Bone Health and Other Endocrine Issues after Transplant or CAR T-cell Therapy

Transcript of Presentation:

(00:02): Susan Stewart: Introduction. Hello. Welcome. My name is Sue Stewart. And I will be your moderator for this workshop, Bone Health and Other Endocrine Issues after Transplant or CAR T-cell Therapy.

(00:14): It's my pleasure to introduce today's speaker, Dr. Angeliki Stamatouli. Dr. Stamatouli is an Assistant Professor of Internal Medicine in the Division of Endocrinology at Virginia Commonwealth University, Massey Cancer Center and Bone Marrow Transplant Clinic. Her work involves managing endocrine cancers and endocrine complications related to cancer treatments, including bone marrow and stem cell transplantation, as well as CAR T-cell therapy. Please join me in welcoming Dr. Stamatouli.

(00:50): Dr. Angeliki Stamatouli: Overview of Talk. Hello, everyone. Thank you very much for the introduction and the invitation. It is an honor to be part of this meeting. So I subspecialize in onco-endocrinology. And as it was already said, I have a clinic embedded at the VCU, Bone Marrow Transplant Clinic, where I have cared for bone marrow transplant patients for the past six years.

(01:13): Today, though, we will discuss about bone health after stem cell transplant. Due to recent advances, the stem cell transplant is now safer, which means that more people are having these transplants and living longer after the treatment.

(01:28): One of the long-term health concerns for people who have had a stem cell transplant is the risk of bone weakness, which can eventually lead to fractures. So because of this risk, it is important for all patients to have their bone health monitored more closely over time. So my goal today is to provide some helpful information about what patients should do after transplant to decrease the risk of fractures.

(01:57): Specifically, I will try to define low bone mass or osteoporosis. I will discuss bone health after transplant and the risk factors for bone loss after treatment. I'll also discuss how to monitor bone health after transplant and what diet and lifestyle interventions patients should follow to improve bone mass. And lastly, I'll briefly discuss treatment for osteoporosis.

(02:23): Osteoporosis is a condition where bones become porous, making them more likely to  fracture. So, what is osteoporosis? Osteoporosis is derived from the Greek words osteo, which means bone, and poros, which means pore or passage. So the combination of these two words indicates a condition where bones become full of holes, making them more likely to fracture.

(02:40): Osteoporosis is quite common in the general population, and especially as people get older. So in fact, in the United States, about half of women and a quarter of men over the age of 50 will experience a fracture due to osteoporosis. Around 300,000 people break their hip each year.

(02:59): Unfortunately, hip fractures can lead to serious consequences. One out of every four people who suffer a hip fracture pass away within a year of the injury. Another one in four might need to move into a nursing home after their hospital stay and may not be able to return home. Additionally, half of those who experience a hip fracture might not be able to regain their previous level of independence and mobility.

(03:27): Looking to the future, the number of fractures each year is expected to increase significantly from 1.9 million in 2018 to 3.2 million by 2040. This increase will also lead to a rise in healthcare costs from $57 billion to over $95 billion annually. So we understand from the statistics the importance of taking steps to prevent bone loss.

(03:53): So this is a question that I frequently hear from my patients. What are the symptoms of osteoporosis? Osteoporosis is called a silent disease because it doesn't usually cause symptoms. The symptoms are typically related to complications from bone loss.

(04:08): Patients could present with fractures after minimal trauma, so they might break a bone from a small accident or fall that wouldn't normally cause such an injury if the bones were healthy. A patient might notice that they're getting shorter over time. This can happen because the bones of the spine may become compressed or fractured.

(04:30): Patients could experience sudden back pain or tenderness. Again, it could be due to a spinal fracture. There could also be some change in the way that they stand or walk. They could also lose their mobility, specifically when fractures lead to difficulty moving around and performing their daily activities.

(04:54): After stem cell transplants, loss of bone density can be much greater than in the general population. So in general, this is a normal process as we age. We usually lose bone density. However, after undergoing cancer treatments, including stem cell transplants, the rate at which bone loss occurs is much faster and a little bit more pronounced. This means that within just one year after transplant, the amount of bone density loss can be considerably more than what would happen because of natural aging.

(05:23): We can see in this table, the percentage of mineral density loss at one year. We can see that the bone marrow transplant could cause 3.3% loss in one year, whereas in normal aging, we can see a much smaller percentage.

