Latest / 'Bone Up' / SABRE: A New Era for Osteoporosis Trials

Transcript

SABRE: A New Era for Osteoporosis Trials · 'Bone Up'

0:00
Hello and welcome to Bone Up, the podcast all
0:04
about bones, how we make them, why we break them
0:07
and if we fully understand them. I'm David Armstrong.
0:11
Hi and I'm Richie Abel and over this series we're
0:15
going to be exploring osteoporosis, bones, what
0:18
we know and what we're yet to discover and we
0:21
hope you will join us on the journey. So for
0:24
anyone keen to learn more about our infrastructure
0:27
of calcified collagen, this is... Bone up! Hello
0:54
and welcome back to another episode of Bone Up.
0:59
what we believe will be the last episode for
1:02
2025. And also the first episode of series four.
1:08
It's hard to believe we're now in series four,
1:10
Richie. Oh, it's incredible. I think we've done,
1:15
what, just over 30 episodes now. When we first
1:19
started this and we were discussing, you know,
1:21
how many should we try? We thought we'd do six
1:22
and that nobody would listen and then that we
1:24
would stop. So thank you, everybody. Really appreciate
1:27
your... listening to the podcast and really appreciate
1:30
your support and we'll keep going because you
1:33
know it's a lot of fun and i really enjoy making
1:36
this podcast with you david it's been a lot of
1:38
fun and we've learned a lot along the way it
1:40
really has been a nice journey it's great and
1:42
i mean we hope this is a sort of a repository
1:44
of knowledge in some ways about you know clinical
1:47
bone disease and about bone research and i know
1:50
some of our listeners dip in and out to episodes
1:52
that they're interested in and others have followed
1:54
us all the way from from the start right to the
1:57
where we are now. So everyone's welcome. We are
2:02
the podcast of record for bone research. So the
2:07
end of another year, Richie, always a bit of
2:10
a roller coaster. How have things been for you?
2:14
It's been a good year this year. We got a couple
2:17
of grants. And earlier in the year, we had a
2:19
really good paper out in a journal called Progress
2:22
in Material Science. It was a collaboration with
2:24
MIT. And basically it sets out a vision for bone
2:28
research for the next decade or so. And essentially
2:31
we've got a lot of people who are studying bone
2:32
using experiments and a lot of people who are
2:35
studying bone by building computer models. And
2:38
actually bone is such a complex material and
2:42
has such a complex physiology that really we
2:46
need to combine those two approaches together.
2:48
So we wrote a paper about how you would go about
2:50
combining modeling approaches and experimental
2:54
approaches together to unlock new knowledge about
2:56
bone and i hope that you know we're going to
2:59
be able to support osteoporosis research and
3:04
i also hope that maybe this new type of research
3:07
is also going to be really good for studying
3:09
rare bone diseases like osteogenesis imperfecta
3:11
diseases that happen across scales in bone and
3:14
that really we don't know that much about the
3:17
physiology of the disease and why the bones break
3:20
which is really exciting Yeah that's really important.
3:23
I mean there's a lot we discover about bones
3:25
I suppose through the door of osteoporosis but
3:28
then it applies to other diseases and even though
3:32
those diseases as you say are rare one of the
3:35
things that... You always learn as a medical
3:36
student is that common things are common, but
3:38
many people have rare diseases. And I certainly
3:41
have a surprising number of people with rare
3:44
bone diseases come to see me at the clinic. So
3:46
it's great to hear that, you know, you're looking
3:49
into the future and maybe establishing a roadmap
3:51
to encourage other researchers as well. Yeah,
3:56
I really hope that we have done that and I hope
3:58
people read it and cite it and that we can drum
4:02
up a bit of support for new research. How was
4:06
your year? It's been a busy year. You tend sort
4:10
of clinically, I think you tend to go through
4:11
phases where you're out advertising osteoporosis,
4:15
explaining the importance of people being sent
4:18
up to the hospital if they have vertebral fractures.
4:21
And then you go through periods where you're
4:22
overwhelmed by the amount of work you have to
4:24
do because you've got all these new patients
4:26
and you've got all these exciting new drugs.
4:28
So it always goes up and down a bit. It's been
4:31
a very busy year. We've had really the new NOG
4:34
guidance out now this year. It's the 2024 guidance,
4:38
but it's been on the website and used not just
4:41
in the UK, but many people from around the world,
4:43
I think, do read the NOG guidance. And it was
4:45
good to be a small part of that. And on a personal
4:49
level, as you know, Richie, our son James was
4:51
married earlier in the year. And James is the
4:55
official illustrator and artist of the podcast.
5:00
Although because we don't pay him, he still has
5:02
to work as an architect. So it was great. It
5:06
was great to be at the wedding in August and
5:07
very best wishes to him. And Sophie, from all
5:11
here at Bone Up, I think we can say. Congratulations.
