- 22 Nov 2022
- 21 min 44
- 22 Nov 2022
- 21 min 44
David Liew chats with rheumatologist Lyn March and trainee physician Jimmy Zhu about the latest in osteoporosis – how to assess risk, lifestyle factors, and the drugs used to treat. Read the full article in Australian Prescriber.
Exercises that are particularly helpful include programs that involve multiple different types of exercises such as focusing on resistance training as well as balance. Even non-weight-bearing exercises such as swimming can help reduce the loss of bone density.
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Osteoporosis, the progressive loss of bone mineral density and micro-architectural deterioration, is incredibly common and can lead to real morbidity, especially related to minimal trauma fractures. The therapeutic landscape is getting increasingly complicated though, so how can we navigate this?
I'm David Liew, your host for today, and in Australian Prescriber, we have an excellent article on treating osteoporosis written by Professor Lyn March, the head of rheumatology at Royal North Shore Hospital and a Professor at the University of Sydney, and Dr Jimmy Zhu, one of her physician trainees.
Lyn and Jimmy, welcome to the program.
LM: Thank you, David.
JL: Thank you.
So, Jimmy, maybe I can ask you, how common is osteoporosis in Australia and who should we be really worried about?
JL: Osteoporosis is quite common in older Australians. It's estimated that up to two-thirds of women and one-third of men over the age of 50 will experience a minimal trauma fracture at some point in their lifetime, and it’s really difficult to estimate the exact prevalence of osteoporosis in the community because it is an asymptomatic disease prior to people presenting with a minimal trauma fracture.
I guess to try and capture that risk is not a straightforward thing to do. Lyn, how can we go about trying to risk-assess the right types of patients who might require assessment, who might be at risk of fracture? How has that evolved over time?
LM: Clearly, the key risk factor is someone who's had a fracture. So if they're over the age of 50 and they've had a fracture, they're significantly more likely to have another fracture. So, if anything else, the takeaway message if you've got a patient over the age of 50, you must assess them for their osteoporosis risk and future fracture.
But also, looking at the MBS criteria for bone mineral density testing in Australia gives a fair clue. So people who are over the age of 70 should be part of routine screening, people with chronic inflammatory conditions like rheumatoid arthritis, anyone on long-term steroids, chronic kidney disease, early menopause as well is a key risk factor and a range of other drugs, but the key thing not to forget is someone who's already sustained a fracture at the age of 50 or over.
What about the assessment of osteoporosis? Do you think that's something that's evolved over the course of time and the way that we see it?
LM: Well, certainly we're lucky here in New South Wales that we have osteoporosis refracture prevention services, so we are actively screening, with electronic search tools, our medical records to identify people who've been through the emergency or in hospital or the outpatients who've actually had a fracture, and screening them in that way, so that has definitely improved.
In terms of other screening, it's more around making sure that we are able to do a bone mineral density on people over the age of 70 as part of the MBS, and trying to actively encourage people to do that. I think that's one of the particular things that hasn't been picked up very well since it's been there. It's available to us to do and we just need to remember to do it.
Absolutely. Jimmy, perhaps you can talk us through the broad building base approach to management of osteoporosis. Before we get to medicines, there really are quite a few options that we should be thinking about, aren't there?
JL: Yes, there are a lot of different lifestyle factors that we can address in the management of osteoporosis because, on top of having brittle bones, quite often fractures are precipitated by things like a fall.
Management such as exercise is crucial in minimising patients' fracture risk. Exercise has been shown to be able to both build up bone density as well as reducing people's falls risks which, combined, will reduce their risk of a fracture. Exercises that are particularly helpful include programs that involve multiple different types of exercises such as focusing on resistance training as well as balance, or some programs that include Tai Chi are also very useful in reducing falls risk Even non-weight-bearing exercises such as swimming that were previously thought not to be helpful in osteoporosis can help reduce the loss of bone density.
Other lifestyle factors that can be addressed include calcium and vitamin D intake as calcium and vitamin D are vital in the buildup of bone and the prevention of ongoing bone loss. With calcium it's recommended that older people get between 1000 and 1300 mg of calcium per day and we recommend as a first line to replace this through dietary sources such as dairy as well as fish and vegetables. Vitamin D is also suggested for people who are vitamin D deficient. Again, we would suggest first line by exposing vitamin D naturally through sunlight exposure but, if required, we would provide supplementation in the form of tablets to aim for a level of at least 50 [nmol/L] if we were planning to start some medical therapy.
