Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. So, osteoporosis is a topic that we've done a couple of times on the Penn Primary Care Podcast. But it's a topic that has had experienced some changes in the last couple years, but also an area that I think we as primary care physicians are increasingly being asked to manage ourselves. And there aren't an infinite number of rheumatologists and endocrinologists in the world, and so a lot of us. But osteoporosis is a very common disease, very common problem. And so, we're often asked to manage this in primary care. And if I speak for myself, I'm not completely comfortable, especially when you get beyond some of the most basic therapies.

So, for that reason, I asked the director of the Penn Bone Center at Penn, Dr. Mona Al Mukaddam, to come back on the podcast to help answer some questions. Hi, Mona. Thanks for coming again.

Mona Al Mukaddam, MD, MS: Yeah. No, thank you so much for having me. Looking forward to answering your questions.

Host: For the audience out there, there was a wonderful podcast done a couple of years ago in which Mona covered a lot of the basics of osteoporosis management, a podcast hosted by Amber Bird and Ronnie Nandiwada. And it was excellent. So please, I think most of that content is still relevant. What I really wanted to do is bring Mona back on to really talk very practically about how we as primary care physicians can maybe get beyond a little bit some of the most basic treatments, meaning the Fosamax and so forth, and do some more advanced treatment on our own.

But first, Mona, I actually wanted to highlight three things that have caught my eye in the last couple of years in osteoporosis care. And I sent you these questions beforehand. But I think the first one is a potentially significant study that came out in 2025 looking at the use of zoledronic acid (Reclast) for patients who are osteopenic to prevent bone fractures down the line.

Now, I know this comes in the context of a history where we started initially with Fosamax and other bisphosphonates treating in the osteopenic range, found that was kind of a mistake. And so, we started to treat only when patients were truly osteoporotic. But now, this trial comes out that suggests a couple of doses spaced five years apart may have benefits. Can you illuminate that for us a bit?

Mona Al Mukaddam, MD, MS: Yeah, absolutely. So, I think, I'm going to first start with answering a question that you did not ask. The way we have shifted in terms of thinking of osteoporosis treatment is really fracture reduction. And I think that's really been the biggest paradigm that we have done. When you look at all the treatment guidelines now, they really now risk stratify patients in terms of the highest risk of fractures and the ones who are at highest risk of fractures are the ones who have had fractures in the past or at having very high-risk of fractures, as calculated by FRAX or because they have very low T-scores.

So, what I try to do with my patients now when I see them is you say osteoporosis, you think about osteoporosis, you think about your bone mineral density and T-scores. But what I care about the most is preventing fractures and not preventing osteoporosis. So, I think that paradigm has shifted, where it's talking about preventing fractures, and not preventing osteoporosis.

The second paradigm that has shifted is allowing us to diagnose patients with osteoporosis if their calculated risk of having a fracture using common fracture calculation tools like FRAX, if it is high enough that it would meet treatment threshold, we can actually define those patients as having osteoporosis as well. And so, I think that was very interesting.

And then, that also goes towards talking about our younger patients who were, as you mentioned in the study in the New England Journal of Medicine study, where they included younger postmenopausal women, so in the ages of between 50 to 60, where they had what we call osteopenia, meaning that they don't have a T-score -2.5 or below, but have a T-score between -1 to -2.5. And they gave them IV zoledronic acid either once, and then followed them for 10 years. And then, another group received IV zoledronic acid at baseline, and then five years later, And then also followed them up for 10 years. And then, the third group, they received placebo at baseline, then five years, and then followed them up for 10 years.

And in that study, it showed that whether you gave one dose of Reclast or you gave two doses five years apart, those patients had less compression fractures in their spine by about 40% compared to those who did not receive zoledronic acid. So again, we are not talking about BMD changes, even though the BMD did improve in those who received zoledronic acid. But the reason why the study was impactful was because it talked about fracture reduction 10 years out the line. So, that was a very impactful one.

Second, you think about why we are concerned about initiating treatment early on with bisphosphonates, is because we understand the cumulative side effects of prolonged use of bisphosphonates. So when you use bisphosphonates for five years continuously, we're worried about the stress fractures happening in the thighbone, which is what we call atypical femur fractures. And so, we're doing drug holidays. And so, that's why we in the past would talk about is your risk of having a fracture high or not? And we wouldn't be treating the patients to prevent osteoporosis per se or we're treating osteopenia per se.

And I think that was a very interesting paper, because now I'm like telling my patients like, "Just take one dose." You know, what is the harm? The side effects are very minimal. You're only taking one dose so we're not worried about prolonged use of this medication. And now, I have the data to tell me that this will reduce the risk of having fractures in the future. So in that sense, I think it has changed how I practice things where I might say, "Just take one dose and see me back in five years." And so, I think that, in that sense, really has changed.

Host: How are you predicting who would benefit from that? I mean osteopenia or low bone mineral density, which you taught us in the last podcast, it is a broad category. You said it's from -1 to -2.5. Virtually, all women fit into that category at a certain time of life, right? So, who gets the IV Reclast once?

Mona Al Mukaddam, MD, MS: Yeah. This is a very interesting question, because we don't see those patients, right? These are not the ones who're coming referred to a specialists. This is for you guys to decide who would get them. I don't know that you have to do this, but you do want to think about the patient and they're maybe using FRAX and calculating the risk of having a fracture. So, that would look at other risk factors: if they have a low BMI, if they've had prior fractures, if their parents have had a hip fracture, and looking at other comorbidities or other medications that they might be on if they have rheumatoid arthritis, if they're on prednisone.

So, I like to joke about this, but my husband's also a physician. And he looks at me, he's like, "You do all these calculations." And he's like, "I can see a person walking into the door if they look like they're going to break their bones or not." And so, I really think clinical judgment continues to be very important when you're looking at the patient. Does this patient look like they're going to fall? Do they look frail? Are you worried about them breaking a bone? And if you are, then just give them a dose of Reclast. And if these are people who are very muscular, really don't look like they're going to fall at all, they don't really need it, then you're less likely to recommend treatment.

I think, if I have to switch and think like a primary care doctor, I think it's important then to go back and kind of remind people when do you order ad DEXA scan? So usually, DEXA scans are ordered for routine screening for postmenopausal women age of 65 and above. So automatically, if you're ordering a DEXA for someone who is younger, there must be some reason as to why you're ordering it. So, that's also something to kind of factor into your decision as to why was this DEXA scan done? Was it done as part of a research study? Was it done because the patient went to some fair where they were offering it? Versus, were you doing it for clinical concerns for osteoporosis? Which I think would also play a role into deciding if you should give that patient one dose of zoledronic acid or not.

