Ep 132 Osteogenesis Imperfecta: All bones about it

this was not super concerning. The concerning part happened ten weeks later when I was kicking around in my crib, just doing my baby thing, and my mom heard a snap and a screen. She rushed me to the er and the X ray showed a broken femur. To make a long story short way shorter, because you can imagine

the questions my parents had to answer about that. I was eventually diagnosed with a rare bone disease called osteogenesis imperfecta, which we call OH or brittlebones for short, because osteogenesis and perfecta is a mouthful. I was born in nineteen eighty one, and I think at the time, there were just a few types. Now there are even more, ranging from incredibly severe to very mild. Mine is a mild form. Mostly my OI seems to affect the long bones of

my legs. I've broken my femurs numerous times, which is not a bone that typically breaks without major efforts. And even though my bones are the most obvious part of my body affected by OI, it evidences in other ways in my body too. It affects my teeth, which isn't common for every person with OI, but mine have always broken very easily. I have some intense sculliosis, which again not everybody has, but it's not uncommon. As an adult,

I am a tower in four foot nine. I work with kids a lot, and they always think it's awesome that I'm usually smaller than they are. The whites of my eyes are a little bit blue. That's a common part of OI called blue scin. So it definitely shows up in my body in all kinds of ways, and obviously, because my body is the vehicle through which I experienced life, it shows up in my life in.

read about OI. They didn't have anything like WebMD to freak out overall the what it is together. There was no support group on Facebook they could use for questions. The three of them just had each other, and somehow they helped me learn to move through the world, a world that's definitely not made for all bodies, with some independence and with a whole lot of joy. My brother came along five years later, and he also has OI.

We both used a wheelchair and a walker most of the time when we were kids because our bones were weak, but our parents would just load them up and we would still go on family vacations or go hang out with family. My mom would pull me through her garden and a wagon. My dad would back the wheelchair up into my grandparents' house every weekend, so I could hang out with them. My big sister, who was always so much cooler and more fun and more awesome, would still

take me out and do things with me. So with my family, I never felt left out. School was a little bit different, and of course it would be The word I usually heard people describe me with was fragile, and for a good reason. Any adult at a school would want kids to be extra careful around you. Sports were huge in my small town, and naturally any kind of contact sport was a heck no for me. But as my friends got more and more into sports, I full on embraced my nerd self and I got into books.

I love to read, and I realized pretty soon I love to write, and even if I weren't disabled, I would have loved writing. But I think my disability was a conduit to the early realization that my imagination is limitless. In the actual physical world, my body has limits, sometimes a lot of them, but my imagination doesn't and it never has, and I learned how to flex my imagination

like a muscle. It's another way I got through the trauma that can come with OHI A specific memory I have of that would be when I would break my leg and I would be at the hospital waiting to get it set, which is a very painful process, And as that was happening, I would close my.

a little stronger as I got older. There's no cure for OI, so my bones are always going to be fragile.

But around the time I started high school, I was able to walk independently without a walker or a wheelchair as long as I was careful, And I realized then, for me at least, sometimes it's just as hard, if not harder, to advocate for your body and your health when your disability seems invisible, even though it isn't, even though it's something that still dictates everything you do in a day as an adult, especially lately, OI has affected my career, but not in a way I thought it would.

I actually get to write for a living, which has been my dream job since I was in third grade. Specifically, I get to write novels for kids. To me, those novels that we read as kids are at the best books. Those are the books that help me trudge through the dark, that helped me realize how brave I could be. My first novel for kids was published in twenty fourteenth Scholastic. My first novel was a contemporary fantasy called a Snicker of Magic, and I got to keep writing more and

more after that, and I love it. But I had never written a character like me who had OI until now. My most recent novel, Hummingbird, came out in August of twenty twenty two, and this one is about a girl named Olive who is homeschooled because she also has osteogenesis and perfecta, and her parents are kind of nervous about all of attending the public school, but she talks them

into it. She goes, and the first day of sixth grade is a disaster, as sixth grade often is, until she hears a story about an enchanted creature in the woods that Grant's wishes, and she decides she is going to find it now. Obviously, Olive, like I said, has brutal bones, HERI is mildlike mind, and at first this wasn't going to be a big part of her story because honestly, I didn't know if people wanted to really

read about how I felt about my disability. The most common line I see in books when a character is disabled is something like, my disability is my superpower, which is awesome, but it's not always how I feel. Most days, I love my life and I'm grateful for my body. I'm grateful I get experienced life inside it, but my body also breaks for seemingly no reason sometimes, and that

