The Advanced Practitioner's Role in Managing Bone Health in Patients With Cancer

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Welcome everyone to this virtual roundtable about bone health and oncology for advanced practitioners. This is a case-based approach, and I'm Carrie Tompkins Stricker. I am an associate professor of nursing at the Thomas Jefferson University in Philadelphia, Pennsylvania, and an oncology nurse practitioner with over 25 years of experience caring for individuals with cancer. Joining me today are three of my colleagues. We have a very representative group: a physician and two other advanced practitioners in addition to myself. I'd like to begin with allowing Dr. Paul Sieber to introduce himself.

Paul Sieber, MD:

Morning. Paul Sieber. I'm a urologist in Lancaster, Pennsylvania, and I function in my group as the advanced prostate cancer chairman.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks Paul. And next I'd like to have Christine introduce herself.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Hi everyone. My name's Christine Cambareri. I am an outpatient oncology pharmacy specialist practicing at the University of Pennsylvania, focusing on solid tumors.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

And last but not least, we have Saneese. Saneese, go ahead.

Saneese Stephen, MPAS, PA-C

Hello everyone. Thanks for inviting me. My name is Saneese Stephen. I've been a physician assistant at MD Anderson for the past 10 years, working in GU medical oncology.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

So just some background, which is probably familiar to many of you on this lecture and recording. We all treat cancer, right? Well, its treatment and the cancer itself can contribute to compromised bone health, leading to painful fractures and loss of mobility that ultimately impairs quality of life. Certain types of cancer have a very predictable pattern of spread to bone. Some of these are those you've heard mentioned already by our speakers. Prostate cancer, breast cancer, and multiple myeloma are among the top. So skeletal-related events, or SREs as we'll refer to them…what are they? Bone metastases most frequently affect the axial skeleton and often cause skeletal complications that are known as these SREs or skeletal-related events.

What are they? Well, they're the fractures, as we've already mentioned. Radiotherapy to the bone is actually also considered an SRE. So is surgery. So is spinal cord compression, and so as hypercalcemia. These events are associated with significant loss of mobility, loss of function, reduced quality of life, increased healthcare expenditures and worse survival. All outcomes we as care providers of individuals with cancer wish to avoid on behalf of our patients.

In prostate and breast cancers in particular, we have to consider the hormonal context and why these individuals are already at great risk of bone loss and bone events themselves even prior to metastatic disease. So why is that? I'll talk a little bit about breast cancer, and then I'm going to hand it off for Saneese to talk a little bit about prostate.

In breast cancer, estrogens play a crucial role. Well, where else do estrogens play a crucial role? In bone growth maturation and maintenance of skeletal integrity. The net action of estrogens on bone is to decrease bone resorption, to drop bone resorption. There are estrogen receptors in the bones expressed on osteoblasts that builds bone, and osteoclasts, which break down bone. And when we interfere with estrogen receptors and we interfere with the effects of estrogen by treating breast cancer, we also put the bone at risk.

I'm going to pass it off to Saneese now. He'll tell you a little bit about prostate cancer and bone loss.

Saneese Stephen, MPAS, PA-C:

Thanks, Carrie. Very similarly to breast cancer, estrogen is also important in men. Many people realize that testosterone is our primary hormone, but testosterone is converted to estradiol via aromatase activity in peripheral tissues. And estradiol becomes a primary estrogen in men and it's involved in bone resorption […], like Carrie mentioned.

So when we're decreasing testosterone, it's multiple ways affecting bone density and bone strength in men. That's why you see testosterone-depleting therapy cause four times as much loss in bone integrity and bone health in people who are taking androgen deprivation therapy. So it's very complicated dynamics between bone health and prevention of bone deteriorating medications. So I think it's important to talk more about it, as we will later on. It's important to note that AR and ER, androgen receptors and estrogen receptors interact with osteoblastic precursors, as Carrie mentioned, and we have significant deleterious effect from androgen receptor drugs, such as Xtandi (enzalutamide), which you'll hear later in one of our cases. But I'll talk more about this as we discuss the cases upcoming.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thank you, Saneese. One thing that's important to note in considering differential diagnosis is that metastatic involvement of the skeleton, both axial and appendicular, typically affects sites across both axial and appendicular and causes pain and bony tenderness, whether subjectively experienced tenderness and/or upon palpation in really acute bone disease or fracture.

There are a variety of clinical practice guidelines addressing diagnosis and treatment of bone mets and prevention of SREs. These include ESMO and ASCO. ESMO is the European Society of Medical Oncology. ASCO is the American Society of Clinical Oncology, and the latter, ASCO, particularly has guidelines in breast cancer, whereas ESMO'S clinical practice guidelines cover all cancers with bone metastases or bony involvement like multiple myeloma.

So what do these address? ESMO talks about imaging and biopsy recommendations that vary by disease. CT and MRI are recommended typically in myeloma. In solid tumors, bone scans are traditionally used for bone mets evaluation in solid tumors, but there has been a huge increase in the use, appropriately, of PET scan. PSMA scans sometimes also have a role in staging for specific situations in solid tumors and FDG PET CT imaging is particularly valuable in addressing early evaluation of response.

You will see on your slide a comparison of the ASCO guidelines that I mentioned for the role of BMAs or bone-modifying agents in metastatic breast cancer compared to bone health ESMO, the European guidelines. And what they currently state in terms of initiation of therapy once bone mets are diagnosed, is that all metastatic breast cancer with evidence of bone mets should be treated with BMAs. However, there's no evidence to initiate these BMAs or bone-targeted agents in patients who don't have evidence of bone destruction. They don't take a stand on preference of one bone modifying agent or the other. The same is true with ESMO, who states that BMAs should be initiated at diagnosis of bone mets and considered throughout the course of disease.