(05:40): There is a reported incidence of bone loss of about 50 to 75% after an allogeneic stem cell transplant and 20 to 65% after an autologous stem cell transplant. The majority of bone loss occurs within three to six months after transplantation, so it could happen quite soon after the treatment.

(06:06): There are several risk factors for bone loss in the general population. So what are the risk factors for bone loss after stem cell transplantation? Some baseline risks are similar to the general population. So genetic or other conditions could contribute to bone loss. Age, race and sex could play an important role.

(06:20): Bone loss is more common in women than in men. Menopause, a family or personal history of fragility fracture, low body weight, a history of osteoporosis due to endocrine disorders that pre- or coexist with cancer could increase the risk of bone loss. For example, patients could have elevated cortisol levels or elevated parathyroid hormone levels before their cancer diagnosis. They could have a history of rheumatoid arthritis and other autoimmune conditions, a history of chronic kidney or chronic liver disease, or of or a history of sickle cell disease or multiple myeloma.

(07:07): Patients' lifestyle could also be playing a role. So if a patient is actively smoking, if a patient consumes excessive amounts of alcohol, more than three drinks a day, or if a patient follows a sedentary lifestyle, these factors could all contribute to bone loss.

(07:23): On the other hand, cancer by itself or cancer treatments could also contribute to bone loss. Chemotherapy can be very toxic to osteoblasts and bone marrow cells, which are the primary cells responsible for bone formation. It can potentially damage the ovaries or the testicular tissue, leading to reduced production of hormones like estrogen and testosterone, which can result in the onset of menopause for women earlier than usual, like earlier than the age of 40, and low testosterone in men. Radiation can also lead to bone loss.

(08:03): The use of glucocorticoids, such as prednisone or dexamethasone, and specifically when they're used for more than three to six month, or medications that have been used for the management of GVHD, such as calcineurin inhibitors, can increase the risk of osteoporosis. One example of these medications is tacrolimus, which some of you may already be taking. It can also lead to bone loss.

(08:26): In some situations, patients who are malnourished either due to nausea because of chemotherapy, for example, or they experienced cancer cachexia could also have an increased risk for bone loss. Cancer cachexia is a condition where patients, because of cancer, lose a lot of body weight. And that eventually results in either loss of muscle mass or fat.

(08:57): Some patients may also experience fatigue because of their underlying history of cancer, and that by itself could reduce physical activity and eventually muscle and bone.

(09:13): Patients who develop graft-versus-host disease are also at increased risk of bone loss. Patients who have had a lot of transfusions resulting in iron overload could experience some detrimental effects on their bone.

(09:27): A bone density scan is an imaging test that monitors patients for osteoporosis. So how should we monitor bone health after a stem cell transplant? This could be monitored very well with one test that is called bone density scan.

(09:39): So what is a bone density scan? It is an imaging test that measures bone mineral density in the spine, hip, and occasionally the wrist. It is a non-invasive procedure. And it helps us understand the risk of fractures and monitors changes in bone density over time.

(10:00): So what to expect during a bone density scan? During the scan, usually the patient lies on a padded table while a machine passes over their body. The scan is painless. And it typically takes about 10 to 20 minutes, so it's a short time interval. The amount of radiation used in a bone density scan is very low, much less than a standard chest x-ray, making it a safe procedure.

(10:24): Patients can eat normally on the day of the test, but they may need to avoid taking calcium supplements for 24 hours before the scan. Patients should wear comfortable clothing without metal zippers or buttons.

(10:39): Bone density scans provide several measures of bone health. So after the bone density scan, the patients receive a report that includes some key numbers and terms. Some of you may have already had the scan, so let's review how to interpret these results.

(10:54): So here's the first score that we are evaluating. It's usually for women who are menopausal or for men who are over the age of 50. And this is called T-score.

(11:10): The T-score compares the bone density to the average peak bone density of a healthy young white female. A T-score of minus one or above is considered normal. A T-score between minus one and minus 2.5 indicates low bone density or osteopenia. And a T-score of minus 2.5 or lower suggests osteoporosis, meaning that the bones are more fragile and at higher risk for fractures.

(11:44): For patients younger than 50 years old, we use a different score. It's called Z-score, which compares the actual bone density to what is expected for someone of the same age, gender, and size. A Z-score below minus two may suggest that something other than aging is causing bone loss, and further investigation might be needed.

(12:07): In addition to the bone density scan, we use the FRAX tool. This is a risk assessment tool that helps us estimate the risk of experiencing an osteoporotic fracture. This tool hasn't been explicitly validated for cancer patients, but we use our clinical judgment when interpreting the results.

