Bone Health after Transplant

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Bone Health after Transplant

Wednesday, May 3, 2023

Presenter: Mona Al Mukaddam MD, MS, Hospital of the University of Pennsylvania

Presentation is 34 minutes long with 17 minutes of Q & A

Summary: Stem cell transplant recipients are at an elevated risk for osteoporosis and bone fractures after transplant which can be disabling or life-threatening.  Learn who’s at risk and screenings and treatments options that can help prevent fractures due to bone loss.

Highlights:

• Osteoporosis refers to porous bones that are low in density and at risk for breaking. It  is a common condition in older adults and is associated with significant mortality and morbidity.
• Transplant recipients often have a significant decline in bone density in the first year after transplant. Transplant recipients have about an eight-fold greater risk of fractures compared with the general population.
• Bisphosphonates are highly effective medications for preventing osteoporosis and fractures. Serious side effects of bisphosphonates are rare, and benefits usually outweigh the risk of these of taking this medication.

Key Points:

(03:01): A fracture is often the first sign of osteoporosis.

(04:39): Risk factors for osteoporosis include family history, smoking, and a low body mass index

(10:48): Osteoporosis can be diagnosed through several methods including a DXA scan.

(14:06): A trabecular bone score (TBS) provides information about the texture of the bone and help risk stratify patients for potential fracture.

(18:46): Recipients of an allogeneic transplant (using donor cells) have greater bone loss than patients receiving autologous transplants (using their own cells).

(19:44): Transplant recipients have additional risk factors for osteoporosis compared to the general population.

(20:43): Adequate intake of calcium is important to lower the risk of osteoporosis.

(22:00): Lifestyle changes can also reduce the risk of osteoporosis in transplant patients.

(22:23):  Frequent scans before and after transplant are recommended to monitor bone density.

(26:14): Estrogen has also been shown to be highly effective at decreasing the risk of fractures.

Transcript of  Presentation:

Note: In this presentation, when the speaker uses the term bone marrow transplants, it includes stem cell and cord blood transplants as well.

(00:00): [Michala O’Brien]:  Introduction. Welcome to the workshop, Bone Health After Transplant. My name is Michala O’Brien , and I will be your moderator for this workshop.

(00:07): It is my pleasure to introduce you to today's speaker, Dr. Mona Al Mukaddam. Dr. Al Mukaddam is an associate professor in the departments of Medicine and Orthopedic Surgery at the Hospital of the University of Pennsylvania. She is also the Director of the Penn Bone Center, where she manages patients with metabolic bone disease after solid organ and stem cell transplants. Please join me in welcoming Dr. Al Mukaddam.

(00:36): [Dr. Mona Al Mukaddam ]: Overview of Talk. Thank you for this kind introduction and for the opportunity to discuss this really important topic. These are my disclosures. I do receive research funding from Ipsen/Clementia, Incyte and Regeneron, and all of that is related to my work in a different disease called fibrodysplasia ossificans progressiva. And so, none of the disclosures are related to the topic that I'm discussing today.

(01:02): For today's talk I'm going to be talking about osteoporosis and low bone mineral density and familiarize you with the terms used in those definitions. I'll talk about the prevalence of low bone mineral density as well as fractures after hematopoietic cell transplant, and I'll identify some of the factors that could contribute to low bone mineral density in both the general population as well as in post-transplant patients. I'll try to review some of the published guidelines about screening and management of low bone mineral density, but a little disclosure, I will be giving you some of my personal recommendations and some of the things that I do in my clinic.

(01:54): Osteoporosis refers to porous bones that are low in density and at risk for breaking. What is osteoporosis? If you look at the term, osteo means bone, porosis means porous bone, so there's holes in the bone. It's bone that is low in density, meaning that you have less bone, it's weak and has a high risk of breaking.

(02:13): If you look at the figures below, the one on the left side, is an image of a bone from the spine of someone who doesn't have osteoporosis. You can see in that figure that this is a figure of a vertebral where there's a lot of bone the bone is very well-connected, and this is strong bone.

(02:36): The figure on the right is that of someone with severe osteoporosis. Not only is the bone less dense, so there's less bone, but you can see that there's a big hole in this bone. So, these bones are not well-connected, and the hole in this bone will make this structure very weak. It can break very easily.

(03:01): A fracture is often the first sign of osteoporosis. What are the symptoms of osteoporosis? Well, unless someone has a fracture, you're not going to know that you have osteoporosis. Osteoporosis is a silent disease until a fracture occurs.

(03:14): Osteoporosis is common and is associated with significant mortality and morbidity. The reason why we care about osteoporosis so much is because one, it's very common; two, it has a lot of associated mortality and morbidity. About 50 million Americans are living with low bone mineral density or osteoporosis that's responsible for about two million fractures yearly. These fractures can be associated with significant mortality and morbidity.

(03:44): In older patients, osteoporosis and surgical remedies can compromise quality of life. In all older patients, after they have a hip fracture, they usually require surgery. That surgery comes with a lot of complications and some patients do not survive the surgery.