Paul Sieber, MD:

So this is what I've described as kind of the classic patient we're seeing these days. And it's interesting, the evolution of prostate cancer, particularly in the era, at least in my location where the USPSTF's guidelines suggest we don't even screen for it anymore. So we're seeing more and more aggressive cancer diagnosis. And this guy is kind of a case in point that also leads to his bone health questions. So this would be a classic 72-year-old gentlemen who underwent a radical prostatectomy some years ago in the mid 2000s here or 2000 teens. And as many of our patients, unfortunately, they're presenting with more advanced disease. And he suffered a biochemical recurrence within a couple of years after surgery, not an uncommon event. Still in the urologist’s court, though, in terms of management at this point in time.

So the decision was made, which is typical for our practice, he's going to receive at that point, salvage radiation therapy, which is no longer…at least at this point a semi-adjuvant treatment, and a short course of androgen deprivation therapy. In our practice, to start to get the ball rolling he would have been first introduced to our androgen deprivation clinic, which I have the pleasure of having had a nurse practitioner I've worked with now for over 20 years who's the lead person who's part of our team and managing both androgen deprivation and bone health.

So he would have gotten the short course of androgen deprivation therapy, and 6 months is kind of critical because it is a point where he's just starting to diverge from the average. That is, his overall increased risks associated with that are just starting to change at 6 months. So that's based on an article that came out actually about 15 years ago, one of the first articles. It was a New England Journal article, actually, looking at a large CR database that says, "Hey, 6 months is about the time frame when androgen deprivation therapy starts to matter in men," and you start to see the graphs of those patients who are treated with androgen deprivation diverge from those who are not.

But he putzed along, and within a couple of years he's got biochemical recurrence again. And I put down 6 months, meaning, hmmm…he's got our attention, this is a rapid progressor. And we're probably going to think about, or the anxiety will push us to potentially do something at that point in time. And we resume his androgen deprivation therapy. So he's reintroduced to the clinic, a DEXA scan is done, which is part and parcel of what our routine is in that clinic, and it shows osteopenia. So that leads to what's the next step. Carrie?

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks, Paul. So what is the next step? I think we can have a robust discussion about this. You emphasized some of the key contextual factors here, and you also laid the foundation for a discussion in talking about how his pace of disease has seemed to accelerate here with that PSA doubling time and he does have some bone health risk factors in terms of this osteopenia. He has still what we call at this point castration sensitive prostate cancer. He's still sensitive to hormones. So I'm going to ask you first, Dr. Sieber. What would you do in this situation, since you presented him? Share your side of the story.

Paul Sieber, MD:

Well, in our practice, we have our own protocols set up. And it actually goes back to the fact that managing bone health is not something that's been around forever. While I was looking at zoledronic acid and denosumab, we're only in the roughly 2000 era. And at that time, since I was involved in all those clinical trials, my partners were naive. So it became apparent that even if they would get a DEXA scan and we start off with looking at calcium and vitamin D. And living here in the north, people are very prone to having low levels of vitamin D. So it's routine for us to measure vitamin D, and it's routine for us to have a discussion about calcium. Some of the earlier recommendations from the AUA suggested though, just give them a calcium supplement. Well, that supplement is indicated when they don't meet the National Osteoporosis Foundation guidelines for how much calcium intake they need. So there's no benefit to give them excess of calcium.

So we start with the discussion about their diet. We start off with a discussion about their vitamin D. We start off with a discussion about simple things, like I call childproofing your house. Getting the thought process. You don't want to have a throw rug. Do you have nightlights? You need to make some lifestyle adjustments, and that's down there under fall prevention. And that's again, fall into having a protocol in place that, again, we're discussing on a routine basis. The question about pharmacologic manipulation becomes a little more complex. This gentleman is a...I call them a tweener. Yeah. He doesn't have frank osteoporosis, which clearly gets into the point where he must have manipulation. There's data suggesting he's at risk. So it's kind of a risk/benefit, at least the discussion with this particular gentleman about where he is. And I think it's a little helpful also to dwell on things like family history. And we tend to aggressively look at the FRAX score to also get an idea besides just bone density.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Excellent points. Just to follow up on some of them before putting this out there for further discussion, the FRAX or F-R-A-X score is a tool that can be used to evaluate risk of...guess what? Fracture. So many of us use that in practice to assess risk. Christine, do you want to add anything to this discussion from your experience at University of Pennsylvania?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Sure. Thank you, Carrie. I would way agree with everything that's already been presented, but an area where I've intervened before is simply in just optimizing the calcium and vitamin D management. Oftentimes you tell patients just start calcium, vitamin D, and that aisle in the grocery store, or even that webpage on Amazon, is overwhelming when you search for that. And helping guide patients too. There are different salt forms of calcium and what the right amount would be.

But also I think the bigger take-home point where I've definitely intervened within the prostate cancer population is talking with patients about “more is not always better.” Your body can only absorb a certain amount at a time. And actually it's recommended that you divide the doses throughout the day for optimal absorption for the calcium. And so that small little tidbit can go a long way with them optimizing what they're doing at home. I always hate for people to buy these supplements and products and not take them correctly to not get their biggest bang for their buck, so to speak, especially when it comes to this simple intervention in addition to diet and lifestyle recommendations for their bone health.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thank you for that. And if I may, a follow-up question for you: As a PharmD and an oncology pharmacist, how do you get access to these patients? What is the role of the advanced practice provider here with respect to education, and how do you integrate that into practice?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

My role as a clinical oncology pharmacy specialist is to sit shoulder to shoulder with oncology providers, physicians, physician assistants, and nurse practitioners, and even shoulder to shoulder with our infusion nurses as well as we see these patients come through clinic for management of their various cancers. Supporting the role of answering drug information questions, helping with chemotherapy order entry and facilitation, counseling patients, getting a lot of supportive care. So my experience with bone health has been more around supportive care management, pain management, finding the right supplements, talking about which supplements are safe in the context of a patient's cancer and chemotherapy, and also optimizing the ones that are available for them to purchase and buy, and even helping them identify which would be the right one for them.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such excellent points, and really emphasizes the role of the multidisciplinary team here and advanced practice providers in particular, in promoting bone health, doing so holistically and in a way that helps to ensure adherence.