(12:28): The FRAX is designed to be country-specific, meaning that it incorporates the specific epidemiology of osteoporosis and the fracture risk factors that are unique to each patient's country. This tool takes into consideration several risk factors, including the patient's age, sex, weight, height, smoking habits, history of rheumatoid arthritis or other immune conditions, whether there is a history of fractures in the patient's parents, and the use of glucocorticoids, among others. And it calculates the 10-year probability of a major osteoporotic fracture. And when I'm saying major osteoporotic fracture, I mean a non-traumatic fracture that occurs in one of the key sites that are more commonly affected by osteoporosis, either the hip, the spine, the wrist, or the shoulder.

(13:24): It also calculates the 10-year probability of a hip fracture. So, it definitely helps us specifically identify for patients who have osteopenia or are in an intermediate situation where they don't have osteoporosis, but we want to understand their risk in order to determine whether treatment should be used.

(13:51): Additional tests may also be done to detect osteoporosis. Except for the bone density scan, we perform additional testing during visits. We do some helpful blood tests, and may order an X-ray of the spine to evaluate for possible fractures, especially if the patient's complaining of very severe back pain. We also try to schedule regular visits with the provider and the patient to discuss potential complications, as well as the risks and benefits of treatment.

(14:22): So which interventions are effective in reducing the risk of osteoporotic fractures? The first step is to make sure that we optimize calcium intake. So our goal is for each patient to take about 1,000 to 1,200 milligrams of calcium from diet, if it is possible, and supplements when we have to. So I usually provide this leaflet. This is from the International Osteoporosis Foundation. It's a two-page leaflet that shows the calcium content of some common foods. This information is available on their website at https://www.osteoporosis.foundation and can be downloaded for free.

(15:06): If patients cannot get enough calcium through their diet, then supplementation is advised. The two main forms of calcium in supplements are carbonate and citrate. And it does play a significant role, which one we will choose for each patient.

(15:27): So calcium carbonate is more commonly available and is absorbed more efficiently when taken with food. The calcium citrate is absorbed equally well when taken with or without food.

(15:40): We are cautious when we are suggesting that a patient take calcium supplements because, in general, we have to limit the calcium intake from supplements to between 500 to 600 milligrams per day. The reason is that high intake of supplements could increase the risk for kidney stones.

(16:01): Now, there are some situations where patients could have a history of malabsorption, or they might not be taking increased calcium through their diet. In this situation, we might adjust our daily recommendation for a supplement to meet the cutoff of 1,000 to 1,200 milligrams. However, we generally try to avoid this approach to minimize the risk of kidney stones. For patients who have malabsorption or are on proton pump inhibitors, calcium citrate is suggested for better absorption.

(16:39): The second step is to optimize vitamin D supplementation. And why is that? Vitamin D is crucial for bone health because it helps with calcium absorption from food in the intestine. It helps with bone mineralization and also reduces the risk of falling.

(16:57): We usually recommend a daily dose between 1,000 to 2,000 units per day for patients who have adequate supplementation, or to maintain levels of vitamin D between 20 to 50 nanograms per ml. I'm using this range because there are differing opinions about what constitutes an optimal level in the blood across various societies. My personal recommendation to my patients is to keep a level between 30 to 50 nanograms per ml. I also provide my patients this table from the International Osteoporosis Foundation at osteoporosis.foundation/patients/prevention/vitamin-d, which shows the vitamin D content proportion of specific foods.

(17:44): The third step is to introduce or optimize exercise in our patients. And again, exercise is very important because it improves strength, posture, and balance, and also decreases the risk of falls. We know that some patients, after the bone marrow transplant, might be very sick, so they might not be able to participate in physical activity. I frequently recommend a physical therapy evaluation after transplant to individualize the exercise plan for each patient, including the type of exercise they should follow and its intensity.

(18:24): For patients who have low bone density, we suggest weight-bearing exercise, such as jumping, skipping, bench stepping, and resistance exercise, like weight training, push-ups, and resistance band exercise. When it comes down to weight training, we usually suggest low weight training. We suggest avoiding bending forward and lifting weights over 10 pounds overhead. Of course, a patient who is in very good physical condition and has been training for a long period of time might be able to lift more weight. However, in general, and specifically for patients with severe osteoporosis, we try to limit the amount of weight each patient should lift.