can be frustrating and painful. I always say my relationship with my body will be the most complicated I have in my life, and that's true, but who would want to read that? So at first, when I was writing about Olive, I just wanted her to be fully, completely confident in herself, figuring out her own way to move through the world. Magic Adventure First crushures all of that good stuff, but it's like I couldn't find the heart

of her story. And then in twenty nineteen, I was walking through the kitchen one night to check the doorlocks and I slipped and dog droll and as I was falling, I heard the snap that water is sickening, terrible sound, and then came this flood of pain, because breaking the

femur is no joke. And in the months after that, I remembered what it feels like to be in that specific place again, to be in physical therapy again, nervous every time something hurts, to not be able to get in some buildings again because there's no access to them. And one night I was playing Mario on the couch beside my husband, having an intense pity party for myself, and I said, I'm broken and I hate my body and I'm frustrated, and he very gently said, hey, your

leg's broken, you aren't broken. And that's what gave me the clarity I needed to write a Hummingbird in a way that was absolutely true to me. All of and I both love our families, we both love Dolly Parton, we both romanticize life and we see the magic in it, and we both have this disability that is sometimes really

frustrating especially all of age. She's twelve. In the story, she is seeing how bodies are changing all around her and how hers isn't, or how it is changing but not quite the same way, and that can be tough. It was tough for me at least. I remembered what it was like to feel left out, to be called fragile. But I also remember the people in my life who loved me and who called out every good thing instead. My parents, my siblings, now justin my husband, my friends.

They've all helped me find these doorways into my imagination, and they've helped me make the life I love that I'm really proud of. So in the story, all of actually sets out thinking she is going to wish away her OI. And I won't spoil it and tell you what happens, but I will say that, like all of I still believe a person's body is the least interesting

thing about them. But having said that, I'm more passionate than ever about writing books where every kind of kid and everybody feels accepted and loved and knows they have a place to belong. No matter how old we are, I think we all just want to know somebody's staving a seat for us in the cafeteria. And because of that book, I am talking a lot about OI now and how it looks in my life, and specifically when I talk to kids. There is one scene I bring up.

There is a scene where all of wonders if she's ever going to have a big life because of her body. She's experiencing gym class for the first time, and that's when her self esteem really starts to tank because she sees how different bodies looks, and she starts asking the big questions, what if nobody ever wants to go out with me because my body doesn't look like other people's bodies? What if I can't have the career I want to

have because of how I look? All of the big hard stuff and the answer to that question, This is what I tell kids, even though it's kind of corny. Yes, you get to have a big, amazing life in the body you are in. You get to fall in love, you get to have adventures and experience so much joy. This is all one small part of a really big story.

And I hope other kids with OOUGHI have never ever doubted that maybe they haven't, and that would be awesome, But just in case, there's somebody out there wondering like I did, if the body therein will hinder them from living the life if they want to have it, won't. I hope kids who read the book, No, there's magic out there waiting for them. They get to experience it in the body therein, and they deserve every good thing

to end. I'll say that in the story, there is a line when Olive says, my bones are fragile, but I am not, and that is how I feel about my body too.

before birth or after birth. Type three was considered relatively severe and progressive, and then type four was considered the most moderate, so somewhere in between types one and type three. 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, still one of my all

time phaves. I think same same, such a great episode, it's 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 imperfecta. 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, prolene, hydroxyproleine, hydroxy lysine, 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 link together to form chains. These chains are called pro collagens. 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 twizzlers.

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 one collagen, which then becomes mineralized to form our hard bones. But type one 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. Can I just throw out the etymology of collagen real quick, because I.

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.

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 fibro 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, col ONEA one and col one A two, And these are two genes that encode for our type one 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 eighty five to ninety percent 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 imperfecta fits that description, and even within that, there are so many different specific mutations that can occur in that.

depending on the phenotype or clinical presentation. At least one paper that I read proposed an entirely different classification system that grouped osteogenesis imperfecta by like metabolism and phenotype into like A through E, and then subgroupings within each of

those obligated. 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 one collagen or the formation or the folding or the mechanics of type one collagen.

