Latest / 'Bone Up' / Where do bone medicines come from?

Transcript

Where do bone medicines come from? · '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
0:45
and welcome back to another episode of bone up
0:58
the podcast I should apologize. I'm just getting
1:02
over the cold. So you might detect in my voice
1:05
that my usual mellifluous tone is a little more
1:08
plangent. Richie, how are you? How are you doing?
1:13
I'm good, thanks. I'm good. I've also got a bit
1:15
of a cold at the minute. I think all the kids
1:17
are back in school and the students are back
1:19
in uni. So it's like infection center, isn't
1:22
it really? I'm really excited about today's episode
1:26
because I think it cuts across science and clinical
1:29
practice. And I think we've got a lot of really
1:32
interesting stuff for the listeners today. But
1:34
I suppose a good place to start is to ask you,
1:38
David, how have you found that your clinical
1:41
practice has changed in the last decade or so?
1:44
Yeah, I mean, it's something a number of us in
1:47
clinical practice have been talking about recently,
1:49
and that is how... What you might call an osteoporosis
1:54
clinic or a fracture liaison clinic has changed
1:57
so much over the last 10 years. And the single
1:59
biggest change is that whereas maybe 10 years
2:03
ago, 1 in 10 or 2 in 10 of my patients might
2:07
have had vertebral fractures and be seeing me
2:10
because they had a vertebral fracture. At most
2:12
clinics now, it's 8 out of 10 or 9 out of 10.
2:17
I think like many specialists, I now run a specific
2:20
fast track vertebral fracture clinic where obviously
2:24
it's 10 out of 10. And vertebral fractures have
2:27
really moved front and center. And that's a huge
2:30
change. You know, even when I think back to,
2:32
you know, the first time I did an osteoporosis
2:35
clinic as a junior doctor back in the late 1990s,
2:38
you would seldom have seen a vertebral fracture.
2:40
You know, they were considered really very small
2:42
print and incidental things. And I suppose the
2:46
biggest reason for them moving front and center,
2:49
first, of course, we understand that they are
2:52
a very strong predictor for other fractures and
2:56
a very strong predictor for high fracture risk
2:59
and for low bone density and for osteoporosis.
3:03
But we actually have medication now that can
3:06
make a big difference to them. Because as we've
3:10
talked before, those first clinics I did 25 years
3:14
ago, We had oral bisphosphonate. That was quite
3:17
a novelty. And those drugs, while good drugs
3:21
in many scenarios, they take their time to work.
3:24
And in terms of, you know, vertebral fractures,
3:27
we now have newer, exciting drugs which work
3:30
much more quickly and are much more effective.
3:34
And that's probably been the single biggest change.
3:38
And that's why, you know, it's one of the reasons
3:41
it's exciting today to talk to Roland Barron
3:45
about his role in the development of one of those
3:47
drugs. And in fact, just his experience over
3:50
many, many years of working in the field of osteoporosis
3:53
and the changes that he has seen. And, you know,
3:57
it's also really been brought home to me recently,
4:01
Richie, just how important this is. I know our
4:03
podcast is quite a modest little enterprise,
4:06
but we do think we're putting... proper evidence
4:10
-based medicine out there in a way that people
4:12
can understand. Quite recently, I had a patient
4:15
come in and really didn't want to listen to anything
4:18
I had to say. I'd read things on the internet
4:21
and was very much against any sort of modern
4:24
pharmaceutical medicine, felt the drugs we were
4:27
giving were sort of causing fractures. And while
4:31
I'm respectful of her, I gave her the evidence,
4:33
we decided to... disagree and she left I hope
4:37
on good terms but it brought it home to me how
4:40
still you know there's work to be done in getting
4:44
this new medicine this new evidence getting it
4:47
out there so people could look at it and so people
4:49
can make hopefully an informed decision about
4:53
what's about what's best for them and it's so
4:56
nice to hear the science discussed as well and
4:59
to hear people who were really there at the coalface
5:03
when the science started like roland to uh to
5:06
tell us about about what that was like now one
5:10
of the things you're going to hear listeners
5:11
is roland talk about the wind pathway and i think
5:15
it might be useful uh to get a bit of an update
5:19
And I think, Richie, you're probably very well
5:22
placed to explain to us exactly what the Wnt
5:25
pathway is and how it's relevant to our bones
5:29
and how it's relevant to the medication we would
5:32
use. Listeners, as David said, Roland is really
5:37
instrumental in developing new medicines, the
5:41
anabolic medicines like romisosomab. Roland and
5:44
his contemporaries... we're able to characterize
5:48
the cell signaling pathways which govern bone
5:51
formation in our bodies and then develop treatments
5:55
that increase the amount of cell signaling to
5:58
improve bone mass. And the cell signaling pathway
6:01
for bone formation is called WNT, which is spelt
6:05
W -N -T. And in our bodies, we have a gene called
6:09
WNT that produces the protein called WNT. And
6:14
that protein travels to our bone cells and it
6:17
stimulates them to form new bone. One of the
6:21
new treatments in the UK now, romisosomab, works
6:24
by activating that Wnt pathway to tell the bone
6:29
cells to form new bone. Wnt is a slightly odd
6:34
word and really it's an abbreviation. And the
6:39
abbreviation stands for wingless integrated.
