Osteoporosis

Hey guys, thanks so much for joining me today. In this episode, we'll be talking about osteoporosis. And I get it, it sounds super boring. You may have died a little inside when you heard the word. Potentially thinking about changing from a cardio session to a nap session. That's how I used to feel as well, but I changed my mind when I realized just how prevalent this disease is and how much of a difference we can make to people if we treat osteoporosis properly. I'm hoping after today, you'll change your mind too. Welcome to Rheumatology for the Royal College, where we aim to bring you reviews that will strengthen your knowledge going into exams and clinical encounters. We hope you'll find it useful and enjoyable, whether you're running, lifting, cooking, grocery shopping, driving, you get the idea. I'm your host, Dr. Karim Ladak, an American trained Canadian rheumatologist. Before we start, my lawyer advised that I should say the information here only reflects what I have in my personal notes and should not be used in isolation in the management of patients, nor for your boards. I'd like to thank the McPherson Institute and Abbey Pharmaceuticals for supporting this podcast through their educational grants. However, it should be noted they have absolutely no editorial say in its production. Definitions We should start with definitions because there's a lot of confusion around this. What is osteoporosis? What is osteopenia? What is osteomalacia? Very, very briefly, osteoporosis and osteopenia refer to low bone mass. They're diseases to do with thinness of the bone. That's what causes them to be weak versus osteomalacia as a mineralization problem. So if you were to look up osteoporosis in a textbook, you might see a definition as follows. It's two parts. A disease of the bone characterized by low bone mass and microarchitectural deterioration resulting in, part two, increased fragility and therefore fractures. Osteopenia is basically like osteoporosis but less intense, less severe. And osteomalacia is different. It's a much less common disease characterized by poor bone mineralization. It has nothing to do with density. These bones can have a normal thickness but are predisposed to fracture because they're soft from a lack of mineralization. That's all we'll say about definitions. Now let's talk about how to actually diagnose it in patients. Diagnosis. In your average postmenopausal woman or male over the age of 50, there are two ways to diagnose osteoporosis. The first, very simply, is using numbers from the bone mineral density or BMD that you get from a patient's DEXA scan. This method was set up by the WHO. They set thresholds with specific number cutoffs for BMDs that define somebody as normal, having osteopenia, or having osteoporosis. You are defined as having osteoporosis if your BMD T-score, not Z-score, T-score is less than or equal to minus 2.5. Very simply, according to the WHO, if you have a T-score of less than or equal to minus 2.5, you've got osteoporosis. Once again, this is not the Z-score, this is the T-score. Then they say that if you have a T-score greater than minus 2.5 but less than or equal to minus 1, so less severe than minus 2.5 up to minus 1, you've got osteopenia or low bone mass. If you have a BMD T-score of greater than minus 1, you've got normal bone mass because you're within one standard deviation of the mean. That's the first way to diagnose osteoporosis. The second way to make the diagnosis of osteoporosis then is clinically. If somebody has a fracture, that's a fragility fracture, meaning it occurred as a result of falling from a standing height or less, regardless of the BMD, they've got osteoporosis. So to summarize, according to the WHO, if your T-score, not your Z-score, if your T-score is less than or equal to minus 2.5, you have osteoporosis. If it's greater than minus 1, you've got normal bone mass. If it's in between, you're osteopenic. Alternatively, if you have a fall that results in a fragility fracture, meaning a fall from standing height or less, you have osteoporosis regardless of your bone mineral density. Those are the two ways to define osteoporosis. Epidemiology. Okay, so I always used to roll my eyes whenever I'd hear about osteoporosis. I thought, what's the big deal? Why would people want to specialize in this super boring disease? Then I realized how prevalent it was and how important it was because half of North American women who are postmenopausal and one quarter of men over the age of 50 are going to have an osteoporotic fragility fracture. If you are a woman listening to this, or if you're a guy and you've got a woman you love, mother, daughter, sister, spouse, whatever, she has a one in two chance of having a fragility fracture from osteoporosis. And if you're a guy, you've got a one in four chance of having an osteoporotic fragility fracture, which is crazy. That means that my mom is at higher risk of an osteoporotic fragility fracture than she is of an MI, stroke, or breast cancer. Most commonly, we see vertebral fractures, hip fractures, and distal forearm fractures. And that's why when you get a DEXA report back, those are the areas most commonly reported. The L spine, total hip, femoral neck, and distal radius. The good news is that despite the prevalence of osteoporotic fractures, half are felt to be preventable and it's super cost effective too. So if we get better at it, we'll help the patients and we'll help our economy. Pathophysiology There are two types of bone, cortical bone and cancellous bone. The proportions vary by site. Cortical bone you'll find more so in the long bones, cancellous bone you'll see more in the spine. Normally, all these bones remodel, quote unquote remodel. This is a coupled process whereby there's resorption by the osteoclasts and there's corresponding new bone formation by the osteoblasts. And they're supposed to be equal. The whole point of this is that the skeleton can adapt to consistent mechanical stresses by reinforcing itself. In fact, it's such an active process that every 10 years we have full skeletal remodeling when the system is working well. And coupling is normally, like I said, balanced. So the amount of resorption equals the amount of formation. After menopause though, after the age of 50, that remodeling really changes. In women in particular, once they lose estrogen, there's a negative balance as osteoblasts start to underfill the areas of resorption. And so you get thinning of the bones. In fact, there's so much here to do with estrogen that right after menopause, women lose up to 7% of their bone mass annually for the first few years. And then after several years, it tends to stabilize. And then they only lose 1 to 2% of their bone mass a year, which is still quite a bit. Risk factors. Okay, so what are some of the major risk factors for osteoporosis? Obviously age. The older you get, the higher your risk. Being a woman, as we've pointed out. Unfortunately, here is one more systemic gender bias that works against women. Menopause. It's important in your clinical evaluations, therefore, to ask if there was early menopause. Because sex hormones, both in men and women, contribute to bone mass. So low estrogen in women, low testosterone in men, can both reduce bone mineral density. In addition to low BMI, a prior fracture, particularly hip or vertebral fractures. According to the Canadian risk stratification system called CAROC, if you've had a hip or vertebral fracture in the past, you're automatically at high risk, quote unquote high risk, for future fractures. But not only personal fracture risk, even family history of fracture substantially increases your risk of future fractures. Why? Because at least half the variance from person to person in bone mineral density is genetic. Medications. There are multiple medications that will reduce your bone mineral density. Steroids. Common. Diaplyptic drugs, like phenytoin. Male hormone depleting therapies, like Lupron, that we use in prostate cancer. Anastrozole that we use in breast cancer. Heparin. Chemotherapy. Depo-Provera