Transcript for Ep 132 Osteogenesis Imperfecta: All bones about it

This is exactly right.

Yeah, thank you for sharing it with us and all of our listeners and so many more with your book.

What the, it's been since season two that we've talked about collagen.

Okay. Oh my gosh. I did. You basically took my whole biology section done.

It's just amazing. It's so good that I can't believe that we've never done it before.

Yeah, which look, I mean, clearly we need to do more collagen-based diseases for sure. There's so many other options. Or sure. But in any case, what's in a collagen phase?

Got to love that. Yeah. We'll post the full recipe for that quarantine as well as our non-alcoholic placebo read up on our website. This podcast will kill you.com. There's no end to what you can find.

I just looked at it and I was like, oh, yep. At least we updated it since we graduated, but it's been a minute.

Well, with that, should we get into the biology of this disorder?

osteogenesis imperfecta is also called brittle bone disease. And that moniker exists because the main symptom or consequence rather of osteogenesis imperfecta is, in fact, bones that are very prone to fracture, bones that break easily and are brittle. But of course, it's a bit more complicated than that. And in fact, osteogenesis imperfecta is a lot more complicated than I realized when we decided to do this episode, I had no idea. It's classic, classic, right? Yeah. So historically speaking, and I promise I'm not stepping on your toes, Aaron, how dare you? I say the word history, and then I have to qualify it. But historically speaking, osteogenesis imperfecta had been classified into like four different subgroups, types one through four. Type one was considered relatively mild and by far considered the most common type of osteogenesis imperfecta. Type two was the most severe and actually lethal, paranoidly, so either shortly before birth or after birth. Type 3 was considered relatively severe and progressive, and then type 4 was considered the most moderate. So somewhere in between types 1 and type 3. Nowadays, though, this classification system does not hold up because we have now identified dozens of potential mutations that are involved and a very wide range of clinical phenotypes or the way that osteogenesis imperfecta presents. And so what we know now is that at its core, no matter what the mutation or mutations are that are involved, and we'll get there. We'll talk about all of that. But osteogenesis imperfecta is broadly speaking, a disorder of collagen formation. So to understand it, let's start first with collagen. Yay, good. And for this, we can harken back to our scurvy episode, all the way back in season two.

Same. Such a great episode. Super fun. If you haven't listened, check it out. But collagen is integral to the story of scurvy, just as it's integral to the story of osteogenesis in perfecta. So collagen is a protein. It's a whole bunch of proteins, structural proteins that happen to be one of if not the most common proteins in our human bodies. and proteins are simply chains of amino acids. That's really all they are. And in the case of collagen, collagen is made of a few different specific amino acids, glycine, proline, hydroxyproline, hydroxylycine, and probably some others, but glycine is an important one. And in a collagen protein, here is the way that it forms. amino acids make chains. They link together to form chains. These chains are called pro-colligence. Three of these chains have to then twist together in a certain way in what's called a triple helix. So if you think of our DNA as being a double helix, this is a triple helix. And this triple helix is what you mentioned Aaron, you can think of it like a pull and peel twistler.

That is what you should be picturing. But then multiple of these twizzlers, multiple of these triple helices, have to then come together in a fairly complex way to form the larger scale fibers and networks that make up collagen as a whole protein. And collagen or collagen happen to be pretty important proteins, like I said. Some papers will tell you that 30% of the dry weight of our body is collagen. I saw that. Yeah, it's massive. I had no idea. Like me either. My new collagen was a big deal, but I didn't know that big of a deal. And it's not just collagen as I've alluded to. There are in fact five different types of collagen, types one through five that make up literally so many parts of our body. These are structural proteins. Collagen makes up our blood vessels, our muscles, our skin, our cartilage, our connective tissue, the basement membranes, which is like where one layer of cells might change to a different type of cells. They make up our hair and of course, our bones integral to today's episode. Of these five different types of collagen, our bones are primarily made up of type 1 collagen, which then becomes mineralized to form our hard bones. But type 1 collagen is not only found in our bones. It's also an important component of our skin, of our tendons, of our blood vessels, and even the structure of a lot of our organs.

I love that. Yeah, that's very accurate. Like college and holds us together. Yeah, exactly. Beautiful. So. Collagen, it's a complex protein. I just keep saying collagen as if it's singular. It's many colleges.

