Thank you very much for the opportunity to present today. I thought this was going to be a very romantic session just between of us. This is awesome to see that everybody came on a Sunday morning. All right, I was tasked to talk about orthobiologics in the knee osteoarthritis in six minutes. I'll try to give you an overview of what I actually use in clinic and what's the evidence behind it. Why do we need to think about biologics? Because we treat most of our biological problems with mechanical solutions. If you see this or diffuse osteoarthritis, that will most likely not get a knee replacement because it's a biological problem. If you think about this, most of the rheumatological conditions require just one antibody to treat that disease, but most of the times what we have done in the past is basically do the shotgun approach where we treat skin disease and hair loss and osteoarthritis with the same compound. We use PRP in the same way for every single condition, and we don't know even what's causing the benefit or any sort of functional improvement. This is why I think we need to go back and rethink, and this is a call to action. We need to understand what the target tissue problem is because it might not be the same to think about a degenerative disease, a catabolic disease, an inflammatory disease. I'm assuming that in 10 or 15 or 20 years from now, we're going to have something that we will be able to get up from the joint and measure and say, well, there's a lot of CTX2, so there's a lot of degeneration in the knee. This is how we need to treat it and not just treat it with the same compound that we treat osteoarthritis or focal condyle defects. And then we start thinking about how to treat it, when and how many times do we deliver these medications, outcomes, and how do we report the outcomes. The goal of orthobiologics in the knee is primarily to treat pain and function, but can we change the structure? That's what most of our patients come to clinic and ask for. Doc, if you inject PRP or BMAC, is that going to regrowth my cartilage? Is that going to make my meniscus look better? So that's what we don't know. There's multiple products out there, cortisone, HA, autologous derived products, and cell therapy. And it's kind of confusing sometimes to know what to use because there's so many literature and press and press pushes and things of that nature that it's really difficult for us to understand what actually works. So I try to summarize this with a light based on limited research or limited evidence, moderate evidence, and strong evidence. Corticosteroids, most of the full disclosure, most of the data that you will see today is part of the AOS guideline that will come out probably this year. 25 studies, 19 high-strength studies, 6 moderate-strength studies. These are studies that are level 2 or 1 compared to placebo, HA, corticosteroid, and basically the extended-release corticosteroid. They only showed only effective to be at short term. One month functional outcomes are very good, 51% versus 19% when you compare it to a control. However, again, this is short-lived. There's a new extended-release steroid that is supposed to last for about six months. There's only one study comparing this, longer pain relief, improved PROs versus the standard corticosteroid, and there's only a marginal added functional benefit. It might be promising if we think about using corticosteroids in this population. So the light is a green just because it has pretty good short-term outcome. Improves pain and function for over three months, good efficacy with severe disease. The extended-release seems to have an added benefit to the immediate-release one. And this should only probably be used for acute flare-ups because there's no long-term effect that corticosteroids have. How about heteronic acid? Twenty-eight studies in the literature, 17 high-strength, 11 moderate-strength. Compared to placebo, corticosteroid, they compare multiple formulations of HA. Most of them did not reach minimal clinical significant difference. Although some of them did reach statistical difference, they did not reach clinical difference. The number needed to treat to make one patient better was 17. So every 17 patients that we treat with heteronic acid will improve one of those patients. And we had a big push because we wanted the American Academy to be able to say, you know, that this would be a treatment authorized in the event that they failed conservative treatment because we want to have this in our armamentarium. But again, this is not a treatment that is as effective as treating one or improving one out of three people. You need 17 people to improve one of them. So this is a yellow because it has a marginal statistical benefit. The effect is less than half of MCID. There's a low number of patients that will actually benefit from it. Cross-linked HA and corticosteroids seems to perform similarly. There's no enough evidence to support the use of HA as a primary treatment for osteoarthritis. How about platelet-rich plasma? We know that this change is based on multiple things. There's multiple studies now saying that it might not only be the platelet-rich plasma or the platelets, but also the growth factors within it and which growth factors you have. And it's highly variable. We did a couple of studies where we looked at how age will basically affect the composition of PRP, BMI, and so forth. Even the time of the day where you get the PRP extracted or the blood drawn is going to change the PRP composition. 21 studies in the literature, 13 high-strength study, 8 moderate studies. This is completely different to what they've seen five years ago in the clinical practice guidelines. There's a lot more evidence on this versus placebo, corticosteroids, HA. Most of them, 19 versus 2, show that it's better than the control. So this is very interesting because this might change how we treat patients or what gets authorized through insurers. There's some studies now from basic science as well as clinical studies suggesting that if you combine this with HA, it might have a synergistic effect. So this is a green light. Interroginating the literature relative to placebo, however, most of them show a superior outcome than HA and other controls. In multiple high-quality studies, superior outcomes relative to corticosteroids and HA, and it might be synergistic with HA. How about platelet-rich in growth factors, PRGF? It's pretty much the same as PRP, so there's no significant difference between both compositions. Sometimes it gets confusing to know what's what, but basically, every