Osteoporosis: A Review of Prevention and Management Strategies *ACPE-Accredited*

[MUSIC] What's going on, I cast in the world, and welcome back to another episode of the core consults, RX podcast. Do you realize we are very rapidly approaching episode 300? No way. Yeah, because we haven't brought that up in a long time, like, yeah, year two ago. We used to, and we didn't get to the 200. Yeah, it was like every week we had to talk about it, but we're less frequent with the episodes now, so it's been picked up in a long, noticeable, I guess. But I just when I was uploading the last episode, I was like, oh my gosh, warm, was it 300? Wow. Huh, that's crazy. It feels like 200 was a long time ago, so it's been, it has been a while since taking a while to 300. Yeah, yeah, a couple kids each kind of slow things down a little bit. But I bet 200, I bet 200 was before either of us had kids that's kind of weird. I don't know how that was like, we had kids into what, 2022? For years, first one? 21, I think, yeah, 21. Okay, we probably had something, so I'm terrible with one of those years. I'm terrible with that. But yeah, so it took us a little bit longer to get here, but that's okay, because we're still going. Everybody said we couldn't, you know, couldn't be known with kids, and here we are. Look at us go. Quality jerk, it's okay. We're making that. But we're trying. We're making it. But tonight's topic is actually one that we've really almost never touch on, I feel like. Yeah. I mean, we'll mention it here and there. We did it in a credited episode a couple of years ago. But we're going to be discussing osteoporosis. We always stick to osteoarthritis, things like that. But porosis, we don't really touch on all that often, I feel like. Yeah, not a lot of the bones. We don't do a lot of bones. And listen, I know what you guys are thinking. Hey, that's probably because you guys don't know much about it. That's not the reason. Well, you might find out. It's only half the reason. But we're going to do, this tonight is an accredited episode to replace, you know, our former osteoporosis accredited episode that is now expired. So for those of you who are free CE members, this is included just like all of our other accredited episodes. It's part of like their unlimited, you know, membership, where you can get access to all of their content. So if you are an unlimited member, listen carefully. Well, we will give you a password at some point during this episode. And you'll use that password to go onto frece.com and access the post-activity assessment for this particular topic in episode. And that includes just a 10-question multiple choice test that you will. I'm sure do great on and that will give you one hour of continuing education credit for listening to this episode. And that is available for pharmacists and for nurses. And, you know, if you're not a member, definitely encourage you, as always, to give frece.com a look. They have a lot of great content and everything from live, you know, lectures. They have many CE's where it's, you know, 15 minutes, you know, very small short increments. And, you know, monographs, they have panel discussions. They have all of our episodes that are accredited on there. And so, whatever your ideal environment is for learning, they have be covered. So thanks to them for continuing to work with us. And we'll jump into some background information here, as always. And before we start going through all these different, you know, meds and, and we'll summarize kind of some of the recommendations from the various guidelines at the end to kind of place hierarchy, you know, to your structure for how these meds should typically be, you know, given to patients first, second, third line, and so forth. Yeah. Because we know that we know osteoporosis is a bone disorder. And it's characterized by a few different things. Low bone density and paired bone architecture and compromise bone strength that can predispose a person to fracture risk. That's why we care, right? Because it increases a patient's risk for fractures. And we know the fractures, especially in the elderly, can lead to significant morbidity and mortality. It's estimated about 10.2 million Americans have osteoporosis and additional 43 million are estimated to have low bone density. And they're at risk for osteoporosis. Currently, osteoporosis is considered to be underdiagnosed and under-treated. And that's primarily because it's a clinically silent disease. So typically, there's not any symptoms until a patient has a fracture. And the fractures aren't even always what you might imagine. Like if I were to fracture my leg, then that would be likely an ER visit for me or doctor's visit to get a cast. But with a vertebral fracture, especially in an elderly person with osteoporosis, it can manifest as just some acute pain for a few weeks and then maybe ongoing pain. But not such that they would feel like they need to go to the emergency room. They probably noticed some stuped posture, kyphosis, stuff like that, as well as just being shorter. Like that said, joke that people who are getting older make that they're shrinking, but a compression factor of the vertebra can cause a two to three-centimeter reduction in height. So those are things that would be noticed, but even still, there's nothing to notice until a fracture happens. And so appropriate screening is important as we'll talk about. Yeah. And like Cole mentioned, aging obviously a risk factor in and of itself. But other factors can complain to, you know, likelihood of bone loss or at least suboptimal peak bone mass. You know, genetics is definitely a factor, diet lifestyle, multiple patients hormonal status, comorbidities, certain medications that they may be taking. But ultimately that bone loss, that suboptimal peak bone mass leads to decreased bone density. And then as well as impaired bone quality. And so that eventually turns into reduced bone strength. And then, you know, like Cole was mentioning that the low trauma fracture risk is going to be, you know, much more elevated. Right. And there's some additional risk factors, kind of more specifically in addition to just getting older in advanced age, female sex. We mentioned low bone, mineral density, race and ethnicity can play a factor. If