So You’re Gonna discuss bone health and androgen deprivation therapy

Joseph Ischia: “Welcome to another episode of So You’re Gonna this is the podcast brought you by the team at Talking Urology where we like to help you deal with the everyday issues that you experience in your urological practice. Today, I have the pleasure of chatting to Dr Eugene Estella. He is an endocrinologist and based in Brisbane with over 20 years of experience of looking after men and their hormone-depleted prostate cancers, and really, probably more important than their prostate cancers is their androgen-depleted bones. So, welcome Eugene it is a pleasure to have you on the podcast.

We are going to start with the importance of bone health. Let me just run through some simple facts to get things started. We know the serum testosterone and estrogen fall to subnormal levels during androgen deprivation therapy. These hormones are important for maintaining bone health and bone mass because they exert antiapoptotic effects on osteoblasts and osteocytes and proapoptotic effects on osteoclasts. This is important because 70% of men with prostate cancer are over the age of 65 and already at risk for osteoporosis. We know that men with known metastatic prostate cancer receiving continuous or intermittent ADT can have significant loss of their bone mineral density and that can happen as early as the first 6 to 12 months. Men who receive continuous ADT will experience bone loss of up to 10% over two years and clinically significant annual bone mineral density decrements of 5% at the lumbar spine, 3% at the total hip and 4% at the femoral neck. The risk of fracture increases by at least 70% for hip and 20% for vertebrae for men on androgen-deprivation therapy. We also know that around 20% of men with prostate cancer on ADT will have a fracture and that is compared to only 12% of men in a match population who are not on androgen-deprivation therapy. So, there are the basics Eugene, is there anything that you would like to add to that or shall we just get straight on to the DEXA scan?

Eugene Estella: Oh, the main thing would be that a fracture for a man on ADT is an independent predictor of their mortality and morbidity. So, if you take everyone at the end of five years, men that haven’t had a fracture 70% of them are still alive whereas those that have had a fracture only 50% percent and though they’re older men, 69 and up on average, it’s still very significant.

Joseph: Good. Let’s get into the nitty-gritty of what we need to do and how we can look after these men. Let’s start with something as easy as what is a DEXA scan and what are the normal ranges?

Eugene: So, a DEXA is just dual energy x-ray absorptiometry and it’s essentially a low dose radiation source pointed at the hip or spine, sometimes wrist, and from that you can get density scores in grams per centimeter squared or a standardized scoring called a T-score which is measured against 30-year olds on average and Z-score which is measured against age/sex matches.

Joseph: And what are the normal ranges for the DEXA scan?

Eugene: So, a normal range is considered anything above -1 as a T-score and then osteopenia anywhere between -1.1 and -2.4 and osteoporosis by WHO standards is anything minus -2.5 or lower.

Joseph: When should we be doing a DEXA scan in men on ADT with prostate cancer?

Eugene: So, it’s a good idea to do one within the first month or two when ADT is initiated it’s worthwhile activating a DEXA scan plus or minus lumbar thoracic spine x-ray just to look for occult crush fractures that pre-exist.

Joseph: And how often should we do it on these men?

Eugene: So, if a man has a very normal bone density scan then maybe once every two years while on ADT or if they have a T-score -1 or below but they’re not getting any treatment, they’re just being observed, then every year.

Joseph: What numbers that you’ve mentioned there, you’ve mentioned -1 and -2.5, when do we consider treatment in men that have just commenced ADT? So, we’re not yet talking about rib fractures in castration-resistant prostate cancer just your run of the mill man starting ADT for prostate cancer. Who do we need to treat?

Eugene: So, anyone that’s -2.5 or lower and then depending on the person and other risks. If they’re in the -1 to -2.4 group and they have multiple other risk factors or particularly they’re older, then FRAX calculator will certainly pick out those that will get the most benefit.

Joseph: All right. What is that? You’ve mentioned there a fracture risk assessment tool. How are they adding to the DEXA scan?

