Hi, everyone. We're going to go ahead and get started. Thanks for being here. We have a treat today. 

Dr. Deborah Kado is a Professor of Medicine at UC San Diego where she is the Osteoporosis Clinic Director for the Health System. She's the Deputy Division Chief in the Division of Preventative Medicine and is also the Medical Director of the UC San Diego School of Bone Densitometry. She got her M.D. from Cornell. She went to Harbor-UCLA Medical Center for her internal medicine residency where she served a year as a Chief Resident. She had her Geriatric Research Fellowship at UCSF and then her clinical Geriatric Fellowship at UCLA. 

She's had a robust career, currently has five ongoing NIH grants. One where she's a PI on is studying the osteoporotic fractures in men. And she's also a member of the Advisory Panel on Hormones, Menopause, and Midlife Health that will be taking place at the ACOG National Conference here in about a month. And today, she'll be talking to us about rethinking an old problem and some new treatments and diagnosis in osteoporosis. So please join me in welcoming Dr. Kado. 

[APPLAUSE] 

Did you want to reset the timer? OK. Thank you so much and particularly to Professor Farber for arranging this visit. I'm so glad to be here to talk about a topic that I don't think I could have predicted in many of your stage in the career. It was because I asked a question about Diet Coke and bone that 25 years later, this is what I'm still doing. 

Just a few disclosures because I will be talking about some treatments. I've received-- sat on scientific advisory boards, et cetera. So just so you know that. 

We're going to talk about, in the next few minutes, just putting osteoporosis into perspective, especially for primary care physicians who have a lot to take care of in a short period of time, the diagnostic capabilities that we have, reviewing a little bit about DEXA but then talking about two new promising emerging techniques to assess people at risk for fracture. I think it would be really important in 2020 to revisit, what do we do about calcium and vitamin D supplementation? What is the state of the literature there? 

Then talk about two FDA approved treatments that are now going to be available. So back in 1995 or so, when I started this, there was maybe just alendronate that came on market. And now we have a whole menu of items to be able to choose from. And then finally, as a geriatric person in terms of my clinical thinking, I wanted to end with a geriatrician's perspective, given that most people who have osteoporosis are over the age of 65. 

So just to review briefly, osteoporosis is a skeletal disorder that is characterized by compromised bone strength that would then predispose someone to fracture, particularly if they were to fall down. And bone strength really reflects an integration of the two main features of bone density as well as bone quality. Osteoporotic fractures are common. And in 2020, about 50% of repeated bone breaks could be prevented if patients are treated appropriately. 

And just to give this slide to show that-- well, let's see. Maybe it's not working. That's weird. Does it work here? No. OK. 

Anyway, 43% of all hospitalisations for women are for fractures. So that's a pretty high percentage. And over 2 million fractures occur per year, of which vertebral or spine fractures comprise 27% and hip fractures 15%. 

And of those fractures, about 300,000 hip fractures occur per year in the United States. And of those, about 50% of them do not regain their previous functional capacity. So it has lifelong implications for people who have hip fractures. About a quarter end up in nursing homes, and 25% or so may die within a year of having suffered from a hip fracture. 

However, vertebral fractures are actually the most common type of osteoporotic fracture. And each vertebral fracture can result in kyphosis, which is the forward curvature of the spine, worsening by about 4 degrees. And it has been shown in studies, large observational studies, multiple populations, that vertebral fractures are associated with an earlier mortality, much like hip fractures, and especially from pulmonary causes. And you can see that. 

First, I'm going to go back to show the mortality risk that with-- the left-hand side, those-- this is a study of 9,700 women, who are aged 65 and older at baseline, who did-- all of them had x-rays where we assessed whether they had vertebral fractures or not. And with increasing number of fractures, as you see on the x-axis 1 to greater than 5, the mortality rate increases even after adjusting for things such as age, smoking, health behaviors. 

Similarly, on the left or your right-hand side with-- this is looking at, in the same population, just looking at rates of bone loss, that by quartiles of increasing bone loss, there is an increased risk of fractures over five to eight years of follow up. The risk of dying is not due to, again, underlying health behaviors, just that they're older, or they're smokers, or have comorbidities. 

So one of the reasons that this may happen, actually both of those cases, when you look at cause-specific mortality from death certificates, there is a higher risk of dying from a pulmonary cause, such as pneumonia or COPD. And with vertebral fractures, you can see that you would have that increasing kyphosis that would lead to compromised pulmonary function, so that if you were to get pneumonia, you'd be maybe less likely to recover as well. 

Again, osteoporosis is one of the top 10 most chronic, costly chronic conditions where it cost, in 2010, they estimated about $30,000 per patient, $11,300 for non-spine fractures, and about $8,300 for vertebral fractures. So when you look at comparison of annual hospital costs per year for older women in the United States, osteoporotic fractures are the most cost. So it'd be really great for the health system, and not to mention for the patients, if you could prevent these fractures. 

And I don't want to forget men. If men are lucky enough to live to be an old age, they also get hip fractures, about a quarter. And if they are unfortunate enough to suffer from a hip fracture, they will also suffer from even potentially greater rates of mortality at that year mark. 

OK. So I'd like to show this slide because I was in residency training in the early '90s. And at that time, not everybody used beta blockers when someone was hospitalized for an acute myocardial infarction. And clearly, the evidence was showing that if you use a beta blocker, you decrease the risk of mortality substantially. 

