The Media and the Science Behind Interventional Orthobiologics

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If I’ve learned nothing else this past decade it’s that the media frequently gets orthobiologics wrong. So today, let’s explore the science behind two common interventional orthopedics procedures to see if they got it right or wrong. Let’s dig in.

The Media and “Stem Cells”

On the one hand, I have been a fan of some of the media coverage on “stem cell clinic “bad actors”. This is a real phenomenon. These clinics usually focus on treating a panoply of incurable serious diseases like ALS, Alzheimer’s, MS, Spinal Cord Injury, etc… They over-promise, collect no data, publish nothing in medical journals, and charge “all the traffic will bear” fees.

On the other hand, in orthopedic care, we have an increasing number of major universities offering PRP and bone marrow concentrate injections to help patients avoid surgery. Why? the data supporting the utility of these procedures has continued to increase and solidify. This is even more true when you compare that level of evidence to the often poor evidence supporting the surgical procedures these injections can replace.

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The Media Firestorm on PRP and Stem Cells

There has been a steady flow of negative media pieces on these procedures. These are usually driven by the press attending media days at the bench science organizations. These groups protect high-value patents on other cell technologies held by university scientists. Bizarrely, we now have the other side of campus (the medical school orthopedic, PMR, or pain management dep[artments) who have begun to add these procedures to the very same universities where these scientists work. Basically, one side of campus dueling with the other.

The Media in 2021

We all remember a time when the media tried hard to tell both sides of any story. However, fewer and fewer Americans today trust the media, IMHO because they see less and less of that type of reporting. For example, these were the results of a recent Gallup poll (1):

-9% in the U.S. trust the mass media “a great deal” and 31% “a fair amount”
-27% have “not very much” trust and 33% “none at all”
-The percentage with no trust at all is a record high, up five points since 2019

As an expert in this field, one of the things I’ve noticed in articles about orthobiologics is the selective quoting of university scientists who oppose these therapies over quoting the published physician experts in this field. In addition, there is little attempt to square quotes with the reality of the published clinical research. So let’s review today how major news outlets did on this topic looking backward from 2021 to 2019.

PRP Quotes

Platelet-rich plasma (PRP) is often lumped together with “stem cells” in news stories even though it contains no stem cells. This is made by collecting whole blood and isolating the healing platelets. Given that about 2/3rds of what we do at Regenexx is PRP, let’s see how two major news pieces did on their positions on PRP.

Kaiser Health News (KHN)-April 2nd, 2019 (2)

“Swedish is one of a growing number of respected hospitals and health systems— including the Mayo Clinic, the Cleveland Clinic and the University of Miami— that have entered the lucrative business of stem cells and related therapies, including platelet injections. Typical treatments involve injecting patients’ joints with their own fat or bone marrow cells, or with extracts of platelets, the cell fragments known for their role in clotting bloodMany patients seek out regenerative medicine to stave off surgery, even though the evidence supporting these experimental therapies is thin at best, Knoepfler said.”

“Lots of hype, little proof

Although some hospitals boast of high success rates for their stem-cell procedures, published research often paints a different story.

The Mayo Clinic website says that 40 to 70% of patients “find some level of pain relief.” Atlanta-based Emory Healthcare claims that 75 to 80% of patients “have had significant pain relief and improved function.” In the Swedish video, Pourcho claims “we can treat really any tendon or any joint” with platelet-rich plasma (PRP).

The strongest evidence for PRP is in pain relief for arthritic knees and tennis elbow, where it appears to be safe and perhaps helpful, said Dr. Nicolas Piuzzi, an orthopedic surgeon at the Cleveland Clinic.

But PRP hasn’t been proven to help every part of the body, he said.

PRP has been linked to serious complications when injected to treat patellar tendinitis, an injury to the tendon connecting the kneecap to the shinbone. In a 2013 paper, researchers described the cases of three patients whose pain got dramatically worse after PRP injections. One patient lost bone and underwent surgery to repair the damage.

In its 2013 guidelines for knee arthritis, the American Academy of Orthopaedic Surgeons said it is “unable to recommend for or against” PRP.

“PRP is sort of a ‘buyer beware’ situation,” said Dr. William Li, president and CEO of the Angiogenesis Foundation, whose research focuses on blood vessel formation. “It’s the poor man’s approach to biotechnology.”

So when you actually look at the peer-reviewed literature, do any of these concerns hold water? Not really. First, let’s tackle Paul Knoepfler’s comment, and then we’ll review the concept seeded in the piece that PRP is dangerous.

