Don't Drop Denosumab Save

Hi, I'm Jack Cush with RoomNow. I'm here with Doctor. Barry Gruber, a good friend of mine who I know from Long Island. Barry was longtime chief of the division of rheumatology at State University of New York Stony Brook, twenty, twenty five years and now is in practice, in Southern Long Island. Barry's had a lot of interest in rheumatology.

One of them has been a longtime interest in osteoporosis. Barry, we're going to grill you today with some questions about osteoporosis, but more specifically about denosumab. Is that okay with you?

Sounds fine.

So the issue is, know, denosumab is an infused therapy. Number one, how are you handling infusions at your site? And then how you're handling denosumab infusions? Has the COVID era changed any of that?

Absolutely. I think we're doing it like a lot of rheumatologists throughout the world are doing it. We no longer have any waiting room. We don't have any patients sitting in the waiting room. All of our routine visits are being done by telemedicine.

So really small amount of staff that are in the office. The infusion center, we have a five chair infusion center under normal conditions. Right now we're using all the empty exam rooms where the patients go in for their infusions and have that isolated room distance from anybody else and of course the usual sanitation, garb, gown, N95s, everything are being used with gallons and gallons of sanitation liquids being utilized between patients so we can safely give whatever biologics or osteoporosis medications that we've been given in the past.

So, is it pretty much the same then for your denosumab injections as your Actemra infusions?

Yeah, I think the same procedure is being held. It's a little bit simpler because it's an injection so the patients can go from the car in the parking lot to come into one of our first exam rooms within the building, get their injection, immediately leaves, go back to their car. So I spend a fair amount of time on the phone for patients that tell me that they've been not outside at all quarantining themselves for the last two months or so and don't want to come in for their proly injections that this is a procedure that we do that we can at least try to optimize their safety.

Well, brings up an important point in this era. People don't want to go out, don't want to go to clinic. Care has been modified and sometimes been modified to the point we're just seeing people less and doing things less. And some of the guidelines have actually said, you know, if someone's really stable, you can space out their laboratory testing. You can maybe space out some of their other infusible therapies a little more like wait another month or two on rituximab.

The question is, and people who are taking Q6 month denosumab, can they space that out?

Yeah, so it's a real problem with danusumab and clearly this is not one you simply can just put off for weeks on end and so the discussion is much more complicated here. There are clearly consequences of delaying dinusumab.

So the literature is replete with a lot of problems where, the bone building rates are lower when you start spacing out infusions. There's an issue when it is stopped. There's rebound fracture rates. Should how can we get that to stick in people's heads as far as what the consequences may be?

Yeah, so let's go through some of the basic pharmacology with danusumab cause it's clearly different having used bisphosphonates for decades. This is a very different pharmacological approach. I mean, obviously it's a monoclonal antibody but importantly so it has essentially zero skeletal retention unlike a bisphosphonate. So as it comes out of the circulation by the end of a six month dosing period, you begin to see at that point in time that bone turnover starts then gearing up and you can follow this with bone turnover markers. And if someone doesn't get their next injection when due within weeks to a couple of months afterwards, you see a rebound phenomenon where bone turnover markers go sky high and that's accompanied by a very rapid decline in bone density.

Basically all the gains you've made for years prior to that are lost within months of time certainly over the course of a year and as you brought up already, the biggest concern is that associated with that a certain percentage of patients get fractures and moreover get multiple fractures in particularly the vertebral bodies and that's been the real concern and I've seen probably a half a dozen patients already that have had multiple vertebral fractures that were late on getting their denusumab.

So what's different about the loss of the tonic inhibition of rank ligand and why that turned so bad so quick?

Yeah, so there's a lot of theories. I mean, first thing is that you're losing the inhibition of rank ligand and the presumption has been that there's probably a pool of pre osteoclasts that differentiated a certain amount and then were held up by the inhibition of RANK Ligand. And once that inhibition is gone, you've got this army then of osteoclasts and osteoclastogenesis that comes on strong that leads to this rapid digestion of the matrix as reflected by CTX markers going sky high and bone turnover rapidly coming on. So it's really, I think the massive amount of osteoclastogenesis that comes on once the RANK ligand inhibition is taken away.

