Hello, I'm sorry I'm not able to join you in person today. We'll talk today about osteoporosis in men. I have nothing to disclose related to this talk, but I do want to mention that Rheumatosoma and Testosterone are not FDA approved for treatment of osteoporosis in men. We will briefly mention both of these in our talk today. So we'll go over some epidemiology related to osteoporosis in men, and then we'll have time to go over a couple of cases that I prepared for us to discuss specific situations in handling fractures in men. The way to look at skeletal health in men is the way you would look at cardiovascular events in women. In women, cardiovascular events occur typically 10 years later than in men, and women usually do worse than men when it comes to cardiovascular outcomes and mortality. And so the flip is that in men, skeletal events usually occur 10 years later than women. The decline in bone density occurs about a decade later than in women. And men generally do worse following a fracture than women in terms of mortality, refracture risk, and morbidity. This is a graph that you may have seen before showing us the accrual of bone over time in both men and women. And what I wanted to show you here is that the peak bone density that occurs at about the third decade of life typically is higher in men than in women. So men reach a much higher peak, they grow much bigger bones than women, and then they maintain that bone density relatively until the age of 50, and then you start having a slow decline in bone density with age. Men don't go through andropause like women go through menopause, and so you don't have a start of a rapid bone loss phase that happens earlier. And so typically you reach a low bone density in men about a decade later than you do in women, typically after the age of 65 or 70, and then it continues to decline, affecting the bone microarchitecture. The pattern seems to be the same in men and in women in terms of trabecular bone loss and cortical bone loss with time. The main drivers of bone density decline is skeletal aging, and the hallmarks of skeletal aging are related to both osteoclasts leading to increased bone resorption. The hematopoietic stem cells that differentiate into osteoclasts, these are precursors for osteoclasts, start differentiating more, so more number of osteoclasts develop with time, but also there is increased maturation and osteoclastogenesis leading to an increased bone resorption. On the other hand, there is a decrease in osteoblast formation, the precursors being the bone marrow stem cells that typically would differentiate into osteoblasts. A bigger number will actually differentiate with age into adipocytes within the bone marrow, leading to increased bone marrow adiposity. And so with less number of osteoblasts, we will have less bone formation. We also have an increased number of osteoblasts going through apoptosis and more going into osteocytes that will accrue a lot of DNA damage and oxidative stress with age. And this will lead to an increase in what we call cellular senescence, where these osteocytes are resistant to apoptosis, but also are not dividing anymore, but rather secreting senescent factors that affect the bone tissue surrounding it. All of this constellation of changes with age lead to a significant decline in bone density with age. When it comes to fracture risk, the fracture risk in men, which is shown on the right hand side, you can see that when it comes to wrist fracture, there is no significant increase in risk of wrist fractures in early postmenopausal age for wrist fractures. In women, typically hip and vertebral fracture increase exponentially after the age of 65 or 70, whereas in men, as I said, it's a decade later. So a significant exponential increase in hip and vertebral fracture in men occur after the age of 75 to 80 and continues to increase with age. Men do worse following a fracture. This is a graph showing us the loss of utility following a fracture. So a broken limb, for example, what is the risk of recovery of the utility of that limb? In men, the recovery is much less than in women over time. And as you would expect, the older the man is, the less chance of recovery following a fracture. But for each age group, if you compare men and women, men do worse for a certain age group compared to women when it comes to morbidity. The first graph here is showing us the risk of having another fracture. This is both men and women, and both have a significant increase of a second fracture following an initial fracture at either of these sites. What about mortality? This is data from Sweden showing us mortality following a hip fracture, 1,000 patients with hip fractures and 2,000 controls, both men and women. You can see that there is an increase in risk of mortality following a hip fracture that increases with age. So the older the man is at the time of the hip fracture, the higher the risk of mortality. But also the mortality remains elevated 22 years later following a hip fracture compared to matched controls. When you compare the mortality in men and women, this is the same data just shown in a graph. You can see that for each bracket, there is a higher risk of mortality in men, which is shown in dark blue, compared to women. And so, as I mentioned, men do worse, so higher mortality, higher incidence of another fracture, higher morbidity following a fracture in men compared to women. But we still do lag behind in terms of screening with the bone density by DEXA, and in the United States, this is mostly driven by lack of reimbursement for DEXA scans for men, despite data showing that it would be cost effective to screen men after the age of 70 or 75 with bone density by DEXA, we still don't get a good reimbursement for that, and so much less men go through screening for