Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. John Leonard. And today on the podcast, we will be talking about bone health and how cancer can impact the bones, including osteoporosis prevention and management. Bone health is a really important issue for patients with cancer, and it's becoming increasingly important as patients live longer and do better and have to deal with a variety of issues in the long-term after cancer therapy.

Our guest for this episode is Dr. Panagiota Andreopoulou. Dr. Andreopoulou is an endocrinologist who specializes in the evaluation and treatments of patients with osteoporosis, metabolic bone disease, and parathyroid calcium and phosphate disorders. She has performed research on a number of different endocrine and bone-related topics and also raises awareness in the community on the prevention, screening, and management of endocrine diseases.

So, I'm really excited to have her here today. Dr. Andreopoulou, thank you for joining me today. It's really great to have you.

Dr. Panagiota Andreopoulou: Thank you so much. it's a pleasure to do this podcast with you.

Dr. John Leonard: Thank you. So, I like to start out in getting to know our guests a little bit and how they end up working in the field that they've chosen to specialize in. What led you to focusing on endocrinology as a specialty and also your particular focus in the area of bone disorders?

Dr. Panagiota Andreopoulou: It really happened early on in medical school. It was out of pure fascination with the intricate hormonal pathways that affect all our organ systems in the entirety of our body. They're critical in keeping us alive and they majorly contribute to who we are, starting from helping create a new life, for example, in the fertility field and during our embryonic and fetal development, childhood, and adolescence, and then to also optimize the quality of our life. So, it's really striking how much of our well-being and the health of all our organ systems depend on the endocrine system.

It's also an exciting field. Endocrinology has rapidly increasing and evolving knowledge and scientific advances. Every day there's something new published and announced. So, it's really a joy to both study and practice it.

And then, I really got involved and interested in bone disorders during my fellowship at the National Institutes of Health.

And of course, osteoporosis is a significant public health issue. It's a highly prevalent condition in the increasingly aging population. As you mentioned, we're pushing the frontiers of both life expectancy in cancer patients and the general population, of course, further and further. Therefore, we have to address this constantly growing public health problem.

A fragility fracture from osteoporosis can dramatically change the quality of life and shorten the life expectancy of an individual. And the fascinating part about osteoporosis is that addressing it really requires us to combine knowledge in biology, chemistry, physics, even engineering. It's truly very challenging and very exciting. So, I do love this field and I really enjoy seeing and making a difference in the quality of life of my patients, cancer patients and non-cancer patients, as well.

Dr. John Leonard: That's a great introduction into our next topic, which is really to get into the importance of bones in the body. I know that everybody understands that bones are literally the skeletal framework of keeping us upright and doing what we do, moving around, et cetera.

But maybe you could just give us a little background on how bone biology works, what's the importance of bones beyond that, and that dynamic that happens inside of our bones every day, and you alluded to some of the chemical aspects and minerals going in and out. What's happening in that part of our bodies on a routine basis?

Dr. Panagiota Andreopoulou: The skeleton is the body's support structure. Part of that protects sensitive structures that are critical for our life. For example, our brain is protected by our skull, our heart and lungs by our rib cage, our spine and vertebrae protect our spinal cord, very important part of our central nervous system. But apart from that support function, it also has other highly important critical functions.

For example, it stores minerals such as calcium and phosphate. Calcium is a critical mineral for us to remain alive, very important for pretty much every cell process in our body. And 99% of it is really stored in our bone as hydroxyapatite crystal. The bones are involved in our calcium and phosphate homeostasis regulation. And the osteocytes in the bone function as an endocrine gland, as far as producing hormones that affect that calcium and phosphate regulation.

And then, one of the critical and unique functions of the skeleton is to provide the anatomical space for storing and facilitating differentiation, maturing really, of our hematopoietic progenitors and precursors of these cells that are really immature, but are capable of generating our entire blood system, hematopoietic stem cells that are found in our bone marrow. They produce red and white blood cells, other immune cells, the osteoclasts that are highly important cells in our bone. Therefore, bone is not just a solid, rigid skeleton.