Host: Yeah, I think that we probably all have a sense of who is at-risk, and to your point that, you know, patients who are on steroids, but the patients who have just sort of thin bones and are petite in stature and so forth. And so, actually, I'm going to bring into this a conversation I had with a wonderful patient of mine who's an MD, a psychiatrist who's very thoughtful, and is 53, and just fits that category. She's very active and exercises regularly, but she's petite in stature. And you would look at her and think that maybe in the future she may have osteoporosis. So, that is, I think, relevant to the discussion of whether or not IV zoledronic acid at some point in the next few years might be a good idea. And as I recall, she's pending a DEXA.

But the other question we had was really tying into the last podcast we did, which I think you've had an opportunity to listen to, on hormone therapy and how that fits into this discussion, because that was a discussion I had with her about whether or not she should consider it. And there was a variety of factors to go into that. We went into all that detail in the last podcast. But when it comes to your population of folks, has it changed at all in terms of how you're thinking about hormone therapy?

Mona Al Mukaddam, MD, MS: So, yeah, I actually did listen to that podcast and it was very interesting. And there's a lot of factors you have to think about when you're thinking about hormone therapy about risks and benefits. And so in anything that we recommend, it's really talking about the risks and benefits of each intervention.

When it comes to bone health, we tend to think of the medications that we have right now, whether Fosamax or Reclast, or denosumab as being way more efficacious in terms of fracture risk reduction compared to estrogen therapy, and also safer in that sense. And so, from our perspective, if I think that my patient is at very high-risk of having fractures and I want to give them effective therapy, then I would be recommending those medications.

But I think that your patient who's a physician who's 53 is maybe not in that category. This is someone where you're talking about how can I optimize her bone health from now to prevent osteoporosis or keep her at a lower risk of having fractures. And that's where I talk about estrogen. We talk about the Women Health Initiative study, when it did look at fracture risk reduction, which it was shown to be efficacious. It was through an oral form of estrogen, which was potentially much higher doses of estrogen than what is now being recommended transdermally.

And so, we all understand and appreciate that estrogen will have favorable effects on bone health, but there's no strong data about fracture risk reduction. And so, I'm never the one who's prescribing the estrogen for my patients. I definitely have a very informed discussion about it with the patients talking about how the pendulum swings.

And I think if you're in the first five years post menopause, considering estrogen is a good idea, if you want to take it for vasomotor symptoms, for other symptoms that you think are bothersome to you. And if they are on estrogen, I do think about it as well, maybe that I don't have to be more aggressive in terms of treating them for osteoporosis or maybe doing DEXA scans as frequently.

So, to shift it a little bit, so if I had a young postmenopausal patient who had a DEXA scan for whatever reason and comes to me with a T-score of -2.5 or -2.6, I'm not necessarily offering biphosphonates for those patients, at least in the past, because I'm like, you know, your risk of having fracture is still very low.

If I start you on bisphosphonates right now, what am I going to do for you in the future when you're 80, 90, and now people are living well into their one hundreds. And so for that patients, like, you know, if you're going to be on an estrogen-based therapy, that's great. It's not going to be the best solution, but it's just going to be delaying our need to start you on an anti-resorptive therapy or an osteoanabolic therapy.

And so, that could be either estrogen as in hormone, estrogen replacement, or it could be an estrogen-like medication. So, those would be like the SERMs, the selective estrogen receptor modulators, which would have some beneficial effect on the bone, some benefit on the spine, but really very little data on hip fracture reduction, and thus fracture efficacy compared to the medications that we have right now.

Host: I want to come back to the SERMs, raloxifene, because we don't talk about it very much, and I think it has a niche role. But let me come back to that. So, it seems that estrogen therapy itself, you said it is a modest effect. And we just reviewed that New England Journal study that you mentioned. So, the patients who are in that category are probably going to benefit from Reclast, because there is data on fracture reduction in that, right? So, that makes a lot of sense.

Mona Al Mukaddam, MD, MS: I think the one thing that I would say though is with that New England Journal of Medicine paper, I would say offering them the IV zoledronic acid is the way I would approach it. I wouldn't say that they have to take it, you have to talk about your patients, think about each patient and what their preferences are.

And in those younger patients, you're talking about fracture prevention 10 years down the line. So, there's not this hurry into doing it as well. And I think patients sometimes feel overwhelmed when we're saying that you have to do this and they want to take their time, they want to think about it, they want to research it. And I know the next question's going to be about exercise. And so, they're going to want to do the exercise, the estrogen, the non-pharmacological ways. And I think we have to respect that as well when it comes to a chronic condition and talking about future fracture risk reduction. So, I think giving them the time to do other interventions is not a bad idea, and that's so different from someone who's had a recent fracture whom you think the risk of having a fracture is very high and very high in the immediate future.

Host: So, this plays into a discussion I often have with my patients now about exercise. And the way I frame it is this, that human beings all will lose muscle mass with age, they'll lose bone mass with age. And that catches up to you pretty much in the 80s, I would say the ninth decade of life, right? Where you look at patients who are 85 and older, what differentiates them health-wise is often not cardiovascular, cancer, other issues, but really issues of frailty. And so, I'm telling patients all the time, you really have to sort of gird yourself against that and plan for that period by really building up muscle mass.

And there's more data coming out now about the value of weight training. World Health Organization now specifically recommends resistance and muscle strengthening exercise twice a week. And I think that we're seeing that now that, historically, for bone density specifically exercise or weight-bearing exercise or structured sort of bone strengthening exercise has been focused on prevention, preventing bone loss. But I did happen to notice an article or two in the last couple years that seemed to suggest that you can actually build some bone on your own with muscle strengthening exercise. Has that changed at all?

Mona Al Mukaddam, MD, MS: I think the way that has changed-- So, a couple things. One is for our somewhat older, more frail patients who have osteoporosis, we're usually telling them to avoid high impact exercises, to avoid falls, don't hurt yourself, don't over bend. And so, we're being very cautious in terms of some of the exercises that they can and cannot do.

And I think that has a bit changed in terms of providing more supervised, more high intensity resistance and impact training in a more supervised manner so that the patients are not hurting themselves with the idea that, you know, that the higher intensity exercise can stimulate the bone-forming cells, the osteoblast, and can stimulate bone formation.

