Bone Marrow Concentrate and PRP: Is Keeling et al Just More Carefully Selected Misinformation?
I’ve written many times that we have an academic orthobiologics problem. There’s also a problem with orthobiologics and orthopedic surgeons. I’ll explore this today through a recent review article published in the American Journal of Sports Medicine that concluded that Bone Marrow Concentrate was no better than PRP, but seems to have carefully selected research to reach a pre-determined conclusion. Let’s dig in.
What is a Systematic Review or Mata-analysis?
This morning we’ll be diving into a systematic review. This is in the category of research papers where lots of studies are reviewed to see if trends in the literature can be discerned. In that same category is a meta-analysis, which is where the results from many studies are pulled apart and pooled to see if a treatment is helpful. However, both of these research endeavors suffer from a serious problem. Let me let someone else do the explaining here:
“The practice of meta-analysis resembles a sort of statistical alchemy. By combining the dregs and dross of individually insignificant studies, the meta-analytician may endeavor to produce the gold of a pooled positive result.
Other times, the meta-analytician may coax the opposite effect. By selectively choosing which studies to include in an analysis, weighting studies unequally, or leaving out studies that practicing experts would say are pivotal, real effects can be erased.” (16)
My Thesis
If you routinely read this blog, you’ll know that I believe we have an academic problem facing orthobiologic research. What I mean is that we have academics who have very little experience in using interventional orthobiologics designing studies, so they don’t know which end is up and routinely make mistakes that to clinicians look ridiculous. One example is we now have multiple studies that claim to use platelet-rich plasma (PRP), but actually used products that have been shown to be just plasma with too few platelets to qualify as PRP.
Today’s paper, however, since it was largely conducted by a large orthopedic surgery group in private practice leads me to a different thesis. Meaning that we have a systematic review that seems to have excluded most of the research it was trying to aggregate. There are really only two explanations for this: incompetence or bias. Since the surgeons who did the review would have easily found the excluded research on a simple search of PubMed, I’ll have to assume we’re dealing with bias. Hence, let’s dive into that rabbit hole as I review this systematic “review”.
Not All Orthopedic Surgeons are In This Camp
Before I get into why I think this review has problems and launch into a discussion about how interventional orthobiologics upsets the surgery applecart, it’s important to note that there are some orthopedic surgeons who see the handwriting on the wall. They have embraced interventional orthobiologics and are trying to foment change in their colleagues. That movement is making progress, but as you’ll see below, they’re pushing a very big rock uphill.
Interventional Orthobiologics Upsets the Orthopedics Hegemony
Here’s my thesis. Orthopedic surgeons have long been kings of the hill when it comes to the definitive treatment of musculoskeletal problems. In a world where the conservative treatment options are steroid injections or physical therapy, that makes sense, as only orthopedic surgeons could deploy solutions that made an attempt at repairing or restructuring bones, cartilage, ligaments, muscles, or tendons. However, with the advent of orthobiologics, all of that dramatically changes. Let’s explore why.
If substances exist that can be precisely injected with imaging guidance that can help tissues heal and reduce the need for surgery, then surgical rates begin dropping, and the status of orthopedic surgery changes. We know this because this is what has already happened in cardiothoracic surgery. For example, as interventional cardiology solutions like x-ray-guided and catheter-deployed stents came into common use, open heart surgery rates plummeted. The cardiothoracic surgeons went from kings of the proverbial heart care hill to only treating severe cardiac disease, with interventional cardiologists supplanting them as the primary providers for cardiac care.
To explore the disruptive impact of interventional orthobiologics further, let’s look at just three of about 100 orthopedic surgical procedures that will soon compete head to head with Interventional orthobiologics. First, let’s take the results of our Perc-ACL injection procedure Randomized Controlled Trial (RCT) and imaging case series (1-3). Based on an analysis of the data, I would estimate that somewhere between half to 2/3rds of every patient in the US who currently now gets an ACL reconstruction can be treated with a precise injection of bone marrow concentrate instead (1). Our case series and RCT data show the same for rotator cuff tears and the need for surgical repair (4,5). Finally, it’s clear based on our published knee arthritis case series and RCT and two RCTs published by Herigou that some percentage of knee replacements could be pushed off many years or not needed at all (6-8,13,14).
Let’s now explore how that impacts surgical rates by looking at how many of these orthopedic procedures are performed annually. On an annual basis, there are now approximately 100K ACL reconstruction procedures, 460K rotator cuff procedures, and 800K knee replacement surgeries that would be impacted. If half of those surgeries are no longer needed, that’s a drop in about 700,000 procedures annually. If you add in the dozens of orthopedic surgeries that would be prevented by the widespread adoption of interventional orthobiologics, millions of surgeries will no longer be needed.
Hence, interventional orthobiologics presents a first-in-history threat to the orthopedic surgery hegemony. On the one hand, it’s potentially devastating. On the other, if this is going to happen, then if you’re an orthopedic surgeon, you need to get a handle on this phenomenon and control it.