So I guess the reason for this Q6 month dosing is its half life is twenty five-thirty days and five half lives, know, kind of takes us to that six month time period and there's not much left after that.

Right. And the six months was determined in early phase one, phase two work that was done looking at bone turnover markers and you see continual suppression of bone turnover throughout just about six months. But after six months you begin to see it starts getting notched up there. And certainly in the early phase two trials and an early prevention trial of phase three trial, they saw that in when they were measuring bone turnover markers that if someone didn't get their denosumab nine months after their last dose of it, they had a sky high turnover of bone markers. They're suggesting that the osteoclasts are just digesting a lot of the matrix away in these people.

So a delay of three months then going out that nine month point would be really disastrous. Then people delay an extra month or really we really got to stick to the six month regimen?

I think there's a little bit of leeway there. The multiple vertebral fractures have been reported that the FDA is added to the label now, Prolia and it's recognized worldwide and I've been on a number of webinars now and talking to people in Europe and Germany and stuff. Most of the fractures occurred somewhere from eight months beyond from the last dose. So I think I tell patients we have a little bit of leeway, know, four to six weeks I think is okay. Although I and others in the field that do a lot of bone work have seen fractures occur as early as four to five weeks after the missed last dose.

You

know, when I have a discussion with a patient now on the phone who's been concerned and canceled their danusumab injection, the scheduled injection, I tell them that the problem is I don't think delaying it a few weeks or even a couple of months that COVID-nineteen is unlikely to be certainly in my neck of the woods, it's unlikely to be a whole lot better a couple months from now. So I encourage them very much so to come in now rather than wait a couple months from now.

Yeah, think it's still hard sell although I'm sure you're encouraging your patients like me to say hey you can go get labs, you can come in and get your denosumab injection because these places are quiet. There's nobody there. You're going be the only one pretty much. And it is safe because especially for this one we're talking about, it's pretty much in and out. Has the COVID era changed your monitoring?

Meaning are you trying to be as rigid in lab monitoring and or the need for bone densities?

Yeah, absolutely. You know, the truth of the matter is there's no guidelines that monitoring is necessary for Prolia other than when we initiate Prolia we make sure that the patients have adequate vitamin D and they're not hypocalcemic. And the concern always is patients with CKD that are more risk for developing hypocalcemia on dMAb. So those probably I'm a little more concerned about doing some monitoring but otherwise yes bone density, it's not going to change what we're doing. I could put off six months a year getting another bone density that's not as critical.

Although we are trying to do bone density as we do them in the office, on many of these patients and they're fine with it but that's certainly not nearly as important as getting the patient just to come in for their injection and get back out in their car and go back home.

Right. So, in addition to the coronavirus and, you know, home sheltering, you know, there are other instances where we may have to delay danosumab. The dentist, that's a special kind of crazy right there and surgeries and whatnot. In this instance where either the patient won't go, can't go, give instructions not to go. What are your alternatives?

Right, so people have been studying this and there are trials underway. People have gone back to using bisphosphonates in this situation. A lot of work's been done with giving and obviously this doesn't help currently but looking at a dose of Xol, zolindronic acid, studies have been done looking at six months following the last dMAb dosing and it's only been partially successful and in some people's hands not successful. And one of the concerns is that when the RANK ligand inhibition is reducing bone remodeling to such an extent, the uptake and efficacy of bisphosphonates really depends on having some active remodeling. So some have discussed allowing you to get past the point where you do for another dMAb and allow some rebound then come in with even if it's an oral bisphosphonate.

I mean alendronate's been looked at, risidronate's been looked at. Again, they're partially successful in mitigating this rebound and preventing all the bone loss you see. There aren't large enough studies to speak to multiple vertebral fractures that are a result in this situation. But that's what I do. In the patients I have no success particularly, you know, you talk about who you're going to be most worried about.