6:43
wingless integrated. And the reason why it's
6:47
called wingless is really fascinating. The gene
6:50
is called wingless because it was discovered
6:52
by accident in the 1970s by scientists who were
6:56
studying wingless fruit flies. And they realized
6:59
that Wnt genes in our body control really fundamental
7:03
processes of growth and development, including
7:07
bone. Ultimately, the new drugs that are being
7:11
licensed now originally came from discoveries
7:15
that were made by scientists in the 70s studying
7:18
fruit flies. I can't pretend I knew that, Richie.
7:22
That is very interesting. I promised you I'd
7:26
have something good for you today. We often say
7:30
how proteins and diseases and all these things
7:32
are named sometimes many, many years before the
7:35
mechanism or the usefulness is worked out. And
7:38
if we had to name them now, we would name them
7:40
something completely different. We're stuck with
7:43
names like tumor necrosis factor alpha and WNT
7:49
and so on. So, yeah, fascinating little story.
7:52
Right. I suppose we should get to our interview
7:54
now. And listeners, we caught up with Roland
7:57
Baron at the ECTS conference earlier this year,
8:01
which was an absolute mine for interviews for
8:04
Bone Up. So I hope you enjoy. So listeners, we're
8:08
very excited with our next guest. We have Roland
8:11
Baron, Harvard professor. Welcome. Thank you.
8:14
I'm very pleased to be here. Back home in France.
8:17
Back home in France. Absolutely. Marseille is
8:21
a beautiful city, we're really enjoying the conference
8:23
here. So, first question for you, how did you
8:27
get into bone? Oh my god, I got into bone because
8:31
I was, as a kid and even until my early twenties,
8:36
passionate about archaeology and prehistoric
8:41
digs. And I was very lucky to participate within
8:46
a professional team from the Musée de l 'Homme
8:49
in Paris. A very famous professor, my first big
8:54
mentor, Professor Leroy Gourhan. very, very famous.
9:00
And we ended up encountering a lot of bones,
9:06
animal bones in some sites, and human bones in
9:11
Neolithic common graves, where slowly I became
9:18
the guy to look at these bones, decide whether
9:22
there was pathology or no pathology, whether
9:25
it was an old man or a young woman or a kid or
9:32
all of that. And slowly I discovered that what
9:38
I was passionate about was really research. And
9:44
that was one type of research. And then I started
9:49
to do biology during my education and so on.
9:53
And I married the two, from the dead bone to
9:56
the live bone. I worked at the Musée de l 'Homme
10:01
for a month in 2011. I used to go there all the
10:05
time. It's a beautiful museum and a wonderful
10:07
location by the Eiffel Tower. You got into...
10:12
basic and clinical research for bone health.
10:16
And you've been studying the physiological mechanisms
10:20
that control bone cells, your osteoblasts, your
10:23
osteoclasts, your osteocytes. And you've done
10:26
lots of really fundamental work into how the
10:29
systems work. And one of your most important
10:32
bits of research would be the Wnt pathway and
10:34
Wnt signaling. Could you tell us about your research?