contraception. There are endocrine abnormalities which predispose to osteoporosis. Hypogonadism, as we've already discussed. So if a man tells you that he's not shaving as much, or he's got poor libido, it's important to look into that as a cause for his osteoporosis. Premature menopause in women. Hyperthyroidism. Hyperparathyroidism. Cushing's. Even transient bone loss during pregnancy and lactation can occur. Malabsorption syndromes, like celiac disease, IBD, gastric bypass, can all reduce vitamin D absorption. Alcoholism. Smoking. Inflammatory conditions that we deal with all the time, like rheumatoid arthritis. And infiltrative conditions, like multiple myeloma. So there are plenty of risk factors for osteoporosis, and it's important to evaluate them when you're doing your clinical encounters with osteoporotic patients. Just to review real quick. If the Royal College was to ask you for seven drugs that lead to osteoporosis, could you name them? I'll give you 15 seconds to think about them. Okay here we go. Steroids. Anti-epileptic drugs, like phenytoin. Male hormone suppressants, like Lupron. Estrogen blockers, like anastrozole. Heparin. Chemotherapy. Depo-Provera. Clinical presentation. Osteoporosis is largely asymptomatic until a fracture occurs. Hip fracture patients will have symptoms obviously, and vertebral fractures can be super painful but they can also be asymptomatic, or anything in between. According to the JAMA Rational Clinical Exam series, no single physical examination maneuver or combination of maneuvers is sufficient to rule out osteoporosis or vertebral fractures without further testing. But there are some things that you should still do on examination. You should get an accurate weight and height, for a couple reasons. If a patient has a weight of less than 51 kilos, the pretest probability of them having osteoporosis is higher. Another reason is that you'll need the BMI for the FRAX calculator. You'll need their height and weight for the FRAX calculation, if that's what you're going to use, and we'll talk about that in a bit. If the patient's had height loss, it may suggest a vertebral fracture. And that's that. A total tooth count under 20 could be suggestive. A wall occiput distance, where their heels and their back are against the wall, if that distance is more than 0 centimeters, it may suggest vertebral fractures. A rib pelvic distance less than two finger breaths in the mid-axillary line may also suggest vertebral fractures. And if the patient self-reports a humped back, quote-unquote humped back, according to the rational clinical exam series, that may also support vertebral fractures. Lastly, it's not just about the bone mineral density that predisposes you to fractures, it's also about your stability and sort of your functional status. So it's good to do something called the Get Up and Go test. This test asks you to get up from a chair, walk three meters, turn around, come back to the chair, sit down. If it takes the patient 12 seconds or longer to do this, they're at high risk of false. Workup Okay, so in terms of workup, remember we talked about two ways to diagnose osteoporosis? The first is fragility fractures, and the second, in post-menopausal women and men over the age of 50, is using the T-score. And if that T-score is less than or equal to minus 2.5, they've got osteoporosis. Well, ergo, it's important to get a bone mineral density. And you get the bone mineral density, or the BMD, from the DEXA scan, D-X-A, that stands for Dual Energy X-ray Absorptiometry, DEXA scan. The DEXA will tell you the bone density and the size, and that's really it. It doesn't actually tell you the mineralization, it can't actually guarantee overall strength. But you infer based on good data that in most individuals, the BMD and the strength of the bone correlate. So that the higher the BMD, the lower the fracture risk. If you remember the anatomical regions that are at highest risk for fractures, it's the hip, the vertebrae, and to a lesser extent, the distal radius. And so most DEXA reports will give you the BMDs in those areas. Usually they'll report the femoral neck, the total hip, the L-spine, and some will give you the distal radius. Now it's not actually the BMD absolute number that matters. It's not that absolute value in isolation, but rather how that patient's BMD number compares to healthy controls in the general population. Enter T-scores and Z-scores. Using the absolute BMD numbers, the T-score and the Z-score can be calculated. The T-score represents the number of standard deviations from the peak bone mineral density in healthy young adults. Based on the WHO definitions, osteoporosis is defined as a femoral neck T-score of less than or equal to minus 2.5. Osteopenia is defined as a femoral neck T-score of greater than minus 0.25 up to minus 1. And normal bone mass is defined as anything over minus 1. Because in that range, you're within one standard deviation of the mean of healthy young adults. The Z-score is very different. The Z-score is used not to gauge bone mineral density in postmenopausal women and men over the age of 50. It's used instead in premenopausal women and men under the age of 50. It represents the number of standard deviations from age-matched controls. Not just healthy young individuals, but age-matched controls. And importantly, you cannot diagnose osteoporosis based on the Z-score alone. When you're using WHO criteria to make the diagnosis of osteoporosis, you can use the lowest score from any of the reported anatomical regions. In other words, if a patient comes in and their BMD T-scores are minus 2.3 in the femoral neck, minus 2.3 in the total hip, minus 2.3 in the distal forearm, but minus 2.6 in the L-spine, you can still call them osteoporotic because the lowest measurement is minus 2.6. So how do we actually screen then? How often do you screen? Who do you screen? American and Canadian guidelines are pretty similar in this respect, with just small differences. The US National Osteoporotic Foundation suggests screening all women once they hit 65 and screening men once they're 70. They also say you can screen individuals younger than that, over the age of 50, if they have risk factors for osteoporosis. The Canadian guidelines are quite similar. They say screen women over the age of 65. They say even men, once they hit 65, screen them. And they also suggest screening individuals over the age of 50 if, quote, they have other conditions associated with osteoporosis, end quote. So they kind of leave it pretty open here for you to decide what you want to do. So again, in Canada, once you're a man or a woman at the age of 65, you should be screened for osteoporosis even earlier than that, over 50, if you have risk factors. And I'm going to paraphrase a little here, but the minutiae are a little ridiculous to memorize and I don't think you need to know them. Some risk factors to consider screening earlier for include the following. If the patient's had a fragility fracture over the age of 40, screen them. If they're on high risk medications, the ones you recalled from me a little while ago, screen them. Prolonged steroids, aromatase inhibitors, androgen deprivation therapy, phenytoin, heparin, etc. More particularly, by the way, the steroid dose matters. It's not just that your patient was admitted with the COPD exacerbation, got 40 milligrams of prednisone daily for five days. That's not enough to merit screening for osteoporosis. They want to see at least 7.5 milligrams a day for three months or an equivalent dose in the previous year. If your patient's a smoker, you can also screen them. High alcohol intake defined as three or more units a day, screen them. Low weight, less than 60 kilos, screen them. Inflammatory arthritis, primary hyperparathyroidism, hypogonadism, premature menopause under 45 years of age, and the list goes on. So now you know who to screen, who to get the bone mineral density studies on, who to get that DEXA on. What do you do with that data? What does a T-score of minus 2.2 in your 52-year-old