Is There Evidence PRP Works?

In the KHN piece, we find this paraphrase from a bench scientist who is NOT a licensed medical doctor, “Many patients seek out regenerative medicine to stave off surgery, even though the evidence supporting these experimental therapies is thin at best, Knoepfler said”. For more information on Paul Knoepfler, see my blog. As it relates to PRP, how accurate is this quote? Not very.

Let’s look at one clinical application, knee arthritis. There are 27 Randomized Controlled Trials (RCTs) to date on using PRP knee injections to treat arthritis. These studies compared PRP to common knee arthritis treatments like steroid shots, hyaluronic acid (HA) injections, or physical therapy (4-21). PRP was as good as HA or better than steroid shots or exercise. We even have studies that show that PRP works when compared to a sham treatment like saline.

Let’s compare the amount and quality of that research to a common treatment for knee arthritis. There are more than 600,000 knee replacement surgeries in the US costing 30 billion. So how many RCTs do we have that show that knee replacement is effective? One measly study which didn’t use a placebo or sham control (23). Hence, when compared head to head, we have MUCH MORE high-quality research showing that PRP works when compared to knee replacement.

Looking back, was the position in the KHN piece on PRP accurate? NOPE. Was it even accurate in 2019? NOPE. How is it possible that a major new outlet got that so wrong? Read on.

Is PRP Dangerous in Tendons?

KHN seems to go out of its way to find someone who will claim that PRP is bad. Why? That’s probably because it fits into the narrative of the story.

Is there any evidence in the thirteen RCTs on the use of PRP in tendons that it’s dangerous? NOPE. So the author of the KHN article gets a big goose egg here for not doing any scientific homework on the topic and quoting a small case series of three patients with no rate of complications rather than more than a dozen randomized controlled trials on hundreds of patients. This was true in 2019 and is obviously even more so today.

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“Stem Cell” Quotes

So now let’s shift gears and look at how accurate the 2019 news stories were in regard to orthopedic stem cell procedures. In this case, we’ll use bone marrow concentrate, which is the most commonly used procedure. Right now we have 4 RCTs that have been performed to test the efficacy of using BMC for knee arthritis (22-25). Three used a very similar mix of pure high-dose bone marrow concentrate and one used a very strange low dose version of BMC with PPP. It’s no surprise that the 3 studies that used the higher dose BMC showed good efficacy while the one study using a low dose did not. However, the three positive studies are often ignored in these news stories in favor of the negative paper.

First I’ll review the KHN piece above and then one published by the New York Times.

KHN

The quote above from the KHN piece on orthopedic stem cell therapy being ineffective in knees is referring to BMC. So is this true in 2021? NOPE, again, the only study, which was done by Mayo Clinic (which still performs these procedures by the way) which didn’t show efficacy used a low-dose + PPP version of BMC. There was one other RCT showing efficacy published and available before this article was published, but was never mentioned. That’s just sloppy reporting. Since then two more RCTs have been published showing efficacy.

The New York Times

Here’s the operative quote from a May 13th, 2019 article (3):

“I believe strongly that it isn’t ethical to charge patients for unproven therapies like these and raise what are likely to be false hopes,” said Paul S. Knoepfler, a stem cell researcher at the University of California, Davis.

He said that some properly conducted studies on platelet-rich plasma suggested it might help, but others did not. As for stem cells extracted from bone marrow, Dr. Knoepfler said well-controlled studies were even scarcer, also with mixed results.

Rigorous studies are essential, because symptoms from arthritis and injuries can wax and wane, making it hard to determine whether treatments work.

In part because of the scant data, no stem cell or platelet treatments are approved by the F.D.A. for orthopedic problems, and most insurers don’t cover them. Still, many patients pay thousands of dollars out of their own pockets.”

Like the KHN piece, the New York Times had the results of one positive study on BMC at the time of writing the article and since then two more studies have been published. So is the Times article accurate in 2021? NOPE. Was it written showing balance in 2019? NOPE. It should have given both studies equal footing and then had experts compare and contrast the two.

Remember that for knee replacement, we have one RCT that shows that it works. For BMC used to treat knee arthritis, we now have three, or two more than for knee replacement. Hence, any reasonable discussion of this topic, even in 2019, would have included the fact that despite having dozens of different knee replacement prostheses on the market, each one requiring an RCT to show efficacy, we only have a single study representing a highly invasive procedure. There should have then been a comparison of that literature to the available data on BMC injections in 2019. This obvious dimension was completely missed by the NYT article.

