The future of bone health

0:00This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. And it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:37In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, co-workers as well. We can make bone. We can make osteoblasts in the lab. It takes a really long time and it's a very low yield, so not super efficient. Something that we're a little bit more excited about more recently is direct reprogramming. So that's an approach where we can actually take skin cells. Right now we can do it in mice and we can basically convert them directly into bone forming osteoblasts much more quickly and more efficiently.

1:21this is Stanford engineering's the future of everything and I'm your host Russ Altman if you're enjoying the show or if it's helped you in any way please consider rating and reviewing it on whatever app you listen to we'd love to get a 5.0 if we deserve it but just tell us what we deserve your ratings help spread the word about the podcast so everyone is clued into the future of everything. Today, Joy Wu will tell us that weak bones or osteoporosis is an affliction that affects both women and men. She's working hard to create new treatments to build strong bones. It's the future of bone health.

1:55Before we get started, another reminder, I always say it, please rate and review the show.

2:06bones are a miracle we have 206 of them we humans and they do support of our stature they protect our organs they make blood products in the bone marrow they make hormones and they store minerals they also heal when we break them so they're kind of amazing but you know what sometimes a large number of us both men and women can get weak bones through osteoporosis weakening and thinning of the bones. This is a problem because it can lead to fractures, fractures in your spine, which can cause pain and disability, and fractures of your hip, which can be very disabling and often associated with lots of other sickness and morbidity.

2:44Well, Joy Wu is a professor of endocrinology at Stanford University, and she's looking hard with her colleagues on ways to build that bone back up with medications. The key piece there is understanding the basic biology and how they are broken down and make sure that we can modulate that balance so we're doing more building up than breaking down. Joy, to start out with, why have you decided to devote your work to bone health? Bones are really fascinating. You know, I think they're sort of underappreciated. They, you know, we're used to the idea that they provide mechanical support and they protect our organs.

3:22But while I was doing my clinical training in endocrinology, I became aware of all the other things they do like producing hormones. And then for the sake of my lab, maybe the most interesting thing is that they support the blood cell production in the bone marrow. So ever since I think high school biology, I've known that hematopoiesis takes place in the bone marrow cavity, but never really thought about it until I was doing my research in bone biology and realized that the bone forming osteoblasts on the inside surface of bone are actually very closely opposed to hematopoietic stem cells and the other lineages of hematopoietic cells.

4:01I mean, it turns out those interactions are really critical for both bone health and normal hematopoiesis. And I've always found the intersection of two fields to be very fascinating. Great, great. Thanks very much. And so when we think about bones, I think just thinking from a non-professional perspective, we think of calcium. So I guess one place to start is calcium and its role in bone health. I guess we have to eat it. We have to absorb it. We have to make sure it gets into the bones. I know we're going to get in a few minutes to some of the disorders of bone biology, but tell me about the role of calcium.

4:36Sure. So calcium is part of the mineral in the bone. That's what makes bones so strong. So calcium and phosphate are stored within the bone. And so it is important to have enough calcium, both through dietary, either calcium-based dairy products or calcium supplements. It's enough to have, it's important to have enough so that our bones can be strong and resist fractures. Yes. And vitamin D plays in there somehow too, doesn't it? Correct. Yeah. So vitamin D is important because that's what helps us absorb the calcium from our diet. So it acts on the intestine and increases the absorption efficiency.

5:13So one thing I wanted to ask, and I think we all know this, but many injuries, you know, you have scars and, you know, sometimes the tissue doesn't grow back. But many of us have broken a bone. And one of the kind of remarkable things is that we, as long as things are working okay, we often get like almost 100 % of our bone back. It's in the right shape. It's still providing strength. Do we understand why this amazing property of bone, where does it come from? Because it seems like it sure would be nice if like our brain or our lungs could do similar things. Yeah, I think the ability of bone to regenerate is really interesting.