And with great interventions from cardiologists across the country and world, that is standard of care. Like, you by first year medical school probably already know that. And so on average, after a heart attack, good 96% of people are going to be on a beta blocker. And if they're not, you're going to think, who is a doctor who's taking care of that patient? Or maybe there is a contraindication to a beta blocker. 

I just told you, in 2020, we have a plethora of medications to choose from to treat osteoporosis. And we are even at less than 23% in someone who has already had a hip fracture. If you have a hip fracture, you're definitely at risk of having another fracture. Why are we doing so poorly? We're just failing terribly. We've got an F. 

And I put the cartoon on the right-hand side because I think that is not only maybe a physician perspective osteoporotic. The orthopedic surgeons are usually the first to see these patients. And they don't necessarily equate fixing something in the OR with medical treatment afterwards. And there's been a lot of negative publicity on the treatments for osteoporosis. So patients are not predisposed to thinking about their disease as osteoporosis. They'd say, well, I just did that because I fell down, and forget it, and go on with life. 

So there's a lot that we can still do in 2020 in terms of improving diagnosis and care of patients at high risk for fracture. We definitely have shortcomings, even with our gold standard. So we're going to talk today about new diagnostic tools that are available and revisit-- a lot of times, now that I do just metabolic bone disease, people come in and say, well, I'm on my calcium and D. So I'm doing what I need to do to prevent my osteoporosis. And finally, we'll talk about fall prevention because that seems to be a piece that my fellow endocrinologists sometimes forget because we're so focused on the drug treatment. 

So this is what a DEXA scan looks like. It's derived from a 2D image. The radiation exposure is really like flying from California to New York. So it's low radiation. 

And multiple studies from across the world have confirmed that if you have low bone density assessed by DEXA of the hip or spine, you are at far greater risk of having a future fracture. And the graph on the bottom shows that with worsening T-scores, negative 1 up to negative 3.5, the risk of hip fractures, particularly after the age of 65, goes up dramatically. The WHO definition for osteoporosis is a T-score that is less than 2.5, which is a standard deviation score that compares someone to a young female at age 30 who is considered to be at peak bone mass. 

When the WHO came up with this criteria for osteoporosis diagnosis via BMD, it was not for necessarily treatment, but just to get a sense of who has osteoporosis. But post all of this, a lot of physicians tend to think negative 2.5, treatment. But let's rethink. Is that the right way we should be approaching this condition? 

So this is a study that interestingly talks about who goes on to fracture based on DEXA BMD. And it's a slide that I like to use because-- let's see if it works. OK, it stopped working. Anyway, so T-score negative 2.5 or lower is osteoporosis. Between negative 1 and negative 2.5 is low bone density or osteopenia. And greater than negative 1 is considered normal bone density. 

So these are the three categories, normal and green, yellow and osteopenia, and red and osteoporosis, and who went on to get a non-spine fracture. And on the left-hand side, you see that in women, it seems like people who are fracturing are really in the yellow and the red, almost in equal proportions, right? And then for the men it's even more surprising because most of the men who fracture seem to be in the yellow, not so much in the red. 

And one can maybe speculate why that might be. Part of it is that we think that maybe men tend to be more active when they're older. They'll climb up on the roofs of their houses to get things and then fracture, and they're at risk because of higher trauma. We don't know. And the proportions are because most of the population is in the osteopenic range to begin with. 

So to do some clinical cases, these are actual patients. A 59-year-old female with a history of hypothyroidism, who at age 55 suffered from a couple of rib fractures, and had been hiking and had an ankle fracture. No big deal. But then, two years later at the age of 57, had T3, T4, T9, T7, T9, T10 and 11 vertebral fractures, which she didn't even know exactly what she did. It wasn't like she had some major trauma fall. 

She had no family history of osteoporosis, went to an outside physician who said, this is not normal. Let's do a bone density DEXA scan. And lo and behold, her lumbar spine T-score was negative 1.3, barely in the low bone mass range. And her left femoral neck T-score was negative 1.1-- again, practically normal, not explaining all these fractures. 

And then at age 59, she had yet another vertebral fracture. These were all diagnosed via MRI because she was just having so much pain, the doctor sent her for MRI. And she had another acute vertebral fracture at T8 and then decides to drive down to San Diego and get evaluated because something is definitely going on, and nobody can explain it. 

The second case is a lady who's 57. She just has a history of bone density diagnosed osteoporosis and hypothyroidism, who the doctor said, let's put you on alendronate, which is the number one treatment. She didn't tolerate it. It upset her stomach. 

Her mother had been on alendronate, never had fractured but passed away unfortunately of leukemia at age 74. She comes in on an outside DEXA scan T-scores negative 0.9 of her spine and negative 2.4 of her left femoral neck. So the 2.9 is an osteoporosis. She by definition has bone density diagnosed osteoporosis and almost osteoporosis of her femoral neck. 

So this segues into the trabecular bone score. What is it? It is a gray level textural measurement that is derived from the DEXA scan. And it's from the spine DEXA images, developed by the French because one thing about the spine bone density is that it gets confounded by calcification of the aorta and osteoarthritic changes. So it's never thought to be such a great measure for osteoporosis risk. 