Regulation

Another issue missed by the New York Times is that both PRP and BMC are exempt from FDA regulation because they are medical procedures covered under 21 CFR 1271.15(b). This same surgical procedure exemption is there because autologous procedures where a surgeon transfers minimally manipulated tissue from one place to another (like a vein taken from the leg to replace a blocked artery in the heart) is surgery and not the production of a drug. Again, yet another facet of the story missed by the NYT.

Complex Issues and the News

The biggest problem I see with these topics is that they are complex. Solid reporting in this area would take months and months of interviewing people on both sides. That might include the bench scientists, but for every one quote of a Ph.D. without a medical license, several academic physicians who offer these procedures would need to be included. In addition, a science journalist would also need to compare the evidence for these procedures to the evidence for the surgeries they replace, which is NEVER done in these stories. Why? I suspect no science journalist wants to take the time to wade into dozens of randomized controlled trials themselves.

The upshot? The press did poorly with these 2019 news pieces on orthobiologics, especially in hindsight. Even worse when you compare the reporting to what we know in 2021. It’s not surprising why many Americans are losing trust in this once-proud institution.

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References:

(1) Gallup. Americans Remain Distrustful of Mass Media  https://news.gallup.com/poll/321116/americans-remain-distrustful-mass-media.aspx Accessed 7/8/21

(2) Kaiser Health News. Elite Hospitals Plunge Into Unproven Stem Cell Treatments. https://khn.org/news/elite-hospitals-plunge-into-unproven-stem-cell-treatments/ Accessed 7/8/21

(3) The New York Times. Stem Cell Treatments Flourish With Little Evidence That They Work. https://www.nytimes.com/2019/05/13/health/stem-cells-fda.html Accessed 7/8/21

(4) Ammar TY, Pereira TA, Mistura SL, Kuhn A, Saggin JI, Lopes Júnior OV. Viscosupplementation for treating knee osteoarthrosis: review of the literature. Rev Bras Ortop. 2015;50(5):489–494. Published 2015 Aug 5. doi: 10.1016/j.rboe.2015.07.007

(5) Uslu Güvendi E, Aşkin A, Güvendi G, Koçyiğit H. Comparison of Efficiency Between Corticosteroid and Platelet Rich Plasma Injection Therapies in Patients With Knee Osteoarthritis. Arch Rheumatol. 2017;33(3):273–281. Published 2017 Nov 2. doi: 10.5606/ArchRheumatol.2018.6608

(6) Tavassoli M, Janmohammadi N, Hosseini A, Khafri S, Esmaeilnejad-Ganji SM. Single- and double-dose of platelet-rich plasma versus hyaluronic acid for treatment of knee osteoarthritis: A randomized controlled trial. World J Orthop. 2019;10(9):310–326. Published 2019 Sep 18. doi: 10.5312/wjo.v10.i9.310

(7) Joshi Jubert N, Rodríguez L, Reverté-Vinaixa MM, Navarro A. Platelet-Rich Plasma Injections for Advanced Knee Osteoarthritis: A Prospective, Randomized, Double-Blinded Clinical Trial. Orthop J Sports Med. 2017;5(2):2325967116689386. Published 2017 Feb 13. doi: 10.1177/2325967116689386

(8) Raeissadat SA, Rayegani SM, Hassanabadi H, et al. Knee Osteoarthritis Injection Choices: Platelet- Rich Plasma (PRP) Versus Hyaluronic Acid (A one-year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:1–8. Published 2015 Jan 7. doi: 10.4137/CMAMD.S17894

(9) Montañez-Heredia E, Irízar S, Huertas PJ, et al. Intra-Articular Injections of Platelet-Rich Plasma versus Hyaluronic Acid in the Treatment of Osteoarthritic Knee Pain: A Randomized Clinical Trial in the Context of the Spanish National Health Care System. Int J Mol Sci. 2016;17(7):1064. Published 2016 Jul 2. doi: 10.3390/ijms17071064

(10) Görmeli G, Görmeli CA, Ataoglu B, Çolak C, Aslantürk O, Ertem K. Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: a randomized, double-blind, placebo-controlled trial. Knee Surg Sports Traumatol Arthrosc. 2017 Mar;25(3):958-965. doi: 10.1007/s00167-015-3705-6.

