Dr. Tucker:

Welcome to the Arthroscopy Journal podcast. I'm Dr. Chris Tucker from the Walter Reed National Military Medical Center, and the podcast's founding editor. Today on the podcast, we are discussing biologics for knee osteoarthritis. I'm excited to be joined for this discussion by a friend and colleague, a thought leader in the field of biologics and an active educator and leader in AANA, Dr. Rachel Frank, from the Department of Orthopedics at the University of Colorado.

Dr. Frank was an author on the article titled, "Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone-Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis," which is currently in press for the Arthroscopy Journal. Her co-authors include John Belk, Joseph Lim, Carson Keeter, Patrick McCulloch, Darby Houck, Eric McCarty, and Matthew Kraeutler. Rachel, congrats on your work, and welcome to the podcast.

Dr. Frank:

Well, thanks so much for having me. Really appreciate it.

Dr. Tucker:

Rachel, as we know, biologics is a real hot topic right now, and I'm excited to get into the details of your specific paper and discuss that more with you. For those who may not be very familiar with you, could you first just briefly tell us a little bit about yourself and your practice, and how you developed your particular interest in this field of biologics in orthopedic sports medicine?

Dr. Frank:

Sure thing, and again, thank you for having me. I just want to acknowledge and really credit the co-authors on this paper, especially Dr. Belk, who really got us going with this. My practice is a sports medicine practice. I practice at the University of Colorado. I do sports medicine and shoulder surgery with a focus on joint preservation. I really got into focusing on biologics as part of my practice, because it really does fall into the category of joint preservation. When we think of joint preservation as surgeons, we think of it as cartilage transplants, meniscus transplants and repair osteotomies, but really we have to respect the biology of the knee or the biology of the joint that we're working on, and certain injectables and other biologic solutions offer us opportunities where we previously haven't had those. That's where I've really gotten interested in biologics as a part of my sports medicine practice.

Dr. Tucker:

Yeah. That's a great way of wrapping it into what we all do in sports medicine. As I said before, biologics is obviously a hot topic right now, and evidenced by what we both saw with our other AANA members down at the annual meeting and then the subsequent Biologics Association Annual Summit, where there were just so many dedicated symposia and ICLs and lectures. Can you just share with us your thoughts on the expansion of the interest and research in the field, and what implications that's having for us in our practice of orthopedics and care of our patients?

Dr. Frank:

It's really interesting. I think that biologics has become very popular due to public interest in having a quick fix for chronic conditions, as well as acute problems such as ligament tears and meniscus tears and rotator cuff tears, et cetera. It's also really driven by industry because the innovation is really rapidly outpacing the research, and that's where we as clinician scientists and as researchers really need to do our due diligence in publishing on our outcomes.

These are the reasons why this is a really exciting field, because we've got research, we've got technology, we've got innovation, and we've got patient demand for these particular tools, these particular injections, these particular procedures. I think the biggest potential implication for us moving forward, or the biggest area where we can have the most impact, is making sure we publish on our outcomes, good, bad or ugly, and really get the truth out there with what biologics can and can't do, so that we can offer realistic hope for our patients.

Dr. Tucker:

Yeah. I share your excitement in the field, and also it does pose to us a challenge with patient education just because of the quality of the information that's out there, and helping patients understand what direct marketing to patients is and whether it's valid or not. Like you said, sometimes technology's outpacing our patient-focused outcomes research, so agree with you. It's a challenge and a blessing at the same time.

For those listeners unfamiliar with biologics in general and these injections in particular, could you just briefly describe for us platelet-rich plasma or PRP, bone marrow aspirate concentrate or BMAC, and hyaluronic acid or HA, and how these things work?

Dr. Frank:

Yeah, absolutely. Biologics ... and the three that you mentioned are the most popular, although certainly there are others ... they fall into a variety of different flavors, so to speak. This is how I describe it to the patients. PRP or platelet rich plasma is an injectable technique, and this is where we draw the patient's blood just from their arm, just like any other blood draw. Then we can spin that blood down in a centrifuge machine, and the spin protocol varies based on the type of PRP that you're hoping to inject, based on the particular company's product that you're using in terms of how their protocol is.

In brief, the blood gets spun down in the centrifuge, and you end up with an end product that has much less volume than the original blood draw. For example, 15 ccs may become four ccs, 60 ccs of peripheral blood may become five to six ccs. Again, it all depends on the system, but the end aliquot contains ideally a platelet-rich construct that minimizes the number of white blood cells and certainly red blood cells, and there's ways to optimize that final spin product based on what you're hoping for. Some applications require a more leukocyte-rich concentration, so to speak, while others require a less leukocyte-rich or a leukocyte-poor end product. You can use the centrifuge to optimize your final product.