So the French developed this. And it has been shown to enhance fracture prediction when used in conjunction with FRAX. And for those of you who don't know what FRAX is, it is a risk prediction score that has been developed by the WHO and boneheads across the world that includes not just increased age and bone density but body mass index, family history of hip fracture, smoking, alcohol use, et cetera, to come up with a 10-year risk estimate of fracture. 

And there is a downside to trabecular bone score. And that's probably-- had anybody heard of trabecular bone score before in this room? Right, is because it's not FDA approved. So even if your radiology department or whoever owns the DEXA in your clinical system has a DEXA scan, they're not inclined to pay for the software because they cannot get reimbursed for this. 

And the French said, I don't care. We got it FDA approved. We know it works. We can use it around the world. And this is similar to the strontium ranelate story that they also produced back in the day that no US patients could get it because they did not want to deal with our bureaucracy. 

This is what it actually looks like. So on the left-hand side of this picture is traditional DEXA lumbar spine bone density where you see that the bone density in these two images looks-- is exactly almost identical at .97, .97. And the manufacturer gives these nice pictures that show the underlying bone spinal bone quality that is in this case normal in the upper hand and almost degraded in the lower hand at 1.24. 

So how does this apply to these patients, because we have it at our research unit? So for the first case, we had all those vertebral fractures with minimal trauma. Her secondary workup with labs and urine tests came back completely negative. No, it wasn't some weird other problem that's causing this. She was otherwise pretty healthy. 

And her bone density again was normal. But her trabecular bone score was degraded. So in this picture of her scan, you can see up on the top is regular DEXA. She's in the green, normal bone density. 

And yet, when you do the trabecular bone score, she's in the degraded osteoporosis range. So this kind of started to make me a believer in trabecular bone score because it was reflecting what actually was happening to the patient. And so she was given IV Reclast. 

The second case was this woman who was getting her test on a Lunar machine that showed osteoporosis on her outside consult. We repeated it again a year later that showed almost identical scores of the same values. But we were able to do the trabecular bone score that put her at 1.44 or normal. And she basically never had a fracture. 

And she was very, very happy at the end of this clinic visit because she really wasn't interested in being on any medications. And the reassuring value of the trabecular bone score made her feel much safer, because she came to my clinic saying, my doctor says I'm going to break in half if I don't get on a medication tomorrow. 

So what did the data say, though? So there's been a meta-analysis of 14 perspective population based cohorts which asks the question, does TBS, trabecular bone score, predict fractures independent of FRAX? And they then looked at 17,809 men and women who were of mean age 72, and followed for an average of about 6 years for hip fracture and any major osteoporotic fractures. 

And in the little graph chart below, you can see that with TBS only, there was a significant prediction of hip fracture at 1.44, relative hazards, major osteoporotic fracture at 1.42. If you added FRAX plus BMD, the risk prediction got stronger for hip fractures at 2.3. And if you used all three measures, FRAX plus BMD plus TBS, it was 3.98 and statistically significant. So the International Society of Clinical Densitometry then again validated that TBS can be used to assess fracture risk. 

All right. The next is biomechanical CT, which is even newer in that it considers both bone strength as well as 3D bone density. And this developer, Tony Keaveny, who's a professor of engineering at Berkeley, thought to take advantage of all those CT scans of the abdomen and pelvis that are done for other reasons, and do a finite element analysis of the hip to see how much strength, how many newtons do you have to virtually exert on that hip to cause it to break? 

And after about 15 years of working on this in his lab, has now developed a clinical tool that on the-- in the picture, you can show that-- see that in the top hip, it's an 89-year-old female who would take about 2,700 newtons force to cause that to break, and after looking at normative data suggests that a force of greater than 3,000 newtons or less than 3,000-- excuse me-- would put someone at risk of hip fracture if they're a woman. And the bottom one is of a male. At 4,000 newtons, he's breaking. 

So he went ahead and used the Kaiser population in Southern California of 111,000 members who-- some of whom had CT scans of the abdomen pelvis done for other reasons, and created a case cohort study where of about 2,000 men and women who had CT scans of that area, who also had a DEXA scan done within three years of that period, to see, how does their measure perform in terms of predicting future hip fractures? And what they found was that that bone strength measure using the finite element analysis did in fact predict hip fractures independent of bone density and that it had a higher sensitivity for testing-- predicting fracture than traditional DEXA. 

Again, the chart shows that hip DEXA does fine. 2.94 for women, 3.3 is statistically significant. But you can see that the hazards ratios are even stronger in terms of the bone strength measures. 

And to validate this, he used the data from MrOS, which is a large prospective cohort study of men over the age of 65 who were recruited from six clinical sites back in 2,000, and found that we assess for hip fractures all along. And he chose a random sample of 210 of these men and then 40 who had had the hip fracture as measured by a mechanical CT measure of bone strength, and followed them for about six years, and showed that in this graph-- I'm sorry this-- it really did work when we tested it literally one minute before this talk started. 

But to give you a sense that if we just used the T-score from regular DEXA, you would have caught about eight men who went on to have a hip fracture. But if you use the fragile bone strength measure at 3,500 newtons or less, you captured all these other men in the black dots. Isn't perfect, but it certainly shows that this test works. 

And there is some better news. Tony's in the United States. He's been working very hard. He with Medicare-- so now, we actually have this test reimbursable by Medicare. 