patient tell you versus a T-score of minus 2.6 in an 87-year-old male tell you? This is important because most fragility fractures occur in individuals without T-score criteria for osteoporosis. And a T-score of minus 2.2 in a 56-year-old woman means different fracture risk than a T-score of minus 2.6 in an 87-year-old male. So what we use is fracture risk assessment tools. These stratify our patients and tell us what their risk is and helps you therefore decide who you should treat. There are two you need to know. The first is FRAX. This is the most commonly used one internationally. It's calibrated for populations of a number of countries. And the second is CAROC. This was developed in Canada, calibrated for the Canadian population. Both tests correspond pretty nicely. There's an over 90% concordance according to Osteoporosis Canada. They will both provide you with a 10-year fracture risk in those over the age of 50 using femoral neck T-scores. I'm going to repeat this because there are some important specifics that you should remember. Both will predict 10-year fracture risk. Both of these are to be used in post-menopausal women and men over the age of 50. Not to be used in men under the age of 50. Both predict fracture risk in individuals who are treatment naive. It does not adjust the fracture risk after treatment for osteoporosis. And lastly, although the DEXA gives you bone mineral density scores for the femoral neck, total hip, L-spine, and sometimes a distal forearm, the only score that you're going to plug into these risk calculators is the femoral neck T-score. Total hip, vertebral scores, distal forearm scores, or Z-scores are not to be used. There are other aspects too to the DEXA reports. Things like TBS, or trabecular bone score, which looks at the texture of the bone and how they're connected. And that's important and can help you clarify fracture risk a little bit further. But it's beyond the scope of what we're talking about today and I don't think it's going to come up on your exams. So let's delve deeper into both of these. The first one I want to talk about is CAROC. This is a very simple risk stratification tool. All it wants is the patient's age, their sex, and their femoral neck T-score. That's all it's going to ask you to start with. Using that, it's going to put your patient into one of three risk zones. Low risk, moderate risk, and high risk. If the patient's low risk, that means their 10-year risk of fracture is less than 10%. If they're moderate risk, it means that their 10-year risk of fracture is 10-20%. And if they're high risk, it means their 10-year risk of fracture is over 20%. It takes account of two osteoporotic risk factors in addition to this. If you have had recent prolonged glucocorticoid use, so 7.5 mg a day for 3 months or more in the last year, it'll shift you up a risk level. If you're in low, you'll go to moderate. If you're in the moderate risk category, you now automatically become high risk. The other risk factor it looks for is that if you've had a previous fragility fracture of the hip or the vertebrae over the age of 40, then you automatically become high risk. That's CAROC. Super straightforward. FRAX is a little bit more detailed. FRAX stands for Fracture Risk Assessment System. It was developed by the WHO. These are the same people who developed the T-score thresholds. It's going to ask you age, sex, prolonged steroid use, and previous fragility fracture, just like CAROC. However, it also considers the patient's BMI, whether the parents had a fracture, whether there's rheumatoid arthritis, whether the patient's a current smoker, whether they have high alcohol intake defined as three or more units a day, whether there's secondary osteoporosis, anything from malnutrition to premature menopause to hypogonadism to type 1 diabetes to chronic liver disease, a bunch of stuff. It would love for you to give it the femoral neck T-score, but interestingly, FRAX has so many other data points, it can predict the 10-year risk of major osteoporotic fracture without that BMD. So if you're in a pinch and you need the 10-year fracture risk and you don't have have an up-to-date femoral neck T-score on your patient, you can actually calculate the FRAX 10-year fracture risk without it. And that's it. That's what you need to know for the bone mineral densities and the DEXA scans. In terms of other investigations you should do in your osteoporosis encounters, get a lateral X-ray of the T and L spine to look for occult vertebral fractures, which are defined as 25% height reductions with disruption of end plates. Why? Because like I just said, it automatically puts you into quote-unquote high risk according to Care Rock. And that makes your decision around whether or not to treat your patient way easier. In terms of blood work you'll want to do on your patients, according to the Canadian guidelines, everybody gets the following, a CBC, look for malignancy, infiltrative disease, creatinine to see if maybe kidney disease is driving your bone disease. And because it affects your medication choices as you're going to see. Calcium, it's important for medications, which can change your calcium levels. 25 hydroxy vitamin D levels. According to Canadian guidelines, you want your level to be 75 nanomoles per liter or higher. In American units, that's 30 nanograms per milliliter or higher. This is the optimal level because it prevents PTH rise. According to the guidelines, as long as you've supplemented the patient for three to four months with vitamin D and their levels meet 75 nanomoles per liter or 30 nanograms per milliliter in the States, you don't need to recheck them again. You'll also want to test for Paget's disease by doing an ALP and make sure that's not elevated. Ideally a bone specific ALP, if you can get one at your center. TSH, just to make sure there's no hyperthyroidism that's driving accelerated bone turnover. And lastly, if it was a vertebral fracture, get an SPEP. There's some additional tests you can consider as well. Like if the situation looks weird, perhaps you have a young male, for example, or disproportionate BMD measurements. So things to consider might be ESRCRP, PTH, serum testosterone and sex hormone, binding globulin in men and NTTTG. Or if the patient has cushingoid features, it might prompt you to do a 24 hour urinary cortisol. The last test that can be quite useful is bone turnover markers. So there are markers that tell you that bone's forming, bone specific ALP and P1NP. And there are markers that tell you bone's absorbing or resorbing, N-telopeptide, C-telopeptide, NTX and CTX. CTX and NTX are particularly helpful to check if you're worried about compliance or malabsorption or just treatment failure. So you can check it before initiating therapy, and then you check it again three to six months after. And if you see a 30% fall in the CTX, you can be pretty confident that the next time you do a bone mineral density, there'll be stabilization or improvement in the bone mineral density levels. Treatment. Okay, treatment, which is the juicy stuff that you guys are all waiting for. Remember your focus is not improving BMD alone. That's just part of the equation. Your main focus is to prevent fractures. So like every other Royal College question, you are going to have non-pharmacologic and pharmacologic management. Non-pharmacologic comes first for osteoporosis, smoking cessation, alcohol moderation, nutrition, appropriate education by referring them to Osteoporosis Canada. Importantly, balance and strength training exercises. So weight-bearing aerobics and everybody's favorite Tai Chi and then optimizing nutrition. Specifically vitamin D, like we talked about, your target according to the Canadian guidelines is 75 nanomoles per liter after three to four months of supplementation, after which time you can stop testing it or 30 nanograms per milliliter in the States. Again, this is 25-hydroxy vitamin D, very different from 125-hydroxy vitamin D whose levels can be normal even with low 25-hydroxy. You also want to optimize calcium. Post-menopausal