Our skeleton's really a very alive organ system with multiple functions. It's very unique because it is constantly regenerated throughout our life. We have this process called bone turnover, bone renewal where there's constantly bone resorption occurring, bone breakdown, and new bone formation, renewing that bone that is resorbed. This is highly important to understand because deregulation of that process can lead to significant disease. And a lot of treatments that we use in addressing bone issues, osteoporosis, bone loss from other reasons, for example, cancer treatments, target that process: deregulated bone turnover.

Our bone has three cell types, mostly osteoblasts. Osteoblasts are cells that form new bone. When they are engulfed in mineral, they become osteocytes, which are about 95% of the type of cells in our bone. And we also have the osteoclasts that are really cells that break down bone, they do the bone resorption. And the fascinating about this is that they all communicate with one another, either by direct cell contact, they touch each other, or through these little tunnels, canaliculi, that send back and forth signals, signaling molecules, and they respond to each other. They are inside this extracellular matrix, this kind of substance that is produced by the osteoblasts and osteocytes and consists of mineral, collagen, there's water in it, there's lipid, other proteins. This consistency varies depending on age and what skeletal site we're talking about. And all of these components together, the bone matrix, and the cells inside it, they contribute to the mechanical and metabolic functions of the bone. So, this is how the bone is constructed.

Dr. John Leonard: We know that cancers can metastasize or spread to the bones, and that's obviously one problem. You can have cancers of the bone cells themselves. And one can also have cancers that involve the bone marrow, as you alluded to. What about the other, let's say, indirect effects of cancer on the bones? That seems to me to be probably one of the bigger areas of concern that's underappreciated with respect to cancer indirectly weakening the bones or having effects on what's going on in the bone's natural physiology.

Dr. Panagiota Andreopoulou: Cancer can affect bone in multiple ways, and that includes both cancer and treatments we use for cancer. There are hormonally active malignancies that can promote bone deterioration, such as cortisol-producing adrenocortical carcinomas or ectopic tumors, neuroendocrine tumors. They produce hormones that can promote bone deterioration.

Apart from those, cancer as a disease, especially at the advanced stages, can definitely affect the strength of an individual. It can lead to muscle loss, of course, bone loss and fractures. So, those effects can definitely lead to more falls, frailty, and these could be indirect effects of cancer as far as weakening of the musculoskeletal system in general. And treatments for cancer, chemotherapy, they can definitely be quite debilitating for many individuals.

There are cancers that arise from the bone marrow, but most often, cancers that metastasize to the bone. So, these are the more common problems that we have to face. Specifically, cancers arising from the bone are not that common. We have osteosarcoma. It is the most common primary malignant tumor of the bone. But nevertheless, it's still a very rare disease. There's only about 900 new cases annually in the United States, so it's really a very uncommon problem. It is most noted in adolescents. But also, there's a second peak in the elderly, individuals in their late 70s.

Most often the bone is a very frequent site for solid tumor metastases, as well as multiple myeloma involvement. And bone metastases remain truly a significant complication faced by patients with some of the most common malignancies, including breast cancer, prostate cancer, lung cancer, renal cancer. There's about half a million individuals in America that suffer from what we call cancer in bone that can cause debilitating skeletal-related defects with severe consequences. They can suffer from bone pain, pathological fractures, spinal cord and nerve compression from fractures in the vertebrae, as well as derangements of calcium and phosphate homeostasis arising from the bone metastases. The major cause of cancer related pain in patients with advanced malignancies is really bone involvement. So, the quality of life of these patients can be significantly affected.

Now, under normal conditions, the bone resorption and formation that I previously mentioned are really tightly linked. There is bone formation occurring at specific sites where previously there was bone resorption, bone breakdown. It's a coupled bone remodeling, as we call it. So, there's a harmony, a balance there, largely dependent on the proper communication between all these cells that are in our bone.