osteoporosis. So as I mentioned earlier, following this first section on epidemiology, I'd like to delve into two cases that will showcase some encounters that we have in men quite commonly in our clinic. The first is androgen deprivation therapy in prostate cancer. This is an 83-year-old man who presents for evaluation of his skeletal health. He was diagnosed with metastatic prostate cancer a year ago, based on elevated PSA. His MRI showed lesion in the prostate with extra prosthetic extension in the seminal vesicles, neurovascular extension, and lymph nodes. He was initiated on androgen deprivation therapy. It's a combination of luprolide, initially was combined with bicalutamide for 30 days, and then he was switched to a combination of abiraterone with prednisone, along with the luprolide. His skeletal history, he did have a bone density screening a few years ago, and it was a little bit low. He's not had fragility fractures. He did have a shoulder fracture during a motor vehicle accident many decades ago. He told me he fell two months ago while playing pickleball. He's currently taking levothyroxine, does not take any calcium supplements or multivitamins, but takes a vitamin D supplement, 1,000 international units per day. Laboratory testing shows a normal kidney function, normal calcium, phosphorus, and alkaline phosphatase. Vitamin D is quite sufficient. His testosterone, as expected, is undetectable, keeping his PSA undetectable as well. Thyroid and parathyroid function are normal. And screening for other secondary causes of osteoporosis, he had a 24-hour urine collection with a good volume, showing us a decent amount of calcium in the urine. And his serum protein electrophoresis does not show any monoclonal proteins. This is his bone density at the spine. I wanted to show you this to highlight the fact that the spine may underestimate the bone density in both men and women. And this is mostly related to arthritis changes that are occurring. So you can see that there are a lot of arthritic changes here, showing us that probably his spine is non-diagnostic. At least a few of these vertebrae are considered non-diagnostic. So we're going to rely less on that and rely more on his hip scan. This is the bone density at the hip. As I mentioned, he had the bone density done a few years ago at the age of 78. And now another bone density following initiation of the androgen deprivation therapy. And you can see that, yes, his T-score is low, but more importantly, he's lost 13%. As you would suspect, most of this is likely happening in the past year that he has been on androgen deprivation therapy. So significant loss of bone. So let's talk about ADT and bone metabolism. I'm going to show you some data related to androgen deprivation therapy. I'm not going to specifically talk about what medications. Androgen deprivation therapy is a mainstay for prostate cancer treatment, typically metastatic prostate cancer. All patients will be started on androgen deprivation therapy. And castrate-resistant prostate cancer will have androgen deprivation therapy along with other additional agents. You see with androgen deprivation therapy, a rapid decrease in androgens and estrogens. This stimulates osteoclast activity, decreasing osteoclast apoptosis, and increase in the osteoblast apoptosis. So again, tipping the balance towards more resorption and less bone formation leading to net bone loss. With age, if you count age alone, typically we lose 0.5 to 1% bone per year. Women with breast cancer going through aromatase inhibitor therapy may lose 2 to 3% of bone in the first year of therapy. This is for using a GnRH agonist. The first year of therapy leads to a loss of 5 to 10% of bone, significantly higher than what you would see in menopause, that you would see in aromatase inhibitor therapy in women with breast cancer. And the bone loss occurs at multiple sites. So this is data for therapy that, depending on these studies, was about one to three years of therapy, showing us a decline in bone density at the lumbar spine, at the femur neck, and at the total hip by a significant amount. So the mean difference was compared to minus 1.5 and minus 1.9 at the hip. And I showed you data for the first one or two years, but as long as the patient remains on androgen deprivation therapy, you will continue to have bone density decline. So this is data showing us where the patients are in terms of their bone density at baseline and 2, 4, 6, 8, and 10 years on the androgen deprivation. Green area, which is osteoporosis, so the bone density, much less men are in the normal bone density range, more developed osteopenia, and significantly more developed osteoporosis with continued androgen deprivation therapy. How does that reflect when it comes to fractures? This is a population-based study from here at Mayo Clinic, looking at the Olmstead County men. This is the data for, in dark blue, what is expected to see with age in the general population, and in light blue are the observed risk of fracture at 15-year follow-up when it comes to men with androgen deprivation therapy. So significantly higher risk of fracture, and this increases exponentially in the first few years of therapy, but continues to increase subsequently and remains much higher than general population. What are the typical sites? In our study, we found that the typical sites are vertebral fracture, much higher risk. The standardized ratio is up to 12 when it comes to thoracic and lumbar vertebral fracture, but you can see fracture everywhere, so overall risk is significantly increased. What are the risk factors? Obviously, age is a higher risk factor, decreased activity, prior diagnosis of low bone density or osteoporosis, and androgen deprivation therapy was a significant risk factor for these men to have a higher risk of