So it could be potentially done at UVA with some help. I've been working on this to get it available in San Diego, and it's not an easy process. You need a champion. 

But this is what the report would look like. And he will let you know that there have been over 24 million CTs done of the abdomen and pelvis. And in 2016, 10% of all Kaiser patients over the age of 65 had that. 

And he also let me know that we're very poor. Due to probably poor reimbursement, that DEXA usage and utilization is just going down, so that only about 10% of the entire population is getting the number one clinical gold standard assessment for osteoporosis. So his argument is that if we used and just ordered the CT of the abdomen pelvis, there's no extra-- real extra costs in getting this type of analysis that may perform better because it's a 3D measure. It's not an approximation of density. And it also has the bone strength measure. 

So in quick summary, we have the DEXA. It works. You have it at UVA. Hopefully, some clinics around the community also have this available. 

We also have the trabecular bone score that I've become more convinced in my practice that it is telling us some extra information, and then the biomechanical CT. So stay tuned for that as it gets adopted hopefully. Tony has a company called ON Diagnostics, and they're working with larger insurers to get this covered. We'll see if he is successful. 

Now for treatments, we've got to start back at calcium and vitamin D. So in 2018, in JAMA, took this chart about what is the clinician and what are the patients supposed to do? So you can see for men and premenopausal women, the USPSTF recommendation is insufficient evidence to show that there is any benefit or harm. And then for postmenopausal women, to give vitamin D less than or equal to 400 international units a day or and calcium less than 1,000 milligrams a day is not recommended. 

But what about more than that, greater than 400 or equal to or greater than 1,000? There is insufficient evidence, and must remark that these recommendations apply to community dwelling adults without osteoporosis, vitamin D deficiency, or a history of fractures, just to be clear. But I thought it was interesting, quote, that they found "adequate evidence." 

Nothing else was sufficient. Adequate evidence that supplementation with calcium and vitamin D increases the risk of incidence of kidney stones. So that's where it came out in 2018. 

So what are we supposed to do? Because a lot of patients, we're really good at taking calcium. In fact, it's still pretty widely recommended, well, probably by you, though the data are really controversial. And older men and women are recommended to take about 1,000 to 1,200 units milligrams per day for bone health and fracture prevention. This is from the Institute of Medicine back in 2011. 

In Western countries, the average dietary intake of calcium is about 700 to 900 milligrams daily. And a good portion of our-- just go to Costco. You can find plenty of calcium supplementation. And 30% to 50% of older women apparently take these supplements. 

What about the randomized controlled trial? We're at an academic center. We're supposed to do evidence-based medicine. What does the evidence show us? 

Well, from a pooled analysis of 26 randomized control trials, there was a reported 11% risk reduction in total fractures, a 14% risk reduction in vertebral fractures, no benefit in terms of hip fracture prevention. And in the largest of those trials, there was no benefit. And in fact, some of those trials suggested that there could be increased risk, even acute myocardial infarction, of women who took 800 milligrams a day versus placebo. So the authors of that study from New Zealand wrote, "Results suggest that widespread untargeted use of calcium supplements in older individuals is unlikely to result in meaningful reductions in the incidence of fracture." 

So we in medicine have been taught to depend on randomized control trial evidence-based medicine. The next best thing are the observational data. So it's really interesting to say, well, what if we assess what people actually are trying to do as by self report? 

Calcium intakes reported by the Singapore Chinese Health Study of over 63,000 women, the Swedish mammography cohort of 61,000 women, and the Chinese Healthy and Nutrition Survey of Men and Women, about 6,000. That's a graph that's on the left here, or right for you guys, which shows that there is a U-shaped association, where if you get less than, say, 250 milligrams per day, you may be at risk on the y-axis for incident hip fracture. 

However, you can see that curve starts going up probably around 800 milligrams a day. So this suggests that maybe you could get too much calcium. We already know from the USPSTF, whatever, that kidney stones are an issue. 

So just returned from the American Society of Bone and Minerals Research, which is my favorite academic meeting that I go to like a religion every year. It was in Orlando this year. They had a lot on calcium and adverse effects because that was one of the questions. Besides having a benefit, should we be concerned about cardiac risk. 

And OB-GYNs and cardiologists, some of them would say, you take calcium, it goes right into your arteries. It's not going into the bones. So reassuringly, in two of those studies, one of 904 from the calcium intake fracture outcome study and then this other study of 121 women who had carotid ultrasound, all kinds of abdominal CTs for aortic calcification, over five years of supplementation at 1,200 milligrams a day, the good news, no harm. 

There was-- didn't seem to be any difference between those who were randomized to calcium supplementation versus placebo. Of course, these are intermediate outcomes, but it was reassuring to see no buildup of aortic abdominal calcification over five years. 

But one thing, when I was sitting in that audience listening to these randomized control results and looking at the tables, it was amazing that every single trial, there was a statistically significant increase risk of having constipation develop during the trial if you were in the calcium group. And I'm a geriatrician. Believe me, constipation is no fun. It's very common as we get older. 

You guys may or may not have heard of the VITAL Study, but it's worth mentioning because it was a huge NIH study that was-- the results of which have been published in the past year. They wanted to recruit more than 20,000 older men and women from the community to randomize them to receive vitamin D 2,000 versus placebo. 

