Protect Your Bones after Transplant or CAR T-cell Therapy

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Protect Your Bones after Transplant or CAR T-Cell Therapy

April 28, 2024

Presenter: Sarah Keller, MD, Rheumatologist, Assistant Professor at the Cleveland Clinic Lerner School of Medicine.

Summary: People who have undergone a bone marrow or stem cell transplant have an increased risk of osteopenia (loss of bone density), osteoporosis and bone fractures. Periodic bone density tests are needed to monitor bone health so that therapies can started early to prevent or reverse bone loss.

Key Points:

• Stem cell transplant recipients are at greater risk of bone density loss and osteoporosis due to side effects of chemotherapy, total body irradiation (TBI), prescribed steroids, calcineurin inhibitors, rapid weight loss and lack of mobility.
•  CAR T-cell therapy does not appear to have the same negative effects on bone health as a stem cell transplant.
• Bone health is especially important to protect because of the incapacitating effects of fractures and the impact of quality of life. Nutrition recommendations and supplementing the diet with vitamin D and calcium, safe weight-bearing exercise and medications that help to build bone and preserve bone density are often prescribed.

Highlights:

(01:49) Chemotherapy agents, total body irradiation, glucocorticoids such as dexamethasone and prednisone, calcineurin inhibitors such as tacrolimus or cyclosporine and hypogonadism can all lead to loss of bone density in BMT and CAR T-cell therapy patients.

(05:01) We face an epidemic of under-diagnosis and under-treatment of osteoporosis, which affects more than 10 million adults in the US, 80% of whom are women. Osteoporosis results in over 2 million fractures annually, the most serious of which are hip fractures which carry an increased risk of death of as high as 30% within the first six months following fracture.

(06:30) Up to 40% of hip fracture patients cannot walk independently in the first year after fracture, and up to 25% can no longer live independently, requiring long term care.

(07:18) Vertebral compression fractures are the most common fractures in osteoporotic patients. These patients then have a higher risk of subsequent vertebral fractures and double the risk of future hip fracture.

(08:49) Bone strength is defined as bone density, (measured by a bone density scan), plus bone quality, which is more complex, but is starting to be measured more frequently by trabecular bone score or TBS.

(10:48) Clinical osteoporosis can also be diagnosed in those who have a normal bone density scan, but who suffer from a fragility fracture, meaning a fracture occurring in a weakened bone due to a fall from a standing height, for example, which should not normally result in fracture.

(12:33) A fracture risk assessment, or FRAX, utilizes demographic factors to predict the risk of major fracture within the next 10 years. Individualized guidelines for receiving scans and additional diagnosis are best clarified by consulting a metabolic bone expert, a doctor with advanced training in osteoporosis.

(19:27) To optimize bone health, daily calcium intake should equal 1,200 to 1,500 milligrams from calcium rich foods such as dairy and leafy greens and supplements. Vitamin D is required in adequate amounts in order to absorb calcium, and 800 to 1,000 international units per day is a commonly recommended amount for adults age 50 and older.

(23:28) Careful weight-bearing and muscle strengthening exercise are both important for stronger bones. Weight-bearing exercise such as hiking or walking stimulates the cycle of bone remodeling, in which old bone is broken down and new bone is built. Muscle strengthening exercise using resistance bands, light free weights, or lifting one’s own body weight in a safe manner helps enormously, as does avoiding smoking and excessive alcohol or caffeine.

(33:57) For at-risk patients diagnosed with osteoporosis, a variety of medications are available to help build bone or to prevent bone breakdown. Bisphosphonates are the most commonly prescribed of these. Despite potential side effects that should be monitored, these medications have revolutionized the treatment of osteoporosis.

Transcript:

(00:00:02): [Susan Stewart]:   Hello and welcome to the workshop, Protect Your Bones after Transplant or CAR T-Cell Therapy. My name is Sue Stewart, and I will be your moderator for this workshop.

(00:00:13): Speaker Introduction. It's my pleasure to introduce to you today's speaker, Dr. Sarah Keller. Dr. Keller is an Assistant Professor at the Cleveland Clinic Lerner School of Medicine, and an Assistant Staff Physician in the Orthopedic and Rheumatology Institute at the Cleveland Clinic. Dr. Keller's current research focuses on osteoporosis and fracture risk following a solid organ transplant, and her clinical focus is osteoporosis and metabolic bone disease. Please join me in welcoming Dr. Keller.

(00:00:49): [Dr. Sarah Keller]:   Thank you so much for that very warm introduction. I am so thrilled to be here with you today. This topic will be about 30 minutes of presentation and then we'll have some questions. I'd like to just get started. As Sue mentioned, I'm a Rheumatologist at the Cleveland Clinic and I see solid organ and BMT patients primarily. I have no disclosures today.

(00:01:15): For the agenda today, first, we'll talk about the impact of bone marrow transplant on bone health. Then we'll discuss why osteoporosis and bone density loss matter and are very important topics. We'll then look at how osteoporosis is diagnosed. And lastly, we'll talk about how you can protect your bones after transplant and the steps that you can take to stay healthy and prevent fracture.

(00:01:49): Risk Factors for Osteoporosis Associated with a bone marrow/stem cell transplant: Chemotherapy, Glucocorticoids, Calcineurin Inhibitors and Total Body Irradiation. There are many risk factors for bone loss after both allogeneic and autologous bone marrow transplant. First of all, induction and consolidation chemotherapy agents can be associated with bone density loss Also, glucocorticoids such as dexamethasone and prednisone are very important triggers of bone density loss, and we'll talk about this in detail in just a moment.

(00:02:17): Calcineurin inhibitors such as tacrolimus or cyclosporine can also lead to loss of bone density as well as conditions that are associated with transplants such as hypogonadism.

(00:02:30): Total body irradiation is another treatment that can lead to low bone density, which can in turn lead to fracture. Having a low BMI or rapid weight loss, being immobile or unable to move or do weight-bearing exercise, having a decrease in vitamin D and calcium intake as well as advanced age can all be associated with bone density loss.