Eugene: So, they take into consideration the big factors. Age is number one for fracture risk. The difference between a man fracturing at 60 versus 75 is massive, it’s exponential. So, we’ll take into consideration age, that it’s secondary osteoporosis, other factors like alcohol, smoking, steroid exposure and it’ll factor in if they’ve had a previous fracture, family history of fracture and what their bone density is and together give a really good idea whether they are going to benefit from getting bone or osteoporotic treatment.

Joseph: So, let’s go through those treatments there. We’re going to keep it simple, remember, we’re just urologists. What are the key steps in bone health management? Let’s just start with, say, the lifestyle modifications. What advice do you give these men?

Eugene: So, the main lifestyle modifications are things they take in, so toxins, smoking, alcohol both make a difference reducing those or cutting out the smoking altogether and then general exercise. Any exercise is good, will reduce your risk of falling and fracture. And then if they are keen and able, then some resistance training will increase their bone density potentially a couple of percent.

So, it depends if they’re— and generally makes them feel better because they also have the other low testosterone symptoms of fatigue and decreased motivation muscle loss, so there are the lifestyle factors.

Joseph: Great. We’ve got a great podcast coming up on the benefits of exercise on men with ADT as well, so we can stay tuned for that. So, you’ve mentioned the simple factors then, how about sort of early easy therapeutics such as calcium and vitamin D. Do you recommend these?

Eugene: Yes. They’re really useful when you talk about other pharmacology. On their own, they have a mild effect. Certainly, if people are deficient in vitamin D, that needs to be replaced before they use any other drugs to prevent hypocalcemia. But if vitamin D levels checked and it’s less than 50 or 60, then the person needs loading up with even 4000 units a day for a few months and then background dosing around 1000 a day to make sure levels are adequate of vitamin D and then calcium around 500 to 1000 milligrams a day. Usually it can be a little bit more in older men over 70 but generally low doses of both are worthwhile.

Joseph: So, if someone’s vitamin D is above 50, you wouldn’t recommend it because admittedly I’ve sort of been giving it to everybody but here you tell me I’m overtreating the vitamin D.

Eugene: Well you can’t. It’s very difficult to overdose on vitamin D and it will cover particularly winter or seasonal variation and so often these men are getting into a stage of life and the treatment itself is kind of a catabolic thing. They’re likely to become vitamin D deficient in time, so I don’t think it’s a bad idea at all to wholesale or give everyone some and then certainly load up vitamin D for a few months in those that are low.

Joseph: All right. So, I touched on it earlier and I didn’t let you finish the treatments that are available beyond these simple measures. So, let’s start with men with osteopenia or osteoporosis just starting ADT. If you’re very concerned, what levels would you consider the pharmacological agents of bisphosphonates or other agents? So, give me the number and then what you would do.

Eugene: So, to give you an idea, if you had a FRAX calculator, a man who is 74 that had a bone density scan, the T-score was -1.5, but otherwise they’re healthy clean living and then they just have testosterone deficiency, the their actual risk of breaking something over the 10-year period, anything, is around 20% and fracturing a hip about 5-6% so even though their bone density is not osteoporotic they haven’t broken anything, they’re one of the men that would really benefit from getting preemptive preventative pharmacological treatment. Otherwise, say, if you had a 65-year-old man with the same parameters, they wouldn’t. They’re about four or five times less likely to break something, so a 65-year-old man and have to have knee osteoporosis like a T-score a -2.5.

Joseph: Because I know a lot of these pharma companies put a lot of time and money into doing these trials to show that they would be primary preventative. But as we know, they’ve all essentially been negative and now we’re really just looking at men with castration-resistant prostate cancer where the absolute indications are for prevention, but that’s really in all comers and we’re really talking about a different group of patients, aren’t we? It’s important to know that these are osteopenic or osteoporotic patients who are going to benefit at this stage.

Eugene: The other risk factors apart from the bone density itself helped give you an idea of what their bone strength is like. Say, anyone on glucocorticoid, it doesn’t matter what their bone density says, they’re going to have weaker bones than the average person. Bone density is the best thing that we have, the ideal would be to take a bone out and try and break it, but you can’t do that. So, we use the bone density, but those other factors have to be considered for each individual when you’re getting ready to start a treatment.