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. And 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 slipperar. 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.

lot less severe. Okay, So this is often associated with that old school classification of type one ostrogenesis imperfecta.

degrees of bony deformity. So this could be things like boeing 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.

as one of those very classic osteogenesis imperfective findings. Importantly, it can also sometimes be a normal finding in newborns, but this is caused by thin scleral collagen, so the collagen in the eye is just not as thick, so then the underlying vasculature 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 in degree of hearing loss, and then dentinogenesis imperfecta, which dentin is your teeth. This is something that can be found more commonly in the more

severe forms of ostrogenesis 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 ostrogenesis 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.

And so can you give me some sort of example for like the three points along the spectrum that you just described, Yeah, in terms of like what the like, what the mutation in the collagen is or how that collagen is different or what is that collagen not doing, 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 biochemistry, I guess of these mutations. I'll be honest that I don't know how much traction this classifiction system has gotten, because like on the NIH website, for example, it still just says like nineteen 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 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, so 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 autosomal 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.

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 perinatally 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 mutator allele to actually have that phenotype right, Whereas with the others, if there's a mutine 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.

rest are so variable that I don't know. I don't know how many of them are denovo 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 autoso more recessive.

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 pulmoneal 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 inbit to inspire appropriately and to breathe enough so that then there is damage to the lungs over time because of that, 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 like 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 yeah, treatment, 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 bisphosphonates. 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 put a cast kind of around your noodle rope.

or procedure. Having attempted this on several occasions, I have concluded that it requires more than a large medical library, a good memory, luck, perseverance, or a high degree of suspicion for quoted sources, I am always left with the uneasy feeling that only the personal perusal of the original publication will convey the author's true thoughts. Meanings seem to change in quoted sources and often contain errors in regard

to context, interpretation, translation, and bibliographic data. Osteogenesis Imperfecta is a case in point.

That's great. But it's a great quote I thought to begin the history of Osteogenesis imperfecta, And honestly, like many it's applicable to many other topics that we've covered, because I think it does sort of force us to think about what is important when tracing the history of a disease and why is it important? You know, is it

that doctor so and so was the first to name something? Maybe, especially if you're that doctor so and so or related to that doctor so and so, or is it the order that things were discovered about a condition, or how the timing of discoveries influence the perception of a disease because of the current social or political climate, or how the discovery of a condition altered the experience of those who had it, or how the discovery changed medicine itself,

or maybe it's like a combination of all those things, and it can be. And don't worry, this is not going to be just a giant philosophical discussion or lecture on how to construct a narrative on the history of medicine. I just thought that this quote kind of served as a good reminder that the stories that we tell are exactly that their stories, and the storytellers themselves choose what does or doesn't go into a story, and they're human.

We're human with biases and flaws and sometimes typos, oftentimes typos. So what does that mean for osteogenesis imperfecta. It means that what I want to focus mostly on today is not who gets priority for the first description of this disorder, but how our understanding of it has grown over time and what that is meant for the people living with this disease, especially as the divide between knowledge and application

has shrunk, but like not entirely at all. Okay, so let's get started with this history by heading back, as we often do, to ancient Egypt. Since osteogenesis imperfecta is associated, of course with skeletal changes, we can make fairly confident diagnoses in skeletal remains that have evidence of the disease, and the earliest of these that I came across is from an ancient Egyptian mummy, an infant from around one thousand BCE. The infant's skull and bones were consistent with

osteogenesis imperfecta, specifically types three and four. I think there couldn't distinguish between those two. But from what I can tell, there aren't references to osteogenesis imperfecta in any ancient texts, or at least any that aren't like incredibly vague, and which I thought was kind of interesting.

of Ragnar Lodbrook. He was the son of Ragnar, and in this poem is the story of how Ivar travels to East Anglia and Northumbria to avenge his father, who was murdered by the King of Northumberland. He was successful, allegedly killing the king a Ella in a horrible way the Blood Eagle.

story that has nothing to do. That's just mostly backstory on this guy Ivar, Okay, And because we don't know where Ivar was buried or if he existed at all or was just like a composite figure in this poem. But if he did exist, his body was possibly burned, So like we can't make a, you know, a diagnosis based on his remains. We can't know whether or not

he had osteogenesis imperfecta. Ivar's mother was said to be cursed while she was pregnant with him, and he was unable to walk and was carried on a shield into battle where he would use a long bow, So maybe he had OI.

so let's move on to the seventeenth century. That is where we have to go from here, and that's when the next possible reference to ostrogenesis improvecta shows up in France in sixteen seventy five, from the philosopher Nicholas D. Malibranche, who wrote that quote. About seven or eight years ago. A young man could be seen at the Incurable's hospital who was born mad and whose body was broken in the same places as murderer's bones are broken. He lived

for about twenty years in this condition. Several people saw him, and the late queen mother, when paying a visit to this hospital, was curious to see him and even to touch the arms and legs of that young man where his limbs were broken.