(00:03:00): This slide is sort of a repeat of the previous one. I want to highlight that steroids are probably the biggest agent that can pose a threat to bone density and lead to bone density loss. When the steroid dose is increased, we see an increase in bone density loss and an increase in fracture risk.

(00:03:19): And here, I want to talk about that. Glucocorticoids is the generic term for different steroids that may be used, and they can lead to bone density loss in several ways. On the far left-hand side of the screen in that green box, you see the words osteoblast and decreased bone formation. That means that steroids affect osteoblasts, which are the bone building cells, and they directly decrease the amount of bone that's built.

(00:03:47): Next to that box, osteocytes are bone cells that are very important and can differentiate or turn into osteoblasts or osteoclasts. Steroids affect these cells as well, leading to problems in terms of differentiating, which is an important part of the bone remodeling cycle.

(00:04:06): On the right-hand side, that box indicates that steroids can indirectly affect osteoclasts and lead to increased bone breakdown or bone resorption. Those are the major ways that steroids can affect bone density loss. All of that can lead to a decrease in bone mass, impaired bone microstructure where the bone is not as strong as it should be.

(00:04:31): On the far right-hand screen, you see that they also can affect muscle and lead to atrophy or muscle loss and weakness, which puts somebody at increased risk of falling. So, all of these things together, decreased bone mass, impaired bone microstructure and increased risk of falls lead to fracture.

(00:05:01): Why Osteoporosis and Bone Density Loss Matter Osteoporosis affects more than 10 million adults in the US, 80% of whom are women. The direct cost is astronomical, estimated to be over 17 billion dollars. However, the indirect cost is far greater, and there are more than 2 million fractures annually due to osteoporosis. So, this is a huge problem.

(00:05:23): We are facing an epidemic right now where we do not diagnose and treat osteoporosis as much as we should, but by diagnosing osteoporosis and preventing fractures, we can increase patient survival, improve quality of life, and decrease the large direct and indirect cost of this disease. So, let's talk for a minute about fractures. Fractures are a huge problem in the world of osteoporosis.

(00:05:52):Hip Fractures. A fracture occurs when a force like a fall is applied to an osteoporotic bone or a bone that is not as dense as a normal, healthy bone. The most dreaded osteoporotic fracture is the hip fracture and hip fractures are associated with increased morbidity and mortality, particularly in the first year following hip fracture. A risk of death after a hip fracture is as much as 30% in the six months following the hip fracture. This is what we really want to prevent by diagnosing and treating osteoporosis.

(00:06:30): As I mentioned, there is more than 20% excess mortality, probably up to 30%, in the first year after a hip fracture in women, and up to 50% excess risk of death in men. A very large number of patients, up to 40%, are no longer able to walk independently in the first year after hip fracture, and up to 25% of patients are no longer able to live independently, requiring long-term care.

(00:06:57): Up to 80% of patients are not able to carry out at least one activity of daily living. These are basic tasks such as running errands, eating, walking, activities that they were able to do before the hip fracture. We see that hip fractures take a huge toll.

(00:07:18): Vertebral compression fractures. I want to also highlight another kind of fracture we can see, called a vertebral compression fracture. This is actually the most common fracture in osteoporotic patients, and like hip fractures, these fractures are also associated with increased morbidity and mortality. When we say compression, we mean that the vertebra in the spine is compressed or not as tall as it should be. This doesn't have to be a true break in the bone, but it's a compression of the bone.

(00:07:47): Patients with a vertebral fracture are at double the risk for a hip fracture. This is why we're very concerned about vertebral fractures, and we consider them to be a marker of disease. About 20% of patients who have a vertebral fracture will have a recurrent vertebral fracture within one year, up to 30% within three years. So, if you have a vertebral fracture, you're at an increased risk for subsequent vertebral fractures, but also for hip fractures. I also want to mention that vertebral fractures can occur in patients on steroids such as dexamethasone and prednisone because these agents tend to affect the spine and they tend to affect the bone density in the spine more than the bone density in the hip.

(00:08:37): Now, we'll talk about how osteoporosis is diagnosed. There are several key components of bone strength.

(00:08:49): Bone strength is defined as bone density plus bone quality. Bone density is what we measure on a bone density scan and essentially this is reported as a certain number that's an aerial measurement of the bone. Bone quality is another component of bone strength, but it's not quite as specific. It has to do with bone turnover, bone mineralization, the microarchitecture and geometry of the bone as well as damage accumulation in the bone over time. Bone quality is harder to measure. There is one way to measure it, and this is called trabecular bone score or TBS. And you might see these studies, as they're becoming increasingly available. At our center, we are starting to do TBS, and it's a way of looking at the microarchitecture of the bone, but for now the gold standard is the bone density scan.

(00:09:54): When we talk about diagnosing osteoporosis, there are several main ways osteoporosis is diagnosed. The first one is by having a low T-score on the bone density scan. And as I mentioned, this is the gold standard. We're going to talk in a minute about how the bone density scan is done, but once the bone is analyzed, if the T-score is low, less than -2.5, that means you have osteoporosis.

(00:10:21): Now, the T-score is a bit complex, but what it basically means is that the radiologist is comparing your bone density to that of a woman at peak bone mass. Every T-score compares your bone density to a standard woman’s bone density at peak bone mass. If it's -2.5 or lower, then this means that you have osteoporosis.

(00:10:48): Fragility Fractures, However, that's only one way of diagnosing osteoporosis. You could have a normal bone density scan or a bone density scan that shows osteopenia, which is slightly reduced bone density, and still have osteoporosis if you have a fragility fracture. A fragility fracture is a fracture that exists, that would not have occurred in normal or healthy bone.

(00:11:15): Some examples of this would be a hip fracture if you fall from standing height. If you're walking on the sidewalk and you trip and fall and fracture your hip, that means you have clinical osteoporosis, regardless of the bone density measurement. And that's because a hip fracture couldn't occur from standing height in healthy bone. Now, it's a different situation if you fall from a height off a ladder, off a tree or a roof or if you had significant trauma such as a car accident. But in general, a low trauma event like falling from standing height should not lead to a hip fracture and it means that you have osteoporosis if that occurs. A vertebral fracture that's found after a fall from standing height is also consistent with osteoporosis, as well as a humerus or arm fracture or a pelvic fracture if you have osteopenia.