Joseph: And what treatment would you consider first line in these men.

Eugene: Simply having osteoporosis or osteopenia being a higher risk then your choices are bisphosphonates whether it be zoledronic acid which is probably the preference for mine because it’s once a year, intravenous, it’s done, the company help supply someone to give it and there’s no real compliance issues which you will get into trouble with oral bisphosphonates, people just don’t take them or just forget to take them once a week or once a month. The other one is done is probably Denosumab. It’s once every six months subcutaneous injection, very easy, low side effect profile and renal function you don’t have to worry about too much, although if you are vitamin D deficient then you can still end up with hypocalcemia. And then, if people have developed bony mets or they are occult bony mets, then it certainly would be the favorable agent over zoledronic acid.

Joseph: So, you prefer the Denosumab in men with the bony metastatic disease.

Eugene: Yes. There are studies going up. Both of them are effective, but it appears that the Denosumab will prevent bony morbidity and mortality endpoints for three or four months longer than zoledronic acid will.

Joseph: Well, there we go. We have a point of difference. Let’s just quickly move onto a different category of men. These are old comers with bone metastatic castration-resistant prostate cancer. Now these are the men where I think, as urologists or clinicians treating prostate cancer, it’s probably one of our worst performing areas in that we under treat these men. So, all these men from what I understand should be on some sort of bone protecting agent. Can you elaborate on that? Is that is that the truth or am I making that up?

Eugene: Well, it’s clear authority PBS listing it’s more oncology treatment than osteoporotic treatment they’re getting like 120 mg double dose Denosumab every month.

Joseph: So, we’re talking of very different doses here as well.

Eugene: Yes, yes, yes, big doses. So that’s a similar treatment that someone with breast cancer or myeloma would get. They are often sicker group and they are risky a group for hypocalcemia and side effects from the drugs. They are the risk group, you know, it’s 1 in 100, 1 in 50 get the osteonecrosis and a good percentage of them, probably 1 in 5 get significant hypocalcemia they’re the group that you really need to make sure people have optimal vitamin D levels, calcium replacement and watch their kidney function if they’re on Aclasta or zoledronic acid.

Joseph: Okay, that is fantastic advice. Let’s get down to the pure practicalities for a moment Eugene. Let’s just run through the different agents we’ve gone through. Zoledronic acid, what dose are we giving and how often? Just to summarize.

Eugene: So osteoporosis only. It’s weird but it’s a slightly different dose. It’s a 5 mg dose once a year, Denosumab 60 mg once every six months, the Actonel or Risedronate 35 mg once a week, so that pretty much covers just about everyone.

Joseph: And how about when we get into the more advanced cancers? What doses are we giving then and how often?

Eugene: Yes, the zoledronic acid then becomes 4 mg which is a 1 mg difference but that’s on the authority drugs, a dose every month, and Denosumab 120 every month.

Joseph: And we’re really bashing through the key points. The initial screening, what do we need to do before we start men on these agents?

Eugene: So, just doing a FRAX, the University of Sheffield from the UK, you can get it on the internet for free, a FRAX calculator just doing it doing it out once at the beginning, with a bone density plus or minus the x-ray of the spine and then basic bloods of the Electrolytes and LFT, vitamin D, parathyroid hormone, you can do thyroid function tests as well but that’s about all, mainly vitamin D, calcium and renal function.

Joseph: And how do we screen for osteonecrosis of the jaw? Do we need to send them to a dentist?

Eugene: Yes. It’s pretty uncommon. It’s worthwhile every one probably at the very beginning. If they haven’t had a dental check within the last year, just having a dental check initially, so that if there’s something that’s significant that needs to be done, they can get it done before they start a treatment. Although on saying that, if it’s just for osteoporosis, the chances of getting osteonecrosis is like 1 in 10,000. It’s very low. It’s only the people that are getting it every month in big doses that run up that high risk of 1 in 100 to 1 in 50.

