Welcome, my name is Dr. Warrick Bishop. I'm a cardiologist, an author and a keynote speaker. I'm CEO of the Healthy Heart Network. I'm all about trying to help people live as well as possible for as long as possible. Heart disease is huge in Australia. Every 20 minutes someone suffers a heart attack. Most of these could probably have been avoided if only we knew what to do. This podcast is all about helping you understand blood pressure, weight, cholesterol for better health. If you enjoy this podcast, I would be honoured for a five-star review. You can share it with your family and friends. It may well save someone you love. Hi, my name is Dr. Warrick Bishop. And thank you for tuning into my podcast and videocastation. Today, I'm interviewing Dr. Helen Cooley, who's a local rheumatologist here in Hobart. Hello, Helen. How are you? Hi, thank you for having me. Look, this has been a series on osteoporosis. In our first episode, Helen and I spoke about what the condition is, what it means, how many people it affects, and really, to a large degree, cost to the community. and some of the diagnosis behind it. In the second podcast, we talked about really the things you should be doing lifestyle-wise to try and mitigate that risk and be sensible about osteoporosis and dealing with it really before it's a major problem because the mortality, morbidity behind it is so significant. In this particular interview, I'd really like to touch on the drugs. There's probably a little bit of complexity there. I don't know too much about it, and I'd love you to share with me, Helen, how you go through these drugs. What are they? How do they work? How do you implement them? Where are the pros and cons? How would you take a patient? Let's take a patient journey on the drugs, say a postmenopausal woman who comes to you with significant osteoporosis. How do you deal with the drug side of things, Helen? Okay. It's a very good question. I think, first of all, we go through what are her risks, what drugs she's currently taking, you know, particularly drugs like prednisolone or cortisone. Can we reduce that, for example? Again, the lifestyle things, what's her diet like? What's her calcium intake like? What's her vitamin D? Has she had a fracture? I think that's very important. In terms of deciding to treat someone with medication for their osteoporosis, it very much has to be patient-centred and the patient fully involved in making the decision. We are also a little bit limited by the PPS in our drug choice. They have numerous funding paradigms for who can get what. So if you've had a fracture, a minimal trauma fracture so that's considered a fall from a standing height then you're eligible for medication if you're more than 70 years old and you have a t-score so that's the score that we use in measuring how severe your osteoporosis is so if it's less than minus three you can start therapy and also if you have a t-score of a more mild T-score of less than minus 1.5 and you're about to start prednisolone or corticosteroid therapy for more than three months because we know that can rapidly impact in a detrimental way your bone density, you'll also be covered. Then in terms of the drugs, we've got a number of options, which are also a little bit dictated to us by the PBS. So we have drugs that a lot of people would be familiar with because they've been around for a long time. So that's a bisphosphonate group of medications. So the oral drugs there are Alendronate or Fosamax, Resetronate, or Alendronate, and they've been around for a long time. They're very, you generally take them once a week on an empty stomach with a glass of water. So if people have significant reflux or they're frail, then we're likely to be lying down. They're not drugs that you would use. And they're very effective drugs, but people have to take them. And we do know that compliance. isn't that great with these medications. Hela, what's the mechanism for the bisphosphonates? How do they actually work? Okay, so bisphosphonates work as an anti-resorptive agent. So in postmenopausal women, your bone... turnover is high people may not be aware but your bone is turning over all the time so your skeleton is younger than other parts of you and when you get into menopause your bone turnover rate increases with the net loss in your bones so these drugs work by slowing the bone turnover rate so that you don't lose bone as fast Okay. And do they alter the quality of the bone or not really? No, no, that should be okay. Yeah. I should mention that these drugs are also used in Paget's disease, which is another high turnover of bone where there is altered bone quality and that can be normalized with these drugs. There's also the intravenous form of... a bisphosphonate called zoledronic acid or a claster or a zameter. That's been around for a long time. And that's usually given as an annual infusion anywhere between three and five years. That has the advantage that it persists for a long time. And if someone's bone density comes up nicely after that treatment, they may well be able to not have any further treatment and we just watch them. The other drug