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BoneUP Live 2025 @ECTS - Part 2 · '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. Welcome
0:55
back to episode two of Bone Up Live, recorded
0:58
here in Innsbruck at the ECTS. We're looking
1:02
forward to bringing you some more interviews.
1:11
Listeners, we're very pleased to announce our
1:13
next guest, Professor John Carey, who's the clinical
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lead for DEXA Fracture Liaison Services and Osteoporosis
1:19
Services at Galway University Hospital. Thank
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you for joining us, John. Thank you for having
1:24
me. It's a pleasure to speak to you. We've had
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to come all the way to Innsbruck to talk to each
1:28
other. That's right. We live on the same island.
1:31
So we'd like to ask you about the talk you've
1:33
given at ECTS on the best use of DEXA for taking
1:37
care of patients. How do you feel DEXA is best
1:41
used? Super. So I suppose fundamentally, just
1:44
so the general public understand, DEXA is a test.
1:48
And like any test, if it's used appropriately
1:50
and correctly for the right people, it provides
1:52
extraordinarily useful information. For anybody
1:56
with a bone problem, DEXA is an essential service.
1:59
Without having DEXA, you can't run an osteoporosis
2:01
service. Unfortunately, for some reason, people
2:05
seem to think in osteoporosis you don't necessarily
2:08
need all these extra tests, but it's not an extra
2:10
test, it's an essential test. For people who've
2:13
never had a fracture, it's used for predicting
2:16
who... most likely fracture it's not a guarantee
2:18
it's a great way to assess people before they
2:21
have a fracture and a fracture is the medical
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word for a broken bone patients are often confused
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they'll tell you i didn't have a broken bone
2:27
i just had a fracture i didn't have surgery i
2:29
just had a procedure on my back so it's important
2:32
to understand that dex is just a test Once people
2:35
have a broken bone or a fracture, that is diagnostic
2:38
of osteoporosis. That's like having a heart attack
2:41
and having a cholesterol test to see if you're
2:43
at risk. So by the same juncture, once your bone
2:46
breaks, that means you have osteoporosis. So
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DEXA is no longer for diagnosis. In people who
2:50
haven't had a fracture, we can also use DEXA.
2:54
to categorise people as having osteoporotic BMD
2:57
or not. But a lot of people who fracture or break
2:59
a bone won't meet that threshold. So that means,
3:02
in science terms, they have a false negative
3:03
test if they break a bone and the test didn't
3:06
show it. On the other hand, if you test the wrong
3:08
people and lots of young healthy people, you'll
3:10
get false positive tests where people had a test
3:13
that they probably shouldn't have done because
3:14
they're not at risk for a fracture in the immediate
3:16
future. And they may show up as quote -unquote
3:19
having a positive test when in reality that's
3:21
probably a false positive because they don't
3:23
have the disease. And there are many other complex
3:26
reasons why that takes place, but in simple terms.
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And I suppose in terms of what we discussed briefly
3:31
today, if people have a fracture and they've
3:33
low bone density, By the DEXA test, they're much
3:36
more likely to have another fracture than if
3:38
they just have low bone density or they just
3:40
have the fracture. And the final thing that sometimes
3:42
people don't understand is once you've made the
3:45
diagnosis, DEXA is still essential, but it's
3:47
not for diagnosis because we have that diagnosis.
3:50
What it's being used for is for monitoring your
3:52
treatment or your response to treatment. Because
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some people, like every disease, will respond
3:56
really well. Some people respond, okay, not perfectly
3:59
or brilliantly, but we're happy with it. Unfortunately,
4:02
like every disease, not everybody responds. respond
4:04
to treatment so the only way to really know if
4:07
people are responding is to follow up bone density
4:09
tests or to see if they have further fractures.
4:12
There are other ways to assess that but they
4:14
would be the main fundamental tools we have in
4:16
an osteoporosis service today. One of the issues
4:20
we see with DEXA scans, as you say, is sometimes
4:23
they're not well interpreted because people don't
4:26
know what question they're answering. What are
4:27
the sort of common pitfalls in interpreting DEXAs
4:30
or that you see DEXAs interpreted incorrectly?
4:33
I'll throw you one. Someone's been told their
4:36
bone density is normal because their T -scores
4:38
plus two at the lumbar spine. Then you and I
4:40
look at the lumbar spine and there's scoliosis
4:42
and degenerative chains. So what are the other
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sort of pitfalls? falls that a GP or a radiographer
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should look for when they're getting a DEXA scan.
