Bone Health after Transplant

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Bone Health after Transplant

Monday, April 19, 2021

Presenter: Joy Wu MD, PhD, Associate Professor and Vice Chair, Basic Research Division of Endocrinology, Stanford University School of Medicine

Presentation is 35 minutes long with 21 minutes of Q & A.

Summary: Bone marrow and stem cell transplant recipients have an increased risk of osteoporosis and bone fractures.  Life-style changes can improve bone health, but in more serious cases, medications may be required. This presentation reviews risk factors and effective remedies for bone problems in transplant patients.

Highlights:

• 5,500 bone fractures occur each year in the U.S. due to osteoporosis (bone thinning).
• People who had a transplant using stem cells from a donor (an allogeneic transplant) may lose 6-9% or more of bone mass of the spine, and 8-17% at the hip within the first year after transplant
• Treating osteoporosis in the general population involves stopping bone breakdown or promoting bone formation. For transplant patients, stopping bone breakdown is important, but bone building medications are rarely used because there is little data on their safety for this population.

Key Points:

(04:04) Fractures in the general population commonly occur in the spine, vertebrae, wrist and hip.

(05:24) Allogeneic transplant patients can lose bone mass in the spine and hip very quickly. Causes include the underlying disease, lowered sex steroid hormones, immune suppression, radiation, chemotherapy, and medications. 

(08:17) Menopausal women can lose 2% of bone mass per year; transplant recipients can lose 3-4% per year.

(11:13) Overall risk factors for bone loss include older age, lower bone density, immunosuppressive medications, family history of osteoporosis, being thin, smoking, excessive alcohol intake, and inflammatory diseases.

(18:26) Fracture risk is highly dependent on bone density and age along with other risk factors.

(21:14) Getting adequate calcium from food or supplements as well as vitamin D is important for bone health.

(23:24) Exercise, balance and flexibility are important to maintaining good bone health and preventing fractures.

(27:44) Osteoporosis in transplant patients is often treated with bisphosphonates to prevent bone breakdown.

(30:56) The benefits of bisphosphonates to prevent fractures outweigh the risks.

(33:32) Properly used, medications along with lifestyle changes are safe and effective ways for transplant recipients to prevent bone breakdown.

Transcript of presentation:

Note: In this presentation the speaker(s) sometimes uses the terms “BMT” or” bone marrow transplant”. For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

(00:00) [Lynne]       Introduction. Hello, my name is Lynne Spina, and I will be your moderator today.

(00:05) Welcome to the workshop Bone Health After Transplant. It is my pleasure to introduce today's speaker, Dr. Joy Wu. Dr. Wu is an endocrinologist at Stanford University School of Medicine. Her clinical practice focuses on optimizing bone health in cancer and transplant survivors. As Vice Chair of Basic Research in the Department of Medicine at Stanford, she also directs research on skeletal development and stem cell therapies for bone. Please join me in welcoming Dr. Wu.

(00:49): [Joy Wu]     Overview of talk.  Thank you, Lynne, for that kind introduction. It's really a privilege to be here today to talk with you about optimizing bone health after transplant.

(01:01) Let me start with some of the take-home messages that I hope you'll remember. The first is that bone loss is quite common after transplant, and that as a result, fractures can occur due to a condition called osteoporosis. These fractures can be serious, but they are preventable.

(01:21) We'll discuss the factors that go into determining an individual's risk of having a fracture, and I'll discuss that this can be influenced by many factors.

(01:32) There are important lifestyle changes that can slow, but usually unfortunately, not reverse bone loss. And finally, we will spend some time discussing osteoporosis medications and treatments, which when used properly can be quite safe and are very effective.

(01:49): Let me start by defining osteoporosis, which comes from the Greek for "porous bone." It refers to a decrease in the amount of bone, or what we call bone mass, that leads to an increase in fragility of the bone and an increased risk of fracture.

(02:10) Osteoporosis is a condition with less bone and it’s thinner in quality. You can see here from the International Osteoporosis this is a rendering of what normal bone looks like. You can see it's quite thick and well-connected, and in an individual with osteoporosis there is less bone and it's thinner in quality.

(02:27) Women have a higher risk of osteoporosis than men. It's estimated that half of all women and about 20% of men will suffer a fracture from osteoporosis in their lifetime. This is all individuals, not just those who had a blood or marrow transplant. And importantly, there are approximately 300,000 hip fractures per year, and unfortunately this comes with a very high mortality rate. About 20% will not survive within that year, and fewer than half are able to resume independent living and walking again. So, this is a disease that's important to prevent because of the devastating consequences.

(03:08) To put the frequency of osteoporosis in perspective, the lifetime risk for an adult at age 50 for women, again, is 50%. This is higher than the lifetime risk of breast cancer, which is approximately one in eight, or 12% of their lifetime. For men, the risk of having a fracture due to osteoporosis is similar to the risk of having prostate cancer, and then the range is 15-20% over a lifetime.

