Rashid Sayyid: Hey everybody, and thanks for becoming a member of us immediately on this UroToday recording. I am Rashid Sayyid, a urologic oncology fellow on the College of Toronto, and I am joined immediately by Zach Klaassen, affiliate professor and program director at WellStar MCG Well being, the place we’ll be discussing one other chapter of the 2024 key updates of the NCCN prostate most cancers pointers that have been revealed in March of 2024. And on this newest model of the rules, we’ve a brand new part discussing rules of bone well being and prostate most cancers, particularly addressing treatment-related bone loss. As beforehand talked about, we’ve these two new sections particularly pertaining to how we handle bone loss and deal with that in sufferers with prostate most cancers, particularly these on ADT. After which secondarily, how we forestall symptomatic skeletal-related occasions in sufferers particularly with bone metastatic CRPC. For this second subject, we’ll be discussing that in a later recording.
However immediately, on this recording, we’ll be discussing treatment-related bone loss for sufferers on ADT. So why is it related to deal with treatment-related bone loss in sufferers on ADT? We all know that hormonal remedy will increase the danger of bone loss, and this danger is exacerbated with an extended length of remedy or delayed testosterone restoration. It is essential to take into account that sufferers on long-term ADT take a very long time to recuperate, and we all know that the proportion of sufferers who recuperate their testosterone is inversely associated to the length of remedy. So it is essential to take into account that though they might be off it, they’re nonetheless hypogonadal and experiencing this adversarial impact. Additionally, take into account that concurrent prednisone use does improve the danger of bone loss, and we all know, particularly in sufferers on abiraterone, that that is related as a result of they need to take that concurrently and in addition with stronger androgen suppression.
And we’ve latest information that was offered at ASCO-GU in 2022 that confirmed, throughout the context of the PEACE-1 trial, that sufferers who have been on abiraterone, and we see right here within the curves, these are the curves in pink, have worse bone mineral density within the lumbar backbone and complete hip when DEXA scans are carried out at baseline, six, 12, and 24 months. So we see right here that ARPI, resembling abiraterone, are much more potent than ADT by way of inflicting bone loss. So after we discuss osteoporosis screening, the aim is to determine the sufferers at elevated danger of sustaining a low trauma fracture who would profit from intervention to reduce this fracture danger. So it goes with out saying, however danger evaluation for treatment-related bone loss ought to happen for all sufferers initiating ADT of any length.
And one solution to carry out this danger evaluation is utilizing the FRAX software or the Fracture Danger Evaluation Device. FRAX is an algorithm that was developed and launched by the College of Sheffield within the UK, and it was developed to estimate the 10-year likelihood of a hip fracture or a significant osteoporotic fracture, outlined as hip, backbone, shoulder, or wrist for an untreated particular person. Importantly, utilizing very simply obtainable scientific danger components for fracture, with or with out info on bone marrow density. So in case you have info from a DEXA scan, you’ll be able to add that to extend the accuracy of this software, however you do not want that to get absolutely the danger, and we’ll go over that within the subsequent slide. It is essential when using the FRAX algorithm that you choose “sure” for secondary osteoporosis for people with hypogonadism as a result of ADT must be thought-about as a type of secondary osteoporosis.
However it’s essential to notice {that a} earlier main osteoporotic fracture, that means a hip fracture or backbone fracture, is taken into account scientific osteoporosis and warrants bone antiresorptive drug remedy unbiased of bone mineral density. So briefly, if these sufferers are being screened and you realize they’ve had a fracture, neglect about all of this and proceed on to remedy. But when they do not, then step one is utilizing the FRAX rating. So that you go to the web, you plug within the hyperlink that we’ve down right here beneath, you get this calculator. You’ve got a seventy-year-old man who involves your clinic, you click on “sure” on the secondary osteoporosis since they’re on ADT, you’re taking a quick historical past and as you see, the variables are fairly straightforward. This affected person consumes three or extra drinks per week. They do not have outcomes of a DEXA scan, so the quantity 12 right here, you simply go away it empty after which increase, you get the danger of the 10-year likelihood of a fracture.
And actually you get two figures right here, main osteoporotic after which hip particularly. And so chances are you’ll ask, nicely, what does 9.1% imply? Is that top, low? We’ll discuss that within the subsequent slides throughout the context of a DEXA scan. So let’s discuss in regards to the DEXA scan, or the Twin Power X-Ray Absorptiometry scan. It is essential {that a} baseline DEXA scan be obtained earlier than beginning ADT in sufferers at elevated danger for fracture based mostly on the FRAX screening and being thought-about for bone-targeted brokers. First step is the FRAX rating. If the FRAX rating is elevated, then they proceed to a DEXA scan. If the FRAX rating is inside regular, then they do not want a DEXA scan and also you need not go down the rabbit gap of antiresorptive remedy, and many others. And so, as we stated, the precise FRAX fracture danger threshold has not but been outlined on this inhabitants, however the NCCN does give us some steerage on this.