5:53And also the developmental biology, most adults have 206 bones, and almost every single one is differently shaped, but they fit together perfectly. So it's really a beautiful example of development. But you're right. So when you have a fracture, for the most part, our bones are able to heal themselves. So we have both cells that break down the bone called osteoclasts and cells that make bone, the ones that I referred to earlier called osteoblasts, and somehow they're able to work together along with all the other cells in the microenvironment and repair that bone pretty much back to normal. It's just amazing, and I've benefited from it once or twice.

6:31And sometimes you get these little aches, like when it's humid out, hot and humid, or cool and humid, you get little bone aches that remind you that you used to have a fracture. Do we know anything about why that happens? Because I think it's a pretty common experience that people say, oh yeah, my old fracture aches when it's cold and damp outside. Yeah. You know, it's interesting. One of the reasons we have to screen for osteoporosis is because for the most part, we don't think that we can feel bones. But clearly when you listen to patients, they can sense, you know, that's quite a common report is that if they've had a previous fracture or sometimes at their joints, there are certainly nerves that innervate the bone and bone marrow cavity.

7:10So it makes sense that they must be transmitting some kind of signals back. And, you know, maybe that repair process didn't happen completely and something changed a little bit about those nerve signals that are sending back. Right. Or I've always thought it's your body reminding you that there's been this accident and let's not try to do it again. Okay. So you said the magic word, or at least one of the magic words for your work is osteoporosis. And I think this is something that's on a lot of people's mind. I don't know if we would call it an epidemic, but it's certainly on, we're seeing a lot of it.

7:43And so maybe give us a landscape of osteoporosis, what kind of health burden it creates for the nation or for the world and where we are in understanding it. Sure. So osteoporosis quite simply is a disease of aging usually that is associated with a decrease in bone mass, the amount of bone we have. And how much bone we have is usually determined by that balance between formation versus resorption. And as we age, the resorption starts to accelerate a little more. In women after menopause, it accelerates even more. That's why women are more prone to having osteoporosis. It's a very common disorder.

8:22So probably half of women over the age of 50 and a quarter of men can expect to have a fracture due to osteoporosis sometime in their lifetime. So it's quite common. So tell me, what are the kind of clinical manifestations? How does somebody know that they should even be worried about this, hopefully before they have a pathological fracture or something that really is life-changing? We'll get to that as well. But what are the symptoms, so to speak, of osteoporosis? Well, so one of the tricky things about diagnosing osteoporosis is there are really very few symptoms. It's a little bit like high blood pressure, right?

8:57It's something that we call silence. So for that reason, we often do clinical screening with bone density scans or DEXA scans. Usually, you know, the warning signs, unfortunately, other than that, are fractures. So what we call fragility fractures. So fractures that happen without a major trauma. So of course, if you were in a terrible car accident, or if you fell off, you know, the roof of the building, you would expect to have some fractures. But, you know, I trained in New England. And so if you slipped on the ice and fell on your wrist, many people have wrist fractures then. And that's the sign that maybe the bones are more fragile than they should be.

9:36Are there other risk factors? You mentioned women after menopause. I was surprised to hear that 25 % of men, because I don't think of osteoporosis as a disease of men. So what are the kinds of risk factors earlier in your life or any time in your life that you can kind of be aware of? So some things are other diseases like some endocrine disorders, hyperthyroidism, hyperparathyroidism. Some medications, glucocorticoids, are a very common cause of osteoporosis, so treatment for inflammation. And the area that I specialize in is largely breast cancer patients, so women undergoing endocrine therapy because you're blocking the estrogen signaling.

10:18they're at significant risk for bone loss and fractures. And otherwise, excessive alcohol, current smoking. It's one of the diseases for which being thin is actually a risk. So people who are on the thinner side of average can have higher risk of fractures. And then there's some genetics. So particularly if you've had a parent who's had a hip fracture, your own risk of fracture goes up. Great. Great. Now, a couple of questions about that. One is, you mentioned glucocorticoids. Many people are on puffers, like for their asthma or for their COPD. Does that increase the risk, or does it have to be systemic pills?