So now our gentlemen has developed biochemical recurrence. Again, it's the end of 2020. His PSA doubling time is still 6 months and PSA is only 1.6, but he's rising on ADT with a testosterone level less than 20. Dr. Sieber, why don't you take the discussion of the case over from here, including imaging and context? And then we'll discuss.

Paul Sieber, MD:

So imaging level, let's start with the last one first. You're making my life difficult. So that's suddenly exploding in our world because the world of PET imaging is taking off with the approval of the PSMA agents. And that's going to continue to evolve as there's two more on the wings that will be approved over the next few months, it would appear. So the idea of this gentleman having nonmetastatic disease at a rising PSA with rapid doubling time is sort of controversial because he probably has mets, we just can't see it. And he may slowly start to disappear. But regardless, let's assume even if he did have a scan and you see a single solitary little lesion, the thought process may be well the same that you're going to think about giving him enzalutamide. And we'll pick on the fact his imaging showed a metastasis, or even if you would argue he has a small lymph node that you had noticed somewhere that you wouldn't have seen on traditional imaging. We're still going to recommend enzalutamide.So a repeat DEXA, yes. For certain. It's been a couple of years since he has had his last DEXA. Let's assume he's still osteopenic, but he's gone from minus 1.6 to minus 2.3, not yet osteoporotic, but significant decline. That's going to get me excited. We're going to reemphasize, how are you doing with your vitamin D? Are you really taking it? We'll recheck his levels. And at this point we're certainly going to add a pharmacologic manipulation because I think this gentleman has significant risk. He's got bone loss, he's got a new drug that causes falls. He's got a new drug that introduces fracture risks. So for all those reasons, we're going to look at that. And we'll probably think about his DEXA mostly just to assess stability over time, just to see where he is, to see what would his rate of fall was. Because again, it starts to add to the concerns about where we're going with this gentlemen.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

All really great points. Saneese, want to add anything to the discussion or talk about how things might look different?

Saneese Stephen, MPAS, PA-C:

Absolutely. I agree, the case has progressed now to becoming castrate resistant disease requiring enzalutamide or another agent in terms of therapy prevention of bone metastasis or other metastasis. So a very interesting point. The enzalutamide in phase 2 trials when they looked at in monotherapy, they did not find evidence of bone density loss from enzalutamide as monotherapy. But in combination with ADT and with PROSPER trial, for instance, that looked at nonmetastatic castrate-resistant disease using enzalutamide, there was an 18% risk of fractures. So I agree with Dr. Sieber, that the patient is getting a higher risk of fractures, and a FRAX score would also help in this assessment. If we were continuing this patient on treatment, it would be with a bone targeted agent at this point. And we would not choose monthly dose at this point in terms of monthly one target medication, but still stick to the q6mo or annual dose.

People are living longer with our novel hormonal agents and introducing a monthly dose at this point may submit them for years and years of treatment. And the treatments that have of course side effects so let's get into later in the case. But of course, we're very cognizant about the complications of fractures and skeletal-related events. So there's no cookie cutter approach. You have to risk-assess each patient for their risk factors and what their goals are and their challenges are in terms of doing monthly therapy versus less frequent therapies. And following them very closely. I think it requires a multi-team approach and a discussion with the patient and working closely and finding what's the best fit for them. But in terms of preventing bone health complications, I agree at this point, we definitely need to start a pharmacologic agent.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such important points. Christine, do you want to add any additional context or points of difference in this case?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Thanks, Carrie. No, I don't have points of difference, but I would say my function also is a lot is to perform education when patients are starting enzalutamide therapy, for example. And I do heavily counsel on the fall risk and kind of reassessing, as Dr. Sieber said, “childproofing” patient's homes and asking how many of these patients are oftentimes getting up at night to use the bathroom or facilities, be it because of their prostate cancer and/or the enzalutamide therapy itself can cause some GI upset and saying, "How close is your bathroom?" or, "Do you wear socks when you go to sleep or you put slippers on, what's in the way? Is there a dog at the foot of your bed?" Kind of reemphasizing this risk for falls and helping them for oversolve for safety before. It's something that we never want, that phone call or that message, "Patient had a fall and is in the hospital” because of something that we could have done to prevent. And so again, I do spend a lot of time focusing on that. I've even had patients saying, "Why are we talking about this? Let's talk about the drug." And so again, those simple things that play a huge role that are necessarily non-pharmacologic in the role of how we can help these patients with their bone health.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such an incredibly important reminder of those fine points and how important education and holistic management are. Before we move off this part of the case, I just want to go back to two points for clarification and education. One is when Saneese, you talked about every-6-month or annual dosing, the intent there is not that you're at this point using doses and schedules of bone-targeted agents as indicated for bone metastases, but rather for bone density management. Correct?

Saneese Stephen, MPAS, PA-C:

Correct. So these are preventive doses. So and a very interesting point that we didn't follow up on what Dr. Sieber mentioned before, with PSMA scans and other more sensitive scans, we may be identifying bone metastases a lot earlier. However, the data for survival is based on prior scans that were used to deal with bone scans, CAT scans, etc. And so far, we have not had any prospective improvement in survival data or skeletal events from targeting patients in this situation early on in continuous bone therapy. So we're really kind of separating out what we have in terms of existing data, with what we potentially can make from future studies on things like PSMA they'll identify a lot earlier. But the point was to do preventive treatment as the National Osteporosis Foundation recommends for patients with osteoporosis or with osteopenia and risk factors. And he certainly has risk factors now with this therapies. So we would at this point do 6-month or yearly treatments.

And the other point that you mentioned about bone metastases, the patient may have it or may not have it. And in our practice with metastatic disease, we would sometimes not start therapy right away, or start it if the patient has active disease after getting some treatments, especially if they're getting SBRT or some other radiotherapy or cryoablation to bone disease. He may not have any active disease that requires treatment. But again, it's what we see. As was mentioned before, there may be other lesions that we're just not seeing, but again, it's hard to make a quantification of the risk factor because all the risk factor studies are done from previous scans.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Let's actually progress this case a bit now then, and take it to the scenario you just mentioned. Let's consider this alternative scenario where at the end of 2020, let's say his PSA doubling time has accelerated, maybe even to 3 months. His PSA is 6.8. Testosterone is still less than 20 on androgen deprivation therapy. But in this case, imaging now shows limited axial bone mets, but he has no pain in the sites of bony mets. I'm going to toss it back to you to talk about just what you were saying. What might you do in the presence of limited bone mets, and why you're doing that? Either you, or one of the other panel members, we've mentioned PSMA a couple of times now. Let's just make sure we orient the audience to what that is and the importance of that in a diagnosis.