10:39
Yeah, so my research from the beginning was centered
10:43
on trying to understand the mechanisms of bone
10:46
remodeling and more recently, bone modeling as
10:51
well. which implied not only understanding the
10:55
origin and differentiation and function of the
10:59
different cells involved, and you listed them,
11:03
osteoclasts, osteoblasts, osteocytes, although
11:05
it's only recently that we are able to do some
11:08
work with that cell type, and the lining cells,
11:12
the quiescent surfaces. So a lot of my work originally
11:16
was on understanding the remodeling process.
11:21
you know, crosstalk and so on. And going more
11:25
in depth in cell biology, I mostly worked on
11:29
osteoclasts, to say the truth. And there, yeah,
11:32
we made some important observations at the time,
11:36
like the fact that the cells acidify the extracellular
11:40
environment, things like that. and the coupling
11:46
phenomenon and how to approach it and so on,
11:50
and how these processes were disrupted during
11:56
pathological processes. Wendt came late in the
12:05
story, really. It came when I was one foot in
12:10
academia and one foot in industry. And we decided,
12:17
as industry at the time, to focus on ultra -rare
12:24
diseases, really, which now is like we're all
12:28
doing that. But at the time, it was not the case.
12:32
And we had identified the group of Matt Warman.
12:38
who was working on osteoporosis pseudoglyoma
12:42
syndrome, an ultra -rare disease, and was trying
12:46
to identify the gene that was mutated in that
12:52
early onset osteoporosis, if you want to call
12:56
it. And it turned out that a team in France,
13:01
actually here nearby, in Nice, was an expert
13:05
of the chromosomal region that Matt had identified
13:11
in humans, so the synthetic region in mice, okay,
13:16
that Matt had identified in humans, but in order
13:21
to find the mutated gene at the time, because
13:26
it was late 90s, early 2000. you needed to know
13:35
a lot of marker genes. And this group in Nice
13:40
had really tremendous knowledge of the synthetic
13:45
region in the mouse chromosome. And with all
13:50
the markers that they had identified, Matt, within
13:55
six months, was able to identify the... the mutated
14:00
gene, which was LRP5. And it turned out that
14:08
LRP5, the first time we heard about it in our
14:13
field, is one of the core receptors for canonical
14:18
wind signaling. And that triggered, not only
14:23
in my lab and in my company, but also in the
14:26
world, a tremendous amount of research. So we
14:32
collaborated with Matt to understand how this
14:37
receptor was linked to bone development and biology
14:43
and so on. We ended up publishing together a
14:47
paper that he cited tremendously, that was in
14:51
sale. Biggest journal in the world. Yeah. And
14:56
the only thing is we are, I don't know, 150 authors
15:03
or something like that. The last three is myself
15:07
and Bjorn Olsson and Matt, the three labs that
15:12
we're collaborating. And I always blamed Matt
15:16
for doing that to us because what he did was
15:19
to include as co -authors all the clinicians
15:22
that gave him blood samples from the ultra -rare
15:28
patients. So it was the way it is. And from there,
15:34
a lot of my personal research, academic research,
15:40
turned to try to understand the mechanisms by
15:44
which all this was happening and the biology
15:48
of this quite complex pathway. Most clinicians,
15:52
and I'm a clinician, will have heard of WNT,
15:55
in terms of anti -sclerostin antibody and treatment
15:59
for osteoporosis. From your point of view, did
16:03
you perceive in the early stages that this was
16:05
a potential pathway for a game -changing treatment,
16:09
or was it purely interest in the science? Well,
16:13
it was a mix. It was a mix. As I said, my interest
16:16
came from my small company at the time. So there
16:22
was an industrial interest, if you want, of trying
16:25
to find new targets for the treatment of bone
16:30
fragility, whatever the cause is. So there was
16:35
that. But quickly, it also became... academically
16:39
extremely interesting. It's a very fundamental
16:42
pathway and very complex, which, by the way,
16:49
explains why with ramososumab you get these changes,
16:55
but they are very quickly counteracted by negative
16:59
feedback loops, because it's a very potent primordial
17:04
pathway. So initially, we didn't know about sclerostin,
17:10
but often when I give my lectures on this topic,
17:14
I call the attention of the fact that in the
17:16
history of medicine, it's quite rare that in
17:20
the same year, three papers came out. So we had
17:25
that one, the early onset osteoporosis. Then,
17:30
what's his name? Bob Recker. in Omaha had identified
17:39
a family with high bone mass, but no clinical
17:45
consequences of it. Just high bone mass. Normal
17:48
guys, but high bone mass. And they went also
17:52
to identify the gene. And it turned out to also
17:55
be LRP5. And their paper came about one year
17:59
after us. But they were engaged into that long
18:02
before. And it's fascinating that you know in
18:06
human not in mouse mutation and all that And
18:11
within one year or a year and a half, you identified
18:15
a gain of function that leads to high bone mass
18:18
and a loss of function that led to low bone mass.