Although she could walk and move without restriction, she suffered unbearable pain anyone touched her. After three months of forced bed rest, she could no longer walk, All bones fragmented and it was impossible to touch her without causing new fractures. The pain increased progressively until she died. On dissection, we found that the upper and lower limb bones, clavicles, ribs, vertebrae and the pelvis were broken. Not a single unbroken bone was found. The bones were thin, tender, and full

of red marrow. Upon manipulation, they pulverized and dissolved like a rotten, wet tree bark. We could sink our fingers into her skull bones, the consistency of which was similar to that found in a fifteen day old neonate. Cartilages and articulations showed no sign of alteration. The internal organs were healthy, and no other signs of her pathological condition were found. It is known that smallpox can cause bony erosion, but in this case, the bones were melted and softened.

What was the cause and nature of their dissolution?

things like that, which can be painful. So certainly pain can be a component of osteogenesis imperfect at Okay.

Then we have the dissertation of Swedish surgeon Olaus jakab Eckmann, published in seventeen eighty eight, which had previously been considered the first scientific description of the disease, even though he considered them to be cases of osteomalaysia that ran in families. So he described four generations living in a mining district with bony disorders resulting in disability, but he just thought that it was Osteomalaysia.

different instances of the first description of this and that. Anyway, personally, what I think is that the first description that really matters is the one from Edmund AxMan in eighteen thirty one, where he describes for the first time the four major characteristics of osteogenesis imperfecta bone fragility, joint hypermobility with easy dislocation,

blue sclera, and a frail body. A couple of years later, Lobstein described a condition he called osteosatherosis idiopathica, an abnormal brittleness of bones, particularly afflicting children and the elderly, also mentioning that it can run in family. It's unclear whether he was actually talking about like a combination of osteoporosis and rickets or actually OI. And so at this point we have okay, we don't have a complete clinical clear picture,

but we have now gotten like a distinct condition. So this is not just like a symptom that people are talking about this is a collection of symptoms, there are recognizable features, and that makes diagnosis a possibility by around like the first half of the nineteenth century, but like a diagnosis of what, because what we now know is osteogenesis imperfecta didn't yet have that name, right, So how

did that happen? Gerardis Vrolik was a professor of anatomy and physiology and of theoretical and clinical obstetrics at the University of Amsterdam in the early nineteenth century.

intact bone. The skull, large and with a high forehead, was fractured, the ribs were very thin, and development overall seemed incomplete. In eighteen forty nine, he published his description and his belief that the infant had a condition he termed osteogenesis imperfecta, stating that he believed, unlike most of his contemporaries, that it was a condition that the infant had been born with, rather than something they had acquired

after birth, as in Rickets. Later re examination of the skeleton in the nineteen nineties led to the diagnosis of

osteogenesis imperfecta type two. Over the second half of the eighteen hundreds and into the early nineteen hundreds, more observations trickled in some that seemed to be more or less a repetition of what had already been published, and others that added a bit more detail to the overall clinical picture, like Spurway in eighteen ninety six reporting on how bluish sclera sometimes happened in association with brittle bones, which was then repeated and elaborated on by Edo's in nineteen hundred,

who hypothesized that quote, the transparency of the sclerotics indicates a want of the quality or quantity of the fibrous tissue forming the network of the various organs of the body, and probably explains the want of spring or toughness in the bones of these particular individuals.

Hereditary hearing loss associated with brittle bones and blue sclera was described for possibly the first time in nineteen twelve in a paper titled four Generations of Blue Sclerotics by British ophthalmologists and Ian T. Charles Allen Adair Dighton, And this observation was repeated by others shortly after, and so like this is just I felt like a list a bunch of people who described a bunch of different things.

And I feel like doing this episode right after Parkinson's made me realize how comparatively rare, or at the very least different the history of Parkinson's was, where there seemed to be like one landmark paper picked up by one

landmark scientist, and then everything grew from there. Yeah, for osteogenesis imperfecta, it has seemed like centuries of incremental progress and repetition, you know, like dozens of people coming in and putting one piece of this thousand piece puzzle together time after time after time.

time is it is this incremental progress. It is this like slight, you know, shedding a light and the light gets brighter and brighter and brighter and hits a wider and wider area.