there's been an osteoporotic fracture in a first degree relative, especially a parental hip fracture, that's indicative of increased risk, low body weight or low BMI, premature menopause before 45 years old, rheumatoid arthritis, secondary osteoporosis, rheumatoid arthritis is significant. A lot of other rheumatologic diseases can as well. And that a lot of times that's related to the steroids, but they typically are on a fair portion of their life managing that. So that kind of goes along with the medications as well. With being on past or present, glucocorticoid therapy, cigarette smoking, alcohol intake of more than three drinks a day, low calcium intake, low physical activity, or immobilization as well as vitamin D insufficiency and deficiency, all increased risk. And, you know, osteoporosis is not something that is only seen in elderly patients. There are cases of, you know, younger adults and even children. Usually there's a certain medical condition, you know, that is associated with them developing osteoporosis. Whether it be, you know, some sort of a hormonal imbalance, you know, primary, secondary, ovarian failure, testosterone, deficiency, things like that. Hypertiroidism can increase the risk of developing osteoporosis at a younger age, cushing syndrome, children with growth hormone deficiency, hyperthyroidism, even diabetes, especially type one, you know, different nutritional disorders, malabsorbed sort of states, you know, Crohn's disease, Crohn's silly act disease, things like that. And then, you know, like Colesid vitamin deficiencies, inflammatory disorders, and then, you know, genetic conditions as well, like cystic fibrosis puts a patient at higher risk. Things like muscular dystrophy, immobility, organ transplant, the list goes on and on. So, this is definitely not only for something that, you know, we have to think about when, you know, we're dealing with geriatric patient population or elderly patient population. But, you know, in some cases, he can affect much younger patients as well. Right. And there's a host of medications that can increase your risk. And I won't list all of them, but I'll highlight a few. And for the most part, there's different mechanisms behind why they are decreasing bone mineral density and increasing fracture risk. I mentioned the glucocorticoids long-term therapy with glucocorticoids. What's happening there is there's increased bone resorption, decreased bone formation, decreased calcium absorption, and it's dose and duration dependent. Now, there's a number of other drugs, anti-seizure medications like finitone, carbonazapine, phenobarbital, bellproac acid. There's also antiretroviral therapy, which increases osteoclast activity, and decreases osteoblast activity. So, in RTIs and in RTIs, for example, protease inhibitors, a number of them. Aromatase inhibitors, like letharzole and anastrozole, reduce estrogen concentration, calcinerin inhibitors, like cycle-supported decorolumus, increase osteoclast activity. For rosamide, can even increase fracture risk, not necessarily affect the bone mineral density, but that can be related to increased calcium or renal elimination. Other ones like PPI's, the risk has been talked about over time. The thought is there's possible calcium malabsorption due to acid suppression for carbonate salts, SSRIs, because of decreased osteoblast activity, SGLT2's, because of alteration in calcium, and phosphate homeostasis, as well as increased bone resorption. So, there's a number of common medications that patients are on that can reduce bone mineral density and increase fracture risk. Yes. And the normal process, as far as bone formation and remodeling, I do think it's a good idea just to kind of touch on this briefly. How is the process supposed to work in the absence of osteoporosis? Throughout our lives, we're going to have episodes where microtromas happen, and the bone is going to undergo both radial and longitudinal growth, and it's continually remodeled when those microtromas happen throughout our lives. And the process of remodeling is supposed to renew the bone strength and minerals, it prevents the accumulation of that damaged bone, and then bone remodeling typically occurs in discrete sites within the skeleton, and proceeds sort of in this orderly fashion, if you will. And bone resorption is typically followed, or in almost all cases followed by bone formation, and they call it coupling. And we have dense cortical bone and spongy, tribicular, or cancelicious bone differ. Those two types differ as far as their architecture, but they do have similar molecular compositions. So both types of bone have this extracellular matrix with mineralized and non-mineralized components. And the architecture of the extracellular matrix is what sort of in parts, the mechanical properties of the bone, and then the bone strength is determined by collagen-based proteins, also referred to as like the, or leading to the tensile strength, if you will. And then the mineralized osteoids are involved with the comprehensive strength. So the rule of thumb is the greater the concentration of calcium, the greater the comprehensive strength. And so, in adults, approximately 25% of the tribicular bone is resorbed and replaced each year. And you can compare that with only 3% of the cortical bone. And so up to 10% of the skeleton is being remodeled at any one time, which is kind of remarkable if you think about it. And continuing on with that, you'll hear us mention osteoclasts and osteoblasts a number of times, especially as we go through the medications and the mechanisms. So we'll kind of, I'll touch on their role in the normal remodeling. So osteoclasts, which are derived from hematopoetic precursors, are what's responsible for bone resorption or kind of breakdown. It's another way to say it, whereas osteoblasts, which are derived from mesenchymal cells, are responsible for bone formation. They're both dependent on each other for production and they're linked in the process of remodeling. Osteoblasts not only secrete and mineralize the osteoid, the mic mentioned, but also appear to control the bone resorption that's carried out by osteoclasts. There's also osteocytes, which are terminally differentiated osteoblasts embedded in the mineralized bone. They direct the