(03:41) This is a fracture cast from the National Alliance for Bone Health, just showing that these are representing the 5,500 fractures that occur every day in the United States due to osteoporosis. That leads to a total of two million fractures per year.

(04:04) Fractures in the general population commonly occur in the spine, vertebrae, wrist and hip. What are the bones that are affected by osteoporosis? The most common fractures occur in the spine, or vertebral fractures. These can be quite painful. They can cause increased curvature of the spine and they can make breathing more difficult.

(04:20) The next most common type of fracture is wrist fracture, usually from somebody tripping, for instance, walking on the sidewalk or at home, and landing on an outstretched hand can result in wrist fractures.

(04:35) Hip fractures, as I alluded to, are numbered approximately 300,000 per year, but can be very devastating and lead to loss of independence. The remaining kinds of fractures that can occur typically involve the pelvis or other bones in the skeleton. Now, this is osteoporosis in general for the population.

(05:01) Transplant patients may have lower bone mass even before transplant depending on the disease or treatment. I'm here today to talk about the risk of bone loss that can occur after blood and marrow transplant. Depending on the reason for the transplant, transplant recipients can often have low bone mass even before the transplant. That's depending on the disease and/or the treatments that have been used in those conditions.

(05:24) Allogeneic transplant patients can lose bone mass in the spine and hip very quickly. And in studies, allogeneic transplant recipients have been reported to lose about 6-9% of bone mass of the spine and, even higher, 8-17% at the hip within the first year after transplant. Another important point to make is that bone loss can occur very quickly, as early as three months after the transplant.

(05:52) Bone loss may occur due to the underlying disease, lowered sex steroid hormones, immune suppression, radiation, chemotherapy, and medications.  Now, why are transplant recipients at such risk for bone loss? There are a number of reasons that contribute to this finding. There is, of course, the underlying disease that led to the need for a transplant. Some of those diseases themselves can lead to bone loss. There can be, for women, low estrogen levels, or for men, low testosterone levels. Both of those, we call sex steroid hormones, are very important for maintaining the amount of bone. In particular for women who go through menopause, that is generally a time when there is significant loss in the amount of bone that a woman has. In women who have gone to treatments that might include total body radiation and/or chemotherapy, they are sometimes forced into what we call premature menopause and lower estrogen levels than expected for age.

(06:53) Many individuals after a transplant may need glucocorticoid treatment, either for immune suppression or for treatment of graft-versus-host disease. And while glucocorticoid treatments can be lifesaving, it can be very tough on the bone and results in loss of bone mass. Immunosuppression is, of course, critical for the success of a transplant, but some of the medications used to suppress the immune system can also lead to bone loss.

(07:25) Other treatments including radiation, chemotherapy can directly impact the bone, as can other medications and comorbidities that can occur on the way to treatment with a transplant. These include using the medications like heparin, which is a blood thinning medication.

(07:45) Diseases and medications that affect the kidney can impact the regulation of calcium and bone mass. Individuals who have issues with nutrition or malabsorption, either from being chronically ill or having intestinal issues. And finally, vitamin D deficiency is quite common, either because of lack of sunlight exposure or being outdoors. So, transplant recipients are at particularly high risk for bone loss because of the many risk factors.

(08:17) Menopausal women can lose 2% of bone mass per year; transplant recipients lose 3-4% per year. To give you a sense for the rate of bone loss, on the left-hand side of this slideshow in the green highlighted boxes are the normal rates of bone loss that occur with age. Declining bone density is a natural part of aging. In men, the rate of decline is approximately 0.5% per year with age. In women who have been post-menopausal after the age of 55, their rates of bone loss are a little bit higher, maybe 1% per year. And in women immediately around the time of menopause that the fastest rate of bone loss that we see under normal conditions, that can approach 2% per year. In the middle to right part of the slide highlighted in a red box, you can see individuals who received the bone marrow transplant. On average, you can see that their rate of bone loss can be 3-4% per year, so significantly faster than we expect with aging.

(09:34) To show just one example of a study, published in 2001 looking at 67 adults who had undergone allogeneic transplants, and they had evaluations for bone density before transplant. Osteoporosis is, as I've mentioned, a significant risk for fracture. Osteopenia is an intermediate condition. It's a risk of susceptibility for bone loss. It does not carry quite the same risk as osteoporosis, but you can see that 49% of these individuals already had evidence of low bone mass, either osteopenia or osteoporosis, even before the transplant. And importantly, within six months of the transplant, this number jumped to 67%. So within six months, two-thirds of individuals had evidence for bone loss after their transplant.

(10:28) This study was in adults, but other studies have shown that bone loss is also common in survivors of pediatric blood and marrow transplant. On the images on the right side of the slide, you can see that the individual who had a stem cell transplant has a greater amount of pink showing on this image. It shows that there had been decreasing bone and an increase in fat within the marrow. This study also showed that even young adult survivors of pediatric transplant can be risked at spine fractures, something that we would not typically otherwise see until a much older age

(11:13) Overall risk factors include older age, lower bone density, immunosuppressive medications, family history of osteoporosis, being thin, smoking, excessive alcohol intake, and inflammatory diseases. Thinking about your own risk for bone loss, the factors that contribute, age is quite significant. The risk of fracture rises rapidly as we get older.