And so, I think that understanding has always been there. There's also some devices like vibration devices where people are looking into whether it's a belt or platforms that people stand on to cause the stimulation to stimulate bone formation from happening to happen. And so, you will find studies and there has been studies in the past and, again, studies that have been published more recently where they look at BMD improvement and you can see significant BMD improvement.

But I will go back to this concept of fracture risk reduction versus BMD improvement. And I'll also go back to, say there's a huge difference between some of my patients that I see that are already very active and already exercising and already doing their yoga and the Pilates, and they walk and they really don't want to be on medications. And then, they find online programs like OsteoStrong. And they say," Okay, This is the treatment I'm going to take." I'm like, "It's not going to make a difference for you." You have to see the baseline patients that were entered in those study, what their baseline activity level was. And of course, you're going to see a lot more improvement in people who never used to exercise before and now suddenly started to exercise.

So, the way I think about exercise is it's extremely important. It is important for their bones. It's important for fall prevention. It's important for their sarcopenia. But it doesn't necessarily replace osteoporosis treatment if someone has had very high-risk of having fractures. And so, that would be similar to like adequate calcium and vitamin D intake. So, the way I try to explain to patients is that I'm going to care about you not breaking a bone for the rest of your life. Adequate calcium intake, adequate vitamin D intake, exercise, fall prevention is going to be lifelong. Medications are going to be episodic. Treatment is going to be episodic. But those things are kind of staple in terms of your treatment when it comes to osteoporosis.

 What we have been doing a little bit more of is in our younger patients who are really healthy and they want to do more than the regular, you know, referral to physical therapy to talk about just balance and low impact exercises and is incorporating physical therapists that are more trained when it comes to osteoporosis care to do this kind of more supervised, high-intensity resistance training. And they seem to like that a lot. They like that we're offering that, and we're not ignoring the importance of exercise because it is actually very important. But that's needed in addition to pharmacological therapy in our high-risk patients.

Host: You made the point in the last podcast that stuck with me that there's not been proof that exercise reduces the risk of fracture. And you made the point earlier in this podcast that this is really all becoming about fracture. And so, increasing the bone mineral density with exercise may be true and certainly, you know, valid. But I think your point is that nothing other than medications has been proven to reduce the risk of fracture. Is that fair to say?

Mona Al Mukaddam, MD, MS: Yes. I think that is very fair to say. But that doesn't mean that they don't reduce risk of fractures, which is the opposite of it, right? So, the problem with everything that I'm saying right now, okay? So in order for a study to be done to demonstrate fracture risk reduction, you're talking about thousands of women, right, and that are followed for three years, six years, ten years. So, these are very expensive studies and they require a lot of time and compliance and monitoring with patients and following up with them on a regular basis.

And so, I think the lack of evidence for exercise or calcium or vitamin D or even the vibration plates and the belts and all of these things is because these studies need to be much bigger, much larger to be powered to see fracture risk reduction.

Now, I talk about this, and I think we probably should meet again in the next three to five years, because as of December of 2025, the FDA has now approved bone mineral density as a surrogate marker for approval of osteoporosis medications, which is completely different from what the approval process had been.

So in the past, bone mineral density was not an appropriate surrogate marker for fracture risk reduction because we know that the bone density by DEXA is only capturing one aspect, which is the bone density on an aerial image, so two-dimenstional image instead of three-dimensional. And it's not capturing the architecture of the bone and a lot of things about the bone quality that are not being captured. And we also appreciated that there's certain medications like strontium that increased bone mineral density, but did not decrease risk of fractures. And so, there was this disconnect between bone quality and bone mineral density. But since in the osteoporosis world, the drug development has been very slow. And people have not been investing the time and the effort into developing drugs.

Host: Because the studies take so long to do and because they're having to refracture and they're so expensive and so forth.

Mona Al Mukaddam, MD, MS: Exactly. And so, there's been such a huge push to allow BMD to be a surrogate marker. But it's interesting because this this has been approved. We don't have any drug right now that's been approved through that process because this just happened recently. But it makes me think every single day of how I counsel my patients and how I talk about I'm only going to prescribe something if it reduces fractures. And so, I think it's going to be a very interesting paradigm that's going to change. And so, I think talking back in three to five years is going to be very helpful to see how we're thinking of things right now once we have new drugs that are approved based on bone marrow density changes and not necessarily fractures.

Host: So, that was great. And I wanted to go through those three questions upfront, because it was relevant and topical and so forth. But now, I want to dig down into the actual drugs and how to prescribe them and get some real practical guidance from you on how to manage folks to the degree that we have to do it on our own.

So, let's just first sort of review the tools when it comes to medications, right? So, Fosamax is the signature bisphosphonate in this category, now dosed once weekly. By the way, Mona, what I'll do is I'll tell you what I know, and then you just correct me as appropriate. And we'll go from there. So, it is dosed once weekly, given for a five-year period. If I identify a patient that I think is appropriate, I will do a basic diagnostic workup to make sure there is no secondary cause. You highlighted that in the previous podcast. A vitamin D, a PTH, magnesium, phosphorus, some of the basic things that you don't want to miss, because they may require other treatments. You want to make sure patients are getting appropriate levels of vitamin D and calcium-- 800 units, right, of vitamin D, 1200 of calcium.

And then, you think about putting them on a medication. Fosamax, let's talk about first. Now, let me just say this. I'm not doing this for the folks who have fractured, and I'm not doing this for patients that have T-scores that are less than 3.0. So, those are the high fracture risk patients. So, those are the ones I'm pretty much sending to you. But I am doing it for the patients who just sneak into the osteoporosis category. Now, they're -1.6 at the femur. And I'm saying, "Well, you know, you're there and let's talk about this." That's where I'm using this medication. I'm doing it for five years. I'm expecting to stabilize their bone, if not improve it, 0.2 or 0.3. And I'm thinking I'm just going to order another DEXA in a couple of years from that start. Is that about right?