(03:55): Also, fractures are associated with significant pain patients after fractures, whether it's hip fractures, compression fractures in their spine or wrist fractures. Many patients lose a lot of their independence. They might require a walker after a fracture. They might require a living in an assisted home after a fracture. It can be associated with significant respiratory and GI issues as well, especially the compression fractures in the spine.

(04:23): All these things are associated with significant healthcare costs. The problem that we face is that because osteoporosis is a silent disease, it continues to be underdiagnosed and treated.

(04:39): Risk factors for osteoporosis include family history, smoking, and a low body mass index. So, who's at risk? As I mentioned, it's a very common disease in the overall population, but if someone has a family history of osteoporosis such as your mom or your dad has an osteoporotic fracture or they have osteoporosis, if you're currently smoking, if you're very thin and have a low BMI (body mass index), if you've had a personal history of fracture, then you're at increased risk of having more fractures.

(05:04): What I tell my patients is that what's good for your overall health is also good for your bones, and usually things that are not good for your overall health are also not good for your bones. Excessive alcohol intake, caffeine intake, and soda intake can have negative effects on bone quality.

(05:20): Medications like glucocorticoids can negatively affect bone quality. And then medications. There's a whole slew of medications that can have negative effects on bone quality. The most prescribed medication, and the one that has the most negative effects on bone quality, is prednisone or in the class of medications that we call glucocorticoids. That includes hydrocortisone, dexamethasone and solumedrol, but prednisone is the most widely prescribed medication. There's also data on high doses of proton pump inhibitors, which are acid suppression medications, as well as seizure medications.

(05:54): And then there are a lot of medical conditions that can be associated with osteoporosis such as hypogonadism or early menopause, so low estrogen in women and low testosterone in men, diabetes, celiac disease, and the slew of other medications that are associated with osteoporosis.

(06:20): Primary preventive screening is an important tool to evaluate bone density and the risk of osteoporosis. Osteoporosis is a silent disease and we want to really try to prevent fractures. So, that's why it's really important to screen for osteoporosis before a fracture happens. That's called primary prevention. The good news is that we do have a very safe and non-invasive technique to try to measure bone mineral density. It's not a perfect technique, it has a lot of limitations, but at least we do have something that is widely available. It's non-invasive, very low dose of radiation, and it can measure the bone density in certain areas of the body, predominantly the hip, spine and potentially the forearm. Then we compare this bone marrow density to a normative database.

(07:09): The next two slides are a bit complicated, but I will spend some time on them just to get you familiar with some of the terms that we use when we're trying to risk stratify our patients and when we're trying to diagnose people with osteoporosis, or osteopenia, or low bone mineral density. These are two terms that you need to know. One is called a Z-score and on the next sllide, I'll talk about the T-score.

(07:34): The Z-score is the standard deviation variance of the bone mineral density measured in the patient and compared to the mean bone mineral density of an age-matched adult reference population. Basically, I'm comparing the patient's bone mineral density at the time of a DXA to their own cohort and we're saying, "How far is the patient from this average bone mineral density?"

(08:03): We use the disease core in our younger patients, and the premenopausal women and men ages 50 and below. If someone's bone mineral density is more than two standard deviations below the average bone mineral density of someone of comparable age, then we say that their bone mineral density is below what is expected for their age. You can see this on this bell curve that this is the normal bone mineral density distribution in the general population. The people at this end tail on the left side are the ones that have low bone mineral density. It's below what is expected for their age, but it could still be normal. It could still be within this normal bell curve, but we just say below what is expected for their age.

(08:55): On the flip side, T-score is the standard deviation variance of bone mineral density from the mean bone mineral density of a young adult reference population. The T-score is basically comparing the bone mineral density of the patient to an ideal or the peak bone mass. And we're saying, "How far are they from this ideal bone mineral density?" We use the T-score in post-menopausal women and men age of 50 or above. A T-score at -1.0 and above is considered normal. Low bone mass, or the term osteopenia, which we don't like to use, is a T-score between -1 and -2.5. And osteoporosis is defined as a T-score at or below minus 2.5. Patients who are in this group where their T-score is minus 2.5 or below who also have a history of fractures, these patients have severe or established osteoporosis.

(10:03): Now, the reason why we use T-score in our older patients is because we appreciate that the risk of having a fracture increases exponentially as we get older. I were to use a Z-score in my 80-year-old patients, I can say all these 80-year-old patients have similar Z-score to each other, they have similar bone mineral densities. But then I would be missing the fact that these patients are at really high risk of breaking bones. If I were to use a Z-score, all these 80-year-olds might give themselves high-fives like, "Hey, hey great, we have very similar BMDs," but a large subset of them really have a high risk of fracturing. So, that's why we use the T-scores instead of the Z-scores in our older patients.

