Read the Full Video Transcript

Rashid Sayyid: Hello everyone, and thank you for joining us today in this UroToday recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and I'm joined today by Zach Klaassen, associate professor and program director at WellStar MCG Health, where we'll be discussing another chapter of the 2024 key updates of the NCCN prostate cancer guidelines that were published in March of 2024. And in this latest version of the guidelines, we have a new section discussing principles of bone health and prostate cancer, specifically addressing treatment-related bone loss. As previously mentioned, we have these two new sections specifically pertaining to how we address bone loss and treat that in patients with prostate cancer, specifically those on ADT. And then secondarily, how we prevent symptomatic skeletal-related events in patients specifically with bone metastatic CRPC. For this second topic, we'll be discussing that in a later recording.

But today, in this recording, we'll be discussing treatment-related bone loss for patients on ADT. So why is it relevant to address treatment-related bone loss in patients on ADT? We know that hormonal therapy increases the risk of bone loss, and this risk is exacerbated with a longer duration of therapy or delayed testosterone recovery. It's important to keep in mind that patients on long-term ADT take a long time to recover, and we know that the proportion of patients who recover their testosterone is inversely related to the duration of therapy. So it's important to keep in mind that although they may be off it, they're still hypogonadal and experiencing this adverse effect. Also, keep in mind that concurrent prednisone use does increase the risk of bone loss, and we know, especially in patients on abiraterone, that that's relevant because they have to take that concurrently and also with more potent androgen suppression.

And we have recent data that was presented at ASCO-GU in 2022 that showed, within the context of the PEACE-1 trial, that patients who were on abiraterone, and we see here in the curves, these are the curves in red, have worse bone mineral density in the lumbar spine and total hip when DEXA scans are performed at baseline, six, 12, and 24 months. So we see here that ARPI, such as abiraterone, are even more potent than ADT in terms of causing bone loss. So when we talk about osteoporosis screening, the goal is to identify the patients at increased risk of sustaining a low trauma fracture who would benefit from intervention to minimize this fracture risk. So it goes without saying, but risk assessment for treatment-related bone loss should take place for all patients initiating ADT of any duration.

And one way to perform this risk assessment is using the FRAX tool or the Fracture Risk Assessment Tool. FRAX is an algorithm that was developed and released by the University of Sheffield in the UK, and it was developed to estimate the 10-year probability of a hip fracture or a major osteoporotic fracture, defined as hip, spine, shoulder, or wrist for an untreated individual. Importantly, using very easily obtainable clinical risk factors for fracture, with or without information on bone marrow density. So if you have information from a DEXA scan, you can add that to increase the accuracy of this tool, but you don't need that to get the absolute risk, and we'll go over that in the next slide. It's important when utilizing the FRAX algorithm that you select "yes" for secondary osteoporosis for individuals with hypogonadism because ADT should be considered as a form of secondary osteoporosis.

But it's important to note that a previous major osteoporotic fracture, meaning a hip fracture or spine fracture, is considered clinical osteoporosis and warrants bone antiresorptive drug therapy independent of bone mineral density. So in brief, if these patients are being screened and you know they've had a fracture, forget about all of this and proceed directly to therapy. But if they don't, then the first step is using the FRAX score. So you go to the internet, you plug in the link that we have down here below, you get this calculator. You have a seventy-year-old guy who comes to your clinic, you click "yes" on the secondary osteoporosis since they're on ADT, you take a brief history and as you see, the variables are quite easy. This patient consumes three or more drinks per week. They don't have results of a DEXA scan, so the number 12 here, you just leave it empty and then boom, you get the risk of the 10-year probability of a fracture.

And really you get two figures here, major osteoporotic and then hip specifically. And so you may ask, well, what does 9.1% mean? Is that high, low? We'll talk about that in the next slides within the context of a DEXA scan. So let's talk about the DEXA scan, or the Dual Energy X-Ray Absorptiometry scan. It's important that a baseline DEXA scan be obtained before starting ADT in patients at increased risk for fracture based on the FRAX screening and being considered for bone-targeted agents. First step is the FRAX score. If the FRAX score is elevated, then they proceed to a DEXA scan. If the FRAX score is within normal, then they don't need a DEXA scan and you don't need to go down the rabbit hole of antiresorptive therapy, etc. And so, as we said, the exact FRAX fracture risk threshold has not yet been defined in this population, but the NCCN does give us some guidance on this.