An Example of This Dynamic Playing Itself Out in Orthopedic Surgery Journals
To explore this phenomenon, let’s look at a recent attempt at a meta-analysis published in the American Journal of Sports Medicine by physicians who work for MedStar. What is that? MedStar is a large orthopedic group that owns outpatient facilities, employs surgeons, and owns orthopedic hospitals and imaging centers. It reported 4.2 billion in 2021 revenues and the group employs 28,000 people. Hence, MedStar has a VERY BIG dog in this race.
The new paper looks innocent enough as it’s a review of the literature surrounding the use of bone marrow concentrate to treat knee arthritis (9). It concluded that bone marrow concentrate has yet to show that it’s superior to PRP or placebo. However, this study is so deeply flawed as to be, in all practical terms, useless. Let’s explore why this is the case.
Inclusion Criteria
If you want to get a specific result out of any literature review, just monkey with the inclusion and exclusion criteria until you knock out all of the studies that don’t fit the conclusion you’re trying to engineer. What does this mean? Inclusion criteria are the parameters for studies you will permit in your review and exclusion criteria are the parameters for the studies you will not review.
Did that happen here? It’s hard to argue otherwise as the authors used exclusion criteria to ax most of the RCT data on bone marrow concentrate use in knee arthritis patients. For example, they excluded our BMC knee OA RCT which was published in 2018 by simply excluding any paper that added BMC together with PRP (6). If the authors had included that level II study, it would have likely changed the conclusion of this review. However, that’s not the only glaring omission.
When I first looked at this new systematic review, I gave the authors the benefit of the doubt and thought that they didn’t include two key studies by Phillippe Herigou because they were published after the date they finalized their review. However, a closer inspection showed that clearly wasn’t the case. The last paper by date that the authors included was a small pilot study by Wells et al that was published in August of 2021 (15). However, two RCTs by Hernigou including 200 patients where BMC was used to treat knee arthritis were published in 2020 (7,8).
Why is the exclusion of these three RCTs a very big deal? They report the results of 248 knee arthritis patients would have been compared to the 60 patients in the level I or II studies reviewed by this MedStar paper. Since all three excluded papers were positive trials, if included, these studies would have completely changed the conclusion of this paper.
Why exclude these patients from this analysis? I’m sure the authors would argue that they wanted to only look at one type of BMC injection for OA, but the heterogeneity of the papers included blows up that concept. For example, the Shapiro paper reviewed used bone marrow concentrate diluted by large volumes of platelet-poor plasma (10). The dilution was so severe that the total cell count was VERY LOW. That product bears no resemblance to the mixture used by Anz who used only bone marrow concentrate (11). Given that we know that PPP has growth factors and cytokines that could impact knee arthritis outcomes, including both of these papers but excluding one, for example, that included PRP is nonsensical (12).
Other Issues
The studies aggregated in this paper have flaws themselves:
- Low Concentration BMC in the Level I and II studies included:
- The Shapiro paper as discussed above used bone marrow concentrate that was very dilute, well below the numbers published by our group associated with better treatment outcomes (13).
- The Anz study reported CFU-f numbers from four of the treated patients with a bone marrow stem cell concentration of 2.5X, which is poor (11). In fact, one patient’s stem cell concentration went way down after “concentration” with the Emcycte system, meaning the number of stem cells based on CFU-fs dropped a precipitous 93%.
- The Wells paper is a tiny case series of 13 patients and is incorrectly labeled as a “Level II” study, but it contains no randomization, control, or comparison group.
- Low Ns
- Only three studies including only 60 unique patients from a randomized trial were included.
- The level III and level IV studies (case series without randomization) included only 239 patients. This is important as while our 2014 much larger case series was cited, it wasn’t included, I am assuming for the same BMC+PRP reason discussed above (11). If it were included, it would have had again, an outsized impact on the results reported, as it contained 616 patients who demonstrated clear improvements with BMC.
- Conclusions that Can’t Be Supported-So how in the world can you get from what you see above, meaning 60 unique randomized patients to the conclusion that BMC is no better than PRP? Looking at the level I and II studies, only one by Anz even compared BMC to PRP and as shown, what they used meets the definition of poorly processed BMC with an average concentration of 2.5X (we routinely use 10-20X). Again, one patient of the four analyzed was injected with 97% more dilute BMC compared to the BMA they pulled.
Summarizing
The new Keeling et al systematic review by MedStar cherry-picked the research which determined its outcome. For example, If the authors had focused on the use of BMC to treat knee OA three key large studies would have dramatically changed the conclusions. That review would have included BMC + PRP just like the published review included BMC + PPP. In addition, that review would have included Hernigiou’s two studies on intraosseous BMC injection. Hence, it’s reasonable to ask the question of why these studies weren’t included, given the severe heterogeneity in the studies they did include.
In addition, the included studies have all sorts of issues themselves. From the level I/II randomized studies only having 60 unique patients to the Anz study which had 1/4 of the sampled injected products in the category of “D-BMA” (Diluted-Bone Marrow Aspirate).