women, at least 1200 milligrams a day. Pre-menopausal, 1000 milligrams a day. There's a lot of discussion previously about whether or not over 1500 milligrams a day leads to excess cardiovascular events. It's not really clear, but your sweet spot's probably just over 1200 milligrams a day for your post-menopausal women. And then according to the Canadian guidelines for preventing hip fractures in long-term care, hip protectors are recommended for adults at a high risk of fracture in long-term care facilities. Medications. All right, quick prelude here. The osteoporosis drug trials looked at three different types of fractures. They grouped fractures into three categories. Vertebral fractures, hip fractures, and non-vertebral fractures. Of the drugs we have available in North America, basically all of them will help reduce vertebral fractures if there's good adherence. Some will also reduce hip fractures, and to a lesser extent, some will also help non-vertebral fractures. An important question is who do you actually treat? So in the US, it's pretty simple. The National Osteoporosis Foundation there said, if somebody's had a hip or vertebral fracture, no question, treat them. If somebody has osteoporosis based on a T-score of minus 2.5 in the vertebrae or the hip, treat them. And finally, if somebody's had low bone mass or osteopenia with a frac's 10-year risk of major osteoporotic fracture greater than or equal to 20%, or a hip fracture risk of greater than or equal to 3%, which the frac's risk calculator will tell you, treat them. Canadian guidelines are a little bit different. With Canadian guidelines, it's all about risk stratified by CAROC or frac's. If somebody's high risk for a fracture in the quote-unquote high risk zone, according to CAROC, meaning that their 10-year risk of major osteoporotic fracture is over 20%, or they've previously had a vertebral or hip fracture, definitely treat them. If they're low risk, meaning that their 10-year risk of major osteoporotic fracture is less than 10%, non-pharmacologic management only. The problem is this gray zone, the moderate risk category, where your risk of 10-year major osteoporotic fracture is between 10 and 20%. This is actually where most patients hang out. It's got the highest number of individuals. And in fact, it's where most fractures are going to occur. Your decision to treat or not to treat patients in the moderate risk category will depend on a few things, including patient preference. You can cheat a little bit and do a lateral T and L spine X-ray. And if you see an occult fracture, boom, they're automatically high risk and you know what to do. Treat them. If they're on high risk medications like long-term steroids, androgen deprivation therapy, aromatase inhibitors, et cetera, treat them. If they have recurrent falls, two or more a year, strongly consider treating them. If they have a spinal T-score that's much lower than their femoral neck T-score, because remember the femoral neck T-score is what we use in FRAX and Kerok, but if their spinal T-score is much lower than their femoral neck T-score, then you might consider treating them. For example, if the femoral neck T-score is only minus 1.9, but the spinal T-score is minus 2.4, you'd strongly consider treating. In terms of the medications, there's some ground rules. First things first, the order of therapy has changed. It used to be that everybody got bisphosphonates first line. That is no longer the case. Practice patterns don't reflect that. And in fact, the Endocrine Society in 2019 released new guidelines in which particularly high risk and very high risk individuals can get denosumab or teriparatitis first line. That's ground rule number one. Ground rule number two, almost always drug therapy is going to be monotherapy. There are several studies looking at combinations such as riloxifene and bisphosphonates, solandronic acid and teriparatide, and for sure they're showing good results, but right now that's not really mainstream. And we'll leave that to the trials and the osteoporosis experts. So we'll discuss the drugs first, and then we'll discuss the order in which to use them, okay? Here we go. The first group of drugs are called the antiresorptives. There are five in this category, only two which are commonly used really. These impair osteoclasts from resorbing bone in remodeling units. Overall, these agents preserve the bone mass and microarchitecture, yet still allow mineralization. They can provide stabilization or a modest increase in the bone mineral density. The first drug on that list is the cornerstone of osteoporosis therapy, and that is bisphosphonates. These are the most common osteoporosis medications. They're potent antiresorptives. Their mechanism of action is that they bind to hydroxyapatite binding surfaces on bones and impair osteoclasts from functioning properly. Examples of bisphosphonates, you probably already know a lot of these. Common ones would include alendronate, also known as Fosamax, rosedronate, also known as Actinel, or zolandronic acid, also known as Reclast, Eclasta, and that's just given very conveniently, annually, IV. In terms of efficacy, they have been shown to reduce all three sites of fractures in trials, vertebral, hip, and nonvertebral fractures. I'm intentionally not mentioning some of the less commonly seen ones, like ibandronate, because some of these other drug studies weren't powered to look at nonvertebral and hip fractures, so we'll just stick to the common ones for now. In terms of adverse effects, generally, these are pretty well-tolerated drugs. With oral bisphosphonates, you can get stomach upset, nausea, abdominal pain, loose bowel movements. They also can be very irritating, and so oral bisphosphonates carry a small risk of esophageal ulcers from irritation of the esophageal mucosa, and that's why we tell patients to chase their oral bisphosphonate tablets with a full glass of water and stay upright for at least half an hour after consumption to ensure that bisphosphonates pass through the esophagus nicely, and that's the reason you gotta be really careful with patients who have esophageal motility disorders, because the bisphosphonate will hang out in the esophagus and has a way higher chance of causing esophageal ulcers and problems. Some patients can get myalgias and arthralgias. The mechanism's not really clear on this one, and it's relatively infrequent. IV bisphosphonates bypass the GI tract and so don't cause the digestive issues or the esophageal issues, but zolandronic acid can, in one-third of patients, cause a flu-like reaction, generally on the first infusion, and it can last a few days at a time, and patients feel really miserable and don't really wanna go back on it, understandably. Those are the common side effects. There are two very rare ones, but which you need to counsel your patients around. The first is osteonecrosis of the jaw. This is an exceedingly rare condition when used in rheumatologic doses as opposed to oncologic doses of bisphosphonates. The risk is probably one out of every 100,000 patient treatment years with oral bisphosphonates. Typically, it occurs following invasive dental procedures, like extractions. What happens is the area of the jaw loses blood supply and it causes necrosis. These can become infected and they can become quite painful. Typically, the good news is that they respond to conservative therapy, and the best way to prevent them is just good oral care and postponing the drug until a planned invasive dental procedure is completed. In terms of dental procedures and timing around bisphosphonates, the American Academy of Oral Medicine recommends that if you want to reduce the risk, just postpone bisphosphonate therapy until invasive dental work is done. If they're already on a bisphosphonate, there's no recommendation on whether or not to stop the drug because bisphosphonates linger in the bones for many years. So stopping it for a few weeks or a few months likely isn't gonna make a huge difference. Easiest thing to do for osteonecrosis of the jaw is just