that's used very commonly these days is prolia or denosumab. So that's an injection into the tummy once every six months, and many of my patients would just do it themselves. And that's also a very effective treatment. And denosumab is a bisphosphonate as well? No, that's a different class. So this works on... It's actually an antibody that blocks a chemical in the bone that switches on the cells that eat up bone a bit faster, the osteoclasts, if that makes sense. Yeah, okay. So I should have guessed that because it ends in MAB, M-A-B. So for anyone listening who doesn't follow medical jargon too much, like I wasn't paying attention, something MAB. normally means that that last three letters refers to monoclonal antibodies. So it's directed to a very specific target. It's called biologicals, I think. This one isn't. Oh, okay, there you go. Yeah, this one actually isn't. And initially there were some concerns about using it, whether or not there might be some issues with infection with this drug, because the thing it blocks is a thing called rank ligand, which is also important in switching on some other signals involved in infection management, but it hasn't proven to be the case, which is good. There's another... Sorry, you said... Dunosumab turns off the osteoclast. Yes. Yeah. And the osteoclast is what breaks up the bone. The osteoblast is what puts down the bone for those who are listening and wondering about clasts and blasts. Okay. Cool. An injection every six months sounds like a nice, easy way to do it. Look, it is, and it's very palatable. We haven't really covered side effects. So one of the things about denosumab, though, is that when you start it, you need to continue it because it does wear off. And then if you miss an injection for a period of time, we have seen people have a rapid loss in their bone density and then present with even one, two or three fractures in their spine. And that certainly became clear with COVID. where people weren't getting to have their injections for various reasons that then were developing fractures. So this isn't a drug that I tend to use in my younger women with osteoporosis as a first line. For completeness, there is another drug called Avista or Riloxifene. Now that's not used so much. It's a very old drug now, but I think it still has its place. Its fancy name is a selective estrogen receptor modifier. So if you like, it sort of tricks the body into thinking that it's still getting estrogen without the potential estrogen side effects. So it almost leaves the body. It tricks the body to think the woman hasn't gone through menopause. Yeah, a bit, yeah. So it's not as effective as the other groups. It's quite good with vertebral fractures, but data around preventing hip fractures is not as good. So it has dropped down the line. There's also newer drugs that we've got, which currently you can't access until you've had a fracture on these other treatments and your bone density scores less than minus three. And these drugs build bone. They're called anabolic agents. So they actually build bone. And there are two drugs that both have different mechanisms of action. sorry, teriparatide, and that mimics the body's parathyroid hormone receptor peptide to bind on and switch on the osteoblast to make bone. Yeah, okay. The second one, it's also another mouthful, is called romososumab. It is a mouthful. You can order that at your local Italian restaurant just about. It's actually got an interesting... Oh, it's a MAP as well, I noticed. It's a MAP as well, yeah. It's also been around for a while but has only been recently approved in Australia. It's actually got a really interesting story that comes from good detective work. They identified families who had, like, super, super thick bone and found that they had a genetic deficiency. I think I'm going to get this round the right way. sclerostin. So they figured, well, if they're a bit sclerostin, no, no, maybe they, sorry, they overexpressed the sclerostin. So they thought, well, we made an antibody. Yeah, sorry. No, I had it around the right way. They were a bit deficient in the sclerostin. So they had this really thick bone. So they figured that if they made an antibody to it, that may be able to help people with osteoporosis build bone. And that turned out to be the case. And what's, did you call it sclerostin? Sclerostin, yeah. It's a substance in the bone. And you need it, I might have to, and you need that to sort of, blocking it allows you to build stronger bone. Yeah. That's interesting. So you've got. The bisphosphonates, denosumab, so the monoclonal directed to increasing osteoclast activity. You've got the... No, it inhibits the osteoclast activity. Inhibits the osteoclast. Yeah, you want to turn up the blasts, turn down the clasts. You've got rilofixin. Riloxifene, yep. Riloxifene, which is the... estrogen receptor modified. That's right. Anabolic agents. Yep. So either of those, but one turns on the osteoblastoma and obviously changes that protein, which is central to building thicker bones. That's right. Yeah. So it binds to sclerostin in the bone and stops it working. And it's also given