4:50
Yeah, so the common things are, the first thing
4:54
actually is who is being scanned and why. And
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that's sometimes... something people don't understand
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if the patient was being scanned say to assess
5:02
the risk of fracture the report should say this
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patient's low risk intermediate risk or high
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risk but it may not it's not for monitoring treatment
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and on the other hand if they've had five fractures
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it's not for diagnosis so that's some a common
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mistake we see where the patient's told they
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don't have osteoporosis they've osteopenia because
5:18
they had a fracture, but the test didn't show
5:21
osteoporosis. So that's probably one of the commonest
5:23
problems we see. Other common problems, as you
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say, sometimes there are other imaging artifacts.
5:29
that pop up that are ignored, like the patients
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had spine surgery and the bone density has gone
5:33
up 80 % because they've had a spinal fusion,
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but nobody actually looked at the image to see
5:38
there's metalwork there. Sometimes, and I'm sure
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you see this just like I do, people have had
5:42
multiple spine fractures since the last DEXA,
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and it looks like the BMD has gone up, but the
5:47
bone is broken. That's why there's a problem.
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And someone then stops their drug even though
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they've now had three extra fractures because
5:52
their bone density has improved. Exactly. But
5:54
it's a lack of understanding of what the scan
5:56
actually shows, isn't it? That's correct. DEXA
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is a much more complex test than any other test
6:01
in radiology because unlike, say, a chest x -ray,
6:04
DEXA has an electronic medical record. So it
6:06
captures information like risk factors, your
6:09
demographics, the treatments you're on, which
6:11
is more than you would get, say, in a regular
6:13
radiology report. On top of that, you also have
6:15
images, which you might have, say, for a chest
6:17
x -ray or a CT scan. But in addition to that,
6:20
you also have measurements like bone mineral
6:22
density, like fat mass, lean mass, or vascular
6:24
calcification. And you may also get a VFA scan,
6:27
which often picks up spine fractures that were
6:29
previously undiagnosed. So there's a lot more
6:32
complexity and clinical information and other
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information with a DEXA scan than you would have
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with something like maybe an ultrasound or an
6:39
X -ray or a CT. So there's a kind of myth out
6:43
there that DEXA, oh, it's just pressing buttons
6:45
and it's just bone density, but it's anything
6:47
but. that bone density is the tip of the iceberg
6:50
there's a lot more information below the surface
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and if it's used really well like any test it's
6:55
very useful information and it's critically important
6:57
to patient care and so yeah it's something that
7:00
doesn't get enough emphasis it's hard to get
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good at DEXA you can't get good in a few weeks
7:05
it takes months or years to really master DEXA
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and we're still learning many years later. So
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the radiologists then who look at the DEXA scans
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Do they tend to be specialists who look just
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at DEXA scans or are they more general radiologists
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that see lots of different types of images? So
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I'm going to couch this a little bit because
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the best radiologists in the world at DEXA are
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obviously brilliant at this and then there are
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other people who have no training in DEXA, just
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like in rheumatology, endocrinology or any other
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specialty. So unfortunately in general radiology
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training a lot of radiologists have, I would
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say, fairly limited training in musculoskeletal
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radiology. So whether it's an MRI, a CT, or a
7:43
DEXA scan it's not their main field and we see
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this and it's reflected in the literature as
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well as in our own country in Ireland where a
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lot of the spine fractures are not picked up
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whether it's an MRI a CT or an x -ray when it
7:55
comes to DEXA DEXA is not part of general radiology
7:58
training, or indeed musculoskeletal radiology
8:01
training in most countries in the world today.
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It should be, and it can be, but it isn't. So
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unless there's a radiologist who's really interested
8:08
in DEXA or osteoporosis or metabolic bone disease
8:12
as a specialty, or the DEXAs are in a radiology
8:15
department where they do a lot of training and
8:16
teaching at DEXA, it's often not part of what
8:19
they've been trained in or they're knowledgeable
8:20
about. In fact, a lot of them may have very little
8:22
knowledge in osteoporosis or other diseases as
8:25
well. So sadly what you see is sometimes some
8:28
poor radiologist who's a great person and a nice
8:30
person might be trained in cardiovascular imaging
8:33
and has suddenly landed with, now you have to
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report all these DEXA scans, they've no training,
8:37
they've no knowledge or access to it. what it
8:40
is they should be looking for and how they should
8:41
be reporting it. And I suppose part of our mission
8:44
with the ECTS, with ISCD and IOF and other organisations,
8:48
which we now have with lots of radiology societies,
8:51
there's now endorsed positions, endorsed by the
8:54
European Radiology Society, the European Skeletal
8:56
Radiology Society, the Radiology Society in North
8:59
America and the Nuclear Medicine Societies in
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Europe and North America, which have all endorsed
9:03
these positions that we do need to have standards,
9:06
we do need to endorse best practice. just like
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everybody else should be given the training and
9:10
the opportunities to train and learn and audit
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and improve as they go forward. You often find
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the DEXA department is almost separate from radiology,
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isn't it? The radiologists don't take that much.