I’ll leave it to my readers to determine if my analysis supported my initial thesis that the paper began with a conclusion and worked backward. In other words, did the authors exclude 248 patients from high-level randomized studies because the authors were biased? Is that due to the ongoing and mounting friction between orthopedic surgery and interventional orthobiologics?
The upshot? It’s my opinion that interventional orthobiologics represents a mounting problem for orthopedic surgeons. It’s also bizarre to me that this paper left out almost 4 times as many randomized treated patients as they included. My opinion is that these omissions were intentional, but ultimately my readers can decide for themselves if they agree or disagree. At the very least, as I have shown, it’s a poorly executed paper that likely never should have been given the green light for publication.
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References:
(1) Centeno C, Lucas M, Stemoer I, Dodson E. IMAGE-GUIDED INJECTION OF ANTERIOR CRUCIATE LIGAMENT TEARS WITH AUTOLOGOUS BONE MARROW CONCENTRATE AND PLATELETS: MIDTERM ANALYSIS FROM A RANDOMIZED CONTROLLED TRIAL. Bio Ortho J Vol 3(1):e29–e39; October 5, 2021.
(2) Centeno C, Markle J, Dodson E, Stemper I, Williams C, Hyzy M, Ichim T, Freeman M. Symptomatic anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow concentrate and platelet products: a non-controlled registry study. J Transl Med. 2018 Sep 3;16(1):246. doi: 10.1186/s12967-018-1623-3. PMID: 30176875; PMCID: PMC6122476.
(3) Centeno CJ, Pitts J, Al-Sayegh H, Freeman MD. Anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow nucleated cells: a case series. J Pain Res. 2015 Jul 31;8:437-47. doi: 10.2147/JPR.S86244. PMID: 26261424; PMCID: PMC4527573.
(4) Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. J Pain Res. 2015 Jun 5;8:269-76. doi: 10.2147/JPR.S80872. PMID: 26089699; PMCID: PMC4463777.
(5) Centeno C, Fausel Z, Stemper I, Azuike U, Dodson E. A Randomized Controlled Trial of the Treatment of Rotator Cuff Tears with Bone Marrow Concentrate and Platelet Products Compared to Exercise Therapy: A Midterm Analysis. Stem Cells Int. 2020 Jan 30;2020:5962354. doi: 10.1155/2020/5962354. PMID: 32399045; PMCID: PMC7204132.
(6) 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.
(7) 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. 2021 Feb;45(2):391-399. doi: 10.1007/s00264-020-04687-7. Epub 2020 Jul 2. PMID: 32617651.
(8) 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. 2021 Feb;45(2):365-373. doi: 10.1007/s00264-020-04571-4. Epub 2020 Apr 23. PMID: 32322943.
(9) Keeling LE, Belk JW, Kraeutler MJ, Kallner AC, Lindsay A, McCarty EC, Postma WF. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review. Am J Sports Med. 2022 Jul;50(8):2315-2323. doi: 10.1177/03635465211018837. Epub 2021 Jul 8. PMID: 34236913.
(10) 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.
(11) Anz AW, Hubbard R, Rendos NK, Everts PA, Andrews JR, Hackel JG. Bone Marrow Aspirate Concentrate Is Equivalent to Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis at 1 Year: A Prospective, Randomized Trial. Orthop J Sports Med. 2020 Feb 18;8(2):2325967119900958. doi: 10.1177/2325967119900958. PMID: 32118081; PMCID: PMC7029538.
(12) Zhang J, Zhang J, Zhang N, Li T, Zhou X, Jia J, Liang Y, Sun X, Chen H. The Effects of Platelet-Rich and Platelet-Poor Plasma on Biological Characteristics of BM-MSCs In Vitro. Anal Cell Pathol (Amst). 2020 Aug 26;2020:8546231. doi: 10.1155/2020/8546231. PMID: 32908815; PMCID: PMC7471809.
(13) Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis. BMC Musculoskelet Disord. 2015 Sep 18;16:258. doi: 10.1186/s12891-015-0714-z. PMID: 26385099; PMCID: PMC4575428.
(14) Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014;2014:370621. doi: 10.1155/2014/370621. Epub 2014 Sep 7. PMID: 25276781; PMCID: PMC4170694.
(15) Wells K, Klein M, Hurwitz N, Santiago K, Cheng J, Abutalib Z, Beatty N, Lutz G. Cellular and Clinical Analyses of Autologous Bone Marrow Aspirate Injectate for Knee Osteoarthritis: A Pilot Study. PM R. 2021 Apr;13(4):387-396. doi: 10.1002/pmrj.12429. Epub 2020 Jul 13. PMID: 32500620; PMCID: PMC8363189.
(16) The Lund Report. Big Data: The Danger in Knowing Less and Less about More and More. David Russo, M.D. https://www.thelundreport.org/content/big-data-danger-knowing-less-and-less-about-more-and-more
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