fracture. This is data combining data from multiple population-based studies, so this is analysis showing us that there is a significant increase in risk of fracture with therapy. However, most of these studies are observational studies, so there is a high risk of bias in these studies, so keep that in mind. I'm not going to go into details when it comes to bone protective agents and how they were studied in men with androgen deprivation therapy. I just wanted to show you that there is a variety of studies that have been looking at these, mostly bisphosphonates, zoledronate, or alendronate, or denosumab more recently, and the duration was variable. But I wanted to show you the result of the meta-analysis, and this tells us that there is significant impact on the femur neck in these studies that tested bisphosphonates in patients receiving androgen deprivation therapy. When it comes to fracture, the data is less robust in terms of reduction of fracture risk in these patients. This one study did show, it's called the Stampede Study, and this is a trial that looked at men receiving androgen deprivation therapy and chemotherapy, but also combined with zoledronate. The dose of zoledronate given in the study was here, four milligrams every three weeks for six doses, and then every four weeks for two years. So they were receiving monthly zoledronate for two years. This is quite a high dose of zoledronate. There was no improvement in zoledronate in terms of overall survival, but there was a significant reduction in risk of fracture. This is the fracture incidence data with the group that received zoledronate compared to the group that did not receive zoledronate. So we do have fracture data that this reduces the risk of fracture, not only improves bone density, but the dose here is to be kept in mind, and we'll talk about that in a minute. What about denosumab? This is a study of 1500 men with non-metastatic hormone-sensitive prostate cancer. They had low bone density or history of fragility fracture, and so they were started on denosumab 60 milligram every six months compared to placebo. And as you can see, there was a significant reduction in the denosumab group at one year, two years, and three years when it comes to new vertebral fracture. So significant risk reduction. And in terms of bone density improvement, this is the bone density with denosumab improved at the lumbar spine, femur, neck, total hip, and distal radius compared to significant decline in the men that were not receiving denosumab but receiving placebo. And so here it's showing us the difference in percentage point at two years, but this was continued even at three years, continued an improvement in bone density. Do denosumab and zoledronate affect other skeletal-related event? And by skeletal-related event, we mean any event that relates to fracture, but also metastasis to the bone. So this is combined data, and this is comparing denosumab versus zoledronate. And in this study, men with metastatic cancer followed for two years receiving denosumab. the dose here was 120 milligrams every four weeks, so monthly, and zoledronate dose was four milligrams also monthly. And as you can see here, the proportion of patients developing skeletal-related events was a little bit higher with zoledronate compared to denosumab, but there was no difference in survival between the two agents. As I mentioned earlier, the dose of zoledronate has been a little bit atypical in many of these studies, so this is a study that looked at the difference in dosing of zoledronate. Now this was a study that grouped many patients, both men and women, and they did not only have prostate cancer. So women had breast cancer, men had prostate cancer, and about 300 had multiple myeloma. And they looked at the difference between two doses of zoledronate, four milligrams monthly versus four milligrams every three months. And so as you can tell, there is a very limited difference between the two when it comes to the development of skeletal-related event or death, so this is combined. A slight improvement with the monthly dose of zoledronate, but this does not occur until later, so closer to the second year of therapy. And so there may not be a signet when it comes to skeletal-related event, but this is the only data that compared these doses in this population. So the dosing is a controversy when it comes to using these agents. The recommendation is if someone has a metastatic disease to the bone or hypercalcemia to use the zoledronate four milligram every either four weeks or 12 weeks, somewhere in between would be reasonable. If you were using denosumab for this indication, it will be 120 milligrams every four weeks, so monthly denosumab. If it is related to bone loss, so you're treating bone loss on bone density, the suggestion is to use zoledronate five milligrams once a year. There is no data showing us that any other doses would do any differently. If you were using denosumab, the typical osteoporosis dose of 60 milligrams every six months may be enough. When it comes to side effects with these doses, so remember that we're giving different doses, and this is looking at these population with higher doses of denosumab and zoledronate, and there was a higher risk of infectious side effects, but also osteonecrosis of the jaw was one to two percent, which is much higher than you would see in osteoporosis treatment. The risk of hypocalcemia was significantly greater with denosumab, and the risk of new primary malignant disease was no different between the two, so denosumab may give a higher risk of hypocalcemia, possibly a higher risk of osteonecrosis of the jaw when you're using higher doses in this population. The general recommendation from the North American societies is someone who does not have metastatic, sorry, someone with