9:20
connection with it it's the dexa radiographer
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who does it and runs it that's certainly my experience
9:25
and that's right excellent dexa radiographers
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in my trust and most of the radiologists don't
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take that much to do with it really which strikes
9:32
patients as odd i think but well that's correct
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and i suppose there's three reasons for it i
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think in medicine we're all we'll all do what
9:38
we're comfortable doing and if i was asked to
9:40
do open heart surgery tomorrow and that'd probably
9:42
be the last thing in the hit list before i go
9:44
home for the weekend and i can understand if
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the radiologist is asked 20 years later with
9:48
no training you have to report this DEXA and
9:50
they're asked about drugs they've never heard
9:52
of like I don't think that's fair and I don't
9:54
think it's appropriate but we always say in DEXA
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there's no I in team and DEXA is probably the
9:59
number one team sport in musculoskeletal imaging
10:01
it needs a really well trained and expert radiographer
10:04
and our nurse it needs the clinician who's prescribing
10:08
the drugs and seeing the patients it needs the
10:10
radiologist who's an expert in imaging and fractures
10:13
and it's everybody working together and you see
10:15
in the best centres in the world where they've
10:17
really cracked this is where everybody's working
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together as part of the team. The people who
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see the patients, the people who prescribe the
10:23
treatments, the people who operate on the patients,
10:25
the fracture liaison services, everybody's as
10:27
part of the same team. And we can all learn from
10:29
each other. That's really heartening to see people
10:33
trying to come together, provide the best care,
10:36
provide holistic care, reach out to their colleagues
10:38
and bring everybody together. Yeah, it's fantastic.
10:42
And I suppose that's what keeps us going, right?
10:43
You know, at the end of the day, unfortunately,
10:45
in life, when people get sick, we can't be successful
10:48
all the time. We won't get it right. And perfect
10:51
is the enemy of good. But we can be better and
10:53
we can improve and we can always learn from others
10:56
and we can always help each other out. And, you
10:57
know, if you talk to a lot of smart people, you
10:59
get a lot of smart solutions. And sometimes the
11:02
problem we had 10 years ago and the solution
11:04
we had was very appropriate back then, but it's
11:06
no longer the solution or the problem may have
11:08
changed. A good example would be, you know, we
11:11
never really saw problems when people discontinued
11:13
treatment 10 years ago, other than, well, if
11:15
you don't take your treatment, it doesn't work.
11:17
But in the last 10, 15 years, we've seen a problem
11:20
with one of our new drugs, where it's a really
11:21
good drug and it's a fantastic treatment for
11:23
the most appropriate people. Unfortunately, what
11:26
we've seen sometimes is people were treated inappropriately,
11:29
they've stopped it, and when they stop it, they
11:30
have this rebound effect, more like an elastic
11:33
band shooting back than, say, the brakes in a
11:35
car. And some people have had catastrophic bone
11:37
loss and fractures. And that's something new
11:40
we've had to deal with. And in DEXA, there's
11:42
many new... extra pieces of software and variables
11:45
and better image quality than we would have had,
11:48
say, even 15 years ago. And that's changed things.
11:50
We can see fractures easier. We can see vascular
11:52
calcification. We have better ways to assess
11:55
bone quality. So things are evolving. Things
11:57
are improving. And that's why we need meetings
11:59
like ECTS and updates and talk to colleagues
12:02
so we can stay abreast of what's happening in
12:04
our field. And then, like you say, working across
12:06
the other societies as well, especially the radiologists.
12:08
I think listeners at home would be happy. to
12:11
hear how much goes on behind the scenes to pull
12:13
everybody together so if you had a million euro
12:16
and i'm not giving you a million euro because
12:18
our podcast doesn't pay for interviews, and you
12:22
could choose to buy more DEXA scanners, or you
12:25
could choose to put that into educating people
12:27
better on how to interpret a scan, or you could
12:30
use it in some other part of your fracture liaison
12:32
service. Where would you put the money? I would
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put the money in DEXA education. In education,
12:36
not in more scanners? That's right. We have enough
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DEXA scanners in the Western world, I think.