(11:24) Lower bone density. If you had a previous fracture, that raises the risk of future fractures even if your bone density is normal because that tells us that there's something about the quality of bone that makes it more susceptible to fracture.

(11:40) As we've mentioned, glucocorticoid treatment, whether for immune suppression or for graft-versus-host disease, can be very detrimental to bone mass.

(11:50) People who have a family history of osteoporosis, especially if one of the parents had a hip fracture, that increases an individual's own personal risk of having a fracture.

(12:04) Individuals who are thin can be at increased risk.

(12:08) Smoking is a risk factor for bone loss, and so smoking cessation is an important part of the lifestyle management. Excessive alcohol intake, more than two drinks per day for women, more than three drinks per day for men, is another contributor to bone loss.

(12:26) Certain inflammatory diseases such as rheumatoid arthritis can increase risk. Then certain other specialty diseases come in medications.

(12:42) Bone density tests can measure risk for bone loss. So how do you identify individuals who are at risk for bone loss? The standard test is something called a bone density test. You may also hear it referred to as a DXA scan. DXA, or D-X-A, stands for dual energy absorptiometry.

(12:57) These are the recommendations from one of the societies that focuses on bone health, the American Society for Bone and Mineral Research. Their recommendations, in general, for the general population, of who should have a bone density test includes: women over the age of 65, men over the age of 70, younger adults over the age of 50 who have a significant number of risk factors as we've discussed on the previous slide, anyone over the age of 50 who's already had a low-trauma fracture. In other words, someone who fractured their wrist just tripping on the sidewalk, who had a spine fracture with minimal trauma, those individuals should be screened with the bone density test. And those who have a condition or medication associated with bone loss, like rheumatoid arthritis, glucocorticoids, or in this case, transplant.

(13:58) I recently had the privilege of sitting on the expert panel for the American Society for Transplantation and Cellular Therapy. It's an organization of professionals who care for patients after blood and marrow transplant. I was part of the committee that convened the recommendations for optimizing bone health management after transplant. I would like to share some of the recommendations from this panel.

(14:28) There are several recommendations for optimizing bone health after transplant. The first is that bone density, or DXA scan, and fracture risk assessment, what we call FRAX, should be done, if not before the transplant, then no later than three months after a transplant. Even if a bone density scan was done prior to transplant, if a recipient is on high doses of glucocorticoids immediately following a transplant, then another bone density scan should be ordered again at three months, and after one year of treatment, and then following every one to two years after that.

(15:02) So, what is a bone density scan? This is what the machine looks like at our hospital at Stanford. It's non-invasive. It means that you just lie on this table and this takes an image both of your spine and your hip, and it turns out a report both of hip and spine bone density. The green bar just indicates where normal bone density is and as it gets lower, you get towards the higher risks of fracture. The blue bars show you what the average bone density would be for the population. These are compared to reference data bases of the same gender, and race, and ethnicity. So for this individual, the bone density is pretty average for age, and you can see that across the population. Bone density declines as we get older.

(16:00) Bone density scans can evaluate the risk of fracture and whether treatment is indicated. Once we have the results of the bone density scan, you can also use this calculator called FRAX that takes into account things like age, gender, height and weight, other risk factors like we discussed, things like having had a previous fracture, or their parent who's ever had a hip fracture, whether an individual is a current smoker, on glucocorticoids, or has diseases like rheumatoid arthritis. In the red box in the bottom right, the calculator will estimate the risk of having a fracture in the next 10 years, either any kind of fracture called a major osteoporotic fracture, or hip fracture. Guidelines for treatment suggest that somebody who has a major osteoporotic risk of fracture greater than 20%, or a 10-year risk of having a hip fracture greater than 3% because they are so devastating, should be considered for treatment.

(17:02) I'd like to make a few points about fracture risk. I mentioned that it was dependent on both bone density and age. This slide shows the effect of age on a risk for fracture. The dotted line across the bottom is the 10-year estimated risk of hip fracture at 3%. That is where the professional societies agree that we should think about treatment when that risk crosses the 3% threshold. Along the bottom, I have the bone density T-scores, and osteoporosis is defined by the World Health Organization as a T-score of -2.5 or worse, and that is shown by the red arrow on the bottom of the slide. T-scores are standard deviations compared to young adults, individuals of the same gender and ethnicity. So what you can see is that ... Then I have the risk of fracture for each age at five-year intervals, from 55 to 80. So what you can see is that a 65 year old woman roughly crosses the 3% line at a T-score of about -2.5. So a 65 year old woman who has a T-score of -2.5, that's right at the borderline of osteoporosis, meets the threshold for treatment.