It's so easy to go straight to the prescribing pad but plenty for us to remember there. I guess once we do get to the prescribing pad though, bisphosphonates really still are our first-line therapy, aren't they? So, when should we be using them and what do we have to consider?
JL: Bisphosphonates are a very good first-line management for osteoporosis. They're in the antiresorptive class so they prevent the further breakdown of bone. They are offered first line in osteoporosis for people over the age of 70 who have an established diagnosis from a bone mineral density scan, which is a T score of less than –2.5, and it's also available for people with T scores of less than –1.5 who have already had an established osteoporotic fracture. Bisphosphonates are a useful first line because their effect is durable and there is the window for a drug holiday later down the line if their bone density were to improve and they weren't to have any further fractures.
Lyn, perhaps I can ask you about this idea of durability in drug holidays. I think the thinking has evolved over the course of time. Where do we stand with that right now?
LM: I guess we've rebounded a bit on that initially saying everyone should stay on them forever, then identifying that in fact there were some risks particularly with long-term use of bisphosphonates and the risk of atypical fracture. Rare but not nice when it happens. And that risk comes on around about the 10-year mark. It sort of gradually increases from five years on. So then there was a big swing back to say right five years, everyone stop. When that's been analysed at that level, sometimes then the fractures that you see because they're still deficient, far outweigh the rare risk of atypical fracture.
So it's really swung back now to certainly assess people at the five-year mark and decide whether they still need ongoing treatment or not, and for that, you're guided by have they had any other fractures during that time period? But also, if they're still osteoporotic or even –2.5, definitely keep going with some therapy at their femoral, neck or total hip, but even –2, some people would say if they're high risk of falls and levels of frailty, you would keep some treatment going.
Many people will need to stay on some form of therapy, almost lifelong for some of them, but really just adjusting, reassessing their ongoing risk is the key message.
Thinking about rare risks as well, the other one that always springs to mind with bisphosphonates is the risk of osteonecrosis of the jaw. It feels like that thinking's evolved a little bit as well, hasn't it?
LM: It has. I think it's probably not as bad as we all thought it would be. But I think our understanding now, particularly with osteonecrosis of the jaw, is that it's not as common. It really is a rare event in patients being treated with these drugs for their osteoporosis, but it's an important message of the dental hygiene and, if people do need a dental procedure, that dental hygiene is strictly adhered to and far less likely to have any troubles at that point. People need to know about it but I think it's definitely been overrated.
There's a lot to reassure our patients with because I guess that's something that does seem scary from the outset. Despite the fact that we have a number of other agents, bisphosphonates really still are in the prime position for a lot of different indications. How do we go about choosing which bisphosphonate is right? Is there a difference for different indications for different bisphosphonates?
LM: Choosing bisphosphonates is really up to the patient's choice largely. Would they like to take a weekly oral tablet or a monthly oral tablet or would they like the intravenous? But of course then you need to bring in potential adverse effects. So because of the oral bisphosphonates and their risk of GI irritation, someone who has gastroesophageal reflux or hiatus hernia and those sorts of things, probably you wouldn't use an oral agent. Then the intravenous, there's the issue of their renal function and you might use an alternative agent such as denosumab, but if normal renal function, otherwise fit and well apart from their osteoporosis and their fracture that they might have had, it does come down to patient choice a bit.
Jimmy, denosumab has become immensely popular in Australia. How does that differ from bisphosphonates in terms of what it does and what are the precautions that we need to take?
JL: Denosumab has recently become quite popular because it's quite a convenient drug to give. It's a RANK ligand inhibitor in the form of a monoclonal antibody and it's given once every six months by the GP as a subcutaneous injection which most patients find quite convenient.
However, the new evidence is that the effect of denosumab wears off quite quickly once patients stop taking the medication or even if they've missed a dose. Their fracture risk very quickly reverts back to their pre-treatment levels. As a result they can develop multiple atraumatic vertebral fractures, which is quite a significant effect.
Because of this new evidence, this has led us to think twice about prescribing denosumab particularly to younger patients as a first-line treatment because there is the possibility that they would need to remain on the medication lifelong. And if they were to try and transition off the denosumab one day, they would have to go through a process of swapping to a different antiresorptive for a period of time to try and minimise their risk of an atraumatic vertebral fracture.
