Rashid Sayyid: Good day everybody, and thanks for becoming a member of us right this moment on this UroToday recording. I am Rashid Sayyid, a urologic oncology fellow on the College of Toronto, and I am joined right this moment 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 had been revealed in March of 2024. And on this newest model of the rules, we have now 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 have now 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 stop symptomatic skeletal-related occasions in sufferers particularly with bone metastatic CRPC. For this second matter, we’ll be discussing that in a later recording.
However right this moment, on this recording, we’ll be discussing treatment-related bone loss for sufferers on ADT. So why is it related to handle treatment-related bone loss in sufferers on ADT? We all know that hormonal remedy will increase the chance of bone loss, and this threat is exacerbated with an extended length of remedy or delayed testosterone restoration. It is essential to remember 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 remember that though they might be off it, they’re nonetheless hypogonadal and experiencing this opposed impact. Additionally, remember that concurrent prednisone use does enhance the chance 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 likewise with stronger androgen suppression.
And we have now current knowledge that was offered at ASCO-GU in 2022 that confirmed, throughout the context of the PEACE-1 trial, that sufferers who had 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 whole hip when DEXA scans are carried out at baseline, six, 12, and 24 months. So we see right here that ARPI, equivalent to abiraterone, are much more potent than ADT when it comes to inflicting bone loss. So once we speak about osteoporosis screening, the aim is to determine the sufferers at elevated threat of sustaining a low trauma fracture who would profit from intervention to reduce this fracture threat. So it goes with out saying, however threat evaluation for treatment-related bone loss ought to happen for all sufferers initiating ADT of any length.
And one option to carry out this threat evaluation is utilizing the FRAX software or the Fracture Threat Evaluation Instrument. 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 threat elements for fracture, with or with out info on bone marrow density. So when you have info from a DEXA scan, you may add that to extend the accuracy of this software, however you do not want that to get absolutely the threat, 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 of as a type of secondary osteoporosis.
But it surely’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 have now down right here under, you get this calculator. You could have 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 short 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 depart it empty after which increase, you get the chance of the 10-year likelihood of a fracture.
And actually you get two figures right here, main osteoporotic after which hip particularly. And so it’s possible you’ll ask, nicely, what does 9.1% imply? Is that top, low? We’ll speak about that within the subsequent slides throughout the context of a DEXA scan. So let’s discuss concerning the DEXA scan, or the Twin Vitality X-Ray Absorptiometry scan. It is essential {that a} baseline DEXA scan be obtained earlier than beginning ADT in sufferers at elevated threat for fracture primarily based on the FRAX screening and being thought of 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 so on. And so, as we stated, the precise FRAX fracture threat threshold has not but been outlined on this inhabitants, however the NCCN does give us some steerage on this.
And so, one potential strategy 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 girl with no extra threat elements, 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 increased, through which case 9.1, then sure, primarily based on the FRAX software, they’re at elevated threat and they need to proceed with a DEXA scan. After which primarily based on the DEXA scan, we’ll discuss concerning the totally different remedy choices. So once more, it is crucial that we undergo this algorithmically so as to be sure that we do not miss any sufferers that come by our clinic. Now let’s speak about 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 once we begin with way of life modification, the NCCN very properly tells us that weight-bearing workout routines 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 workout routines 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 examine 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 strategy versus extra of a hard and fast, randomized managed trial protocol, that are the 2 sufferers extra more likely to adhere to and thus have improved purposeful outcomes?
And as we see right here, sufferers who basically chosen their very own most well-liked train routine had been extra more likely to be adherent to this routine at six months. So three-quarters versus solely half. And when it comes to a outcome, they’d improved fatigue ranges at this similar time interval. So it is actually essential that we interact our sufferers, perceive what works for them, what would not, after which primarily based off that, tailor that to their desire.