by a monthly injection. So have you got many patients on these new anabolic agents? I've got a few, not so many with, on the Romasozumab, but certainly with the teriparatite I have, yeah. Yeah, okay. And you're, just when we go back to the original sort of intro. Yeah. Dealing with a postmenopausal woman who's come to you, do you step through these agents? I mean, you say it's obviously fairly. important that you become very specific and tailor your therapy to that yes yeah yeah i i do um again as i said one of the things was so we'll assume it's um you know a post-mental woman with a fracture so that that's the major group um and they have the most choice and where all these studies have mostly been focused at because they're the biggest group of people affected. Poor old men have missed out, but they now are being included more in trials than what they were 30 years ago. It's actually reverse sexism for once. Yeah, yeah, yeah. Well, we've been guilty the other way with cardiac trials. Yes, you have. So it's a matter of talking them through how they feel about having an injection. I may come back to a little bit more about the side effects. So certainly with the oral agents, some people think, yep, that's fine. I can have my alendronate once a week on a big glass of water, go for a walk, have a shower, then come back and eat my breakfast. That's no problem. If they had bad indigestion symptoms, I wouldn't go there at all. The intravenous zoledronic acid is very convenient. That's intravenous bisphosphonate. Some people who get, you need to have enough vitamin D and have normal kidney function to have that drug. Some people get quite bad aches and pains with it for 24, 48 hours. Often that can be quite nasty. And so we tell our patients to have plenty of paracetamol about the time. It usually doesn't occur on the second and third infusion, but it can be a hard sell, as you can imagine. With the bisphosphonates, the elephant in the room I have to talk about is a dental complication, which dentists in particular get very worried about, but it's actually quite rare. in our group of patients. So they are concerned about a condition called osteonecrosis of the jaw. So that means if you have invasive dental therapy, such as not a teeth clean or a tooth filling, but say you have a dental extraction, you have a risk that it won't heal properly and you have exposed bone in your mouth. And it can be very painful and difficult to treat. But the incidence in our group of patients is about one in 20,000. it's not a big risk at all, whereas your risk of having a fracture, you know, some of these women, their risk of having a fracture is, you know, 30% or 40%. So it is about just going through that with the patients. And I do ask them to have a dental check and if they need work done. get it done before you start your treatment. And it just takes that anxiety out of the situation. These bisphosphonates are used in the treatment in some cancers too, particularly breast and prostate cancer, and they have these treatments much more frequently and have a higher risk of osteonecrosis. John, they've also often had radiotherapy and can be generally a sicker group of patients, but it is something to talk to the patients about. Look, I think, we all recognise there isn't a zero-risk world. And that conversation, I think most, in my experience, all patients are pretty open to that sensible discussion, saying, look, this is a very small risk. We can't get rid of that. Your greater risk is this. And the equation is that you're more likely to benefit. Very hard to sidestep any risk at all. Yeah, that's right. So it is talking them through. And some women may really like the idea of just having an injection once every six months in their tummy. We do do the dental check, et cetera, for that as well, but osteonecrosis, because that has also been reported with the denosumab as well. And as I've mentioned, I do stress to them they need to keep going with it. And the reason why I prefer not to give it to younger women unless I really have to is one question that we don't know about treatment with osteoporosis is, you know, can patients have a drug holiday at five to ten years, which is a different concept to treatment for, say, hypertension or diabetes, for example. rheumatoid arthritis because once you get to about five to ten years, particularly with these two group of drugs, because we've turned your bone density, bone turnover down, there is a risk of an atypical fracture which does seem very ironic and they tend to occur in certain places of the inside of the femur and it's probably related to the fact that the bone turnover is down. It's rare. It is rare, but it is something, again, that I have in my mind when I'm talking to a 60-year-old with osteoporosis and a fracture compared to like a 75, 80-year-old with osteoporosis. What do you mean by an atypical fracture? How do you mean it's different? Because it's not a typical fracture where you've had a fall, and it tends to be in a certain place on the inside of the femur bone and can present just with bone part. And it's just like a little crack. It's not all