(10:48): Osteoporosis can be diagnosed through several methods including a DXA scan. How do we diagnose osteoporosis? If you go back to the first slide that I showed you, osteoporosis is basically low bone density, bone that is weak, and is more likely to break. That's the true definition of osteoporosis. But in the clinic, how can I make that diagnosis? There are several ways I can do that. One is by looking at the T-score. A T-score of minus 2.5 or below on a DXA scan in postmenopausal women and men 50-years old or above, can be used to diagnose osteoporosis.

(11:21): Also, any patient that has a history of a fragility fracture, meaning a low trauma fracture, a fracture from a fall of less than standing height, are diagnosed with osteoporosis, because these patients are telling me that the quality of their bone is not very good and they've already broken their bones. That diagnosis can be made regardless of their DXA scan results.

(11:46): There's a subset of patients that have osteopenia or have a low bone mass. And if we look at their other risk factors, like if they've had fractures before, if their parents have had a fracture, or if they have a low BMI, we can calculate their risk of having a fracture in the coming 10 years. If their risk is more than 20% for all major osteoporotic fractures or more than 3% for hip fractures, we can diagnosis them with osteoporosis as well.

(12:21): There are multiple risks for osteoporosis independent of bone mineral density. What is FRAX? The way I try to explain it to my patients is that we talk about osteoporosis, but what I really care about is their risk of breaking a bone. And what I'm really trying to prevent is a fracture. We all appreciate that low bone mineral density is one of the risk factors that can contribute to an increased risk of fractures, but a lot of other factors play a role, as well. Age is a huge risk factor. The older you are, the more likely you're going to break bones. Females are more likely to break their bones than males. Also, weight. and if the patient has had previous fractures, or their parents have had hip fractures, if they're smokers, if they're currently getting prednisone, if they have rheumatoid arthritis, if they're drinking excessive amounts of alcohol, there's a lot of risks, independent of bone mineral density, that can be associated with increased risk of fractures. So, that's why FRAX was developed.

(13:26): There are a lot of other fracture tools available worldwide, but a lot of the guidelines published in the United States use FRAX to better risk stratify patients. So, that's where you get this 10-year probability of having a fracture and you get these two numbers for major osteoporotic fractures as well as hip fractures More than 20 for major osteoporotic fracture is high, more than three for hip fracture is considered to be high. As you can see in the table below, right under this red box, you can see there is a tab that says, "Adjust with TBS."

(14:06): A trabecular bone score (TBS) provides information about the texture of the bone and help risk stratify patients for potential fracture. TBS, trabecular bone score, is a relatively newer software that can provide information about the texture of the bone. Now we're not only looking at how much bone there is, but we're looking at the distribution of this bone. The trabecular bone score can be derived from spinal images obtained during the DXA scan. This is not an extra procedure that you have to get done. A lot of centers have that as part of their DXA machine, so at the same time when you’re getting your DXA images, they can also provide this trabecular bone score number.

(14:49): The trabecular bone score is used to better risk stratify patients. If someone has a low trabecular bone score, their calculated risk of having a fracture by FRAX will be higher. We don't use trabecular bone score to define whether someone has osteoporosis or not. We don't look at T-scores or Z-scores when it comes to trabecular bone score because they don't have the same meaning as bone mineral density. And we don't use them to monitor treatment effects, because we don't have any data to support the use of that to monitor treatment effects.

(15:29): Just to summarize some things about osteoporosis. Osteoporosis is very common in the general population. It affects both men and women, but women are more likely to break bones. It is a silent disease. You're not going to know that you have osteoporosis unless you break a bone, and that's why it's very important to do a DXA scan for screening prior to a fracture occurring.

(15:51): Since I've been invited to give this talk, you can imagine that this is probably also common in patients who have undergone hematopoietic cell transplant. So, I'll go over some of the data that has been reported specifically in patients after transplant.

(16:11): This is a paper that was published in May almost two decades ago. It looked at about 280 patients who received a donor stem cell transplant. These are allogenic transplants. They looked at the change in bone mineral density in these patients at three months, six months, 12 months, 24 months, 36 months and 48 months after their bone marrow transplant.

(16:40): People receiving allogeneic transplants (using a donor) can have a significant decline in bone marrow density in the first year after transplant. I'm going to focus on the two lines in the middle, so the one with the open circles, which is the spine, and the closed triangle, which is the femoral neck, which is part of the hip. Those are the two locations that we really look at. We don't really look at total body or the ward triangle. If you focus on those two lines in the center, you can see that in the first three to six months, you have a pretty significant decline in bone mineral density that persists to 12 months. But in the spine, there seems to be some recovery in the bone mineral density with time versus the femoral neck, which is part of the hip. The bone mineral density stays stable for the most part.

(17:26): What about fractures? As I mentioned, we talk about bone density, we talk about osteoporosis, but I really care about fracture risk. Well, this is a paper that was published in 2015. It was a retrospective study looking at over 7,000 patients who received a transplant. Some of them received an allogeneic transplant [a transplant using donor cells]. Some of them received an autologous transplant, meaning they received their own cells instead of donor cells, and there were several indications as to why they received their bone marrow transplant.