(18:26) Fracture risk is highly dependent on bone density and age along with other risk factors. On the other hand, if you are 80 years old, you can see that even at a normal bone density of minus one, that individual's risk of fracture is already very close to 3%. Conversely for those who are younger than 65, for instance a 55 year old woman, her T-score could be closer to minus three before it reaches the threshold for treatment. So again, fracture risk is very much dependent on both bone density and age.

(18:57) The number of risk factors also matters. This is a hypothetical case of a woman who is 65 weighing 150 pounds, five foot six inches in height, and her calculated risk of hip fracture over 10 years, depending on the number of risk factors that she has. Those are listed on the right. They include things like having had a previous fracture herself, having a parent with a hip fracture, being a current smoker, being on glucocorticoids or steroids, having a disease such as rheumatoid arthritis, or consuming excessive amounts of alcohol. You can see in the graph that the risk of fracture rises very quickly with an increasing number of risk factors. Your doctor when you speak with him or her will factor in the number of risk factors that you have in trying to assess your overall chances of having a fracture.

(19:59) Several life-style factors can improve bone health. All right. Let's talk about what we can do, lifestyle-wise, to improve bone health. The recommendations from the Surgeon General's Report in 2019 offers a few lifestyle interventions that can be very beneficial. Get enough calcium and vitamin D. We'll go into that in more detail on the next slide. Be more physically active. Exercise has many benefits including lowering the risk of fracture. Reduce your risk of falls, so this means things like making sure that if you have rugs, throw rugs or small rugs, area rugs, that they are well tacked down on the floor, or just get rid of them completely. That you perhaps have a night light for those middle of the night trips to the bathroom so that you don't trip and fall in the dark. Wearing shoes that are comfortable and safe. Maintaining a healthy weight is another important approach. Don't smoke, or if you do currently smoke, work on stopping. Limit alcohol use. And finally, share with your doctor any medications that you might be taking that could be weakening your bones.

(21:14) Getting adequate calcium from food or supplements is important. How much calcium should you be taking? I counsel my patients who are at risk for bone loss. It's older adults who are those who have the risk factors we've talked about. Keep it in the range of 1,000 to 1,200 milligrams daily. This is from all sources. Dairy products are a terrific source of calcium. I've listed here a few: milk, yogurt, cheese. Each serving of dairy products is roughly 300 milligrams, so three to four servings a day would be sufficient. You can also get calcium in other sources of the diet. Orange juice is often fortified, cottage cheese, other foods have calcium.

(21:55): If you're not someone who enjoys having three to four servings of dairy products per day, many adults do not, you can take calcium supplements. The important thing to remember is that your body can only absorb about 500 milligrams at a time, and so if you're going to take calcium entirely from supplements, you might want to divide those doses into 500 milligrams in the morning and 500 in the evening. If you're taking acid blocking medications, so H2 blockers, proton pump inhibitors, you need a form of calcium called calcium citrate. But otherwise, calcium carbonate is fine. Calcium citrate is marketed under a brand name like Citrical. Calcium carbonate is available as Os-Cal or Tums and in many generic forms.

(22:48) Vitamin D needs should also be met. Vitamin D is also important. It helps your intestines to absorb the calcium with high efficiency. For most individuals, the recommended intake for vitamin D for those who are at risk for bone loss is in the range of 800 to 1,000 international units per day. We have two forms of vitamin D available, vitamin D2 is a plant-based supplement, vitamin D3 is the form that we naturally produce in the skin when we have sun exposure or an animal-based. Both of those are fine to get you to that goal.

(23:24) Exercise, balance and flexibility are important to maintain. Let's talk about exercise. The recommendations of the American Heart Association are that we get 150 minutes of moderate exercise, for instance walking, or 75 minutes of vigorous activity a week. To make it easy, I recommend for most of my patients that they be active for at least 30 minutes per day, and then on top of that, strength training two to three times a week, either using weights or resistance bands. It's very beneficial for bone health.

(23:55) Balance and flexibility are also important and are also things that can decline with age, so yoga, Pilates, those kinds of exercises can also be very helpful. If you want more information, the National Osteoporosis Foundation has guidelines for lifestyle interventions including some suggestions for exercise that you can find on this URL shown here.

(24:24) Medications for treatment are recommended for those meeting certain guidelines. In the last few minutes, I want to cover medications for the treatment of osteoporosis. The first question is always, "Do you need medications?" By now, excuse me, you would've had a bone density scan, you would've had a FRAX calculator. In the guidelines from the expert consensus panel and from bone marrow transplant societies, these are the general recommendations.

(24:51) So for individuals who do not require glucocorticoids, for example for GVHD, it's recommended that medication be considered for those who had a fracture after age 50. Again, this is a low trauma fracture, so breaking a wrist, tripping on the sidewalk, or perhaps having a spine fracture. Post-menopausal women, or men over the age of 50, who have osteoporosis on a bone density scan, meaning a T-score lower than -2.5. Finally, the third category, those who have an estimated 10-year risk of major osteoporotic fracture greater than 20% or hip fracture greater than 3%.