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They're sometimes in the wrong place. They're
12:45
sometimes in the right place. But the fundamental
12:48
problem in health care, not just osteoporosis
12:50
care around the world today, is waste. And we
12:53
see GDP is going up at X rate in every country
12:56
around the world. It's different by country to
12:58
country. But health care is far outstripping
13:00
the rise in GDP. And new technology is wonderful.
13:03
It's not just in osteoporosis. We're seeing lots
13:05
of really interesting... nice pictures, science,
13:08
but something that's maybe not very helpful clinically,
13:11
and a vast sums of money being spent in this
13:13
new technology. And yes, we have this really
13:15
good test, which is very cheap, extraordinarily
13:17
cost -effective, and life -saving or life -altering
13:20
for patients, and we're not using it very well.
13:22
So I would put the money in making sure everybody
13:24
has very good foundations in clinical densitometry.
13:27
That will save money, that will save lives, and
13:29
that will be a much better investment in the
13:31
future of her. people yeah so people know what
13:34
to do with the information that they're getting
13:36
because i'm sure like like like me um you see
13:39
people they've been told they're they have osteoporosis
13:42
and a dexa their t -scores minus 2 .5 but as
13:45
you say they don't need treatment and there's
13:47
people on the other side of the fence who have
13:48
multiple fractures but they've been told they
13:50
don't have osteoporosis because their t -scores
13:52
minus 2 .4 and they're not getting treatment
13:54
and the dex is not the problem it's it's the
13:58
interpretation it's the person ordering the result,
14:01
getting the result back and knowing what to do
14:03
with it then. That's absolutely right. So we've
14:05
done a very conservative estimate around quality
14:07
decks in Ireland. And just so the listeners are
14:10
aware, we've been teaching best practice decks
14:12
of courses in Ireland since 2009. across the
14:16
board, from paediatrics to adult to body composition.
14:19
And yet today, a conservative estimate that we
14:22
have come up with, and we're working with the
14:24
ECTS on this, is that about if 1 % of the DEXAs
14:28
resulted in the harm that we're seeing from poor
14:30
quality DEXAs, that outstrips the annual cost
14:33
of providing DEXA services alone. That's about
14:35
100 million a year wasted in Ireland. And we're
14:38
seeing that every day. And we've written to the
14:39
government, and we've written to the administrators,
14:41
but they're not listening. We know from the literature
14:45
that DEXA errors are more in the range of 20
14:48
% to 50 % of scans. Now, thankfully, a lot of
14:50
those are minor errors, but there are major errors
14:53
happening all the time. Like, as you say, people
14:55
are told they don't have osteoporosis, even though
14:57
they've had multiple fractures. And on the other
14:59
hand, somebody who had a scan because they're
15:01
worried about their bones, who probably has very
15:03
healthy bones, but they're small or there's something
15:05
else that just makes the bone density look a
15:07
little bit... abnormal when really it's probably
15:10
normal for them. I tell patients you wouldn't
15:12
say you're normal. because you have brown eyes
15:15
and abnormal, because you have blue eyes, that's
15:16
normal for you. And just so patients understand,
15:19
the modern definition of normal is somebody who
15:21
hasn't been examined properly. So if you do tests
15:24
in people today with really sensitive testing
15:26
equipment, you'll over -diagnose any condition.
15:29
And there's really good evidence that we're over
15:30
-diagnosing osteoporosis in younger, otherwise
15:33
healthy people, and under -diagnosing it, which
15:35
has been something we've all been working towards
15:37
for a long time. And just so the listeners understand,
15:40
the mortality, the morbidity, and the health
15:42
care costs us. with osteoporotic fractures in
15:45
Europe today are the same as cardiovascular disease
15:47
and cancer. And yet, when you look at the funding
15:49
and the support for those diseases, it vastly
15:52
outstrips what we have for bone care. You saw
15:55
multiple famous people like Ennio Morricone died
15:58
of complications following a broken leg. But
16:01
nobody said he died from a hip fracture or he
16:04
died from osteoporosis. And yet, you know, Pelosi,
16:07
I think, she had an accident and she had surgery
16:10
recently. but nobody said she had osteoporosis
16:13
and she had a hip fracture. And, you know, famous
16:16
basketball player who did the fight scene with
16:19
Bruce Lee back in the 1980s and still holds the
16:22
NBA record for the highest scoring ever. He fell
16:25
and broke his hip. But the whole articles and
16:27
all the newspapers say, well, he's got prostate
16:28
cancer and he's getting prostate cancer treatment.