(17:56): When compared to the general population of comparable age, patients who received a bone marrow transplant had an eightfold risk of increased fractures than the general population. Not surprisingly, age was a huge risk factor. You can see on the figure on the right on top part, older patients, age 60 and above, had a significantly higher risk of breaking bones and had more fractures compared to the younger patients below the age of 60. Patients who underwent a transplant for multiple myeloma have a significantly higher risk of having fractures compared to those who received this for solid organ transplantation or hematological malignancies.

(18:46): Patients with allogeneic transplants have greater bone loss than patients receiving autologous transplants (using their own cells). In summary, we do recognize that bone mineral density declines after transplant and that usually happens in the first six to 12 months. There seems to be some recovery in the spine bone mineral density, but less so in the hip. We do recognize, I didn't present some of this data, that patients who received donor cells, the allogenic stem cell transplants, seem to have greater bone loss than patients who receive their own cells. That's probably because of the body's reacting to the donor cells more, so they have more prolonged and greater post-transplant cytokine release. They're more likely to develop graft-versus-host disease, and so they're more likely to be on prednisone and higher doses of immune suppression treatment which has been shown to be associated with an increased risk of fractures, especially in the older population.

(19:44): Transplant recipients have additional risk factors for osteoporosis compared to the general population. Osteoporosis, it's multifactorial. There are many reasons why someone develops osteoporosis, and that holds true in patients who underwent a transplant. Some of the risk factors of osteoporosis are similar in the transplant recipients as in the general population. But there are also other risk factors related to transplant such as graft-versus-host disease, hypogonadism or low estrogen or low testosterone, other comorbidities associated with low calcium, low vitamin D, being on steroids, chemotherapy, renal or liver dysfunction, and having multiple myeloma that can be risk factors as well.

(20:43): Adequate intake of calcium is important to lower the risk of osteoporosis. Guidelines. The take home message for me, my kids and all of my patients is to get adequate amounts of calcium. The recommendations can vary a little bit depending on age and sex, but in general we recommend about 1,000 to 1,200 milligrams of calcium a day. We really encourage our patients to get it through dietary sources like milk, cheese, yogurt, almond milk, more so than supplements. But if they do need to take a calcium supplement, try not to take more than 500 to 600 milligrams of calcium from supplements. For patients who've had stomach surgery, are on heartburn medications, or have GI graft-versus-host disease (GVHD), calcium citrate is better absorbed than calcium carbonate. Obviously, in patients who have malabsorption, they might require much higher doses of calcium intake.

(21:40): We aim for a 25 hydroxy vitamin D level, usually between 30 to 50 nanograms per ml, but we really try to shy away from excessive supplementation because excessive supplementation, especially with calcium, can increase the risk of kidney stones and maybe potentially cardiovascular problems.

(22:00): Lifestyle changes can also reduce the risk of osteoporosis in transplant patients. Exercise, fall prevention, physical therapy and early mobilization is extremely important. Smoking cessation and using the lowest dose of prednisone needed, and doing regular weight-bearing exercises is important as well. These guidelines are based on published guidelines, as well as my personal recommendations.

(22:23):  Frequent scans before and after transplant are recommended to monitor bone density. We recommend doing a DXA scan before a transplant for all adult patients aged 40 or above. And in our younger patients, we recommend doing a pre-transplant DXA if they've been on prednisone, five milligrams per day, for more than three months, or if they've had fractures. We recommend post-transplant DXA in the first year after a transplant for everyone, and then follow up DXAs every one to two years based on their ongoing steroid use or if their bone mineral density was low at baseline, and their Z-score is already less than minus two.

(23:11): Pharmacological treatment before transplant to minimize the risk of osteoporosis may be appropriate for some patients.  In terms of pharmacological therapy, I think that the recommendations are going to be extremely variable. We know that bone marrow density loss is going to happen after transplant, so should we aim for treatment before transplant in people who have a T-score of less than minus 1.5 (classically referred to as osteopenia) I think the people that we should definitely treat are the ones who have osteoporosis by DXA, or have had a fracture history, or have a very high risk of fracture. People who clearly have osteoporosis, those patients definitely should be on treatment. Treatment should also be considered in someone who's had significant bone loss on a follow up DXA scan.

(23:55): The good thing is we do have medications that are highly effective at decreasing risk of fractures and are relatively safe. We have medications that decrease bone loss, and I'm going to review them in this slide. And then we have medications that stimulate bone formation, and I'll go over some of those medications in the next slide.

(24:23): Bisphosphonates are highly effective medication for preventing fractures. The most widely studied medication in general, but also in post-transplant patients, has been bisphosphonates. Bisphosphonates can be given either in a pill form or as an infusion. They have been shown to be highly effective at decreasing the risk of hip fractures as well as compression fractures in the spine, anywhere from 40 to 70%.