And so, one potential method is you set the edge of a 10-year main osteoporotic fracture, which was 9.1% within the case instance that we gave and better than that of a 65-year-old white lady with no extra danger components, which was outlined as 8.4% within the US. So if someone comes by your clinic, you plug within the numbers and also you get a rating of 8.4% or larger, by which case 9.1, then sure, based mostly on the FRAX software, they’re at elevated danger and they need to proceed with a DEXA scan. After which based mostly on the DEXA scan, we’ll discuss in regards to the totally different remedy choices. So once more, it is essential that we undergo this algorithmically with the intention to guarantee that we do not miss any sufferers that come by our clinic. Now let’s discuss optimizing bone well being in sufferers with prostate most cancers. Particularly, we’ll be specializing in the classes of way of life modification and calcium and vitamin D supplementation.
So after we begin with way of life modification, the NCCN very properly tells us that weight-bearing workouts for half-hour per day, steadiness coaching and secure motion methods are key, along with limiting alcohol consumption in addition to smoking cessation. And actually, everyone knows that weight-bearing workouts are essential, however are there actually any methods the place we will enhance affected person compliance and thus purposeful outcomes? And there is a very nice research that got here out by the College of Toronto a few years in the past that checked out sufferers on ADT after which requested the query, if we undertake extra of a patient-driven or desire method versus extra of a hard and fast, randomized managed trial protocol, that are the 2 sufferers extra prone to adhere to and thus have improved purposeful outcomes?
And as we see right here, sufferers who primarily chosen their very own most well-liked train routine have been extra prone to be adherent to this routine at six months. So three-quarters versus solely half. And by way of a outcome, that they had improved fatigue ranges at this identical time interval. So it is actually essential that we have interaction our sufferers, perceive what works for them, what does not, after which based mostly off that, tailor that to their desire.
Subsequent, by way of the rules for the final inhabitants by way of supplementation, the NCCN does advocate that for calcium, that the sufferers eat 1,000 to 1,200 milligrams day by day. This may be from meals and or dietary supplements, so if they will get that from their meals alone, that is completely nice. Subsequent, by way of vitamin D, and this actually varies geographically based mostly on daylight publicity and the supplementation of the diets as nicely. The goal is a serum degree of 30 to 50 ng/mL, and clearly you’ll be able to complement that if wanted. After which particularly by way of pharmacologic remedy for males who’re 50 years or older with low bone mass, and that is outlined as osteopenia, the T-score between -1.0 and -2.5 on the femoral neck or complete hip by the DEXA scan with a 10-year likelihood of hip fracture of at the very least 3% or a 10-year likelihood of main osteoporosis-related fracture of at the very least 20% based mostly on the FRAX screening.
An rising, and we’ll see this over the subsequent few years, facet of this survivorship setting for these sufferers is how can we do higher? Ought to we simply proceed with the identical suggestions which were there for a few a long time or is there a special angle? And one of many new areas of analysis is giving high-dose vitamin D for these sufferers particularly. And we noticed this revealed not too long ago this yr the place we had a section 2 trial which investigated high-dose weekly vitamin D, outlined as 50,000 models per week for placebo for about six months in prostate most cancers sufferers beginning ADT throughout the prior six months. And it is essential to keep in mind that it isn’t simply placebo, it is placebo plus 600 models per day of vitamin D and 1,000 milligrams per day of calcium for each arms. So it actually is not an all or none, it is an all plus customary versus a regular method to supplementation.
What’s actually attention-grabbing is that sufferers within the high-dose vitamin D arm skilled much less complete hip bone mineral density loss and it is actually clinically significant. So we see the variations listed below are -1.5% versus -4.1%, though this isn’t statistically vital, after we have a look at absolutely the figures, it’s significant for our sufferers. And it is essential to notice, essentially the most vital profit was recognized for these sufferers with a baseline 25-hydroxy vitamin D degree lower than 27. We all know that 25-hydroxy vitamin D is the energetic substrate of vitamin D. And we see right here an enormous distinction, which is smart that sufferers who’re poor at baseline actually profit essentially the most from this tremendous physiologic supplementation. Additionally they noticed within the trial that there was much less femoral neck bone mineral density loss, -1.7 versus -4.4. So we see this on the hip and the femoral neck, which we all know are two frequent websites of decrease extremity fractures with critical morbidity issues afterward.
And what’s additionally essential is that there was no distinction in adversarial occasions or toxicity between the teams, we may even see some variations, specifically within the urologic world close to stone formation. And this may occasionally seem with longer-term follow-up, however in the intervening time the proof is kind of promising and we should always maintain that behind our minds and perhaps focus on that with choose sufferers, notably these with the bottom baseline ranges of vitamin D. At this level, we have talked about all of the suggestions for sufferers on ADT by way of way of life and calcium vitamin D supplementation, however what about treatment-related bone loss in sufferers receiving ADT, particularly the usage of antiresorptive brokers? At this level, I am going to flip it over to Zach. He’ll go over the proof for these totally different brokers that we see within the desk which can be authorised and the suggestions for utilizing them on this high-risk inhabitants.
