Peter L. Salgo, MD: Put some of this together for me. There’s the anti—RANKL [RANK ligand] drugs, right? We’ve got teriparatide and abaloparatide. We have got these 3. We have the anti-RANKL, we’ve got the teriparatide, and the abaloparatide. Where do they all fit? How do you use these drugs, clinically?
Andrea J. Singer, MD, FACP, CCD: Just to sort of group them for a moment: The new drug, romosozumab, as well as teriparatide and abaloparatide, would be considered our bone-building drugs. Denosumab, which is the RANK ligand inhibitor, along with the bisphosphonates are considered antiresorptive medications.
Peter L. Salgo, MD: OK. So they could potentially be complementary?
Andrea J. Singer, MD, FACP, CCD: They can be complementary, and there have been some small studies done looking at combinations of the drugs. Usually we use 1 drug at a time, except sometimes in very severe cases. But again, the more options we have in the armamentarium, the better we are—not only to be able to match an appropriate therapy with patients based on risk but also to think about patients’ preferences. As we discussed earlier, this is a chronic disease that is going to require long-term management. Teriparatide and abaloparatide, by label, are recommended for no more than 2 years of total lifetime use, either alone or in combination. Romosozumab, at the current time, is recommended for 1 year of use. But people don’t become risk-free after 1 or 2 years of therapy, so we have to follow it with something. That’s where the sequencing can become very important, and we need other options to be able to say, “Well, what do we do now?”
Peter L. Salgo, MD: Or other labeling. It’s possible, you know.
Andrea J. Singer, MD, FACP, CCD: Do you know somebody at the FDA?
Peter L. Salgo, MD: I know nobody at the FDA. I deny this under oath. I guess 1 of the ways you might want to look at this is people should get these drugs, and we’re going to go into money in a minute, because I have a bad feeling about this. But you should reserve these drugs perhaps for people at high risk for fracture?
Claire Gill: Well, that’s up to a patient and the physician. I think that’s what’s most important. It’s a decision between the physician and the patient, or the healthcare provider and the patient, regarding in what order the drugs are given and how they’re given.
Peter L. Salgo, MD: OK, well, let’s try to get a definition. What is, by definition, high risk for fracture? Is there a number?
Thomas P. Olenginski, MD, FACP, CCD: We talked about a continuum of risk. I’ll give you my personal continuum. The highest risk is the patient who has a clinical hip fracture, a clinical vertebral fracture, or multiple vertebral fractures, who is kyphotic and hunched over and didn’t have any acute pain. I think any other fracture coupled with low bone density is high risk, along with other risk factors. T-score for bone density, we know, matters. We didn’t talk about something called the FRAX tool, which incorporates bone density and clinical risk factors, without which we would not be treating patients with those risks. And really, it’s a quantifiable thing. Then there’s the patient on steroids, and there are different groups of patients on steroids. You have to factor that in with what the patient wants, what the patient has access to, and what the patient can reasonably afford. And it’s within that context that we try to make a shared medical decision.
Andrea J. Singer, MD, FACP, CCD: Before we go on to price, I just want to come back to the cardiovascular piece. For many providers, with romosozumab, with the new drug, that is going to be the thing that makes them go, “Whoa.”
Peter L. Salgo, MD: It’s a nonstarter.
Andrea J. Singer, MD, FACP, CCD: And for patients too. That might be a nonstarter. A couple of quick things. As Tom mentioned earlier, of the 3 trials that we discussed, it was only in 1 trial, in ARCH, where we saw this imbalance. That risk was in major adverse cardiovascular events defined as heart attack, stroke, or cardiovascular death.
Peter L. Salgo, MD: That’s big stuff.
Andrea J. Singer, MD, FACP, CCD: That’s big stuff. And knowing the prevalence of cardiovascular disease that increases with increasing age, we’re talking about the same population. Data were very carefully looked at by some independent cardiovascular groups to sort of say, “Is there a plausible biologic reason? Can we identify the population that might be at highest risk?” And with multiple looks, there was nothing that was really able to be found. Amgen went back and sort of looked at the animal studies, and mechanistically again, doing some additional studies, nothing was found. So the way the warning reads in the label, if somebody has had a heart attack or stroke in the preceding year, they should not receive the drug. If somebody has cardiovascular risk factors, one needs to speak with their healthcare provider to balance risk. Relative risk…
Peter L. Salgo, MD: I was going to ask about that.
Andrea J. Singer, MD, FACP, CCD: So the hazard ratio was 1.87 in the ARCH trial, meaning an 87% increased relative risk. That sounds huge, right?
Peter L. Salgo, MD: That’s not small.
Andrea J. Singer, MD, FACP, CCD: When we look at absolute risk, the risk in the group on alendronate was 1.1. The risk in the group on romosozumab was 2%. We’re talking about a difference of 0.9%. I think that may help people get their heads around it a little bit more. Relative risk is a harder concept, and that number sounds huge. But if you double a relatively rare event, it’s still a relatively rare event.
Peter L. Salgo, MD: But isn’t it fair to say that they looked at lots of mechanisms of other drugs that increase cardiovascular risk? The 1 that comes to mind most recently is some of these newer NSAIDs [nonsteroidal anti-inflammatory drugs], which increased your cardiovascular risk, no doubt about it. But they still, to the best of my knowledge, don’t know quite why. They couldn’t really say, “Well, we understand the mechanism.”
Thomas P. Olenginski, MD, FACP, CCD: The dose of rofecoxib that got it off the market was 50 mg, which was a lot higher. It was that which put a complete boxed warning around every nonsteroidal. There are some nonsteroidals that demonstrate good evidence that I’m not sure you could actually do that—naproxen being 1. So I think we have to be careful.
Peter L. Salgo, MD: All that I’m saying is not that these drugs are good, or these drugs are bad. Simply the lack of understanding of a mechanism doesn’t mean the mechanism isn’t there.
Thomas P. Olenginski, MD, FACP, CCD: Sure.
Andrea J. Singer, MD, FACP, CCD: Absolutely. I think at the end of the day, what this says is that we have to have a thorough discussion with the patient in front of us, so they are well informed. To the best that we can, we look at risk factors. We look at the knowledge that we have, and then we balance benefits and risks and determine if this treatment is right for the individual patient sitting in front of us.