16:30
But nobody said he had a hip fracture and osteoporosis
16:33
from the prostate cancer treatment. And that's
16:36
where it's missing. Everyone said the princess
16:38
died of a broken heart. So non -medical people
16:40
understand the heart's important. The princess
16:43
died. But nobody said the father died from a
16:45
broken back or the mother died from a broken
16:47
hip. And that's a gap we have to fill as educators.
16:49
And when you see it announced that a celebrity
16:52
has declared they have some disease or other,
16:54
you're sort of hoping it might be osteoporosis,
16:56
but it never is. Yeah, well, I don't know that
16:58
we'd ever hope somebody has a disease. No, that's
17:00
the wrong way to say it. But you're absolutely
17:01
right. You understand. The Pope broke his hip
17:04
and nothing happened. Ronald Reagan broke his
17:06
hip and nothing happened. So Queen Paola had
17:09
two spine fractures and then she fell and broke
17:10
her hip. And I understand. She wasn't on treatment
17:12
for osteoporosis. But I think as osteoporosis
17:15
experts, we have to explain this, and there's
17:17
something lost in the messaging. And I think
17:19
one of the great things I flagged today was...
17:21
For the first time ever, 14 Bone organisations
17:24
around the world who are involved in either the
17:26
assessment, the imaging or the management of
17:28
Bone are finally agreed and we have a clear message
17:31
for the rest of the world because I think that's
17:33
a game changer. If we all have different messages
17:35
and the message is a bit confused, it's hard
17:37
to get traction. If we're all on the same page
17:39
and we're singing off the same hymn sheet and
17:41
it's a clear, simple message and easy for people
17:43
to understand. then we're going to make progress.
17:46
From the science perspective, easy to put at
17:48
the top of a grant application when you're trying
17:49
to hit the reviewers hard with the importance
17:51
of what you're doing. I feel that osteoporosis
17:54
research loses out a lot to dementia, Alzheimer's,
17:57
cancer, because people do seem to be more serious
18:00
somehow. That's right, and again, a lot of that
18:03
is media, communications, and I think as experts
18:05
it behooves us to get better at communicating
18:08
the right messages and to work together to agree
18:10
on what those messages should be. It's absolutely
18:13
brilliant that you're out there and you're fighting
18:15
for your patients and fighting for patients everywhere.
18:18
It's really wonderful. Thank you for coming to
18:20
talk to us today. Thank you. It's been a pleasure
18:22
and I appreciate your support for osteoporosis
18:25
patients everywhere. It's lovely. Thank you very
18:27
much. We'll get the message out there. Yeah.
18:36
Welcome, listeners. We're really pleased to announce
18:38
our next guest today. We have Professor Monet
18:40
Zaidi from the Mount Sinai School of Medicine,
18:43
where he's the endowed chair, the professor of
18:46
clinical medicine. He's professor of pharmacology
18:49
and director of the Mount Sinai Center for Translational
18:52
Medicine. Welcome. Thank you for joining us today.
18:55
Thank you. It's really great that you've made
18:57
time. I heard your talk this morning. I think
19:00
it was one of those presentations that will stay
19:02
in your mind for a long time because... It was
19:05
a subject I thought I knew something about and
19:07
you introduced a whole new area to talk about.
19:12
I often tell my patients, I hope they listen,
19:15
that when their oestrogen levels fall at the
19:17
menopause, their bone turnover goes up and they
19:19
lose bone. And our thinking about this other
19:22
hormone, FSH, is that it just rises and that
19:25
doesn't mean anything very much. But you've told
19:29
a fantastic story this morning. And I'd love
19:32
if you told some of it again now for us, just
19:34
how important FSH is. What have you discovered
19:37
about FSH and bone? Thank you very much for the
19:41
invitation. So the textbook has always told us
19:46
exactly what you just said, in that estrogen
19:49
falls, there's bone loss after the menopause,
19:53
there is the onset of obesity. and there is some
19:58
level of mental deterioration that occurs in
20:01
some women. However, there's a phase in a woman's
20:05
life which is very early, about two to three
20:09
years prior to the last menstrual period, in
20:14
which you see significant amounts of bone loss,
20:18
the onset of adiposity, and mild cognitive decline.
