Laszlo Ormandy Distinguished Professor of Orthopaedic Surgery
Reversing Bone Loss Due to Osteoporosis
Current drugs for osteoporosis can only slow or stop progression of bone loss. What’s gone is gone. Duke University Professor Shyni Varghese has built a new molecule that rebuilds bone—and may transform osteoporosis treatment.
Elizabeth Witherspoon: Hello, and welcome to Rate of Change, a podcast from Duke Engineering, dedicated to the ingenious ways that engineers are solving society’s toughest problems. I’m your host for today’s episode, Elizabeth Witherspoon.
Whether it will someday be you, or is already affecting someone you know, loss of bone density is an inevitable part of aging. Bones that are less dense are weaker and more prone to break. As a population, we are living longer and, therefore, osteoporosis–the disease of bone density loss, whose name literally means porous bones–is affecting more people.
According to the National Osteoporosis Foundation, one in two women and up to one in four men will break a bone in their lifetime due to osteoporosis. For women, the incidence is greater than that of heart attack, stroke and breast cancer combined.
Current drugs for osteoporosis can slow or stop the progression of further bone loss once treatment begins. However, none can strengthen or rebuild bone density that is already lost.
Shyni Varghese is working to change that and making significant progress. Varghese, who is professor of mechanical engineering & materials science, biomedical engineering and orthopedic surgery at Duke University, has demonstrated in mice that a new molecule – the beginnings of a drug treatment – can not only stop bone loss, but reverse it all the way back to the same density as healthy mice. Keep listening to find out how.
Shyni Varghese: The focus of our lab is solving biomedical problems. And so, we have a focus on musculoskeletal systems, that is, the cartilage, joints, skeletal muscle, bone, et cetera. We also go back to animals. We look at how we can improve the ability of the organisms, in this case, it’s the mice or the rat, to promote regeneration. In that case, we are looking at bone regeneration, like osteoporosis, fracture healing with aging. And another case is also with the injury to joint, right? So, if you have a joint injury and that is an ACL rupture or meniscus injury that leads to osteoarthritis. So, we mimic that in an animal model. And now, we are trying to develop therapies that can slow down the progression of osteoarthritis or even treat them. So, we interface biology, stem cell biology, molecular biology, materials science and engineering.
Witherspoon: It’s a very interdisciplinary group of students and postdocs working in Varghese’s lab where they leverage everyone’s expertise to create these structures. Can you help us understand what regenerative medicine is?
Varghese: So, if you think that we all have the ability to heal, all our tissues have the ability to heal. But with time our ability to heal declines. This could be aging, or it could be comorbidities like diabetes, or like lifestyle, like obesity, smoking, all those things, right? So, the question, what we are asking is that can we create new approaches that can regenerate the tissue. It is already compromised and now it can repair itself. Or we can add the cells, so they are the building blocks and use the cells to repair. It could be a cell transplantation, so that could be a regenerating medicine. So, I have a wound, now I wanted to heal it, it is not repairing, so now I take stem cells, which you can make this tissue, transplant them, and then prime the cells so the cells become the tissue that we want, so they can contribute to the tissue regeneration.
The other way is that, now I can just create approaches, like in this case, it is a small molecule, or a cytokine, or a growth factor, deliver them to the defective site and rejuvenate the tissue, and now make the endogenous cells to become very healthy and then start repairing the tissue. So, we can do either way, right?
So, in the case of regenerative medicine means creating approaches so that we can regenerate tissues that have been compromised.
Witherspoon: So, tell us about the work you are doing to address osteoporosis.
Varghese: Initially, I was very interested in bone regeneration. A bone is one tissue which can heal, it has very good at repairing ability. However, a significant number of people have failures in healing, like they don’t heal very well. We started interested in knowing that, “Okay, can we just to make that… develop strategies so we can improve the healing.”
And then we created a biomaterial, that is where we used all our material science to create the scaffold of the bone tissue in the lab and started throwing stem cells on top of it and trying to see that how this material is directing the differentiation of these stem cells into bone forming cells. And we have identified a mechanism that is involved in this process, the biological process that is involved in this process, and that involves adenosine.
Witherspoon: Adenosine is a molecule that occurs naturally within the body and controls many of its processes. Most notably, Varghese’s prior research has leveraged how it plays a large role in healing of bone at the site of a fracture. She developed biomaterial implants that can hold the body’s own adenosine for a longer time where it is needed while also delivering an additional localized dose to promote healing.
Varghese: Then we started asking how the adenosine is providing signals for the cells to form bone-forming tissues. And, also, if you think about the bone, it is highly remodeling, that means it also forms the bone and it is also degenerate the bone, so it is balanced. So, we wanted to understand, when that balance is perturbed, you get osteoporosis. That means there is more degeneration rather than more bone resorption, or degeneration compared to the formation or building of the bone tissue.