Mona Al Mukaddam, MD, MS: It is. I think so. Yeah. So, I just wanted to talk about one more thing, because you gave me the questions beforehand. And it's so hard for me not to jump. But I do think that when we talk about, again, osteoporosis treatment, and you can see all the guidelines right now are really talking about risk stratification and how sequence matters. And so, I think that the fact that you recognize automatically that the ones who have a T-score of -3 or -3.5. And the ones who've had fractures, and I think that's one all of the guidelines keep highlighting multiple compression fractures, hip fractures, spine fractures, more than one fracture, fracture while on therapy. So, fracture is really kind of the ongoing theme that this specific category of patients where we think that there are very high-risk of fractures, that we want to be thinking about starting them maybe potentially on bone-building medications. And so, I think that category is very important and we will talk about it later, but I just wanted to highlight that we do think that treatment sequence does matter. And in those patients, if you're not comfortable starting bone-building medications, they should be referred to us.

But thinking about the run-of-the-mill osteoporosis T-score between -2.5 to -3, no history of fractures, no side effects, doing an oral bisphosphonate seems very reasonable. The problem with the oral bisphosphonate is not only the GI side effects that can happen, but more so the compliance as well as the poor absorption of the medication. I don't know if I expect primary care doctors to necessarily do this.

But at least what I do in my practice and I do prescribe sometimes oral bisphosphonates even in my practice, is I would check bone markers in those patients. So, the marker that I check is the C-telopeptide, which is a marker of bone resorption or bone breakdown. And I do like to check it at baseline. And then, if they come back in a year to two years, check it again and see if it's coming down by about 50% or not, and see what their bone density, how it improves, or it stays the same, improves, or it's coming down, because I think this is an opportunity that you don't want to say like three to five years and miss this opportunity where they're not really absorbing it, they're not really taking it, and it's not really effective for them.

And in those patients where I feel like the C-telopeptide, the marker did not go down, that I would want to switch them to the infusion instead. That way, it's guaranteed it's going to be in their system. It's very efficacious. And I feel much more comfortable in that sense. I think the ones who are on oral, maybe you want to see them back sooner, maybe in a year or two, not longer than that. If someone's on an infusion, as you saw from that study, five years, it seems to continue to work. And so, I would probably want to monitor the orals a bit more closely than the ones who are on an infusion just because of the lack of absorption and compliance issues.

Host: This is exactly why I had you on the podcast, kind of highlight this for me. This is really helpful. So, let's just talk about C-telopeptide. I order it, it comes back to me. I get a value. I've never ordered this, so I don't know, what it looks like when it comes back. So if it's high, it suggests that that the patient is resorbing bone causing less bone density, right? And so, I want to reduce that, right? So, I want to do something that will reduce the C-telopeptide. So, what kind of numbers do you get when you order it, just on a standard patient?

Mona Al Mukaddam, MD, MS: So, I think this is a very important point, and that's why I don't know if I'm expecting the primary care doctors to do it. But once you're comfortable doing it and you've been doing it for a while, you get a sense to these things. So, the first thing to know is the limitations of this assay. So, the C-telopeptide, first of all, has to be done eight o'clock in the morning and has to be done fasting because the normative values that you have are based on non-fasting, eight o'clock in the morning, it follows a circadian rhythm. So, the levels go down during the day and with food.

The other thing is to realize that this assay, the values are so different based on which lab it's done. So if you try to be as consistent in terms of the lab that it's done, that would be very helpful. They give you multiple ranges and the ranges can vary quite widely between like a hundred to a thousand. And so, the range is very different. And so, this value is so different for each individual. So as an absolute value, it might not be as helpful, but it's helpful to watch it as a trend to see how this is trending.

And when you say high numbers, you're not going to see a number that is like above the upper limit of normal. What you see is a high number in the upper range or in the upper half. And when we have someone on therapy, we're usually looking for that range to be in the lowest quartile of normal, which usually is around 200 to 300. And so if someone is like not going down below 300, their bone density is coming down. It's not improving. It's still very low. Then, you'll like, "Okay, let me switch to the infusion of zoledronic acid to bring that number down lower. So, those are kind of the things that I look at, but it does require to be comfortable reviewing those results. Because like I said, there is a lot of variability with those assays. There is a lot of variability from one person to the next. And some people, like 10% of the population live with low bone markers. And so, those people are going to be much harder to interpret those results if you didn't have that baseline one to know that they this is where they live. They live in the lower quartile at baseline. And so, then, it becomes harder to use that as a helpful marker.

Host: When did you say you would recheck it? Let's say I put a patient on Fosamax PO. When would you check that as opposed to when you're doing a DEXA? Is a two-year DEXA reasonable or do you check it in a year? And how do you time the C-telopeptide before that DEXA?

Mona Al Mukaddam, MD, MS: First things first, that means that you are including now C-telopeptide in kind of your baseline screening labs in order for this to be helpful. So, I think that's something that's very important to now think about. If you aren't going to be doing this, you are now including C-telopeptide in your baseline evaluation.

If I want to be aggressive with this patient and I really want to know how they're doing, I would do three to six months later, that's when I would do the CTX. If it's someone that I'm like, "I'm okay, if they didn't want to be on treatment anyway," then I would just say, "Come back in a year" and do a DEXA and C-telopeptide at the same time in a year, but not before three to six months.

Host: So, the rest of the tools primary care physicians are probably not as comfortable with. And so, let's talk about zoledronic acid or Reclast. Let's talk about denosumab or Prolia. And then, I do want to get back to the anabolic agents, and understand those a little bit more in depth. Even if I'm not planning to prescribe them, I do want to understand them better. So, I think of zoledronic acid or Reclast as an option, of course, if somebody cannot take PO. I do think of it as a stronger agent, meaning it will improve that DEXA more than I will expect from Fosamax alone. And so, if I'm a little nervous about a patient, they're on the edge, they're -2.9, "I haven't had a fracture, but I'm a little nervous about it," I might instead choose Reclast. And then, I would do that once a year for three years with a DEXA at a year. And now, with your guidance, I'm probably checking a C-telopeptide as well at baseline and at six months or so.

Mona Al Mukaddam, MD, MS: Yeah. With Reclast, you don't need to do the C-telopeptide at six months, to be honest. If someone's getting the IV zoledronic acid, you can decide to do once a year for three doses. And then, the C-telopeptide becomes very helpful when we're doing drug holidays. You do it at the end of the treatment. And then, you do it afterwards just kind of when they're on the drug holiday to see what to do.

Host: So, just to reiterate the point that you made before that, with Fosamax, you're really not sure of the absorption or the adherence. And so, that's why you're checking it there. But know that the patients are getting the infusion yearly, and so you're comfortable with that and you're doing that for three years. It is true that I should expect an improvement in their DEXA that is greater than what I would expect with somebody simply on Fosamax-- with Reclast, is that right?