(00:12:16): Any of those fractures with lower bone density indicate that you also would have clinical osteoporosis. Likewise, if we find vertebral fracture on imaging, which means you would have osteoporosis as well, regardless of the bone density score.

(00:12:33): Fracture Risk Assessment (FRAX)

The last way in which we diagnose osteoporosis is with something called the FRAX score, which is the fracture risk assessment. And this is a score that takes into account certain demographic factors and predicts your risk of having a hip fracture or a major osteoporotic fracture over the next 10 years. If your risk of a hip fracture is greater or equal to 3%, or your risk of a major osteoporotic fracture is greater or equal to 20%, then the consensus is that that risk is high enough that you should be treated for osteoporosis. These are the ways that we would diagnose or recommend treating osteoporosis.

(00:13:20): Now, I want to talk about a DXA scan or a dual energy X-ray absorptiometry scan. This measures bone density. It doesn't measure bone quality or geometry or any of those other aspects we mentioned, but it does measure density. A DXA scanner is a radiographic machine that produces high energy and low energy X-ray beams. That's why it's called dual energy. The amount of radiation that you get with a DXA scan is equivalent to an X-ray. That means it is very low radiation, much lower than a CT scan, for example.

(00:13:55): The X-ray beams come from a tube, filtered before going through the patient. We're going to look at a drawing of this in a minute. The X-rays that are absorbed by bone are measured for each beam, and then bone density is determined based on energy differences between the two beams. The radiation energy is then detected and then converted into this measurement of aerial density, which is why you'll see that's reported in grams per centimeter squared.

(00:14:28): How is the scan obtained? As I mentioned, it's essentially an X-ray. X-ray comes from an X-ray tube. It's a beam that's then filtered and passed through the patient. The energy that passes through bone is absorbed and then what is not absorbed by bone is detected on the other side. The difference between what is absorbed and what is detected is determined and then that's converted into that measurement in grams per centimeter squared.

(00:15:04): When do you get a bone density scan? Well, in general, screening guidelines vary, but most groups recommend screening in women who are age 65 or older, regardless of any other medical diseases or medications. The National Osteoporosis Foundation has additional guidelines. They recommend screening for women over 65, for men over 70, and also for post-menopausal women, and men in the 50 to 69 range, depending on risk factor profile.

(00:15:40): That means that if you have a family history, or you've been on prednisone, or you've been on other medications that lead to an increase of bone density loss you should be screened. And likewise, post-menopausal women, as well as men aged 50-69, with a fragility fracture as an adult should also be screened.

(00:16:01): This is for the general population, but what about in specific circumstances like in daily glucocorticoid use? If you're on steroids, then we have a lower threshold to screen, and again, the recommendations vary by group. The American College of Rheumatology recommends that all patients on glucocorticoids get a bone density scan at the start of treatment. If the adult or patient is 40 or older, they should have a bone density scan within six months of starting glucocorticoids, and adults under 40 should be screened with a bone density scan if they have a history of osteoporosis or other significant risk factors. Patients on glucocorticoids regardless of other medications and other conditions should have a bone density scan at the start of treatment.

(00:17:00): What about the transplant population? Ideally, a bone density scan should be obtained prior to transplant, and this is the case for solid organ transplants as well as bone marrow transplants. We should have a baseline bone density scan. The rate of bone density loss is highest in the first three to six months after BMT. We want to know prior to BMT what the baseline bone density is. You should get a repeat scan at least every two years. If your bone density is in the osteoporosis range, which is a T-score less than 2.5 or the osteopenia range, which is a T-score between -1 and -2.5, you should have a bone density scan every year if you're on steroids.

(00:17:52): We just talked about how osteoporosis is diagnosed. Now, let's talk about what you can do and how you can protect your bones after transplant.

(00:18:05): How often to get a bone density scan. As I mentioned, it's really important to get bone density scans, and these are not done routinely as much as we would like. Make sure your doctor or provider orders a bone density scan, if not before your transplant, then as soon as possible after transplant. And then you want to make sure you follow up with regular bone density scans, as I said, every two years if your bone density is in the osteoporotic or osteopenic range, and every year if you are on steroids.

(00:18:37): Many transplant centers, such as the one where I work at the Cleveland Clinic, work closely with the metabolic bone clinic. Patients who undergo transplant come to our clinic and get a full assessment on their metabolic bone health, ideally before transplant, but if not, as soon as possible after transplant.

(00:18:55): However, if there's not a metabolic bone clinic that's associated with your transplant center, you can request to see an expert in metabolic bone health. And this would be someone who has additional training in osteoporosis. They could be a rheumatologist like I am, an endocrinologist, an OB-GYN doctor, a family medicine doctor, a woman's health doctor. But essentially, you want to make sure that you have a metabolic bone expert meeting with you and reviewing your bone health and your risk factors for osteoporosis.

(00:19:27): Optimizing calcium intake. The next thing that we want to talk about is optimizing calcium intake. It's recommended that you get 1,200 to 1,500 milligrams of daily calcium, including dietary intake and supplements. The total intake can include dietary sources such as dairy and leafy green vegetables. There are many foods that are calcium fortified. However, if you're not getting enough from your diet, then you should add supplements to get to that 1,200 to 1,500 range. Many places online have information giving you the amount of calcium per food, and you could look up, for example, the Bone Health and Osteoporosis Foundation or the International Osteoporosis Foundation and you'll get a breakdown of how much calcium is in common foods.

(00:20:19): If you are going to take a calcium supplement, make sure that you take it at least twice a day and even ideally three times a day to maximize absorption. This is because we really can't absorb more than 300 to 500 milligrams of calcium at once. I tell my patients that they should be getting about 400 milligrams in the morning with breakfast, 400 with lunch and 400 with dinner. That would be an ideal regimen.