Saneese Stephen, MPAS, PA-C:

Okay. So you have patients with bone mets who may have still hormone sensitive disease, and you may have as this patient, he may be developing or has developed already castrate resistant disease and subsequent bone mets. So there's two different buckets here. We have two different patients that we treat very differently. So there are some recommendations from some groups.

Patient starting with bone mets, with some type of bone agent that they've also noted, not necessarily for castrate sensitive disease. And that's based on a couple of different trials. We have actually a STAMPEDE trial that led to the approval of docetaxel as upfront therapy. And they looked at over 2,900 patients and put them in different arms. One of the arms with Zometa, a bisphosphonate with standard of care. Also, Zometa/docetaxel and standard of care by self. Overall, studies showed that Zometa with standard of care, or Zometa with chemotherapy had no improvement in survival skeletal risk factor development, or progression failure free survival in terms of a disease in bone, in patients who had bone metastases, or were high risk at developing bone metastases.

So this is the hormone-sensitive group. There's also a trial from JCO by Matthew and group and they looked at about 600 patients. And they also looked at patients on ADT and bone mets and compared a Zometa group versus a non-Zometa placebo group. And they also found no benefit in survival, SRE, or failure-free survival in these patients, in hormone sensitive disease with bone mets.

So we're very cautious about starting people on continuous therapy. Once they start these agents they generally continue on indefinitely in some cases on the right setting. So in the hormone sensitive setting bone mets we still do not start a bone targeted agent. But if they become castrate resistant, which this patient is also at this point developing, we would start medications to further minimize the risk of bone related injuries or falls and complications.

But I think based on these trials important to look at the patient separately in context, and not all patients fit the trial patient. So everybody's situation is different. If they have a family history of fractures and advancing age and other risk factors that we know put them more at risk, we may want to start something more and more frequently. So it takes a discussion with the physician, with the pharmacist, with the patient of course, and the family, before we come to a decision-making point.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thank you. So I'm going to open this up to the panel. Any key points you want to make in terms of management of this gentleman now that he is castration resistant and still has the same report in context, in terms of bone loss, that we talked extensively about earlier?

Paul Sieber, MD:

I think this guy highlights, hey, he needs bone targeted treatment for his osteoporosis, or significant bone loss, but maybe not for his cancer. Then we move to the fact that he's got limited metastasis. And as Saneese says, we worry a little bit about cumulative toxicity to these drugs. So if we look at the original trials, the old trials, the ones that I was involved with 20 years ago, those guys had significant burden of disease. And with better imaging we're finding limited disease. So does this guy justify--and it's never ever been risk stratified--does he justify a high dose of treatment now? Monthly zoledronic acid, or at least quarterly, or monthly denosumab? That's a question mark that goes back to what we've talked about earlier. The art of the game.

And I might take a guy like this who has limited actually metastasis who's on treatment, and let's just say, he's on denosumab every six months, and I'll look at a bone turnover marker. And it's easy for me to do because we use urine N-telopeptide, and I'm a urologist. So guess what? Everyone that walks in my office, the first thing they do is they go to the bathroom and give us a urine sample. So I use that frequently. So if this guy doesn't normalize, I'm looking for a below 50 in my lab for N-telopeptide. I may think about, maybe his cancer is more progressive than I thought was otherwise happening, and I'm going to adjust my course for this guy.

That's probably not a likely scenario, but it does occasionally happen. Or even if you're watching him and he doesn't seem to be progressing otherwise, I will occasionally look at serial N-telopeptide to see if this guy's going up on his N-telopeptide that I may want to introduce the idea of, we need more of an SRE bone treatment versus an osteoporosis treatment. So I think it's kind of, it's a little catchy there because the prostate world, and again as Saneese said, there's a difference between castrate resistant and castrate sensitive. And in the castrate-sensitive state now, especially with our newer agents, we can keep people non-metastatic for some years, these days, especially with traditional imaging.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thank you. Again, the context of how improved survival with all the primary agents we have to treat the primary cancer itself, how that affects the context of supportive care decisions is so crucial in this case of bone health. How does that play out in your world, Christine, with your role as an oncology pharmacist? And is there anything you want to add to management of this case as well?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

So to your point exactly, Carrie, we are blessed to be in situations now where patients are living so much longer, and it may not even be on a lot of active treatment, or very intensive treatment for their cancers, but we are managing some of these long-term effects, bone health being one of them. Within the prostate cancer population there are other comorbidities that kind of pop up because of what we do to them to manage their disease, bone health being one of the bigger ones and kind of making sure that patients continue to get the appropriate imaging and measuring of appropriate biomarkers if that's what's being followed. And continuing on therapies, I think we often see this in breast as well, which I know we're going to talk about. If patients are feeling good a lot of the time it's easy for some of those other long-term supportive care things to fall off.

As we're learning, as we have longer and longer survivors of metastatic disease, that some of these other non cancer-related symptoms and management of it has long-term impacts that we're finding are impacting overall survival as well. So I think it's important to not minimize that and important to begin that conversation early in someone's diagnosis and be on top of it. Kind of like we've been talking throughout this case, that it is the conversation about minimizing fall risks and optimizing nutrition, diet and exercise as a patient is able. And so that's kind of honed in and zeroed in from day one, and continued for these patients that we are having as long-term survivors with advanced disease.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Well, that brings us to really closing out this case with a discussion of duration. As we are stating here, patients with prostate cancer, including castration resistant, and patients with metastatic breast cancer, are projected to live significantly longer than what we used to quote as 2 or so years due to novel treatments. So making the importance of this duration discussion of bone modifying agents is a crucial discussion point. A recent study just published in 2021 is the first systematic review summarizing the available data on efficacy and toxicity of bone modifying agents after two or more years of exposure. And that'll be in your references, audience listening today. This included three prospective and nine retrospective studies that looked at side effects and adverse events. We're going to get into these in our next breast cancer case.

