Single-Injection Hyaluronic Acid in the Treatment of Knee Osteoarthritis

Speaker 1Thanks everybody for joining us again. Uh, we're going to do a deeper dive on the

Speaker 2management

Speaker 2of NEOA, non-operative management of NEOA,

Speaker 1and

Speaker 1also look a little bit at the single-injection hyuronic acids that have now recently come onto the market. So here are my disclosures for you to review.

Speaker 1So we're going to explore the use of single Injection HAs and treatment algorithm for OA. We're going to identify patient and treatment factors that predict a favorable response for HA treatments and guide treatment selection, and then we

Speaker 1can look at the differences in efficacy, the science

Speaker 1and clinical applications of the various HHA products that are out there.

Speaker 1So, obviously, in the context of COVID, there are a lot of issues that we need to address. And so, some of those issues are listed here. And these are the patients that really are going to be struggling with managing their Knee way, especially the ones that may have more severe disease, uh, that have struggled all along and actually are ready for Surgery. But obviously, now we have uh different factors that are coming into play.

Speaker 1So, I've got a number of patients who had to cancel their total Knee replacements. I've had older patients or patients with significant comorbidities that are sick or scared uh to have Surgery and they want to wait until it's all over. Uh, we've had patients that are COVID positive that can't have Surgery and have to get it rescheduled and then get to the back of the queue.

Speaker 1We've got high-risk patients that want Surgery. So do we do those, uh, cases, uh, despite knowing what's going on and potential, uh, transmission of the virus, uh, if they're exposed at the hospital or in the community at Physical therapy or what have you, or do we simply say, no, you can't have the Surgery and we just manage them the best we can.

Speaker 1Patients that live in rural communities, uh, where access is shut off or diminished. How do we treat them? And obviously, there's a big push to move a lot of these surgeries out of the Inpatient setting, uh, to the Outpatient setting. So, if that happens, uh, are the ambulatory facilities ready for, uh, patients that may need to stay more than one day? Pain control obviously is a big deal in terms of transitioning from anti.

Speaker 1to an Outpatient setting. If you're in an ambulatory Surgery center, you can't have ER readmissions, that gets really scrutinized, uh, very closely. And then post-operative complications, again, uh, scrutinized very closely. So, you have to pay attention to these outcome variables that are, are important, but may not have been necessarily top of mind or you may not have paid attention to as closely, uh, in the traditional uh Inpatient paradigm.

Speaker 1We know OA is changing and it's becoming much more prevalent in our younger patients. It's moving to the left. And you can see the trend here of patients developing OA is really growing, especially in the 45 to 64 year old age range. You know, and it's not uncommon for me to be doing a Knee Replacement in someone's.

Speaker 150, 55 years old. Whereas 1015 years ago, I think there would have been a food fight at our indications conference, uh, if you were going to do a Knee Replacement and someone who's 50. It just wasn't done. But now, it's almost commonplace or not commonplace, but it's, it's not unusual for us to be doing, uh, these surgeries. Now, we can look at the growing, uh, uh.

Speaker 1Uh, numbers of NIOA, uh, in a couple of different, uh, contexts. We can blame it on, uh, increase in population, right? So, that explains for about 11% of the growth. We can blame it on obesity. That explains about 23% of the growth, but there's still a significant number of patients who are developing OA where we don't necessarily have a clear epidemiologic explanation for why that growth is there.

Speaker 1If we look at the number of total joint replacements, it is growing significantly. You can see the number here uh in the Medicare patients, uh, where, uh, the number of total Hip and revision Total Knee Replacement patients is growing significantly. And actually, as an orthopedic surgeon, as a total joint surgeon,

Speaker 1Uh, the revision burden is, uh, just as concerning, uh, for me because we're slowly losing, uh, the number of surgeons that are willing or able to handle, uh, the revision burden. And so, as the Primary Total Knee Replacement volume grows, you know, what happens to that revision burden as well?

Speaker 1If we look at a different model, uh, modeling out and projecting out how many Total joint replacement patients uh we'll be seeing, you can see there's a significant, uh, increase projected out to 20-30, uh, in the most recent, uh, uh, projections, uh, that, uh, have been done, uh, again, using, uh, the, uh, insurance data, uh, that, uh, is available.

Speaker 1So, why do we see this growth or what are some of the things around NOA that makes it difficult for cartilage to heal? I think the two biggest issues or the two most practical problems are the fact that cartilage is avascular and a neural. So, it's avascular, so it has very poor reparative potential, and it's a neural. So, you really can't feel it as cartilage is being damaged, which is a good and bad thing. You can't feel it, so you can't tell it's being damaged. But if you could feel it, you'd probably scream in Pain every time you took a step.

Speaker 1Right? One of the key factors is this uh uh constituent of articular cartilage called glycoso amioglycans. So, this is a molecule within cartilage that gives us its compressibility and its ability to absorb shock and absorb sheer and compressive stress. And so, as we age, the size of these molecules diminish and the concentration of these molecules diminish. And this is where Hyaluronic acid really fits in and is a potential target.

Speaker 1If we look at OA, it's a very complex biological process. So, it's not simply wear and tear, mechanical destruction of the articular cartilage and of the bone and of the ligaments. You can see here, there's a complex interplay of cytokines and chemokines and all kinds of cellular mechanisms and cascades that are happening that are driving away. So, there's a lot of biology going on here. It's not just simply your tires wearing out on your car, if you will.

Speaker 1And so this is a depiction of some of the cells signaling and some of the cellular, uh, mechanisms, uh, that are impactful around managing NOA.

Speaker 1So, you can see here what kind of grossly it looks like you've got the smooth hyaline cartilage that coats the end of the joint. And as OA sets in, you can see it starts becoming rough. And so, as the cartilage begins to degrade, you have a biological process on top of a mechanical process. And so, it kind of just perpetuates.

Speaker 1Definitely until you can break that cycle. So, this is from a couple of Knee scopes that I did. This is a healthy Knee. You can see the smooth white articular cartilage here on the femur, and then compare that to this arthritic Knee, where you can see all that articular cartilage worn away. This pink stuff is actual bone, so completely worn out articular cartilage, the meniscus here all chewed up, looks like somebody took a weed whacker to it.