18:21
Coincidence just at the same year both those
18:23
things appeared? Absolutely. And the third paper
18:25
is even more incredibly in the history of medicine
18:28
in my mind, was the paper from Wim van Hoole
18:33
and the group in the Netherlands that identified
18:37
the gene. causing sclerostosis, which, as you
18:43
know, is a sclerostin. And lo and behold, the
18:49
mutations in the high bone mass was a single
18:53
-point mutation in the LRP5 receptor that led
18:58
to a low affinity for sclerostin. explaining
19:03
the whole story. All the jigsaw pieces suddenly
19:05
appeared in the same year? Absolutely. And were
19:08
you talking to each other among the groups? Did
19:11
you all know you were all working on Sclerostin?
19:13
No, nobody knew. No, we were trying to do one
19:17
thing, they were trying to do something else,
19:19
and it turned out that the three things are the
19:23
full explanation of the whole story. that this
19:27
pathway is essential in bold mass. regulation.
19:33
Do you get a thrill when you know that people
19:35
around the world are now getting a drug which
19:37
has changed their lives based on something that
19:40
you do? Oh yeah, absolutely. I see patients and
19:42
their lives have been changed by getting romosuzumab
19:45
and it's thanks to the work that you did 20 years
19:47
ago. It's not just me. Yeah, I know, but you
19:50
were a big part of this. We were a part of it
19:52
and that's very rewarding, absolutely. And when
19:58
I left industry, Of course, companies that were
20:04
working on all of that called on me to, you know,
20:08
be an advisor. So I've been on the SAV of all
20:12
this drug development. And RomoSosumab's story
20:17
is fascinating, from the basic science, the clinical.
20:23
and the drug development side. Even the history
20:27
of sclerostiosis as a condition and the groups
20:30
of people that affected it. You know, when this
20:33
paper came out on sclerostiosis, I don't remember
20:35
if it's the original paper, probably it is, there
20:39
was also heterozygotes, haploinsufficient. This
20:47
told the whole industry that if we can regulate
20:52
sclerostin, we don't need to be zero. We need
20:56
to be 50 % or 60 % or 70 % or whatever. We will
21:01
increase bone density. The surprise has been
21:06
two things. One, that when the first... especially
21:11
the the clinical trials when phase one was done
21:14
in particular suddenly we realized that it's
21:16
also anti -resorbing that was not clear from
21:21
the pre -clinical studies that's very interesting
21:24
because you know we do think of it as a duo we
21:26
lump it together anabolic therapy but it's not
21:29
it's a dual action it's a dual action yeah absolutely
21:33
So you didn't know that from the start? That's
21:34
something you discovered as you went? So there's
21:36
even an extra benefit? Yeah, absolutely. It was
21:38
discovered really after the phase one, when we
21:43
saw the phase one data. It was, wow, because
21:47
we didn't see that before. And the second surprise
21:51
is not a good one, that one, is the fact that
21:53
the effect is very limited in time. You know,
21:59
after six months, you're back to baseline in
22:01
terms of bone formation. But in that time, you
22:06
can build a tremendous amount of bone, which
22:09
is going to reduce people's fracture risk. Tremendous.