And so, one potential approach is you set the threshold of a 10-year major osteoporotic fracture, which was 9.1% in the case example that we gave and greater than that of a 65-year-old white woman with no additional risk factors, which was defined as 8.4% in the US. So if somebody comes through your clinic, you plug in the numbers and you get a score of 8.4% or higher, in which case 9.1, then yes, based on the FRAX tool, they are at increased risk and they should proceed with a DEXA scan. And then based on the DEXA scan, we'll talk about the different treatment options. So again, it's very important that we go through this algorithmically in order to make sure that we don't miss any patients that come through our clinic. Now let's talk about optimizing bone health in patients with prostate cancer. Specifically, we'll be focusing on the categories of lifestyle modification and calcium and vitamin D supplementation.

So when we start with lifestyle modification, the NCCN very nicely tells us that weight-bearing exercises for 30 minutes per day, balance training and safe movement strategies are key, in addition to limiting alcohol consumption as well as smoking cessation. And really, we all know that weight-bearing exercises are important, but are there really any techniques where we can improve patient compliance and thus functional outcomes? And there's a really nice study that came out through the University of Toronto a couple of years ago that looked at patients on ADT and then asked the question, if we adopt more of a patient-driven or preference approach versus more of a fixed, randomized controlled trial protocol, which are the two patients more likely to adhere to and thus have improved functional outcomes?

And as we see here, patients who essentially selected their own preferred exercise regimen were more likely to be adherent to this regimen at six months. So three-quarters versus only half. And in terms of a result, they had improved fatigue levels at this same time period. So it's really important that we engage our patients, understand what works for them, what doesn't, and then based off that, tailor that to their preference.

Next, in terms of the guidelines for the general population in terms of supplementation, the NCCN does recommend that for calcium, that the patients consume 1,000 to 1,200 milligrams daily. This can be from food and or supplements, so if they can get that from their food alone, that's totally fine. Next, in terms of vitamin D, and this really varies geographically based on sunlight exposure and the supplementation of the diets as well. The target is a serum level of 30 to 50 ng/mL, and obviously you can supplement that if needed. And then specifically in terms of pharmacologic treatment for men who are 50 years or older with low bone mass, and this is defined as osteopenia, the T-score between -1.0 and -2.5 at the femoral neck or total hip by the DEXA scan with a 10-year probability of hip fracture of at least 3% or a 10-year probability of major osteoporosis-related fracture of at least 20% based on the FRAX screening.

An emerging, and we'll see this over the next few years, aspect of this survivorship setting for these patients is how can we do better? Should we just continue with the same recommendations that have been there for a couple of decades or is there a different angle? And one of the new areas of research is giving high-dose vitamin D for these patients specifically. And we saw this published recently this year where we had a phase 2 trial which investigated high-dose weekly vitamin D, defined as 50,000 units per week for placebo for about six months in prostate cancer patients starting ADT within the prior six months. And it's important to remember that it's not just placebo, it's placebo plus 600 units per day of vitamin D and 1,000 milligrams per day of calcium for both arms. So it really isn't an all or none, it's an all plus standard versus a standard approach to supplementation.

What's really interesting is that patients in the high-dose vitamin D arm experienced less total hip bone mineral density loss and it's really clinically meaningful. So we see the differences here are -1.5% versus -4.1%, although this is not statistically significant, when we look at the absolute figures, it is meaningful for our patients. And it's important to note, the most significant benefit was known for those patients with a baseline 25-hydroxy vitamin D level less than 27. We know that 25-hydroxy vitamin D is the active substrate of vitamin D. And we see here a big difference, which makes sense that patients who are deficient at baseline really benefit the most from this super physiologic supplementation. They also saw in the trial that there was less femoral neck bone mineral density loss, -1.7 versus -4.4. So we see this at the hip and the femoral neck, which we know are two common sites of lower extremity fractures with serious morbidity considerations afterward.

And what's also important is that there was no difference in adverse events or toxicity between the groups, we may see some differences, namely in the urologic world with regards to stone formation. And this may appear with longer-term follow-up, but for the time being the evidence is quite promising and we should keep that in the back of our minds and maybe discuss that with select patients, particularly those with the lowest baseline levels of vitamin D. At this point, we've talked about all the recommendations for patients on ADT in terms of lifestyle and calcium vitamin D supplementation, but what about treatment-related bone loss in patients receiving ADT, specifically the use of antiresorptive agents? At this point, I'll turn it over to Zach. He'll go over the evidence for these different agents that we see in the table that are approved and the recommendations for using them in this high-risk population.