Speaker 1So, I think one of the big challenges in diagnosing and managing NOA is, number one, getting the severity of the disease, uh, appropriately. And so, the key to that is getting the appropriate X-ray. And one of the X-rays that routinely gets ignored or in the non-ortho world, uh, is, is not known, is getting the notch view or the tunnel view or the Rosenberg view. And this is an AP X-ray with the Knee flex at about 45 degrees. So, you can really bring into profile.

Speaker 1That portion of the femur where you would expect the articular cartilage to be worn out, which would be the posterior condyles. So my routine X-rays that I get when I have a new patient with chronic Knee OA is this. So I get a merchant view or sunrise view. So we're getting the Patella sitting in the trochlear groove on profile. I get a lateral view. I get a standing AP Knee X-ray, and I get a standing notch view or tunnel view like I described. And this is where the patient flexed about 45 degrees.

Speaker 1And so what that does is bring into profile that area of the Knee where we expect that cartilage to cartilage wear to be. So, this is the same exact patient, OK? I had them stand and took a standard AP Knee X-ray. Then I had them do the tunnel view or the notch view, and look what happened. That medial joint space completely collapsed because we're bringing into profile that area of the Knee where we would expect that articular cartilage to wear out. So, this X-ray, you could grade as.

Speaker 1possibly a KL-2, call it mild, maybe moderate NOA. This is a bone on bone patient X-ray. So, this patient, I probably would have treated with NSAIDs. This patient actually may need a Joint replacement, right? And so, if we don't get the appropriate X-rays, what do we do? We then inappropriately treating the patients. And then when this patient doesn't necessarily respond to our treatment plan, what do we end up doing? We start blaming the patient, right? They're malingerer or it's the patient or, you know, super tentorial or what have you.

Speaker 1The issue is we don't want to look in the mirror and realize that actually, we didn't diagnose them appropriately.

Speaker 1This is another example of an X-ray pitfall, the problem with getting supine X-ray versus standing X-rays. So, this is the same exact patient. Uh, they came to me with their X-rays on a CD and I asked the patient, were you standing or laying down? And they said they were laying down. And so, this was the X-ray they handed me. I redid the X-rays in my office and I asked them to stand and lo and behold, what do we see? So, when I had them stand, we had complete collapse of their.

Speaker 1surface. So, when you order the X-rays, you have to really explain to the uh uh radiology tech techs or the imaging center that you're sending the patient to exactly what you're looking for. So, you want weight-bearing X-rays, I want an AP X-ray and a notch view. I want a sunrise view or a tunnel view to see what's going on with the Patella, because oftentimes you'll have severe patellofemoral Arthritis that you won't pick up on the standard AP or lateral Knee X-ray.

Speaker 1And so, next time you're flying and you're on Delta, and you're looking at the back of the magazine and you can see someone's using lasers or magnets or something to regrow cartilage, you now can appreciate what they were doing. Uh, they took the same exact X-ray, uh, with the patient laying down and standing and magically, uh, grew their cartilage, uh, to convince you to use this, uh, new, uh, innovative Technology.

Speaker 1So, this is a, a, a picture that I took during Surgery. You can see right here where that wear is, right? It's along the posterior condyle of the femur. And when we're taking an AP Knee X-ray, this is what we're imaging. We're not imaging this posterior aspect. When we take that notch view, this is the aspect of the femur that we're bringing into profile. And there's plenty of literature and science out there demonstrating that the notch view is actually more sensitive and better for assessing severity of the disease than the standing AP Knee X-ray.

Speaker 1So, once we've diagnosed Niawei, what are our treatment options? So, the traditional paradigm is this, right? And this is what's stuck for many, many years. It's using Arthritis pills, Advil, Aleve, Motrin, Tylenol, what have you. If those don't work, then we move on to steroids. And if those don't work, then we move on to Surgery. So, the challenge here is introducing everybody and allowing them to understand that there are a lot more treatment options that are out there beyond the simple paradigm that we've been working in for so long.

Speaker 1And so this is a treatment pyramid that I like to show. And so, we start, especially with E OA with these simple treatments here, exercise, Physical therapy, weight loss, so on and so forth. As Arthritis progresses, we start getting more aggressive with simple analgesics, more, uh, and then we start using prescriptive uh treatments, and then we start getting the more interventional treatments.

Speaker 1Such as blocking the geniculate nerves, uh, injections, prescription-strength, uh, anti-inflammatories, uh, so on and so forth, and then ultimately Surgery. And HA injections, you can see, are best utilized when we're talking about mild to moderate NOA. And a lot of the recent literature and a lot of recent information supports the fact that HA injections work best when we use them.

Speaker 1With mild to moderate Arthritis. So, this is a nice uh algorithm out of the, uh, one of the rheumatology journals that really highlights all the options that are out there. And if you're not familiar with this, this may be one where you just simply want to photocopy and tape at your desk, uh, and that way you have a reference uh as you see these patients, so you know where to start and kind of work through all the different treatment options that are out there.

Speaker 1So, I've been talking about HA injections. And so, what exactly are HAs? So, yuronin is a polysaccharide found in all tissues and body fluids of vertebrates as well as in some bacteria. It's interesting because it's one of the very few molecules that's completely preserved across all animal species. So, if you can preserve it, you can actually move it between species without any issues.

Speaker 1a rooster or bacteria or whatever into a human. So, if I can purify it, I can actually use it and the body will recognize it as being normal. So, it's a linear polymer of exceptional molecular weight of multiple kilodoltons. It's abundant in loose connective tissue. It's synthesized in the cellular plasma membrane. It binds to the proteoglycans to stabilize the structure of the extracellular uh extracellular matrix.

Speaker 1And so it's found intrinsically within the Knee joint. And like I said, as OA progresses, the concentration and the size of that molecule, uh, diminishes over time.

Speaker 1And one of the big, uh, changes that we see is your articular alteration, structural changes, uh, within the Knee. And so the subchondral bone, when the subchondral bone starts seeing those, uh, forces, that's when patients start seeing or start feeling the Pain and the dysfunction associated with, uh, kneeOA.