(11) Lana JF, Weglein A, Sampson SE, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med. 2016;12(2):69–78. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227106/

(12) Tavassoli M, Janmohammadi N, Hosseini A, Khafri S, Esmaeilnejad-Ganji SM. Single- and double-dose of platelet-rich plasma versus hyaluronic acid for treatment of knee osteoarthritis: A randomized controlled trial. World J Orthop. 2019;10(9):310–326. Published 2019 Sep 18. doi: 10.5312/wjo.v10.i9.310

(13) Lin KY, Yang CC, Hsu CJ, Yeh ML, Renn JH. Intra-articular Injection of Platelet-Rich Plasma Is Superior to Hyaluronic Acid or Saline Solution in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized, Double-Blind, Triple-Parallel, Placebo-Controlled Clinical Trial. Arthroscopy. 2019 Jan;35(1):106-117. doi: 10.1016/j.arthro.2018.06.035.

(14) Huang Y, Liu X, Xu X, Liu J. Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis : A prospective randomized controlled study. Orthopade. 2019 Mar;48(3):239-247. doi: 10.1007/s00132-018-03659-5.

(15) Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-Rich Plasma Versus Hyaluronic Acid Injections for the Treatment of Knee Osteoarthritis: Results at 5 Years of a Double-Blind, Randomized Controlled Trial. Am J Sports Med. 2019 Feb;47(2):347-354. doi: 10.1177/0363546518814532.

(16) Yu W, Xu P, Huang G, Liu L. Clinical therapy of hyaluronic acid combined with platelet-rich plasma for the treatment of knee osteoarthritis. Exp Ther Med. 2018;16(3):2119–2125. doi: 10.3892/etm.2018.6412

(17) Buendía-López D, Medina-Quirós M, Fernández-Villacañas Marín MÁ. Clinical and radiographic comparison of a single LP-PRP injection, a single hyaluronic acid injection and daily NSAID administration with a 52-week follow-up: a randomized controlled trial. J Orthop Traumatol. 2018;19(1):3. Published 2018 Aug 20. doi: 10.1186/s10195-018-0501-3

(18) Su K, Bai Y, Wang J, Zhang H, Liu H, Ma S. Comparison of hyaluronic acid and PRP intra-articular injection with combined intra-articular and intraosseous PRP injections to treat patients with knee osteoarthritis. Clin Rheumatol. 2018 May;37(5):1341-1350. doi: 10.1007/s10067-018-3985-6.

(19) Louis ML, Magalon J, Jouve E, Bornet CE, Mattei JC, Chagnaud C, Rochwerger A, Veran J3, Sabatier F. Growth Factors Levels Determine Efficacy of Platelets Rich Plasma Injection in Knee Osteoarthritis: A Randomized Double Blind Noninferiority Trial Compared With Viscosupplementation. Arthroscopy. 2018 May;34(5):1530-1540.e2. doi: 10.1016/j.arthro.2017.11.035.

(20) Lisi C, Perotti C, Scudeller L, Sammarchi L, Dametti F, Musella V, Di Natali G. Treatment of knee osteoarthritis: platelet-derived growth factors vs. hyaluronic acid. A randomized controlled trial. Clin Rehabil. 2018 Mar;32(3):330-339. doi: 10.1177/0269215517724193

(21) Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic Acid Versus Platelet-Rich Plasma: A Prospective, Double-Blind Randomized Controlled Trial Comparing Clinical Outcomes and Effects on Intra-articular Biology for the Treatment of Knee Osteoarthritis. Am J Sports Med. 2017 Feb;45(2):339-346. doi: 10.1177/0363546516665809.

(22) Centeno C, Sheinkop M, Dodson E, Stemper I, Williams C, Hyzy M, Ichim T, Freeman M. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up. J Transl Med. 2018 Dec 13;16(1):355. doi: 10.1186/s12967-018-1736-8. PMID: 30545387; PMCID: PMC6293635.

(23) Hernigou P, Bouthors C, Bastard C, Flouzat Lachaniette CH, Rouard H, Dubory A. Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study. Int Orthop. 2020 Jul 2. doi: 10.1007/s00264-020-04687-7. Epub ahead of print. PMID: 32617651.

(24) Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int Orthop. 2020 Apr 23. doi: 10.1007/s00264-020-04571-4. Epub ahead of print. PMID: 32322943.

(25) Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O’Connor MI. A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am J Sports Med. 2017 Jan;45(1):82-90. doi: 10.1177/0363546516662455. Epub 2016 Sep 30. PMID: 27566242.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile

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