(19:17): In addition to the above, we suggest that patients follow a balanced diet - low carbohydrate, high protein - stop smoking, limit alcohol intake to less than two drinks per day, lower the dose of prednisone or other steroids, and, if possible, maintain good vision.

(19:37): Lastly, I provide some information to patients on how to fall-proof their home. Again, this comes from the International Osteoporosis Foundation website at osteoporosis.foundation/patients/prevention/falls-prevention. And what I suggest is that patients try to remove objects that they can trip over, keep all areas of the house well lit, repair loose carpets, install handrails by the bathtub or shower, and keep items at an easy-to-reach level.

(20:06): There are guidelines for when to start pharmacologic treatments for bone loss. They differ for patients who have not received glucocorticoids for GVHD and those who have received glucocorticoids. Now, when should we start pharmacologic treatment?  We'll discuss some of the indications based on the latest expert panel opinion for bone health management after stem cell transplant from the American Society for Transplantation and Cellular Therapy. And in general, the recommendations divide the patients into two major groups, those who have not received glucocorticoids for GVHD and those who have received glucocorticoids.

(20:32): Patients’ age can also influence the timing of pharmacologic treatment for osteoporosis. So for patients who have not received glucocorticoids for GVHD, we usually start pharmacological treatment if the patients have a history of fragility fractures after the age of 50 years. And again, as a reminder, fragility fractures or osteoporotic fractures happen when bones are weakened by osteoporosis and can break easily even from minor impacts or falls from own height.

(21:01): We usually suggest this for postmenopausal women and for men older than 50 years who have a femoral neck, total hip or lumbar spine T-score of -2.5. For patients who are older than 40 years of age, have a T-score between minus 1 to minus 2.5, and have higher FRAX score -specifically they have a 10-year probability for major osteoporotic fracture of more than 20% or a 10-year risk of hip fracture of more than 3% - we also suggest treatment.

(21:43): Now, for patients who received glucocorticoids for GVHD and are older than 40 years old, we will suggest treatment if they have a history of fragility fractures. We will also suggest treatment for men who are older than 50 years of age and for postmenopausal women who have a femoral neck, total hip, or lumbar spine T-score of minus 2.5, or have a major osteoporotic fracture risk of more than 10%, and a 10-year probability of hip fracture greater than 1%. As a reminder, it was 3% in patients who were not on steroids.

(22:32): For patients who received glucocorticoids and are younger than 40 years of age, we suggest treatment if they have fragility fractures or if they have hip or lumbar spine Z-score of minus three or lower, or if they have rapid bone loss greater than 10% at the hip or in their lumbar spine over one year. Obviously, these patients are usually receiving high doses of steroids, - more than 7.5 milligrams every day for more than six months.

(23:23): There are three major categories of osteoporosis medications and they work in different ways. So what are the osteoporosis medications? So in general, the primary goal of osteoporosis medication is to strengthen the bones and reduce fracture risk. We have three different categories of these medications. The first category is called antiresorptive. And what they are doing is they're slowing down the bone resorbing cells which break down the old bone, allowing the bone building cells to work more effectively. So they're strengthening the bones and they reduce the fracture risk.

(23:58): The second category is called anabolic medications. What they're doing is simulating bone formation, which leads to stronger bones and a decrease in fracture risk.

(24:10): The third category is the hormonal medications. They may improve bone density, specifically when estrogen and testosterone levels are low in women and men, respectively.

(24:21): Here are some examples of some of the medications in each class.

(24:26): For antiresorptives, bisphosphonates are used most frequently. They can be administered orally, for example, Alendronate or Risedronate, or they can be given through the vein, with Zoledronic acid being the most common. Denosumab is also in this category, and is given through an injection every six months.

(24:48): When it comes to anabolic medications, we have here, again, two different medications: one of the PTH or parathyroid hormone receptor agonists, such as Teriparatide or Abaloparatide, and the other medication is called Romosozumab.

(25:09): For hormonal treatments, Raloxifene is the one used in patients who have breast cancer, and also estrogen for females and testosterone in males.

(25:23): From the three categories of medications, the use of antiresorptive medications is suggested as the first choice. And in some situations, the hormonal treatment. The anabolic medications are not routinely suggested due to a lack of efficacy and safety data. But if we feel that, in some situations, anabolic should be used, we should evaluate the risks and benefits for the patient before starting them.

(25:51): So let's go with the first class, the antiresorptive medications. Again, as we discussed, this is the first-line therapy for prevention and treatment of osteoporosis in stem cell transplant patients. They're important for some patients with multiple myeloma who they might be using them before and after stem cell transplant.