Speaker 1So, what are the mechanisms of action for HA treatment in osteoarthritic Knee? So, there's data showing that it can actually help protect the articular cartilage or the chondrocytes. It helps stimulate the body to make more normal endogenous uh protoglycans and glycosamamino glycans or HA. It's got anti-inflammatory properties. It's got mechanical modifications. So, again, if you can stabilize

Speaker 1articular cartilage. It will help mechanically, uh, with the Knee, uh, potentially it can help with the subchondral bone, which is where you feel a lot of the Pain because remember, that's where the nerve endings are. And so as the cartilage wears away, uh, the next, uh, really structural component is the subchondral bone. And that's where the nerves are, which is why the patients begin feeling Pain. And it's got analgesic effects as well.

Speaker 1So, in terms of chondro protection, uh, it's uh has significant data around its ability to reduce or improve inflammation and thereby reducing the matrix metalal proteinases, which are the degradative enzymes that attack the articular cartilage and break down the articular cartilage. Again, as I mentioned, the synthesis of protoglycans.

Speaker 1glycosamammio glycans, enabling the Knee or the synovium to produce more normal endogenous HA and its anti-inflammatory effects. Again, hat in hand with MMP, uh, because it's those pro-inflammatory cytokines that drive the MMPs that then drive the destructive uh uh processes that we see with articular cartilage. And all this happens through the CD44 uh receptor.

Speaker 1Um, the viscous nature of HAs has been shown to lubricate the joint capsule, and we think that, uh, degeneration potentially, uh, can be prevented, uh, via this reduction in friction. And believe it or not, actually, this is one of the Primary, uh, approvals that the FDA allowed to bring HHS to the market. HA injections are actually considered a device by the FDA, believe it or not. And it was because of these initial mechanical properties, uh, that the FDA.

Speaker 1felt that this was actually a device, but, uh, that has, uh, since changed and the, uh, the FDA is thinking about this a little differently. But needless to say, today, uh, and in the past, actually, uh, HA injections are actually considered a device, uh, by the regulatory bodies here, uh, in the US.

Speaker 1You can see, uh, the HA injections, uh, help, uh, with the subchondral bone. Again, that's where a lot of the Pain potentially can be derived from. Uh, and it's got, uh, uh, potential analgesic effects. If we look at animal models, uh, if you harvest the dorsal root ganglion in animals that were exposed to HA, you see a down regulation and Pain receptors, uh, at the CNS level, uh, as well. Uh, so both centrally and then also, uh, peripherally.

Speaker 1So, you can see clinically that uh there's a significant improvement in the behavior of articular cartilage uh in patients that receive uh HA injections compared to patients that don't. Uh, when we take, uh

Speaker 1Uh, uh, uh, urine samples from patients that received HA versus patients that did not. You see a reduction in cartilage breakdown, uh, proteins and molecules in the patients that received HA injections compared to the patients that did not. When we look, uh, uh, in vitro, also, uh, and clinically, uh, at its ability or at the body's ability

Speaker 1To produce uh more normal protoglycans and glucosamminoglycans. You can see, uh, both, uh, with Ultrasound and with histo, uh, that the patient's able to produce more normal, uh, HA uh as well. And so, here's a kind of a complex slide showing the complex cellular mechanisms and, uh, and, uh

Speaker 1communications that happen in the ability of HA uh injections uh to reduce inflammation uh within, within the Knee.

Speaker 1Again, data here showing that HA injections actually significantly suppress or reduce matrix metalloproteinase production within the synovial tissue. This was a study done out of LSU Shreveport where they took the different HA products on the market and they challenged.

Speaker 1The synovium from patients that had synovium biopsied from the Knee. They challenged it with IL1 beta, which is a very strong pro-inflammatory cytokine, then introduced the different HA products and found a significant reduction in MMPs, matrix metalloproteinases, when that tissue was exposed to the Hyaluronic acid.

Speaker 1Uh, you can see here studies around the lubrication or mechanical aspects, uh, around HA, uh, and then additional studies here looking at the impact of HA on subchondral bone and subchondral bone changes.

Speaker 1Again, uh, when we look at the dorsal root ganglion and we looked at the impact of HA injections, we see a down regulation. This was a study in an animal model, looking at the animal's ability to stand on the limbmb.

Speaker 1Based on the amount of Pain they had, and so the joints that received HA injections were able to tolerate stances, were able to tolerate forces much better than when not receiving HA or the vehicle or the control.

Speaker 1So, around HAs there's a fair amount of controversy. So, back in 2013, the American Academy of Orthopedic Surgeons came out with their guidelines, and what they found or what the evidence suggested is that there are only 4 treatments that had any evidence to support their use in the management of OA. So, exercise, weight loss, NSAIDs, and osteotomy.

Speaker 1So, as an orthopedic surgeon, we begin to struggle because based on these guidelines, really, there's no treatment, there's no treatment option where the evidence conclusively supports its use. And so, I submit to you, exercise, weight loss, and NSAIDs, most of my patients when they hit my office have actually tried that. So, I can't really tell my patients, well, those are really the only treatment options that I can support or that the evidence supports and certainly offering osteos.

Speaker 1ot om y to our bone and bone bone patients doesn't really make any sense clinically. If we look at the tried and true treatments that we've got, so, steroid injections are, are actually uh neutral. So, there's actually no definitive evidence to support their use. And if you look at opiate use, actually, uh, the WAS guidelines actually have a neutral recommendation on usage of opiates, uh, for management of NOA.

Speaker 1Right? So, we know that these recommendations are in the process of, of being evaluated as we speak. The new guidelines should be coming out shortly. But nonetheless, the guidelines currently that are in play are these, and the HA injections actually had a negative recommendation.

Speaker 1So you can see the science supporting what we do is actually pretty limited and, and fairly sparse. And really the only three treatments that are supported by the science would be the three treatments that really are impractical when the patient hits my office.