5:16
And of course, I did meet a few doctors at the
5:18
wedding who, believe it or not, were listeners
5:20
to the podcast. So that was sort of encouraging
5:22
as well. it's surprising isn't it when you're
5:26
out and about how many people you meet who uh
5:28
who listen to it it's really good and thank you
5:30
all for tuning in it really helps us to keep
5:32
going yeah so i mean i i was just doing a clinic
5:35
this morning an osteoporosis clinic getting patients
5:38
started on new drugs and um you know one of the
5:41
things people do ask is about new drug development
5:45
and i suppose why it takes so long to get drugs
5:48
to the market i do sometimes explain to patients
5:51
that i've been to conferences i've heard about
5:53
drugs and development it seems ages and ages
5:55
until we actually can get it you know get into
5:58
the clinic and we have an excellent guest for
6:03
our our episode today very exciting i think we're
6:06
both really excited to speak to to our guest
6:09
today and um she has done some work in this area
6:14
which is not discovering a new drug not discovering
6:18
a new screening program But discovering a different
6:22
way of doing research and a different way of
6:25
analysing research, which may be a complete game
6:28
changer going forward, isn't that right? One
6:31
of the problems we have is to show a new drug
6:35
works, you have to show it reduces fractures.
6:39
And that can take a long time and a lot of patience.
6:44
Literally a lot of patience. And therein lies
6:47
the problem. So listeners, you know that if a
6:50
drug is going to be approved for use in people,
6:53
it has to go through a clinical trial. And the
6:55
clinical trials have to show that using the drug
6:58
to treat people improves their outcomes, improves
7:01
their health. And obviously, when we're talking
7:03
about osteoporosis, the thing everybody worries
7:06
about is fractures and preventing fractures.
7:10
Clinical trials in osteoporosis have to demonstrate
7:13
that a medicine reduces. the risk that people
7:17
will sustain a fracture and that's actually very
7:20
hard to do. First of all fractures are relatively
7:25
rare which means that you have to run the trial
7:27
for a long time and to have many many people
7:31
in the trial in order to be able to detect a
7:34
reduction in the risk of a fracture and that
7:37
means that the trials are very expensive which
7:41
is bad for the companies running them. and also
7:44
really really long which is bad for patients
7:46
because it means everybody has to wait longer
7:48
to get new medicines and the real kicker is is
7:52
that if a trial has to be long and have a lot
7:54
of patients in it you're going to get a lot of
7:56
dropout along the way you know not everybody
7:58
can make it to the end of the trial you lose
8:00
people they move home change the contact details
8:03
which means you've got to stack up a trial with
8:04
even more people to make sure that you get through
8:07
to the end with enough people to be able to compare
8:09
your treatment group, say with a placebo group.
8:12
And that's really, really difficult to do. We
8:16
need ways to get drugs to patients more quickly.
8:20
And so if there was only a way that we could
8:23
prove drugs were effective at reducing fractures
8:27
without having to wait years and years and years
8:29
for lots of people in the trial to have fractures.
8:32
I think this is a really good time to introduce
8:35
our next guest for today. Welcome listeners back
8:42
for another episode of Bone Up. Today I'm really
8:44
pleased to announce we've got an excellent guest
8:46
for you, Professor Mary Buxine. Professor Buxine
8:49
is the Maurice C. Mueller Professor of Orthopaedic
8:52
Surgery at Harvard Medical School, a leader in
8:55
the world of osteoporosis research and somebody
8:58
I've looked up to for many years as I've been
8:59
doing my research. Past president of the ASBMR,
9:03
the American and also International Bone Society
9:06
in the world. co -lead of the study to advance
9:09
BMD as a regulatory endpoint, SABR, which we're
9:12
going to be talking about today. And this could
9:14
be a really big bang moment in the search for
9:17
new and better osteoporosis treatments. Welcome,
9:20
Mary. Welcome, Mary. Thank you for making the
9:24
time to speak to us and indeed wrestling with
9:27
the technology so that we're all in the same
9:29
room at the same time today. Thank you both.
9:33
It's really a pleasure to be here and I look
9:34
forward to this conversation. Oh, wonderful.
9:39
Mary, you're somebody really wanted to interview
9:41
since we got the podcast started a few years
9:43
ago. We're really pleased to have you here. I
9:46
just want to get started with something that
9:47
might surprise some of our listeners. You're
9:50
one of the world's leading experts in bone health
9:53
and bone health research, and you're working
9:54
to change clinical guidelines. But actually,
9:58
you're an engineer. What drew an engineer to
10:01
study bones? Oh, that's such a great question.
10:04
Thank you for that. So you're right. I have my
10:08
undergraduate and graduate degrees in engineering,
10:11
mechanical engineering. When I finished undergraduate,
10:14
I also have a degree in economics. And the original
10:18
plan was to get an MBA and go into business with
10:21
this engineering degree and make lots of money.
10:25
And I had an internship one summer and a desk
10:29
job in an office, and I found it dreadfully boring.
10:35
finished undergrad, I started looking at graduate
10:36
school. And at that time, the field of biomechanics
10:40
and bioengineering was relatively new. And that
10:43
really appealed to me because I was always fascinated
10:45
by the human body, but I didn't really want to
10:48
become a doctor or a physician. And so I applied
10:53
to graduate school and just literally by chance,
10:57
I ended up with a project that was related to
10:59
the effects of exercise on bone health. And that
11:03
resonated with me so much. I joined the group
11:07
at Stanford and I was super fortunate to have
11:10
co -advisors as an endocrinologist, Dr. Robert
11:14
Marcus, and my engineering advisor, Dennis Carter.