(26:12): When we use antiresorptive medications, we want to ensure that calcium and vitamin D levels are at goal before and during treatment to prevent low calcium levels a few days after the administration of the medication.

(26:25): Of course, all medications have some toxicities that we should be aware of. The oral bisphosphonates can cause inflammation of the esophagus. And so we usually provide some specific instructions on how patients should properly take these medications. We suggest taking them on an empty stomach, take them in the morning, try to not lie back in bed, and take them with plenty of water.

(26:53): The intravenous Zoledronic acid can cause flu-like reaction after administration. So we advise patients to take acetaminophen before the infusion and for 48 hours afterward, and try to keep themselves well-hydrated.

(27:10): Both the oral bisphosphonates and the intravenous Zoledronic acids are not safe in patients with advanced kidney disease. In this situation, we use another medication called Denosumab. The Denosumab should be given every six months. If we delay or we have to discontinue this medication, that could increase the risk of fractures or worsen bone density, so we have to be very cautious about how we stop this medication.

(27:41): Another toxicity, which is kind of late onset and quite rare, is called atypical femoral fractures. This is very common in oncology patients. And these fractures usually occur in the thigh bone, in the femur, just below the hip joint, or in the middle of the thigh, as we can see in the x-ray on the right side. They're considered atypical because they happen in an unusual part of the bone and often with little or no trauma.

(28:15): So why do patients develop this complication? Because usually, the antiresorptive treatments in general, and specifically the bisphosphonates, work by slowing down the natural process of bone breakdown, which can lead to changes in how bones repair themselves over time. So this bone remodeling process may increase the risk of atypical fractures in some cases. So in this situation, we limit the bisphosphonate use to three to five years, unless there is a different condition that requires extending their use or we have to use them more frequently.

(28:54): Another complication is called osteonecrosis of the jaw. So osteonecrosis of the jaw is, again, a very late and rare complication. And it's a condition where the jawbone starts to weaken and die due to a lack of blood supply. This can lead to exposed bone in the mouth that does not heal properly.

(29:17): Antiresorptive treatment can affect the jaw bone's ability to repair itself, particularly after dental procedures or trauma, by altering the normal bone remodeling process. Different risks contribute to this. Invasive dental procedures such as tooth extractions or implants can increase the risk, as well as the duration of use of older antiresorptive treatment. Poor oral hygiene even before the initiation of the treatments, smoking, or pre-existing dental conditions could also contribute to the risk.

(30:00): It is more commonly found in patients who are taking Denosumab. And what is suggested is a comprehensive dental exam and elimination of oral infections before starting antiresorptive treatment in order to prevent this complication from happening.

(30:15): Another complication after stem cell transplant is avascular necrosis. Avascular necrosis is also known as osteonecrosis. It's a condition where bone tissue dies due to a lack of blood supply. Symptoms of avascular necrosis include joint pain when moving or even when resting, and limited range of motion.

(31:20): The management of avascular necrosis is usually handled by other specialties, for example, orthopedics. So we won't discuss about treatment options here, but definitely this is something that most of our patients need to be aware.

(31:34): So, in summary, bone loss is very common after stem cell transplant. Multiple risk factors are associated with bone loss, including genetics, lifestyle, and the cancer by itself.

(31:55): Regular monitoring for bone loss is essential before and after stem cell transplant.

(32:01):  Dietary modification and lifestyle changes are very crucial to prevent bone loss and improve bone health.

(32:08): Bisphosphonates are the treatment of choice for managing osteoporosis.

(32:12): So thank you very much for your time and attention. I would like to open the floor for any questions you may have.

Questions and Answers:

(32:23): Susan Stewart: Thank you, Dr. Stamatouli, for that excellent presentation. Very comprehensive. We do have a lot of questions, and we're going to try to get to as many of them as possible. The first question is, does CAR T-cell therapy affect bone health? This person has noticed that her posture is affected after CAR T. She's leaning forward more often, and wonders if this is due to some bone issue.

(32:50): Dr. Angeliki Stamatouli: Well, this is a great question. Definitely, that should be explored either by the oncologist, or an endocrinologist, by doing a bone density scan to assess their bone loss. CAR T therapy can definitely affect the bone, although not the same extent as a stem cell transplant, but could definitely have some effects. Also, would suggest having an x-ray of the spine to make sure that this change in posture is not due to an underlying fracture that has already happened.  It might not be related to the CAR T treatment. It could be due to the underlying disease.