timing and the location of the bone remodeling. The problem in osteoporosis is the coupling mechanism between the osteoclasts and osteoblasts, this thought to be unable to keep up with the constant micro-trauma to the trabecular bone. So for example, osteoclasts require weeks to resorb bone to break it down, but osteoblasts need months to produce new bone. And on average, bone formation takes four to six months to be completed. So any process that increases the rate of bone remodeling will result in a net bone loss over time, if that makes sense. In really bone remodeling, you can categorize into four sequential phases. Activation, resorption, reversal, and the formation of a new osteon in the process is the same in both cortical, spongy, trabecular, and cancelia's bone. Activation is defined as the conversion of bone surface, basically followed by the differentiation of osteoclast precursors into mature osteoclasts, and that happens during the resorption phase, and then the reversal phase osteoclasts start to compete with the resorption process and produce signals that are directly, as well as indirectly, initiating bone formation. And then that final formation phase, like Colin mentioned, the mesenchymal cells differentiate into functional osteoblasts, which then develop into the bone matrix. Yeah. We mentioned aging, being a significant risk factor. And aging and loss of gonadal function are the two most important factors that contribute to developing osteoporosis. In studies, bone loss in women accelerates rapidly in the first years after menopause. The lack of gonadal hormones is thought to upregulate osteoclast progenitor cells, estrogen deficiency leads to increased expression of rank L, rank ligand by osteoblasts, and decreased release of OPG. Increased rank ligand results in recruitment of higher numbers of pre- osteoclasts, as well as an increased activity and lifespan and ability of the mature osteoclasts. And to give a little bit more specific, as far as the hormonal factors, estrogen in particular does have many positive effects on bone remodeling, the whole process as a whole. And that is involved with patients of male and female gender. And basically, action is there to help to maintain a normal bone resorption rate. So, estrogen suppresses the proliferation and differentiation of osteoclasts. And it's also going to increase osteoclast apoptosis. Estrogen also will decrease the production of several cytokines that are stimulators of osteoclasts. Some of those that you may be familiar with interleukin-1, interleukin-6, TNF alpha. And these are going to increase that, you know, osteoclast apoptosis when you suppress those cytokines. And then testosterone also plays a role in bone health as well. It's been identified as having some direct effects on bone resorption and osteoblasts. Most of the testosterone's bone effect is related to its metabolism to estradiol. Obviously, testosterone by way of aromatase can be converted into the estradiol. And, you know, that leads to the above, you know, the estrogen bone effects that we just mentioned. So, testosterone does play a role. And so, we will touch on, you know, both males and females as far as treatment later on. Right. Right. And because of what estrogen does, if estrogen is deficient, it's going to increase the proliferation, differentiation, and activation of new osteoclasts and prolongs the survival of mature osteoclasts. Estrogen deficiency also increases calcium excretion. It decreases calcium gut absorption. It also, estrogen deficiency can be seen in other settings like anorexia, as well as lactation, interestingly. And, you know, because estrogen is such a prominent role, you know, when we think about your process a lot of times, we sort of, you know, our minds sort of automatically go to, like, postmenopausal female patients. But, like I mentioned, male patients are, you know, still, some, you know, less likely, but still a population that we would have to treat for osteoporosis. To, you know, they are, you know, statistically at lower risk for developing osteoporosis, as well as having fractures as a result. And that's essentially because of statistically larger bone size, as well as greater peak bone mass. And then increase in bone width with aging, that's seen with male's fewer falls, you know, against statistically and shorter life expectancy, unfortunately for colon may. But with aging, you know, sex hormone binding globulin will start to increase. And that will result in less free testosterone. And thereby less testosterone that's available to be converted into estrogen. And so, the estrogen is inhibiting bone resorption in men, however, androgen deficiency also increases that rank ligand release in bone resorption. The most common risk factors when it comes to men, developing osteoporosis are going to be things like smoking, alcohol abuse, low body weight, weight loss, in general age, long term, glucocorticoid use, androgen deprivation therapy, and low testosterone concentrations. You may also hear the term osteo-malatia when people are referencing osteoporosis, and not really know what that is, but they are different. The difference is really related to bone consistency. In osteoporosis, the bones are porous and brittle, but osteo-malatia, the bones are soft. And the reason for that is the normal human skeleton is composed of about 60 percent mineral component, which is calcium, hydroxyapatite, and 40 percent organic material, namely collagen. In osteoporosis, the ratio of these two, the mineral to organic material ratio, is normal relatively. It's in the reference range, within the reference range. In osteo-malatia, the proportion of mineral composition is reduced relative to the organic material content, leading to the softer bones, and not as porous and brittle as in osteoporosis. And when we're actually assessing a patient to see if they have any osteoporosis or the lead up to that, which is osteopenia, the more mild version, there's a simple calculation risk tool that we can use called the fracture risk assessment, and this is looking at the risk of a tenure from probability of a fracture with bone mineral density. And the questionnaires includes things age, sex, weight, height, and then it goes through basically a yes or no series