20:23
Now, at this time, The very famous SWAN study,
20:27
the study of women's health across nations, which
20:31
was funded by the National Institutes on Aging
20:35
in the United States, showed that during this
20:38
time, estrogen levels can be relatively normal,
20:42
whereas FSH levels... follicle -stimulating hormone
20:47
levels are actually on the rise. And the reason
20:49
why they're on the rise is to compensate for
20:52
a failing ovary. So you do get estrogen that's
20:55
relatively normal before it falls off and FSH
20:58
that's rising. So we thought that the bone loss,
21:03
the adiposity, and the cognitive decline that
21:05
occurs during this, what we call late perimenopause,
21:09
cannot conceivably be explained by estrogen.
21:13
And at that time, the hypothesis was that an
21:17
elevated FSH may play a role in the pathophysiology
21:23
or the pathogenesis of these three conditions.
21:26
Now, we were a bone group, so we started off
21:29
with bone. And we found that, yes, there was
21:32
clear effects of FSH on bone, on bone cells.
21:37
So that, for example, if you took... an osteoclast,
21:40
which is a cell that removes old bone and sticks
21:44
some FSH on it, it resolves more bone. It lives
21:49
longer. And there are more cells that are generated.
21:52
Similarly, the osteoblast, the activity dampens
21:56
if you expose it to FSH. And so we were able
22:03
to prove it through some early genetic experiments
22:06
where we took out 50%. of FSH from a mouse by
22:12
knocking out the gene. So one copy of the gene
22:15
was knocked out and we got a high bone mass phenotype,
22:19
which was due to an elevated, reduced resorption
22:24
and an elevated bone formation. And then fast
22:28
forward a number of years, we suddenly discovered
22:30
that when we developed an antibody to FSH that
22:34
blocks its action on the receptor for FSH, we
22:39
found that these mice also lose body fat, which
22:44
came as a surprise. We didn't believe it. We
22:47
had it reconfirmed by a variety of other groups.
22:51
But when it was confirmed, it was now two diseases
22:54
that we could potentially treat with a single
22:57
FSH blocking agent. So it took about 10 years
23:01
for us to reach that conclusion from where we
23:04
started in early 2003, we again serendipitously
23:10
discovered that FSH was a direct regulator of
23:15
cognition. That is a memory, at least in the
23:19
mouse model. And that could explain the two to
23:23
three -fold higher risk of Alzheimer's in postmenopausal
23:28
women, the faster rate of progression, and very
23:33
much more importantly, the higher symptom burden.
23:36
which has never really been related to estrogen
23:38
because there have been clinical trials where
23:41
estrogen has been utilized in these women with
23:45
very mixed results. Notably, there has either
23:47
been improvement or no change or even a reduction
23:52
in memory. So we think that FSH could be a target
23:57
in postmenopausal women for the prevention of
24:00
these three conditions, which affect millions.
24:06
of women worldwide so it's the it's not it's
24:10
not that the oestrogen is not having effect we
24:12
still believe the oestrogen levels falling do
24:14
you have an effect on bone but it's that the
24:17
other hormone produced by the pituitary gland
24:19
that goes up we've now you're saying that it
24:22
actually has an effect as well so it is a composite
24:25
we have never said that oestrogen does not have
24:27
a role reduced oestrogen has a role oestrogen
24:31
is clearly a bone protective hormone So I think
24:35
it's a mix of the two that happens, and that's
24:37
why women keep losing bone, because FSH is high,
24:42
estrogen then lowers, and so there's a dual effect.
24:47
If I give my patient what we call HRT, I think
24:51
in America you call it MHT, if I replace the
24:54
estrogen, do I need to not worry, the FSH falls,
24:58
I'm happy, or would I like to give them your...
25:01
your FSH blocker that you're talking about as
25:04
well. That's very important. So in late menopause,
25:07
later in the years of menopause, hormone replacement
25:10
therapy or estrogen replacement therapy has been
25:12
widely utilized. And the Women's Health Initiative
25:16
showed that it clearly has an effect on fracture
25:19
risk. Now, the mechanism is perhaps both direct
25:23
and indirect. Directly, it would act on bone
25:27
cells. to prevent the osteoclast from removing
25:31
bone. But it also suppresses through a feedback
25:34
FSH levels. And there have been some very small
25:39
studies that have documented that the extent
25:43
of FSH suppression relates to the extent of bone
25:46
protection. Now that is a hard tease out. In
25:55
a lot of women, when you give them estrogen,
25:57
and we've seen that in clinical practice, both
25:59
you and I have seen that, FSH levels don't fall.