In addition, the omega 3 fish oils were of interest. So they did a factoral factor design of their trial where they could give both. This is factorial design. This was designed and led by JoAnn Manson from the Harvard School of Public Health. They actually got 25,871 women and men over the ages of 55 and 50 respectively to get either D3 and fish oil versus and fish oil placebo, D3 placebo and fish oil, D3 and fish oil, or placebo D3 and placebo fish oil. 

And this was published in the New England Journal in the past year. Showed, if you look at the curves, no difference in any outcome cardiovascular or cancer. They hadn't yet published yet what happened because everybody would assume that vitamin D would be good in terms of your bone, right? That's what I prescribe. And let's see what happens. 

All right. So they use the same trial. Mean age of 67, followed for 5 years, looked at the vitamin D3 2,000 group versus the placebo group. And they assessed falls, because there are lots of data that had suggested-- randomized controlled trial data even-- that vitamin D prevents falls. 

In fact, the American Geriatrics Society had put in their fall prevention guidelines that make sure check the vitamin D, and make sure you're giving it. They've since taking that away. So let's see what happened. There was no difference. They had plenty of falls over five years that they assessed. So supplemental vitamin D did not help prevent falls in the men and women who were randomized to receive the vitamin D 2,000 daily versus placebo. 

What about bone? We hear rickets, kids, vitamin D is definitely important for bone mineral metabolism. What do we find? In their sub-cohort of 771 women in this-- just women-- followed for two years. They had the vitamin D25 hydroxy measured. They looked at not just DEXA but peripheral QCT to look at 3D bone density. 

54% of this population had low bone density, and there were no differences in any of the bone outcomes at two years. Negative study. Not published yet. These are preliminary results. So we'll see them probably come out in some general medical journal soon, I'd say, within a year if what they presented at the meeting holds up under peer review. 

But this did come out in JAMA very recently. I don't know if you've seen it. It's called the Bone Density and Bone Strength Calgary Vitamin D Study from Canada. They looked at 400 versus 4,000 versus 10,000 international units of over three years. And in this chart, you can see that in all three groups there was actually a decline in bone. 

And this is by 3D bone density. And it seemed that the higher the dose, the worse you were doing. There's not statistically significant differences between the groups, but it's certainly not what one would have expected based on what we knew. So that's not great news. 

And they also showed that the higher the dose was, the worse it was. And so the authors concluded that among healthy adults, higher D supplementation resulted in a statistically lower wrist bone density. And the tibial bone density was lower in particularly the high vitamin D group, suggesting, again, more is not better. So how do we explain this? I'm still seeing patients in bone clinic. What am I going to tell them now with these latest data in the past year? 

If we go back-- I don't know if it was Robert Heaney in the 1990s or someone-- I'll just say the National Academy of Medicine, the experts have said vitamin D is probably a threshold nutrient. And there was a huge controversy between the endocrinologists in, say, the IOM in 2011 when they looked at this. How much vitamin D should we take? 

IOM said, if you're deficient clinically, that's 20 nanograms or less, maybe you should consider-- you should treat vitamin D deficiency as it is currently defined. 20 to 30 nanograms per ml. That's insufficiency. The Endocrine Society et cetera, the Bones Society still said, no, no, no. Let's get everybody over 30. 

But this graph would say, in terms of calcium absorption, you really see an uptick in the very, very lowest ranges of serum vitamin 25 hydroxy vitamin D. The bone density, again, you see that effect in the second line. And then the risk of osteomalacia and deficiency, rickets of course, is-- all reaction is happening on the lower end of the spectrum of vitamin D. 

I'd also like to remind you that clinically, we measure 25 hydroxy vitamin D. That is the storage value. That is not the hormone that's considered to be active. It's the 1,25, that I hydroxy vitamin D. 

So we also have to think, what is that measure? What are we really measuring there? So stay tuned with vitamin D. 

All right. But what are you supposed to do? So interestingly enough, about 3/4 of Americans say that they take at least one dietary supplement per day. This is via the FDA. 

And vitamin supplements are big business. $4 billion back in 25 years ago to $40 billion industry in the United States today. And now, we have recent studies that are published that show that maybe with calcium and vitamin D, perhaps there's no harm for cardiovascular risk. So that's reassuring. And I think the American Cardiology Society had determined when they looked at this that there didn't seem to be risk in those trials even with the calcium supplementation. 

But perhaps there's vitamin D harm in terms of higher doses based on the 3D structure that was published here in JAMA in the past year. And there may be harm in altered-- terms of altered calcium metabolism and higher doses of vitamin D. So to say-- when your patient comes in, say, I know I have low bone density, but I'm taking calcium and vitamin D, you may have to spend a few minutes re-educating in what the evidence actually shows us now. 

So what should you do? For calcium, I think that perhaps getting enough in your diet would be a reasonable recommendation, and even from calcium fortified foods rather than buying a supplement. Why do I say calcium fortified foods rather than a supplement? It's because, actually, the RDA recommend-- is very good with labeling and making sure that what's in-- it says it's on the label is actually what you're getting as opposed to supplements, which are not FDA regulated. And we don't know what we're getting. We're going based on trust. 

And for vitamin D, only if you're really insufficient. And for bone, people come to bone. I'm still using the 30. But, I mean, you could have a debate with me and maybe convince me otherwise based on the data that are out there. But it's a slow process. 