Bone marrow, or concentrated bone marrow aspirate, it's commonly referred to as BMAC, but it's actually better thought of as concentrated bone marrow aspirate. It's the same principle as PRP, in that we're drawing autologous fluid from the patient and then spinning it down in a centrifuge machine. In this case we don't take it from the blood, we take it from the bone marrow, and the bone marrow can be harvested in a number of different areas, including the iliac crest, either anteriorly or posteriorly. It can be harvested from the distal femur, from the proximal tibia, from the calcaneus, from the proximal humerus. Really any bone that has bone marrow, you can use a Jamshidi needle and harvest the bone marrow.

Then again, you take a certain number of ccs of bone marrow, such as 60 ccs is pretty conventional for most of the commercially-available systems, and then that goes into the centrifuge machine. It gets spun down, and ideally that's a higher level of order, so to speak, in the MSC cell lineage, or mesenchymal signaling or stem cell lineage. Ideally, instead of just getting platelets and growth factors like you would for PRP, you're getting some MSCs. We all know, unfortunately, that MSCs don't come in a high amount even when concentrated, and so really the end product is a lot of growth factors, more so than the actual MSCs. This is what patients come to us and think about with respect to, quote/unquote, stem cells. When they think of bone marrow, they're thinking of stem cells.

Then finally, HA, perhaps the cheapest and most easy to inject, but the most controversial when it comes to insurance coverage and if it benefits patients or not. That's HA. That's hyaluronic acid. It's a naturally-occurring substance within all of our joints. Then different companies make different variations of HA injections, and these don't require any spin or any blood draw or bone marrow harvest. These are already ready to go off the shelf, and they can be injected as a single dose. More commonly they're injected as a series of injections, one to two to three to even five per joint, spaced out once weekly or once every other week for a few weeks. Ideally, this will help lubricate the joint, whether it's the knee or elsewhere, and provide improved pain relief and reduced discomfort, improved function.

The biggest challenge with HA in 2023 is insurance coverage. With PRP and bone marrow, insurance typically does not cover them, so it's not really controversial in that regard. The patients know that they have to pay out of pocket. For HA, they have an expectation that their insurance will cover them, but often HA injections are not covered by insurance here in 2023.

Dr. Tucker:

Yeah. It's a wonderful summary, thanks. Getting right to it, your article has one of those titles that gets right to the point and draws us all in as readers, speaking to the efficacy of various injections specifically for knee osteoarthritis. Your stated purpose was to systematically review the literature to compare the efficacy and safety of those three you just described, the PRP, the BMAC and HA injections, for knee osteoarthritis. Can you tell us how you and your authors set about answering that research question, and then review for us your key findings?

Dr. Frank:

Yeah, absolutely. Again, all credit to the co-authors. They really put in so much work for this, and so I was just grateful to be included and to be part and help contribute. We did the classic orthopedic book report, a systematic review and meta-analysis, and we did a network meta-analysis to try to assess the data, and basically looked at exclusively Level 1 studies that compared the clinical efficacy of either PRP to bone marrow, bone marrow to HA, HA to PRP, et cetera, basically comparing at least two of those three injection therapies, and then tried to see how they did.

The analysis involved both a non-network meta-analysis as well as a network meta-analysis, which allows you to indirectly compare two things that have not been directly compared. Ideally, we'd have great studies that compare all the variables that we want as a single factor and everything else is controlled for, but we know in the real world that doesn't really work. Network meta-analyses really help us understand the statistical relevance of some of these studies. We found, overall, 27 studies. Again, all were Level 1 that met inclusion criteria with many, many patients, over 2,000 patients, the majority of which underwent PRP or HA, and then only 226 in these 27 studies that underwent bone marrow. The results were interesting, and the title really shows the headline.

The results show that when you looked at all the different patient reported outcomes that were presented in these 27 studies, that either PRP or bone marrow seemed to do better than those patients who received HA alone. The take-home point is that potentially this higher level of autologous biologic therapy provided a superior result compared to HA. While HA patients still did well, they just didn't seem to do as well as the PRP or bone marrow patients.

I think ... and we'll probably get into this ... there are certainly some limitations to this study, and so I would be careful drawing major conclusions from this, because it's all dependent on the data in to give us the data out, but it certainly was interesting for us to see that the autologous fluids, the autologous biologics, seemed to have a better impact on patient reported outcomes than the commercially-available HA injections.

Dr. Tucker:

Considering this included 27 studies, like you said, they're all Level 1 prospective randomized trials, we understand they all have their limitations like you just mentioned, but they're all pretty convincing evidence that patients who are getting the autologous PRP or BMAC could expect to experience better outcomes than HA. What's your thoughts? Do you think this really finally closes the book on this question, or do you think there's still room for debate and ongoing research?