stay in good communication with the dentist and before starting the drug, chat with them first. The second very rare side effect is something called atypical femoral fractures. These are fractures that occur in the femoral diaphysis or shaft. They result after minimal or no trauma. They manifest with pain in the groin or in the thigh. X-ray of the femur will show a transverse or oblique fracture in the lateral cortex. A classic description from radiology is a quote-unquote beaking of the cortex. Usually these require surgical intervention unless you catch them very early. Patients get super freaked out when you tell them about this side effect, but it's really important to remind them that the risk of normal fracture overall is substantially higher than atypical femoral fracture, which is duration dependent. And after five to 10 years of therapy is when you start seeing these. And even after 10 years of therapy with bisphosphonates, the risk is still probably one out of a thousand. In terms of contraindications, like we already discussed, upcoming dental work is one. And the other important one is renal failure because of hypocalcemia and because bisphosphonates are cleared out by the kidneys. So oral bisphosphonates, generally you're really safe if your patient's GFR is above 30, likely even safe if your GFR is down to 15. Certainly do not mess with zolandronic acid though in a chronic kidney disease patient and do not dose them if their GFR is under even 35. Forget 30, 35. So that's bisphosphonates. Drug number two is denosumab, also known as Prolia. This is a humanized monoclonal antibody. The mechanism of action is that it's a rank ligand inhibitor. So it inhibits the rank system. Rank normally encourages osteoclast differentiation and activation. Therefore blocking its activator, aka rank ligand, will block osteoclast activation and resorption. It's dosed at 60 milligrams every six months. And the effects are pretty impressive. In the initial New England trial that came out in 2009, they had a 10% increase in vertebral bone mineral density by three years and 5% in the hip by three years. And we start seeing reduced fracture rates even within one year of therapy. And these bone protective effects continue to progress over 10 years. In terms of adverse effects, hypocalcemia is a pretty big one, especially those who already have hypocalcemia and hypovitaminosis D at baseline. And so calcium should be checked at least annually. The nadir of calcium occurs day seven after the dose. Additionally, long-term therapy has shown a probable association with osteonecrosis of the jaw and atypical femoral fractures, though the association is less clear than with bisphosphonates. There are some other relatively unique side effects with denosumab. A very small, small portion of patients will get eczema and 0.4% of patients in the trials got cellulitis. So you want to be careful if you have a diabetic patient who has recurrent cellulitis or diabetic foot infections, putting them on Prolia just because of that risk of cellulitis. Also, this one's kind of random, but there actually is a statistically significant increase in flatulence. I don't know the mechanism for it, but it's there and it's real. So if your patient complains about extra gas since you started them on denosumab, it's a real thing. Unlike bisphosphonates, Prolia does not need to be renally dosed and is safe in chronic kidney disease with the exception of hypocalcemia, which is obviously going to be a concern in your renal patients. Important side note before we leave Prolia and move on to the next drug, and that is that if you stop denosumab for whatever reason, there will be a rapid loss in bone mineral density gains back to pretreatment levels with a rise in bone turnover markers and a major risk of multiple vertebral fractures over a very short period of time. So you need to make it clear to the patients that if they get on Prolia or denosumab, they need to stay on that therapy in the longterm or at least switch to a different therapy when they're done. And actually switching from denosumab to zolandronic acid around the eighth month mark may be the best maintenance for bone mineral density compared overall with PO bisphosphonates and with teriparatide. So drug number three, our third antiresorptive is hormone therapy. Specifically, I'm referring to estrogen here. It's probably already clear, but this therapy is specifically for women. If the woman has a uterus, in other words, if she has not had a hysterectomy, you need to combine the estrogen with progesterone to prevent endometrial cancer. In terms of effectiveness, it's pretty effective stuff. Estrogens prevent bone resorption and the Women's Health Initiative found a one-third reduction in vertebral and hip fractures and a one in four reduction in non-vertebral fractures. Problem, however, was the side effects and that's why there's so much caution around this medication and why you don't see it too frequently. According to Canadian guidelines, it can be first-line therapy for osteoporosis in women who also have menopausal symptoms requiring treatment. The National Osteoporosis Foundation published their position paper in Osteoporosis International back in 2014 and they said, quote, because of the risks, hormone therapy should be used at the lowest effective dose for the shortest duration to treat moderately severe menopausal symptoms and should be considered primarily for women within the first few years of menopause, end quote. So let's break that down. So they start off by saying because of the risks, well, what are they talking about? Estrogen therapy has a ton of risks. Breast cancer, endometrial cancer, DVTs, PEs, MIs, strokes. So lots of side effects. They also say it should be used primarily within the first few years of menopause. So shouldn't be used in individuals who are over the age of 60 or more than 10 years out from menopause. The reason being because that's when the heart attack and cerebrovascular risks become much more pronounced. And it's the same deal as denosumab. When it's stopped, bone loss can be fast and so you need something else to solidify those gains, whether it's denosumab or bisphosphonates or whatever else. Otherwise, you're gonna be losing all the gains that you made with estrogen therapy to start with. Overall, you're probably not gonna be seeing estrogen therapy very much for osteoporosis and it makes sense. Even Osteoporosis Canada says given the adverse effects, there may be an unfavorable risk-to-benefit ratio and other treatment options should be explored first. Keeping along the lines of hormone modulation, we'll move on to drug number four, which is CIRMs, Selective Estrogen Receptor Modulators. There are two big ones, riloxifene, which is classically used to treat osteoporosis and tamoxifen, which is more used in our breast cancer survivors. So riloxifene, this is an estrogen agonist antagonist, depending on the organ. In the vertebrae, it's an agonist, which exerts significant anti-resorptive properties, preventing bone turnover and so reducing your risk of fractures. It does work nicely in this situation. However, we don't see that same improvement in the hips and non-vertebral sites with riloxifene. In terms of adverse effects, you are not gonna get uterine cancer like you do with estrogen and in fact, it reduces your risk of breast cancer, but there's still a risk of PEs, DVTs, and strokes. Additionally, it also causes hot flashes. Tamoxifen too, I tried to dig into that data. Although it's more used for breast cancer, there were a couple of database studies I found, one out of Manitoba in the Journal of Clinical Oncology and one in Rheumatology International, which was also from a database, this one being a Taiwanese database from 2015. And both actually showed good results even in the hip, not just the vertebrae. So tamoxifen probably does confer some benefit as well, just like riloxifene. In terms of indication for these drugs, you're only gonna use them in post-menopausal women who have a low risk of PE and DVT and ideally in