11:18
And I think that set me off on this path of studying
11:22
bone health. Amazing. I didn't realize you'd
11:27
done economics as well. Yeah, it's probably very
11:32
relevant, actually, to the world we live in today
11:34
in terms of new drugs as well, isn't it? You've
11:37
got all the right background. One of the things
11:41
we wanted to talk to you today was about the
11:43
Sabre project. And anyone who has worked either
11:46
as a clinician or as a scientist, I think, in
11:49
looking at development of new drugs is aware
11:52
that. What we've been interested in up to now
11:55
is fracture as a night comes. So we're only interested
11:59
if the new drug prevents fractures or reduces
12:02
the risk of fractures. Tell us how the Sabre
12:05
project has changed that or has aimed to change
12:08
that, if you would. Yeah, I'd be delighted to.
12:13
Maybe as you know, this has really been a passion
12:16
project. I wrote the first paper on using surrogate
12:21
endpoints in osteoporosis trials in 2008. And
12:25
we started the SABR project in 2013. And you're
12:30
correct that up until now, to show that new treatments
12:34
are effective for osteoporosis, our clinical
12:36
trials have to wait until fractures to occur.
12:39
And that, as you are aware, and I'm sure your
12:41
listeners are aware, requires pretty large and
12:45
pretty long and then thus fairly expensive studies.
12:49
And that has really inhibited innovation in the
12:53
field. And so what we aim to do was use data
12:58
from this large database, and we can talk about
13:01
this, to show that the change in bone density
13:05
measured by a standard non -invasive test that
13:08
we're all familiar with, DEXA, could accurately
13:10
predict the impact of treatments on fracture
13:13
risk. And we have been able to do that, and we
13:17
can talk more about that. But I really think
13:19
that by streamlining drug development, hopefully
13:24
this landmark decision, we hope to hear very
13:27
soon, will spur more discovery, innovation, and
13:31
investment in the osteoporosis field. And were
13:35
you able to relate changes in bone mineral density
13:39
directly to percentage changes in fracture risk?
13:43
Was it as clear as that? Yes, absolutely. So
13:47
maybe take one step back and talk a little bit
13:49
about the data we were able to acquire. So I
13:52
think importantly, we were very fortunate to
13:55
have the support of the foundation for the NIH,
13:58
which is a group that facilitates public -private
14:02
partnerships. And we were fortunate to have a
14:07
number of companies, over 10 companies, gave
14:11
their data to this database so that we could
14:15
do these analyses. And we ended up with over
14:19
160 ,000 individual patients with bone mineral
14:23
density and fracture outcomes from 52 different
14:26
trials with 16 different mechanisms of action
14:30
for the drugs. And so it's a really robust data
14:33
set to be able to ask the question, does a change
14:37
in bone density predict the fracture outcomes?
14:40
And was there any difference between different
14:43
drugs? Because with a lot of interest, you know,
14:45
in how osteoanabolics work differently from anti
14:48
-resorptives. So does increasing your bone mineral
14:51
density with an osteoanabolic, for example, does
14:54
that prevent further fractures to a greater or
14:56
lesser degree than increasing it with an anti
14:58
-resorptive, my patient might ask? Exactly. That's
15:00
a super great question. You may be familiar with
15:04
the fact that we don't have that many osteoanabolic
15:06
trials. So we have three trials in our data set.
15:10
And so we cannot do a specific analysis by drug.
15:16
We were able to look at anti -resorptive therapies
15:19
versus all therapies and show that all of the
15:24
therapies basically fall on the same regression
15:28
line, meaning they have the same relationship
15:30
between this change in BMD and the fracture risk
15:34
reduction. So it was very reassuring that whether
15:38
you were an osteoanabolic drug with a very large
15:41
change in BMD and a very large reduction in fracture,
15:45
or a CIRM, selective estrogen receptor modulator,
15:49
lower increase in BMD, and smaller effect on
15:53
fracture, that we were able to generalize this
15:56
relationship across classes of drugs. And of
16:00
course, that's very important because you want
16:03
to be able to use this for future trials where
16:05
there may be different mechanisms of action that
16:08
we haven't studied yet. So I think the generalizability
16:11
is very important. Mary, the data set you analyzed
16:15
for SABRE was enormous. Did the study throw up
16:18
any surprises? You know, not really. I would
16:24
say everything has actually been pretty reassuringly
16:33
predictable in that larger increases in BMD.
16:37
are associated with greater reductions in fracture
16:40
risk. I think a few of the smaller trials, like
16:44
real small trials that may have been from the
16:46
phase two studies, where they weren't sufficiently
16:49
powered for fracture endpoints, we have a few
16:53
outliers there. But none of the larger trials
16:56
that actually had enough subjects with appropriate
16:58
number of fractures, there were no surprises
17:02
there. Were there any differences between different
17:07
parts of the body? Because again, this is something,
17:11
you know, patients will ask me. So is there a
17:13
greater predictive value, let's say, at the spine
17:16
than at the hip? You know, we often, as you know,
17:21
hip BMD is quite predictive of sort of the general
17:24
risk of a fracture, which is something I always
17:26
remind patients. Does increasing BMD at the hip,
17:29
for example, reduce your risk of a forearm fracture?
17:32
Or was that data not, could you not get that
17:35
from the data? That's an excellent question.