Zach Klaassen: Thanks a lot, Rashid. Nice overview of the primary half of the dialogue. In order Rashid talked about, we’ll go over the antiresorptive brokers subsequent, beginning with the bisphosphonates, and this encompasses zoledronic acid or alendronate. You may see the mechanism to the proper within the determine. And that is actually the inhibition of farnesyl pyrophosphate synthase, which is essential in selling attachment of the osteoclast to the bone. And the NCCN does need to spotlight the unwanted side effects of those brokers, and this consists of an acute section response, joint ache, hypocalcemia, osteonecrosis of the jaw, nephrotoxicity, which is essential to dose modify for people who do have renal insufficiency, ocular toxicities, in addition to atypical femoral fractures with use of greater than three to 5 years of the agent. Subsequent, that is denosumab, you’ll be able to see the mechanism once more right here on the proper. And this can be a monoclonal antibody that binds to the RANK ligand and competitively inhibits the RANK receptor.
Unwanted effects are sort of much like the bisphosphonates, the NCCN notes hypocalcemia is essential, osteonecrosis of the jaw, and actually make a definite level of getting all these sufferers beginning denosumab to have a complete dental analysis previous to initiating remedy in addition to atypical femoral fractures with extended use. There are additionally a number of danger components for denosumab-associated hypocalcemia. This consists of blastic bone metastases, renal impairment, vitamin D deficiency, a scarcity of calcium or vitamin D supplementation, pre-existing hypoparathyroidism, hypomagnesemia, in addition to a historical past of getting a gastric bypass operation. So the NCCN has a number of suggestions particular to the utilization of denosumab. The primary one is renal monitoring, not required, however must be thought-about, particularly in sufferers with creatinine clearance of lower than 30 mL per minute. Secondly, calcium, creatinine, and vitamin D ranges must be checked earlier than remedy. The third advice is periodic monitoring of serum calcium ranges whereas on remedy. And the fourth advice is stopping denosumab can lead to rebound bone loss and fracture.
The NCCN recommends administration of at the very least one dose of a bisphosphonate, seemingly zoledronic acid, 4 or 5 milligrams to forestall rebound bone loss and fracture on the time of stopping denosumab.
So actually what it comes right down to is which agent is healthier, and there isn’t any high-level proof at this level, however that is an attention-grabbing community meta-analysis revealed in 2021 of 15 research. And this evaluation discovered that every one bone protecting brokers, aside from risedronate, considerably improve lumbar spinal bone mineral density, with zoledronic acid having the very best bone mineral density acquire. Secondly, all bone protecting brokers and denosumab considerably elevated complete hip bone mineral density. Once more, denosumab results in the very best bone mineral density acquire after we’re wanting on the hip facet. Lastly, denosumab was the one agent to considerably cut back the danger of vertebral fractures with a danger ratio of 0.40, statistically vital 95% confidence interval. So actually the take-home message from this research is that denosumab could probably outperform different bone protecting brokers, however the usage of a bone protecting agent is essential when clinically indicated whatever the mechanism.
What about follow-up for bone protecting brokers? The NCCN does have three suggestions for follow-up. The primary is the annual evaluation of the fracture danger utilizing the FRAX evaluation software, which Rashid properly laid out. And that is for all sufferers on androgen deprivation remedy in addition to those that will stay hypogonadal after finishing ADT. And that is notably for older males who do not essentially have restoration of their testosterone after stopping ADT. The second advice is for repeat DEXA scans in a single to 2 years for these nonetheless on ADT. The third advice is for these on bone protecting brokers, they need to acquire a follow-up DEXA scan after one yr on remedy. Nonetheless, there isn’t any consensus on the optimum method to monitoring the precise effectiveness of those bone protecting brokers.
What in regards to the length of remedy? There isn’t any consensus guideline for the way lengthy sufferers must be on bone protecting brokers, however there are a number of suggestions for concern of long-term points and long-term danger. And which may be a vacation from the bone protecting agent at three to 5 years, which can be thought-about based mostly on the agent utilized, the steadiness of the bone mineral density, the prior fracture danger, in addition to the long run fracture danger for these sufferers. So that is, at this level, actually an individualized evaluation. Moreover, bone mineral density must be monitored each one to 2 years after suspending remedy. And remedy must be resumed if the bone mineral density declines considerably or if the affected person subsequently develops a brand new fragility fracture.
So in conclusion, it is essential to acknowledge that ADT does improve the danger of bone loss. Osteoporosis screening ought to embody utilization of the FRAX algorithm, which is definitely accessible on-line. A baseline DEXA scan must be obtained earlier than beginning ADT in sufferers liable to fracture based mostly on FRAX screening. We have to optimize bone well being, and this not solely consists of calcium and vitamin D, however applicable pharmacological remedy with both zoledronic acid, alendronate, or denosumab when clinically indicated. And actually this can be a name to motion to optimize bone well being for these sufferers. That is the primary point out of optimizing bone well being within the NCCN prostate most cancers pointers, which has traditionally been underutilized amongst these at-risk sufferers.
We thanks a lot in your consideration. We hope you loved this UroToday dialogue of the NCCN 2024 updates specializing in bone well being.