women who are at risk of breast cancer. You can probably also feel reassured that if your patient is on tamoxifen because she's a breast cancer survivor, she's likely getting some bone protection. The last anti-resorptive drug number five, we're just gonna spend a split second on it, is calcitonin. Nobody uses it anymore as the long and short of it. What you see is the oral form, not the intranasal form. It actually did work. It almost halved the risk of vertebral fractures, but it was withdrawn from several markets, including the Canadian one because of prostate and liver cancer. And that's it. Five drugs that are anti-resorptives, misphosphonates, denosumab, hormone therapy, CIRMs, and calcitonin. The last group of drugs is anabolic agents. So these actually stimulate building of the bones. The older of the two is PTH analogs. Specifically in Canada, we're seeing a lot of teriparatide or Forteo. This drug is injected under the skin subcutaneously every single day for up to 24 months. The mechanism of action is that it's a PTH analog. And so a lot of you are thinking to yourselves, hold on, PTH is the primary driver for calcium and phosphate and normally directly affects bone metabolism and causes thinning of the bones. That's why hyperparathyroidism causes thin bones and predisposes to osteoporosis and you're bang on. However, this is a different exposure pattern of parathyroid hormone and that's what changes the effect on the bone. A daily pulse of teriparatide in contrast to constantly elevated PTH levels like in hyperparathyroidism, a daily pulse of parathyroid hormone will disproportionately affect the osteoblasts and cause them to increase activity as compared to the osteoclasts. And so while you do see some overall remodeling of the bones, there is a favorable balance towards an anabolic state. So did it actually peg out? Clinically, absolutely it did. We saw a 74% reduction in vertebral fractures and a 39% reduction in non-vertebral fractures with teriparatide. Abalaparatide, which is not available in Canada, is even stronger. When we specifically talk about hip fractures, however, with these drugs, the data is less clear, but according to a meta-analysis, there probably is hip protection as well. Most of these gains, most of this pretty impressive reduction in vertebral fractures and non-vertebral fractures, and again, not definitively hip fractures, but certainly vertebral fractures and non-vertebral fractures, most of those gains occur within the first 12 months of therapy. In terms of adverse effects, usually these drugs are pretty well tolerated. Some people get some headaches, nausea, arthralgias. You can get a transient hypercalcemia, and so early on you may also get orthostatic hypotension, which may be related to that. But those are most of the issues we've seen in humans. However, two things to note. The first is that in rat studies, some of the animals developed osteosarcomas. These were in rats who were exposed to significantly higher systemic concentrations of Forteo or teriparatide than humans get. It's unclear what the relevance is in humans because it's a different species with a substantially higher dose, but nonetheless, we do not use teriparatide for this reason, in anyone who's at risk for osteosarcomas. This means anybody who's had prior radiation to their bones, anybody who's had a history of bone cancer or metastases to their bones, or anybody who has Paget's disease of the bone. And for that reason, before you start teriparatide, you must get a bone-specific ALP, or at least an ALP to rule out Paget's disease. We also don't have safety data past two years, and because of that, most people stop the Forteo after two years. Once again, most of the gains anyway from Forteo or teriparatide occur within the first 12 months of therapy. Last couple of things with Forteo here. So you may hear about a transient loss of bone mineral density in the hips using teriparatide, and this is true. However, the thought process around it is that older, more calcified bone is being replaced by younger, less calcified bone. And so the bone mineral density readings aren't as strong. However, if you do QCT modeling, which is a measurement of bone strength, the younger, less calcified, sort of less dense bone on bone mineral density testing is actually stronger than the old, more calcified bones. When you stop teriparatide, just like denosumab, just like hormone therapy, you must place the patient on an antiresorptive to prevent loss of the gains that you created with teriparatide. Otherwise, their bone mineral density will fall off over time. And now for the last drug, romasozumab or Avenity. This drug is pretty much brand new. It's the first new medication that's come out in about a decade in the osteoporosis world, and it's amazing. It's a monoclonal antibody against sclerostin. Sclerostin is a cytokine that normally inhibits the WNT pathway. And that pathway is what encourages osteoblast formation. So if you can block sclerostin, you block the inhibition of the WNT pathway, therefore osteoblasts start to form. Basically, you're inhibiting the inhibitor. And what ends up happening is you get both formation of new bone, given all the activated osteoblasts, but you also get alterations in bone homeostasis that lead to decreased resorption of bone as well. So Avenity or romasozumab touts itself as a quote-unquote dual effect drug, which is unique from Forteo or teriparatide because teriparatide does not reduce resorption. The trials for romasozumab showed efficacy within 12 months. Specifically, they had impressive improvements in vertebral, hip, and nonvertebral fractures. Because it's been such a brand new blockbuster drug in osteoporosis, it's probably good to know at least one or two of the three trials that came out with Avenity. There were three big trials. There's FRAME that looked at Avenity versus placebo, ARCH that looked at Avenity or romasozumab versus alendronate. And then there was STRUCTURE, which compared teriparatide with romasozumab. Let's look at ARCH and STRUCTURE in a little bit more detail. The reason I bring up ARCH, which was alendronate versus romasozumab, isn't just because of the impressive reduction in vertebral and hip fractures. They saw a 50% reduction in spinal fractures and a 38% reduction in hip fractures, which is amazing. The reason I bring it up is because there was a very small, but real, completely unexpected increase in MACE, or Major Adverse Cardiac Events. So it's a composite of MI, stroke, and cardiovascular death. The absolute number was still quite small, but nonetheless, a statistically significant increase. The other study that I want to bring up is STRUCTURE. And the reason I bring that up is because it was a bone mineral density study, not a clinical fracture study. But it was a bone mineral density study where the developers of romasozumab said, let's throw it all in there. Let's compare ourselves to the strongest agent on the market, which at the time was teriparatide. And they went head to head. And what they found was that there was significant superiority on the part of romasozumab versus teriparatide. Specifically, there was at least a 3% to 4% superiority in the mean bone mineral densities of the hip, L-spine, and femoral neck in romasozumab compared to teriparatide. Now this is bad news for the PTH analogs. Why? Well, number one, romasozumab, believe it or not, is substantially cheaper than teriparatide. So right off the bat, Avenity should be getting more business than Forteo. Number two, the injections which you need for Avenity or for romasozumab are once a month as opposed to daily for teriparatide. Number three, there are other reasons why you might prefer it. For example, romasozumab clearly shows benefit in optimizing the hip bone mineral density after just 12 months versus teriparatide can't claim that directly. They can only claim that through meta-analysis data. Now the problem is because romasozumab is such a brand new drug, even though it works beautifully, the indications aren't as clear. According to the FDA, one