11:04Yeah, that's a great question. So mostly we think about the systemic, so oral or IV steroids. And really, we're talking about pretty high doses for prolonged periods of time, more than three to six months continuously. So in the days, for instance, in many rheumatologic disorders, before they had all of these new immune modulatory agents, it was quite common for patients to have very high doses of steroids for months or years on end. Thankfully, we're seeing less of that now. I think many of the diseases that used to be treated predominantly with high dose steroids, there are a lot of other alternatives now.

11:40Great. And another thing is, as someone myself who is, let's just say, not getting younger, I'm very aware of increased recommendations for weight-bearing exercise. And you're seeing more people at 50, 60, 70 years old going to a gym and lifting weights. I presume this is at least partially motivated by bone health reasons. Is that right? Yeah, no, I think of it as the opposite of, you know, when we send astronauts up into space, they actually lose a tremendous amount of bone density because of being in microgravity. So we do need to continuously load our bones. They're very responsive to mechanical forces.

12:15So one of the ways that you can mitigate bone loss is to really be diligent about strength training. And one of the things that's become clear is that you always want to challenge yourself. So even as you get older, you might not be lifting the same amount of weight as you did when you were 20 years old, but it should still be enough to constantly challenge and build strength. Great. So, okay, now I have one personal anecdote, which is that yesterday at my doctor's appointment, I was one and a half inches shorter than my peak height when I was, you know, a young man, let's say 30 years ago. And I was very surprised that my doctor offered me, he actually wound up not recommending it, but he said, oh, maybe we should think about a DEXA scan.

13:01And I was surprised by this, but he said, because of my loss of height, you know, this would probably might be because of my vertebrae kind of, I guess, kind of getting squished. And so is this loss of height? Is this something that people are paying? Obviously, I'm very concerned about it. All of a sudden, I knew this was happening. Of course, this wasn't the first measurement, but it reached an inch and a half of yesterday. And so it was kind of like, wow, I'm going to have to like change my driver's license. So I guess my question is, is this a normal process, a little bit loss of height? And does that indicate an increased risk for osteoporosis?

13:38I'm now thinking about my 25 % of brethren, which I might be joining. Yes, exactly. So I mean, it is an important point that I always try to make that we think of osteoporosis mostly as a disease of women, but it is something that affects men. It tends to be later in life than for women because there is not really a menopause equivalent, but it is underdiagnosed and undertreated for men. So usually, you know, I start to really think about it when the height loss is two inches or more, but it's, you know, I think not a bad idea to get screening because it is often underdiagnosed in men and because there are a lot of things that we could do to sort of mitigate the bone loss.

14:17There are a number of reasons why people can lose height over time, but I think the one that you're worried about, and I would be wanting to rule out as well, is spine fractures. So your vertebrae should be rectangular boxes, but over time they can sometimes compress slightly, sometimes compress all the way. And those are the spine fractures, vertebral compression fractures. And those are definitely a sign of fragility and osteoporosis. So it's something to think about for men. Yeah, well, thank you. I was blaming my running because of the pounding on the asphalt, but we'll see. And that's a story that we won't have to go into anymore.

14:57Okay, let's get to one of the areas of I know of your strongest interest, and you mentioned it briefly before, which is especially the interaction of bones with cancer. And we think about this in many ways. You already mentioned that some sorts of chemotherapies can reduce the calcification and the strength of the bone. We all have heard about bone metastases being a kind of terrible outcome of some cancers. So maybe give us the landscape of the relationship between bones and cancer, which I'm sure is quite complex and is what you focus on. Yeah. So it's an area where sort of my clinical practice in my laboratory-based research really dovetail quite in a very satisfying manner.

