Thank you so much. These are my disclosures. Probably most important is that I was in a trial with Zimmer on some of these topics. So this is what we're going to be talking about. It really comes down to bone marrow lesions. So we need to understand what we are treating, its impact on osteoarthritis, and how calcium phosphate is a solution. We'll be looking at does it work and is there something better. So terminology is important. This started with bone marrow edema because of what we saw in T2. But we realized that this is really a poor term histologically. So we've moved to the term of bone marrow lesion. But even with that, there's a lot that can go into that. They can be cystic, non-cystic. They can be related with cartilage, osteoarthritis, and obviously a lot of different mechanisms. So it's important to understand what we are treating. So when we see a bone marrow lesion, like anything from an ACL or patella dislocation or hyperextension, that is not what we're treating. What we're really treating is a mechanical overload, osteoarthritis, or subchondral insufficiency fractures. And so when we think about this, we have to understand what is really happening in that subchondral bone, and that's kind of what lies beneath. And there's been multiple basic science studies that have shown that there's a high metabolic activity with increasing bone remodeling, subchondral fibrovascular ingrowth, reduced bone marrow volume, and increased cytokines. And this also leads to areas of trabecular bone fracture. So when we frame this, we have to understand that the knee is an organ system, and osteoarthritis is really an organ system failure. So not only is the cartilage being affected and the synovium, but it's really that bone. And all of them work together for this organ system failure. So when we look at the literature, we know that these bone marrow lesions can really affect three different things. And first and foremost is that they are highly associated with cartilage loss. So when we have these bone marrow lesions, we can see that the cartilage lesions will progress. The size is also predictive of the cartilage loss. And if they're present, they're going to have increased cartilage loss over two years. Second, bone marrow lesions are highly predictive of OA symptoms. And I think this is really important because this has really driven a lot of our treatment. It is truly the strongest predictor of the clinical symptoms, and it's an independent predictor of the ability to bear weight. It's highly associated with pain, as you can see with those with and without bone marrow lesions here. And size is associated with the onset and increase in joint pain, as well as pain severity. And then third, it increases our risk of total joint arthroplasty, and it's really one of the strongest predictors that a total knee arthroplasty will be done. So if the lesion, the bone marrow lesion is size or increasing, we know that it's going to actually precipitate your progression towards a total knee arthroplasty. And in total, a nine-fold increased likelihood to progress towards a total knee arthroplasty if a bone marrow lesion is present. So these are bad. And unfortunately, we don't always know how that regression will happen, and it's not always reliable. And so if there is this enlargement of lesion, we know we're setting up these patients of osteoarthritis towards a knee replacement. So what do we know about treatment? And this is a study from Jimmy Cook looking at an animal model with a bone marrow lesion with osteoarthritis. And what they found, if you added calcium phosphate, it provided that structural integrity, allowing that healing response and an inflammatory response to subdue, and there was remodeling over time and maintained architecture at two years. So currently, if you look at the literature for this, the indications are truly for patients with moderate to severe osteoarthritis with pain in that compartment over the bone marrow lesion. What do we know from the clinical studies? Well, this all started in 2012 with this case report by Dr. Sharkey. These were patients who wanted to delay a total knee arthroplasty, and they failed their previous conservative measures, a lot of which have already been detailed. And they put calcium phosphate into this lesion. And they saw a resolution of their pain up to 31 months and resolution of the bone marrow lesion. This was followed up with two case series, one by Dr. Farr looking at his patients. And notably here, what they found is a significant decrease in pain within that first six weeks. And if you had that relief of pain, a lot of times those would be successful treatments. Only 25% continued to have pain and eventually went on to some sort of arthroplasty. Another case series by Dr. Cohn and Sharkey, again very similar. These were all patients who were indicated for a total knee arthroplasty who had failed conservative measures. They had moderate to severe osteoarthritis in that same area of the bone marrow lesion. They all had improvement in pain and function, but only 70% survivorship at two years that went on towards non-arthroplasty. So in total, you can see the rest of the studies that are out here, not many. But they do show promising results, early improvement of pain, improvement in function, improvement of gait, high patient satisfaction, and the conversion to arthroplasty ranges between 8% to 25%. But it's not always been that rosy. One of our studies from our friends at NYU, in their way of looking at it with their patient population, showed only 55% favorable results. And there are some case reports out there of some pretty devastating issues with significant bone pain that's been persistent in even osteomyelitis. There's been five systematic reviews that have looked at this. If you look at this in total, similar to the nice stoplight that Dr. Jorge Chala put out there, I would say our evidence is right in the middle. It's safe, low complication rate, it reduces pain, and it increases function. But there's still a lot of bias in the literature, and there's no randomized trials. So this is our biggest dilemma, who's the right patient? And there's a lot of things that we still do not know in regards to this treatment that's outlined here. The biggest thing is, are we going somewhere different? And that's where I would tell you that biologics are on the way. Intra-oste injections with either PRP or BMAC have shown to be very effective based on the early literature that we have, with better results than intra-articular injections with early pain relief and delay of total knee arthroplasty. So this is what we have for platelet-rich plasma at the current time, six short-term studies. All of them have shown improvement in pain and patient report outcomes, and better than an intra-articular injection. For bone marrow aspirate concentrate, again, these are the literature that we have currently out there. It is safe. The short-term results are very good, with reduction of the actual bone marrow lesion and up to about 75% of the patients, improvement of their pain and patient report outcomes. We have two long-term results as well that have shown a postponement or avoidment of the total knee arthroplasty in conversion of only 20% to 25%. They've also looked at some factors in these long-term studies as what influenced success, and that can be the alignment or persistent bone marrow lesion of over three square centimeters at two years. So here's what my final thoughts are. I think subchondroplasty or calcium phosphate will remain in our toolbox at the current time. I think that we have a great future with some biologic treatments. We have a significant need for high-level studies so we can really determine who is the best patient for all these treatments. Thank you. Thank you, David. One second, Armando. So, David, my struggle is I come across the knee arthroplasty surgeons. They come in the room, and they say, you've got to be kidding me. The problem's in the joint. They're going to have a total knee. Stop limiting their lives and inject it, and disclosure, I am a subchondroplasty user. So now, how do I answer my knee arthroplasty colleagues? Can you turn on this mic? Thanks. I think our knee arthroplasty partners are going to be extremely busy in the future years. I think as many of these patients that we can delay, their arthroplasty is really important. And eventually, they may get there. But these are really useful treatments. I think a lot of our patients do not want an arthroplasty. There's a lot of fear with that, as well. It's not always a perfect operation, as well. Anywhere up to 16% of patients can still have pain with a knee arthroplasty. So I think this is really some of our future to keep people active with their own knees. Okay. I bring to the stage a dear friend of mine.

bone marrow lesions

osteoarthritis

cartilage

mechanical overload

total joint arthroplasty