Dr. Frank:

I wish it closed the book, but I don't think that it does. I think that there's still certainly room for ongoing research. The biggest challenge with understanding biologics is the personalization of the biologic. If you and I were both to have bone marrow drawn right now, my bone marrow drawn in me, your bone marrow drawn in you, spun down in the same exact centrifuge machine using the same proprietary system and then injected into our knee, we both might feel great. We both might say our pain, if we had baseline pain, improved, we both might say nothing happened, or we might have different results.

The challenge is, whatever's going on in your knee at baseline ... and I hope your knee is pristine ... is going to be different than whatever's going on in my knee at baseline, and the vast majority of these studies simply can't account for that. The variability in what we're putting in and the type of patients that we're putting it into makes it so that it's very difficult to draw conclusions.

In addition, many of these studies involve trials, but some involve patients where there is a cash-pay component to this, and so that's a variable that we often have challenges accounting for as well. Because when patients pay for a service, they have an expectation that the service is going to go well, so that's a variable that's not accounted for in this and in many biologic studies.

Finally, the difference of study outcomes with respect to which PROs were used, which follow-up time periods were used, be it three months, one year, two years, et cetera, it creates so much variability that we can't just say definitively PRP is the best or bone marrow is the best, or they're better than HA. I just think this gives us some evidence to help guide our patients. If they're saying, "Well, Doc, you've given me these three options, what should I do," I can look at a study like this and say, "Well, in the literature, PRP or bone marrow seems to do better than HA, so I'd probably do one of those." If we're comparing PRP to bone marrow, it becomes a little bit more difficult.

Dr. Tucker:

Yeah. They say always the best studies generate more questions than answers, and this one certainly I think fulfills that. Like you said, the individual nature of it is a super unique confounder for studies. As a follow-on question, do you think that this is an answerable question? Do you think we can control for that individual nature of it by standardizing the concentrate used, the concentration, the number of cells and all that, or is this just something that's going to perpetually be debated like the biceps tenodesis forever?

Dr. Frank:

I think the biceps tenodesis will be debated forever. I think with this it's challenging, because we can certainly standardize what we're putting into patients. We can design a study, a multicenter national or international study to use this company's PRP with this much blood, drawn at this time of the day when patients are fasting or not fasting. We can control so many of those variables, but what's difficult to control is, even if we're doing this, say for example, in patients with exclusively K&L grade 4 knee OA or K&L grade 2 knee OA, we know that everyone is different with respect to symptoms. We all have those patients that have K&L grade 4 bone-on-bone knee OA that are running marathons and have no pain, and then we have those patients with no joint space narrowing that have significant pain.

That's the challenge, is that even if you're going to take patients who are age, sex, comorbidity matched, and then matched based on K&L grade, people have different responses to pain. I think that's where the field of injectables, be it biologics or anything else for osteoarthritis, is always going to be a very difficult thing to draw definitive conclusions and say, yes, this works in this patient. Whereas if you're studying an ACL reconstruction surgery, we can debate graft choice all the time, but we know that ACL reconstruction gives you a stable knee. If you don't have an ACL, you typically don't have a stable knee. You get an ACL reconstruction, you get a stable knee. It's a little bit different in terms of the subjective nature of pain associated with arthritis, despite potentially objective findings.

I know that's a long-winded way of answering this, but I would say the subjective response of patients to pain despite objective data of arthritis will be a variable that I think we'll have a lot of difficulty accounting for in any study, and that's going to make any biologic or injectable outcomes-based study close to impossible, to say this is what works in this patient population.

Dr. Tucker:

Yeah. That's wonderful insight from a clinician scientist's point of view on the challenges of managing and investigating this topic. Along those lines, I was hoping you could perhaps just tell us about your own personal clinical experiences, and how the use of biologics and these injectables is fitting into your current practice.

Dr. Frank:

I'll answer that with two different biases because I use biologics and offer these to my patients, but I'm also a patient who receives biologic treatments, and so I have a bias with that. Now, a lot of patients come to my office, for better or for worse, as I've developed a little bit of a reputation with biologics, and what I would say is when patients have bone-on-bone arthritis, this is not something I typically offer them, even if they're coming and asking for it.

I think the data for grade 4 bone-on-bone arthritis with respect to PRP or cells or HA is just very, very controversial, and the cash-pay nature of offering PRP or cells makes it a little bit difficult. I think that if they're coming in specifically because they want to avoid knee replacement and they want to avoid any challenge with respect to having surgery, and they really just want a biologic treatment and they're saying, "Look, I understand that this may not work, this is 50/50 at best or even worse, but this is what I want to do," I'll offer it to them.