of questions. Previous fracture, parent-fractured hip, like Colin mentioned earlier, is the patient smoking? Are they on glucocorticoids? Do they have rheumatoid arthritis? Do they have secondary osteoporosis? And they consume three or more units of alcohol per day, and then they also will use something called the t-score, the femoral neck bone mineral density, and that can be derived from what Cole will talk about next. Yeah, those are derived. Our dexascans. Yeah, our dexascans, they're derived from the dexascans, which stands for dual-energy x-ray, ebsorb-tometry, and it's currently the standard for the evaluation of bone mineral density, and it would be needed to diagnose somebody with osteoporosis. It's used to calculate the bone mineral density at the lumbar spine, hip, and proximal femur. And the data is reported out, either as t-scores, like Mike mentioned, which a t-score is the value compared to that of a control subject, who are at their peak bone mineral density. It also reports out z-scores, which are a value compared to that of patients that are matched for agent sex, a similar agent sex to the patient that's being evaluated, and so it's more of a relative reporting of the score. All right, so when we're actually looking at which patients were going to screen for osteoporosis in the first place, there's a few different guideline recommendations that are out there from our folks with the endocrine societies, the ACE guidelines, they recommend bone mineral density testing in women who are age 65 and older, postmenopausal women that have a history of fracture or multiple fractures without major trauma, and with osteopenia that has been identified with radiographically or starting long-term systemic glucocorticoid therapy for three or more months, and then also perimenopausal or postmenopausal women with risk factors for osteoporosis, if they're willing to actually consider pharmacologic interventions as well, so things like low body weight, taking long-term glucocorticoid therapy, which they do, again, define as three or more months, or a family history of osteoporotic fractures, and then other indications for bone mineral density testing, they include things like early menopause, patients who are currently smoking, and excessive consumption of alcohol, and secondary osteoporosis, you know, that is likely, then we should also do bone mineral density testing. There's also other recommendations put out by the National Osteoporosis Foundation from 2014 that include men in their recommendations, so they say women age 65 years and older, but they also say men age 70 years and older, regardless of clinical risk factors, but if somebody has clinical risk factors, they also recommend it for younger postmenopausal women and women in menopausal transition, if they have those risk factors, or men age 50 to 69 with clinical risk factors for fracture. All right, so you've done the screening, you have gotten the data back from the Dexascan, let's talk about, you know, the actual diagnosis, and so the National Osteoporosis Foundation guidelines basically say that diagnosis of osteoporosis can be made in a postmenopausal woman or in a man over the age of 50, who is at an elevated risk fracture, you know, is basically if they have any of the following, the t-score is negative 2.5 or less at the spine or the hip, and that's, you know, like Cole mentioned, given that information's gotten through the Dexascan, the hip fracture with or without bone, mineral density, testing, vertebral, proximal, humerus, pelvis, or in some cases, distal forearm fracture in the sitting of low bone mass, which would be classified, essentially, as osteopenia, and that is, again, confirmed by Dexascan, and then a patient with a frax score with 10-year risk of hip fracture, if 3% or greater, or for major osteoporotic fractures, 20% or more in a patient with osteopenia. The American Association of Clinical and Dechronologist also has some guidelines for diagnosis from 2020, very similar, but with some differences, just know that that is out there. Also, the World Health Organization has some definitions for osteoporosis based on bone mineral density. For example, they would say normal would be a t-score of minus 1 and above, with the bone mineral density within one standard deviation of the mean level for a young adult reference population. They would say osteopenia, or low bone mass, is between 1 and 2.5 standard deviations, which is a t-score of minus 1 to minus 2.5. Then they would say osteoporosis is a t-score at or below minus 2.5, ins secure or established osteoporosis is a t-score at or below minus 2.5, with one or more fractures. Yes. All right. Before we jump into the treatment options, and you know, almost to the password real quick for those of you who are free CE members. So today's password is going to be bones 25. So B-O-N-E-S 25, the letters and bones are all capitalized, and then the number 25. Bones 25. So you know it. Yes. And again, you go onto free CE.com's website, or you know, that website, and you'll look for this particular episode under, you know, our list of credit episodes that are on their platform, and it'll ask for this password, and then that'll give you your access to the post-activity assessment. So I'm sure you all will do fantastic. All right. Medications. We'll start off with a very widely utilized medication class, and oftentimes first line therapy are Biz Phosphonates. A lendronate, we'll start there. I'm sure a lot of you are familiar with a lendronate brain named Phosphamax. It is approved for osteoporosis in men, as well as post-menopausal women, and in patients also that have glucocortal cord induced osteoporosis. And it has been shown to increase spine and hip bone mineral density. It's specifically in post-menopausal women, and then some well-conducted controlled clinical trials indicate that lendronate also reduces the rate of a fracture at the spine, hip and wrist by 50% in patients with osteoporosis. Typically treatment consists of a 70 milligram tablet one time weekly, and it has to be taken, while the patient is sitting upright and has to be taken with a large glass of water, and it has to be given 30 minutes before eating in the morning. There's also a combination available that includes calcaciferol, vitamin