So forgive us for the grammatical errors here. But because these are complex proteins, it is then understandable that there are a lot of places where things could get a little wonky. And we talked about some of that in our scurvy episode. There is some like deep biochemistry that we could get into about like the triplet complexes and how they have to form with every third amino acid being glycine and et cetera, et cetera. But if we just think of making a protein as starting with a set of building blocks, like connects, those are the best ones I can think of. You know those toys? Yeah, yeah. So if each of these blocks are amino acids, these have to fit together to make a specific type of strand, and then each of these strands have to fit together in this precise way for this triple helix to be formed in the correct way so that it's strong enough. and able to then fold and twist together to build larger structures. At any and all of these levels at the amino acid level or at the triple helix level or at the larger structural level, there could be things that get a little bit messed up. and therefore cause issues with the strength of that collagen. Osteogenesis imperfecta is a group of genetic-based disorders of collagen production, either affecting the quantity of collagen that's produced or the quality of that collagen. That's what it is at its core. So older textbooks, like I mentioned, older papers will describe it specifically as an autosomal dominant disorder, meaning that it's coming from a mutation in a gene on not our sex chromosomes, but our autosomes, and that will cause disease even with just one copy present. As opposed to lots of the other genetic diseases that we've covered on the podcast where you have to have two copies of a mutated gene to be able to have disease like cystic fibrosis or sickle cell. And that's because that in the past osteogenesis imperfecta was considered to be caused by mutations specifically in one of two genes, COL1A1 and COL1A2. And these are two genes that encode for our type 1 collagen, the most abundant form of collagen in our bones and our skin and tendons and lots of other things. And it is still true that the vast majority of cases of osteogenesis imperfecta, about 85 to 90% of cases, are caused in this way by autosomal dominant mutations in these two genes, or at least one of these two genes. The genes that are encoding for type one collagen, but not every case of osteogenesis and perfective fits that description. And even within that, there are so many different specific mutations that can occur.

Yes, 100%. In our cystic fibrosis episode, we talked a lot about that. And to reflect that, there are no longer considered only four classes of osteogenesis in perfecta. Most papers that I read said there's about 19 or 20, depending on the phenotype or clinical presentation, at least one paper that I read proposed an entirely different classification system that grouped osteogenesis imperfective by metabolism and phenotype into a through e and then subgroupings within each of those. complicated. But the point is we now know there are dozens of different specific genetic mutations in a whole bunch of different genes and locations on different genes on various chromosomes at this point, but they all end up affecting either the production of type 1 collagen or the formation or the folding or the mechanics of type 1 collagen.

Yeah, great question. So when it comes to the typing of osteogenesis and perfecta from what I can tell it's still a little bit messy and maybe like in the process of undergoing revision because there are different papers that proposed different ideas on how to classify it. Okay. But a lot of effort has been made to try and link known genotypes, so like known and found specific mutations to people, to individuals that are living with osteogenesis and perfecta, regardless of the symptoms, if that makes sense. Okay, because as we all talk about one hope is for things like gene therapy or targeted therapy and so knowing what the mutations are help in that respect, but as we'll also talk about in some ways, you can also treat more broadly, if that makes sense. Yeah, yeah, yeah. So kind of both end. But it is true that these different mutations can lead to really variable degrees of disruption to the structure of collagen and therefore really huge variation in terms of symptoms and clinical findings. The way that I think of it is depending on what the mutation is, you can think of replacing that sturdy twizzler rope that you could use to build stuff or like the connects rope. with like cooked spaghetti noodles or uncooked spaghetti noodles or like a nylon rope that's like slippery or right like just a lot of different ways that things could change that all lead to bones that are more easily fractured but not necessarily all in the same way. Now another important part of the story of osteogenesis and perfect is that not all mutations involve the formation of collagen. One of the most common mutations is in fact a null mutation that causes normal collagen production, but at half the amount that is typical. Okay. So you can imagine that collagen that is formed the way that it should be has the same strength, but because you just have less of it, the overall symptoms tend to be a lot less severe. Okay. So this is often associated with that old school classification of type one osteogenesis imperfecta.