So why? Just because sun exposure should be sufficient, but now we use sunscreen because we don't want to get cancer of the skin, melanoma in particular. So it's just harder to get in that vitamin D if you're deficient. 

Moving on to drugs. So there, like I said at the beginning of the talk, we've got all these agents that have been around since 1995, some since 2008, 2010, that are effective in preventing incident fractures. But the anabolic therapies were even more attractive because they helped build bone. 

And we've had teriparatide available since 2002. But now we have abaloparatide since 2017. And then most recently since 2019, romosozumab, that has been very exciting because not only is it thought to be anabolic in effect but also has an antiresorptive effect as well. So very mimicking biology in terms of bone accretion and normal bone biology. 

So what are the evidence that got these through the FDA? For abaloparatide, it's PTHrP and binds the parathyroid receptor type one and has anabolic effects with modest stimulation of bone resorption compared to teriparatide. And in that trial-- it was called the ACTIVE trial-- they enrolled women ages 49 to 86 who had bone density T-score of less than 2.5 but greater than negative 5 and a history of fracture, either a low trauma fracture or vertebral fracture, with their primary pre-specified endpoint being one or more incident morphometric vertebral fractures, meaning that it was a change seen on X-ray that was done at base between baseline and follow up. And the second endpoint was a non-vertebral fracture. And then they had some exploratory outcomes in terms of other major osteoporotic fractures. 

This trial had three arms. Two of them were you get randomized to either getting the drug, abaloparatide, which is a subcutaneous injection once daily, versus placebo injection once daily, versus teriparatide injection once daily. It was a little unusual because if you were assigned to the teriparatide group, you actually knew you were getting teriparatide because it was already available on market. But the other two groups didn't know what they were getting. 

And what they were-- found was that after the 18 months, the risk of new vertebral fracture was decreased by 86%. It was highly statistically significant. Non-spine fracture reduced by about 43% and major osteoporotic fracture by 70%. Clinical fracture, which was defined as a fracture causing you to go to the doctor, was reduced by about 43%, also statistically significant. 

This is just the figure that was published that shows that in the first 18 months, there was definitely a reduction in any clinical fracture. After that, though-- and this bears mentioning for the teriparatide group-- with these anabolic therapies, if you just stop the medication and they're doing this daily injection, you will just lose that bone density over time. 

So every anabolic therapy or even some of the other therapies have to end up on an antiresorptive to maintain those bone density effects. So generally, that's a bisphosphonate. And so that's what they did in this trial. Then after the 18 months, everybody got put on alendronate. 

And so there were no differences in the next six months between the treated groups in terms of incident fractures between the 18-month and the 24-month period. But then again, continuing on beyond that, there still seemed to be a benefit in those who had taken the abaloparatide versus those who had taken placebo and then the alendronate. So this drug was FDA approved based on that trial in April of 2017. 

So it was 2,400 women. What were the side effects reported? Mainly dizziness, nausea, and palpitations. I can tell you from my clinical experience and using this drug in a handful of patients that palpitations have definitely been something that I've seen myself. 

And then main things are that it's not approved for treatment, just like teriparatide, for more than two years because we don't want just continued anabolic effects on our bone and skeleton, because in the rats that were given 30 times the dose, both in the teriparatide trial and the abaloparatide trial, there was a development of osteosarcoma. So if your patient has had radiation to the skeleton, Paget's disease, something like that, this drug you would not want to use. 

The thing that's made patients of mine decide they want to be on this drug as it comes off the FDA is the fact that you don't have to refrigerate it. And it's still pending FDA approval for men. But the patients who have been on it for two years now and have gotten the repeated bone density, they are very, very excited that their bone density has improved significantly. 

The next one is romosozumab. And this is exciting because it's a monoclonal antibody that inhibits sclerostin which works in the signaling pathway for bone metabolism. It increases bone formation and decreases bone resorption. 

So the first trial that they did that was published in the New England Journal back in 2016 was of 7,180 women aged 50-- I forget how old they were-- 55 to 90, with T-scores of negative 2.5 to negative 3.5 at the total hip or femoral neck. They were treated with romosozumab man versus placebo, which were two shots once monthly for a year. And this just shows the design of the study. 

So what happened? Oh, they got followed up. Again, romosozumab, you just don't stop. They followed up with denosumab, which is the twice yearly injection that was FDA approved for treatment of osteoporosis effective in preventing hip fractures and all non-spine fractures. So they all got put on that at the end. 

And what you see from this is that there was a significant 73% reduction in fracture of vertebral fracture at 12 months. And at two years, when both groups were put on the denosumab, there was a continuing 75% risk reduction in those who got the romosozumab in the first 12 months. 

Then they decided to do another study of sicker patients who couldn't be put on placebo at the 12 months. So they used alendronate as the control group, where they then got 4,000 women, aged 55 to 90 with a T-score of less than 2.5. And they had to have had a moderate or severe vertebral fracture, or at least two mild vertebral fractures, or some kind of fracture history to get enrolled into this study. And in this case, they were given either alendronate from the beginning or romosozumab, the same dose as the other trial. And then after the year period, they were then-- everybody was put on alendronate. 

So what they showed was again very significant, 47% risk reduction in incident new vertebral fracture. That continued to show efficacy after 24 months of follow up when both groups were on alendronate. And the survival curves show that there was separation over 48 months, that the curves didn't converge. So there was definitely a benefit of being on this romosozumab, very effective improvements in bone density of the spine and the hip at the 12-month period. 