(25:39) For those who are taking glucocorticoids for GVHD, it depends on age. Individuals who are over the age of 40, it's similar to the recommendations before that if you had a fracture, that you probably have a history of fracture over age 40. Again, postmenopausal women or men over the age of 50 who have osteoporosis on a bone density scan. This time for those who have an estimated 10-year risk, that's a little bit lower, so only 10% for major osteoporotic fracture and 1% for hip fracture. Because age plays a significant role, adults who are under the age of 40 are quite protected from fracture, so treatment for young adults is only recommended if they've already had a fracture or if there's evidence of very severe or rapid bone loss.

(26:31) Treating osteoporosis involves stopping bone breakdown or promoting bone formation. Finally, what are the approaches for treating osteoporosis? The amount of bone that you have, quite often on my patients, is a balance between bone that is being newly formed, analogous to the brick layer on the right, competing with bone that is being broken down, analogous to the jackhammer on the left. We have two general strategies for treating osteoporosis. We can either stop bone breakdown, on the left, or we can actively promote bone formation.

(27:06) Bone building medications in transplanted individuals are not currently recommended. I've shown some of the categories of medication on either side. There's very little data for the safety of bone building medications in individuals with a history of blood and marrow transplant or with malignancies, and for that reason I don't recommend them except in very special circumstances and close consultation with a specialist. So, we're not going to talk about the medications that promote bone formation. The vast majority of medications used to treat osteoporosis fall in the category of preventing bone breakdown.

(27:44) Osteoporosis in transplant patients is often treated with bisphosphonates to prevent bone breakdown. In particular, I want to highlight the category called bisphosphonates. These are the medications. They are typically used to treat osteoporosis in transplant patients. In the upper row is oral bisphosphonates. You may be familiar with some of them by their brand names: Fosamax, Actonel, and Boniva. Highlighted in bold are the two that have been approved for the treatment of glucocorticoid-induced osteoporosis, so particularly relevant for those who are on high doses, for example, for GVHD. Most of these medications are given as weekly tablets, except for Boniva which is a once-a-month tablet. The advantages of these medications are they're very safe and effective. They significantly lower your risk of fracturing.

(28:41) These drugs have some disadvantages and limitations. Some of the disadvantages, they can be associated with heartburn because the pills can be irritating for the esophagus. These medications are somewhat limited for individuals who have kidney disease or lower kidney disfunction. Finally, Boniva or ibandronate, is not in bold because it has not been shown to reduce all kinds of fractures, so there's a preference for using alendronate, which is Fosamax, or risedronate, which is Actonel.

(29:11) For those individuals who have heartburn who can't tolerate the pill form, I recommend intravenous bisphosphonates, the middle row, called zoledronic acid, or marketed under the brand name Reclast. This is a very convenient medication. It's an intravenous infusion that's given once a year. It has very similar efficacy, it's very effective at decreasing fracture risk.

(29:38) The disadvantages, again, it cannot be used in those who have significant kidney disfunction. Some individuals tell me that they get a mild flu-like reaction, particularly with the first infusion. If anyone has had their COVID vaccine, these symptoms are very similar to what's been reported for the vaccine reaction. But that's largely with only the first infusion and future doses don't seem to trigger the same reaction.

(30:09) Denosumab is another option but with little data for transplant recipients. There's a second overall class of medication that can be used to treat osteoporosis by preventing bone breakdown, and that's a medication called denosumab, marketed as Prolia. It's a monoclonal antibody against that protein called RANK ligand. It's given as an injection in the clinic every six months. The advantages are that it can nicely increase bone density and it's an option in those who have some kidney disfunction. However, there are very few safety and efficacy data in blood and marrow transplant recipients, although there are trials ongoing. So, I generally recommend the first two categories, either oral or intravenous bisphosphonates.

(30:56) The benefits of bisphosphonates to prevent fractures outweigh the risks. Now, I've been practicing medicine for a very long time, and I've heard many of the concerns that people come into my clinic with. There's a natural inclination to favor natural remedies over medications when possible, to emphasize lifestyle instead of medications. I have many patients who note that they are sensitive to different kinds of medications. There have been reports in the media that have made people somewhat nervous about some of the osteoporosis medications. And then it's not uncommon that somebody might have a personal connection with someone who took a medication and had an unpleasant side effect, for instance, heartburn.

(31:40) So, I want to put into perspective the benefits and risks of treatment. Shown here in gray bars are the number of fractures that would happen in 100,000 patient-years. So for instance, if we had 10,000 women treated for 10 years, you would expect several thousand spine fractures over that time, fewer number of wrist fractures, and a smaller number of hip fractures. Bisphosphonates used over this time would significantly decrease that. You can see here it cuts down by several thousand, the number of fractures. Also, it decreases the number of wrist fractures and hip fractures.

(32:21) The long-term, very rare side effects of bisphosphonates include osteonecrosis of the jaw, and what we call atypical fractures. You can see that these are exceedingly rare, and in fact, only seen in individuals who have been on medications for more than 10 years, especially in the case of atypical fracture.