D3, and the combination of lendronate with vitamin D3 or Phosphamax+D, really got creative with the name there, and that's indicated for the treatment of osteoporosis in men with increased bone mass. Now, the bioavailability of lendronate is significantly reduced when a patient takes it with food. Even orange juice or the studies that have shown that black coffee can drastically decrease the absorption or the bioavailability, and there's been some studies, and there's a particular national register-based open cohort that included over 38,000 patients that suggest elderly patients who use proton pump inhibitors in conjunction with lendronate have a dose-dependent loss of protection against hip fracture. So, another thing to keep in mind, if you have a patient on long-term PPI use, maybe assess whether they still need to be on it if they are also taking a bisphosphonate or lendronate, in particular, that was where the data is. Maybe a good reason to get them off that PPI if they don't need it anymore. That's right. And bisphosphonates, ultimately, what they're doing is their anti-resorbitive agents. They're going to reduce osteoclast activity, which at first glance, you know, they're not improving osteoblast activity. So, how would you see an increase in bone mineral density? But it kind of goes back to the bone remodeling cycle that we talked about, where the osteoblast activity can't keep up with the osteoclast activity in these individuals. So, if you're decreasing the osteoclast activity, it'll give the osteoblast some time to catch up, and you can see increases in bone mineral density different than some of the other agents we'll talk about later on. But another one is racetrinate. It's branded as actinel. There's also a racetrinate delayed release branded as atelvia. It can be given daily, weekly, or monthly, and also has a combination with calcium pill, is actinel with calcium. And in its studies, getting it approved, it showed a reduction in vertebral fractures by 41%, and non-vertebral fractures by 39% over three years. Then we also have ibandranate or boniva. This is another bisphosphonate that can be given once monthly, and it's actually available as an intravenous formulation that is given every three months as well. Intravenous bisphosphonates, definitely great options for patients who are, intolerance to taking them orally, or for those who adherence is becoming an issue, and they're not taking their medication at the correct dosing interval. However, ibandranate has actually not really been shown as far as efficacy in non-vertebral fractures and clinical studies, so may not be the ideal choice for every patient, but it is still out there, and it does have, I would say, more convenient dosing schedule. Speaking of more convenient dosing schedule, there's also Zola Drone. Wait for it, which is branded as reclast, which is a once yearly intravenous. Now we're talking. I'd be infusion. So it can be used for osteoporosis in men, women, or glucocorticoid-induced osteoporosis. It's considered the most potent bisphosphonate that's available, and it can increase bone mineral density. At the spine by around four and a half percent, the hip by around three, three and a half percent compared to placebo, and over three years it reduced the incidence of spine fractures by seventy percent, hip fractures by forty-one percent, and non-vertebral fractures by twenty-five percent in post-menopausal women. Now you might be thinking, these sound great, you know, we care their osteoporosis. Let's give them to anyone who we suspect. There are some potential complications with this phosphonate therapy, and a lot of it revolves around the treatment length, and then having to implement what are called drug holidays. So in 2011, the FDA updated the prescribing info for Zola Drone Acid, and basically they wanted them to provide an improved information regarding the risk of kidney failure. There's been acute kidney injury that has required dialysis, and even fatal outcomes that have been reported to the FDA following the use of reclast. The drug is contraindicated in patients with moderate to severe renal impairment, which, you know, creatinine clearance less than thirty-five is how they define that, or if there's evidence of an acute renal impairment. The risk of acute kidney injury will also be increased if the patient is having the reclast code administered with any type of nephrotoxic or diuretic-based medications. They're severely dehydrated before, after the administration of the drug, or patients that are more advanced in age. And then in 2012, the FDA made a safety labeling change for bisphosphonates, which included Zolodronic Acid, to advise of the risk of atypical femur fractures, as well as osteonecrosis of the jaw. The fractures occur with minimal or no trauma. They may present as groin pain weeks or months after the fracture, and they're rare, but they have been noted in patients on long-term anti-reserve to therapy, which includes not only bisphosphonates, but also Denosi Mab, or Pearlia that we'll talk about later on. The incidence of the osteonecrosis of the jaw, you know, if we're looking at patients that are on anti-reserve to therapy for osteoporosis, it's estimated basically between one and every 10,000 and one in 100,000 per year of use. So this risk is only very minimally at that all increased compared with the general population. However, you know, it is still a potential increase. And the contrast to that is that the use of IV bisphosphonates, as well as the Pearlia in cancer patients, to reduce complications of metastonic cancer, results in the administration of substantially higher cumulative doses. And so, you know, because of the increased dosage used for those particular indications. And so therefore, the atypical femoral fractures and osteonecrosis of the jaw are going to be more commonly seen with IV bisphosphonates, or the Denosi Mab or Pearlia, when they are being used as part of cancer treatment. But nonetheless, it gets kind of lumped in because it's all the same class. And then, in 2012, the FDA made safety labeling changes for zelodronic acid to warn against a few different or a couple different adverse reactions. The acute phase reaction that happens within three days of the administration