So reported incidence of ONJ was 1% to 2% in the first two years, but then rose after that. So it rose a bit after two years ranging from 5.3, to in some series as high as 20 over 20% of ONJ, which is osteonecrosis of the jaw. Rates of hypocalcemia were as high as 14.4% in denosumab, but clinically significant hypocalcemia was much, much, much less. Highly uncommon ranging from one to 2%. Nonetheless, we're going to integrate these concepts into our next case in breast cancer.

And incidents of severe decline in renal function was 3% or less. These all emphasize the importance of having discussions of duration. So as Moe says that BMA should normally continue indefinitely including into the hospice setting. Although they do note that treatment may be interrupted for folks with good prognostic features such as oligometastatic disease, a perceived risk of bone complications and durable response to their primary cancer treatment, their systemic treatment.

Some other things that are important to consider, denosumab in particular, when discontinued, you'll have rebound. We've seen bone resorption. And recent evidence suggests that vertebral fracture risks could quickly return to pre-treatment levels. And so that has led to ESMO guidelines recommending that if denosumab is stopped for more than 6 months, we should be suppressing that rebound bone breakdown or osteolysis with this phosphonate treatment during that period of time. Now some of the limitations of the studies are that they were in a non-cancer population in terms of this bone resorption, but we often, in clinical practice, have to apply learnings from outside our very particularized domain of clinical decision-making, to make informed decisions in our patient population.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

In this next segment, we are going to talk more about duration, and we're going to talk about those AEs that we didn't yet address in the prostate case, but we're going to move into a breast cancer case as context for this discussion. In this segment, we will be diving further into some of the AEs, or adverse events, associated with the use of bone-modifying agents. Christine will introduce our next patient, a woman with breast cancer. Go ahead, Christine.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Thanks, Carrie. So building upon what we've already talked about today, I'm going to introduce patient M.S. She is a 58-year-old female who was originally diagnosed at age 55 in 2016 with post-menopausal stage 2B invasive ductal breast cancer. Her disease was node positive, estrogen and progesterone receptor positive, and HER2 negative. Her comorbidities include type 2 diabetes, managed with metformin only, as well as hypertension, for which she's on hydrochlorothiazide and lisinopril. In the fall of 2016, she was treated with Taxotere and Cytoxan for four cycles followed by daily letrozole for her hormone positive breast cancer. At the time of initiation of adjuvant hormonal therapy, in January of 2017, she had a DEXA scan which showed normal to mildly osteopenic bone mineral density. Subsequently in January of 2019, she presented for routine follow-up to her medical oncologist reporting mild pain in her central chest, her breastbone area, that she began noticing prior to the Thanksgiving holiday weekend after she had been moving around furniture in preparation for hosting guests at her home.

The pain was mild and intermittent, but progressed and became constant. Imaging was done based on the symptoms she was submitting to the medical oncologist and chest x-ray and plain films of the sternum showed a lytic lesion occupying more than half of the surface area of the sternum with moderate bony destruction. A follow-up bone scan that was prompted because of the chest x-ray plain film showed diffuse uptake in the sternum, but fails to reveal any other site of bone metastasis. CT scans of the chest, abdomen, and DEXA scan show a 4% decline in bone mineral density of the L spine over the last 2 years.

Her T-score is now -1.9, and in the right hip, her T-score is -1.3, with the associated decline of 3%. looking at her labs in conjunction with what her imaging had shown, we saw normal CBC with differential and platelets, normal liver function tests, except for elevated alk phos of 172. Her serum creatinine is 1.5 milligrams per deciliter, which correlates to a creatinine clearance of 51. Her calcium and electrolytes are within normal limits. At this point, based on these updated imaging and patient symptoms, her medical oncologist starts her on fulvestrant, 500 milligrams intramuscularly, a systemic therapy for her metastatic disease with a loading dose every 2 weeks for 1 month, and then continued monthly dosing. And I'll hand the case back over to Carrie now.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks, Christine. So this is a kind of case I've seen many times in my practice as an oncology nurse practitioner. This is a postmenopausal woman who a couple years after early diagnosis or diagnosis rather than early stage breast cancer has now recurred with her hormone-sensitive breast cancer. She already comes into that recurrence with some bone loss from aging and from her own treatment with an aromatase inhibitor, which robs the bone of estrogen. She also has some critical comorbidity context to consider when initiating treatment for bone loss prevention or prevention of skeletal-related events. You know, what is that? Well, she is on some hypertensive meds. She has a long history of hypertension and she has some renal insufficiency and she has bony destruction. So she does, although she only has limited bony disease in the sternum alone, she has bony destruction there.

So we've got to see her serum creatinine already of 1.5, as you said, and she's going on another agent Faslodex or fulvestrant. That is going to further rob her bones of the estrogen needed to maintain mass. So I'd certainly be doing another DEXA scan in this case to see where she is. I'd certainly be making sure she's still on her calcium and vitamin D. We've talked extensively about those issues so I'm not going to go into them more here. I would monitor her DEXA, probably yearly.

I'd be looking at x-rays and bone scans or PET scans every three months while on treatment. We've already talked about what that treatment would be. And in my case, she's got lytic disease. I mean, neither ESMO nor ASCO guidelines would refute that she needs to start at this point, even though it's only in a solitary location. I'm curious if your colleagues at Penn, whom I know you spoke with about this case, had a different take on it. You know, would they consider radiotherapy here in addition to bone modifying agents? What were the discussions you had about dosing and schedule with them? Where or how are you factoring in the fact that she has renal insufficiency in making decisions about therapy? Tell me a little bit more about what they had to say.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Sure. And so to comment on other management of where this disease was with the single site, a few of the providers that I spoke with said that they would consider radiation oncology, certainly a consult to get an opinion on if it's something that would be worth doing and allowing the patient to be involved in that decision making. But almost everybody said that they would be starting a bone modifying agent. And when I probed on, so which one would you use? there was heavy discussion around there's not necessarily a preference, but where people feel like their hands are tied or they're driven one way or another to choose zoledronic acid over denosumab sometimes unfortunately is insurance driven. But in this situation, when we were talking about where the patient's creatinine clearance fell, she was on the cusp of what I recommend the limits are.