Speaker 1And so, uh, there's a lot of uh discrepancy between the specialty organizations uh that are out there. So, the ACR or the American College of Rheumatology, uh, recently came out with their guidelines and what they found was the choice to use Hyaluronic acid injections in new patients who have had inadequate response to non-pharmac.

Speaker 1The therapies, topical and oral NSAIDs, and intra-articular steroids may be viewed more favorably than offering no intervention. So, again, a little different than, than what the orthopedic surgeons say. If we look at ARC, which is a federally funded uh agency, uh, what they found was HA improves functions, health-related quality of life, and may delay.

Speaker 1Total Knee Replacement in the Medicare patients. So patients that are 65 and older. If we look at the American Medical Society for Sports Medicine, they recommend the use of HA for appropriate patients with NEOA. Uh, the Eurovic Group, uh, unanimously agreed viscosupplementation is effective treatment for mild to moderate NEOA.

Speaker 1And so, there's a lot of discrepancy between especially organizations around the use of uh HA injections, uh, in NOA. Uh, so you can really find, uh, differences of interpretation of the science, depending on who you ask, and where you go. Um, so if we look at some of the science that's out there, what do we see? So this is a

Speaker 1published by Doctor McClendon, one of the, uh, kind of foremost uh uh uh outcomes researchers in the Arthritis space. And what they found was the intra-articular benefit of HA and their treatment appropriateness. So, in patients, uh, without comorbidities, uh, what they found was the appropriateness of HAs here are uncertain, uh, and then uh

Speaker 1But they found that it should be conditionally recommended, uh, but in these patients here, multi-joint type OA or multi-joint OA, uh, it's not necessarily appropriate, but it's not approved in the US for management outside the Knee. So, really, when we look at the data, uh, in terms of Knee OA only, you can see they've got a conditionally recommendation here.

Speaker 1So, one of the Other challenges around a NOA is the Kellighan-Lawrence scale. So, the Kellighan-Lawrence scale is how we assess disease severity. Uh, grade 4 is bone on bone patients, grade 0 is basically a healthy looking Knee, and then, uh, obviously, uh, the different gradations between, you know, mild to moderate Knee OA is really grade 2s and 3s, and then grade 4.

Speaker 1I, uh, uh, bone on bone. And the challenge with this is they only use a standing AP Knee X-ray. No merchant or sunrise view, so you can't tell if there's any patellofemoral OA and no notch view or tunnel view. So you, you really, uh, in studies that use the KL score, may be including a lot of patients with more severe disease, uh, and really skewing the data. And so, a lot of the guidelines, especially WAS guidelines,

Speaker 1were based on studies that use the KL score and didn't really screen out uh the more severe patients. So you can really hone in on who the patients are responding to, uh, NIOA. Um, but with the later studies or the newer studies, you're really starting them to pay more attention to the types of X-rays that they're getting and really not include KL 4 patients and really focus on the KL 2 and 3 patients.

Speaker 1So it's confusing, but, you know, we have to synthesize all this information the best we can to try to deliver the best options uh for our patients.

Speaker 1So, what are the different HA treatments that are out there? So, typically, there's single injections versus multiple injections, and the multiple injections can be weekly from 3 to 5 weeks. There's some newer ones that are actually 2 injections, uh, 1 a week for 2 weeks. They're also divided into low molecular weight versus high molecular weight. To get to high molecular weight, usually you have to manipulate the HA molecule. To a certain extent, some of the older HA products that are out there really manipulated the molecule.

Speaker 1to a big extent, and patients would develop an allergic or immunologic reaction to that. The newer HA single injections that are out there high molecular weight injections that are out there manipulate the molecule a lot less so the body doesn't see it as being abnormal. And then there's avian versus non-avvian HA injections. There's a lot of interest in the newer products moving to non-avian uh uh products because it's easier to purify. You don't have as much contamination uh with the avian-derived products that are out there.

Speaker 1So if you look internationally in terms of the HA injections that are out there, there's a fair number of these injections all over the world. Uh, but the ones that are highlighted here with the arrow are the single Injection, uh, treatments that are most available here in the US. And you can see the ones here that are FDA approved on this list.

Speaker 1So, when we look at the data, uh, comparing uh single-injection HA products to multi-injection products, this is one of the studies that did that. So, this is a study out of China comparing a single-injection HA product called Durallane to a multi-injection five-injection series called ARTS or SPARTs, which is kind of the, the grandfather of the HA injections on the market.

Speaker 1And what they did was a non non-inferiority study to see how the single Injection stacks up to 5-weekly injections of another HA products. Again, you can see here, uh, you're starting to see in the Research that they're excluding the patients with bone on bone uh OA in our Research, and we're really focusing on the patients with mild to moderate, NOA, uh, and you had to see that the patients needed to have some baseline characteristics in order to be included in the study.

Speaker 1So what was the study designed here? They received 5 weekly injections of Suparts. Uh, in the group that got the Duralanne, they got 1 Duralan and then kind of 4 sham injections weekly, uh, thereafter. You can see 160 or so patients in each arm.

Speaker 1Um, study duration was 26 weeks, and the, uh, variables of interest were Womack, Pain and function, which are kind of the classic, uh, Pain and function scores in the NIOA literature. And then we are starting to see a lot of interest in responder rates. So not only are we looking for something that's statistically significant, but we want to start understanding if the results are clinically meaningful as well.

Speaker 1And so what did they find? They found basically no difference between the Suparts Group and the Duuralane Group. So they established, or they helped establish that the single Injection products are just as good as the multi-injection products that were on the market.

Speaker 1And so you can see, uh, the responder rates. So not only statistically significant, but clinically significant improvement, uh, both in the single Injection group compared to the multi-injection group that you see here. The Other thing that I pay attention to in a lot of these studies is the use of rescue medications. So, it's one thing to circle Pain scores and functional scores on a sheet of paper. It's another thing to.

Speaker 1monitor what the patients are feeling by figuring out what rescue medications they're using. So, it's actually an interesting variable to monitor and pay attention to. And what you found was no difference, uh, in the Dulane group compared to the Sars group in terms of rescue medication, uh, usage as well. And the adverse events as expected, uh, would be low with these treatments.