(00:20:50): It's also important to optimize vitamin D intake. Sources of vitamin D include vitamin D from the sun, vitamin D from diet and vitamin D from supplements. The National Osteoporosis Foundation recommends 800 to 1,000 international units of vitamin D per day for adults aged 50 and older. There is some controversy as to what level you should obtain on your blood work. At our center, we recommend having a level over 30. Some places have a different level that's recommended.

(00:21:24): It is possible to have too much vitamin D, although vitamin D toxicity is not a very serious health problem. If your level is above the normal range, I just recommend decreasing it to get it into the normal range. It's not going to cause a lot of harm, but your body doesn't need that much vitamin D.

(00:21:42): It is important to have vitamin D, though, because in order to absorb calcium we need adequate vitamin D. And in addition to the impact on calcium absorption, severe vitamin D deficiency may be important in neuromuscular weakness and falls. We want to make sure we have optimal vitamin D.

(00:22:03):Vitamin D supplements. Many patients are not able to get vitamin D from the sun or from diet such as milk. So that's when you really want to make sure you're taking a vitamin D supplement. The vitamin D supplement might be part of your calcium supplement. Some supplements such as calcium citrate or Citracal have calcium and D combined. So, check the labels really carefully in your supplements.

(00:22:27): Also, check your multivitamin that will have some calcium and some D, but you want to make sure you're getting about 800 to 1,000 of D if your D is in the normal range. If your D is low, then you will need to take a higher dose to get to normal range and I'll have you ask your doctor about what dose is appropriate for you. Sometimes if patients are very low, we do a high dose of 50,000 units one time a week for 12 weeks to get people into the normal range.

(00:22:57):Foods that contain vitamin D. Now, here's a list. It's a little hard to read; of foods that contain vitamin D. In general, fish, mushrooms and cheese are really high in vitamin D, and some other products as well. But many things are fortified, such as bread or tofu. I always tell patients to check labels carefully. If you're getting vitamin D solely from your diet, and a lot of people aren't able to, that's when you should really look to supplements to help.

(00:23:28): The Importance of Weight Bearing and Muscle Strengthening Exercise, The next thing that you can do in addition to calcium and vitamin D, is to make sure you're doing weight-bearing and muscle strengthening exercise. These are the two main types of exercise that are really important in bone health. Weight-bearing exercise includes running, jogging, walking, hiking, high-impact aerobics, dancing, stairs. But I always tell patients you don't have to run or jog.

(00:23:55): A lot of people can't run or jog, but walking is a very important form of weight-bearing. The importance of weight-bearing has to do with the cycle of bone remodeling. Bone is always being remodeled in your skeleton. That means that old bone is broken down and new bone is being built. And weight-bearing exercise impacts the cycle and helps stimulate that cycle of bone remodeling. That's why it's important.

(00:24:21): In terms of muscle strengthening, you want to be lifting weights using resistance bands. It doesn't have to be heavy, but you do want to have some impact on the bone. This can be lifting your own body weight, as in squats or lunges, functional moving, using free weights or bands, but it is important to do muscle strengthening as well as weight-bearing. Balance is an important component of this too because balance is something that can be improved.

(00:24:51): You can practice balance. If your balance is good, then you're less likely to fall, and if you're less likely to fall, you're less likely to fracture. So, balance is an important component of exercise.

(00:25:03): How much exercise do we recommend? You should really aim for at least three times per week and about 30 minutes per session. But I always tell patients to start at what you're able to do, and this might be a low level, this might be gentle walking on a flat surface, whatever the level is for you, start there and progress slowly.

(00:25:26):Exercising too vigorously can increase the risk of injury, including the risk of fracture, so you really do want to be careful. A lot of people walk their dogs, which is a great way of being outside and doing weight-bearing exercise. But I do caution patients to be really careful about walking dogs. I've had a lot of patients fracture by falling either from getting caught up in the leash or the dog kind of pulling them. When working out or when you're walking, think about all the ways you can minimize your risk of falling while you're doing it.

(00:26:03): Activities to Avoid if You Have Osteoporosis. That brings me to activities to avoid. You want to avoid things that put excessive force on your spine, especially in forward flexion. This is important because certain yoga or Pilates positions have you bending all the way forward or twisting, and that can put a lot of force on the spine and can actually increase the risk of compression fracture. I always recommend if you're doing a class, make sure you let the teacher know if you do have osteoporosis or osteopenia, that you want to be really careful with your spine. You want to avoid certain movements that put extra force on your spine.

(00:26:40): You also want to avoid activities that increase the risk of falling. These would be things like horseback riding or downhill skiing in some cases, although not in every case. I have many patients who do downhill skiing, but you do want to decrease your risk of falling and also avoid activities that require sudden forceful movement or require a twisting motion unless you're really used to this. Even twisting in yoga or Pilates can put extra force on the spine and lead to a fracture. Be really careful about the way in which you move your spine.

(00:27:18): I tell patients to avoid things like horseback riding, extreme skiing, downhill skiing, boggle skiing, bungee jumping if you have osteoporosis and particularly if you've had a fracture before.

(00:27:33): I also tell patients to be careful not to lift too much. For my patients with osteoporosis, I tell them not to lift more than 10 to 20 pounds. When you're doing weight-bearing exercise and lifting weights, you don't need to lift heavy weights. You can lift three pounds, five pounds. I have patients who lift one pound. It's not about the weight, it's about the repetitive motion of lifting something light over time.

(00:28:00): We also want to modify other risk factors. There are many risk factors that exist for osteoporosis. We're not going to go over all of them here. And obviously many of them cannot be modified. You can't change the fact that you have a family history of osteoporosis, for example. Advanced age or being a woman or having gone through menopause, those are all things we can't modify.

(00:28:25): Cutting back on smoking, excessive alcohol and caffeine consumption can improve bone health. But when it comes to smoking, excessive alcohol and caffeine consumption, that's where we can really cut back or stop to improve health overall, but also to improve bone health. If you're someone who has very low sunlight exposure or low vitamin D, you can optimize your vitamin D intake. If you are intolerant to dairy and you don't get a lot of calcium in your diet, you can take a supplement to make sure you're getting adequate calcium.