We want to be above 60 mils per minute for creatinine clearance for using zoledronic acid. And so a lot of the providers that I spoke with and myself included would feel like we would recommend starting Xgeva, 120 milligrams monthly for a period of 2 years for this patient. I think another thing that is important before initiating any kind of bone modifying agent therapy, which will come into play when we talk a little bit more about the AEs later on for osteonecrosis of the jaw prevention is assessing what this patient's dental status is as well. And seeing if she seen a dentist or has a history of significant dental co-morbidities that either need to be handled preemptively or where we're at to make sure that we can, again, have that level-setting conversation for side effects that can occur with initiating these kinds of therapies, especially for a 2-year period, which is what we are potentially starting her up to do.

I think the role for radiation therapy also came into play with this oligometastatic site is painful to the patient. And so how offering something like radiotherapy could help the patient's pain over time and support with using things like nonsteroidal anti-inflammatories and steroids, if that's appropriate based on her risk factors, which it looks like. I don't know if I would necessarily push a lot of the NSAID use like she said, she was already doing just because of where her serum creatinine is. And because her kidneys are already taxed with her history of chronic hypertension and being on those medicines. So it's definitely a balance of how to offer her symptomatic relief while preserving target end organ function, while getting some of these other therapies on board for her.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such a great case. It really allows us to discuss so many contextual factors here. And while Dr. Sieber, you and Saneese particularly at the moment specialize in GU malignancies, I think there are many aspects of this case that you could comment on in terms of at this time point of initiating therapy. And in this case, the choice seems to lead more towards denosumab because of her renal insufficiency. What else would you add? Like what else do we need to be thinking about even with denosumab and renal insufficiency in terms of supportive care management? Saneese, do you want to take that one on?

Saneese Stephen, MPAS, PA-C:

Sure. I know there's not great recommendations on which DTA to start. So I'll comment on that first a little bit. There's been several trials that in multiple myeloma, also on breast cancer and prostate cancer, where they compared head to head denosumab versus zoledronic acid. And denosumab seems to have a superior efficacy in terms of preventing the first skeletal related event. And they actually combined all three cases and a meta-analysis several years ago, and also found the benefit overall was with denosumab. But regardless there's not a recommendation to start a specific bone target agent. That decision really weighs on multiple factors, including potential side effects and renal function. Zoledronic acid has acute phase symptoms with myalgias and fever that you don't see as much with denosumab. The renal function is certainly a big issue and we have to renal dose the zometa based on the creatinine clearance, which you don't so much with denosumab.

We still check renal function with denosumab, even though it's not metabolized by the kidney. There's a higher risk of hypercalcemia and hyperphosphatemia once the renal function is diminished, even with denosumab. So that kind of gets into the caveat of how to dose and when to monitor and would monitor and treat hypocalcemia and hypophosphatemia prior to giving monthly or regular denosumab injections. The other point is duration. I think duration, and I think in this breast cancer patient, you mentioned 2 years of denosumab, you know, the trials that looked at duration with previous bone targeted agents with Zometa was very different terms of, as you know Zometa, zoledronic acid, is actually incorporated into the bone matrix, and it can have long standing work even after you stop it in 2 years. It's a very different mechanism, as you know, for denosumab, which is a monoclonal antibody.

And there's the limitation on duration is not as clear with denosumab. And as Christine mentioned, there's also the potential of side effects once you discontinue denosumab. So in a way you're almost married to the drug when you start it. You're kind of giving it indefinitely, I think in many cases, because of the rebound osteolysis and potentially vertebral fracture risk. You're giving it pretty much lifelong. I don't necessarily think we would be giving it in the hospice setting. I think because of the cost factor, even though that's more recommended, considering the hospice setting, I don't see how that's logistically possible because of cost issues and continuing therapy of that nature and hospice would not be reasonable. But I'll stop there. And you know, maybe Dr. Sieber can pick up on the other comments.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Yeah. Particularly duration, we're going to take our case into hypocalcemia and ONJ, so if you could briefly comment Dr. Sieber on duration issues?

Paul Sieber, MD:

Well, I think without a doubt duration is a problem. And then that's why I think in my space, in the castrate resistant prostate cancer space, that's why, and Saneese said the same thing earlier, we try to be a little cautious up front, but you have to still deal with osteoporosis. So that's the dilemma. And in this case we're going to make this abrupt change here at 2 years. Well, what if the lady's osteoporotic now? So you can tell an osteoporotic, we're not going to treat you? We're just going to take our chances because the agents, whether it's zoledronic acid or denosumab, stabilize bone loss. There's a modest improvement of bone density. But if you have a significant osteoporotic, they're not going to suddenly be normal. They're going to be a little less osteoporotic at least by their T-score. So I think you're still having, again, a lot of breast cancer patients running around for a lot of years, they still have bone health issues. So it kind of complicates things a bit. I think you have to pay extra attention to her oral care. You have to pay extra attention to maybe we're going to have to at some point stop, but I don't think you can get away with ignoring what we do with our long-term bone health.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such good points. So hypocalcemia, one thing just to be super clear about in the use of denosumab is that while it can be used at the same dose, even in renal insufficiency, the issue is that it does increase the risk for hypocalcemia in that scenario. We are going to be extra cautious about ensuring that the patient is taking calcium supplementation on top of whatever dietary amount she's getting. And we're going to be monitoring calcium regularly. You know, we had carried this case further through to talk about her presenting to clinic with symptoms of hypocalcemia. And I'm going to abbreviate that here and say she had come in feeling a little dizzy with some tingling in her extremities. She had a cold in her household and essentially what we find out is that due to her symptoms, she had stopped her calcium vitamin D because she was taking so many other things for her cold.

