Rashid Sayyid: Whats up everybody, and thanks for becoming a member of us at the moment on this UroToday recording. I am Rashid Sayyid, a urologic oncology fellow on the College of Toronto, and I am joined at the 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’ve a brand new part discussing ideas 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 deal with 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 matter, we’ll be discussing that in a later recording.
However at the moment, 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 chance of bone loss, and this threat is exacerbated with an extended period of remedy or delayed testosterone restoration. It is vital to remember the fact that sufferers on long-term ADT take a very long time to get better, and we all know that the proportion of sufferers who get better their testosterone is inversely associated to the period of remedy. So it is vital to remember the fact that though they could be off it, they’re nonetheless hypogonadal and experiencing this adversarial impact. Additionally, remember the fact 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 should take that concurrently and in addition with stronger androgen suppression.
And we’ve current knowledge that was introduced 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 purple, 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, equivalent to abiraterone, are much more potent than ADT by way of 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 period.
And one strategy to carry out this threat evaluation is utilizing the FRAX instrument or the Fracture Danger Evaluation Software. 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 serious osteoporotic fracture, outlined as hip, backbone, shoulder, or wrist for an untreated particular person. Importantly, utilizing very simply obtainable medical threat elements for fracture, with or with out info on bone marrow density. So in case you have info from a DEXA scan, you possibly can add that to extend the accuracy of this instrument, however you do not want that to get absolutely the threat, and we’ll go over that within the subsequent slide. It is vital 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 vital to notice {that a} earlier main osteoporotic fracture, which means a hip fracture or backbone fracture, is taken into account medical osteoporosis and warrants bone antiresorptive drug remedy unbiased of bone mineral density. So in short, if these sufferers are being screened and you understand they’ve had a fracture, overlook 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 under, you get this calculator. You might 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 simple. 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 growth, 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 you might ask, properly, 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 in regards to the DEXA scan, or the Twin Power X-Ray Absorptiometry scan. It is vital {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 needn’t 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 steering 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 larger than that of a 65-year-old white girl with no further threat elements, which was outlined as 8.4% within the US. So if any individual comes by way of your clinic, you plug within the numbers and also you get a rating of 8.4% or greater, wherein case 9.1, then sure, primarily based on the FRAX instrument, 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 in regards to the totally different therapy choices. So once more, it is crucial that we undergo this algorithmically with a purpose to make it possible for we do not miss any sufferers that come by way of 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 life-style modification and calcium and vitamin D supplementation.
So once we begin with life-style modification, the NCCN very properly tells us that weight-bearing workout routines for half-hour per day, steadiness coaching and protected motion methods are key, along with limiting alcohol consumption in addition to smoking cessation. And actually, everyone knows that weight-bearing workout routines are vital, however are there actually any strategies the place we will enhance affected person compliance and thus practical outcomes? And there is a very nice research that got here out by way of 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 more likely to adhere to and thus have improved practical outcomes?
And as we see right here, sufferers who primarily 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 by way of a outcome, that they had improved fatigue ranges at this similar time interval. So it is actually vital that we interact our sufferers, perceive what works for them, what does not, after which primarily based 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 devour 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 tremendous. Subsequent, by way of vitamin D, and this actually varies geographically primarily based on daylight publicity and the supplementation of the diets as properly. The goal is a serum degree of 30 to 50 ng/mL, and clearly you possibly can complement that if wanted. After which particularly by way of pharmacologic therapy 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 least 3% or a 10-year likelihood of main osteoporosis-related fracture of at the least 20% primarily based on the FRAX screening.
An rising, and we’ll see this over the following few years, side 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 unique 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 12 months the place we had a part 2 trial which investigated high-dose weekly vitamin D, outlined as 50,000 items per week for placebo for about six months in prostate most cancers sufferers beginning ADT throughout the prior six months. And it is vital to keep in mind that it is not simply placebo, it is placebo plus 600 items 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 typical 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 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 vital to notice, probably 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 a giant distinction, which is sensible that sufferers who’re poor at baseline actually profit probably the most from this tremendous physiologic supplementation. In addition 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 severe morbidity issues afterward.
And what’s additionally vital 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 on the subject of stone formation. And this may occasionally seem with longer-term follow-up, however in the interim the proof is sort of promising and we must 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 life-style 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 authorized 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 best within the determine. And that is actually the inhibition of farnesyl pyrophosphate synthase, which is vital in selling attachment of the osteoclast to the bone. And the NCCN does need to spotlight the uncomfortable side effects of those brokers, and this consists of an acute part response, joint ache, hypocalcemia, osteonecrosis of the jaw, nephrotoxicity, which is vital to dose modify for those 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 possibly can see the mechanism once more right here on the best. And it is a monoclonal antibody that binds to the RANK ligand and competitively inhibits the RANK receptor.
Negative effects are form of much like the bisphosphonates, the NCCN notes hypocalcemia is vital, 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 consists of 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 at the least one dose of a bisphosphonate, probably zoledronic acid, 4 or 5 milligrams to stop rebound bone loss and fracture on the time of stopping denosumab.
So actually what it comes right down to is which agent is best, and there is not 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 enhance lumbar spinal bone mineral density, with zoledronic acid having the best bone mineral density achieve. Secondly, all bone protecting brokers and denosumab considerably elevated complete hip bone mineral density. Once more, denosumab results in the best bone mineral density achieve once we’re trying on the hip side. 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 research is that denosumab might doubtlessly outperform different bone protecting brokers, however the usage of a bone protecting agent is vital 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 instrument, 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 12 months on therapy. Nevertheless, there is not any consensus on the optimum method to monitoring the precise effectiveness of those bone protecting brokers.
What in regards to the period of therapy? There isn’t a consensus guideline for a 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 soundness of the bone mineral density, the prior fracture threat, in addition to the long run 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 embrace utilization of the FRAX algorithm, which is definitely accessible on-line. A baseline DEXA scan must be obtained earlier than beginning ADT in sufferers susceptible to fracture primarily based on FRAX screening. We have to optimize bone well being, and this not solely consists of calcium and vitamin D, however applicable pharmacological therapy with both zoledronic acid, alendronate, or denosumab when clinically indicated. And actually it is 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.