So speaking of which, shall we talk about what the symptoms are? Mm-hmm. All right. So I said already, there's a really wide range of phenotypes, but they all share a lot of things in common, most notably fractures, bones that break easily, result in many often fractures. In more severe cases, we can be talking about dozens to even hundreds of fractures, even early in childhood. Other really common findings are things like short stature varying degrees of bony deformity. So this could be things like bowing of the bones of the legs or curvatures in the spine like scoliosis or even curvatures in the bones of the hand. And these types of changes can happen both as a result of the bones themselves, just not being as structurally sound, like not able to support the weight of the body and from the fractures themselves and the remodeling thereafter, especially when it comes to fractures in the spine that can end up leading to scoliosis, for example. Another really common finding in osteogenesis imperfecta is blue sclera. So the whites of the eyes appearing blue. And this is kind of described in a lot of medical textbooks as one of those very classic osteogenesis imperfecta findings. Importantly, it can also sometimes be a normal finding in newborns. But this is caused by thin, sclaral collagen. So the collagen in the eye is just not as thick. So then the underlying vascular church in our eyes is more prominent because of that. So they appear blue, like the whites of the eyes. Hearing loss is another really common symptom. It's not always present and it's not always severe hearing loss or complete hearing loss. But it often happens especially with time and by the time people reach adulthood. And this can result either from damage to or disruption of the bones in the middle ear and can result in like really wide variation and degree of hearing loss. And then, dintinogenesis imperfecta, which dintin is your teeth. This is something that can be found more commonly in the more severe forums of osteogenesis imperfecta, but it essentially is when teeth, especially baby teeth, much more than adult teeth, which I find very interesting and I don't have a great explanation for. are not fully formed, they're small and they often appear either like yellow brown or gray blue and they are a lot weaker than a typical tooth or a typical baby tooth even is. So those are kind of the main symptoms of all of the various forms of osteogenesis imperfecta, the degree to which this causes impairment, either physical disability or leads to chronic illness really can vary. Some people might not ever be diagnosed until adulthood, if at all, where some people might be diagnosed in utero, and some may not survive childhood, because of how many problems they end up having because of this, and there's everything in between.

So it really can depend. One of the papers that I read that tried to propose a newer classification system tried to break these down by the types of mutations and like the The biochemistry, I guess, of these mutations. I'll be honest that I don't know how much traction this classification system has gotten because like on the NIH website, for example, it still just says like 19 different types and so. grains of salt and all, but it really can vary. Some of the less severe phenotypes might just be impairments in either the amount of collagen that's produced, so like a null mutation where you're making half of the amount of collagen, but it's normal collagen otherwise, or mutations that impair the ability of a normally formed collagen like monomer to assemble down the line. It's like just the assembly part of it. Other more severe mutations might be from genes that are involved in modifications of collagen, more down the line, like after the collagen is formed. Now, it gets modified in a way that makes it really structurally unsound. Okay. These tend to be less common and are recessively inherited, so they're not horizontal dominant. There are other mutations that could also be more severe that are involved in the way that collagen folds and cross links. Again, like down the line, so like you have a normal Twizzler rope. But when you're trying to link a whole bunch of those Twizzler ropes together, it just doesn't work correctly. So there's a huge variety.

It's a great question. So it is really interesting. The autosomal dominant types, again, are the ones that we probably knew a lot more about and are historically the ones most considered osteogenesis imperfecta and those type one through fours. Those are the null mutations and those are mutations that can be in the collagen genes themselves. And so they are impairing the assembly of those collagen fibros and those collagen strands. Even within that, there's huge amounts of variation in terms of what the phenotype could be, right? Because again, that was like what we thought of when it was just types one through four, which is anything from relatively mild to perinatal lethal. But then there are so many other recessive types that are more about mutations, not in the collagen genes themselves, but in the modifications of collagen, in the cross-linking of collagen, in the things that happened down the line where you would need to have two of the mutated allele to actually have that phenotype, right? Whereas with the others, if there's a mutation in the collagen gene itself, even if you make some typical collagen, some proportion of your collagen is either abnormal or missing, and therefore you have some symptoms of disease.

Oh, that is such a good question. I don't actually know. I didn't really see that number anywhere. And I think part of the reason is that most of the numbers that I have are really just that 85 to 90% of cases are mutations in those two genes that encode for type 1 collagen, COL, 1 A1 and COL, 1 A2, 85 to 90%. of osteogenesis and perfect is that. That is autosomal dominant. The rest are so variable that I don't know. I don't know how many of them are denove on mutations versus genetic within families. It's also so many of them. Many have been found in only one or a handful of patients. And so they're so rare that it's really hard to even know, especially with something that's autosomore recessive.