of the drug where symptoms can include fatigue, bone pain, arthritis, myelages, influenza leg illness. And then symptoms you usually resolve within three days, but can take longer, sometimes a week to two weeks to resolve, and then some symptoms may persist even longer. There's also been hypersensitivity reactions that are presenting as bronchospasms, you know, interstitial lung disease, and it can reaccur if, you know, with a rechallenge of the medication. Yeah. And historically, long-term data regarding the optimal treatment length for bisphosphonates as well as the risk for fracture and osteoenacrosis of the draw-along term was lacking. And it still isn't perfect. There was one Canadian study with about 52,000 women looking at bisphosphonate treatment for at least five years. And they found that the risk for a typical femur fracture was relatively low in the first five years, though there was a risk. But in the two years following that, it significantly increased almost doubled. And it does appear that longer treatment periods with osteoporosis is going to increase that risk, which is why after about five years of therapy, the general recommendation is to reassess. So if the patient is at high fracture risk at that time, it may be reasonable to continue it and just take on the risk of atypical femur fractures or osteoenacrosis of the draw. But if the patient is determined to be at lower risk, it may be able to be stopped for a period, take a drug holiday, reassess their fracture risk and reconsider it going forward. So the ACE guidelines recommend that if the fracture risk is no longer high, patient has remained rather fracture free. Like Luke Coles mentioned in the drug holiday, should be considered to a five-year period of using a bisphosphonate. And then treatment should continue up to an additional five years if the fracture risk remains high. High fracture risk patients' drug holiday may be considered after six to ten years of treatment for zoolidrinate, consider a bisphosphonate after three years in high risk patients, or until fracture risk is no longer high, and then continue for up to six years in very high risk patients. The ending of a bisphosphonate holiday, they recommend should be based on individual patient circumstances. Bone mineral density, bone turnover markers should be monitored, and treatment should be restarted when the density declines substantially. Bone turnover markers increase where there's an increase in fracture risk or of actual fracture occurs. Then restarting therapy should be considered. There's also other guidelines published by the American Society for Bone and Mineral Research from 2016, giving similar but slightly different suggestions about how long to treat, whether it's intravenous or not intravenous, and how long to do a drug holiday and in what patients. So just know that that's the thing, and that you should be considering it, especially if you note that the patient's been on it for five years, that it might need to be re-evaluated. So we've talked about bisphosphonates, very commonly used class of medication. We also have selective estrogen receptor modulators, one being a brand name of Vista or Reloxaphine, and it is a SIRM, it's abbreviated, it's indicated for the treatment and prevention of osteoporosis in specifically postmenopausal women. The dose is usually 60 milligrams given orally every day, and it can also, you know, there should be given in combination with calcium and vitamin D. It was the first SIRM that was studied for breast cancer prevention, and it decreases bone resorption through actions on estrogen receptors, basically. Reloxaphine has been shown to prevent bone loss, and there's data in women with osteoporosis that is demonstrated that this agent can cause a 35% reduction in the risk of vertebral fractures. It's also been shown to reduce the prevalence of invasive breast cancer, and Reloxaphine is, you know, still not without its own risk, and it actually has been shown to increase the incidence of DVT stroke, as well as hot flashes. So, you know, to think of it as kind of working on some of the same routes is, you know, and its activity like estrogen. And so, you know, that same risk that we think about when we're talking about hormonal contraception and all that good stuff. Yeah, so it has a box warning for that risk, and so Reloxaphine may be most useful in younger postmenopausal women without severe osteoporosis. It's been shown to increase bone mineral density, interestingly lower LDL serum concentrations in one small study. I mean, the endometrium was not stimulated. There was one study from 2010 where pooled mortality data was collected from some large clinical trials for patients who are on Reloxaphine 60 milligrams per day, and when compared to placebo, all cause mortality was 10% lower in older postmenopausal women receiving Reloxaphine. The primary reduction was in non-cardiovascular non-cancer deaths, but it still has that box warning for the DVT, the death from stroke, the pulmonary embolism, those things to be aware of. Then we have our parathyroid hormone analogs, and the first one that was available was teraparitide, or under the brand name Forteo. It's a recombinant human parathyroid hormone. 1-34 parathyroid hormone, 134, and X is anabolic agent for the treatment of osteoporosis. You'll hear these referred to as anabolic sometimes. It's indicated for the treatment of women with postmenopausal osteoporosis who are at high risk fracture, who have been intolerant to previous osteoporosis therapies, or if they have osteoporosis treatment that has failed to increase their bone mass, then this can be another option that they try after that. It's indicated in men with idiopathic or hypogonatal osteoporosis, who are also at high risk for fractures, who have been intolerant to previous therapy, or if the osteoporosis therapy has failed. Then the teraparitide is also approved for treatment of patients with corticoid induced osteoporosis as well. There are some labs you need to get before starting Forteo treatment, which is actually generic now, or I can't remember if it's a biosimilar, if it's a generic, but there are generic forms. Parathyroid hormone, serum calcium, vitamin D, need to be monitored. Notably, this drug and the other one