might consider romasozumab for osteoporosis treatment in post-menopausal women who are at quote-unquote high risk for a fracture. And they go on to define that as a history of an osteoporotic fracture or multiple risk factors for a fracture. It remains to be seen where romasozumab will have its niche. In terms of dosing, like I alluded to previously, romasozumab is Q monthly injections and that goes on for 12 months. After that time, just like denosumab, hormone replacement therapy, teriparatide, you need to consider an anti-resorptive so you don't lose the gains that you made. In terms of adverse effects, usually it's pretty well tolerated, some arthralgias, some headaches, potentially injection site reactions just like the other subcutaneously administered drugs. But don't forget the MACE, M-A-C-E, major adverse cardiac events that we found in the ARCH study. It's very small, overall 2.0 versus a 1.1% in the alendronate group. But nonetheless, it is a real risk. And it's for this reason romasozumab is contraindicated if a patient's had an MI or a stroke within the last year. So that's it for the drugs. There are five anti-resorptives and two anabolic agents that you should try to remember. In terms of the order of therapy, it used to be everybody would get bisphosphonates first line. Why? Because they're cheap, they're effective. We do see a 40% lower vertebral fracture risk. We see a 30% lower hip fracture risk. We see a 20% lower non-vertebral fracture risk. And it's great for your run-of-the-mill bread and butter patients who are in the moderate risk zone, meaning 10 to 20% 10-year risk of osteoporotic fracture who need something to protect their bones if they have normal creatinine. However, given shifting practice patterns and the new position paper by the Endocrine Society in 2019 in patients who are high risk or very high risk, one might consider other options as first-line therapy. Certainly, dinosumab is a great first-line option for someone who's high risk. You can also consider it if the patient's got a low GFR, like less than 30, or if you're concerned that they're malabsorbing or that they're not totally compliant with their medications because it's administered subcutaneously only once every six months. And for whatever reason, it seems to work quite well in glucocorticoid-induced osteoporosis, as well as for women who are on aromatase inhibitors for breast cancer. Teriparatide is another great option for post-menopausal women who are at very high risk of a fracture. So you might define that as someone who's got a T-score in the osteoporotic range and a fragility fracture, or someone who has a T-score in the very severe range of less than minus 3.5. According to the Canadian guidelines, hormone therapy can also be considered first line for menopausal women who require treatment of osteoporosis and their vasomotor symptoms. Though realistically, generally hormone therapy and CIRMs are way down on the list. And lastly, while romososumab is truly a blockbuster drug that's doing so well in terms of trial data, in terms of costs compared to teriparatide and dosing scheduling, there are no guidelines on it yet because it's so new. Okay, nice job guys. That concludes what I think are the basics and some for your average osteoporosis encounter. Quiz time. Let's just do a quick eight question quiz to make sure we're all on the same page and our knowledge is consolidated nicely. I'll give you a few seconds to answer each question. So here we go. Question one, what information does the C.A.R.R.O.C. risk stratification system want you to give it? I'll give you 10 seconds. Age, sex, femoral neck, T-score. Not the total hip, not the vertebrae, not the distal forearm, just the femoral neck and the T-score, not the Z-score. A history of steroids within the last year and fracture history. If you have a hip or vertebral fracture, that automatically makes you a high risk individual. Good job. Okay, question two. What is your vitamin D target? Okay, so in Canada, 75. If you're using American units, 30. Along the same lines while we're on that topic, what other blood work do the Canadian guidelines want you to get when you're doing a basic osteoporosis encounter? Give you 10 seconds. So along with 25-hydroxyvitamin D, you need a CBC, a creatinine, calcium, ALP, ideally a bone-specific ALP would be great, TSH, and if you have a vertebral fracture, then an SPEP as well. All right, question three. Name the bone turnover markers. There are two that indicate formation and there are two that indicate resorption. Give you five seconds. All right, formation, bone-specific ALP. P1, NP. In terms of resorption, CTX and NTX. C-telopeptide, N-telopeptide. Nice. Question four. What is the GFR cutoff for oral bisphosphonates? Okay, for oral bisphosphonates, 30 to be safe. And if you want to be a little bit more risky, but probably still safe, 15 for oral bisphosphonates. IV, on the other hand, would be 35. Question five. What unique adverse effects does denosumab have, Prolia, compared to oral bisphosphonates? Give you five seconds. Okay, skin stuff. So eczema and a very small number of patients will get cellulitis, which is why you want to be careful about denosumab in your diabetics with recurrent skin soft tissue infections or your obese diabetics. Interestingly, and I don't know how to explain this one, flatulence is a thing that happens with denosumab. Also, it's probably got a slightly stronger predilection for hypocalcemia than bisphosphonates. The nadir occurs seven days after the dose, and so you should check it at least annually. You're not renally dosing denosumab, thankfully, unlike bisphosphonates, but you do have to watch that calcium level. Okay, question six. What is the indication for hormone replacement therapy in osteoporosis? All right, so menopausal women within the first 10 years of menopause or under the age of 60 who have moderately severe vasomotor symptoms, you use the lowest dose for the shortest duration, the reason being because of the side effects. Breast cancer, endometrial cancer, and that's why you need to use progesterone with estrogen. Stroke, MI, the risks of those really take off after the 10-year mark, and that's why we use it in women who are less than 10 years out from menopause. And then DVT and PE. Question seven. The popular bisphosphonates, denosumab, hormone replacement therapy, gromasosumab, all work on the vertebrae, hip, and nonvertebral areas to reduce fractures. How about raloxifene? Right, so raloxifene, which is a serum, has only been shown to reduce vertebral fractures. How about teriparatide? Give you two seconds for this one. Teriparatide in the trials has only been shown to reduce vertebral and nonvertebral sites, not clearly hip. Last question. What is the major side effect for gromasosumab that was discovered in the ARCH study? MACE, major adverse cardiac events. Very small risk, but this is the reason that gromasosumab is contraindicated in individuals who've had an MI or a stroke within the last year in particular. Some extra stuff. Excellent work. If you have a little bit more time, a little bit more energy, and you want just a smidge more data in case it comes up on your exam or a clinical encounter, I'm gonna talk to you about two things. The first is duration of therapy and drug holidays. So let's get the easy ones out of the way first. For Tao, teriparatide, very straightforward. Max duration of therapy with teriparatide is two years because past that you start worrying about osteosarcoma risk. Either way, you see most bone mineral density gain within the first year of therapy. You must follow it up with an antiresorptive agent to maintain the gains you've made on treatment. Otherwise, you'll start to see Easy drug number two, denosumab. After five years of therapy, reconsider the risk with denosumab. However, if the risk does remain high, feel free to continue it. Safety data looks good as far as 10 years out. Something to note though, is that your BMD will decline very quickly within two years to pretreatment levels once you stop the