So based on this, this drug also became FDA approved, after somewhat of a delay, in April of 2019. So for those of you who are a little bit aware of the side effects that have caused your patients not to want to be on something like alendronate, it's because of the well-publicized osteonecrosis of the jaw as well as atypical femoral fractures that were reported in people who had been on long term bisphosphonate use. So now that we're aware of that, they did look at these cases, and they were rare but detected. So we know that's a risk. 

In terms of the osteonecrosis of the jaw, I went to speak to the American Academy of Oral Medicine. And the dentists and oral surgeons who are interested in this area do believe that it is because people have underlying periodontal disease. 

So anybody who's using these drugs should ask about whether people are getting regular dental care. And particularly those who are oncologists who put patients on high doses of denosumab and zoledronic acid, that will help reduce the incidence, which is about 1 in 1,000 in high doses for cancer prevention metastases to the bone. In osteoporosis, we see it so rarely, but I still ask about dental hygiene. 

But the signal that caused a delay in this has been cardiovascular events that were not detected. There were only 44 total versus 41 in the FRAME study. But in the sicker women, there was 32 versus 13. And this caused a significant delay in FDA approval. 

And when it finally got FDA approved last year, there's a black box warning about cardiovascular events. Turns out that it may just be to chance. In fact, I was just meeting with one of my colleagues who is looking to publish. 

They did a Bayesian analysis of these data that suggests that it's not a true finding. But I say, put it out on the live market. We're going to see. And I'm certainly not going to be prescribing this to my patients who have a history of cardiovascular disease. 

I'm a geriatrician, like I said. Fall prevention is probably the most effective, in my opinion. So in this, when patients come to see me, it's about fracture prevention. 

But if you prevent the falls, you're going to be so good at preventing fractures, because most people are concerned about hip fractures. And 95% of all hip fractures occur because someone has fallen. And the CDC knows that. It's a big problem. 

So about 30% of our community dwelling older adults have a fall every year. 30%, 1 in 3. And 1 in 5 of those falls result in some kind of injury. And if you've fallen in the past year, your risk of future falls is much higher. 

So what's the evidence? We're evidence-based now in 2020. Well, there've been a lot of intervention trials for fall prevention, multifactorial interventions, at least seven good quality trials that have looked at comprehensive geriatric assessment, looking at balance, gait, vision, postural blood pressure, medications. Multiple medications could be a risk for falls, environment, cognitive and psychological health. 

Then there are exercise intervention trials. You start exercising, working specifically on balance. You can improve and decrease your risk of falls. And so the US Preventative Health Services Task Force actually said, guess what, overall there's both-- both types of interventions work. But exercise does a little bit better than the multifactorial environmental kind of assessments. 

So in clinic, primary care, whatever, cardiology, nephrology-- I don't care what it is-- rheumatology, assessing fall risk is very easy to do. You just have to open your eyes and watch. Some of us never touch patients anymore because we have all these other imaging modalities. But just watching them try to stand up, usually if I'm interviewing them and in clinic, we're going to start doing an examination, I ask them to stand up. They stand up, and if they use the arms of the chair, I tell them to sit right back down because I want to see if they can get up without using their arms. 

And if they can't get up without using their arms, that's a risk factor right there. If they're weak, then we have something called the semi-tandem stand and tandem stand in geriatrics, developed by Mary Tinetti, where we just ask if they can put their feet close together, one kind of side by side. And then if they pass that, all the way one foot in front of the other. 

And if they're really good at that, then I ask them to close their eyes. It gets a lot harder. And if they fail that, they probably should be made aware that their balance is going to go down with age, and they should be working on it to help prevent it. 

So when we talk about exercise, especially in the older generation, they're thinking gym, put on clothes. That may not jive with their expectations of how they're aging. So I like to talk to them about conceptualizing, being aware of their body in space, and to them discuss what their goals are. Why are they even coming to the doctor? I mean, I can help them. But they have to be invested in their own health. 

And that there's a multitude of interventions that one could do. It doesn't mean buy a gym and then go to the gym three times a week. It could be just being active and aware in the body. You can use videotapes. There's so many-- take walks. 

So just get active. Use your body, be aware of it and space, and even working on the chair stand at home or getting 14 ounce cans of beans and lifting them up and down, and being aware of posture. All of that can have a benefit in terms of health, not just falls but overall functional good aging. 

Again, in 2020, you hear about American College of Physicians number needed to treat. I'd like to just revisit this because that's what we use to say, is it worth it when you think of evidence-based medicine? So depending on which reference you use, I wanted to take it back to statins because I happen to be running a randomized controlled trial on muscle strength. And one of the exclusion criteria for these patients over the age of 65 is that they couldn't be on a statin. 

I found out everybody in La Jolla who's over the age of 65 is on a statin. Well, according to one study at least, statin used-- to prevent one death over one to six years, you need to treat 250 people. They're getting that in La Jolla. But interestingly, you need to treat about 197 people to get harm, which I guess in this case was described as the muscle aches and pains that are commonly prescribed-- talked about. 

So on the right-hand side is osteoporosis medications. Number needed to treat to prevent a fracture. We're talking not too many people, anywhere from 11 with teriparatide to 28 with raloxifene, which I didn't discuss. It's a selective estrogen receptor modulator. 