22:12
I mean, the clinical trials are very demonstrative
22:15
of that. Honestly, I'm sure a lot of patients
22:17
prefer just to take it for a few months. At what
22:21
point did you realize what a game changer this
22:25
was? At what point did you think, wow, we can
22:29
help a lot of people. Well, I think that the
22:32
early animal studies, the knockout, the first
22:39
preclinical studies with the antibodies and so
22:43
on, it was clear that the tremendous impact on
22:47
both cortical and trabecular bone and the speed
22:51
at which it happened was unique. I remember seeing
22:58
the first data from Amgen, you know, when you
23:02
see, you know, double fluorescent label along
23:07
bone surface, like 100 % of the surfaces. Yeah.
23:10
We had never seen that before. A lot of treatments
23:15
which are being developed and tested in mice,
23:17
though, never make it to humans because it doesn't
23:21
really translate. It doesn't really extrapolate
23:23
to humans. Were you ever worried that though
23:25
it was working in mice, it might not work in
23:27
humans? No, because I remind you that it all
23:30
started from humans. Yeah, you have the sclerostiosis
23:33
to prove that, yeah. This is a reverse. It's
23:37
not like we worked in mice and then tried in
23:40
humans. It was discovered, the entire story,
23:45
in humans. And then we went in mice to use them
23:49
as a tool, not to figure how it works. Wow. For
23:53
young scientists listening, this is a really
23:54
amazing example of how to do research back from
23:58
humans. We know you've done some work on osteocytes
24:02
as well. Recently, more recently. I'm not known
24:05
for that. Oh, I was going to ask you some hard
24:07
questions. I'll ask you simple questions. You
24:09
can go, you can go. We talk to students and I
24:13
talk to patients and explain to them how osteoblasts
24:16
work and how osteoclasts work. We don't talk
24:18
that much about osteocytes, even though they
24:22
are... by far the most abundant cell in the bone,
24:25
much more common than osteoblasts or osteoclasts.
24:29
And we are discovering more about how they work
24:31
and how they live in their lacuna. And they respond,
24:35
I think, to mechanical loading quite well. Do
24:40
you think the time will come we will develop
24:42
specific drugs and pathways and mechanisms to
24:45
manipulate osteocytes specifically? Or do you
24:49
think we will just come to understand how the
24:50
drugs we use affect osteocytes? So let me answer
24:54
that question by going back to sclerosin. You
24:58
have to remember that the only source we know
25:02
of within... the bone microenvironment at least,
25:06
but really mostly the whole body, but let's say
25:09
just within bone, is the osteocyte. So the story
25:14
is an osteocyte story. We know these molecules
25:18
work at very short range. So it is one of the
25:23
rank ligand being, of course, one of the others.
25:29
cytokines that the osteocytes make to regulate
25:35
the activity of cells along the bone surface.
25:38
So in a way you could say, you cannot say it
25:46
too seriously, but... you know, to some degree,
25:50
that with ramososumab, we are targeting the osteocytes.
25:53
Osteocyte, yeah. Okay. Now, strange enough, we
25:58
do not know much, and I always think that it
26:01
would be interesting to look at that. We don't
26:03
know much about what ramososumab, for instance,
26:07
does to the biology of the osteocyte itself.
26:12
It would be an interesting, at least academic,
26:14
question to address. Do you think if we did understand
26:18
that, we may, for example, use romosuzumab slightly
26:22
differently? If we understood just how it worked
26:24
in the osteocyte, we might be able to tweak it
26:27
in some way to make it... Not romosuzumab, but
26:31
we know now that the other dominant Wnt antagonist
26:39
in the... bone microenvironment is also made
26:43
primarily by the osteocytes. It's DKK1. Yeah,
26:47
DKF. And we also know that when we treat with
26:54
ramososumab, it's... primarily, not only, but
26:58
primarily DKK1 that serves as a negative feedback
27:02
loop. In other words, because the system perceives
27:07
that wind is too much activated, the cells make
27:12
DKK1 to block it. And that's why the effect goes
27:15
off so quickly, because the DKK1 goes up. Exactly.
27:19
And so Amgen... made by specific antibodies where
27:25
one arm is against sclerostin, the other against
27:29
DKK1. And the effect is even more spectacular.