(00:28:52): There are many medications that lead to bone density loss and osteoporosis. And I always tell patients, if you need to be on steroids or a proton pump inhibitor or chemotherapy agents, then you have to be on those medications. We can't modify that, but we just want to be aware of what medications you're on because we can modify certain aspects.

(00:29:14): For example, proton pump inhibitors affect the calcium absorption in the gut. This means that if you're on calcium carbonate or Tums, it won't get absorbed properly if you're on a proton pump inhibitor such as Prilosec or Omeprazole or Protonix. But you could take Citracal or calcium citrate, that would be properly absorbed. It's just important to be aware of the medications you're on and of anything you can do to minimize your risk of osteoporosis and bone density loss.

(00:29:46): Low body weight, I want to mention, is a risk factor for osteoporosis. In extreme cases, I tell patients who are very, very underweight to try to get to a BMI of 19, but we do know that folks who've lost weight rapidly or who have always been at a low body weight have low bone mass and that leads to an increased risk of fracture.

(00:30:05): This brings us to what else can we do to prevent fracture. We talked about calcium and vitamin D optimization. We talked about getting bone density scans on a regular basis so that you are aware of what your bone density is. And then we talked about modifying those risk factors you can modify, but some people will need treatment, and this is beyond calcium and vitamin D.

(00:30:34): Who needs treatment for osteoporosis? Who needs treatment? Well, this is going to be people who have a T-score of -2.5 or lower or people who have had a fragility fracture such as a hip fracture or a clinical vertebral, humerus, pelvis fracture with osteopenia. If you've been found to have vertebral compression on an X-ray or on a CT scan, then you should definitely speak to your doctor or a bone health expert because this could mean that you have clinical osteoporosis regardless of bone density, but that would be an indication for treatment in and of itself.

(00:31:13):If the risk of fracture over the ten-year period, the FRAX is high, then we also recommend treatment. Some people who are on long-term prednisone require treatment even if they don't have any of the other things we just discussed. Just being on long-term prednisone at a certain dose means that you should probably be on treatment to prevent osteoporosis and fracture.

(00:31:38): So just to spend one minute on prednisone, if you're on chronic prednisone for more than three to six months at a dose of 7.5 milligrams a day or greater, then you should be treated, or you may need to be treated with osteoporosis medications. At our center, we would treat a patient who was on prednisone at a dose of 7.5 for three to six months or longer with medications to prevent bone density loss.

(00:32:07): Now, this is a somewhat controversial area because there's a lack of consensus about which patients should receive therapy to prevent bone loss and fracture in the transplant world, but certainly patients who have lung, heart, liver and bone marrow transplant who are going to be on prednisone at the dose of 7.5 or greater for three to six months should be treated with medication beyond calcium and vitamin D. There are many different societies that have guidelines for clinicians, but I just want to mention this because not everyone is aware of these guidelines. If you're going to be on prednisone for a long time, make sure you talk to your doctor about treatment with osteoporotic medication.

(00:32:50): Now, the duration of therapy of osteoporotic medication might be as short as just one year. It might be for a very short period of time while you're on the high dose steroids, but it should be something that's taken into account.

(00:33:07): Osteoporosis medications. Let's talk about osteoporosis medication now. We have mentioned nutrition, calcium, vitamin D. K2 is also something I get a lot of questions about. K2 is important in absorbing calcium and vitamin D. You're probably getting enough K2 in your diet.

(00:33:22): We don't recommend additional K2 supplements, but in addition to these dietary nutrition aspects, there are medications that prevent bone resorption. These are medications, such as calcitonin, SERMs, which would be Evista, for example. Bisphosphonates such as alendronate or Fosamax, and we'll talk about some others in a minute. And then anti-RANK-Ligand would be denosumab or Prolia. These are all medications that prevent bone breakdown.

(00:33:57): Then there are medications that build bone. These medications have really revolutionized the field of osteoporosis. This includes PTH analogs, which means parathyroid hormone analogs. They are medications that work like parathyroid hormone. They are called teriparatide or Forteo, abaloparatide or Tymlos. And then there is a sclerostin inhibitor, which is called romosozumab or Evenity. These are all very powerful medications that build bone. Your doctor would determine if you needed a bone-building medication or a medication that prevents bone breakdown.

(00:34:39): Now, we're going to talk a little bit about osteoporosis medications. Bisphosphonates make up the biggest category of [osteoporosis] medication that we use. They're the most commonly prescribed medications in this country and in the world. They come in pill form or an injection or an intravenous form. Alendronate, risedronate, ibandronate are all pills that are taken once a month or once a week. It's really important that when you take these medications that you take them first thing in the morning on an empty stomach and that you don't lie down or take anything else by mouth, including food or pills for 30 to 60 minutes. This is so the medication is properly absorbed. You should also take them with a tall glass of water to make sure that it goes down smoothly.

(00:35:34): Side effects of bisphosphonates. The most common side effect of these medications is that they can affect calcium and cause esophagitis or esophageal issues. They can worsen reflux disease, but they're fairly good at preventing vertebral and non-vertebral or hip fractures. An oral medication might be right for you, but again, this would be a conversation between you and your doctor or provider.

(00:36:00): Zoledronic acid or zoledronate is the IV version. It's the best version of the bisphosphonate medication. This is given as an infusion once a year. And again, it can affect calcium. It can also cause something called an acute phase reaction where you would get fever, joint pain, muscle ache and flu-like symptoms that last for several days. Out of all the bisphosphonates, zoledronate is the most effective, and we see the best data with this medication in the spine.

(00:36:35): I'm going to briefly go over some other medications, raloxifene or Evista is a serum, and it affects estrogen. This does a decent job at preventing vertebral fractures, but you can see it doesn't do as good of a job as our bisphosphonate medications, and we really don't have great data on hip prevention. For some people, this is the right choice though, because it also can reduce your risk of breast cancer.