You're most worried about the people that have already had prevalent fractures, already had vertebral fractures. Those are the ones that are highest risk, the ones that still have very frail skeletons and so those are the people that if I absolutely can't get them to come in, I'll give them a prescription for alendronate or you know an oral bisphosphonate and encourage them at least as a stopgap measure until we can get them back into the office setting and get another injection. I think that's the next best thing we can do. And by the way, raloxifene has been looked at and seems to be ineffective in this regard. So I think the only thing we could consider is giving an oral bisphosphonate to tie people over.

So, I'd seen some literature in the past about sequential therapy or sequencing of therapy. Is this what we're talking about by using the bisphosphates or are there other sequential regimens to consider?

Well, when people are now talking sequential therapies in the field of osteoporosis, they're really looking at the anabolic therapies followed by antiresorptive. So Roma followed by dmAb etc. You know, a number of groups have done some very nice work looking at, some of the new anabolics whether it's the PTH analogs or whether it's, Roma and then coming in with different antiresorptives. This is a unique situation, this COVID situation because we're talking about someone who's doing okay staying on dMAb and now suddenly they can't come in for an injection. So I don't think this is someone you'd want to put on an anabolic because Roma first of all requires them to come into the office.

So that's out of the question. And the PTH analogs, least teriparatide has been a problem following dMAb with seeing a lot of rapid loss in the early stages especially in cortical rich parts of the skeleton. As far as abaloparatide, there's just no data. But getting someone started on a home injection like that is moving mountains in this kind of population. So I don't think that's realistic.

I think we're really left with just trying to tide them over with our bisphosphonate.

So Barry, you forgot you're talking to a real bonehead and by I don't mean like an osteoporosis maven here. DMAB is the nosumab. Roma is romecizumab. Okay, I just want to make sure I got that right. So what about people who have fractures on Prolia?

What are your options?

Well, again remember any one of these osteoporosis medications are never a 100% effective. So it's always a question of how do you define what the target should be for effective therapy success. This is discussed as it is in the RA field and you know all of our chronic diseases what's considered target and is a fracture considered failure therapy and you know I scratch my head with this stuff all the time because we know none of these drugs are 100% effective, particularly when you start with someone who's got a very frail skeleton that if they develop a compression fracture of a vertebrae and they're on dMAb, does that mean I have to blow the whistle and say, all right. But sometimes I do in the regular setting, I'll sometimes switch them over to an anabolic particularly if there's been a series of say vertebral compression fractures are on dMAb now that we have RheumNow available and PTH analogs, I'll switch them for a year or two years depending on what the agent is to an anabolic and then come back to an anti resorptive such as dMAb.

Okay. Well, know, let's end with an easy one, but still is out there that this is a biologic drug. You know, your RA patients are also on, you know, an IL-six inhibitor or something. And now you're adding another biologic. Is an immunosuppressive risk from denosumab?

And are your patients on denosumab at any higher risk for infection and things like that?

Good question and it's been kicking around for a long time. Unfortunately, there is data. There's data looking both at animal models and in humans and at least infusing even though rank ligand probably plays some important roles as a membrane receptor in the innate immune response. There is very little data to suggest that suppressing it with monoclonal antibody chronically leads to any clinically significant immunosuppression. This has been looked at again just by typical flow cytometry measurements, immunoglobulin measurements, all the kind of things you can do to see whether there's any detectable immune suppressor effect and then it's been looked at clinically.

Jeff Curtis and others have looked at this in our patients that are getting other biologics for our diseases. Whether we add dmAb on top of that, do we end up seeing more serious infections, more hospitalizations, more prolonged causes with pneumonia, etcetera. And the answer to date has been no fortunately. So I don't think we should be concerned about the immunosuppressive effect of dMAb in the current setting that we're in or beyond.

Barry, great review. Thanks for your expertise. We really appreciate it. Now's the time that we need this kind of information. Hope to check-in with you soon.

Take care. Say hi to Long Island for me.

Okay, be safe, Jack. Okay.