And the harm for alendronate, which is still the number one prescribed medication, 16 people to prevent a fracture, 2,000 people to get that atypical femoral fracture. So when you're talking about risks and balances benefits, clearly the benefit is higher, but these drugs are not to be prescribed and then forgotten about. I mean, now statins, we used to measure their LFTs at three months and make sure there are no liver or toxic [INAUDIBLE]. But we kind of even abandoned that mostly. 

And so people are on statins forever. But maybe they prevent cancer. I mean, there are reasons to be on statins. I'm not dissing the statins. I'm just saying that for alendronate, that's not a drug that you can forget about. You have to think about how long you're prescribing it. 

And then my favorite part of the slide may be even the fall prevention because the data are even stronger. Now, the numbers needed to harm are listed as zero. But I don't know if that's because they didn't assess for harm or what the deal is, because things happen in life. But there were none reported. And again, the numbers are even smaller than for the medication. So we're talking 4 to 11. 

So let me see how I'm doing on time. Oh, pretty good. Oh, 55. I'm almost done. OK. 

So comparing osteoporosis to another common age-related disease, hypertension. I like to think about that osteoporosis is like hypertension. It's common, affecting over half of the older adults. It's a silent disease, much like osteoporosis, until it manifests as a stroke, or a heart attack, or as a fracture. And the sequelae from a hip fracture or stroke have long term health and lifestyle implications. 

But osteoporosis is not like hypertension in that it can be diagnosed in several ways that we talked about. Even a fragility fracture from standing height or less should make you think, this person may have osteoporosis. And the difference is usually with hypertension, you can be on a medication almost for life, unless you start getting postural hypotension or other issues going on. But for sure for bones, none of these treatments are for life. 

Osteoporosis is like hypertension in that the lifestyle choices one makes can help effectively avoid these consequences of osteoporosis as well as uncontrolled high blood pressure. And there are multiple choices today to treat these conditions. 

But it is not like hypertension in that an astute clinician can make a presumptive diagnosis with just looking at the patient. It's harder to just look at a patient and get a sense of what their blood pressure is. And the number needed to treat is actually lower to prevent a vertebral fracture, say 16, compared the number needed to treat to prevent a stroke, which is about 120. 

Just to summarize, bisphosphonates are still the number one medication for treatment. It was FDA approved back in 1995. Compliance is an issue. So zoledronic acid, which is the IV form given once a year to once every 18 months, is very well-tolerated. You've got to check the kidney function. And there are even studies and debates as to whether bisphosphonate use can lead to less mortality risk over time. That's another lecture right by itself. 

But we have challenges because as we get older, we have competing priorities. There's a lot of misinformation and mistrust out there. Patients who do fracture don't actually think that they have an underlying disease. 

It's not as simple as prescribing medication and forget about it. There's a lot of discussion that goes on to help someone figure out how to prevent a fracture. So it's time consuming. And primary care physicians have a lot to deal with in their short time of an outpatient visit. 

That being said, fall prevention is key with little associated harm. So all of us as we're aging should think about fall and fall risk and assess it, and that we have a lot of FDA approved treatments for osteoporosis. And in general, the benefits do outweigh the harms. Particularly, if they've had a previous fracture, if they have very, very low bone density, family history, and if they're looking like they're going to topple over when they get off the-- then you know you're dealing with someone you may be seeing in the ER for a fall and a fracture. 

So none of this work could have been possible without some of my colleagues over from different institutions over the years. And finally, thank you so much for your attention. And we're at 58 minutes. 

[APPLAUSE] 

Given that it is 1:15, we'll have time for one, maybe two questions, if anybody has one. 

Thank you for a thoughtful discussion. I'm a transplant nephrologist. And so everybody that comes to see me has already passed through stage 5 CKD, which changes everything, right? 

So you have FGF23. You have the degradation of vitamin D. You have calcifications and high phosphorus, all the stuff. Plus we throw meds at them. 

So we've gone away largely from DEXA scans because the bone biopsy studies have shown they're not very [INAUDIBLE] and they-- the treatments alendronate tend to cause frozen bone. So what should we do? 

Yeah. So I don't know if you know Jo Ix, but he's my colleague and Chief in Nephrology at UCSD. And we've just gotten an R01 funded, where when patients present with-- they have to have CKD, which is only defined as less than 60. So pretty mild. 

But we're going to get bone tissue. And we're going to look to see, because it is so hard to do. We actually now-- since coming to UCSD in 2012, we have the bone biopsies. 

And that woman, the first woman who had all the vertebral, we actually biopsied her, and she has no osteoblasts. She has normal kidney function, but that's what we've been doing, is we're trying to get a better handle of what's going on. Is this adynamic bone disease? What is it? 

And we're finding the gamut. So it's looking, like everything else, personalized medicine may be some of the answer. But I do have a few transplant patients who I'm afraid to use the meds for because denosumab can lead to severe prolonged hypocalcemia in those. And so I don't like to use any of them. 

Right. 

So I really focus on the fall prevention aspect as much as possible. Paul Miller, who you may or may not know of, he's a cowboy. He's out there putting the anabolics-- I don't know for how long, or but there's no evidence to really suggest that's going to help. 

Yeah. Thank you. 

Any other questions anybody has? Dr. Kado, thanks for being here. 

Thanks. 

[APPLAUSE]