(00:37:00): Denosumab is an injection medication given every six months. It is a very powerful medication at preventing bone breakdown and we see very good results with this medication in terms of fracture prevention. It can affect calcium and it can cause joint pain and muscle pain. The biggest issue with denosumab is if you stop it, there's an increased risk of fracture because you can rapidly lose bone density. So, I tell patients that you don't stop denosumab abruptly, and in fact, we usually don't like to stop it at all. If you're going to have to go on it, make sure you can continue it every six months, and if you have to stop it for some reason, talk to your doctor or provider about how to do that safely.

(00:37:43): Teriparatide and abaloparatide are medications that act like parathyroid hormones. They're given as daily injections and they're given for two years. These are medications that we don't give if you have a history of radiation. And that's because there was a previous warning that they can increase the risk of osteosarcoma in rats. However, they're very good at building bone. And lastly, romosozumab is a medication that probably has the best data for preventing vertebral fractures. It's given as an injection once a month, but we don't give it if you've had a heart attack or stroke in the past year because it has a black box warning that it increases the risk of these events.

(00:38:22): Summary. With all the bone building agents, we have to follow them with a medication that prevents bone breakdown, I can talk about that more in the question section. I am going to wrap up this part of the talk. We talked about how BMT can impact bone health, why osteoporosis and bone density loss matter, how osteoporosis is diagnosed, and then how to protect your bones and the steps you can take to prevent osteoporosis and fracture. I will be very happy to take any questions that you have.

Questions and Answers

(00:38:54): [Susan Stewart]:   Thank you, Dr. Keller, for an excellent presentation. We have a lot of questions and we're going to try to get to as many as we possibly can. And we'll start with this one. Due to GI issues, I cannot eat enough calcium for my osteoporosis, what do you recommend?

(00:39:13): [Dr. Sarah Keller]:  Yeah, this is a very common issue, and a lot of calcium can cause GI issues. And in this setting, I recommend a supplement and I'd recommend something like calcium citrate or calcium carbonate. As I mentioned, if you are on a proton pump inhibitor, make sure you take calcium citrate or Citracal as that will get absorbed better than calcium carbonate.

(00:39:39): [Susan Stewart]:   All right, next question. Can decreased bone mass weaken one's teeth as well?

(00:39:47): [Dr. Sarah Keller]:    Not generally speaking. Teeth metabolism is different than bone metabolism. The pathophysiology and the changes there are very different, but bone weakening can affect the jawbone.

(00:40:02): [Susan Stewart]:   Okay, next question. Is there a safe level of prednisone? How low does the dose need to be to reduce the risk?

(00:40:11): [Dr. Sarah Keller]:   Well, that's a great question and this is something that we discuss all the time in my field because we prescribe a lot of prednisone. As I mentioned, if you're on 7.5 milligrams a day or more, that we know has a significant impact on the bone. Generally speaking, if you're at five milligrams or lower, we don't think this impacts the bone quite as much.

(00:40:33): However, it's not clear if there's really a safe level of prednisone as any additional prednisone you take can cause some side effects and toxicity. But under five, I would say the risk on the bone is low enough that you wouldn't need treatment just for that level of prednisone.

(00:40:52): [Susan Stewart]:   Great, thank you for that. Next question. Is a loss of several inches in height within a year or two likely to be due to compression fractures?

(00:41:03): [Dr. Sarah Keller]:   That's a great question. You definitely want to report any loss of height to your doctor or provider. Now, there are many different causes for height loss, but several inches in one to two years would be concerning to me and I would certainly get x-rays of the spine to make sure there's no compression. So anytime you've had two inches of height loss or more, we want to evaluate and make sure it's not due to compression of the spine.

(00:41:29): There are other causes of height loss. You can have degenerative disc disease for example, or osteoarthritis in the spine, and that can lead to height loss. But certainly, anything over two inches, make sure you mention this, and I would recommend getting x-rays to see if it's due to osteoporosis.

(00:41:47): [Susan Stewart]:   Okay, thank you. The next question. Does topical estrogen help diminish the progression of osteopenia?

(00:41:56): [Dr. Sarah Keller]:  Oh, this is a great question, actually. And I have to confess, I don't have all the data at my fingertips, but estrogen in general, as I think this person knows, does decrease the risk of bone loss. So, if you go on hormone replacement therapy with estrogen, that can decrease the risk of bone loss.

(00:42:17): Topical estrogen such as a patch probably does as well, but not to the same extent as oral estrogen. However, I do believe there's data that topical estrogen does decrease the risk of bone density loss.

(00:42:31): One thing I didn't mention is that when you go through menopause, you can rapidly lose bone density. You can lose up to 10% of your bone mass per year for 10 years. For women, going through menopause is one of the biggest risk factors for osteoporosis. And there are many situations in which hormone replacement therapy, either with oral or topical estrogen, is the right treatment. So that's something you should definitely talk to your doctor about if you're interested.

(00:42:58): [Susan Stewart]:    Great. All right, the next question is about CAR T-cell therapy. Does CAR T-cell therapy also impact osteoporosis?

(00:43:07): [Dr. Sarah Keller]:   This is a great question and I know the title of my talk was Car T, and I didn't talk about it nearly as much, and that's because we don't have as much data on CAR T therapy when it comes to bones. We don't think it decreases bone density loss to the same extent as BMT. So, there is not the same association with CAR T therapy as there is with bone marrow transplant.

(00:43:36): [Susan Stewart]:   All right. Next person wants to know if you have severe osteoporosis, is it okay to go to a chiropractor for treatment?

(00:43:45): [Dr. Sarah Keller]:   Oh, this is a fabulous question. This is a question I get every day. What I tell my patients is that you want to make sure you tell anybody you're seeing whether it's a chiropractor or you're going for a massage or physical therapy, anyone who's going to be putting hands on your body, you want them to know that you have osteoporosis, and that if it is severe, then you certainly want to tell them that.

(00:44:07): Now, the thing about going to a chiropractor is that some of the manipulation they do can increase the risk of fracture. So, when my patients ask me for my opinion, I often say that if you have severe osteoporosis or you've had a fracture in your spine, then I would not personally go to a chiropractor.