Mona Al Mukaddam, MD, MS: Yeah. So, I think if you kind of think about the improvements, it's not drastically different. But, you know, you would talk about like 5% versus 7% or 8%. But definitely, the IV Reclast, the zoledronic acid as a bisphosphonate, it's a much more potent antiresorptive therapy separate from absorption and compliance issue. And then, if you add on the compliance issue, you're going to see that the IV zoledronic acid is more potent than the orals. And so yes, you would see more improvement in bone mineral density compared to the oral bisphosphonates. And then, from the studies, we know that the fracture reduction is more efficacious with IV zoledronic acid compared to the oral bisphosphonates.

I think that, as primary care doctors, you should be comfortable ordering IV zoledronic acid. I really do think that should be kind of under the umbrella of what primary care doctors are able to do. Denosumab and Prolia, I will talk about it. I actually don't want primary care doctors to be ordering it at all. I would actually be more comfortable with primary care doctors ordering osteoanabolic therapies versus ordering denosumab. But I'll talk about that in a second.

So, in terms of the IV zoledronic acid, the patients are terrified of taking it for multiple reasons. They feel that they're going to take an infusion and it's going to stay in their body, and they have a side effect, they're going to continue to have side effects the rest of the year. I try to reassure them, I've been doing this for over a decade. The real side effect that could happen for that IV zoledronic acid is really the flu-like symptoms. And the flu-like symptoms occur 12 to 24 hours after the infusion, they can get muscle aches, low-grade fever, feeling unwell for two to three days, and staying very well hydrated, drinking at least two glasses of water. And I preemptively give them Tylenol 500 milligrams, 30 minutes before the infusion. And then, they can take it every six hours after the infusion for the first couple of days. And that really seems to help with that flu-like symptoms. I tell them "The flu-like symptoms, I promise you it goes away."

Sometimes it could be pretty miserable. You're in bed,. So, please, don't plan anything major, like no conferences, no weddings, nothing major that you're going to in case you end up being in bed. But it goes away. And it's the worst with the first infusion and gets much better with subsequent infusion. So, I think having that kind of counseling and preparing them is very, very helpful. They end up trusting you more and more willing to do it the second time.

And I try to explain that the medication continues to work because of how it resides in the bone and how it inhibits the enzymes. But the drug itself will no longer be in your blood if there were to measure the drug amount in the blood. And so, I think that helps them a little bit to kind of understand how the medication works for a year, but how the side effects won't linger on for a year.

You want to make sure that their calcium is appropriate in the blood, they're getting at adequate calcium, their kidney function is good, their vitamin D levels are good. Theoretically, low calcium can happen after the IV zoledronic acid, they can develop hypocalcemia. Obviously, this is a medication approved for treatment of hypercalcemia, but really has never happened with any of my patients where I know that their kidney function is good, their vitamin D level is good and their calcium is good and they have adequate calcium intake. In those patients, really, hypercalcemia is not a problem. Most of the medications that we have for osteoporosis that work by reducing the amount of bone being removed or what we call antiresorptive therapy. Most of them will have the concern for the two side effects that patients are terrified about, which is the osteonecrosis of the jaw and the atypical femur fracture. So, patients are terrified of these side effects. But you have to give it to them. You have to explain it to them, like what are the risks.

And so, when it comes to the osteonecrosis of the jaw, I tell them it's basically, your jaw being exposed, jaw bone being exposed, getting infected. And that doesn't heal for over eight weeks. That's the definition of osteonecrosis of the jaw. It tends to happen after invasive dental work like dental implants or dental extractions. And it usually happens in cancer patients who are getting the infusion once a month or every three months as part of their cancer treatment. They're actively undergoing chemo, radiation, they're on prednisone, they have diabetes. So, they have other risk factors.

We do have like a table in our guidelines where they go over the risks of side effects from this medication compared to like being hit by lightning or a motor vehicle accident, some other stuff that could happen. And it just really helps that you're more likely to be hit by lightning than for that to happen with an oral bisphosphonate, the osteonecrosis of the jaw.

So, giving them those numbers and having them understand like, yes, we understand this risk can happen. Yes, we are aware of it, but it's really low. And I usually tell my patients before initiating treatment, like, "If you are going to be undergoing any invasive dental work, get it done now. I'll delay starting the bisphosphonates. And then, you can start with bisphosphonates after you're done with your dental work.

If they do need invasive dental work while they're on therapy, they should do that dental work because whether they stop the bisphosphonate or they don't stop the bisphosphonate, the effects of the bisphosphate are still in their system. So, sometimes dentists insist that patients stop it and I say, "Fine. If you want to stop it, it's fine. Hold it for two months, three months. You want to hold it, it's not a problem for me. I don't know how much it's going to make a difference in terms of the healing process. And so, usually, they ask me for clearances and I always say, "If your dentist says you need to get it done, just get it done. There's nothing that I can do to clear you." But that's kind of the dental issues that patients are scared of.

And then, the stress fracture in the thight bone is something that can happen. And that's really with prolonged use of these medications. And that's why we do courses of treatment. You're not on these medications for the rest of your life. But yeah, I think IV zolendronic acid is definitely something that, as primary care doctors, you should be able to and comfortable ordering.

Host: What do you quote for your patients going on IV zoledronic acid, Reclast, what do you quote them in terms of the risk of osteonecrosis of the jaw?

Mona Al Mukaddam, MD, MS: It's like one in a hundred thousand, but that's for like spontaneous with an oral bisphosphonate. The risk is like 1% or even higher for cancer patients. And so, the risk is like so different. And then, similarly with the atypical femur fractures, it's like one in a hundred thousand patients if you've been on bisphosphonate less than five years. And the risk goes up by a hundred fold if you've been on it over five years.

And so, that's kind of the numbers that I give my patients when I'm discussing those things. And I talk about it straight on. I acknowledge it straight on. And I talk about their fears and their concerns and what the fractures are, and I make it as scary as possible as they want it. So, I'm not like diminishing how bad they are. But then, talking about what is the actual risk of that happening?

Host: Yeah. I'm working with a medical student now who's also a dentist. He's training to be an OMFS and took him aside knowing we're going to do this podcast. And I said, "Can you tell me about osteonecrosis of the jaw?" I mean, you've seen it right? What does it look like? And he said it's a spectrum. He says a wide spectrum. In general, he said anytime you're doing invasive dental work, you need a bone to heal. So, you need a bone to fill a hole or to grow and fill a hole, much like the skin would fill a hole of a skin wound. And he said that's very slow because patients have agents in their system that are keeping them from doing that.