Speaker 1So, again, uh, a fair number of single Injection, uh, products, uh, that are on the market, and you can start to see, uh, we're seeing a lot more, uh, interest in, uh, especially in the newer treatments that are out there, uh, in non-Avian formulations compared to the avian formulations in the past.

Speaker 1So, I was part of a study, uh, group trying to figure out, you know, because the science was somewhat limited, can we start figuring out to the best of that ability that we can based on whatever, uh, literature was available, uh, you know, what are some of the practical applications for the HA products, uh, HA treatments that are out there. So, we came up with a lot of these different clinical scenarios that a lot of us see kind of in the real world and based on the science and our, uh, expert consensus.

Speaker 1We felt that these were kind of the three products, uh, or 3, scenarios, uh, where, uh, HA really had both expert consensus and literature or science to, to support their use. And then, uh, in these following categories, felt that, you know, uh, it was unclear with the literature and us as clinicians, uh, that have knowledge in this space, we're also unsure, you know, whether, uh, these HAA injections are appropriate or useful in those scenarios.

Speaker 1So, this is a nice head to head study, uh, taking the scientific literature that's out there to compare steroid injections to HA injections and steroid injections are kind of our tried and true treatment. And what they found was steroid injections actually win early on, which makes sense and that's what we see clinically. But as time goes on, steroid injections wear off very quickly, but we see a sustained benefit in the HA injections over time up to 26 weeks, uh, compared to steroid injections.

Speaker 1So we did a health economic study because I also want to look at this from the perspective of a payer or someone that's taking risk in, in management, uh, the payment, managing the payments of NIOA. And so what we did was we used an administrative claims database and we looked at all the patients that had a Knee Replacement and then we looked backwards to see how long it took.

Speaker 1From the time of diagnosis until they had a Knee Replacement as a function of the number of HA injections that they had. And so what we found was up to five-course treatment, a 3.6-year reduction or delay in time to Knee Replacement compared to the patients that did not receive HA injections. So, again, these are patients with significant disease.

Speaker 1And how long did it take to get a Knee Replacement? And we were able, or at least the data shows that there's a correlation between uh HA injections and time to Knee Replacement.

Speaker 1So there's a lot of data and a lot of interest looking at

Speaker 1What are the best treatment options for NOW? And it'd be almost impossible to design the perfect randomized controlled trial, right? Because we'd have to have 10 different arms. We'd have to follow these patients out for a long period of time and hope that they didn't cross over or have all Other issues. And so, from a big, big data perspective, it's impossible to design a, a randomized study or a level one study to answer that fundamental question.

Speaker 1So, we have to start using or employing big data principles to try to figure out what the best treatments are. And that's what we call a network meta-analysis. So, this was a study done by Dr. Banneroo to, to start using kind of these newer big data principles to try to understand what the optimal treatment options are for NIOA. So, he took 137 randomized Clinical trials, and he separated them out to the uh within the different treatment arms. So, you can see all the different treatment arms within all of those RCTs. And I submit that

Speaker 1This is probably uh uh covers uh the breadth of different treatment comparisons that we would shoot for, right? So, steroids versus placebo, Tylenol versus Naprosyn, Naprosyn versus HA Injection, so on and so forth. And so graphically, this is what it looks like. And so, the bigger the circle, the more patients that had that treatment arm in all these studies. The challenge is how do we compare Naprosyn to ibuprofen and Celebrex to ibuprofen?

Speaker 1Right? So, what we have to do is see how Naprosyn behaves with these Other treatments, how Celebrex behaves with these Other treatments, uh, where there's overlap with Motrin, and then we try to figure out what that comparison is to ibuprofen, uh, to Celebrex and Naprosyn. And so, that's what a network meta-analysis does is it employs these correlations, these big data principles to try to figure out uh how different variables behave when there's no direct comparison.

Speaker 1And what did they find? What they found, generally speaking, is injections performed better than pills. And of the pills, diclofenac had a better efficacy than all the Other treatments. The Other thing I want to point out is intra-articular placebo. So saline actually did better than Tylenol.

Speaker 1OK? So that's interesting. I I want you to digest that for a minute. Of the injections, what they found is HA injections perform better uh than steroid injections.

Speaker 1So, how is this that an intra-articular placebo actually performed better than Tylenol? We've all taken Tylenol. I've taken Tylenol. It works. It's useful. So, how is it that a placebo doesn't do, uh, performs better than Tylenol? Well, let's kind of dissect this a little bit. What is an intra-articular placebo? It's actually Injection of saline into the joint. So, is intra-articular placebo actually a placebo?

Speaker 1So, this was actually a picture of a Knee scope that I did. So, this is the same patient. This is looking in the supratellar pouch, and you can see the synovitis in the suprapatellar pouch. So, I took a quick picture of this and I went and did my treatment, you know, debrised the meniscus, what have you. I came back to that same exact spot and look at what I found. The synovitis was completely gone. Now, I didn't do

Speaker 1Anything to this tissue. I didn't touch it. I didn't do anything Other than look at it. So, what happened during those 5, 1015 minutes? All we did was we flushed saline through the Knee in this area, right? I didn't actively do anything to this tissue. So, what does that tell you?

Speaker 1When saline is actually introduced into the Knee, it actually can change the biology. It can actually change the synovitis in the joint. So, intra-articular placebo here actually did something. It's actually considered an active control. So, it's not actually a placebo in the traditional sense that we think like a sugar pill.

Speaker 1So, when you look at the older science and you look at the older Research, they actually used intraarticular saline as their control group and called it a placebo and didn't actually adjust or control for it.

Speaker 1So, if we start looking at intra-articular placebo as not a placebo, as actually something that's doing something, and we try to control for it, what do we find? Well, this was a study that actually did that. And so, what they found was when you don't control for the impact of intra-articular saline, these are the results that you find, Intraarticular steroids, HA Injection, high molecular weight versus uh uh low molecular weight.

Speaker 1But when you control for the placebo effect, quote unquote, right? Intra-articular saline is actually does something and when you control for that effect, look at what you find. All of a sudden, what traditionally was considered not working actually shows that it's working, right? So, you have to do the science, you have to do the appropriate statistics, you have to understand what's going on in order to meaningfully interpret the data that's out there.