17:38
We looked at all BMD sites, so total hip, femoral
17:43
neck, and lumbar spine. Not all the trials had
17:48
all of those because our trials are, you know,
17:50
some of them are 30 years old, right? But there
17:53
was, spine did not necessarily perform better
17:58
than hip. And we chose the total hip because
18:02
it has high reproducibility, which you want in
18:06
this kind of study. And it had a strong association
18:09
with all fracture types. To your point, spine
18:13
did a little bit better for predicting the effect
18:16
on vertebral fractures, but the change in total
18:21
hip bone density was able to predict fractures
18:24
at the spine, non -vertebral fractures, and hip
18:28
fractures. That's interesting. It seems almost
18:31
slightly counterintuitive sometimes, or certainly
18:34
when you're explaining this to patients, but
18:35
it's really good that that came out of this data
18:38
as well. Yeah, and I think it's important to
18:41
remember when we're thinking about, you know,
18:44
the goal of the SABR project is to advance regulatory
18:49
methodology, not necessarily to use these data
18:55
for interpreting changes in an individual patient.
18:58
So the important thing when I say change in BMD,
19:03
we are really talking about the difference between
19:06
the increase in BMD in the treated group. versus
19:10
the change in BMD in the placebo group. So we're
19:13
not talking about a change from baseline in an
19:16
individual patient. Rather, our change in BMD
19:20
refers to the difference between the treatment
19:22
group and the placebo group. And I think that's
19:25
really important to keep in mind in interpreting
19:28
the SAVR outcomes. Thinking about what this is
19:33
going to mean for the world of osteoporosis,
19:36
you mentioned at the very beginning, that osteoporosis
19:40
trials are complicated and long. How will using
19:44
BMD as a surrogate help companies and scientists
19:48
develop new treatments? Great question. So what
19:52
we think and what we have proposed to the regulatory
19:56
agency, the FDA, is that BMD could be used as
20:01
the primary endpoint. And that is going to mean
20:06
a smaller trial. and perhaps a shorter trial.
20:11
Our data suggests that the two -year change in
20:14
BMD works really well and that the 18 -month
20:18
change in BMD also works pretty good. A 12 -month
20:22
change in BMD didn't seem to have quite as strong
20:25
an association. So I think that companies who
20:30
are considering developing new therapeutics will
20:32
be able to do trials that will be smaller. They'll
20:37
still be two years or 18 months to two years
20:39
in duration. And that will be a lot easier than
20:42
waiting for fractures to occur. I mean, the last
20:46
very large trial that was done, Odana -Kadib,
20:49
had almost 15 ,000 patients in it. So we think
20:52
that at a minimum, you will need to have 500
20:56
patients, perhaps, in order to show that the
21:00
change in BMD can predict the fracture outcome.
21:05
Wow. So that's a startling reduction in the length
21:09
of the trial, the number of participants that
21:12
have to be recruited in, I guess, the overall
21:14
cost of the study as well. And ultimately, listeners,
21:18
I guess this is going to mean that potentially
21:21
drugs can be tested more quickly and get approved
21:24
more quickly and get to patients more quickly.
21:28
Exactly. Which is wonderful news. And I must
21:33
say on reading the outcomes of this, of course,
21:35
it struck me in the past it was easier almost
21:38
to prove. fracture risk reduction when your placebo
21:42
group was literally a placebo nowadays ethically
21:46
it's much harder to do a study with a placebo
21:49
because you can't leave someone with a new vertebral
21:52
fracture on calcium and vitamin d for three or
21:55
four years so it's all if you're just using fractures
21:59
an outcome it's going to be harder to prove that
22:01
so it's brilliant that we have this now we're
22:03
getting so many new drugs And the placebo arm
22:08
is always going to be quite a good drug as well.
22:10
I think that's one of the things I must think
22:12
it struck me as particularly useful and encouraging
22:15
from this. Also, I will point out, we have looked
22:19
at, there aren't very many, but we've looked
22:21
at the combination and sequential trials. So
22:24
the trials that have an active comparator and
22:26
or compared, you know, sequential treatment.
22:31
Fortunately, they also fall on the same regression
22:34
line. And so it's very reassuring that the interpretation
22:37
of a study, if a sponsor wanted to do a trial
22:42
with an active control, so not using a placebo,
22:46
that you would be able to interpret the change
22:49
in BMD or the difference in BMD between the treatment
22:53
group. And now it's not a placebo group. It's
22:56
an actively controlled group. should work the
22:59
same. And that was also very reassuring, just
23:01
sort of the robustness of this relationship.
23:04
Maybe that's been the most surprising thing that
23:06
it continues to work so well. One of the things
23:09
I really like about the bone world is it really
23:12
does seem to be at the cutting edge of a lot
23:14
of science. Having gone through the experience
23:17
of developing a biomarker that the FDA hopefully
23:21
will approve as a surrogate, what have you learned?
23:25
And do you think that your Your approach could
23:28
be a blueprint for researchers working in other
23:33
medical disciplines like dementia or heart disease,
23:36
etc. Would they also be able to copy what you've
23:39
done and develop biomarkers as their endpoints?