drug. Therefore, once you stop denosumab, Therefore, once you stop denosumab, give them another agent so you don't lose the gains that you've made. Probably the best one to go with is actually zolandronic acid. And then the last drug in terms of duration or holiday is bisphosphonates. So we've classically been taught that you shouldn't continue oral bisphosphonates past five years, you shouldn't continue zolandronic acid past three years. Instead, if you look at practice patterns and you look at the 2019 Endocrine Society statement paper, they say every three to five years reassess the risk and if still high, continue therapy. American guidelines appear pretty comfortable continuing oral bisphosphonate therapy up to 10 years and IV bisphosphonate therapy up to six years. Data from extension studies even shows ongoing benefit past that. Though remember the longer you're on therapy with these drugs, the higher the risk of side effects. I'm particularly thinking about atypical femoral fractures here, which are duration dependent. When you reassess your patient after the three to five year mark, if you feel that they're a low to moderate risk, consider a drug holiday. That's a three to five year period where you temporarily discontinue their medication. And it seems like when you do that, if they've been on zolandronate or they've been on alendronate, the benefits are retained nicely during these five years. When you go on a holiday, reassess their risk every two to four years. And if something changes, like they have a fracture or they have new clinical risk factors or they have a decline in their bone mineral density, say for example, a consistent 5% fall in the bone mineral density, that would prompt you to restart therapy either with the same agent like a bisphosphonate or you could change class. The last thing I'll say about bisphosphonates is that the optimal frequency of dosing of zolandronic acid is not super clear. There's a group from New Zealand that's quite well known led by Dr. Reed. It seems like they love zolandronic acid because they've published a lot on it. And to improve the longevity of their drug, what they've tried is they actually dose every 18 months up to six doses. Even with these longer dosing intervals, they still see improvement in the bone mineral densities. They also suggest a nice way to gauge when your next dose is due is to check the CTX or CT lipeptide prior to the subsequent dose. When it starts to go up back towards pretreatment levels, it's time for another dose. And while we're on the topic of monitoring, when it comes to serial bone mineral densities, according to Canada's Choosing Wisely campaign, you should not be repeating the bone mineral density more than every two years. This is also based on multiple guidelines as they say a minimum of two years may be needed to see a significant stabilization or improvement in the bone mineral density. The guidelines go on to say that if the patient is stable and or low risk, then every five to 10 years even could be reasonable intervals for repeating dexastatase. scans. But this obviously changes based on the clinical picture. Now the absolute last thing, if you're interested, is just a brief discussion of steroids and osteoporosis. So we know that glucocorticoid-induced osteoporosis is one of the most common secondary forms of osteoporosis. We know that bone loss develops within as little as three to six months on steroids, and we know that the risk is there even with doses as low as 2.5 to 7.5 milligrams a day. Though the higher the dose, the longer the duration, the more likely you are to have bone loss. Bone loss actually is at its peak in the first five years, meaning earlier on is when you have the most bone loss. And this is also reflected in the fact that fracture incidence is highest in the first five years, especially vertebral fractures. Now the nice thing is that osteoporosis therapies can maintain bone mineral density while on steroids. The problem is that we don't know the appropriate duration of treatment, and until recently we haven't had great guidelines on when to utilize therapy. In 2017, the American College of Rheumatology released glucocorticoid-induced osteoporosis guidelines led by Dr. Buckley from Yale. It's full of really elaborate treatment algorithms and goes through a variety of situations, but I'm going to try to break it down as simply as possible. So first things first, they say that within six months of starting steroids, you need to assess fracture risk. That means a bone mineral density and a FRAX or CAROC if the patient is at least 40 years old. If under 40, they still recommend a clinical assessment, but also support a DEXA if there are other risk factors present. For example, excess alcohol, malabsorption, smoking, etc. In terms of treatment, as soon as somebody's on 2.5 milligrams a day of prednisone, they are getting non-pharmacologic management. The pharmacologic management is pretty easy once you're over 50 because it all goes back to your risk again. So if you're low risk, meaning your 10-year risk of osteoporotic fracture is less than 10%, no pharmacologic treatment. If you're a high-risk individual, meaning your 10-year risk of fracture is more than 20% or you've had a previous osteoporotic fracture, then they make a strong recommendation that you do go on treatment. And they prefer PO bisphosphonates and to a lesser extent, IV bisphosphonates, teriparatide, denosumab, or riloxifene in that order. The grey zone is the moderate risk individuals. These are people who have a 10-year risk of osteoporotic fracture between 10 and 20%. The guidelines make a conditional recommendation that you still treat these individuals. It's not a strong recommendation like the high-risk group, but certainly a conditional recommendation in this moderate group. With younger patients, it's a little bit trickier because they're still suffering the bone loss that older patients will suffer. However, they tend to gain back a lot of that lost bone when these steroids are discontinued. The other problem with them is that you have a lot of women of childbearing age in this demographic. So think, for example, your patients with lupus nephritis, who you put on pretty decent doses of steroids. If you have a young woman who's had lupus nephritis, do you feel comfortable putting her on bisphosphonates? And so the guidelines kind of help with this. They say if you're over 30 and your total dose of steroid in one year will be at least 5 grams of prednisone, then they make a conditional recommendation that you treat. Why? Because once you have at least 5 grams of prednisone in a year, the risk of vertebral fractures is markedly increased. They also suggest that you may want to treat those who are on ongoing doses of prednisone at least 7.5 milligrams a day and have features of moderate to high risk. This includes young individuals who have had a prior osteoporotic fracture, whose Z scores are less than minus 3, or who demonstrate a 10% loss of bone mineral density in a year. The caveat is if you are going to treat a woman of childbearing age, they suggest that you ensure she is on effective contraception and not planning on becoming pregnant. And if you do end up having a patient who's a woman of childbearing age, again on contraception, not planning on future pregnancies, then you use either an oral bisphosphonate or teriparatide. But even they are not really well studied in pregnancy. In terms of reassessments, do a clinical assessment every 12 months in these individuals, but get a DEXA scan every one to three years according to the guidelines as clinically indicated. And that's it for today, guys. Great job on making it through this topic. You deserve a well-earned break. If you enjoyed today's session, please subscribe. I would also tremendously appreciate your feedback in the form of an Apple podcast review, or feel free to email me with suggestions for future episodes, content accuracy, or sound issues. My email is room for the R-C, that's R-H-E-U-M-F-O-R-T-H-E-R-C at gmail.com. Have a great one.