Speaker 1So, this is the most recent study that we did. We did a, uh, we used the Blue Cross Blue Shield database, and we looked to see the impact of steroid injections versus HA injections on their impact on adverse outcomes, health economics, the total cost of care in a group of 4.

Speaker 16 million patients within the Blue Cross Blue Shield database. And what we found was a significant reduction in adverse events or a correlation uh with a reduction in adverse events in the HA uh patients within the Blue Cross Blue Shield database compared to the steroid patients. But what was really intriguing or what was really interesting is the impact of HA injections on Pain and actually, more importantly, opiates.

Speaker 1So, when we looked at the Total Knee Replacement patients compared to steroid patients, compared to the HA patients in the Blue Cross Blue Shield database, what we found was a huge increase in opioid use in the total Knee replacements in the first year as expected. That's intuitive. You had Surgery, a big Surgery, I would expect a huge amount of opiate use. But look what happens after year one.

Speaker 1The opiate use in the Total Knee Replacement patient actually drops to the level of the HA group. The steroid patients actually have a higher opioid use compared to Total Knee Replacement patients and the HA patients, right? So, in this era of this opioid epidemic, that's really a national emergency right now.

Speaker 1You can see what's going on with the difference uh in utilization of steroids, uh, versus HA. And in fact, HA injections are actually

Speaker 1Reaching the level of Total Knee Replacement in terms of opiate use, uh, and certainly much better than steroids using this. And so, what does this mean in terms of dollars and cents? So, we take into account, uh, uh, uh, opiate use, uh, adverse events, and all of this. Look at what we see a significant reduction in costs and healthcare utilization in the HA group compared to the steroid group. And as expected, uh, Total Knee Replacement would be significantly higher. So, that's, if you will,

Speaker 1Control, we would expect Total Knee Replacement hires. So that kind of helps internally validate that this data makes sense. And you can see a significant reduction in costs and healthcare utilization in the HA group, uh, compared to the survey group. So, when it comes to it from a payer's perspective, you know, uh, and payers that don't want to cover HAs or struggle to allow their physicians, to cover, uh, to use HA injections on their patients, you start to wonder if this is a penny-wise, uh, pound foolish mentality.

Speaker 1So, again, uh, a significant, uh, difference and improvement in the HA patients uh compared to, uh, the steroid and total Knee Knee Replacement patients, uh, no matter how you slice it.

Speaker 1So, in conclusion, there are numerous non-operative interventions for the treatment of NOA. Recent studies suggest that steroid injections within 3 months of performing Joint replacement may increase our risk of infection, which we need to be leery of and sensitive to. Many now recommend waiting 3 months after their last steroid injections before performing a Total Knee Replacement.

Speaker 1Um, we know HA has been shown to be an effective non-operative treatment and single Injection HAs, uh, can be as effective as multi-junction, uh, HAs, uh, in the past.

Speaker 1With that, uh, I will pause and thank you for your time.

Speaker 2Hopefully you enjoyed learning a little bit more about Osteoarthritis, Hyaluronic acid, and various treatment options that we have. So, time now for the Q&A section.

Speaker 2We've got a button at the bottom of the screen Q&A chat function. So you can see some of the questions that are starting to come in. And for those of you that are audio only, I'll go ahead and read the questions, uh, and see if we can provide some helpful answers. Most of the questions that are coming in are very practical questions, kind of day to day, how to manage AA injections, how to manage OA, uh, just kind of how, how do I make our lives and our patients' lives go a little more smoothly.

Speaker 2So, the first question is, what's your thought on using a combination of HA Injection and steroid Injection 1 to 2 weeks apart to help manage Pain? So, I think in terms of pure labeling and FDA indications, steroids and HA injections are not meant to be mixed. But what we do find from a practical perspective in the real world is depending on the HA injections, a lot of physicians have to use steroids because some of the

Speaker 2HHA preparations that are out there are actually cross-linked to such an extent that they actually create an immunologic or allergic reaction when you use it. So, look at the HA products that use some of the older uh uh high molecular weight HAs, those that were, you know, 1015, 20 years old, um.

Speaker 2have a significant amount of cross-linking. And so, when you cross-link that molecule to that extent, it creates a fairly prolific, uh, allergic or immunologic response in some patients, otherwise known as pseudosepsis or acute systemic or acute inflammatory response. And so, in those instances, what physicians have done over time is they've realized that this is a problem.

Speaker 2Problem. And so they'll either premedicate with steroids, uh, add steroids a day of, or then chase it with steroids a week or two later if the patient has that kind of prolific, uh, allergic response. A lot of the products do not have that reaction, uh, because they're either not cross-linked in the same way or not cross-linked at all. And so, that's something to be aware of. And that may be what that, uh, uh, uh.

Speaker 2listener is referring to is using steroids that are kind of injection-specific, where they almost have to use steroids because of the way the molecule was designed. So, take a look at the products that you use currently and just ensure that they're not, uh, kind of the older, uh, highly cross-linked molecules, uh, which really create the need to use steroids when you, in my opinion, I try to reserve steroids for really severe bone on bone patients and not use them in patients with mild to moderate neo.

Speaker 2Next question is, what is the recommendation on how often HA injections can be used in a twelve-month period? Uh, Insurance will approve or cover HA Injection once a year. If a patient is willing to pay for the Injection out of pocket, then what is the appropriate time to repeat the Injection?

Speaker 2So most of the data that's out there really goes out to 6 months, and HA injections, you know, formally, as far as the FDA goes, uh, show efficacy out to 6 months. Now, that's not to say you can't use your clinical judgment and feel that, you know, if the patient, uh, the clinical scenario warrants using them more frequently or less frequently, that you can do it. The only issue is who's going to pay for it. So, insurance companies

Speaker 2Companies in general, some of them will only pay for it every 6 months. And if you want to use it more frequently, then it's the patient's decision and your decision. Number 1, to use it more frequently. And then number 2, if the insurance denies it, uh, then, uh, up to the patient if they want to pay out of pocket. So again, remember, the insurance company is not telling you you can or cannot use it. What they're saying is, we're only going to pay for it within this time frame.

