Don't Drop Denosumab

hi I'm Jack Clifford room now

I'm here with dr. Barry Gruber good

friend of mine who I know from Long


Barry was longtime chief of the division

of Rheumatology it's state university of

new york Stony Brook 2025 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 gonna grill you today with some

questions about osteoporosis but more

specifically about the notion of that I

said okay we do sounds fine

treat so the issue is you know the most

you know some app is infused therapy

number one how are you handling

infusions at your site and then how you

can leave the know some app infusions is

has the co video change I mean that

absolutely I think we're doing it like a

lot of rheumatologists throughout the

world of doing it we've 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 probably 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 Ghorab gown and 95s

everything of 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 the no cement

injections as your like Tamra 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 and the parking lot to come

in to one of our first exam rooms and

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

for their parlez injections that this is

a procedure that we do that we can at

least try to optimize their safety well

that brings up an important point in

this era people don't want to go out

don't wanna go to clinic care has been

modified and sometimes been modified 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 the Milton OSA man

can they space that out yeah so it's a

real problem with de new samam 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 to Newsome and so yeah their

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 of when it is


there's rebound fracture rates what what

should what 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 the new semantics is

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 do 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 four 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 a probably a half a dozen patients

already that have had multiple vertebral

fractures that were laid on getting

there the newsom ab so what is it what's

different about the the loss of the

tonic inhibition of rank ligand and and

why that turns so bad so quick yes it is

a lot of theories i mean the first thing

is that you're losing the inhibition of

rank lie again and the presumption has

been that there's probably a pool of pre

osteoclasts that differentiated a

certain amount and then we're held up by

the inhibition of rank ligand and once

that inhibition is gone you got this

army then of osteoclasts and osteoblasts

to genesis 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 osteoclasts to Genesis

that comes on once the rank like in

inhibition is taken away so I guess the

reason for this q6 month those thing is

it's half-life is twenty five thirty

days and five half-lives you know it

kind of takes us to that six month time

period is not much left after that right

and and the six months was determined an

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

that in when they were measuring bone

turnover markers that if someone didn't

get their denisa may have nine months

after their their last dose of it they

had a sky-high turnover of bone markers

they are 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 it would be really disastrous and

then ultimately people delay an extra

month or really we really got to stick

to the six-month regiment I think

there's a little bit of leeway there the

multiple of atiba fractures army

reported that the FDA is added to the

label now Pro LeAnn'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 you know four to six weeks

I think is okay although I 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 I you know what I when I have a

discussion with a patient now in the

phone who's been concerned and cancelled

their the Newsom Abbe 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 Cova 19 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 I think then

I think it's it's still hard sell

although I'm sure you're encouraging a

patient's like me to say hey you can go

get labs you can come in and get your

denote something I've been injecting

because these places are quiet there's

nobody there you're gonna be the only

one pretty much and it is safe because

especially for your for this one we're

talking about it's pretty much in and

out what are you has the kovat ear

attained 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 to the

matter is

there's no guidelines that monitoring is

necessary probably other than when we

initiate perlier 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

and email 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 so in

addition to the coronavirus and you know

home sheltering you know there are

others instances where we may have to

delay to know some map you know the the

dentist that's a special kind of crazy

right there and surgeries and whatnot

and in this instance we're either the

patient won't go can't go given

instructions the structures not to go

what are your alternatives right right

so people have been studying this and

there are trials underway people have

gone back to using bisphosphonates in

this situation yeah a lot of works been

done with giving and obviously this

doesn't help currently but looking at a

dose of Zoll so when it's opened Roenick

acid studies have been done looking at

six months following the last

dmap 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 dmap but

allow some rebound then come in with

even if it's an oral bisphosphonate

alendronate has been looked at

rescission eights been looked at again

they're partially successful in

mitigating this rebound and preventing

all the bone loss you see there are

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 if you talk about

who you're gonna be most worried about

you're most worried about the people

that have already had prevalent

fractures already had

Pratibha 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 type 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 them as phosphates or as

our there are others other sequences

sequential regimens to consider well

when people are now talking sequential

therapies in the field of osteoporosis

they were looking at the anabolic

therapies followed by anti resorbed oh

so Romo followed by dmap etc you know a

number of groups have done some very

nice work looking at some of the new

antibiotics whether it's the PTH analogs

or whether it's Romo and then coming in

with different anti resort those this is

a unique situation this covert situation

because we're talking about someone

who's doing okay staying on demand 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 Romo first of all requires them

to come into the office so that side of

the question and the PTH analogs at

least teriparatide

has been a problem following DMAP with

seeing a lot of rapid loss in the early

stages especially in cortical rich parts

of the skeleton

as far as a ballot parrot I there's just

no data but getting someone started on a

home injection like that is moving

mountains and 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 RO bisphosphonate

so Barry you forgot you're talking to a

real bonehead and by I don't mean like

an osteoporosis because maven here D map

is the no sub map Romo is Roma Sousa map

right okay I just wanna make sure I get

that right so what about people who have

fractures on for Lea what are your


well again remember any one of these

osteoporosis medications never a hundred

percent 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 100%

effective particularly when you start

with someone who's got a very frail

skeleton that if they develop a

compression fracture of the vertebrae a

neuron d-mail does that mean I have to

blow the whistle and say alright 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 there on demand now that we

have Romo 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

resort of such as dmap okay well you

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 aisle 6

inhibitor or something and now you're

adding another biologic is there is

there a immunosuppressive risk from the

no some a band or your patients on the

no some a but any higher risk for

infection and things like that yeah 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 and many globular

measurements all the kind of things you

can do to see whether there's any

detectable immune suppressive effect and

then it's been looked at clinically Jeff

Curtis and others have looked at this

you know our patients that are getting

other biologics for our diseases whether

we add dmap on top of that do we end up

seeing more serious infections more

hospitalizations more prolonged courses

with pneumonia etc and the answer to

date has been no fortunately so I don't

think we should be concerned about the

immunosuppressive effect of Dammam in

the current setting that we're in or

beyond okay very great review and thanks

for your expertise we really appreciate

it now is the time that we need this

kind of information

hopefully checked in with you soon take

care say hi to Long Island for me okay

be safe check okay