27:34
Okay. Turns out that they were already very much
27:38
engaged in the development of denosumab, romosumab,
27:42
excuse me. And therefore, you know, from an industry
27:46
point of view, you don't stop. Yeah. Right. However,
27:52
uh there are there is a company that picked up
27:55
on that and uh that i think just made a phase
27:59
one oh okay so offer just a dkk1 blocker or one
28:03
that does both and i mean in mice anyway we know
28:11
that when you do that you increase like double
28:16
the speed and the amount of bone however it also
28:21
fades out. Fades out because we know of, I don't
28:26
know, 10 or 12 wind antagonists. And the system,
28:31
each time you're going to turn on... Yeah, it
28:33
will escape somewhere else. Yeah, that's... We've
28:37
really got to see behind the curtain here of
28:39
the future. This is very exciting. Yeah, yeah.
28:41
We're going to include this as part of the ECTS
28:44
conference episode. I think we need a separate
28:47
episode for this. This is too good. So... So
28:50
basically, if I understand you right, then you're
28:51
saying that there's going to be another medicine
28:53
in the pipeline, which might be even more potent
28:56
and even better than that. Yes. Wow. Patients
28:59
will be very happy to hear that. Yeah, that is
29:02
exciting. And I suppose then the question will
29:04
be, because I don't know if we have time to get
29:06
into the cardiovascular question with the rhumacizumab.
29:09
We can talk about it. I'm not an expert on that.
29:11
However, I was close to the project as an advisor.
29:21
What I can say is, first of all, if you look
29:24
in the literature about sclerostin and atherosclerosis,
29:30
for instance, you find... Essentially whatever
29:35
you want. So some people reported that it is
29:38
increased in atherosclerosis. Some people say
29:43
that it is decreased. Some people say that when
29:45
it's increased and you block it, you make things
29:49
worse. Some people say that you do the opposite.
29:53
The Amgen UCB group did very extensive studies
29:58
with the animal models that are available. They
30:02
are not perfect. and have not found any link
30:07
between sclerostin and atherosclerosis. Add to
30:15
that that in the very extensive animal studies
30:19
and so on, there's never been any indication
30:23
that there is really something. At the recent
30:28
meeting last year, There was a whole discussion
30:32
on the topic. And one interesting question is
30:37
what it does to vascular calcification and whether
30:42
by enhancing bone formation, as we do, we also
30:48
favor vascular calcification, which could be
30:51
part of cardiovascular issues. As you know, the
30:58
consensus in the field so far is that we do not
31:04
know of a direct link between the two. So we
31:09
are waiting to see. And again, I'm not a clinician,
31:14
but in Japan, where ramososumab is used extensively,
31:21
they've done... post -marketing research. And
31:28
so far, there's absolutely no signal of an increase
31:33
in strokes. you know osteoporosis doctor I'm
31:38
obviously obliged to talk through this with people
31:41
and occasionally I've had people one or two patients
31:44
who don't want to take romacizumab and there
31:46
are people who I don't think have any significant
31:48
cardiovascular risk and I'm disappointed because
31:51
I don't really think it's a risk for them or
31:53
I think the relative risk the relative risk is
31:55
a different you know a different degree absolutely
31:59
But at the moment, we still feel we have to share
32:01
this, which is good. That's fair. But perhaps
32:06
in the longer term, that perception will fall
32:09
away and we'll be able to use the drug more widely.
32:11
But of course, you have to put yourself in the
32:14
shoes of the patient. Yeah, exactly. Which is
32:16
that you're putting one side, I'm going to prevent
32:20
potential future fractures. Exactly. Yet I may
32:25
induce a stroke. So it's kind of difficult. It's
32:31
difficult, and we have to be entirely fair and
32:33
open all the time with people. But that's why
32:36
it's really good for us to come and talk to scientists
32:39
and talk about research so that my patients know
32:43
that. The advice I'm giving them comes from proper
32:47
science, proper research. I'm not being told
32:50
by someone. I'm not making it up. It's all based
32:52
on clever people doing their best to understand
32:55
how the body works. Think about the story of
32:59
Terry Paratide and also sarcoma. It took 20 years
33:07
on the market before the black box was removed.
