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This was an interesting week. It ended with a conference in Las Vegas with me yelling at my colleagues about how they needed to tame the stem cell wild west and then an uninformed bench scientist in Vermont threw orthobiologics under the bus. The two events couldn’t be any farther apart, so I figured it was time to teach bench scientists about EBM in orthobiologics.

The ISSCR, Bench Scientists, and the Stem Cell Wild West

These days I have more in common with my bench science colleagues than not. The stem cell wild west has spun so far out of control that I’ve become one of it’s biggest critics. The ISSCR, the main stem cell bench scientist organization has also been beating that drum for more than a decade.

My medical colleagues and alternative health clinics are so out of control that I can barely even call what I see the Wild West anymore. We now likely have thousands of clinics that have popped up selling fake umbilical cord treatments and exosomes for just about every medical condition with a name. They are even targeting aging itself. There is no data that shows that what they’re using has any effect on these conditions. Most have no idea of what’s even in what they inject or the content on their websites as those are now often run by third party marketing companies. To call this the wild west seems not enough. It’s the world’s biggest medical scam that has existed in modern times. It makes the Laetriille cancer scams of the 70s look like they were selling Tic Tacs.

Understanding EBM and Logical Fallacies

One of the more frustrating things with the ISSCR bench scientist crowd is that they often fail to learn much about the existing orthopedics evidence base. Hence, when these stem cell bench scientists are quoted in news stories, they often lump orthobiologics in with the stem cell wild west. I suspect that this is because very few of them know much about the existing level of evidence in orthopedics much as I wouldn’t know about the existing level of evidence for how the hedgehog pathway does or doesn’t impact IPS cell differentiation. It’s just not something I look at every day.

Given that my bench scientist colleagues like to use the term “Unproven” for orthobiologics, logic would dictate that traditional orthopedic care must then be “Proven”. Regrettably, that’s where we have trained scientists using multiple logical fallacies. Here we’ll focus on one called Bifurcation (false dilemma).

The bench scientists only give reporters two options: that the science behind the medical care (in this case orthobiologics) is “Proven” or “Unproven”. This is a false dichotomy as there is a third option in Evidence-Based Medicine, the “Best Available Evidence”. This means that many times doctors and policymakers use evidence which is less than level 1 to aide treatment decisions. This lack of a Proven/Unproven dichotomy in real healthcare evidence has been acknowledged by experts trying to provide treatment guidelines for governments (1). So this concept is nothing new and is well established in Evidence-Based Medicine.

The Best Available Evidence and Orthopedics

If you apply the false dichotomy used by bench scientists to orthopedic surgery, it’s a mess. For example, a recent review in the British Medical Journal pegged 80% of orthopedic care as “Unproven” (2). One of my colleagues, Don Bufford, recently reviewed the top orthopedic journals and found that the average level of evidence for new orthopedic publications wasn’t level 1 or 2, but level 3. So the best you can do in orthopedics is to use “Best Available Evidence”.  Hence, saying that orthobiologics are yet “Unproven” is fine, as long as you qualify that most of orthopedic surgery is similarly unproven. In fact, a university scientist not using that qualification would be disingenuous at best.

The University of Vermont Example

Orthobiologiocs recently got lumped in with the stem cell wild west when a University of Vermont bench scientist was asked about a local Regenexx clinic. He used the same “Proven/Unproven” false dilemma that obviously doesn’t apply well in orthopedics. This has happened numerous times where bench scientists have even thrown their colleagues across campus in the Orthopedics/Sports Medicine department under the proverbial bus.

So let’s examine his false dilemma against what the University of Vermont Health System says about orthopedic care online. The page clearly shows that the University of Vermont Health Network offers corticosteroid injections and viscosupplementation:

“Our providers offer advanced treatment options for non-surgical injuries and conditions.

Injections

Injectable cortisone is a powerful anti-inflammatory medication: a synthetically produced steroid that lasts for a longer period of time than the cortisone your body naturally produces. It is injected directly into joints such as shoulders, elbows, wrists, knees, and ankles to decrease inflammation, which can subsequently decrease pain. Cortisone injections usually work within a few days and the effects can last up to several weeks.

Viscosupplementation therapy is an appropriate treatment for people with knee arthritis that has failed to respond to more conservative therapy. We use an injection of hyaluronic acid called Euflexxa® for viscosupplementation.”

The problem? We have evidence that the cortisone (corticosteroid) injections used by UV health are ineffective for knee arthritis, their most common use and the injections can cause cartilage damage (3,22). Did the UV bench scientist know this medical literature, likely not. The evidence base for whether viscosupplementation (knee gel or hyaluronic acid injection) works is all over the map. Meaning most large meta-analyses say that the benefit is still unproven (4).

Interestingly, the current best available evidence would support what Regenexx offers for knee arthritis and NOT what UV offers. Meaning that we use Platelet Rich Plasma about 80% of the time to treat knee arthritis. We have 2 randomized controlled trials where PRP was used for knee arthritis and compared to a cortisone injection and found to be more effective (5,6).  We also have 15 randomized controlled trials where PRP was compared to knee hyaluronic acid (HA) injection. In 13 of those, PRP was found to be superior to HA for the treatment of knee osteoarthritis (7. 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 20, 21). Two showed that the PRP worked about the same as HA (15, 19).

Hence, the UV bench scientist had his facts backward. The university he works for doesn’t offer “Proven” medical care for non-surgical treatment of knee arthritis, rather “Unproven” care that in one instance has been shown in randomized controlled trials to make the problem worse. What Regenexx is offering in Vermont is closer to the “Proven” standard or at least better than what UV Health offers based on the best available evidence. This is something the reporter totally missed, which is understandable given that the reporter relied on a Ph.D.

The upshot? We need university bench scientists to understand evidence-based medicine as it applies to orthopedics and orthobiologics. At this point, they ‘re clearly are not familiar with this literature. Instead, they’re committing logical fallacies left and right. For the average person who likely does this many times a day, this sounds like no big deal. However, since this is a group driven by science, I would expect them to learn and change from knee jerk reactions to actually providing quotes that fit the statement to the existing science.

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References:

(1) Gavine, A., MacGillivray, S., Ross-Davie, M. et al. Maximising the availability and use of high-quality evidence for policymaking: collaborative, targeted and efficient evidence reviews. Palgrave Commun 4, 5 (2018) doi: 10.1057/s41599-017-0054-8

(2) Lohmander LS, Roos EM. The evidence base for orthopaedics and sports medicine: scandalously poor in parts. Br J Sports Med. 2016 May;50(9):564-5. doi: 10.1136/bjsports-2016-g7835rep.

(3) McAlindon TE, LaValley MP, Harvey WF, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA.2017;317(19):1967–1975. doi: 10.1001/jama.2017.5283

(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) 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

(7) 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

(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) 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.

(10) 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

(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) 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.

(14) 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.

(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) Kompel AJ, Roemer FW, Murakami AM, Diaz LE, Crema MD, Guermazi A. Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Radiology. 2019 Dec;293(3):656-663. doi: 10.1148/radiol.2019190341.

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