(32:44) So to reframe in a different way, this is a representation of the number of fractures that can be prevented by treatment, so this is the benefits of treatment compared to the number of cases that you might see of osteonecrosis of the jaw or atypical fractures after five years of treatment or 10 years of treatment. Treatment durations of five years, you can see that there are very few adverse events compared to the numbers of fractures that can be prevented. So in appropriately selected patients, the benefits of five years of treatment far outweighs the risk.

(33:32) Properly used, medications along with lifestyle changes are safe and effective ways to prevent bone breakdown. And with that, I want to return to the take-home messages. We've talked today about the fact that bone loss can be common after transplant for a variety of reasons, that fractures that result from bone loss or osteoporosis can be serious, but are preventable. Now, the person's risk of fracture depends on several factors, including age, bone density, previous fracture, fracture history, family history, and medical conditions. Lifestyle changes can certainly slow the rate of bone loss, but if somebody has osteoporosis, that's typically not enough to reverse the bone loss, and therefore we need to think about medications. But when used properly, these medications are very safe and effective.

(34:24) And with that, I thank you for your time, and I believe we have time to take questions.

Question & Answer Session

(34:33) [Lynne]      Q & A. Thank you, Dr. Wu, for this informative presentation. We will now take questions. As a reminder, if you have a question, please type it into the chat box on the lower left-hand corner of your screen.

(34:46) So, the first question is: what is the risk for a patient who had an autologous transplant? And that is, for those who are not sure what that is, it's a transplant using your own cells.

(35:01) [Joy Wu]      Right. That's a great question. The risk of bone loss after transplant is influenced by a number of things, so both the initial reason for the transplant and the conditioning regimen. So if the conditioning regimen is, let's say, less stringent for an autologous, then the risk may be slightly lower, but it's still something that an individual's physician should be aware.

(35:31) [Lynne]      This is a question about calcium and vitamin D, which you did touch upon. But specifically, this person is saying that she is a woman of 70 years old and how much calcium and vitamin D should she take?

(35:46): [Joy Wu]      Right. So to keep things simple, I generally recommend to my patients that they take 1,000 milligrams of calcium. Again, that can be diet or supplements combined. If it's supplements, it should be no more than 500 milligrams at a time because their body can't absorb more than that. And then for vitamin D, also 1,000 but this time it's international units. As long as those totals are met, it can be done any number of ways. I have patients who take combined calcium and vitamin D supplements. I have individuals who prefer to get the calcium from diet who, for instance, eat dairy products, but take a vitamin D tablet. So, as long as it's roughly 1,000 milligrams of calcium and 1,000 international units of vitamin D.

(36:39) [Lynne]       The next question: after stopping steroids, how long does it take for the bone to heal? Is it necessary to take medication to repair the bone?

(36:52) [Joy Wu]      It depends on how much bone loss there has been. It also depends on the cumulative amount of time and the dosing of the glucocorticoids or the steroids. So for somebody who has had very substantial bone loss well into the osteoporosis range, it's unlikely that the body can recover entirely on its own, even when steroids are stopped. However, for somebody who's been on low doses for only a brief amount of time, the body might be able to recover from that.

(37:27) [Lynne]      Multiple myeloma patients often take high dose dexamethasone once a week. Does that confer the same risks of taking glucocorticoids for GVHD?

(37:43) [Joy Wu]      Yes. Dexamethasone is a form of glucocorticoids and high doses increase the risk substantially of bone loss. Multiple myeloma in itself is one of the diseases that can cause bone loss. The myeloma cells can eat away at the bone, and so these individuals would be in the category of high risk.

(38:09) [Lynne]      Next question: who do I go to for a bone test? I am four years out from transplant, and no one has suggested it.

(38:18) [Joy Wu]      Right. So, a couple of options. You can ask your primary care physician. There are some different that focus on bone and they can order, or you can discuss with your bone marrow transplant physician. One of the reasons I participated on this expert panel was to raise awareness among physicians who care for patients with blood and marrow transplants that bone loss can be an issue, and to increase awareness of who should be screened. You could take, for instance, the slides from this talk and share them with your transplant physician, and if it's agreed that you fall in the categories of risk that I discussed, then to order a bone density scan.

(39:08): [Lynne]      Is osteopenia or osteoporosis still a significant risk factor if the patient never received steroid treatment or developed GVHD during or after the transplant, but did have TBI, total body irradiation?

(39:27) [Joy Wu]      Sure. TBI can also affect the bone. The radiation passing through the bone cells can have effect on the ability to form bone normally. The risk conferred by osteopenia and osteoporosis is still present. Exactly how high that risk is depends, again, on the age of the individual, whether they have other risk factors. But you can have osteopenia, osteoporosis from TBI alone, or even without any of those treatments.

(40:01) [Lynne]      Next question: does Prograf or Jakafi affect bone health?

(40:10) [Joy Wu]      I apologize. I'm not an oncologist, so I'm not familiar with the medications, but I can tell you that many of the medications used for transplant can have secondary effects. For instance, if somebody went into premature menopause. But I can't comment specifically on the oncology medication.