26:03
And that probably relates to the duration of
26:07
the elevated FSH. In some patients, it does fall.
26:11
And there has to be a larger study where those
26:14
correlations need to be established. So where
26:16
does this potential therapeutic that we now have
26:20
as a monoclonal antibody... which is humanized
26:25
and should go into clinical trials in the next
26:27
nine months or so, in a phase one clinical trial,
26:30
which is against a very well -defined portion
26:36
of the molecule, that's FSH, that binds to its
26:39
receptor. And so it blocks the entry of FSH into
26:43
its receptor. This should be used as a prevention,
26:48
ideally. for postmenopausal bone loss, visceral
26:52
adiposity, and early memory loss. Because once
26:55
these things set in, it's hard to get them back
26:58
again. That's incredible. What a wonderful treatment
27:04
that could be, preventing decline in three chronic
27:08
diseases all at the same time. It is admittedly
27:12
an ambitious goal. Even if one works, it's going
27:16
to be okay. Our best mouse data, though, quite
27:22
interestingly, is an Alzheimer's disease. I mean,
27:25
there's a very clear prediction of memory loss.
27:29
As I showed you, I had a little movie, but the
27:33
thing won't work otherwise. It did work later
27:36
on after I think you moved on. It did start to
27:39
work, so you could see that. Oh, really? Okay,
27:41
in that case. There was a mouse that went around
27:44
in circles, and there was a mouse that went to
27:46
the platform and just stayed there. Yeah, you
27:48
could see. And maybe I missed this bit. So are
27:50
there FSH receptors in neural tissue in the brain,
27:54
or how do we believe that has a direct effect
27:56
on cognitive function? So there are a couple
27:59
of areas which regulate memory, one of which
28:04
is the dentate gyrus of the hippocampus and the
28:07
granular cell layer. is what is really regulating
28:11
hippocampal -dependent memory, such as, for example,
28:14
spatial or even recognition memory. There are
28:17
other areas in the brain, such as cortical areas,
28:20
intrarenal cortex in particular. And honestly,
28:23
I'm learning neuroscience as we go along. These
28:25
two areas are critical for memory functions.
28:29
Interestingly, the FSH receptor exists in these
28:33
areas at fairly high levels. And that's why we
28:37
think that it is... real phenomenon in terms
28:40
of the expression of these receptors now. The
28:42
FSH receptors in other regions of the brain as
28:44
well, and if you map out the mouse brain, you
28:48
see that FSH receptors are there in over 300
28:51
regions of the mouse brain. Their function is
28:55
pretty unclear at this point in time. How long
28:59
will it be before you start to get the results
29:01
from the Phase 1 trial? So we opted to do our
29:08
clinical trial in Liverpool, England, as opposed
29:10
to the United States. And we're working very
29:13
closely with Richard Fitzgerald, Professor Richard
29:16
Fitzgerald, who is a top -tier clinical trialist
29:21
and really specializes in phase one early clinical
29:24
trials. We've known each other now. He's been
29:28
a part of our meetings. And once we get the antibody...
29:34
manufactured to a clinical grade, which we've
29:37
just about started doing. That takes about nine
29:39
months, and we've got to do some formal toxicology.
29:42
So in about nine to 12 months, we should, if
29:47
we're lucky, get the first patient injected.
29:50
Wow, that's really exciting. I suppose the other
29:53
question came into my mind, and I know I mentioned
29:56
it to you earlier, men produce FSH as well? And
30:00
I don't want to muddy the waters, but potentially,
30:04
is this a treatment for male patients as well,
30:08
or are the FSH levels too low in men? Well, no,
30:11
the FSH is produced by males. It rises by about
30:15
3 .5 % a year. It is a molecule that is involved
30:23
in the production of sperms. So it could be a
30:27
molecule that... is used for reducing sperm numbers,
30:32
but we haven't actually checked that. The antibody
30:38
could be utilized for that purpose. In males,
30:42
if it is driven, if the bone loss or the memory
30:47
loss or indeed the weight gain is driven by FSH,
30:51
and there are certain conditions where it could
30:53
be driven by FSH. For example, I showed some
30:58
data from Denmark where the testes were taken
31:01
out because of prostate cancer to reduce testosterone
31:04
levels. And in that situation, an antibody against
31:09
FSH could be utilized to prevent that bone loss.
31:13
So if FSH is rising or it drives... these conditions,
31:18
that's when it's going to be used maximally.