However, in context of cancer in bone disease, this balance is really lost. In metastases, the bone remodeling process becomes imbalanced. It's what we call uncoupled. And basically, we have higher bone resorption, bone breakdown rate, because both the tumor cells or cells around them -- in what we call the microenvironment of the tumor -- produce these factors that really stimulate the cells that cause the bone breakdown, as well as inhibitors, substances that slow down the function of cells that make bone of the osteoplasts, and they also block bone repair. So, that's really the critical problem that's happening.

Dr. John Leonard: Perhaps you can give us a very quick overview if you talk about, first, patients without cancer, who should be screened for bone issues and how? And then, we'll move to patients with cancer, which groups of patients based either on their diagnosis or their treatment should we think about screening?

Dr. Panagiota Andreopoulou: As far as the general population is concerned, all scientific societies pretty much are in agreement that postmenopausal women 65 and older should have a screening test for osteoporosis to assess risk of fracture. And then, there's significant agreement as well that even women younger than 65 with risk factors or diseases that are associated with bone loss should also be screened. The consensus is less as far as men are concerned. However, most of the endocrine societies, they still recommend that men over age 70 should be screened for osteoporosis. And of course, all men and women with a fragility fracture, which is a fracture that occurs from low impact, like fall from a standing height, for example, or a spontaneous compression fracture in the spine.

As far as who is at high risk to treat, that's a very wide category. It encompasses numerous conditions and diseases. For example, it could be hormonal disorders such as hypercortisolism, hyperthyroidism, hyperparathyroidism, multiple chronic diseases, chronic kidney disease, lung disease, liver disease, malignancies that are treated with endocrine therapy, such as breast cancer and prostate cancer, for example. Other medications, use of glucocorticoids; diabetes nowadays, both type 1 and type 2, is considered a major risk factor for poor bone quality. So, there are numerous conditions at high risk for bone loss and osteoporosis.

Specifically, as far as cancer patients are concerned, definitely patients that are receiving chemotherapy, even radiotherapy, which can be associated with high risk of fracture locally at bones that are in the field of radiation, for example. Patients that receive hormonal treatments, as I mentioned, for breast and prostate cancer, these are some of the categories that absolutely have to be screened at the start of treatment, and then possibly treated preventively for bone loss or having active surveillance with frequent testing to decide at which time point to intervene to prevent further bone loss and fragility fractures.

Dr. John Leonard: What tests do you generally recommend that patients do who are at risk?

Dr. Panagiota Andreopoulou: The test that we usually use as a gold standard is what we call the dual-energy x-ray absorptiometry. The DEXA, the very well-known bone density test. It's very old. We've used it since the late '80s. It's based on the fact that there is a very clearly demonstrated relationship between the bone mineral density measurement and fracture risk. And it's a very simple test to do and very cost-effective. It's a two-dimensional measure of bone density. It can be done in the office. It measures the bone density at the lumbar spine, which is our lower back, our hip and our wrist. The radiation is very, very low. It's lower than an airplane flight. And it's very easy to do.

Now, what is it based on? Well, basically, it measures the number of standard deviations by which a patient's bone mass falls above or below the mean peak bone mass for a healthy 30-year-old female. Truly, we're trying to assess how much bone loss has occurred compared to normal bone density, which is that of the healthy younger individuals, and take into account, what is the age of that person, concurrent risk factors, and then make a decision if those measurements are clinically significant as far as risk of fracture and treatment.

We do know that every one of these standard deviations, the T scores, that are reported is associated with relative risk of fracture increased by about double fold. And it can also include the test vertebral fracture assessment in the software that can detect compression fractures that could potentially be silent, such as are 30% of compression fractures in the spine, meaning not associated with pain, but really ominous as far as future fractures. Vertebral fractures are associated with five-fold increase in risk of more fractures and a double increase in risk of non-vertebral fractures. So, this is the gold standard we use.