the way through, but it can go all the way through. So these are just things that I have to think about and talk through with patients when we're talking about treatment. Okay. Any sort of side effect issues with the anabolic agents? Well, certainly the teriparatide is given as a once-daily injection for 18 months, so that can be a bit tedious. But my patients are pretty good at learning how to do it and they just get on with it. The romososumab is given monthly as a subcutaneous injection. The teriparatide treatment's limited to 18 months, again, because in the beginning when they did the studies, they do animal studies and found that rats getting a lot of this drug. way above what would be the doses we use in humans to develop cancer in the bone, a sarcoma. So it's been limited to 18 months treatment, although more recently the FDA, the drug authority in America, have taken off that black box warning because it just isn't seen in people. There is some concern, and it was part of the reason for the delay in the romososumab coming to the market that early studies suggested that there was more heart issues, heart attacks. They're not entirely sure of the mechanism, but it's possible that sclerostin plays a role in vascular homeostasis. So that wouldn't be a drug I'd give to someone with bad heart disease. Okay. And the selective estrogen receptor modifiers? Yeah. They don't have a lot of side effects. Some people do get flushing. If there is a history of leg thrombus, like a DVT or a pulmonary embolus, I wouldn't use them. They do offer a little bit of protection for breast cancer, so that is appealing to some women. But if they've got severe osteoporosis, that's not the drug for them. Yeah, okay. And we don't currently combine therapies at the moment. You don't combine therapies? No. Okay. That's interesting. Is there a reason why you don't combine? Well, I think there's a little bit of lack of data about the efficacy. There is some stuff coming with giving. In an ideal world, we'd probably like to give people the anabolic drugs first and then step down to the other ones. But currently in Australia, we can't do that. And it probably relates more to cost. that sort of is changing. There are some studies now looking at giving like the anabolic agents like some teriparatite and a bit of denosumab at the same time to really augment people's bone density gain, but that's not done commonly. Yeah, okay. We certainly use multiple agents simultaneously. for blood pressure and for cholesterol these days. And we're able to use lower doses and get, if you like, an additive effect. So the lower doses, lower risk of side effects, multiple different targets, we get better results actually. So it'll be an interesting space in the future. Helen, this has been a fantastic walk through the pharmacotherapy and we'll wrap it up. But what I was going to end with is... You've got the floor speaking to perhaps some of the listeners who are maybe men in their middle age, women in their middle age. What's your advice about them looking after themselves and their best bone health into the future? What would you be recommending? Well, I think best bone health really reflects best. general health is the the if you like the practical things around your bones reflect good cardiovascular health reduces your risk for cancer etc so that is exercising regularly not smoking you know a good diet that is got lots of leafy greens is quite varied getting exercise you know all these really basic what sound like kind of motherhood things but i think really they're all the stepping stones, if you like, to good health as we age and hopefully can minimise your risk of having a fracture and needing medication. And are there any particular target groups who you might say, look, 70 is perhaps a little bit late to be starting to identify osteoporosis because you'd rather identify it earlier? Are there particular groups? Look, I think probably... around perimenopause time, probably age 50 for a lot of things is a good time to start thinking about what you're doing in terms of your exercise and other lifestyle things. Obviously, if you have conditions that are associated with an increased risk of osteoporosis. then your bone density should be addressed. And certainly if you have a fracture, it needs to be thought about then. And that's often an area that is missed a lot. Someone can have a low trauma fracture and nobody thinks about measuring their bone density. Yeah, okay. Well, what a very interesting series of conversations about osteoporosis. Thank you so much for sharing. I hope you've got... If you've got half as much out of this as I have, you will have got a lot. What a great summary of osteoporosis, lifestyle and pharmacotherapy. Thank you so much, Helen. Pleasure. For those listening, I do appreciate you tuning in. Until next time, live as well as possible for as long as possible and look after your bones. Join the Healthy Heart Network and become part of our growing community. Do you want to know more about your heart health and know more about your risk of heart attack? 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