And so her calcium showed that she was hypocalcemic with a normal albumin. She had a calcium level of 6.3 and it had been 9. So also she had worsened from a creatine clearance of 51 to around 30 due to her recent viral and illness causing dehydration. So that's sort of the perfect storm of where hypocalcemia could manifest. And in her case then we held her Xgeva that day, encouraged her to resume her calcium and vitamin D along with oral hydration at home, and gave her infusion of fluids in clinic. So, Christine, do you want to round that out, that case in terms of just following up to make sure she gets back to where she needs to be, etc.?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Sure. And so like Carrie mentioned, this is the perfect storm and situations I've definitely been involved with where it's easy for some of the other therapies to fall off. I think offering immediate supportive care to kind of quote unquote tank the patient back up with hydration, if appropriate and then a decision that can be had in the collaborative care team offering a calcium gluconate infusion while there, if appropriate again, considering your patients specifically something that is definitely reasonable. I think making sure the patient is trending back with her calcium is the next important kind of follow-up point. And so a plan lab check, I think a week after seeing the patient in clinic makes the most sense. And in this case specifically, we design that a week later, the calcium was up to 7, which is better than where we were at. So we're seeing the benefit of hydration, our calcium gluconate, and the oral repletion being incorporated again, and her renal function is slowly getting better, so not back to where it was, we're at 43 mils per minute, so not back to her 51, but again, better than where we were. The discussion can be had, you know, I think at this point it doesn't make sense to bring her back in for Xgeva right now, or for her denosumab. Let's wait until her next visit when she's in for her next monthly fulvestrant dose. So 3 weeks later, her calcium is again to 8 and her renal function is back to its baseline, the patient is hydrating at home, adequate calcium vitamin D on board. Everyone's over this cold that made its way through her home. And so now I think the position where we're at as providers and what we should do next for this patient is, should we give the next dose of Xgeva or denosumab? Honestly, you can go either way.

So I think you could argue let's hold it maybe 1 more month and see if it gets better, but then you can also make the point that because of the disease she has, it doesn't make sense to hold, but we're doing risk versus benefit for what's the right time interval. And so, again, like we talked about, or like Dr. Sieber said in our ivory towers or on paper, it makes sense, yes, 4 weeks, no matter what let's keep going, but real life happens. And sometimes we do need to extend the intervals based on our patient specifically, and not necessarily that cookie cutter approach. And so what I've seen done often in this kind of we're managing to our patient and doing the dance, so to speak, with our patients specifically. And in this case, she might be someone that we could say needs to be on every-6-week dosing to maintain those adequate calcium levels so she doesn't bottom out and it's more so driven by maybe her more compromised renal function that she has based on her chronic hypertension and things that she has going on.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Saneese?

Saneese Stephen, MPAS, PA-C:

I think ONJ of course is very real. I've seen several patients in the past 2 years who have had ONJ so, you know, assessing the patient is very important and getting the right consults in quickly and interrupting the dosing is important. The guidelines are very not concrete on duration of interruption. You have to look at 2 weeks up to 3 months of interruption in some cases, but I think it depends on the healing of the patient's gum and the context with the discussion with the dentist that'll drive that decision-making. But I think the interval dosing data is out for the REACT group publishing some data, and also as a data from reduced trial that's coming out at the end of next year that's going to talk about interval dosing in prostate cancer, as well as breast and myeloma. So I think we're anxious to see if interval dosing three or less frequent dosing can be useful without putting further risk for the patient.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks for bringing us back to supporting data and ongoing trials and advancing the discussion of this case to ONJ. So where we left off with the portion of the hypocalcemia case, let's consider that she did go on a modified dosing schedule and was on every-6-week dosing to maintain adequate calcium levels. Perhaps she just didn't rebound. And now it's 16 months into her XGEVA. This is the scenario where ONJ could become an issue over time as you saw from those earlier data. After 2 years, she's not quite there yet, but we certainly know it's over time, that risk of ONJ or osteonecrosis of the jaw becomes an issue. Let's say in this woman's case, she not seen a dentist in over a year due to the COVID pandemic. It's real. Right? She's having some teeth issues, and dental evaluation does recommend she receives a few extractions and new implants.

These are real dental procedures that increase the risk of osteonecrosis of the jaw. So she's talking to us about whether or not she can schedule those dental procedures. Her disease remain stable on faslodex. she's on every-6-week denosumab. So in my practice extraction is a risk for sure, but so is an abscess. So we need to allow her to have this extraction if it's dentally indicated. We want to try and avoid implants though for sure during bone-modifying therapy. Increased risk of skeletal-related events is going to be a risk we're taking during a drug holiday, but she clearly needs a drug holiday if she's getting a full extraction, in my opinion. We want to bring in the multi-professional team on decision-making so that we can make a case by case basis for her here. So I'm going to throw it back to you all. Should we be holding her Xgeva, like I strongly would recommend in my particular practice? How long? What else are you considering during this drug holiday so that she can get her extractions? Let me start with you, Christine.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Thank you, Carrie. Yeah, I would agree withholding, with your sentiments, especially since the patient is having active issues. I would say if you can compromise or make a plan with the dentist, like Saneese had mentioned, I think having open lines of communication and making sure that the patient goals are ongoing. Again, we're looking at patients with advanced disease that are living much longer. Bone health is very important as is mouth health and dental health and the risk associated with each of those procedures, extractions carry less of a risk, although they do carry a risk for osteonecrosis of the jaw.

Implants are definitely, because of where the dentist is manipulating the bone more, so that we are more worried about that patient having an increased risk of ONJ. And so kind of discussing again in now that we're looking at our patient in this specific situation, does it make sense to do extractions right now with a shorter drug holiday of a period of a week before the planned extract? Make sure she's been off of the therapy for a little bit and after the extraction waiting at least a month or a month and a half before considering resumption of her denosumab.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

So Dr. Sieber, what would you concretely do? How would you hold? For how long? What would you consider when reinitiating?