So really in terms of that durability, I guess perhaps that can be an important factor for many of our patients in terms of selecting an agent, Jimmy, would it be fair to say?
JL: Yeah, the effect is much more durable compared to denosumab. That's part of the reason why with bisphosphonates there is the possibility of a drug holiday for some patients, whereas when we're commencing someone on denosumab, we do counsel them that it's likely going to be lifelong therapy if they do elect to start this medication.
In terms of some of the things that we are concerned about with bisphosphonates, can we exonerate denosumab? So I guess I'm thinking atypical fractures, also thinking about osteonecrosis of the jaw. Where do we stand with denosumab?
JL: Denosumab is also associated with a very, very small risk of atypical femoral fractures as well as osteonecrosis of the jaw as quite a few of the other antiresorptive agents. It does seem to be less common than bisphosphonates and it is more common when it's used in higher doses such as the doses that are used for bone metastases in cancer or for myeloma rather than the doses that are used for osteoporosis.
Right. Well, let's talk about some of the other therapies and, Lyn, I think that over time we've seen an evolution in the way that we deal with menopausal hormone therapy. I mean that seems to have been an evolving story over the course of time. Where do we stand with that right now and osteoporosis?
LM: There's evidence from hormonal therapies that we have in terms of raloxifene, the selective estrogen receptor modulator that's available. Early data on that showed perhaps it really only prevented vertebral fracture and not hip fracture. Subsequent studies haven't really been done but it's still a useful agent in people who can't tolerate the bisphosphonates or denosumab or who have trouble.
Also, hormone replacement therapy for the longest time was used but didn't actually have any fracture risk reduction associated with it. But by the time we sort of found out that in fact hormone replacement therapy such as tibolone and those do have a fracture reduction risk, they then became the concern of increased heart disease and venous thromboembolic events associated with the HRT. So it keeps it as a second-line agent behind those other agents, but still very useful particularly in women in that sort of 55- to 65-year age group. When you're thinking this lifelong therapy, maybe there's that transition and counselling them and monitoring in anyone with high risk of breast cancer or strong family history, you probably wouldn't use it. Albeit the risk is quite low but a slight increased risk.
It's still a useful second-line agent, particularly in younger women and perhaps also in those women who have even had an atypical fracture because some of the atypical fractures we've seen in people who've kind of started in that very early postmenopausal period before they've fractured and then been on them for quite some time and then present first with their atypical fracture. In that bracket, we would sometimes use hormone replacement therapy.
Why don't we use more teriparatide, why do we have a time limit on the teriparatide that we use, and where do you think it really belongs in our therapeutic algorithm?
LM: That's a tricky one. Well, currently it sits as a third-line agent. Both teriparatide and romosozumab are available to us now as anabolic agents that actually build up bone, not just prevent the turnover. One, because they're a bit more expensive, but two, they have some caveats around the duration of therapy. Teriparatide is a daily injection that's not acceptable to all people as a first-line agent, and the time limit was put on because of the osteosarcoma that was identified in rats that has not ever been shown to be an issue in humans. But that's our sort of 18 months. Internationally, I think they allow two years. And romosozumab, as you know, the anti-sclerostin antibody, very powerful bone builder, but a slight cloud over it with the slight increase of risk of significant cardiovascular events.
How should we transition after these limited courses of anabolic therapies, whether it be teriparatide or romosozumab? How do we manage the transition off those agents back to antiresorptives in isolation?
LM: If you look at some of these agents in someone who is severely osteoporotic and you use them first line and build their bone up and then switch over to an antiresorptive agent, it might be a better way to use them. But we don't have that available to us so we can hypothesise that it might be better, but at the moment we need to use those agents in people who are fractured when they're on therapy and their bone mineral density is still showing very low T score –3 and that they've still got severe osteoporosis despite antiresorptive therapy.
But, having said that, it's really important that they do transition onto something because otherwise they will gradually lose their therapy. There's not been large trials done to say you definitely must do it this way or that way. Some data suggesting maybe the oral agents work better than the intravenous agents, but I still don't think that's clear cut as long as they go onto an antiresorptive agent after that.