Speaker 2So in your clinical judgment, if you feel that it's appropriate to use these injections more frequently, then you just, you and the patient just simply have to decide who's gonna pay for it because the insurance is only gonna pay for it every 6 months or there or around that.

Speaker 2But again, you have to look specifically at that clinical scenario, uh, and the patient's insurance plan.

Speaker 2So the next question is, what is your thought on physicians who use HA therapy after Total Knee Replacement? So again, there's no data, no science to really support its use in and or around Total Knee Replacement. My personal opinion is any intraarticular Injection done with metal and plastic in the vicinity has the potential to cause infection.

Speaker 2And I think for most orthopedic surgeons that may be listening, an infection in a Total joint replacement is an absolute disaster. So you have to really decide and have an informed decision-making process with the patient to understand what the consequences are, what the risks and benefits are of doing an Injection in the vicinity of an implant or prosthesis.

Speaker 2And in my opinion and in my clinical practice, I don't think the risk of developing an infection is worth any potential benefit from an HA Injection around the Total Knee Replacement. But again, I want to be clear, there's no science that you can fall back on to justify that. So that's simply going to have to be a clinical decision you make and a risk that you're willing to take, because at this point in time, there's no science to really help you one way or another.

Speaker 2Next question is what, what do you, if one Injection does not seem to help the patient, what do you, what do you do, I think if one Injection does not seem to help the patient? Can you give another one within a certain amount of time?

Speaker 2Um, absolutely. So, you know, not all injections are created equal. Uh, Different injections have different molecular weights, different concentrations, different volumes, uh, different levels of purity. Um, so, I think, again, in your clinical judgment,

Speaker 2You're just like any Other drug, right? When we look at diabetes or hypertension or any Other treatment that we do, we have a number of different options. And if one option doesn't necessarily work, then we go on to another one. So, you know, I think it's your clinical judgment and I think

Speaker 2You know, an NSAID, for example, you know, some patients get more better relief with Aleve, some get better relief with Advil, others with ibuprofen, right? And so, I think you can use that same thought process, uh, where if one Injection doesn't work, is it reasonable to try a different one? Absolutely. Um, they're all a little different and they all may work differently. And especially if you look at the high molecular, higher molecular weight injections compared to.

Speaker 2to the lower molecular weight injections, there's absolutely differences, uh, in, in how those injections perform. So, again, uh, you know, you may want to decide also that maybe there was a, a, a technique issue, right? Maybe you didn't get it in the joint, which is why it didn't work. And so, we're blaming the Injection as opposed to the provider or uh the technical aspect. Again, as providers and physicians, uh,

Speaker 2we, we

Speaker 2really dislike

Speaker 2looking in the mirror and, and thinking that maybe it was our issue and not the product or device's issue, right? And so, you know, you're not perfect 100% of the time. So, maybe uh there is an opportunity to try it again or use a different uh Injection as well. So, I think there's a lot of variables that come into play if a particular Injection doesn't work as to why it didn't work.

Speaker 2Um, can you give another within a certain, uh, amount of time? So, again, absolutely, I think in your clinical judgment, if you feel, uh, that, uh, uh, giving an Injection in a short period of time, patient got benefit, and you think another 1 may help, you know, then, uh, that's between you and the patient. But again, you have to be sensitive to the insurance and the payment process and whether or not it's gonna be a Reimbursement. And if it's not gonna be a Reimbursement, it's a, a question, uh, with the patient of whether they'd be willing, uh, to pay out of pocket.

Speaker 2Um, please comment on.

Speaker 2on the use of HA in the Shoulder and Hip. So, again, in the US, in the United States, HA injections are only FDA approved to be used in the Knee.

Speaker 2If you choose to use it in the United States on Shoulder and Hip, it is off-label and you have to have that appropriate discussion, uh, with the patient, uh, about the risks and benefits of that. And they probably won't be covered, uh, by the insurance. And so the patient will have to pay out of pocket. So, that's a.

Speaker 2Entirely different discussion that you have to have with them. Now, internationally, Canada and Other places, it is approved and on label to be used for the Hip and the Shoulder. And in those international locations, uh, then it's appropriate and it's justified and actually approved to be done so.

Speaker 2Are there any Other upcoming treatments, technologies, uh, to look out for? So, there are a number of developments in the OA space that I think are, uh, interesting, uh, to look out for. There's a lot of interest. I, I think probably a lot of people recognize PRP stem cells, uh, placental tissue, uh, a lot of work being done. The data and the science.

Speaker 2it is still controversial. Uh, Most of the position statements by the specialty societies still do not endorse these injections, uh, necessarily because the science really is all over the place. It's been poorly done, not well controlled. You, you'll hear these anecdotal stories or these small case series of how well patients are doing.

Speaker 2So, right now, for the most part, it's a cash-only, uh, out of pocket expense. Um, there is data to support its use, but the robustness of the data, uh, and the evidence around that data is, is still has a long way to go.

Speaker 2Um, Other, uh, new innovations, uh, and opportunities that are coming up for management of OA are targeting, uh, the nerves around the Knee, the geniculate nerves, the superficial or deep geniculate nerves, whether it's burning them or freezing them. Uh, a lot of interest in the Pain management space or interventional orthopedic space, uh, around, uh, managing.

Speaker 2NOA Pain by targeting the sensory nerves. So, again, uh, that treatment doesn't address the basic biology. It's simply hiding, uh, the Pain, uh, surrounding the Pathology. Uh, but for a lot of patients, maybe those patients that have severe bone on bone neOA, uh, that aren't candidates for arthroplasty or aren't candidates for Surgery, maybe too young, too old, too unhealthy, morbidly obese, what have you.

Speaker 2Uh, those may be potential options, uh, targeting the geniculars, superficial or deep burning or freezing, uh, to help manage the Pain in conjunction with Other treatments. And I don't think there's a single silver bullet. I think what it is, is, uh, a combination of treatments, an ecosystem of treatments where you dial some stuff up, dial some stuff down. That's not to say you can't use steroids

Speaker 2and freeze the nerves.