15:35So clinically, I think there's sort of two major issues that we're very interested in. One, of course, is that when cancer is metastatic or widespread stage four, one of the most common sites that cancers of many types like to go is to the bone. And there are a variety of reasons for that. It's thought that since under normal circumstances, your bones are supporting hematopoiesis and those interactions between osteoblasts and blood cells, it's thought that cancer cells can somehow hijack those molecular signals. And that might be why cancer cells are somehow recruited, enticed to go to the bone marrow and sort of take up residence and become metastases.

16:14So certainly there's a very strong interest because it is such a common feature of widespread advanced late stage cancers that it's something that we've as a field been really working hard to try to understand so that we can prevent. More commonly, at least within breast cancer, 95 % of women are thankfully diagnosed when it's still early stage. So localized still to the breast. But because the majority of breast cancers are estrogen or progesterone receptor positive, the good news is that we can use endocrine therapy, hormone blockade, to try to reduce the recurrence. And of course, that's the predominant goal.

16:54But that comes at the cost that when you reduce estrogen in bone, bone loss is a well-known effect. And so my clinical practice is largely based on trying to mitigate the bone loss in women who are undergoing endocrine therapy for their breast cancer. Yeah. So what kind of tools do you have? I can see that this is like a terrible dilemma because, of course, curing the cancer and hitting it as hard as the patient can tolerate to try to clear it is the number one goal. But then if you're successful, there's a lifetime of bone health that becomes a very important issue. How are the medications for helping build bone, especially in the folks who are having osteoporosis, either from what I'll call natural causes or because of intensive chemotherapy or the cancer process itself?

17:41Yeah, and sometimes those overlap. A lot of women who are diagnosed with breast cancer are, in fact, postmenopausal. And so you could already have underlying causes for bone loss that are then aggravated by the endocrine therapies. therapies. So fortunately, we have really good medications that we can use to manage this process. So I tell patients that the treatment of osteoporosis is pretty straightforward. We have two choices. We can either block bone resorption by the osteoclast, or we can promote bone formation by the osteoblast. So the first class of medications are the anti-resorptives, and they are by far the most commonly prescribed for routine osteoporosis, but also they work very effectively in patients with cancer who might be losing bone either directly because of chemotherapy or because of endocrine blockade, as we were discussing.

18:33So those medications work really well. In the lab, one of the things we're really interested in is that the anabolic treatments for osteoporosis, the ones that stimulate bone formation, the physicians are still not quite sure whether they're safe in cancer. And the reason is because, at least in animal studies, the original anabolic agent was recombinant parathyroid hormone. And there's quite a bit of interest in PTH acting on the bone marrow microenvironment to stimulate hematopoiesis. In fact, it's one of the things that we study in the lab. Hematopoiesis is just the creation of blood cells that happens in the bone marrow.

19:11Correct. Thanks for clarifying. Right. So, again, the osteoblasts are really important for supporting the production of these blood cells. in the marrow. And there's a lot of evidence from animal studies that parathyroid hormone and its receptor in bone play an important role in that process. And so the worry is that if you use recombinant parathyroid hormone to promote bone formation, and I mentioned earlier that maybe cancer cells like to hijack some of these signals within the bone marrow, maybe we're actually making the bone marrow microenvironment more welcoming to cancer. That's a theoretical concern.

19:45But it's because of the lack of safety data, it's something that physicians have been reluctant to use bone forming medications in cancer patients. But it's one of the things we've been studying in the lab. And actually, we found that if you're a mouse with breast cancer, we can actually decrease bone mets by treating with recombinant PTH. So we're trying to understand sort of the mechanisms and hopefully someday translate that for patients. And of course, one thing that I think you said it already that promotes bone growth is estrogen. But giving that to a woman with breast cancer, right, is kind of out of the question because of its potential role in stimulating the breast cancer cells.