33:10
Yes, and that's something I don't feel I have
33:12
to talk to people about now. Absolutely. But
33:15
when you did have to, it put almost everyone
33:17
off it. Of course. As you would imagine. Of course.
33:20
So my prediction, but it's already dangerous
33:22
to make predictions, is that it's going to happen
33:24
with ROMO. I think a lot of people hope that
33:28
will happen, yeah. A while ago, I took a deep
33:30
dive into the clinical trial data, and when ROMO
33:33
was compared to a placebo, there was no cardiovascular
33:36
signal. When it was compared to alendronate,
33:39
there was, but that might say more about the
33:42
effect of alendronate and its potential ability
33:44
to reduce cardiovascular side effects. Right.
33:47
There is that, and there is, you know, the randomness
33:50
of clinical trials. Yeah. Because even on the
33:53
alendronate arm, there are weird events. If you
33:57
look at the Kaplan -Meier curve, for the first
34:02
three months, there are zero events. Yeah. And
34:05
then between 1 .6 and... nine again zero events
34:09
which is extremely it's it's yeah it's unusual
34:12
yeah absolutely yeah i must say i've always tended
34:15
to feel it could well have been the bisphosphonate
34:18
being protective that it's not a it's not a pure
34:21
placebo group it's a slightly treated group yeah
34:25
that's There's been some discussion. And also
34:27
the patients were, if I recall, four or five
34:30
years older on average, and they already had
34:34
one fracture. So it's a different population
34:37
between the frame and the arch clinical trials.
34:43
Okay. We're going to have to draw it to a close.
34:46
Thank you so much for talking to us today. My
34:48
pleasure. It has been a huge honor for you to
34:50
join our podcast. My pleasure. I mean, we look
34:56
forward. You were central to developing actinil,
34:59
resedronate. You had this major role in developing.
35:04
Romosuzumab. You need a third one now before
35:06
you retire, surely? You're working on a third
35:08
one before you retire. And you started the IFMRS.
35:11
We spoke to February. Absolutely. We haven't
35:14
even had time to cover that. You founded IFMRS.
35:17
What a contribution you've made to millions of
35:20
people with osteoporosis around the world. Thank
35:22
you. Thank you very much. I hope it's not the
35:24
end, but it might be. David, I really enjoyed.
35:33
interviewing Roland, I felt like we were kind
35:35
of in the presence of greatness. What were your
35:37
takeaways? Yeah, I mean, if you're outside the
35:41
world of osteoporosis and research, you don't
35:42
realise just what an important figure Roland
35:44
has been for many years internationally. We were
35:48
very honoured that he came to speak to us. Do
35:51
you know the single biggest thing really I came
35:53
away with for speaking to Roland was just his
35:55
enthusiasm for the subject and the reason he
35:59
did what he did was that he was interested in
36:01
it. And I find that chimed very much with me
36:05
in that I do bone because I'm interested in bone
36:08
and because I enjoy seeing people with bone problems
36:12
at clinics and being a doctor in that way. And
36:14
Roland told us how he started out, he had an
36:17
interest in archaeology and paleontology and
36:20
bones. And he just followed that where his genuine
36:23
interest took him. And it led him to be part
36:26
of some major discoveries which have changed
36:29
the lives of... you know, tens of millions of
36:32
people around the world. And I think for anyone,
36:35
you know, for any sort of early career grade
36:38
person, whether they're a scientist, whether
36:41
they're a doctor, whether they're a radiographer,
36:43
whatever they're doing, you know, if it interests
36:45
you, then follow it. You know, that's what to
36:48
do, because that's what will give you a fulfilling
36:50
professional life. And, you know, in Roland's
36:54
case, allow you to make a huge difference to
36:56
people around the world. And again, it's just
37:00
I really enjoy learning about the basic science
37:03
of things. And you'd be surprised perhaps how
37:07
much time I do spend sometimes talking to patients
37:10
about basic science, because I think patients
37:13
are interested to learn how their bodies work.
37:16
And I have no doubt that if you understand how
37:18
a drug works, you are more likely to take it,
37:23
more likely to comply with it, more likely to
37:25
have confidence in it, you know. And it surprises
37:30
me almost sometimes when I find myself explaining
37:33
to patients in some depth about how cells work.