Speaking beyond what's necessarily available to us right now, this idea of sequential therapy, how do you think that's going to evolve over the course of time? It seems like that's already been an evolving story as it stands.
LM: Yes. I think it'll just keep evolving, but whether we'll see large randomised trials that truly help us make an evidence-based decision is a little bit doubtful.
Okay. Jimmy, how do you go about monitoring the therapies that we have and their impact on osteoporosis?
JL: The first thing to monitor is how the treatments have had an effect on the patient, if they're tolerating the treatments well or if there's anything that could be limiting their compliance. For example, if they were getting significant reflux with their oral bisphosphonate, then we would consider changing them to a different agent and, secondly whether or not they've had another fracture. So if they have had another fracture, then we'll need to reevaluate our treatment and whether or not they'll be suitable for one of the anabolic agents. If they've remained clinically stable on the treatments, then we'd recommend repeating a bone mineral density scan or a DEXA scan every two to three years to monitor if they've had any gains or losses in their bone mass. We suggest testing out the same practice on the same machine because there can be some variability between different machines and different practices. And so the same machine allows for some consistency between readings.
If they have gained bone mass, that's reassuring to show that the treatment is working and we would continue onwards until they've reached the five-year point of needing to reevaluate the ongoing need of treatment. If they have shown bone loss in between their two scans while on treatment, then again we would have to reassess what the reason for the bone loss was, whether or not it was a medication compliance issue or if there's a problem with absorption. For example, some people with previous gastric surgeries or bariatric surgeries may not tolerate oral bisphosphonates or absorb them as effectively, which may consider swapping to a different form of bisphosphonate such as an intravenous bisphosphonate for their ongoing treatment.
Now, Lyn, can I ask you about bone turnover markers and where you use them in your practice?
LM: Bone turnover markers are tantalising. You think that they should be helpful for us and as a single one-off study, perhaps not so helpful, more to look serially within an individual patient. In Australia we only have the CTX available on the MBS for reimbursement and only once a year. The CTX is a marker of bone resorption and the P1NP is the other key marker that we would use quite frequently in the clinic setting, but not reimbursed by MBS. It is a marker of bone formation. But in someone who's actively osteoporotic and in trouble, both of those will be high and then we would hope with treatment that they'll come down.
Probably by at least six months those markers should be coming down with oral agents. With denosumab, the markers come down far more rapidly than that. We're allowed to do a bone mineral density at that 12-month marker as well to see if people are responding. Often the bone mineral density hasn't changed much, but it's quite reassuring to know if you've got a baseline CTX and that 12-month CTX to know that actually that's responding and then the bone mineral density improvement will follow subsequently because the actual reduction in fracture risk we may not see for two or three years.
CTX in particular was being used also by dentists at one stage, to screen whether there was going to be a risk for ONJ. I don't know that that's held up very well, but if people have very low bone turnover markers, well, you know that you're suppressing them well, but they might be at higher risk of things like ONJ and also atypical fractures, which is why they might also not respond so well to things like anabolic agents after they've had the fracture. So it's still not an exact science. It's still very important that it's done at the same time of the day. So the first thing in the morning preferably for those markers to be consistent.
So where do you think that the research is evolving across osteoporosis? What are you excited about that the future might hold?
LM: Well, I think we are going to get better at risk prediction and knowing the people that we can stop it in. With denosumab, it's well documented that they slowly go back to where they were before, but it's a small percentage, maybe 10% at most who get this rebound phenomenon. So better risk prediction of who those people would be. Similarly, of the other adverse effects. So knowing a little bit more about atypical fracture, that we are getting a good body of evidence of that. A little bit more on the sequential therapy, I think that's quite tantalising if you switch between agents and you do see this improvement in bone mineral density. I don't think we've got evidence that it improves fracture risk reduction and we know that there is that discordance between what happens to bone density and the risk reduction. So I would think that we'd see a little bit more in sequential therapy. We should be able to work bone turnover markers a bit better to fully inform us.
Well, plenty for leading researchers like yourselves to be working away at. So thank you for joining us today, Jimmy and Lyn.
JL: Thank you very much.
LM: Thanks, David.
Professor March and Dr Zhu have no disclosures. I am on the Drug Utilisation Staff Committee of the Pharmaceutical Benefits Advisory Committee. The views of the guests of the host on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew and thank you once again for joining us on the Australian Prescriber Podcast.