Paul Sieber, MD:

I'm going to defer to my oral surgeon. I mean, I think they have a sense that this is a bad actor, so I want them to tell me their thoughts before I make my decision. I'm willing to look in their mouth and say, Oh, their jaw, the gum looks okay. But if they feel like they may look okay into the surface, below the surface, I think there's really trouble brewing. This guy's got a rotten mandible. I think there are certain cases. They just say, this person needs to be off drugs indefinitely. So I really rely on their insights along with just looking in their mouth, which is something I've gotten used to after the years of playing around with this stuff to say, Hey, they're healed. They're not healed. But again, I think it's collaborative with the oral surgeon. That's absolutely critical.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Saneese?

Saneese Stephen, MPAS, PA-C:

I agree with both Christine and Dr. Sieber. A dental oncologist who's familiar with bone targeted agents and the impact on gum and dental issues is probably the best person to address this with.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Sometimes folks aren't as lucky as we are to have access to those specialists though so I want to make sure that we meet the needs of our broader audience. What I would say in that regard is have a conversation. Get on the phone with the dentist, even if it isn't a credentialed oral and maxillofacial surgeon. You know? Talk to the dentist in your community and make these decisions together. So interdisciplinary collaborative care is super crucial here. We do have data to help support us in decision making. We'll share some of those references with you, but they include things like the International ONJ Task Force that recommends that treatment should be withheld after invasive dental surgery in patients receiving denosumab or IV or high-dose bisphosphonates, although there's limited data to support that decision. In Italy, they suggest that bisphosphonates and denosumab should be held for at least for a week prior and for 6 weeks following, but note that that's purely based on expert opinion.

So we really do need to have collaborative discussions. To prevent all of this we want to talk to our patients about maintaining excellent oral hygiene whenever possible and the risk of MRONJ, so osteonecrosis of the jaw, is low, but not non-existent. It's approximately 1% in patients exposed to zoledronic acid. It is still though 50 to 100 times higher than in placebo, and again, the overall incidents in denosumab for cancer patients was just north of 1% as well, about 1.7%. So it’s a real risk to consider.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

We have discussed so many crucial points about prevention of skeletal-related events, complications of bone metastases, complications of bone loss in our patients, predominantly with solid tumors like breast and prostate cancer today. Many of the principles we discussed apply beyond to myeloma, to lung cancer and to other diseases. We're going to close out now this discussion today by talking just a little bit more in conclusion about the important role that advanced practice providers fill. We heard a lot about the PharmD role. We've integrated each of us, Dr. Sieber, the collaborative clinic with a nurse practitioner with whom he practices. Saneese, you've shared a little bit. But why don't you share with us a little bit more, to close out this discussion, your perspective on the important role that APP has played in caring for individuals with metastatic disease with bone involvement or at risk for the same?

Saneese Stephen, MPAS, PA-C:

Sure. Thanks, Carrie. And it's an excellent talk, that entire panel today. I think we've covered so many topics that I wanted to discuss in summary, but overall APPs are growing in terms of how much they're working with medical doctors, oncologists, and this general field of oncology care. And, really, we spend a lot of time with the patient in terms of educating patient and family. Patients entering this situation of new diagnosis of metastatic disease, very apprehensive, tons of labs, tons of tests is very overwhelming for them. So we really had to sit down with them and take a deep breath and go over things step-by-step, make sure they understand us in a manner that's appropriate for them based on their education level, their background, and cultural sensitivity is very important. So we want to make sure we educate them about the risks, how to explain the risks, how to discuss prevention, how to discuss treatment selection, treatment options, how to monitor on treatment, and all these things happen over not in one session, on a continuous basis.

And it's very important to work with, collaboratively as was mentioned previously, with all the different team members, including other APPs pharmacists, and physicians. So as a PA and nurse practitioner, we work with our one or maybe a group of physicians, very important to know their style of practice, their rationale for decision-making. And many times we mirror what they do because we work with them and you want to be on the same page with them. But you should also be able to have a dialogue with them in terms of understanding what's driving their decision-making and be able to support, and contradicting a view if you have one. But I think it's very important to educate yourself, to know the data, and to be able to have that conversation and especially to present to the patients in a manner that they can understand it.

And finally, I think skeletal-related events, you have to be able to be cognizant thinking about that. So a patient has new pain or new complaints that are seem mild at first, if you work them up and follow them, it may be something that you could address early. If it's something that's looming with weakness or spinal cord compression, it's very crucial to get dexamethasone-R started early. So I think the complications of bone therapy, be it ONJ or skeletal-related events, as a clinician, we have to make sure we have a very quick kind of assessment and looking for it very closely.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thank you for that, Saneese. I guess, particularly with relation to the role of the advanced practice provider, I would say, I agree with everything you say, and on top of that, this issue of supportive care management really just feels so centered, so much my wheelhouse in my role as a nurse practitioner, I have to laugh. One of my colleagues doesn't even look at the DEXA scan reports in particular. He says, "You're the expert here." But also we do have very interdisciplinary discussions, particularly when oncology treatment decisions have to be made in conjunction. Anybody else want to make a brief statement or share any clinical pearls, parting words on this topic overall, or particularly with relation to the advanced practice role?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

I think I would just echo the comments that were made. And I think more and more in practice we're learning, it truly takes a village and everyone's different perspectives.

I think everyone on this panel could read the same journal article and take away different things that they would take to change their practice, outside of the "we should use this therapy or that therapy", but kind of how you incorporate it and how you would make sure you remember it when you come across a patient case and a decision point or when you're counseling or talking with the patient. And I think that's why it's so important to focus on the interdisciplinary care that can be offered because of what we can each bring with our own flavor and spin on it, based on our practice and experiences.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

What a privilege to have this discussion with all of you today. To the audience, thank you so much for joining us. And I do want to thank my colleagues again, Saneese Stephen, Paul Sieber, and Christine Cambareri, for taking time out of their very busy day to have this discussion and share their insights on how interdisciplinary approaches to bone metastasis and bone health management are so crucial. For more information, please visit JADPRO online at advancedpractitioner.com. Thank you so much and have a wonderful day all!