(40:33) [Lynne]      The next question: I am 11 years out from BMT. I have avascular necrosis in hips, knees, and ankles. I've been told by orthopedic specialists that they cannot perform stem cell therapy on me to treat my hips and the tear in my L4 and L5. What research is being done using stem cell therapy on BMT survivors?

(41:01) [Joy Wu]      Avascular necrosis is a common complication of high doses of glucocorticoids, but it's a separate condition from osteoporosis. It refers to the fact that sometimes parts of the bone lose their blood vessel supply and then have trouble functioning normally. That's a question that's best discussed with somebody, an orthopedic surgeon, for example.

(41:32) [Lynne]      Here's another one about avascular necrosis. I am 35 years post-transplant and have avascular necrosis in my joints. First question is: is hyperbaric oxygen treatment an option to reverse further damage, and if a joint replacement is required, is it important to have it performed by someone experienced with BMT patients?

(42:00) [Joy Wu]      So again, avascular necrosis is a different condition. It's treated by orthopedic surgeons. I can't really comment. It's not my specialty.

(42:14) [Lynne]      What if you have an overactive parathyroid gland that elevates calcium levels? Is that good for bone health? If not, what do I do about it?

(42:28) [Joy Wu]      An elevated PTH level, or a condition we call hyperparathyroidism, is quite common and becomes more common as adults get older. It can lead to high calcium levels, and when that happens it is not good for bone. Elevated calcium levels and continuously elevated PTH levels are actually associated with osteoporosis. The primary treatment for hyperparathyroidism is removal of the parathyroid gland that is making too much PTH, but that's something that should be discussed with an endocrinologist and an endocrine surgeon.

(43:15) [Lynne]      I have been on prednisone for some years. Apparently, this is what has been my spine leading to stenosis. What should I do?

(43:28) [Joy Wu]      Prednisone leads to an overall thinning in the amount of bone, that is osteoporosis, and raises the risk of fracture. For that, generally, the recommendations are treatment with the medications that I discussed, so bisphosphonates in particular. In terms of stenosis, that sounds like an anatomic issue and that would be in the domain of a surgeon, a neurosurgeon or an orthopedic surgeon.

(44:15) [Lynne]      I think the next question came from someone who had a pediatric transplant 10 years ago. They had no GVHD, no fractures. They said, "I have never had a bone density scan before. I did have a severe jaw bone infection two years ago. My primary care physician did not recommend a density scan because I'm in my 20s. Should I be concerned about my bone density?"

(44:42) [Joy Wu]      That's a great question. Most of the bone density research has, of course, been done on older adults because that's where it happens most commonly. We don't have a large amount of information for young adults. I think that's a conversation to have with your primary care physician or your transplant physician about whether a screening bone density might be helpful, perhaps as a baseline. It's unlikely in somebody who's only in their 20s, unless they have had a fracture history or very, very severe osteoporosis, it's unlikely that it would merit medications, but it might still be a good idea to know where you're starting from as you get older.

(45:28) [Lynne]      All right, next. Does vitamin K help with bone health?

(45:33) [Joy Wu]      There are studies on vitamin K, pre-clinical studies, meaning in animals, that suggest that it's beneficial. Vitamin K is certainly an important part of some of the enzymes that work in bone. But to my knowledge, there has not yet been a large clinical trial in people to prove the benefits of vitamin K, so stay tuned, but not currently one of the recommended supplements.

(45:59) [Lynne]      Is the bone damage caused by multiple myeloma the same kind of bone damage caused by osteoporosis?

(46:09) [Joy Wu]      The bone damage caused by multiple myeloma, it both aggravates the normal process of osteoporosis, but the myeloma cells themselves can contribute to destruction of bone. It is a little bit different than osteoporosis alone.

(46:33) [Lynne]      Is there a rest period after five years of bisphosphonates therapy? How long is that rest period?

(46:41) [Joy Wu]      That's a great question. As I showed, the risk of these very rare side effects, like jaw necrosis or atypical fractures, appears to be related to the length of time on treatment. So for most individuals, I recommend a drug holiday or a pause from the medication after five years, as long as the risk from fracture is not too great. The length of the drug holiday for most individuals should be one to two years. Within one year, the risk of jaw osteonecrosis and atypical fracture goes back to almost zero, or baseline I should say. Within two years, the risk of regular osteoporosis fractures begins to rise because your treatment has been paused.

(47:34) [Lynne]      I was given zoledronic. First year, no problems. Second year, side effects of major muscular weakness for 48 hours. What would be an alternative as I am scared to take it again?

(47:50) [Joy Wu]     Yeah, no, I understand. I can't comment on the specifics. I'm not familiar with the details, but it is more common to find that those who have a reaction to zoledronic acid, or Reclast, experience it their first time. It typically gets better the second time, or future doses. It's a little unusual to have a worse reaction the second time, so I would be sure to talk to your doctor about whether anything else might have been going on. But the ... I think it very much depends on individual circumstances, so I can't really provide medical advice on this one.