With respect to my own knee, I'm a PRP patient. I've had really good relief and results with PRP, and so I often will share that with my patients and let them know that things seem to be working for me, but it may not work for them. I always do let them know about the out-of-pocket cost and the potential for no change. I also tell them that these are not shown to be disease-modifying treatments. These are symptom-modifying treatments, and we can still expect their arthritis and degenerative changes to progress.

Dr. Tucker:

I think that's fantastic advice, and your approach to counseling patients is really insightful and I think something all of us can learn from, especially younger practitioners or those who are just getting into biologics. I think that's a great way to present it to the patient, as we always do, providing options, but specifically like you said with biologics, which can be a slippery slope, with biases and cost factored in.

I know we had talked earlier about biologics being this rapidly-growing field, and I know we've touched on this already about potential future studies about these injectables and PRP and BMAC for the knee, but I was just wondering, from a more global perspective, what your thoughts are as far as the most exciting area of development right now in biologics as a whole, maybe not even just with injectables, and what you see as the next biggest thing coming down the pipeline.

Dr. Frank:

Well, it's a super exciting field, for sure. I think for me, my excitement with this really comes into two different areas. I think the injectables, and trying to figure out who the ideal patient is and what the right sequence and frequency of injections might be. I think if we can solve that or at least get some better understanding of that, there's a lot of people in this so-called tweener position where they're too young for joint replacement, too active potentially for joint replacement, but too advanced in their disease progression to undergo traditional joint preservation surgeries. This is where I think we really have an opportunity to harness the power of biologics. We just don't know 100% which ones we should be using yet.

I think the other aspect of biologics that really excites me with regard to future application and research is surgical augmentation. We see this with rotator cuff repair with scaffolds, patches, et cetera. We see this with cartilage repair, meniscus repair and restoration, and augmenting with biologic scaffolds. I think we're getting close to figuring out the secret sauce, so to speak, where we can figure out what we need to inject to help improve our surgical outcomes and make more biologic reconstructions that last longer, and ideally prevent or at least delay significantly joint replacement, et cetera.

Dr. Tucker:

Yeah. Rachel, I think you provided us a really wonderful summary of just what's out there, with currently available data on biologics and especially these injectables for the knee. Did you have any other closing remarks you wanted to share with us before we wrap up?

Dr. Frank:

Thank you so much for having me. I think biologics, it's incredibly exciting. It's also incredibly controversial, because of the inappropriate and illegitimate use of biologics that some clinicians just seem to keep on doing. Again, for those, taking money from these poor souls, promising them that their bone-on-bone arthritis will be cured or reversed, and we've all had stories of this. We've all seen stories of this. I think we have to have a responsibility within ourselves to offer what we think is appropriate for our patients, but also to lay the crepe about what these products and procedures can, and most importantly, can't do.

I think we have to do a good job and a better job at reporting what we are doing in the literature, documenting how we're doing biologics, what our outcomes are, and being honest with our outcomes. It's interesting. In the social media world, particularly on Twitter and other social media channels, there's usually two camps when a PRP article or a biologics article is posted, and there's a lot of docs who say this is voodoo and we shouldn't do this, and then there's a lot of docs that say, "I swear by it," and the answer's probably somewhere in the middle, once we figure out what the ideal patient is and what the ideal treatment is, and we're still working on that. There certainly are patients that benefit from these treatments, even some you might not expect to.

I think the bottom line is, for us as clinicians, we have to be honest with our patients, honest with ourselves, and try to really practice ethical medicine and make sure we don't overpromise what these treatments can do. I think if we do that, we have an opportunity to offer our patients a minimally invasive solution for some of their problems, where previously they didn't really have these solutions. I would just implore anyone listening who uses biologics in their practice, make sure you study your outcomes and then report on what you find. It's not only going to help you in your practice, but it's going to help the next generation of clinicians and researchers but also the next generation of patients, and that's what it's really all about.

Dr. Tucker:

Absolutely. Rachel, I want to congratulate you again on this work and all of your work, and thank you again for sharing your time and your thoughts with us today.

Dr. Frank:

Well, thank you so much. Really appreciate it.

Dr. Tucker:

Dr. Frank's article, titled, "Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone-Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis," is currently in press for the Arthroscopy Journal, which is available online at www.arthroscopyjournal.org. This concludes this edition of the Arthroscopy Journal podcast. The views expressed in the podcast do not necessarily represent the views of the Arthroscopy Association or the Arthroscopy Journal. Thank you for listening. Please join us again next time.

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