31:21
Yeah, that's interesting because I get more referrals
31:23
from my oncology colleagues now treating men
31:25
with prostate cancer who then turn up with osteoporosis
31:28
or fractures and sometimes the options are limited
31:31
so potentially that's a very exciting new pathway,
31:35
a new area. Now they're using GnRH agonists rather
31:38
than orchiectomy, at least in the United States
31:40
we don't do orchiectomies. But in certain parts
31:43
of the world it is done and that's how an antibody
31:47
such as this could be utilized in males the talk
31:52
you gave today was absolutely fascinating and
31:55
you told it very well and you explained the story
31:57
it's amazing that in your career you've been
32:01
able to go from doing basic science asking questions
32:04
about how the body works through to developing
32:07
an antibody and getting ready to test it in people
32:10
right so this was actually a transformational
32:14
concept which was You know, when you make these
32:18
new discoveries, when you come up with something
32:20
new, there's always a pushback. And so we had
32:23
a lot of pushback from the estrogen world in
32:25
the case of TSH from the thyroid world. But we
32:29
left it for other people to confirm. And I think
32:32
that a lot of people have confirmed these findings.
32:35
I showed some of that, how these findings were
32:38
confirmed. And so the physiology, I think, is
32:41
fairly well worked out. The second issue was
32:44
how do we... use this phenomenon to base a therapeutic
32:49
upon, which we established the concept using
32:53
mouse work, mouse polyclonal, and then mouse
32:56
monoclonal antibodies. And then there was the
33:00
fork on the road. Do I go and align myself with
33:04
pharmaceutical industry or with biotechnology
33:07
folks? create a spinoff and raise money for venture
33:14
and get taken over. The choice that we collectively
33:18
made and my team made was to do it ourselves,
33:21
which is actually very rare. The level that we've
33:25
gone to is very rare in an academic medical center
33:28
to happen. And so we developed a platform which
33:34
was highly rigorous. which was fully transparent
33:37
that the FDA could come and inspect. We recruited
33:40
consultants who worked in the pharmaceutical
33:44
industry in various domains, for example, pharmacology,
33:47
toxicology, CMC, which relates to manufacturing,
33:50
and IND submissions, that's the investigational
33:56
new drug submissions to the FDA and to the MHRA
33:58
in this case in England. And so we created a
34:02
platform where we could... produce data without
34:08
going to a CRO or without giving the stuff away
34:13
to pharma or to biotech at that early stage.
34:15
Because we were concerned that if we do that,
34:20
there is the odd chance that it could be shelved.
34:23
And since we had made the discovery, we were
34:26
passionate to get this into people. And I think
34:29
that realization would hopefully come true. It's
34:33
to your enormous credit, I think, the way that
34:35
that you did that and i mean not only is the
34:37
work that you have done superb but i think the
34:40
way you presented it and the way you told the
34:42
story this morning was a a textbook example of
34:45
how you should do a presentation at a conference
34:47
like this. It was really excellent and inspiring
34:50
and logical and I think it's to your great credit
34:53
the way you've taken this through. Yeah, I wanted
34:55
the younger generation to understand how to move
34:59
this along and not to give up. I mean, as you
35:02
would imagine, we had bumps in the way and everything
35:06
has bumps in the way and so the entire portfolio,
35:09
including, for example, If you have to inject
35:13
an antibody into people, you have to have it
35:15
formulated. If I give it to a CRO to get it formulated,
35:20
it would cost a million dollars. We did that
35:23
ourselves because I recruited a formulation guy,
35:25
and he created 217, I believe it was, combinations
35:31
of excipients, a variety of molecules to keep
35:35
the antibody stable in solution. Now we have
35:39
evidence of thermal stability, of colloidal monomeric
35:43
structural. It's a very stable solution to inject
35:46
into people. So those kind of things take time
35:49
and effort and reduce cost and keep it within
35:53
your own domain so that you can actually keep
35:56
a tab on it. That's amazing. Thank you so much
36:01
for sharing your time with us today. We know
36:04
you're really busy. Thank you very much. Thank
36:07
you for having me. It's been inspiring. I'm really
36:09
excited to see the results of this work coming
36:11
through. Thank you. We'll have to catch up with
36:14
you and find out how it goes. Absolutely. Always
36:17
be available. Thanks. Listeners, thank you for
36:25
tuning in to episode two of Bone Up Live 2025.
36:28
We hope you enjoyed it. We have more live interviews
36:33
coming in episode three, which should be released
36:35
soon. Bye now.