Yeah. Yeah. So in terms of what does it mean for a lifetime, it can vary hugely. But in terms of when it is either lethal or results in severe disease, some of the most severe manifestations come from its effects on the bones in our torso and on our heart and lungs itself, or themselves. In the cases of these more severe disease manifestations, it's cardiopulmonary issues, heart and lung issues that lead to the most severe morbidity and mortality. So what we can see is recurrent lung infections like pneumonia and eventual heart failure as a result of lung disease, which is called core pulmonal. And this is very often due not to problems in the lungs themselves, but skeletal issues, rib fractures, recurrent rib fractures, severe scoliosis, things that eventually lead to dysfunction or the inability to inspire appropriately and to breathe enough so that then there is damage to the lungs over time because of that. Okay. Or in some very severe cases, it's respiratory failure in that perinatal period because there's not enough structure to be able to keep the lungs open. And because collagen also makes up our vasculature, there can be independent issues that arise with the cardiovascular system, our heart, including aortic root dilation. So the part of your aorta that attaches to the left ventricle of your heart, getting a little bit dilated, which leads to regurgitation or backflow of blood. back into our heart instead of making it out into the rest of our body, which then leads to increased pressure in the heart, which can also lead to heart failure down the line. So those are some of the more severe things that can happen as a result of this collagen issue, both in our vasculature, but also just in the bones that make up our whole body.

Yeah. Across the board, the most important component of treatment is actually physical therapy. So it's a lot about strengthening muscles to protect these bones. The other component of treatment is with medications, and we don't have great options yet. But one really common group of medicines are called biz phosphonates. These are the same medicines that we use to treat osteoporosis. And what they do is help with bone deposition, like mineralization, and they decrease bone turnover. It's not fixing the problem, especially if the problem is the way that the collagen is formed. But the theory is that it helps strengthen the bones, like putting a cast kind of around your noodle rope. Okay. The idea behind this is that it would then prevent fractures. But apparently, if you can't tell by how much I'm hedging, the data is a little bit equivocal so far on whether or not it actually prevents fractures.

It's so it's just such a huge array of possible symptoms and consequences, resulting from a huge array of mutations. So I won't be surprised if someday all of these various classifications end up being considered different diseases in some respects, quite honestly.

Oh, the easiest TLDR is that you actually can't absorb collagen through your GI tract. It's too big. So it's only either amino acids that make up collagen or I think it's like hydrolyzed collagen, which is like what you probably take in a powder that's like little teeny tiny bits of collagen in your collagen powder that you might drink. There's like very mixed data on whether or not it does anything. to drink your collagen. Okay. Okay. But I would love to do a whole episode on it. Let's do that.

A whole many theories. Yeah. Yeah. Add it to the list.

So, speaking of interesting air in, I don't think that I can ask where did this come from, but like, how did we get here when it comes to instances in perspective?

That is, because it's Yeah, I mean, bones are often what we look to see about so many other diseases. And so it is interesting. It is, it is.

But it was just that he couldn't walk. That's the only, yeah.

Not only makes no sense. It also, why does it sound weirdly familiar?

Yeah. It's always mom's fault. Yeah.

Yeah. Yeah.

I mean, certainly, yes, especially because these fractures are painful, like breaking a bone is incredibly painful. So it's not that this disruption in collagen disrupts in any way, all of the nerves and everything else that's involved. So the fractures themselves are going to be painful. The way that bones heal might lead to additional kind of damage on the line like we talked with the scoliosis and things like that, which can be painful. So certainly, pain can be a component of osteogenesis in perfecta.

Yeah, that is interesting, because Rick gets which we already did this season. And Scurvy are all definitely on the differential that is when it comes to osteogenesis and perfect. Yeah. Yeah.

Yeah. I mean, I wonder if that reflects not only how variable osteogenesis and perfect it can be, but also how much more rare it is comparatively.

There are so many other diseases and disorders that we could cover that also have to do with collagen. I was like deep diving on our earlier's Danlos while I was researching for this.