37:37
Patients are fascinated about that. They love
37:39
to hear that. And it's one of the privileges
37:42
of doing this podcast, actually, is to get to
37:45
talk to people who do this work. People like
37:47
you, Richie, as well, who do the really important
37:49
basic science work. And to be able to share that
37:52
with the people who will benefit from hearing
37:55
it. I'm sure as a... As a scientist and as a
38:00
wind pathway fan, as we now know, you must have
38:04
found that very interesting. Yeah, it was amazing.
38:11
Over the years, I've read about the wind pathway
38:14
so much. It was fascinating to talk to Roland
38:18
about it and how the discovery came about. And
38:22
I thought he was so... Listeners, it's hard to
38:26
get across how transformative... roland has been
38:29
the the discovery of the wind pathway has led
38:32
to lots of new treatments and those new treatments
38:35
like romasosomab use monoclonal antibodies and
38:38
monoclonal antibodies were kind of discovered
38:41
in the late 1990s and it was thought straight
38:44
away that they could be a very good tool for
38:48
treating many many many diseases but it was in
38:51
bone the Roland and his contemporaries were able
38:57
to make it work. So this is like discovery upon
39:01
discovery. And it really shows that bone research
39:05
is actually very cutting edge in comparison to
39:09
many other fields. And I don't think we get that
39:12
message out to the wider world enough. One of
39:16
the things I really liked about Roland was his
39:18
story. Like you were saying, he just has a love
39:20
for the subject. He came from archaeology. And
39:23
I find that really fascinating because I came
39:25
from archaeology and paleontology as well. And
39:28
I suppose, you know, you kind of get excited
39:31
about bone and bone physiology. And in a way,
39:35
that kind of leads you towards the more medical
39:36
aspects and towards medical research. I was really
39:41
kind of heartened to see how he talked not just
39:45
about himself and his own research. But the other
39:48
groups who were working at the same time and
39:51
making similar discoveries that overlapped with
39:54
his and talking about how several groups released
39:56
papers in the same year and they didn't know
39:58
they were all working on it. But when you put
40:00
all that work together, then you can unlock the
40:04
secrets of these bone pathways. And I thought
40:06
that was really amazing. It's a community of
40:09
people that have led to these new treatments.
40:13
The other thing is, listeners, you know, you
40:15
heard it here first, you know, these new medicines
40:17
that will work to increase new bone formation
40:20
by also targeting the dick -off pathways. Roland
40:27
talked about new medicines which are in development
40:30
that could target the wint and dick -off at the
40:32
same time, and therefore, I guess, be much more
40:36
potent medicines for... preventing osteoporosis
40:40
and preventing fractures which is absolutely
40:42
amazing. Roland's been such a massive figure
40:45
in our field for so long and he's still he's
40:48
still coming out with the big hits it's amazing.
40:51
It's one of the things patients say to me well
40:53
you know this is great but but you know what's
40:55
next is there anything in the pipeline and it's
40:57
great to be able to learn that there are things
40:59
in the pipeline and I suppose one of the questions
41:02
people sometimes say The teriparatide or the
41:07
abaloparatide or the rumicizumab, it's worked
41:10
really well for me for 12 months, 18 months.
41:13
Why can't I just keep going with it for five
41:16
years or 10 years the way I did with the bisphosphonate?
41:19
But the effects of all those drugs wear off.
41:22
And, you know, the tick -off pathway, as we were
41:26
talking about, that may be a... it may be a secret
41:30
to preventing the wearing off effect of romacizumab,
41:33
if I understand that correctly. And it's certainly
41:37
very exciting. You know, we've had two episodes
41:40
talking about new drugs in the last two years.
41:43
I don't think we anticipate having a third new
41:46
drug very soon, but it is fascinating to sort
41:50
of learn where the, you know, from what direction
41:53
the new developments might be coming and give
41:55
people the hope that... that there are even newer
41:58
things around the corner. Ever better and better
42:01
treatments. Absolutely. Okay, listeners, we hope
42:06
you've enjoyed the show today. We really did.
42:08
See you again soon. Bye -bye. Bye now.