23:42
Again, such a great question. I would say there's
23:45
a few things related to that question. One is,
23:49
I think that this whole effort shows the power
23:54
and potential of this public. private partnership
23:57
and that the data sharing from clinical trials
24:01
was essential for us to be able to do this. And
24:05
hopefully it spurs others to also share data
24:09
from clinical trials so that these types of analyses
24:12
can be done in other areas. And then the second
24:15
part is, yes, we will be the first ones to have
24:18
gone through this formal regulatory process that
24:22
was set up by the FDA. actually in 2016. And
24:27
ours will be the first efficacy endpoint to be
24:31
approved using this process. And I think it will
24:34
provide a blueprint for other therapeutic areas
24:38
to follow along, maybe mimicking what we did,
24:42
given they would have also similarly large data
24:45
sets with a surrogate endpoint or biomarker and
24:49
the clinical endpoint. That's amazing. listeners,
24:53
another world leading example of bone research
24:56
that can have impact well beyond bone and on
24:59
other diseases as well. It's really nice to hear.
25:03
I'm going to ask a sort of devil's advocate question
25:06
because I'm from Belfast and we like stirring
25:08
things up, as you know. You're from an engineering
25:13
background. You've done work. I was looking back
25:15
at some of your older papers on QCT and imaging
25:18
modalities which look at quality of bone. On
25:22
the podcast here, we've talked a lot about this
25:24
over the years about the elasticity of bone and
25:27
hydration of bone and how the things that go
25:31
to... increasing your risk of fracture are not
25:33
all contained within bone mineral density these
25:35
other things as well is there a chance that if
25:39
we focus now purely on increases in bone mineral
25:42
density that new treatments which may improve
25:46
bone quality may find it harder to get in or
25:50
that people will say well we're not interested
25:52
in improving bone quality unless it improves
25:54
bone mineral density if that becomes our sort
25:58
of only only marker Again, a really excellent
26:03
question. You know, we've thought a lot about
26:07
that. And of course I have, because this has
26:09
been my active area of research for decades,
26:12
right? I hope the FDA aren't listening and ask
26:15
you that question next week. No problem. Usually
26:19
it's the other way around. OK, so and I will
26:24
come back to your question, but let me diverge
26:26
for a second. Usually it's the other way around.
26:28
Like, what about a drug that improves BMD but
26:32
has a bad effect on bone quality or doesn't improve
26:35
bone strength? So then you would approve something
26:38
that folks would take and it's actually not good
26:41
for their bone. That would not be good. And so
26:44
the one way that. we think that won't happen
26:48
is that the regulatory requirements will stay
26:51
the same for preclinical studies, so animal studies,
26:55
to show that the increase in bone density is
26:58
associated with an increase in bone strength.
27:01
And the classic example where that didn't work
27:04
so well was fluoride treatment. So again, several
27:07
decades ago, fluoride increased bone density,
27:10
but did not have any effect on reducing fracture
27:14
risk. When you go back and look, the preclinical
27:17
data would have shown that. So the rabbit studies
27:21
and rat studies had increases in BMD, but no
27:24
increase in the mechanical properties of the
27:27
bone. And so we think that going forward with
27:30
SABRE, that given a strong preclinical package
27:34
in combination with showing that BMD increases
27:37
in patients, that we can be reassured. that drugs
27:42
that are approved under this pathway will have
27:45
positive effects on fracture risk. Okay, now
27:48
to your other point, let's go back to that. It's
27:52
a good question. If a new therapeutic improved
27:56
bone quality, but had a very limited effect on
27:59
BMD, I think we would probably have a tough time
28:05
getting it approved through this. So that might
28:08
be, you know, someone who would then want to
28:11
do a fracture trial and they could do a vertebral
28:14
fracture trial, you know, which aren't as large
28:17
as some of the other trials that have tried to
28:19
show efficacy for hip fracture. I was thinking
28:23
just particularly, you know, sort of people with
28:25
diabetes and this perception that the bones may
28:29
be less elastic, there may be more collagen cross
28:31
-linking, you may actually have higher BMD than
28:33
you would expect. Let's say, you know, with all
28:36
the developments in diabetes where we were able
28:38
to potentially improve fracture risk, but it
28:41
may not actually change BMD that much. So, but
28:44
yeah, I think that's a fair, we can still go
28:47
and do those other studies then is probably your
28:49
answer to that. Yeah, and we did show even within
28:52
the... the SABRE database, we looked at patients
28:55
with diabetes. There are some in nearly every
28:58
trial. And even within them, the change in bone
29:03
density would predict fractures. And we also
29:06
showed the efficacy of treatments broadly across
29:09
patients with diabetes. So I think it would still
29:13
work in that case. I'm trying to think of an
29:18
example, if we had anything that... improves
29:21
bone quality and has no effect on BMD. I can't
29:26
think of anything off the top of my head. That
29:29
doesn't mean that someone isn't working on it
29:31
and that it might not come in the future. And
29:33
then we'll have to think about it very carefully.
29:38
I suppose the original trial designs will still
29:40
be there if somebody wants to use them. Exactly.
29:46
Mary, when we looked at your papers and looked
29:48
at your research across your career, You've done
29:51
a lot of different things in your research. Studies
29:54
of ex vivo bone samples to look at how structure
29:59
and chemistry affected the strength. You're one
30:02
of the pioneers of using new in vivo imaging
30:05
techniques like PQ, PQ, HRPQCT. Team bone up
30:16
there. It's all right. He let this bit out. If
30:19
I make a mistake, Mary, he keeps it in. If he
30:21
does, he edits it out. I love that. And you did
30:25
in vivo studies of people looking at how bone
30:27
density and bone structure relates to their fractures.