We started asking that there are two key cell populations, the one which is building the tissue and the one is degenerating. So, we started asking the questions, how adenosine is, what type of signals that adenosine influence on these cells? If I take the cells and throw some adenosine on top of the cells, how do these cells behave? And, we noticed that the adenosine allows the cells to build the tissue, but also prevent or inhibit the degeneration. So, if you look at the current osteoporosis drugs, what they do is that they prevent the resorption, that means the regeneration, they don’t allow to build the tissue. So, now we have a drug that is adenosine molecule that does both the things.
So, we created an osteoporotic model in mice. In fact, we are looking most in the post-menopause because osteoporosis affects women more than men, and then we started treating the animal. And we found that the animal, in fact, build a bone and they reversed osteoporosis. So, it is a very efficient molecule, it is pretty inexpensive, but now we have to work out the safety, efficacy, et cetera, that is a different story. Fundamentally it works, now, we need to figure out how we can translate it if we wanted to treat patients.
Witherspoon: I understand that one of the challenges you have to overcome is targeting the adenosine to the bones and bypassing the rest of the body, so that you won’t have unwanted side effects and that you did that by developing a nanocarrier – some sort of specialized transportation molecule to carry the adenosine. Tell us more about that.
Varghese: We have a nanocarrier. We can definitely target that to the bone tissue, but the nanocarrier also goes into other tissues. They also go to lung, for example. So now we are trying to change some other properties so we can minimize their going into other tissues. Even though they go into the lung tissues, we don’t see any side effects.
And now we have another nanocarrier where what we did is not really that we are targeting them to go to the bone tissue. Whenever you have a lot of bone degeneration, the pH is very low. The bone tissue is more acidic. So, now we have a linger which is responsive to the pH. So whenever that sees the low pH, it will release the drug. So, we have a stimuli, in this case it is the pH, and we use the pH as a stimuli to release the drugs.
Witherspoon: So, the nanocarrier senses the low pH in the bone, releases the drug, begins telling it to stop thinning and to even rebuild.
So, when you say it reverses the osteoporosis, how many years back are you able to reverse the bone loss?
Varghese: So, we had a control which doesn’t have osteoporosis and we compared to that healthy control. So, it was very similar to the healthy control.
Witherspoon: This took them back as if they didn’t have any osteoporosis at all? How advanced was the disease in those you treated?
Varghese: So, they have the osteoporotic fractures and a lot of bone degeneration but it’s very hard for me to compare that to a human because I just don’t know how to compare it, but we saw a significant bone degeneration, the one without the treatment displayed a lot of degeneration.
Witherspoon: How far into the future do you think we are from this being available to human patients?
Varghese: To be honest with you, at this minute, we have patents on the technology and all the formulation, et cetera, a couple of disclosures, and even the U.S. patent. We have some interest in starting up a company and doing some larger animal model, et cetera. So, I think 5-10 years minimum because clinical trials are extremely time-consuming and also economically very expensive. We have some plans of taking these technologies to translate into clinic. I have a graduate student who has some interest in taking the technology out after he graduates. We are looking into starting up a company and then seeing how far we can go and how we can advance the technology, yes.
Witherspoon: What inspired you to get into all this research and what keeps you so passionate about it?
Varghese: I have trained in a basic polymer science field as a PhD student. And then when I started seeing that people are using these polymer systems to create tissues, something which was very hyped at that time, was tissue engineering. So, I got very fascinated. As a scientist, you can help people when you solve a problem, a medical need, so that people can have a better life, right? So, the same way as a scientist, I can really be passionate about my work. I can push boundaries within the scientific field and make an advance that can solve a public health problem or any medical problem, for example. And health problem is one of the biggest problems of our generation, or any generation, right? Because aging, a lot of diseases, et cetera. It affects everyone. It is not a problem only for the rich or for the poor, it has no boundaries, ethnicity, no gender boundaries, financial boundaries, no social economic boundaries, right? Everyone will have the challenges from the medical problems. Working in that field, you are really helping everyone. So, if I create a solution that can be applied to everyone in the world, then I’m really contributing to the humankind. So, that is something which makes me passionate about the research.
And the second thing is training the next generation of students. The passion is very contagious and it’s exponentially, like I train one student and when they become a faculty, they train another 10 students, then each of those students go and train multiple students. So, you are just really making a bigger impact because it’s not just you, it is all your students and everyone associated with you.
Witherspoon: I hope you’ve enjoyed hearing about Professor Shyni Varghese’s research to address osteoporosis. You can keep up with her progress – and more science like it – at pratt.duke.edu. To hear more inspiring stories like this one, be sure to subscribe to the Rate of Change podcast. Thanks for listening.