20:25Right. So we certainly don't want to give estrogen itself. There are some very cool pharmacology in the selective estrogen receptor modulators or CIRMs like tamoxifen, which acts as a sort of partial agonist in bone, but an antagonist in breast. And so they're used very effectively to both prevent and limit the recurrence of breast cancer because, again, they block the effects of estrogen in the breast while being somewhat protective in the bone. This is The Future of Everything with Russ Altman. We'll have more with Joy Wu next.

21:15Welcome back to The Future of Everything. I'm Russ Altman, and I'm speaking with Joy Wu from Stanford University. In the last segment, we got a tutorial about the basics of bone biology. Say that 10 times fast. In this segment, Joy is going to tell us about some exciting work with stem cells. You can take a skin cell and turn it into a bone cell. It's a miracle. Joy can do it. And she'll tell us what's the status of getting more bone cells to build up bone more quickly and effectively in patients who need it. So Joy, I know that you have an active research effort in the use of stem cells. And my guess is that you talked about the osteoclasts, which break down bone, and the osteoblasts.

21:56And it seems to me that maybe, and you can tell me if I'm right, getting more of those osteoblasts and having them be more aggressive in the creation of bone would be a great thing in some cases. So where are we? And tell me about the stem cells in bone biology. Yeah, you're absolutely right, Russ. We're really interested in how to have osteoblasts make more and stronger bone and how to stimulate them. One of the limitations of the bone building medications I mentioned earlier is that at the moment, they all have to be delivered by a needle, which, as you can imagine, makes them less popular. So some are daily self-injections, some are monthly injections in the clinic.

22:31Wouldn't it be great if we had a pill, for instance, that could stimulate bone formation? So we've been interested in a number of approaches in the lab. The first is just understanding the signaling pathway. So why is it that recombinant parathyroid hormone works to activate your osteoblast? And is there a way that we can accomplish the same thing, again, maybe in a pill form or bypassing? One of the sort of conundrums in the clinical world right now is that the effects of PTH only work for about a year or two. And so you can build bone for about two years, and then it sort of levels off. And so there seems to be some kind of set point the body recognizes.

23:10And the other challenge is that once we stop the anabolic agent, that bone goes away very quickly unless we immediately follow it with an anti-resortive medication. So, you know, one of the great mysteries is how do we build new bone, make bones stronger, and then keep it there? And so that's one of the things we're studying from a signaling perspective. So let me ask about that, if I could. I'm sorry to interrupt. You said it works for a year or two and then stops. Is it stopping because it's gotten you to a normal bone density and so we all should be perfectly happy and it won't go past normal?

23:45Or is it not even getting to normal and for some reason just petering out before you get to the point that you would say this is a perfectly normal bone? Yeah, it's a great question, you know, whether the set point is recognizing some sort of normal. I think for the most part, it seems to be, you know, more just as much as you can get over one to two years and then it plateaus. And there's a lot of theories in the field right now. One of them is that maybe the stem cells that give rise to osteoblasts got exhausted and you just simply ran out of the, you know, workhorses of bone formation. And so you need a little time to recover.

24:25there does seem to be some sort of set point recognized because as I mentioned if you stop the medication without doing anything else it will all disappear very quickly the osteoclast will sort of break down the bone again and you'll basically go back to where you started so you don't want to spend two years giving yourself injections every day only to end up where you were before you did that good well I'm sorry about that interruption I just was very interested but You were talking then about the signaling systems and what you're studying to try to get around all this. Yeah. So certainly understanding how parathyroid hormone works, it intersects with another pathway called Wnt signaling.

25:06So those two right now are the targets for the two classes of bone building medications that we do have available. So clearly they're very effective at building bone. And we're trying to understand how they work and whether we can accomplish them in a safe and sustained manner. The other approach we're taking is, like many other labs, trying to see if we can harness the power of stem cells to make osteoblasts. So we've tried a number of approaches. We've used embryonic stem cells, what we call induced plipotent stem cells, where you take skin cells and reprogram them. And we can make bone. We can make osteoblasts in the lab.