30:29
And you've also taken part in a lot of clinical
30:32
research, clinical trials, development of new
30:36
technologies to use CT scans to diagnose people
30:39
with osteoporosis opportunistically, etc. How
30:43
do you fit? all of this in did you did you have
30:49
clear trajectory at the beginning like a plan
30:52
that you wanted to work through step by step
30:54
or did you sort of have to take things if they
30:57
as they come how how did you navigate through
30:59
all that wow that that's a big question I certainly
31:04
did not have a clear plan let's just go with
31:06
that and I kind of followed where the research
31:12
led me and Initially, I had started my PhD work
31:18
was in human subjects and looking at the effects
31:21
of exercise on bone. Then I went and I wanted
31:25
to do some mechanistic studies. So then I learned
31:27
how to do animal research. And then I came back
31:30
to clinical research because I thought, well,
31:32
that's really the really impactful stuff. And
31:35
we need to be able to translate our animal work
31:37
into humans. So it kind of has been a thread
31:40
along the way to be able to combine. Both. But
31:45
I can't say I had a specific path in mind. It's
31:49
been a little bit just follow where the good
31:52
science takes you and hopefully have an impact
31:56
in the end. It's interesting. Yeah, I very much
32:00
got the feeling that you were following what
32:03
you loved and enjoyed doing. And all this is
32:07
so relevant. I've just finished a clinic this
32:10
morning. I had a conversation with a patient
32:13
in her 10th decade about exercise and about the
32:17
benefits of exercise with bone. And she was very
32:20
keen at doing this, even though she was in her
32:23
90s. And I was explaining a little about the
32:26
research that... know that was behind that and
32:30
i had a patient not long afterwards and we were
32:32
talking about the increase in bone mineral density
32:34
and how even though the sabre study is not for
32:37
individual patients but how the patient could
32:39
be reassured that the increase in bone mineral
32:41
density in the real world would reduce her risk
32:46
of having further fracture and that sort of research
32:49
it's so relevant actually in the clinic and so
32:52
relevant to patients because patients love to
32:53
hear that you know i'm not just inventing all
32:56
this it's actually coming from, you know, from
32:58
research and the work that you do is so relevant,
33:01
you know, not just in Harvard or Imperial, but,
33:05
you know, sitting here at outpatient clinics
33:07
in Northern Ireland, seeing, you know, patients
33:09
just coming in day to day with osteoporosis.
33:12
Well, it's really great to hear that and has
33:16
been a goal of mine all along. I can say, as
33:19
we talked at the beginning, I fell into it, but
33:22
I will say it has been incredibly rewarding.
33:26
to be in a field of predominantly women's health.
33:29
Certainly men have osteoporosis as well, but
33:32
to be able to support clinicians in this field,
33:35
to have those difficult conversations with patients
33:38
and motivate people to take care of their bone
33:40
health. And I'm going to keep on that path as
33:43
long as I can. That's great. And why do we have
33:47
more research on men with osteoporosis, Mary?
33:50
Why do we have more? Sorry, can you read? Why
33:53
do we not have more research on men with osteoporosis?
33:57
I actually think we have quite a bit of research.
33:59
More lately, the Mr. Ross study has done some
34:02
fantastic studies looking at risk factors for
34:05
fractures for osteoporosis. No, I think certainly
34:08
you're true, really. I know, just thinking, looking
34:10
back over the studies over the years, you know,
34:11
you always have to end up saying to patients,
34:13
of course, all these studies were done in women
34:14
and not in men. It's okay. We'll take it. You
34:19
know, there's plenty of other examples that go
34:21
the opposite. So, you know, it's all right for
34:23
osteoporosis to be done, studies to be done in
34:25
women. I'm not going to apologize for that. I
34:31
think one thing maybe I'll bring up, you know,
34:35
in talking about my background, certainly one
34:37
of my interests and passions has been understanding
34:40
the non -BMD aspects of bone strength and sort
34:46
of this. The SABR project is so focused on BMD,
34:49
it seems to fly counter to a lot of my other
34:53
research. And I think when we started the SABR
34:57
project, we also collected QCT scans from all
35:02
the clinical trials. And I was very excited about
35:05
that aspect of it. So we could use the 3D information.
35:08
And certainly I thought we would have a better
35:10
predictor. There are in all of the phase three
35:15
clinical trials. 800 CT scans in patients who've
35:20
been treated with osteoporosis therapies with
35:23
fracture outcomes. So as you can imagine, that
35:27
pales in comparison to the 160 ,000 individuals
35:32
who have BMD measurements by DEXA and fracture
35:35
outcomes. So as much as I really wanted to look
35:38
at that, the practical... aspects of being able
35:42
to do that analysis precluded moving forward
35:46
with QCT as the outcome. So that being said,
35:51
you know, so we move forward with BMD and it
35:54
really applies, as I've tried to emphasize, to
35:57
the regulatory pathway and the testing of new
36:00
therapeutics in osteoporosis. Now, if we take
36:04
a step back, the other thing we want to do is
36:06
reduce risk in the individual patient. And there,
36:11
I think we're still understanding how we can
36:13
best use advanced imaging, ultrasound, water
36:18
content to better identify someone who maybe
36:22
has normal BMD or lowish BMD, but still might
36:27
be at high risk of fracture because they have
36:29
deteriorated microarchitecture or deficiencies
36:33
in their bone quality. So I can still put the
36:36
two together, even though they seem like they're
36:38
very... disparate areas of research. Yeah, that's
36:43
interesting because, you know, you seem to be
36:44
such a champion almost of this, you know, looking
36:47
at quality of bone. And now, I don't think they
36:50
go against each other, but I just wondered, do
36:52
you thought it in any way sort of, not undermine,
36:55
but, you know, did it almost go against what
36:57
you've done before? But we need to look at both,
36:58
don't we? We need to look at quality and quantity.