(33:33): Susan Stewart: This person wants to know once diagnosed with osteopenia, can that be reversed?

(33:43): Dr. Angeliki Stamatouli:  Definitely. That's why we need to detect low bone mass early, as this allows for a full evaluation. We can definitely make some changes in lifestyle. As we discussed before, try to optimize calcium and vitamin D intake. Try also to introduce some exercise. And in some situations, if there is a higher risk for fracture, we would suggest treatment. We use some of the treatments that we already discussed. The frequency may vary, but we do recommend it in certain situations to prevent further bone loss.

(34:25): Susan Stewart: The next question is can you clarify what the difference is between osteopenia and osteoporosis?

(34:34): Dr. Angeliki Stamatouli: So this is based on the bone density scan, as we said before. Osteoporosis, obviously, is a condition where the bone becomes a little bit more porous. It's at higher risk for fractures. That's why we suggest treatment.

(34:53): Osteopenia is a 'gray zone," in which the bone density is not normal and it's not at the level of osteoporosis, but in this zone where we're usually assessing other risk factors, where a patient could have low bone density. And based on the risk, we can determine how to manage them further. So it's like an intermediate situation where you do have bone loss, but not to the point that the bone is very porous.

(35:29): Susan Stewart: Great. Understood. The next question is, do you recommend a DEXA scan more frequently than Medicare allows?

(35:39): Dr. Angeliki Stamatouli: That depends on the circumstances. Medicare usually allows a bone density scan every two years. But in patients who had a bone marrow transplant, specifically if they are on treatment or if we know that they are at higher risk for fracture and we want to protect them, we could request the bone density to be ordered more frequently, every year. Once a year is enough, I believe. And again after justifying why we request that, sometimes Medicare will cover it.

(36:29): Susan Stewart: Oh, that's good to know. This gentleman wants to know when do you do your first DEXA scan after an autologous stem cell transplant? And he also wants to know how does Zometa figure into maintaining bone density?

(36:47): Dr. Angeliki Stamatouli:  So first of all, our general practice at VCU, is we order the first bone density scan one year after transplant. But theoretically, six months after the autologous stem cell transplant, we could potentially order a bone density scan to detect potential bone loss.

(37:08): The medication Zometa is the intravenous form of antiresorptive medications that we discussed before. It's called like a Zoledronic acid. These medications slow down the bone resorbing cells that break down the old bone and allow the bone building cells, which are called osteoblasts, to work more effectively. This way, they strengthen the bones and reduce the fracture risk.

(37:45): Susan Stewart: This person is seeking clarification on why you recommend avoiding bending and lifting weights over 10 pounds above their head. Is that a lifelong precaution? A temporary precaution?

(38:01): Dr. Angeliki Stamatouli: So this is a precaution that our patients should take, specifically when they're at very high risk for fractures, because if they're lifting abruptly an increased amount of weight, there is a risk that they could cause further fractures.

(38:22):  This precaution should be taken for a period of time when we are managing low bone mass. When a patient is in a safe range, of course, and as they increase their stamina and strength, this cutoff could change.

(38:42): Susan Stewart: Okay. This person wants to know whether arthritis affects osteoporosis.

(39:00): Dr. Angeliki Stamatouli:  No, not directly. Arthritis is a different situation. Actually, if a person has rheumatoid arthritis, this could be a risk factor because it's an autoimmune condition. But if a patient has osteoarthritis, this is a separate situation. Obviously, it doesn't have direct effects, but indirectly, if a patient has severe osteoarthritis and is not able to be active, that eventually could have some detrimental effects on the bone, but there is no direct relationship.

(39:36): Susan Stewart: This gentleman wants to know when supplementing vitamin D, should you also supplement vitamin K too?

(39:45): Dr. Angeliki Stamatouli:   This is suggested in some situations, but I'm more cautious with vitamin K replacement, specifically for patients who have a history of blood clots, because it could have some effects on the blood clotting process. So I would be very careful. And I would ask my provider whether or not the replacement of vitamin K would be helpful and safe.

(40:15): Susan Stewart:  Okay. This person wants to know specifically which blood tests are used to determine bone health.

(40:23): Dr. Angeliki Stamatouli: So that's a very good question. Thank you. So usually, when we start the evaluation, we always want to check calcium levels for every patient, and the vitamin D levels. The renal function, we'll check liver function tests, and specifically one test that is called alkaline phosphatase. This shows whether or not some patients could have some conditions that could increase the bone turnover. We're assessing the thyroid function and also one hormone that is called parathyroid hormone that plays a crucial role in the bone metabolism. Of course, sometimes we individualize the blood workup and we do some more specialized testing, but this is where we start.