I can't wait to try right after this break. So one of the first papers that I read for researching this episode described osteogenesis imperfecta as a quote, fairly common rare disorder, which, oxymoron, I don't know what that means. But the stat that was quoted in that paper as well as pretty much every paper that had statistics was that osteogenesis in perfect is found in one in 15 to 20,000 births every year. Okay. So if we air in math this, would you know I'm going to? According to Google, there are 140 million births every year. And the CDC says that in the US, there are over just a little over 3.6 million births every year in the US. So if we assume on the low end, one in 15,000 people are born with osteogenesis. In perfecta, that would be worldwide just over 9,000 people born with OI every year and 240 in the US each year. Okay. Now, since these are birth statistics, they are very likely underestimates because these are going to reflect relatively more severe forms of osteogenesis and perfecta because there are always going to be people that don't end up getting diagnosed until later in their life because of less severe phenotypes or just not being diagnosed in infancy for one reason or another. A couple of papers that I read cited an estimated prevalence of 25 to 50,000 people in the United States living with OI. But it was very disappointingly difficult to get any additional data on prevalence worldwide. surprises me. I know. And these are a whole variety of genetic disorders, but I couldn't find almost anything in terms of the estimates on like what is the variability geographically across the globe because of course there's going to be some. And there does seem to be some variability but there were so little data and the data that I found was like reported quite differently in the few countries that it was reported in like this many cases per 100,000 versus per 10,000 births in this country. So like it was really hard to make any meaningful comparisons in other countries aside from the US. So I apologize. I just couldn't find it, but in any case, this is certainly a rare disorder, but as always, the more that we think about it and look for it and research it, the more that we find. So in terms of where we stand with current research, again here, I found less than I was hoping for, but not nothing. There is one new drug very new drug making headlines big time that's in phase two and three clinical trials right now. This drug is a monoclonal antibody that specifically, this is really interesting to me. It inhibits a small protein called sclerostin, which is a protein that is involved in the remodeling of bone. So the idea behind this is that by inhibiting the action of this protein, you end up having increased bone formation and decreased bone resorption that could lead to stronger bones and less fractures and increased quality of life.

Yeah. Yes, so your bones are almost constantly, like your body is reserving bone and then remodeling bone. And this process also happens a lot during the growth process. Like growth of bone is not just like this one off, like your bone grows process. There's like The college and parts of bone have to grow. The mineralization deposit has to happen. It's a whole process. This would be a fun whole episode, honestly, to do about bone, osteoplasts and osteoclasts. But in any case, it's a process that happens over time. Your bones are dynamic.

I'm sure potentially. Potentially, yes. I don't know any more details about it. I just know that the idea behind this is that if in the case that you have bones that are already more fragile, you want just an increase in bone formation, kind of in the same way that bisphosphonates are leading to more mineral deposition and less of the remodeling, if that makes sense. Yeah, yeah, yeah. The good thing about this particular treatment is that it is not mutation specific. This has the potential to help regardless of most of the underlying causes or mutations involved in osteogenesis in perfecta. It's still very much in clinical trials. I have no idea. Time will tell if it's effective or not. And I really expected to find a lot more because this is a genetic disorder, because many of the cases are autosomal dominant disorders, and we know the genes that are involved, a lot more information on where we stand with gene therapy, but I really didn't find much.

Yes, definitely, definitely. That's the vast majority of all treatments, prior and current effect.

Yeah. The osteogenesis imperfective foundation has some information on other trials that are ongoing. And there are a number of other additional targets that are being looked at in terms of other ways to try and treat mostly, like you said Aaron, the bone components of osteogenesis imperfecta. There are also studies being done, importantly by Baylor College of Medicine, to look at mental health and quality of life overall in people living with osteogenesis imperfecta, which is always an overlooked part of any chronic disorder story, quite honestly. Yeah. And a really important one at that. That's what I have so far. It's not as much as I would have liked. Please let me know listeners if I missed something major because I'd like to know if there's more out there. But if you'd like to learn more, who have we got sources for you?

I have a number of papers. Some of my favorites were three different papers just titled osteogenesis and perfect. I've got to love the simplicity of it. Two that were from the Lancet, one that was from major reviewed disease primers, always a favorite. There are a whole bunch more a paper about collagen if you want a deep dive on that. And papers about the current understanding, the different classifications. And of course, investigations into treatments. You can find the list of sources from this episode and every single one of our episodes on our website, this podcast will kill you.com under the episodes tab.

Yeah, thank you so much. Thank you also to Blood Mobile for providing the music for this episode and all of our episodes.

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