37:00
Yeah, and so I think the way that the SABR project
37:03
works, having the preclinical data, ensuring
37:07
that the... new bone that's formed under a treatment
37:11
is of good quality, sort of fits together in
37:14
the big paradigm. And then we think about how
37:16
can we better identify individual patients who
37:19
are at highest risk is where some of the more
37:23
advanced technologies are. I mean, BMD does pretty
37:26
well. I mean, we do have to admit that we have
37:28
a very good biomarker for fracture risk and better
37:32
than what's used in many other therapeutic areas.
37:35
So let's be clear. But we're always striving
37:39
to do a little bit better and to really find
37:42
the patient who, you know, should be treated
37:45
with an osteoanabolic therapy or should be treated
37:49
with an anti -resorptive therapy. And having
37:52
these additional tools, I think, is going to
37:55
allow us to have more sensitivity and specificity
37:58
in identifying those individual patients who
38:01
should be on treatment. Yeah, I mean, we really
38:05
do hope that it leads to new drugs and to getting
38:09
new drugs regulatory approval more quickly so
38:12
that I can get to use them in the clinic. Exactly.
38:14
Just think, imagine an oral osteoanabolic or,
38:19
you know, an anti -resorptive, a new anti -resorptive
38:23
therapy that people are not afraid of taking
38:28
because they're not worried about the very rare
38:30
side effects. So I think. We have lots of very
38:35
exciting bone biology. And with a new and more
38:40
manageable regulatory pathway, we're already
38:43
beginning to see investment and interest in the
38:46
field, you know, sort of in developing these
38:49
new therapies. So I think we're going to see
38:52
some exciting things in the next few years. It's
38:57
really interesting that research into trial development
39:02
is going to unlock new treatments and maybe have
39:06
a bigger effect than some of the research into
39:08
the basic physiology and mechanics that govern
39:11
bone fractures. It's really wonderful to see
39:14
that. You know, it's interesting. It was a hypothesis
39:17
that if we were able to be successful, that it
39:20
would prompt this innovation and interest in
39:24
new drug development. And, you know, to be quite
39:27
honest, we're seeing it. investors talking about
39:31
osteoporosis again, and we're seeing interest
39:34
in the investment space in osteoporosis. So it's
39:38
happening. So we just need the FDA to come out
39:41
with their ruling pretty soon. And then as another
39:44
fact, we're not going to stop with the FDA. We
39:47
are going to hopefully move to the European regulatory
39:50
agency and also in Japan because it's important
39:54
not just to have it in the US. Yeah, I went to
39:59
San Francisco a few weeks ago and there's a lot
40:01
of investors who are very, very excited. They've
40:04
kind of got their finger on the button ready
40:06
to go. They know this could be a big bang moment.
40:10
I'm keeping my fingers crossed for you that you
40:12
get a positive decision back from the FDA. When
40:15
you do, we're going to have to have like an emergency
40:17
podcast, I think. I was going to say, we're going
40:19
to have to update the podcast with new information
40:22
to add to the end of this when we hear from the
40:26
FDA. Hopefully, very soon. We should record two
40:31
different endings, Richie, a happy one and a
40:33
sad one. You know the way to deal with these
40:35
things and then edit them in depending on what
40:38
happens. Mary, it's been really lovely talking
40:42
to you today. Thank you for your time. It's been
40:46
a pleasure talking to you both. And I hope I
40:48
was able to explain a little bit what Sabre is
40:51
about and what we hope it's going to do for the
40:53
field. Thank you, Mary. It's been great. I'm
40:56
sure a lot of listeners are going to get in touch
40:57
to say thank you for this episode. I think it's
41:00
going to bring hope to a lot of people, not just
41:02
people who have osteoporosis who are living with
41:05
the condition, but also to their families and
41:07
future generations as well. That is the hope.
41:12
We have a big burden of this disease. currently
41:15
under treating and under diagnosing. So we have
41:19
some work to do. I also hope that the interest
41:23
in women's health in general and the empowerment
41:27
of women to have a bigger voice to take care
41:30
of their own health is going to translate into
41:34
taking care of their bone health. And I think
41:36
we will see hopefully a greater interest in individual
41:40
patients demanding new treatments. demanding
41:44
information and better care for their bones.
41:48
Yeah, I think it's really important. We've talked
41:50
a lot about this, about empowering our listeners
41:52
and, you know, empowering people to ask for new
41:55
treatments, because even still with osteoanabolics,
41:57
a lot of it is still patient -driven, you know,
42:01
saying I've had a vertebral fracture, I need
42:03
this treatment. So absolutely, more power to
42:06
your elbow, as they say. Yeah, and not to say
42:09
that the treatments we have are not good and
42:12
not effective. I think just always having more
42:15
options for that conversation between the patient
42:19
and the physician is going to be a good thing.