(41:18): Susan Stewart:  The next person wants to know if they're diagnosed with osteopenia and are on continued prednisone, is it expected that the osteopenia will progress to osteoporosis?

(41:34): Dr. Angeliki Stamatouli: Well, this is definitely a risk. So I would suggest discussing this with their provider, based on their bone density results and the amount of steroids that they have been taking, to determine when to initiate treatment to protect their bones. And obviously, I would definitely suggest taking optimal calcium and vitamin D supplements.

(41:59): Susan Stewart:  Next question is, can you recommend which calcium and vitamin D supplements specifically we should use? If not, what should we be looking for in evaluating different brands?

(42:12): Dr. Angeliki Stamatouli: I usually do not discuss brands with my patients, but I usually try to get my patients to understand which calcium supplement would be ideal for them. As we discussed, there are two different forms, like calcium carbonate and calcium citrate. If a patient, for example, takes medications to control reflux - they're called proton pump inhibitors, Omeprazole, Pantoprazole - I usually suggest calcium citrate. Also, this is a form that I suggest in patients who have history of malabsorption because it has been found that this could be helpful. And so definitely I try to understand their background, history in order to determine which supplement will be optimal.

(43:05): When it comes down to vitamin D intake, I usually prefer the daily replacement. It has been shown in studies that it's preferred. And again, the amount of vitamin D depends on the underlying vitamin D level and also what the risk is for falls and the underlying past medical history of the patient.

(43:34): Susan Stewart:  Thank you for that. This person wants to know if you could talk about Butyrate and its impact on osteoporosis.

(44:09): Dr. Angeliki Stamatouli: So actually, Butyrate is a fatty acid. And this has been linked to bone health, and specifically in osteoporosis. But the data that we have are not very strong. Definitely, they do have some effect on the bone, but we don't have very good studies to say whether or not this could be a direct relationship that we could support for our patients.

(44:49): Susan Stewart:  What are your thoughts about using a weighted vest for osteopenia?

(45:00): Dr. Angeliki Stamatouli:  Well, again, this is a very controversial topic, whether or not this vest could be used. Definitely, there are some positive effects that have been found in some animal studies and in some studies in humans. I would say that I would discuss the specific vest the patient has. And I would definitely try to ensure that the impact on the spine will be low, will not have a high impact. But it could have a potential positive role.

(45:45): Susan Stewart:  This woman said she had osteoporosis before she started cancer treatment, which included steroids. She has a stem cell transplant scheduled for this summer. Should she ask for a bone marrow scan before her transplant? Which of her doctors should she go to for my bone concerns; her primary care doctor, oncologist, or a transplant specialist?

(46:11): Dr. Angeliki Stamatouli:  That's a very good question. So this is actually something that we do suggest. For patients who already have some risk factors, having a baseline bone density definitely should be very, very helpful. This way, we can determine how severe the bone loss is and try to be protective.

(46:35):  Sometimes we don't initiate treatment just before the stem cell transplant, to avoid complications before the transplant. But definitely, we could optimize and change the lifestyle in order to prevent as possible further bone loss.

(46:52):  Now, the specialty. Everybody could order a bone density scan, meaning the primary care physician, OB-GYN, or the oncologist. However, if there is already preexisting osteoporosis and you need more advice for management, I would suggest visiting either endocrinologist who could have more experience with cancer patients. In some institutions, rheumatologists are also assessing bone health.

(47:19): Susan Stewart: Thank you. The next question is, can decreased bone mass weaken my teeth as well?

(47:28): Dr. Angeliki Stamatouli:  That's a good question. So not directly. In other words, in patients who have a history of osteoporosis, they could have some effect on the bone, meaning that they might have some bone loss that could extend to the jawbone, and that could eventually result in dental issues. Some patients complain of tooth loss, or they might have some periodontal disease, or they might have impaired healing after dental procedures, but there is no direct relationship.

(48:10): Susan Stewart:  This gentleman wants to know how often should a person with multiple myeloma get Zoledronate infusions after transplant?

(48:24): Dr. Angeliki Stamatouli:  So actually, the Alendronate is a medication that is being given through the mouth. Probably what we mean here is the Zoledronic acid that is given through the vein. And for patients with multiple myeloma, it is called Zometa.