Zach Klaassen: Thanks so much, Rashid. Great overview of the first half of the discussion. So as Rashid mentioned, we'll go over the antiresorptive agents next, starting with the bisphosphonates, and this encompasses zoledronic acid or alendronate. You can see the mechanism to the right in the figure. And this is really the inhibition of farnesyl pyrophosphate synthase, which is important in promoting attachment of the osteoclast to the bone. And the NCCN does want to highlight the side effects of these agents, and this includes an acute phase reaction, joint pain, hypocalcemia, osteonecrosis of the jaw, nephrotoxicity, which is important to dose modify for those that do have renal insufficiency, ocular toxicities, as well as atypical femoral fractures with use of more than three to five years of the agent. Next, this is denosumab, you can see the mechanism again here on the right. And this is a monoclonal antibody that binds to the RANK ligand and competitively inhibits the RANK receptor.

Side effects are kind of similar to the bisphosphonates, the NCCN notes hypocalcemia is important, osteonecrosis of the jaw, and really make a distinct point of having all these patients starting denosumab to have a comprehensive dental evaluation prior to initiating therapy as well as atypical femoral fractures with prolonged use. There are also several risk factors for denosumab-associated hypocalcemia. This includes blastic bone metastases, renal impairment, vitamin D deficiency, a lack of calcium or vitamin D supplementation, pre-existing hypoparathyroidism, hypomagnesemia, as well as a history of having a gastric bypass operation. So the NCCN has several recommendations specific to the utilization of denosumab. The first one is renal monitoring, not required, but should be considered, especially in patients with creatinine clearance of less than 30 mL per minute. Secondly, calcium, creatinine, and vitamin D levels should be checked before therapy. The third recommendation is periodic monitoring of serum calcium levels while on therapy. And the fourth recommendation is stopping denosumab can result in rebound bone loss and fracture.

The NCCN recommends administration of at least one dose of a bisphosphonate, likely zoledronic acid, four or five milligrams to prevent rebound bone loss and fracture at the time of stopping denosumab.

So really what it comes down to is which agent is better, and there's no high-level evidence at this point, but this is an interesting network meta-analysis published in 2021 of 15 studies. And this analysis found that all bone protective agents, except for risedronate, significantly increase lumbar spinal bone mineral density, with zoledronic acid having the highest bone mineral density gain. Secondly, all bone protective agents and denosumab significantly increased total hip bone mineral density. Again, denosumab leads to the highest bone mineral density gain when we're looking at the hip aspect. Finally, denosumab was the only agent to significantly reduce the risk of vertebral fractures with a risk ratio of 0.40, statistically significant 95% confidence interval. So really the take-home message from this study is that denosumab may potentially outperform other bone protective agents, but the use of a bone protective agent is important when clinically indicated regardless of the mechanism.

What about follow-up for bone protective agents? The NCCN does have three recommendations for follow-up. The first is the annual assessment of the fracture risk using the FRAX assessment tool, which Rashid nicely laid out. And this is for all patients on androgen deprivation therapy as well as those who will remain hypogonadal after completing ADT. And this is particularly for older men who don't necessarily have recovery of their testosterone after stopping ADT. The second recommendation is for repeat DEXA scans in one to two years for those still on ADT. The third recommendation is for those on bone protective agents, they should obtain a follow-up DEXA scan after one year on treatment. However, there's no consensus on the optimal approach to monitoring the actual effectiveness of these bone protective agents.

What about the duration of treatment? There is no consensus guideline for how long patients should be on bone protective agents, but there are several recommendations for concern of long-term issues and long-term risk. And that may be a holiday from the bone protective agent at three to five years, which may be considered based on the agent utilized, the stability of the bone mineral density, the prior fracture risk, as well as the future fracture risk for these patients. So this is, at this point, really an individualized assessment. Additionally, bone mineral density should be monitored every one to two years after suspending therapy. And therapy should be resumed if the bone mineral density declines significantly or if the patient subsequently develops a new fragility fracture.

So in conclusion, it's very important to acknowledge that ADT does increase the risk of bone loss. Osteoporosis screening should include utilization of the FRAX algorithm, which is easily accessible online. A baseline DEXA scan should be obtained before starting ADT in patients at risk of fracture based on FRAX screening. We need to optimize bone health, and this not only includes calcium and vitamin D, but appropriate pharmacological treatment with either zoledronic acid, alendronate, or denosumab when clinically indicated. And really this is a call to action to optimize bone health for these patients. This is the first mention of optimizing bone health in the NCCN prostate cancer guidelines, which has historically been underutilized among these at-risk patients.

We thank you so much for your attention. We hope you enjoyed this UroToday discussion of the NCCN 2024 updates focusing on bone health.