(24:50): Things to think about if someone has a graft-versus-host disease is that want to try to avoid the orals because they can exacerbate or cause GI discomfort. With the infusion, the most common side effects are flu-like symptoms, but we really shy away from using them in someone who has kidney failure or kidney dysfunction. For patients in stage four, stage five or end stage renal disease, those medications are absolutely contraindicated.

(25:17): Denosumab is highly effective at reducing fracture risk. Denosumab (Prolia®) is given as an injection every six months. It's also highly effective at decreasing the risk of fractures. However, it can increase the risk of infection, so it's something you think about if someone is on immune suppression as well as on prednisone. It can cause pretty significantly lower calcium levels causing hypocalcemia in someone who has renal dysfunction or end stage renal disease. The other issue with Prolia® is that it's extremely reversible. Once you start taking this medication, you must continue it every six months. You can't abruptly stop it without talking to your doctor about a very cautious and good transition plan. In here there are two terms, AFF and ONJ, which are atypical femur fracture and osteonecrosis of the jaw, that I will talk more on the coming slide.

(26:14): Estrogen has also been shown to be highly effective at decreasing the risk of fractures. I do think that in younger patients, in younger women who've gone through early menopause or stopped getting their periods early, estrogen is something to consider. But you need to think about breast cancer risks, stroke, heart attacks, and blood clots with estrogen therapy.

(26:42): The other types of therapies that I talked about, the ones that stimulate bone formation, are very highly effective when thinking about compression fractures in the spine. All three of them have no data on decreasing the risk of hip fractures. The other thing is that, with the first two medications which are teriparatide (Forteo®) and abaloparatide (Tymlos®), those are given as subcutaneous injections that the patients would give themselves every day for two years. Those medications are contraindicated in patients who have had skeletal radiation or radiation to their bones. That's because of data that in rats that showed it can increase risk of bone cancer. We also don't give it to children with open growth plates.

(27:32): Romosozumab (Evenity®) that was just approved in 2019, so it's been on the market for four years. It has some of its own side effects. It does have a box warning about increased risk of heart attacks and strokes. Atypical femur fractures and osteonecrosis of the jaw have been reported with the use of Romosozumab (Evenity®). These are the medications that we have in the United States for treatment of osteoporosis in the general population.

(28:08): When it comes to transplant patients, bisphosphonates are still considered as a first line therapy and they've really been the most studied in transplant patients. Denosumab was only studied in 33 females, so we really have very limited data on the use of denosumab. Estrogen, I recommend it for my younger patients with hypogonadism or low estrogen. I was not able to find any studies with the use of teriparatide, abaloparatide (Tymlos®) or romosozumab (Evenity®) in transplant patients. That being said, I have used them in my patients, especially in patients who've had multiple compression fractures in their spine.

(28:50): Bisphosphonates are the medication that transplant recipients will be most likely to be prescribed to prevent osteoporosis.  The ones that we have available in the United States are alendronate (Fosamax®), risedronate (Actonel®), ibandronate (Boniva®), and zoledronic acid (Reclast®). The doses can be variable. Alendronate (Fosamax®) can be given daily, but we never do that. I usually give it 70 milligrams once a week. Risedronate (Actonel®) also can be given daily, weekly, or monthly, but I also prefer the weekly dose dosing. Ibandronate (Boniva®) can be given daily, monthly, or intravenously every three months. I rarely use ibandronate (Boniva®) because it does not have any data on decreasing risk of hip fractures, and it's one of the least potent medications that we have when it comes to bisphosphonate, so I don't use that frequently. What I do use most frequently is zoledronic acid (Reclast®) which is given as an infusion once a year.

(29:56): The side effects. I already saw one question about the dental issues, and so the reason why I put the slide in here with these ugly pictures isn't to scare you away from these medications. It's to show you that I acknowledge that these side effects can happen, but I want to really go over how rare these side effects are and to talk about the risk /benefits ratio as to why we prescribe these medications.

(30:22): Bisphosphonates can have side effects but their benefits usually outweigh the low risk of serious side effects. In bisphosphonates, the short-term side effects with the pill is really the stomach side effects. So, problems with swallowing, inflammation in the esophagus, and in the stomach, and it can cause ulcers.

(30:37): With the infusion, in someone who has underlying kidney failure, we do worry about worsening renal dysfunction or increasing in the creatinine. The most common side effects of the infusion is flu-like symptoms: muscle ache, low grade fever, just feeling unwell for two to three days after the infusion.

(30:56): In my practice, what I have been seeing is a lot of reluctance from my patients to receive these medications because they're so concerned about long-term side effects. The two side effects that get a bad reputation in the media are , first, atypical femur fractures, which is a stress fracture that can happen in the thigh bone. If you look in the figure below, this is an x-ray of the thigh bone where you can see some changes in the cortical bone. You can see near the arrow, where there's some thickening of the bone, that there's a small fracture line. It's very hard to see, but if you look at the figure next to it on the right, you can see that this bone just snapped and it broke, and that can happen without any trauma.