And so, he said, "And so you then you can get super infection and other issues." He says sometimes it's just a couple weeks of antibiotics and that's the only problem. Sometimes it requires mandibular resection and reconstruction, but that's highly unusual. So, it was very interesting to get his insights, a person who's seen this professionally a number of times.

Mona Al Mukaddam, MD, MS: I think that's a very important point, talking about the spectrum as well. It's not like yes or no. Like, it could be as simple as, you know, someone having non-healing jaw thing. And all they require is like antibiotics to swish and swallow.

And I think also the other thing that has shifted as I've been doing this now for a while, in the past, I'm like, if anyone has osteonecrosis of the jaw, I'm never going to give them bisphosphonates again. No, I give them bisphosphonates again. I talk to their oral surgeons. I talk to their dentist. And we talk about risks and benefits. And we talk about the circumstances the first time that led to them having osteonecrosis of the jaw and how can we maybe decrease the dosing of the bisphosphonates, do it differently so that we're not running into the same problem. But it's not an absolute contraindication if someone's had history of osteonecrosis of the jaw. And it's also speaking to the spectrum of this condition.

Host: I want to get to the anabolic agents. I want to leave you some time. But I do want to spend a little bit of time on Prolia, because there are primary care physicians around the country who prescribe Prolia all the time. I've been somewhat scared of the drug, I think. I do, by the way, prescribe it. The circumstance in which I prescribed it are only patients who have come to me on it, cannot find another provider to give it. They're new for their dose. And I'm like, "Okay, you just got to get your dose." I have one patient who's 90-years-old. And I've talked with one of our endocrinology colleagues. And I've just kept her on it then that's been fine.

But let me just cut to the chase on Prolia (denosumab). I mean, I see it as a more potent agent than Reclast in terms of bringing bone back. It is every six months. If you delay it more than a month after your scheduled infusion, you can get rapid bone loss. So, it's scary from that perspective, I think. You have to stay on top of it. And then, there's this whole issue of how to come off of it because you don't want to keep people on these agents forever because of the risk of femoral fragility fractures. And that's been the issue with Prolia.

Now, I do understand that there is a protocol now whereby you would give someone Reclast before their last infusion of Prolia to potentially keep them off of it. But one of your colleagues explained to me that Prolia is really-- if you're not dating osteoporosis, this is a marriage, you know, you're going to be--

Mona Al Mukaddam, MD, MS: I like that one.

Host: She was saying, "I reserve that for my elderly patients that are probably just going to need something the rest of their lives, and I don't think they're going to live terribly much longer." And so, that's what I'm using it for. So, that's my spectrum. Can you correct me on any of that?

Mona Al Mukaddam, MD, MS: I think everything you said is spot on. I would just highlight a couple of things. One thing is that delay of Prolia is not only associated with rebound bone loss that's very exaggerated, but it's also associated with multiple compression fractures. So, I think that's something that is really important and something that we in our office have seen specifically with oncology patients like breast cancer patients who were started on medications that would negatively affect their bone quality, aromatase inhibitors, chemo and radiation, and were started on denosumab by their oncologist, given for three to five years. And then, told them everything looks good, you stop it. And then, they come to us with multiple compression fractures in their spine. And so that's very important to keep in mind.

The second thing is that, with denosumab, we only have published data regarding safety and efficacy for up to 10 years. So, we don't have anything else beyond 10 years. And the other thing that we do know is that that rebound bone loss that happens and these compression fractures that happen happen more often if Prolia was started in younger patients compared to older patients and how long they've been on Prolia. So, the longer you are on Prolia, the harder it is to get you off of Prolia. And so, that's why in younger patients, I don't want to do Prolia. Because, like I said, people are now living well into their 100s. And so if you're having a 50-year-old or a 60-year-old start on Prolia, what am I going to do with them when they're 20 years down the line, 30 years down the line? We have no safety data beyond 10 years. So, that's one concern that I have. One of the many concerns that I have.

The second thing, and we know this, and this is very reproducible as well, you remember how I talked about risk stratification and sequence matters. And sequence really matters, and especially with denosumab. And so, we know that oral bisphosphonates and the use of IV zoledronic acid might blunt the benefits of some of the bone-building medications. But with denosumab, if you were to switch someone from denosumab to the daily injection, the bone-building medication, you actually have bone loss that happens in the hip. And so, really, sequence matters in that sense.

And so, I never switch someone from denosumab to an osteoanabolic therapy, because they actually lose bone densities. If someone's on denosumab and I feel I want to escalate their osteoporosis treatment, I cannot now switch them to osteoanabolic therapy. I have to do add-on therapy, which is sometimes not covered by insurance, and it's very expensive.

And so, your boxing people into Prolia, right? So, Prolia is so hard to get off. And so, I usually don't like to start with Prolia. And the only time I actually refer to the ACP guidelines, to your guidelines, is when it comes to them stating that denosumab is second line therapy. I think where our organizations like the Endocrine Society or the ACE and our bone societies, they have continued to say if someone's had high-risk of fractures, they have osteoporosis. All of these medications are considered first-line and people who are at very high-risk. We would really encourage you to start with osteoanabolic therapy.

But I really think that Prolia, although approved as a first-line therapy, should not be considered first-line therapy, especially in younger patients. And yes, Prolia is an excellent drug. Patients love being on it. They tolerate it very well. Their bone densities look so much nicer and it goes up. And they're really, really happy with those results. But we have to think about what's going to happen in five years, 10 years. And so, before I initiate anyone on Prolia, I'm talking to them about what are we going to do? What's our exit plan? What is our long-term plan? And then, I tell my patients my own father is on Prolia. He's 84 years old. He has CKD. He had a compression fracture. I told him, "You're going to be on Prolia for the rest of your life." And so, that was a decision that was made on initiation of Prolia. And he hadn't been on any other osteoporosis therapy before.

And so, I'm not saying that I don't use it, and I'm not saying that I don't use Prolia as a first-line. But I think for primary care purposes, if you think your patient needs to be on Prolia, I think if you're not comfortable doing the osteoanabolics, you should not be comfortable doing the Prolia either. Because I think you would want to do the osteoanabolics first before doing the Prolia. And when you're starting the Prolia, you're really boxing in those patients and reducing their ability to take other medications in the future.