42:24
Wonderful. Thank you. Thanks. Thank you both.
42:30
Wow, that was a really interesting discussion
42:34
with Mary. And I always feel as we get to the
42:38
end of these discussions, we're cutting them
42:39
short. There's so many other things that we could...
42:42
you know, we could talk about and we could draw
42:44
out. Of the things that Mary said today, Richie,
42:48
which sort of stand out for you or which do you
42:51
think are most important for your practice? I
42:57
suppose the most important thing for me is just
42:59
the inspiration. Mary comes across as a true
43:05
visionary. One of the first to show that surrogate
43:08
endpoints could be used in osteoporosis trials.
43:11
Through Sabre, Mary's taken that to quite an
43:14
extraordinary scale. Pooling data from 160 ,000
43:18
participants across dozens of trials and many
43:22
mechanisms of action is an enormous task. And
43:29
listening to Mary describe the science, the regulatory
43:31
processes, the public -private collaborations
43:34
behind Sabre, it was clear to me how much determination
43:38
and persistence this must have taken. from Mary
43:42
and the whole Sabre team. I think what really
43:46
struck me is despite the magnitude of this work,
43:50
Mary's really grounded in people. During the
43:54
interview, Mary talked about ethics, equity,
43:57
data sharing, creating more options for conversations
44:02
between patients and clinicians. Goal always
44:06
seemed to be getting better and safer treatments
44:09
to patients sooner. I've listened back to the
44:13
episode a couple of times now, and every time
44:16
I listen back, I catch something new. There's
44:18
another insight, another layer to what Mary was
44:20
saying. And I just keep coming away with more
44:23
and more appreciation for her work and her vision
44:27
and really her values. It's something that we
44:32
see again and again in these podcasts when we're
44:35
talking to the really top people in Bone. They're
44:39
fighting for people. And they're fighting for
44:41
equity and they're not doing this for themselves.
44:44
And that's really wonderful. What were your takeaways?
44:51
One thing I was reflecting, I think afterwards,
44:53
we talk a lot about communication and how important
44:56
it is as a doctor, as a research scientist, to
45:00
be able to communicate with patients. I realize
45:02
how important it is to be able to communicate
45:05
with. the people who pay for drugs, with commissioners,
45:09
with politicians, with government. You have to
45:12
be able to communicate the need for drugs, the
45:15
devastating effect osteoporosis has, and the
45:19
potential benefits of getting new drugs online
45:22
more quickly, and how Mary can go from being
45:25
in the lab doing that sort of work to making
45:28
presentations to the FDA. and how those both
45:32
are very important in getting drugs to the patient.
45:35
It's not just the science, but it's communicating
45:38
that science to commissioners and to government
45:44
because ultimately people have to pay for these
45:46
things. I think the other thing I find sort of
45:49
reassuring about it was in some ways it was perhaps
45:53
easier, if I can put it like that, to do research
45:55
20 or 25 years ago. When any new drug that came
45:59
along was compared simply to placebo, to giving
46:02
calcium and vitamin D, essentially just doing
46:05
nothing or a dummy drug, it's really ethically
46:08
impossible to do that now. If I have patients,
46:11
let's say, with new vertebral fractures, I can't
46:13
have a group of several thousand patients that
46:16
I just give calcium and vitamin D to any longer
46:18
to compare my new drug with. I've got to give
46:21
them an effective drug. the the dummy arm if
46:25
you'd want to say or the comparator arm of trials
46:27
is no longer a placebo it's quite an effective
46:30
drug and therefore if you want to show your new
46:33
drug is even better than that you're going to
46:36
need more patients and longer trials to show
46:39
a benefit in terms of fractures and the fact
46:43
that we if you know when this is approved and
46:46
we've we've seen the data from sabre and it's
46:48
very impressive if we can use improvement in
46:52
bone mineral density as a surrogate outcome and
46:55
get new drugs approved in that basis then it
46:57
will it will lead to as you said quicker trials
47:01
faster trials and most importantly getting these
47:04
new drugs to my patients more effectively um
47:08
and that's very exciting you know and it's we
47:12
talked i think maybe just after we you know we
47:15
switched the microphone off you know the story
47:18
about in the big gold rush in america in the
47:21
1800s and the people who sort of made money out
47:24
of it were not the prospectors there were those
47:26
who sold the tools and in many ways you know
47:30
that's what mary is doing she's laying down the
47:33
groundwork she's selling the tools if you want
47:36
to say for future generations of researchers
47:38
for drugs that have not yet been developed so
47:42
that they have a faster and easier and better
47:45
way to show that they're efficacious for patients.
47:49
And that's, you know, that's really exciting
47:51
and really important. Yeah, the most important
47:55
research in research is researching research.
47:58
Isn't that exactly? Really inspiring episode.
48:06
Listeners, I really hope you enjoyed that. for
48:10
our lives our children's lives and our grandchildren's
48:13
lives the work that we heard about today is going
48:16
to have a massive effect and that's really wonderful
48:18
so we hope you've enjoyed today's podcast we
48:22
hope you've enjoyed all the podcasts from 2025
48:25
if this is your first then do go back and have
48:28
a listen to all the amazing people we have spoken
48:30
to and all the really interesting things we have
48:33
spoken to them about and We hope we will see
48:37
you in 2026. Until then, Merry Christmas and
48:42
Happy New Year. Bye now.