we'll talk about cannot be given for more than two years in total lifetime, because there's a concern for increased risk of osteosarcoma. A higher incidence was seen in high doses in animal studies, though they haven't really collected human evidence to evaluate, but in animal studies, it was seen so they limited to two years. There are some contraindications to Forteo, for example, pre-existing hypercalcemia, severe renal impairment, can be used in pregnancy, breastfeeding mothers, or with the history of certain malignancies, bone metastases, or skeletal malignancies, or if the patient already has an increased risk for osteosarcoma. These would be instances like pageant disease, unexplained elevated alkaline phosphatase, or prior certain radiation therapies, external beam and implant, as well as children and young adults with open epiphysees or prior radiotherapy of the skeleton cannot have it. And when parathyroid hormone is given continuously, both osteoclastic and osteoblastic turnover increase, and we get this net loss of bone. However, intermittent subcutaneous administration, parathyroid hormone in a dosage of 20 micrograms per day, has been demonstrated to induce a very active anabolic phase with bone mass increasing up to 13% over two years in the spine into a lesser degree in the hip, as well. Mentioned this therapy being used in men and women, but it's again a deal for bone density decline while the patients are actively on bisphosphonate therapy, bone density stabilization while on extremely low level bisphosphonate therapy, or if a fracture has occurred while on bisphosphonate therapy, and then even very low initial bone turnover rate for which, you know, anabolic effect is clearly warranted. The teraparatide should be considered in younger and older postmen, a possible woman with severe osteoporosis as well. Most of the studies with the parathyroid hormone analogues have been performed in women. The medication decreases the risk of vertebral and non-vertebral factors similar to bisphosphonates. When given for the maximum of two years, the gains in minimal density with the parathyroid hormone are secure and can't even be augmented with bisphosphonate therapy to slow the reduction over time. Otherwise, it will slowly deteriorate, to deteriorate back to pre-treatment levels. Interestingly, there was a study that showed that the combination of parathyroid hormone with bisphosphonates had decreased benefit compared to either one alone, so generally they're recommended to give separately and in sequence. There was one guy who decided to challenge that result in performer's own study by giving his colleagues with them. Yes, colleagues. He was his guy and his colleagues. A cosmon was his name, but he decided to give three month on and three month off pulses of teraparatide while the patients were on weekly elendronate bone mineral density and the spine increased above that of the elendronate only arm. The pulsed regimen appeared to take advantage of the three to four month so-called anabolic window where the markers of bone formation rise more quickly than the markers of bone resorption. So, cosmon was out to prove something though I don't know of any guidelines that recommend that, but I bet you there's somebody out there that doesn't. For sure. And then, for austinicosis of the jaw, teraparatide has been possibly shown to be useful as a joint of therapy and there's been three cases that have been reported in which teraparatide has been used successfully in patients with bisphosphonate associated osteunochrosis of the jaw. And then, we also have bowel aparatide or timelose is approved in 2017 for women and in 2022 for men indicated for treatment postman-posal woman with osteoporosis and then to increase the bone density in men at high risk for fractures and that is defined as a history of osteoporotic fracture, multiple risk factors for a fracture or patients with failure and intolerance to other available osteoporosis therapies. They did a study in women that was called the active trial and then there was a study called the Atom trial that was done to gain its approval in male patients. And the active trial included more than 2,000 women. They were given subcutaneous bowel aparatide and it was associated with significant reductions in the relative risk for new vertebral fractures. The relative risk reduction was 86% non vertebral fractures at 43% reduction and that was compared to placebo. The absolute risk reductions were 3.6 and 2.0 respectively and the benefits were evident regardless of age, years since menopause, presence or absence of prior fracture and bone mineral density at baseline. So, to definitely some solid results from that study. The Atom study in men showed an increase from baseline in mineral density at 12 months of 8.5 versus 1.2% in the Timelo's versus placebo groups. Timelo's has similar contraindications to Forteo. It has a box warning or I should say that it had a box warning regarding increased risk of osteosarcoma based on rat studies. Interestingly, it was removed in 2021. The warning was, though still, the recommendation is to avoid using this in patients who were at increased risk of osteosarcoma and still, it's only recommended to use for a max of two years in a patient's lifetime. And then we also have a monoclonal antibody known as Romo-Sazumab or avenity. This works by inhibiting sclerostin and this increases bone formation and it also decreases bone resorption. It was approved back in 2019 and that was for postmenopausal women who are at high risk of fracture. It has been shown to reduce vertebral fracture rates in this patient population. There is a study called the fracture study in postmenopausal women with osteoporosis or the frame trial. And it was the phase three randomized controlled trial that included over 7,000 postmenopausal women. In those patients had a t-score of -2.5 to -3.5 at the total hip or femoral neck. One year of treatment with Romo-Sazumab reduced vertebral fracture rates by 73% compared to placebo. And then further reduction of vertebral fracture risk occurred in the second year following transition to denossumab in that study. I should point out that foretell you and Tim Lose are both self-administered, outpatient medications. The devices are very similar