Host: So, let's talk about the osteoanabolic agents. And by that, we are talking about three drugs. Their trade names are Forteo, Tymlos, and Evenity. Their generic names, let's see if I get this right, teriparatide, abaloparatide and romosozumab. You're going to say that much better than I do.

Mona Al Mukaddam, MD, MS: No, no, no, it's fine. You know what? It's great.

Host: Yeah. So, let's say I'm a primary care doc in the middle of rural Pennsylvania, which my brother is by the way. And I have a patient who just comes in with a compression fracture. I do a T-score. I do a DEXA. She's got -3.2 at the spine, and I want to get her out of danger more quickly. So, that's what I'm looking at with these drugs. Which of these are you looking at giving her, and how would you choose between them?

Mona Al Mukaddam, MD, MS: Yeah. So, all right, a couple of things. First, you want to rule out any other causes for a compression fracture. So, sometimes doing an SPEP and UPEP and making sure it's not myeloma and not the pathologic fracture is also very important. And the way I try to explain osteoanabolic therapy for my patients, I say, we have two major ones, just to make it simple in their mind because then it becomes too confusing.

I say we have a daily injection, which is given for two years. And then, we have one which is given as a monthly injection. That's given for 12 months for one year. The daily injections have been around for much longer so that we have a much longer safety profile on those medications. But in someone who's had cancer or someone's had radiation to their bones or has high calcium problems or history of kidney stones, maybe that's not the best medication for them because that medication can increase calcium, can increase risk of calcium in the urine, potentially kidney stones, and is not recommended for patients who've undergone radiation to their bones or at increased risk of having bone cancer. That was based on data in rats. When they were given much higher doses of these daily injections, which are the PTH analogs, they had increased risk of bone cancer. Versus, you know, Evenity, which is the romosozumab, which is given as a monthly injection for 12 months, has been out now for just over six years. So, it was approved in April of 2019. And it still has a box warning regarding cardiovascular problems. So if anyone's had a heart attack or stroke in the year prior, they should not be on this medication.

No one has done a head-to-head comparison, although we do think that maybe romo is a bit stronger than the daily injections. The way I present it to patients is I tell them, "These are the two options and these are the major differences in those medications." And some patients go with, "I want something that's been out there for much longer and it's safer. And it's a daily injection. If I have a side effect, I stop it. It's short-acting. It comes out of my system." And then, I have patients that say, "There's no way I'm going to do a daily injection. I'm so scared of needles. I cannot do this to myself." And they would prefer the monthly coming in every month to get the Evenity. Sometimes insurance dictates which medication we can prescribe because Evenity is still pretty expensive.

And the other factor, and I know we're not talking about men, but Evenity is not approved for men. And so, the daily injections are approved in men versus Evenity is not approved in men. And so, that also might be a deciding factor depending on who the patient is.

But I do offer both, for the most part, if there's no contraindication, either way, I really leave it up to the patients, kind of what their preferences are in terms of which one to do. And it's always very, very important to explain to patients after osteoanabolic therapy, whether it's the monthly injection for a year or daily injection for two years, they have to follow it with an antiresorptive therapy to lock in those gains. I would usually do IV zoledronic acid, Reclast, or if someone has CKD or, I think they're going to be on it for the rest of their life, they're going to be on denosumab.

Host: Just to summarize that when we talking about the paratides, that are daily injections, teriparatide and abaloparatide, so Forteo and Tymlos. Now, we're all kind of living in the GLP age now, right? And our patients are getting more comfortable giving themselves weekly injections. But I imagine it's a little harder sell on a daily injection, especially for a condition where there's a lot of aesthetic gains with weight loss that people perceive, you know, "I want to lose weight, I want to feel better." But with this, you're just sort of preventing the next fracture. It's a little bit of a different sell.

Mona Al Mukaddam, MD, MS: It's harder. Yeah.

Host: Yeah. So, do you have difficulties with that? How big a needle is it? Where do you inject all these things?

Mona Al Mukaddam, MD, MS: Yeah. Absolutely. So, this is so funny because I think I shame people now with telling them it's exactly the same needle that you do with the GLP-1s, right? And so, it's a very small needle. And what I have found to be very helpful is I have pens and needles in my room all the time. I show them the pen, I show them how small the needle is. Most of them cannot even see the needle. And they're like, "Oh, it's that easy," because it's a pen that's prefilled with a medication that you just have to dial up the dose. It's the same BD needles that like type 1 diabetics-- before I used to say, like, type 1 diabetics, those kids that have type 1 diabetes do these injections five to seven times a day. So, that was my first shaming strategy. And now, with the GLP-1s being approved, it's like, "The whole world is on GLP-1s and they're taking these injections. I'm sure you're going to be able to take this." So, those are some of my strategies, not shaming strategies, but some of my strategies to convince patients to do those daily injections.

And the other thing that I do tell patients is I'm here to make your quality of life better. I want to strengthen your bone to decrease your risk of having fractures. And if you feel that this is intolerable, you're having intolerable side effects, whether it's the bony pain or the injection pain, or this is really not compatible with what you would like, you can stop it. That's fine. It's not a problem. But let's try and see.

And so, I think knowing that this medication is extremely short-acting, knowing that, if they really don't like it, they can stop it. And having pharmacy support is actually very helpful to get patients on board and taking the drug. And I've had many patients say, "We're so sorry we gave you so much pushback. This was so easy." But yeah, those are some of the strategies I use.

Host: The point you made earlier is even if they stopped it earlier, you'd want to lock in whatever gains they have with a Reclast infusion, right? Yeah. So, that sounds easy. It sounds like I could do that, right? If I'm prescribing GLPs, I could probably prescribe these drugs as well. And then, let's just talk about Evenity, you said as a monthly injection. Is it given at home or given in the office?

Mona Al Mukaddam, MD, MS: So, the Evenity is an injection under the skin. The dose of the drug cannot be given as one injection, so it's given as two injections at the same time. It's subcutaneous. It has to be administered by a nurse. So, patients can either go to the infusion center. Some of them do it in our office, but they cannot self-administer it themselves. And it's given, yeah, once a month for 12 months. Romosozumab is one of the most interesting agents we have because this is the first-time we have an FDA-approved drug that works as a dual agent. So in the first three to six months, it's stimulating bone formation, and then afterwards it's working as an anti-resorptive agent. It's actually doing both. So, it's both stimulating bone formation and reducing the amount of bone being removed. And we think of it as being the most efficacious drug, because in 12 months only, the bone marrow density in the spine improved by 12%. There's 70% risk of fractures in the spine in 12 months only. So, these are similar numbers to what we see with a daily injection, but over two years instead of 12 months.