(48:37) [Lynne]      The next question is from a person that likes to run. After the transplant, is running advised for a man over 70 if he has been running regularly for over 30 years?

(48:51) [Joy Wu]      Running is a great exercise, I think, especially if you've always been a runner. My patients who are runners tell me that they really can't stop. It's a part of their life and a very important part of their health, both physical and mental, so there's no reason you can't run with osteoporosis. You of course want to be careful that you, for instance, your shoelaces are double knotted. Take every precaution you can not to trip and fall. I would say that for anybody thinking about bone health, it is also important to build strength training into your regimen, so two to three times a week, either with weights or resistance bands. But there should also be some emphasis on strength training.

(49:37) [Lynne]      Does it matter what type of food I take vitamin D supplements with? I have read online that vitamin D should not be taken within an hour of drinking milk, for example.

(49:51) [Joy Wu]       I generally don't restrict the timing of vitamin D. It's well absorbed, and I'm not familiar with any recommendations. Calcium sometimes it's more about not taking with medications, for instance, thyroid hormone replacement. Calcium can block the absorption of thyroid hormone, but for vitamin D I generally don't restrict the timing of that medication .... for that supplement, sorry.

(50:23) [Lynne]      Does having an autologous transplant increase the risk of osteoarthritis?

(50:32) [Joy Wu]      Osteoarthritis is generally something that occurs from wear and tear, and it's quite common as you get older. I'm not a rheumatologist, but I don't think I can think of a reason why an autologous transplant would specifically increase the risk of osteoarthritis.

(51:01) [Lynne]      The next question: I have multiple myeloma and after transplant, I am now given Zometa by IV infusion once a year. I also take Citrucel over-the-counter. Is that all right? I do have osteopenia.

(51:19) [Joy Wu]      Right. So, Zometa is another name for Reclast, the intravenous medication I mentioned. It's a very good medication for those with myeloma or after transplant. This certainly sounds reasonable. I would say that you should discuss with your physician how many years you might be treated before considering a holiday, if appropriate.

(51:44) [Lynne]      Another question. Do you have comments on Xgeva?

(51:47) [Joy Wu]      Xgeva is another name, a different dosage, for the medication Prolia that I discussed as an alternative to bisphosphonates. It also blocks bone breakdown. It is most commonly used by oncologists for cancers that have spread to the bone, for instance, breast cancer, lung cancer. It can be used in myeloma patients who have bone involvement. It is a higher dose than Prolia, but works in the same way. For transplant patients I mentioned that there is still not a whole lot of data on the safety of Xgeva after transplant, and so it is not my preferred first-line treatment. I would recommend caution.

52:46) [Lynne]      Other than dairy and supplements, what other foods can increase calcium?

(52:52) [Joy Wu]      Other sources of calcium include fortified orange juice, firm tofu, green leafy vegetables do have some calcium. For instance, canned salmon or sardines, especially if the bones are present, are there. You can Google for the list of calcium-contained foods and how much calcium is present. The National Osteoporosis Foundation has such a list, and you can sort of assess your own diet on how much calcium might already be present.

(53:34) [Lynne]      Are there situations when zoledronic acid would be given more frequently than yearly? If so, what are the risks if given quarterly versus yearly?

(53:46) [Joy Wu]      Yeah. So, zoledronic acid, or Zometa, can be given monthly or quarterly for individuals who have cancer that has spread to bone. It is a higher dose than we use for osteoporosis, which is once a year. But the oncologists do use it at a more frequent dosing for metastatic breast, lung, also sometimes for myeloma. It is very effective at decreasing the adverse events of cancer in bone, things like fractures or spinal cord compression, those sorts of adverse events. But it also at this dose increases dramatically the risk of osteonecrosis of the jaw and atypical fractures.

(54:38) [Lynne]      I noted in your chart Boniva is shown as a tablet monthly. I'm receiving three milligrams IV every three months. Is this as effective? I have an avulsion fracture of anterior-inferior iliac spine and calcaneous fracture since being on Boniva.

(55:01) [Joy Wu]      Right. You're right. Boniva is one of the bisphosphonates that is available both as a monthly tablet, in oral form and for quarterly intravenous infusions. For osteoporosis, it is quite effective, so it's a good choice. It has not been proven to decrease as many kinds of fractures as the other bisphosphonates. However, any of them is far better than not having any treatment alone, so it is an effective medication.

(55:35) [Lynne]      All right. Now, we're winding down. We just have a few more minute left, so I'm going to take this last question. It is: I have had two bone density scans after my BMT. Interesting is that the last one in 2020 showed improvement in my bone density. Is this a good indication of decreased fracture for me at my age, 66 years old?

(56:02) [Joy Wu]      Right. I can't comment on details without looking at the bone density. It sometimes happens that if an individual had a bone density while they were on, for instance, high dose glucocorticoids and then years later had a second one not on that, you might see some recovery. But it would be important for your doctor to look at the report carefully to make sure that it wasn't any kind of technical artifact.