Of course, nowadays technology -- which is based a lot on specific techniques used in research -- in the bone field is evolving. We now can use a CT bone mineral density quantity assessment, which is for assessment of volumetric bone mineral density, which is more reliable as far as measuring bone mass in patients with degenerative spine diseases that could definitely affect the measurement by the traditional bone density test. We use special software in the bone density test, the trabecular bone score assessment, that can try to recreate the microstructure of the bone, and that is a quality measurement that is independently associated with fracture risk regardless of bone mineral density. It's a very, very helpful measurement as well. And in the research bone field, of course, there's really amazing techniques used to assess bone strength. Unfortunately they're not yet used in clinical practice, but this is probably the future of a fracture risk assessment.

A lot of the fracture risk assessment relies on getting a thorough history. Looking at the patient, getting a very good interview, asking about their personal fracture history, family history, which is a very strong predictor of fracture risk. Parental hip fracture history is stronger than even the age of the person, for example. Personal medical history, what medications they're taking, concurrent or past illnesses, all of these are very important in trying to establish if this person potentially has poor bone quality, as well as low bone density, which is based on the actual measurements.

Dr. John Leonard: I have to say that this is a really important issue and one that has opened my eyes a bit. Some people may know I treat patients with lymphoma and many of our patients get a regimen of chemotherapy that includes a drug called prednisone, which is a steroid hormone. And as you know well, Dr. Andreopoulou, that can cause bone issues. You know that better than I, of course, being that it's a hormone. But there have been relatively recent studies screening patients that have been treated and often cured of lymphoma with a really high fraction of people having significant bone loss. And it's something that the awareness around that risk and what to do about it is a really important one. So, thanks for highlighting the screening parts of things. And as you note, the history of the nature of treatment that a patient has received is a key part of that.

I know a lot of research is going on, a lot of new drugs, and new approaches to try to minimize bone loss or prevent bone loss or treat bone loss once it's happened. Maybe you can give us a bit of an overview. Because I think that's so important that not only can we identify a problem, but we can also address it or at least prevent it from getting worse.

And I'm going to also ask you about taking vitamin D. People are very into vitamin D, and I know as an endocrinologist that's a big issue, and your take on the importance of that and where that fits into prevention and treatment.

Dr Panagiota Andreopoulou: The very important part of addressing bone issues and maintaining skeletal health is really things that patients can do on their own. And that includes general population and cancer patients. For example, exercise, physical activity, it can attenuate bone loss. It can increase and preserve muscle strength and power, reduce the risk of falls -- and fragility fractures often happen after a fall. And all of these interventions can reduce risk of fracture. Exercise has to be tailored to the desired outcome. So, there should be some variety, and it should include some challenge for the individual.

Weight-bearing exercises are highly important, such as walking, jogging, stair climbing, jumping rope, whatever they can do, of course, keeping in mind that we should also reduce the risk of falling from some of these intense exercises. Those make the bones and muscles work against gravity and stimulate making new bone. Strength training exercises, weightlifting, squats, step-ups, they can increase muscle and bone strength and help us improve posture and balance. And then, flexibility exercises: yoga, stretching, tai chi, they have been shown to really improve range of motion and prevent injury, as well, and increase flexibility. So, exercise can reduce falls by 20-40%. Very, very important.

Another intervention an individual can do on their own is making sure that they have proper nutrition, as well as supplements if necessary. Calcium, for example, is the principal bone mineral that gives the hardness to the bone and maintains the structure. And the bone, of course, as we said, is a very large nutrient reserve for calcium. We have to keep in mind when we do not take enough calcium in our diet or supplements, then we can't meet the demands of growth and the demands of calcium that our body needs that stimulates bone loss, bone resorption. Bone mass drops, and fractures can occur this way, because our body will use our bones in times of need, and we'll take the calcium reserves from our bones in order to maintain a normal calcium level and sustain pretty much all these critical functions for life. So, unbalanced withdrawals deplete those reserves and reduce the bone strength. Therefore, it's very important to make sure we take enough calcium.