(00:44:27): However, I know there are many excellent chiropractors out there, and if you let them know about the degree of osteoporosis, perhaps they can modify their adjustments. But the nature of going to a chiropractor is that they're going to be putting pressure on your spine, sometimes cracking the spine. And this is where we need to be very mindful about the increased risk of fracture. At the very least I would tell your chiropractor you have severe osteoporosis, and if you've had a fracture or your bone density is very low in your spine, I would really think twice about having somebody put pressure on your spine.

(00:45:03): [Susan Stewart]:   Okay, next question. Does the form of calcium matter in calcium supplementation?

(00:45:11): [Dr. Sarah Keller]:   That's a great question. Generally speaking, no, although I did mention before if you're on a proton pump inhibitor or a medication that decreases stomach acid, you want to be on calcium citrate. The other thing is if you've had kidney stones, you also want to be on calcium citrate because the citrate component helps decrease kidney stone formation. I often recommend calcium citrate for those reasons, because many people have either had a kidney stone or are on a proton pump inhibitor. If you don't have those conditions, however, then you could take something like calcium phosphate or calcium carbonate.

(00:45:50): [Susan Stewart]:   How often should a person with multiple myeloma get zoledronate infusions after a bone marrow transplant?

(00:46:01): [Dr. Sarah Keller]:   That's a great question because zoledronic acid is used to treat multiple myeloma. It's also used to treat other cancers such as breast cancer or prostate cancer to help prevent metastasis to the bone. In these cases, we work really closely with your transplant team and your oncologist. From a bone perspective, if you're on the zoledronic acid to treat osteoporosis, and that's the only reason, then we give it once a year.

(00:46:33): However, if you're on zoledronic acid to treat multiple myeloma, it's given much more frequently. And if you undergo a transplant and you no longer need that zoledronic acid for the myeloma itself, then we would time it once a year for osteoporosis. However, it's a very close discussion between all the different providers because the dosing is different based on the condition we're treating.

(00:46:58): [Susan Stewart]:   All right, the next person would like to have you discuss avascular necrosis, also very common with the use of steroids. What are the treatment options?

(00:47:07): [Dr. Sarah Keller]:   This is a great question, and yes, it's unfortunately very common. This is interesting because it was thought that bisphosphonates such as zoledronic acid treated avascular necrosis, and I'll just mention just so we're on the same page, AVN or avascular necrosis is death of the bone, and it can happen in certain conditions. It can happen with high dose prednisone use or significant prednisone use. It was thought that bisphosphonates treat avascular necrosis.

(00:47:36): However, the data is really not very compelling. In our center, we don't use bisphosphonates to treat AVN solely. In terms of treatment options, physical therapy, pain management, and when it's severe, those patients undergo hip replacement if it's in the hip, or surgery depending on the joint affected. But we don't use bisphosphonates to treat AVN itself.

(00:48:05): [Susan Stewart]:   Does the carbonization in seltzer water contributes to additional bone loss?

(00:48:13): [Dr. Sarah Keller]:   Great question. I'm a big fan of carbonated water, so I looked this up myself specifically. No, it does not. If you have seltzer without additional caffeine, bubbly water for example, that does not increase the risk of bone density loss or fracture. However, sodas that are dark-colored such as Pepsi’s and Cola's that have caffeine do increase the risk of fracture. And we recommend cutting back on those kinds of sodas. They have caffeine, which can be a risk for osteoporosis in large amounts. They also have phosphoric acid. For those reasons, I recommend avoiding the darker colored Cola's, but bubbly water and seltzer are totally fine.

(00:48:57): [Susan Stewart]:   If you take weekly dexamethasone, do you convert that to the equivalent of daily prednisone to understand risk?

(00:49:07): [Dr. Sarah Keller]:   That's a great idea, yes. That's what I would do. I would convert that to get an equivalent of prednisone because the recommendations and guidelines really look at prednisone. If you can convert that or have your doctor do it, and if that dose is more than the equivalent of 7.5 milligrams a day for three to six months, then yes, you would qualify for therapy to prevent osteoporosis. But that's a very good point. We have many different kinds of glucocorticoids and steroids that we use, and we have to convert those numbers to the prednisone equivalent to determine the risk.

(00:49:45): [Susan Stewart]:   What can I do to treat the damage the lesions do to my spine and sacrum, compression fractures in lumbar, thoracic and sacrum? I still struggle to walk long distances, and at the end of the day, I'm usually in pain, particularly if I had an active day.

(00:50:05): [Dr. Sarah Keller]:   Well, first of all, I'm so sorry to hear that you had fractures, and the pain can last for a long time after fracture, sometimes as long as six months. It depends on the kind of fracture, but if you have fractures in the spine, there is data that calcitonin can help with pain from those fractures. That is something you could ask about. It's a nasal medication that you would use to help with pain. It used to be used to treat osteoporosis, but it's not as good as some others. So, you could ask about calcitonin.

(00:50:38): However, there are also procedures that could be done if someone has had vertebral fractures, which is called kyphoplasty. This is not recommended for everyone though. Most people who have a vertebral fracture heal on their own, but it can take a very long time. What we usually do is have you meet with a spine doctor as well and work on pain control, sometimes therapy, but it can take a very long time to recover. You should go back to baseline in terms of your pain. Then your mobility should go back to baseline too. But it can take many, many months if you have had those fractures.

(00:51:18): Make sure you talk to your doctor about going on a medication that builds the bone if you're a candidate for a bone building medication too, because there's some thought that the PTH analogs — I mentioned, Forteo or Tymlos — can actually help with fracture healing. I would ask your doctor about calcitonin, Forteo or Tymlos if you're a candidate for those because they can all help with the pain and fracture healing process. Otherwise, it's really supportive care.

(00:51:48): [Susan Stewart]:   All right, this person wants to know, her doctor has prescribed Xgeva every three months, and she's wondering if that's too often.

(00:52:00): [Dr. Sarah Keller]:   That's a great question. Xgeva is another name for denosumab. Denosumab, when it's used for cancer reasons, is called Xgeva. When it's used for osteoporosis, we call it Prolia. For osteoporosis, we give it every six months. When it's used for cancer reasons, it's actually given more frequently, and it has been studied to be given every three to four months.