The original study that was done to compare this drug to placebo did not see any cardiovascular risk factors, but the drug company wanted to compare it to Fosamax. And so, it was in the study that they did where they had 4,000 women, slightly older than the original study, and they randomized them to half of them getting Evenity and half of them getting Fosamax. And it was in that study that there was an imbalance with the heart attacks and strokes that happened with the patients who received Evenity compared to Fosamax, which was 1.1% in the Fosamax group versus 2% in the Evenity group. That's the data that we have regarding Evenity and cardiovascular problems. And so, that's how they've earned the box warning about do not give it to someone who's had a heart attack or stroke in the year prior. That's the only guidance we have. So, someone's had open heart surgery five years ago, you could still give it. So, it's only people who are having active cardiovascular problems.

Some patients who are older are scared to do that, understandably. They say, "I don't want to have a stroke." I try to kind of explain all of these things to them as we're prescribing Evenity. I personally would be more scared of someone who has a lot of cardiovascular problems or maybe had PE before, DVT, not potentially doing it even though it's not technically contraindicated. It's not approved in men.

And then, the other thing is because it has that quality of bone resorption, it's an anti-resorptive agent. It decreases the amount of bone being removed, the osteonecrosis of the jaw and the atypical femur fractures have been reported with this medication as well, although we think it's going to be less so than with denosumab, which is Prolia, or zoledronic acid, which is Reclast. It does happen with those agents as well.

Host: But you don't see that with the paratides, I'll just say you don't see that with them.

Mona Al Mukaddam, MD, MS: So, we don't see that with teriparatide or abaloparatide. And teriparatide now, they have biosimilars and generics. So, it's not only Forteo, the brand name.

Host: Do you check a DEXA in a year? Is that what you would do when you have somebody on this? I guess C-telopeptide is not as much of an issue because you know that you're putting somebody on an agent that they're taking and prescribing and so forth.

Mona Al Mukaddam, MD, MS: Yeah. Bone markers in osteoanabolic therapy is interesting, because I have a lot of colleagues that do check bone formation markers. I haven't found them to be as helpful because, to me, if it's going to change my management, I will do it. But if it's not going to change my management, I don't do it. And so, I haven't figured out a way how they would change my management. So, I have not been checking bone formation markers, when someone's on osteoanabolic therapy.

Host: Well, this is something that's changed from this discussion for me, because I would've not thought to check C-telopeptide in patients on Fosamax because I thought, "Well, that's what endocrinologists do." But in reality, endocrinologists only check it in patients who are on Fosamax, because you want to make sure that they're getting the medication, right?

Mona Al Mukaddam, MD, MS: Yeah. And that's so provider dependent, I have to say, right? So, this is definitely provider dependent. All the guidelines say consider checking bone markers. But it's not like you have to check bone markers. And so, I think it is definitely provider-dependent. But my thought process is like, "Is it going to affect my management, yes or no?" And if it is, I will do it. And so, I kind of try to provide the rationale as to why I would do those things, because it would affect my management when it comes to oral bisphosphonates.

Host: This has been a great discussion. We're hitting the end of the hour here. I do want to ask you, and didn't give you this heads up on this, but is there anything that you think primary care physicians need to know that you see in your practice? You mentioned some of the dangers about denosumab and some of the things that you see, but is there anything else we're sort of doing wrong that you would like us to stop doing or maybe start doing?

Mona Al Mukaddam, MD, MS: I think you guys do a fantastic job. Honestly, as primary care doctors, I don't know how you're able to manage all these health issues. So, I don't know if I would ever say that you guys are ever doing anything wrong. I'm always amazed by all the things that you are able to do. And yeah, the denosumab is definitely something that I would say please refer to us before you start denosumab.

The second one I think is the risk of fractures and defining osteoporosis if someone's FRAX is high, I think that would be very helpful and something that I am working with as well to if radiology or the DEXA reports can be worked on so that you're able to get these drugs approved. Because I think sometimes what happens if someone has like osteopenia and not osteoporosis, you might have a hard time getting IV zoledronic acid approved or getting a repeat DEXA approved. And so, as per our ACE guidelines, you can define patients as having osteoporosis based on high-risk of fractures.

And so, I think that one is important too. For practical reasons, it's important for you guys to know because I think it'll help you with kind of insurance approvals and monitoring of your patients when you're reframing this and saying, "Oh, they do have osteoporosis."

Host: Yeah. And historically, I think some of us are a little less comfortable defining osteoporosis by FRAX scores. It is just easier to look at a number and say, "Oh, you're there" or "You're not there." But to the point you made earlier in the podcast, this is all about fracture reduction. And that's what the FRAX score is telling you, right?

And there's also this data that suggests patients who are osteopenic, who get just one dose of Reclast, do better. That maybe somebody who's in that sort of borderline and has a FRAX score that suggests that they're at increased risk or their osteoporotic could just do that for now, and then go from there.

Mona Al Mukaddam, MD, MS: So, I don't know if in terms of like reminders, so the FRAX, you put in the calculator and gives you two numbers. And it tells you what is the 10-year risk of having a hip fracture. And if that's more than the 3%, that's high. And major osteoporotic fracture, if it's 20% or more, that's high. So, 20% and 3%.

Host: Yeah. And I'm always trying to remind myself of that when I look at my DEXA scan, I'm looking for 3s and 20s, you know, the threshold's there.

Mona Al Mukaddam, MD, MS: It's hard. It's hard. It's a lot for you guys. It's really hard for you guys to do all of these things. And so, hopefully, we can help out more in creating more pathways and more reminders and better access as well.

Host: Well, Mona, this has been great. And so if I ever do find myself plopped down in the middle of rural Alaska and I have to manage osteoporosis on my own, I actually feel much more qualified than I did an hour ago. So, this has been a great discussion.

Mona Al Mukaddam, MD, MS: Absolutely. Thank you so much for having me. This is always so much fun. And, yeah, I'm always around if you need any help. Thank you.

Host: With that, I want to thank Mona for joining us formally, and then also thank the audience for joining us, and please come again next time.