And vitamin D, vitamin D is a hormone. Vitamin is a misnomer. It is a hormone that is acquired from diet and from skin synthesis upon exposure to the ultraviolet B rays, to sunlight. And basically, vitamin D helps absorb calcium. This is one of its major roles. Serum levels do decline with aging, because skin synthesis declines with aging, as well as absorption decreases with aging. So, it's very important when we take calcium that we also take vitamin D. They work together.

And as far as other elements of our nutrition, we encourage calcium-rich foods. Dairy is one of those foods. Consumption of fruit and vegetables is encouraged. And we really discourage consumption of too many cereal grains, meat, because they can negatively affect the acid-base balance in the bone.

Dietary salt also is something that we try to decrease, not as much for improving blood pressure as everybody knows, but because also dietary salt promotes urine calcium excretion and calcium loss. So, these are some of the measures that we can take to slow down the rate of bone loss.

In the setting of osteoporosis, we have to intervene in order to reduce risk of fractures. All of these measures, proper nutrition, calcium, and vitamin D supplements, they're very important in slowing down the rate of bone loss especially exercise, promoting bone formation, increase in bone density with these measures and the fracture risk reduction is small. Therefore, in individuals at high risk, we have to initiate some type of treatment.

The most commonly used treatments are really antiresorptives, medications that slow down bone loss. The very well-known and oldest treatment is bisphosphonates, compounds that have a high affinity for the calcium crystals. They concentrate in the skeleton and they decrease bone resorption. They really are picked up by the osteoclast and they inactivate them. They've been around for over a hundred years, but we've been using them actively for osteoporosis treatments since the 1970s. They're oral and intravenous agents that have been shown to reduce risk of fractures at the spine, for example, by up to 65%. They're highly effective. Interestingly, they're also associated with survival benefits. So, patients who are being treated with these medications, they actually live longer, partly because they have a decreased risk of hip fractures that can be deadly, as well as possibly other benefits that lead to longevity. A hot area of research right now is the possibly beneficial effect of bisphosphonates in the cardiovascular system, which is really exciting.

Another potent anti-resorptive is denosumab, which really decreases the maturation and proliferation, multiplying really, of these bone breaking cells, the osteoclasts, while they're still in the bone marrow. Therefore, it markedly decreases bone loss, highly effective in reducing risk of all types of fractures as well. And we do have other medications that stimulate making your bone. These are anabolic treatments, mostly the parathyroid hormone analogs of teriparatide and abaloparatide, as well as an anti-sclerostin inhibitor, which is called romosozumab, which is very, very effective. These are newer drugs and there's not much research, especially in the cancer field. But it seems that they may have some role in offsetting bone loss, for example, from radiation, patients that receive radiation. So, they seem to help attenuate these effects of certain chemotherapies and radiation on the bone. There's a lot of research in the early stages on the effect of these anabolic agents in malignancies that we haven't been traditionally using clinically, but hopefully they will have more of a role in the future.

Dr John Leonard: Well, this has been a wonderful overview and, it's been really great to have your insights. Any last takeaways that you think patients and their families should know about this issue if they're dealing with cancer?

Dr Panagiota Andreopoulou: The takeaway message as far as the view of an endocrinologist is that cancer itself and its treatment can severely impact skeletal health and increase morbidity and mortality, in patients with cancer. However, we can offset a lot of these effects by screening properly and early for bone loss, adoptive preventive lifestyle modifications, being more proactive with what we can do for our health, and our bone health, and welcoming treatment strategies, including pharmacological treatment that can counteract this negative impact of cancer and its treatment to a significant degree.

Dr John Leonard: Well, thank you so much. This has been a great discussion. And I want to invite our audience to download, subscribe, rate, and review CancerCast on Apple Podcasts, Google Podcasts, Spotify, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover a bit more in depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. Thanks for tuning in.

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