Speaker 2Or you can't use HA and burn the nerves or what have you. Uh, there's a lot of interest in bracing. So, neuromuscular electrical stimulation, NMES, uh, bracing. Some data out there where if you stimulate the quads, uh, and improve the strength of the quads and the thigh muscles, that Knee OA Pain, uh, can be mitigated and maybe reduced as well. So, I think it's combining different solutions.

Speaker 2Uh, based on the needs of the patient to get them the optimal outcome, uh, that they're looking for. And ultimately, obviously, Surgery is on the table as well, but obviously, it's expensive, uh, a fair amount of risk, especially compared to these non-operative, uh, treatments. Uh, but we are, our toolbox is growing. Our armamentarium is growing. Uh, there's a lot of, uh, new innovations coming out. So be on the lookout for that, uh, because, uh, I think the paradigm is definitely changing.

Speaker 2Uh, given that there are so many, uh, different brands of gels, do you normally start with one specific brand? How do you choose high versus low HA, uh, concentration or molecular weight?

Speaker 2So, again, there are a number of different AA products that are out there. I think you have to use your clinical judgment. What we're typically seeing is a shift away from avian-based uh HA injections, uh, to non-avvian and typically those are uh bacterially derived. Uh, Again, remember, HA is a very unique molecule. It's one of the few molecules that's completely preserved across all animal

Speaker 2species.

Speaker 1So,

Speaker 2whether you're

Speaker 1a worm,

Speaker 2A chicken, a

Speaker 2bacteria or a human, we can move that molecule between species without a problem so long as we can purify it and the body doesn't look at it as being abnormal. So, if you have uh uh contaminants or proteins attached to it, uh, then the body potentially can react to it.

Speaker 2So, because of that, I think there's been a shift by a lot of the manufacturers to move away from avian-based to non-avvian based, uh, uh, products. And so, with that, uh, comes less, uh, uh, purity issues and the ability to kind of move it between species with less of a problem. So, that's one aspect, uh, to look at. Now, low molecular weight versus high molecular weight or cross-linked HAs. I think, uh, there's a lot of interest in single-injection HAs. Uh, predominantly, I think efficacy.

Speaker 2Potentially, if you look at some of the products, uh, the length of impact is longer than some of the older, uh, high molecular weight, uh, products that are out there. But also, I think convenience, so patient convenience. Do you bring the patient back, uh, one, just one time, uh, and so they can, if they're working, uh, get back to work, it's less time off work, or bring them back weekly for 3 weeks or 5 weeks. I know in my

Speaker 2practice,

Speaker 1uh, especially

Speaker 2my young working

Speaker 2patients, if I do 1 Injection a week for 5 weeks, you know, that means they have to take a lot of time off work.

Speaker 2You know, and unfortunately, I'm not necessarily running on time. And so, maybe I'm an hour behind or something. So, if you think about it from a working uh uh person's perspective, they've got to take sick leave, right? So, maybe they try to schedule your appointment around lunchtime. Uh, so, maybe they have the time off, maybe not. Maybe they gotta take an entire afternoon just to get one Injection for 5 straight weeks. You know, that's an inconvenience to the patients. So, I've got a lot of my, especially my younger working patients that ask for the single Injection.

Speaker 2Uh, products purely because just from a practical perspective, uh, they're working and they can't get the time off. And then you layer COVID on top of this, they have no more sick leave, right? They have no more annual leave. They had to burn it all or some of the companies are, are forcing their employees, uh, to use their, their time off. And so, you know, I think the dynamics of healthcare are changing. The needs of the patients are changing. So, I think the convenience, uh, and the Efficiency that the single injections afford, especially, uh, for some of our patients is important. Another factor to consider.

Speaker 2are patients that may be paying out of pocket or fixed income that have straight Medicare, right? For them, you know, price may be important. So, the cost of the HA injections, uh, if they're gonna pay cash may be important to your patients. And so, there are some older products that are out there where that may be priced, uh, more competitively for the patients that are looking for, uh, uh, cost-effectiveness, uh, versus convenience. So, I think there are a lot of factors, practical factors that come into which

Speaker 2HHA products you use, when you use them, how you use them, why you use them, based on the needs of the patients. Um, and then you have to marry that with the science, uh, and the efficacy data that's out there, the safety data that's out there. So, it's not really a clear-cut answer that I can give. But I will tell you, you know, some of the companies that are out there, uh, offer very convenient, uh, uh, HA packages, if you will, kind of one-stop shopping, if you will. So, I would kind of look out, uh, for that.

Speaker 2Uh, that offer kind of the breath because again, from the office Practice Management perspective, uh, we like, uh, really working with companies that kind of offer it all, uh, one-stop shopping so we can have all the different varieties of HA products so we can, uh, really fine-tune and personalize, uh, the treatment plan, uh, for our individual patients. So, I, I encourage you to kind of look for, uh, those companies, uh, that offer that, uh, ability.

Speaker 2Um,

Speaker 2Let's see. Where does PRP stem cells uh fit in your algorithm? So, again, as I mentioned earlier, uh, those, uh,

Speaker 1uh,

Speaker 2treatment options are cash based options. And so for a lot of my patients, it's not, especially my fixed-income Medicare patients, they're not really an option, but if my patients can afford those treatment options,

Speaker 2I, I think it's, it's, it's an opportunity for them. I make sure they understand that the science is really unclear, doesn't really support their use one way or another. And so, if they can afford to spend the money and they want to try it, uh, there's very little harm, and I'm OK with offering it or doing it. Uh, but again, I take a lot of time.

Speaker 2Time to explain to the patients that the science really is not there, and they have to be prepared that spending that money, uh, will not, uh, get the results that they necessarily hope for or expect. But if they're willing to take that chance and willing to take that risk, then it's their money and they can certainly, uh, have that option if they want.

Speaker 2So, with that, uh, I don't see too many Other questions, uh, on our list. I think that was the last question.

Speaker 1So we will, uh,

Speaker 2end, uh, this portion of the program. Thank you for your time.