We also had a growing recognition that many body systems were involved in the condition, like, not just bones, not just bones and eyes. There were many, many, many different organ systems and body systems involved, and we had some diagnostic criteria. But what we didn't have by the first half of the twentieth century is any real framework around why why are the bones prone to fracture? Why are the sclare of blue?

the many types of collagen. All of that background information and technology wasn't there until the nineteen sixties and seventies. But once these pieces came together, once collagen types one through four and all the major steps in biosynthesis had been identified, then finally people could start to get some clarity not only on how collagen worked, but what happened

when it didn't work right. And just like what you said, Aaron, because collagen is so abundant in our bodies, literally the most abundant protein, and because it functions in so many different ways, it can go wrong in just an unbelievable number of ways.

of ostrogenesis imperfecta. And so out of this, out of this kind of just whirlwind couple of decades of research, there was a great progress in genetic research in understanding the precise nature of those changes in collagen, and that has led to a greater understanding overall of the disorder as well as, like you said, Aaron hopes for treatment in the form of gene therapy. But like we talked about in our Parkinson's disease episode, all of that new information,

while hugely important, doesn't necessarily translate into current application. With the introduction of physiotherapy, rehabilitation, and improvements in orthopedic surgery, we had come a long way in preventing and treating fractures in people with ostrogenesis imperfecta since those earliest descriptions. Until nineteen eighty seven, there was still no medication that could help with bone density, loss or pain, despite dozens

of attempts. That year, a case study was published that described a twelve year old girl who was diagnosed with osteogenesis imperfecta after a spontaneous hip fracture. Her physicians prescribed bysphosphonate, or a type of bysphosphonate drug that had been used previously with some success in people with juvenile osteoporosis and other types of conditions where bone mass loss was a feature.

Until this case, no one had apparently tried this drug on osteogenesis imperfecta, and over the course of a year, X rays and blood analysis showed increased bone mass, which was amazing. After years of no effect, no effect, no effect, finally there was a drug that showed some promise. A bunch of studies followed, and it seems like it does actually help with at the very least improving bone mass, if not necessarily pain or fracture risk or overall bone growth.

But that alone is fantastic because there's really not been anything before then. And Aaron, I know you're about to tell me some more about like gene therapy and hopefully other potential medications. I only made it to the nineteen nineties with my research, but I think that one thing that's really crucial to talk about that kept coming up in some of these papers, although not enough is not just the potential health benefits of these medications, but also

how they can improve quality of life. Fear of fractures, anxiety about going outside or being active, caution when it comes to everyday life and activity, isolation, or feelings of being different. These are all commonly reported themes in studies that try to examine the lived experience of people, both children and adults with osteogenesis imperfecta, And of course not every experience is the same, but I think that it's important to talk about and recognize the non physical effects

that ostrogenesis imperfecta might have on someone. And certainly things like OI groups and awareness campaigns have been fantastic for building community and providing resources to people with osteogenesis imperfecta

as well as their caregivers. But there's still a long way to go when it comes to treatment and access to that treatment, because we know it's got to be expensive, just has to be, so, Aaron, here's where I turn it over to you to tell me what those up and coming probably expensive treatments are, and you know everything else about where we stand with osteogenesis imperfecta today.

twenty thousand berths every year. Okay, so if we air in mathis, which you know I'm going to, According to Google, there are one hundred and forty million berths every year, and the CDC says that in the US there are over just a little over three point six million berths every year in the US. So if we assume on the low end, one in fifteen thousand people are born with osteogenesis imperfecta, that would be worldwide just over nine thousand people born with OI every year and two hundred

and forty 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 in 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 twenty five to fifty thousand people in the United States living with OI, but it was very disappointingly difficult to get any additional data on prevalence worldwide.

versus per ten thousand births in this kind, 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. Can I ask a question about bone remodeling? Sure?

and osteoclass and like. But in any case, it's a process that happens over time. Your bones are dynamic.

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. And you know what else just occurred to me is that it seems like the very few treatments we have so far are mostly targeting bone, not any of the

other organs or tissues affected by osteogenesis imperfecta. Yes, definitely, definitely, that's the vast majority of all treatments prior and current through that. Yeah. 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 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?

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 dot Com under the episodes tab.