non-metastatic prostate cancer receiving androgen deprivation therapy and high risk of fracture to consider denosumab as a first line, and if contraindicated, then bisphosphonate would be a reasonable alternative. The optimal duration is unknown, and I would also say that the optimal dosing is unknown for these patients. If the patient has metastatic castrate-resistant prostate cancer, so bone mats, denosumab, or zoledronate at the metastatic bone dose that I mentioned earlier, there is insufficient evidence to try to use these doses for castrate-sensitive disease, and these guidelines mention considering treating if someone has low bone density but at a higher T-score than what you would normally treat the general population. These are very vague, and I think this is on purpose because there is just not enough data to guide us here. I feel that the European Society for Medical Oncology gives us a little bit better algorithm to use, which I try to follow more in my practice. So, this is the guidance from the European Society. Patients with cancer receiving chronic endocrine treatment known to accelerate bone loss. So, typically, this would apply for both women with breast cancer receiving aromatase inhibitor therapy or men with androgen deprivation therapy. If someone has a T-score less than minus 2.0, you would recommend exercise, calcium, vitamin D, and consider either denosumab or bisphosphonate therapy. If someone has a T-score better than minus 2 at any site and no other risk factors, then only calcium, vitamin D, and exercise while monitoring bone density. Any patient that has at least two of these risk factors older, age 65 or older, T-score less than minus 1.5, history or current smoking, low BMI, family history of hip fracture, personal history of a fracture after the age of 15, or use of glucocorticoids for greater than six months, any of two of these risk factors should also, irrespective of the T-score, you should consider initiation of therapy, again, with either denosumab or bisphosphonate. Notice that there is, the North American societies had a slight age of recommended denosumab over bisphosphonate in this population, given limited data that denosumab may reduce skeletal-related events better. But again, as I would say, as I mentioned earlier, dosing and frequency and duration of therapy remains a big controversy and a big unknown in this population. Moving on to a different case, a case of vertebral fracture. This is an 82-year-old man who sustained recent vertebral fractures. He woke up one day with severe acute back pain. He always had back pain, this is a chronic issue for him, but he noted a severe pain upon awakening one day. He does not recall having had a fall or trauma in the preceding days or weeks prior to this event. He used to run for 34 years, but he stopped about four years ago because he's starting to have arthritis. He's not able to run as good anymore. He's now riding bikes. He walks, alternating every other day, about two to three miles every time. His past medical history includes cataracts. He's done surgery for that. He has mild asthma. He takes propium, but has not used any steroids for his asthma in the many years recently. He eats a lot of calcium-rich food per day. He also takes a centrum silver. This is a multivitamin that contains about 300 milligrams of calcium and about 1,000 units of vitamin D. He separately takes an additional vitamin D of 1,000 international units daily. Basic lab testing, normal kidney function, calcium and phosphate are normal, vitamin D is sufficient, and thyroid function is normal. Screening with serum protein electrophoresis shows no monoclonal gammopathy. These are his x-rays showing us that he has age-indeterminate, I would say, fractures, both thoracic fracture. This is severe fracture here and here. This is moderate fracture. At the lumbar spine, you also have severe wedging. Then this is a biconcave fracture here as well. Vertebral fracture is a big burden in both men and women, but significantly also in men. This is the data from Norway showing us the prevalence and the distribution of vertebral fracture in both men and women. Notice that the prevalence in men is possibly slightly higher, 14%. This is about 1,200 men and 1,600 women in the general population, so quite prevalent vertebral fracture, but notice that it increases with age. As we mentioned earlier, in men, this occurs mostly after the age of 70, but it can occur at a slightly younger age. The distribution is noted here, typically mid-thoracic, so you see a lot at T6, T7, and then also at the thoracolumbar junction, you have an increased risk. But in men, which is the lighter blue, you have more thoracic vertebral fracture than you do lumbar. This is data from Europe overall comparing different sites of fracture, so hip, vertebral based on radiographs, so not clinical vertebral, radiographic vertebral fracture, and wrist fracture. We've mentioned earlier that wrist fracture are higher in women, but I wanted to show you that the vertebral fracture in men typically start occurring after the age of 70, 75, you start seeing, I'm sorry, 75 or 80, where you start seeing an increase in risk of vertebral fracture in men when looking at overall European data. What about the United States? This is data from the Mr. Oz study. This is 6,000 men aged 65 years or older and followed up over about five years. So this is the risk of clinical vertebral fracture, clinical, that presented clinically, significant increase in the risk occurs after the age of about 75 to 85. And then the proportion of radiographic vertebral fracture is also quite high. So comparing that, you do have a risk of finding radiographic vertebral fracture that were not presented clinically as you would have seen in men. So this is the risk of radiographic