(31:42): That risk of atypical femur fractures is extremely low. The risk of that happening in the first three to five years while on bisphosphonates is close to one in 100,000 patient years. The risk increases tremendously the longer you are on these medications. If you've been on it for more than five years, that risk can go up to 100 in 100,000 patient-years. Whenever I'm prescribing bisphosphonates, I do this for three to five years. This is no longer a lifelong medication, and I really try to minimize these rare side effects.

(32:17): Osteonecrosis of the jaw is a very rare side effect of bisphosphonates. The other side effect that has been reported is osteonecrosis of the jaw. In my patients, if I'm seeing them for only osteoporosis and they don't have any other health issues, I usually tell them that you're more likely to be hit by lightning than that for osteonecrosis of the jaw to happen. But there are other risk factors that can cause osteonecrosis of the jaw such as radiation treatment, cancer, and being on steroids. In the transplant population, that risk of osteonecrosis of the jaw is going to be higher, and it's probably closer to one in 10 out of 1000, and not one in 100,000, which is what we quote for our other osteoporotic patients with no other health issues.

(32:59): What osteonecrosis of the jaw is, basically, is that the jawbone becomes exposed and can get infected. This is a really severe case of osteonecrosis of the jaw. There are different stages that can happen after invasive dental work, like a dental extraction or a dental implant. It does not happen with dental cleaning. That shouldn't be an issue. It's more with more invasive dental work that osteonecrosis of the jaw happens. Sometimes treating it with just oral antibiotics or even just swish and swallow antibiotics can help, but sometimes it requires more invasive procedures and debridement for the osteonecrosis of the jaw to heal.

(33:48): In summary, osteoporosis and fractures are common in the general population and are associated with significant morbidity and mortality. Hematopoietic stem cell transplant is associated with bone loss, and has been shown to increase risk of fractures, mainly in patients who are receiving glucocorticoids. Biphosphates have been shown to prevent bone loss in transplant patients and have been shown in the general population to be highly effective in decreasing risk of fractures. With that, I'm going to open the floor for questions, and thank you for your time and attention.

Question and Answer Session

(34:29): [Michala O’Brien]:  Thank you, Dr. Al Mukaddam, for this excellent presentation. We'll now begin the question-and-answer session today. Our first question is, "What are the treatments available for transplant survivors with osteoporosis and bone fibrosis?"

(34:46): [Dr. Mona Al Mukaddam ]: I think I did mention some of those treatment options. Definitely, you need to talk to your doctors about other comorbidities. We went over a lot of those treatment options, but you really want to see what other health issues you might have, to see if there are any contraindications for using these medications.

(35:11): What is important to note? Some of the things that I talked about in terms of lifestyle changes, calcium, and vitamin D. Those things are extremely important and do not replace pharmacological therapy. If you were to start medications, it doesn't mean that you can slack off on all the other things. You really need to continue to do all those other things and discuss additional medications. But usually, it's going to be bisphosphonates.

(35:39): [Michala O’Brien]:  "I currently have osteopenia and I have been told I need Reclast®. How long after visiting the dentist can I wait before having Reclast®?"

(35:50): [Dr. Mona Al Mukaddam ]: This is a very important question and really that's why I put this out there. It all depends. You're going to go see the dentist and if the dentist is just doing a dental cleaning, then you can get your infusion the next day and it shouldn't be a problem. If you are undergoing a dental extraction or a dental implant, I would usually talk to your dentist and say, "Is everything healed? Any more plans for other invasive dental work?" And if there really isn't, then I would go ahead and schedule the infusion of Reclast®.

(36:22): That being said, a lot of my patients get their infusion and then six months later ,they have an infection in their tooth and they need to get dental work done. At that point, I would have a discussion with the dentist. If they need to get the dental work done, let them go get the dental work done. The risk is still very low for osteonecrosis of the jaw to happen. And if someone needs the dental work ,and it's emergency-necessary, then go ahead and get the dental work done. I'm always happy to talk to dentists about the risks and benefits of certain medications, but if someone's actively having fractures, they've broken every single bone, I'm going to start treating them. I don't want them to have a hip fracture and end up in the hospital and something bad really happens. It's really about personalizing this, in a way, and seeing each patient's own risk of having a fracture versus the patient's own risk of having osteonecrosis of the jaw and trying to balance those two things.

(37:26): [Michala O’Brien]:  “Is estrogen supplementation beneficial for slowing down the worsening of osteoporosis?”

(37:32): [Dr. Mona Al Mukaddam ]: Yes. There's a Women's Health Initiative study that was done where postmenopausal women were given estrogen and their risk of having a fracture decreased by about 30% in the hip and in the spine, and it can prevent the bone loss from happening. The issue with estrogen is more about how much estrogen you need for it to be effective? And at that dose, what is the risk of having a blood clot and increased risk of breast cancer?

