel decided to try collagen after hyaluronic acid offered no lasting relief from the pain (he wrote about his experience in a STAT First Opinion piece). “I didn’t think it helped me, and the BMJ article drew a similar conclusion,” he told STAT in an email. The average effect of the hyaluronic acid injections is about 2 points beyond placebo effect on a pain scale that runs from 1 to 100.

Part of the difficulty for patients is that industry-sponsored research abounds, and can skew data to paint a picture of success for products that won’t make a dent in their symptoms. While some unproven products, like certain vitamin supplements, are relatively benign and affordable, viscosupplementation can cost thousands of dollars and present real risks, making for a different calculation, said Cara Cipriano, an associate professor of adult reconstruction at the Perelman School of Medicine at the University of Pennsylvania. “Then I think that becomes problematic,” she said.

In a 2016 study of patients with knee osteoarthritis treated with hyaluronic acid, patients received an average of 3.6 injections at an average cost of more than $300 per injection. The result is major money, sometimes paid out-of-pocket, sometimes covered by Medicare or insurers, for a dubious treatment. That financial incentive could be driving continued use, she said.

“This isn’t the first attempt to look at the value of viscosupplementation. And there are other organizations and groups that have performed very thorough reviews of the literature and essentially arrived at very similar conclusions,” said Cipriano, chief of orthopedic oncology at Penn Medicine. The American Academy of Orthopedic Surgeons issued clinical guidelines in 2013 and doubled down in 2016, advising against the use of hyaluronic acid injections for patients with knee osteoarthritis.

Abundant data show viscosupplementation fails to alleviate symptoms in those with advanced knee osteoarthritis, and should not be used as a first treatment (topical therapies have shown more promise), but more investigation is needed to figure out if hyaluronic acid could help certain subgroups of patients, researchers told STAT.