Joseph: Well, that’s good to know. If you had to pick one or two of the key side effects or monitoring points that we need to make with patients on these drugs.

Eugene: So, the main ones would be particularly on Aclasta, doing an Electrolytes and LFT which just covers calcium, creatinine and a vitamin D. And then on Denosumab, again, it’s really just the same. Just an ELFT to see that their calcium is okay. Because if people are going get into hospitalized side effect trouble, it’ll be through renal shutdown and severe hypocalcemia with tetany or seizures.

Joseph: And how does osteonecrosis of the jaw actually present? What will the patient come in and tell you?

Eugene: Yes. It’s not as brutal as internet photos will portray with half the jaw missing. I think most people present before that happens. The only cases I’ve seen of it are essentially they feel with their tongue, say, where the wisdom teeth used to be, so most commonly at the very back, and just feel like there’s a raw area, not painful necessarily. And then when you look at it with a torch, it’s just like a 1 cm bare area that is a little bit yellowy. And then the treatment of the people I’ve known that have had it, they’ve had to stop the bone drugs and the dentist just derided the dead tissue and 2 out of 3 have healed up. It took a year but it healed up. And then one, just has ongoing trouble that’s just kind of festering. It’s not dissolving their jaw but it’s it just hasn’t healed up yet.

Joseph: You’ve really tried to raise the bar here for urologists. Now, they’ve got to look in patients mouths as well but I think they’re up to it Eugene. I have great confidence in them.

Eugene: The patient will feel it.

Joseph: You’ve been wonderful. I reckon we’re getting close to the end here. A couple of things to finish here. What do you think is one of the biggest mistakes you see urologists make when they’re considering the bone health of their men with prostate cancer?

Eugene: I don’t think they make mistakes. It’s really just with most people, like, just initiating something. Just take just taking that point to the side, most urologists wouldn’t have a FRAX calculator on their laptop or on their screen.

Joseph: I think you can be sure that Eugene.

Eugene: That’s all I would do. Just on the computer, get the link for the FRAX calculator and it’s so simple to use. You click a couple of buttons with the person there and then it spits out a number for you to look at.

Joseph: Absolutely. So we can put that in the show notes. We’ll put a link to that calculator and if urologists don’t want to this themselves, obviously they need to get them along to their colleagues such as you to take care of this side of things for them.

So, if you wanted to tell a urologist one thing that they can improve the management of the bone health for their patients tomorrow, so assuming they have done the calculator, what is one thing that we should be telling our patients, warning our patients or getting them to do? If you could choose one of all those myriads of options you’ve presented so far?

Eugene: Well, if they’ve done the FRAX calculator, they could easily ask the patient to see their local doctor to say, “They’ve got a high risk of osteoporosis, can you treat their bones? Because a lot of general practitioners do it all the time for everyone else, so that’s an easy thing to do. Just alert their main doctor to look at it and treat it or you can even ask the patient to do that and then they can follow that up themselves.

Joseph: Wonderful. Well, Eugene, it has been an absolute pleasure to chat to you. I think that bone health is incredibly important and something that we’re becoming more aware of and certainly with the development of men’s health clinics and the increasing role of endocrinologists in the chronic management of these patients who are living for a long time on a multitude of treatments for advanced prostate cancer. So, thank you very much for chatting to us today and I look forward to chatting to you again soon in the near future hopefully about all things urology.

Eugene: All right. Thanks Joseph. Thanks for having me.

Joseph: So that’s it for today folks. We hope you have enjoyed our discussion around bone health. We also hope that you have learned something new and will join us again next time. Take care. Remember to send all feedback to feedback@talkingurology.com.au. You can subscribe through Apple podcasts or wherever you get your podcasts, and check out the website at talkingurology.com.au. You can follow us on Twitter @talking_urology to get all the latest news and notifications of past and upcoming podcasts.

You’ve been listening to Joseph Ischia and Eugene Estella. Produced by Joseph Ischia and Cara Webb. And a special thanks to our sponsor of this episode AbbVie.

So You’re Gonna the practical urology podcast for those who love urology. Proudly brought to you by AbbVie

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