(38:01): And so, in my younger patients where I worry less about blood clots and breast cancer, estrogen is really important and it would be very helpful. But in the older patients where we now worry more about heart attacks, strokes, blood clots, and breast cancer, that's really where we are concerned about side effects. I personally feel that bisphosphonates are more effective and safer than estrogen.

(38:29): [Michala O’Brien]:  This person is four years out of transplant and they're wondering when do they need to get a bone test, and who do they go to get the bone test for?

(38:38): [Dr. Mona Al Mukaddam ]: The recommendation is everyone after transplant should get at least one DXA scan. If they haven't had one yet, I would say go ahead and get one. Your primary care doctor should be able to order it, your oncologist should be able to order it, your gynecologist should be able to order it. You can just reach out to them and say, "Hey, I attended this talk, and I had a transplant, and I would like to know what my bone density looks like."

(39:05): [Michala O’Brien]:  “What do you know about using vibration plate therapy for increasing bone density?”

(39:13): [Dr. Mona Al Mukaddam ]: There have been several studies on the use of low vibration platforms or devices. If you look at the data in mouse models where you can force them to stand on the platform and compliance is 100%, those vibrations seem to stimulate the bone forming cells and bone density can improve. There have been several human trials using these platforms and the data on them is all over the place. The biggest issue is compliance. Patients don't really stand on the platform. The other issue, if you look at those human clinical trials, is that every study used a different platform that has a different amplitude of vibration, a different frequency and different requirements on how long they wanted the patients to stand on the platforms.

(40:02): Overall, in patients who were compliant , and were using it, you would see some benefits in terms of bone density improvement. The problem is none of these studies looked at any fracture data, so we don't know that these medications decrease the risk of fractures. And whenever we're trying to recommend interventions, pharmacological interventions, or expensive interventions, I would like to have some data showing they can decrease the risk of fractures. My take home, when it comes to my patients, is that I don't recommend it, but if my patients ask me about it or if their gym already has a platform, I say, "You know what? Go ahead, go for it."

(40:37): I don't have one specific brand to recommend. Their prices can range from several hundred to several thousands of dollars. And so, it could be really expensive and I don't want my patients to think they need to do this to better improve their bone density. But if it's readily available to them, and they can do it, go ahead. There's no harm in doing it if you're safe and you don't fall, and the vibrations are usually very minimal, it's a relatively very safe intervention. If you're able to do it, go for it. I don't know how much better it would be from just regular walking, but if it's available, definitely go for it. There is very little harm.

(41:22): [Michala O’Brien]:  “How does avascular necrosis affect surgical outcomes in hip joint replacements?”

(41:32): [Dr. Mona Al Mukaddam ]: It's a hard question to answer, because I'm not a surgeon. I know I have a secondary appointment in orthopedic surgery, but I'm actually an adult endocrinologist and I'm not a surgeon. This is probably going to be different for each patient. Avascular necrosis of the hip that can happen from steroids. Sometimes bisphosphonates have been used for this indication to prevent the collapse from happening. But I think it's not a question that I would be able to answer and it's probably going to be very much patient-dependent.

(42:10): [Michala O’Brien]:  “How effective is Prolia® in building backbone mass in males?”

(42:16): [Dr. Mona Al Mukaddam ]: Prolia® is approved for both men and women and it's a very highly effective medication. Although it doesn't directly stimulate bone formation, it decreases bone removal very well, and you can have improvements in bone mineral density, and it can decrease the risk of fractures by about 60 to 80%. It's a highly effective medication.

(42:39): The problem with a Prolia®, though, is if you're on it, you need to be on it and it's every six months. The advantage of Prolia® is that it can be given to people who have renal dysfunction, versus the infusion of Reclast® which I can't give to people who have renal dysfunction. Prolia®, I can. And so, you'll find a lot of patients who are post-transplant and who have chronic kidney disease are going to be on Prolia®. It's a highly effective medication. You just have to be careful to watch the calcium levels and continue taking it every six months. Do not stop Prolia® without talking to your doctor and coming up with a good transition plan.

(43:21): [Michala O’Brien]:  “What is the risk of bone loss for a patient who has had an autologous transplant?”

(43:30): [Dr. Mona Al Mukaddam ]: The data are very similar to what I presented for allogenic transplant. The data that I showed was actually very old. It's probably much better now because they use different immune suppressions and try to minimize prednisone as much as possible.

(43:48): [Michala O’Brien]:  This patient has compression fractures due to prednisone from GVHD. They're not taking that now, but they're taking hydrocortisone, due to adrenal insufficiency. Will this make things worse for me?

(44:04): [Dr. Mona Al Mukaddam ]: No. The hydrocortisone is absolutely necessary for survival and we give the lowest doses possible. Hydrocortisone for adrenal sufficiency is absolutely important and not something that you can even think about getting off without making sure that your adrenals have picked up. And so, whenever it comes to prednisone, the risk of prednisone causing compression fractures and osteoporosis, it's really about the dose and the duration. The higher the dose of prednisone and the longer you are on it, the worse it's going to be. Hydrocortisone can have negative effects on bone density, but using the lowest needed dose is necessary and should have minimal negative effects on the bone density.