to an insulin pen. They're both used for about a month. You have to attach an edel to it. You dial up a dose and then you inject it subcutaneously. You keep it in the fridge and in that kind of thing, common side effects are dizziness, orthostatic hypotension, sometimes like arrhythmias, like heart benign arrhythmias, relatively benign arrhythmias. So you inject patients and check those themselves. The affinity is a syringe that's administered, but it has to be given in a healthcare setting by a provider. It's once per month or once every 28 days I believe. So the patients would have to go in once per month to have this administered. And so having to be aware of that is important. Eventity also has a box warning regarding increased risk of myocardial infarction, stroke, and cardiovascular death. It should not be initiated in patients who have had an MI or stroke within the preceding year. And it's important to evaluate their cardiovascular risk profile before starting it. And of course, if they have any of these events while they're taking it, it should be discontinued. But certainly they should be aware of that before getting started on it. And then we also have dynosamab or prolia. And we will talk about where these kind of fall as far as the guideline recommendations here in just a little bit, because we're not going in order with these, just so we're all on the same page. But dynosamab prolia, it's another marclinal antibody. It's directed against the receptor activator of the nuclear factor capobit, or capobeligan, or rankleigan, which is a key mediter of the resorbid phase of bone remodeling. I talked about that earlier. Dynosamab decreases bone resorption by inhibiting osteoclast activity. It was approved back in 2010. It has shown benefit in cancer patients, patients with postmenopausal osteoprosis, and then also in men with low bone mineral density. And it is a 60 milligram subcutaneous injection given every six months. Dynosamab also can be considered in certain patients with renal insufficiency. You know, the impaired kidney function does not significantly affect the metabolism or excretion of the drug. So it can be used in that patient population as well. So this is another one where you would have to have this administered by a health care provider. It's only every six months, so it's less often, but patients do need to go in and wouldn't need to go in and have that done. One important point about prolia is that it's kind of dangerous to stop it, or I should say adherence is very important. It has been uniquely associated with rebound, lumbar vertebral fractures after discontinuation. The vertebral fractures are often multiple and occur within months of the time that the next dose of Dynosamab would be due for administration. So it should be continued indefinitely, or would need to be followed by bisphosphonate therapy, if that is not contraindicated, to reduce the risk for rebound lumbar vertebral fractures. So highlighting this upfront with a patient is certainly important for adherence purposes. I can't recall the exact timeframe that you can kind of be pasted and still be in a safe window, but it isn't a very long time, like a few weeks kind of thing. So it's important to have it consistently and into long time. All right, so let's put all that together. We'll look at guidelines from the American College of Physicians. They have a few different recommendations in regards to osteoporosis. Clinicians should use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in post-menopausal females that have been diagnosed with primary osteoporosis. That's a strong recommendation from them. Then they also suggest that clinicians use Dynosamab as a second-line pharmacologic treatment to reduce the risk of fractures in post-menopausal females. Then also in patients who have contraindications to or experience adverse effects with bisphosphonates as well. Then they suggest that clinicians use the Sclerosin inhibitor, the romo-suzanab, or recombinant paratyroid hormone, followed by bisphosphonate to reduce the risk of fractures, only in females with primary osteoporosis with very high risk of fracture. Basically, the rationale behind these is that bisphosphonates had the most favorable balance among benefits in harm, patient values and preferences cost as well was considered. Again, that patient population of post-menopausal females with primary osteoporosis, that should be the first-line drug. Dynosamab had a favorable long-term net benefit, but bisphosphonates are much cheaper. Then the benefits of recombinant paratyroid hormone, where the Sclerosin inhibitor may have outweighed harms compared to placebo in select patients that were in that post-menopausal female group. They had also a very high risk of fracture. Then bisphosphonates and Dynosamab were associated with high risk of osteunochrosis of the jaw as well as atypical femoral fractures. Then that romo-suzanab is associated with adverse cardiovascular events. Then we don't have long-term data with the paratyroid hormones. For men, it's pretty much the same thing with primary osteoporosis. They recommend bisphosphonates first, probably a second, and then considerations for the other paratyroid hormone therapies as well. They also mention patients with osteopenia and what to consider. They basically kind of give a guy consider this kind of a throwaway recommendation, but they say that the clinicians have to take an individualized approach to whether or not to start bisphosphonate therapy in females over the age 65 with osteopenia to reduce the risk for fractures, saying consider the cost, consider the risks and decide if it's worth it for that patient to potentially decrease their risk before they reach a T-score of osteoporosis. And there you have it, folks. We are literally right at an hour right on it. Well, yeah, actually, when we throw in the intro music, it probably won't be it will be a little after. That's fine, you know, it's neither here nor there. But the music though, got to, it wouldn't be a blog gas if you didn't have the intro. Can you just start talking? I'll start, I'll start beat boxing. Oh, yeah, that's what happened then. Just ratings, just clameting. But that's what we got for you also. 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