(00:52:20): But I would definitely ask your doctor what protocol they're following, because if the protocol is treating cancer, that's one thing. If the protocol is for osteoporosis, then it should be every six months. Also remember that you can't stop that medication abruptly because you can lose bone density rapidly and have a fracture. There are some providers out there who are giving a medication like Xgeva for five years and then stopping it abruptly. So be aware that if you're going to stop it, you should go on another medication so that you don't rapidly lose bone.

(00:52:56): [Susan Stewart]:   For spinal pain, I've had MedX physical therapy recommended, which uses significant resistance while bending back. Is this not a good idea if you have osteoporosis?

(00:53:10): [Dr. Sarah Keller]:   Right. I would just be very cautious about bending the spine and I do tell people to avoid fully bending their spine either forward or backward, also to avoid twisting. As I said before, you could tell the therapist you're working with that you have osteoporosis and don't want to put undue pressure on your spine. If you're doing exercises at home, I would definitely recommend avoiding fully bending over or bending backwards or twisting because this can lead to an increase in fracture of the spine.

(00:53:41): [Susan Stewart]:   Do topical steroids affect the body the same way as systemic steroids, for example, skin creams and Restasis eye drops?

(00:53:56): [Dr. Sarah Keller]:   That's a great question and the answer is no. Oral steroids, IV steroids, those injection steroids, increase the risk of bone loss much, much more than topical steroids or steroid eye drops. However, if you do use medications like steroid eye drops for a long period of time, that can cause other issues such as an increased risk of glaucoma and pressure changes in the eye.

(00:54:22): What I tell patients is that those oral steroids and IV steroids pose the biggest threat. Having steroids injected into a joint such as a knee is not nearly as concerning from a bone loss perspective. Topical steroids are far, far less concerning, as are nasal steroids. If you're inhaling steroids through an inhaler or using nasal steroids, those are also less concerning. They pose less of a risk. Topical poses the least risk because it's not all absorbed systemically. In fact, very little is absorbed systemically. So no, the risk for topical is not concerning to me at all.

(00:55:01): [Susan Stewart]:   “I was taking an Xgeva every three months as part of my multiple myeloma treatment. I just had an autologous stem cell transplant and my Xgeva has been stopped for three months. Should I be taking it?”

(00:55:18): [Dr. Sarah Keller]:   You can be off a medication like Xgeva for several months. The data we have for osteoporosis is with Prolia, and we give it every six months. There are different protocols obviously for bone marrow transplant when Xgeva is being used, and I would just ask your doctor to confirm that there's no loss of bone from stopping Xgeva. But if you're off for only three months, that shouldn't be a problem. It's really when you are off it for long periods of time, six months or longer. But I will say that in different fields, denosumab, Xgeva in oncology, Prolia in osteoporosis, is dosed differently. I have seen a lot of variation with this. Therefore, it's worth having a conversation and talking to your doctor or provider just to make sure that you're not going to rapidly lose bone if you're off for too long. Three months shouldn't be too long, but I think it's still worth having a conversation about the dosing interval and dosing frequency.

(00:56:21): [Susan Stewart]:   This person would like you to discuss Reclast infusions, when they're appropriate to use?

(00:56:29): [Dr. Sarah Keller]:   Reclast is zoledronic acid. In the osteoporosis world, we call it Reclast. In the oncology world, it's called Zometa. Our dosing for osteoporosis is five milligrams, once a year. I generally use Reclast quite frequently because it works really well. The data's very good at preventing hip and vertebral fracture and it's easy for patients because it's not a pill that you have to take a certain way that you could forget. It's an infusion that we give once a year. There are many, many patients for whom I prescribe this medication. If you've had a fracture, it's also a good medication because it prevents fracture in the spine and hip with pretty good numbers. It's not as good as a bone building agent, so if somebody has had a hip fracture, I might use the PTH analog or Evenity instead.

(00:57:25): But then again, a lot of this is based on patient preference and sadly, on insurance. Sometimes we do use Reclast for patients who had hip fractures as well, but essentially anybody with osteoporosis or osteopenia with an increased risk of fracture could be a candidate for Reclast, as long as their kidney function is adequate. You can't have injured kidneys or severe kidney disease and get Reclast because it could injure the kidneys further, so there is that consideration. You also have to have normal calcium to get Reclast, but it's a great medication for people with osteoporosis.

(00:58:01): [Susan Stewart]:   Are whole-body vibration devices good for osteoporosis or avascular necrosis?

(00:58:09): [Dr. Sarah Keller]:   The data here is really not complete. What I would say is that what I recommend is weight-bearing exercise. It doesn't necessarily need to be a whole-body vibration device, and I wouldn't recommend this if you have AVN, but you could consider using it. I have many patients who do, although there's no data saying that this is better than what we recommend, which is standard weight-bearing and resistance bands and weights.

(00:58:44): [Susan Stewart]:   Okay. And unfortunately, this is going to have to be our last question. We're running out of time, but the question is with myeloma and a lot of lytic lesions in the ribs, back and shoulder, which doctors are the best ones to work with for my bone plans?

(00:59:00): [Dr. Sarah Keller]:   Oh, that's a great question. I think what you want to do is make sure you get a bone density scan and see if you have osteoporosis. If you do, you want to see a metabolic bone doctor, and you don't have to have osteoporosis to see a metabolic bone doctor. You could have height loss, or you could have a family history, or you could have other conditions that put you at risk. Even if you haven't had a bone density scan, you can see a metabolic bone doctor to be evaluated. I don't think it ever hurts to ask for a referral to someone if you have a question about bone conditions such as osteopenia or osteoporosis.

(00:59:37): [Susan Stewart]:   And with that, we're going to need to end the workshop. I want to thank you on behalf of BMT InfoNet and our partners. I'd like to thank Dr. Keller for a very helpful presentation and for the audience who sent in many, many good questions. They were very enlightening. Please contact BMT InfoNet if there is anything else we can do to help you and enjoy the rest of the day and the rest of the symposium week. Thank you.