(48:37): This is actually a question that I cannot answer because this depends on the underlying condition, like the multiple myeloma itself. There are different protocols that the oncology team has been using. And the frequency depends on the disease. Some patients have been taking it monthly, some patients every three months, and some patients every six months. I would definitely have a discussion with the oncologist to determine the frequency.

(49:08): Susan Stewart: Next question is, are whole body vibration devices good for osteoporosis or avascular necrosis?

(49:18) Dr. Angeliki Stamatouli: So again, I would be very cautious with these devices because they could definitely be beneficial for individuals who have osteoporosis. Definitely could increase the bone density and reduce the risk of fall.

(49:39): However, it's very crucial to use this device with low intensity vibrations. And I would discuss, again, with my team whether or not you could consider starting these programs. But they're not very clear. The literature is not very clear about the benefit of these devices.

(50:03): Susan Stewart:  All right. This person has another endocrine question. She asks, is secondary adrenal failure common after BMT for AML arising from CMML? She's experiencing currently this problem. Wants to know what your recommended treatment plan for this is in light of severe osteoporosis also being present?

(50:31): Dr. Angeliki Stamatouli:  Yes. That's a very good question, actually. So first of all, secondary adrenal insufficiency is a condition that could happen in patients who have been taking, for a long period of time, higher dosages of steroids than what their body makes. So usually, if a patient takes more than - I will use prednisone as an example - more than 7.5 milligrams for more than three weeks, they could have an increased risk for secondary adrenal insufficiency, and specifically when they take it longer, for more than three to six months. This could be a situation that occurs independently of the underlying condition. It's not happening only in AML. It could happen to all the patients who have been taking high doses of steroids. It's a very serious situation. We definitely need to replace the steroids because the patients could be at risk for adrenal crisis. So we definitely recommend taking the lowest possible dose of steroids in order to prevent them from having other complications.

(51:43): In this situation, because the steroids are very crucial for life, I would definitely suggest continuing to take them. And down the road, I would re-evaluate whether or not their adrenal glands are starting to work again when the patient is taking the minimum dose of steroids. And I would try, if possible, to eventually wean myself off the steroids. But that should be done under the guidance of the treatment team that is managing the patient, after re-evaluating the option but in general, if a patient takes a dose of steroids that is close to what their body makes, it doesn't have such a detrimental effect on the bone as with high doses of steroids.

(52:42): Susan Stewart: All right. We've got a couple questions from people who want to know what the role of Prolia is in treating osteoporosis.

(52:52): Dr. Angeliki Stamatouli: So Prolia is, again, a very good medication because it could help the bone to increase bone mass in the spine and the hip. This is a medication that we are using specifically for patients who are having renal dysfunction. We discuss the risks and benefits with patients who elect to start with this medication.

(53:20): I think what is very important is to understand that this medication, even though it is effective, needs to be handled with caution. The reason that I'm saying that is because if you abruptly stop this medication, you could reverse what you have achieved so far with a treatment, and actually you could have an increased risk of fractures. So it is definitely a good option. Definitely something that we should consider for every patient treated with osteoporosis. But I would definitely have a discussion about the duration, how long you need to take it, and also how you will be weaned off the medication.

(53:57): Susan Stewart: All right. Understood. The next question is, does bone loss following stem cell transplant stabilize after the first year?

(54:09): Dr. Angeliki Stamatouli:  Well, it depends because usually it's not just the stem cell transplant. There could be other risk factors that could also be contributing to bone loss after the one-year cutoff point.

(54:20): As you know, some patients could experience GVHD. This is a condition where patients require high doses of steroids. So sometimes these factors could also contribute to bone loss.

(54:36): In this situation, I usually suggest monitoring the bone density until we don't have other risk factors that further decrease the bone mass. However, in patients who do not have other conditions, in some situations, yes, bone density could be a little bit more stable just because patients are recovering, are able to participate in their nutrition, are able to participate in exercise, and of course, they're feeling much better.

(55:15): Susan Stewart:  This will need to be our final question. Does Tacrolimus contribute to bone loss?

(55:21): Dr. Angeliki Stamatouli: Yes, it could have some effect on bone cells as well.

(55:24): Susan Stewart: Closing. Okay. With that, we're going to have to wrap it up. I want to thank Dr. Stamatouli for an excellent presentation. And for the audience, thank you for your questions. This was an excellent question and answer session. Please contact us if we can be of any help.