time you use a blood-derived product that is concentrated to increase the platelet concentration and decrease the leukocytes and the red blood cells, this is pretty much what they have. It's a more purified composition, but it actually does equally in regards to pain and function. So there's three studies, two level one studies, one level three studies. They all have a benefit in comparison to the control, however, as there are not a lot of evidence on this, there's no recommendation, at least from the guidance from AOS. We performed this network meta-analysis trying to look at what are the things that will cause a significant benefit or a significant clinical difference in patients, and what we saw was basically that intraticular PRP, PRGF, and HA significantly improved pain and function. PRP and PRGF had the largest clinical improvement, and intraticular corticosteroid had no significant long-term benefit. So we will keep repeating this over and over because I think in repetition we will learn these concepts, which are simple to understand. PRGF and PRP had improved long-term outcomes, improved pain and function. Both formulations were superior to HA. PRP performed very similar to PRGF, and there's more evidence needed to understand if one or the other will be better. How about bone marrow aspirate concentrate? There's only one randomized clinical trial from the U.S., from Shane Shapiro, the Mayo Clinic, 25 patients, a very well-designed study, bilateral OA. In one of them they injected BMAC, $2,500, in the other one saline, $0.25. Similar pain relief, similar outcomes on MRIs. So this is something to consider when we're talking to patients and making them understand this might not be any better than just injecting saline to your knee. So there's a limited recommendation. There's only four randomized clinical trials with very confusing outcomes. When I get asked, what do you use, BMAC or PRP, there's a significant amount of evidence for PRP and not so much for BMAC. I can do it in clinic. There's no significant morbidity associated with it, so I think PRP for those cases might be better. So for BMAC it's a yellow. There's preliminary evidence supportive of BMAC in some regards. It's no better than other blood-derived products so far in the literature. And more clinical studies are needed. How about stem cells? This is the main question that I have when I think about stem cells. Am I only treating the symptoms or can I treat the structure? We just published this systematic review and meta-analysis where we basically assess the literature showing that most of them will improve the symptoms and the function, but it's unreliable as to whether this will improve the structure of the knee. There's two studies that show a marginal benefit in cartilage volume, and there's six studies that show a marginal benefit, again, on cartilage quality. But when you look at the literature, the evidence is very low. There's a poor study design, high risk of bias, and large heterogeneity. So it's hard for us to know if there's really a structural issue or a structural improvement. When I talk to patients, I usually say this will not improve your cartilage. This will not heal your meniscus territory, but most likely than not, it will improve your pain. And we don't know if this might be better for your structure moving forward. There's two things why FDA has not approved this. One is that we don't understand signaling of stem cells very well. And the second thing is that we don't know how to stop the proliferation of those progenitor cells. Why is this important? Lori Goodrich at CSU showed in a very elegant study that when she injected PRP with stem cells into cartilage defects of animals, 30% of those created bone because those cells lost the signaling that they needed to transform or the environmental signals that they needed to transform into cartilage. And this is one of the reasons why FDA has not approved this, because we don't understand them very well. The second thing is proliferation. As we said before, we were doing this study with Johnny Hewitt at the StemMed Clinic where we basically cut the perineurum of a nerve and replaced that with stem cells. At one year, it was almost completely regenerated. But at three years from then, it became a huge tumor. So we don't know how to tell them to stop once they achieve their outcome. Those two things, I think, are the main things that are holding us back in regards to how far we can get with stem cells. So preliminary evidence is supportive of stem cells. However, we need a lot more literature on this. The study design is very poor so far, so we need highly randomized clinical trials, mostly improve symptoms and function, but we don't know if the structure will be affected by it. And safety continues to be a concern. So again, this is a yellow light. In conclusion, we need to better understand what are we treating. Processing and indications are still not clear. Relatively good overall outcomes have been shown with minimal complications, but studies are very short-term, follow-up, and also the study design is not very strong. So we need more evidence. I will encourage everybody in this room to help us with the research. Thank you very much. Jorge, thank you. I just want to wait, Dave. We're going to have a general rule. So Jorge, only because you're young and you know my reputation, you went at 11 minutes and 7 seconds for a six-minute talk. So great material, but the rules are the rules. So for the rest of you, at six, you're cut off, just so you know. I do want to make another comment to tell you that you heard all of this, so how would you comment to some of us, someone's living in, I come from New York City, but I'm going to, in Wyoming, a 50-year-old, Kellgren-Lawrence II, terrible pain, doesn't want the total knee. Two arthroplasty surgeons said it. So what are you putting in that person? Now what are you putting in that person? Which drug? Cortisone. So you're putting in cortisone. Cortisone fails. What are you putting in? Doesn't want a total knee. You think this is going to be easy? Anodobrase, HA, and PRP, if there's a unicompatibility issue. Great. Okay. So it's also very interesting to hear, you know, the, be careful what we publish. We are the only profession that wishes our own demise. It's noble, and Michael Porter has said it in all seriousness, but no one in the business world would do what we do, okay? We're looking for the answers to help people, but we're also cutting our income. Just remember that.

orthobiologics

knee osteoarthritis

treatment

evidence

stem cells