(44:51): We basically acquire bone density up to the age of 20 and 30, and then afterwards, between the ages of 20 to 30, our bone density stabilizes, and then after the age of 40, we're all on a downward decline. After menopause, when we have acute estrogen deficiency, the bone density declines. And so, in terms of where someone is at who's age of 30, it depends on how much this therapy negatively affected their bone density at that point.

(45:19): Now they might be at the slightly lower baseline. But later in life, what's going to happen is there's going to be the same bone loss that will happen after the age of 40, where you can see this decline in bone mineral density. And in females, when they're going through menopause, the estrogen deficiency will cause a rapid decline. For that person, they might be starting off now at a slightly lower baseline because of their transplant, and then in the future they'll have the same kind of bone loss as in the general population, but because they started at the lower baseline, they might progress into the osteoporosis a bit earlier.

(45:56): [Michala O’Brien]:   “In your talk you mentioned that they should limit their calcium supplement intake to five to 600 milligrams. Can you explain why?”

(46:09): [Dr. Mona Al Mukaddam ]: If someone's having malabsorption and you're not absorbing your calcium -there' are blood tests that can suggest that you're not absorbing your calcium - there's a very good chance you need to be on significantly higher doses of calcium supplementation. The reason why we recommend only 500 to 600 milligrams of calcium supplementation in the general population is because there's definite data that shows that in people who were taking excessive amounts of calcium supplementation just lose the calcium in the urine. Then they end up having kidney stones. Kidney stones are extremely painful and can have negative effects on the kidney function in the future.

(46:49): That data is from the Women's Health Initiative study showing people who are taking excessive calcium supplements can have increased risk of kidney stones. The way I try to explain it to patients is, our body will try to do everything it can to maintain the same level of calcium in the blood. So, if you're just taking more, your body will just get rid of it in your kidneys which will increase your risk of having kidney stones. There's really no benefit of taking more than that.

(47:18): The second part is that the data shows that calcium supplementation is associated with an increased risk of heart attacks and strokes. These are all more association studies, not prospective studies, but for that reason we say get your calcium from your diet and then 500 to 600 from supplements, and that way we are ensuring that you're getting enough calcium that would benefit your bones, but you're not taking too much that could negatively affect your kidneys and your heart.

(47:50): [Michala O’Brien]:  Here's another Reclast® question. How long do the flu-like symptoms after an injection last? I've had muscle and joint pain from chronic GVHD for three years, so I'm concerned about adding additional chronic pain.

(48:08): [Dr. Mona Al Mukaddam ]: The flu-like symptoms happen in about 20 to 30% of patients. Not everyone who gets the Reclast® will get flu-like symptoms. It's 20 to 30%. It's not an insignificant amount, but it's clearly not everyone. The flu-like symptoms are usually worse with the first infusion and then they get much better with subsequent infusions. With the first infusion, the flu-like symptoms usually last two to three days. Rarely, rarely, rarely have I had it happen where it lasted seven to 10 days, rarely. Usually it's two to three days, and if you drink a lot of water, stay very well hydrated, take Tylenol before and after the infusion, that really helps to alleviate some of those flu-like symptoms.

(48:52): [Michala O’Brien]:  This will have to be our last question. “What types of exercises are most important for bone health? Weightlifting versus yoga, running or walking?”

(49:06): [Dr. Mona Al Mukaddam ]: Well, all those options that you mentioned are actually good for bones, but usually we talk about impact exercises, so we want to do something like walking, light jogging. With those impact exercises, the fact that your foot is hitting the ground causes vibrations that will cause bone stimulation.

(49:24): We also focus a lot on core strengthening exercises and balance exercises, to decrease the risk of falling. And then we also talk about lightweight, so doing some upper body lightweight exercises is important as well. What we want to avoid, depending on how bad the osteoporosis is or if you've had compression fractures in the spine, are high impact exercises that could potentially injure your spine more. So, you don't want to do running or sprinting, you don't want to do jumping jacks. You want to avoid some of the high impact exercises that could injure your spine. You want to avoid over rotating your spine and over bending your spine because that can also cause injury to the spine.

(50:12): A lot of patients who have joint pain really like to do bicycle riding and swimming. Those exercises don't seem to help the bones. You don't have that impact in the vibration, so they don't really seem to help the bone density.

(50:24): But dancing is great. Tai Chi, yoga, Pilates. These are all great exercises, but you just want to be careful that you protect the spine and avoid the exercises where you're over bending the spine and you're over rotating the spine.

(50:45): [Michala O’Brien]:  Closing. Well, on behalf of BMT InfoNet and our partners, I'd like to thank Dr. Al Mukaddam for the very helpful presentation. And thank you to the audience for your great questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.