Subsequent, when it comes to the rules for the overall inhabitants when it comes to supplementation, the NCCN does advocate that for calcium, that the sufferers devour 1,000 to 1,200 milligrams each day. This may be from meals and or dietary supplements, so if they’ll get that from their meals alone, that is completely fantastic. Subsequent, when it comes to vitamin D, and this actually varies geographically primarily based on daylight publicity and the supplementation of the diets as nicely. The goal is a serum stage of 30 to 50 ng/mL, and clearly you may complement that if wanted. After which particularly when it comes to 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 whole hip by the DEXA scan with a 10-year likelihood of hip fracture of not less than 3% or a 10-year likelihood of main osteoporosis-related fracture of not less than 20% primarily based on the FRAX screening.
An rising, and we’ll see this over the following 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 have been there for a few a long time or is there a distinct angle? And one of many new areas of analysis is giving high-dose vitamin D for these sufferers particularly. And we noticed this revealed lately this yr the place we had a part 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 do not forget that it is not 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 normal versus a normal strategy to supplementation.
What’s actually fascinating is that sufferers within the high-dose vitamin D arm skilled much less whole hip bone mineral density loss and it is actually clinically significant. So we see the variations listed here are -1.5% versus -4.1%, though this isn’t statistically vital, once we have a look at absolutely the figures, it’s significant for our sufferers. And it is essential to notice, probably the most vital profit was identified for these sufferers with a baseline 25-hydroxy vitamin D stage lower than 27. We all know that 25-hydroxy vitamin D is the energetic substrate of vitamin D. And we see right here a giant distinction, which is sensible that sufferers who’re poor at baseline actually profit probably 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 widespread websites of decrease extremity fractures with critical morbidity concerns afterward.
And what’s additionally essential is that there was no distinction in opposed occasions or toxicity between the teams, we may even see some variations, specifically within the urologic world close to stone formation. And this will seem with longer-term follow-up, however in the intervening time the proof is kind of promising and we must always hold that at the back of our minds and perhaps talk about 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 when it comes to 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 will flip it over to Zach. He’ll go over the proof for these totally different brokers that we see within the desk which might 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’ll be able to see the mechanism to the correct 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 contains an acute part 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 may see the mechanism once more right here on the correct. And this can be a monoclonal antibody that binds to the RANK ligand and competitively inhibits the RANK receptor.
Negative effects are sort of just 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 threat elements for denosumab-associated hypocalcemia. This contains blastic bone metastases, renal impairment, vitamin D deficiency, an absence 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 of, 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 suggestion is periodic monitoring of serum calcium ranges whereas on remedy. And the fourth suggestion is stopping denosumab can lead to rebound bone loss and fracture.
The NCCN recommends administration of not less than one dose of a bisphosphonate, possible 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 is not any high-level proof at this level, however that is an fascinating community meta-analysis revealed in 2021 of 15 research. And this evaluation discovered that each one bone protecting brokers, aside from risedronate, considerably enhance 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 whole hip bone mineral density. Once more, denosumab results in the very best bone mineral density acquire once we’re wanting on the hip facet. Lastly, denosumab was the one agent to considerably scale back the chance of vertebral fractures with a threat ratio of 0.40, statistically vital 95% confidence interval. So actually the take-home message from this examine is that denosumab might 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 threat 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 suggestion is for repeat DEXA scans in a single to 2 years for these nonetheless on ADT. The third suggestion is for these on bone protecting brokers, they need to get hold of a follow-up DEXA scan after one yr on remedy. Nonetheless, there is not any consensus on the optimum strategy to monitoring the precise effectiveness of those bone protecting brokers.
What concerning the length of remedy? There is no such thing as a 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 threat. And that could be a vacation from the bone protecting agent at three to 5 years, which can be thought of primarily based on the agent utilized, the steadiness of the bone mineral density, the prior fracture threat, in addition to the longer term fracture threat 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 crucial to acknowledge that ADT does enhance the chance 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 prone to fracture primarily based on FRAX screening. We have to optimize bone well being, and this not solely contains 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 to your consideration. We hope you loved this UroToday dialogue of the NCCN 2024 updates specializing in bone well being.