vertebral fracture in women and the general population, keeping in mind that we should be screening for vertebral fracture that could be silent. So the point that I wanted to make here is that there is significant geographic variability when it comes to the incidence of vertebral fracture. I showed you data from Europe, data from specifically Norway, and data in the United States. And it seems that in the U.S. there is a significantly higher risk of vertebral fracture for both men and women compared to Germany and Sweden based on this graph, as I showed you also earlier. What are the risk factors? This is also from the Mr. Oz study. So from the United States, men with vertebral fracture and men without vertebral fracture, they seem to be slightly older. The age difference was not significant. But what is different is their frailty. So at baseline, men who have vertebral fracture at baseline have a higher frailty. They are more frail. They've had history of falls at a much higher rate, and they have a lower bone density both at the hip and at the spine. So low BMD, falls, frailty, possibly age. These are the main risk factors for vertebral fracture in this population. So speaking of frailty, physical performance and vertebral fracture, this is also from the Mr. Oz study. They looked at baseline physical performance of men, and they followed them up over time to see what is the likelihood of developing a fracture. And this is the baseline physical performance. They did repeated chair stands, leg power, narrow walk, walk speed, and grip strength. And they scored the physical performance. Zero is best, and three or more is the worst performance. And you can notice that the more frail, so less physical performance, there is the higher risk of developing a fracture. Model one is adjusted for the lumbar spine, smoking, age, and other risk factors, and number of comorbidities. And model two is adjusted for a previous history of vertebral fracture. And even then you can see that you have a significant higher risk, even if someone has a vertebral fracture previously, significantly higher risk if they are frail with low physical performance to have more vertebral fracture. What about mortality? So vertebral fracture does actually predict mortality. So this is men who the general population is in light blue, and these are the risk of having a hip or vertebral fracture is shown in green. And you can see that in younger men having a vertebral fracture is actually quite morbid and can cause significant higher mortality risk. But also in older men, less so than hip fractures. Hip fractures is a big predictor of mortality in older men, but vertebral fractures do so as well. So I mentioned earlier screening for vertebral fracture. So if we have someone with risk factors, what is the value of screening? And this is screening using a VFA, vertebral fracture assessment on the bone density DEXA machine. And so this is the rate of detection of clinical vertebral fracture compared to obtaining it on the VFA. So definite vertebral fracture risk, which is shown in green, significantly high. And then based on someone with FRAX calculated high risk of major osteoporotic fracture or hip fracture, again, high probability of finding a moderate or definite vertebral fracture on the VFA imaging. So there is value in terms of screening with vertebral imaging in some patients. The Bone Health and Osteoporosis Foundation used to be known as the National Osteoporosis Foundation in the US recommends vertebral imaging in men, even asymptomatic, if they are 80 years or older with a T-score of minus one or lower, 70 years or older if the T-score is minus 1.5 or lower, or any men over the age of 50 with additional risk factors, including having had a fracture after the age of 50, height loss of four centimeters, or prospective loss on follow-up by more than two centimeter, or men on glucocorticoid therapy. And we talked about the case of androgen deprivation therapy, and you can make a case that this is a high risk for vertebral fracture, as I showed you. And so this is something you could consider also in your risk factor profile. What about efficacy for the medications in men? So in the last two slides, I just want to show you the, I'm not going to go over this in details, but I showed you here that many of these agents are approved in men for fracture risk reduction. This is the data showing us all of these improved bone density in men, vertebral fracture risk reduction, and non-vertebral fracture risk reduction listed here specifically in men. And what I wanted to show you also that rhomosozumab and testosterone, both not approved by the FDA for use in men, but rhomosozumab has actually been shown to increase BMD and possibly reduce the risk of vertebral fracture, even though the numbers were quite small to show clinical statistical significance. So the guy that I showed you, the 83-year-old gentleman who presented with spontaneous vertebral fracture, his bone density was non-diagnostic at the lumbar spine with all these fractures. His lowest T-score at the femur neck was minus 2.3. I gave him the option to initiate therapy with an anabolic medication, such as teriparatide, but he didn't want to do daily injections. And so we had a discussion about off-label use of rhomosozumab. He wanted to go with that. So I initiated him on rhomosozumab monthly for 12 months, and then followed by alendronate weekly. And I also recommended physical therapy to improve his posture and reduce the risk of further vertebral fracture. And he's remained fracture-free at 14 months follow-up. And with that, I thank you for your attention, and we'll be taking questions.

osteoporosis

men's skeletal health

bone density decline

fracture risks

androgen deprivation therapy

osteoporosis screening

treatment strategies