FAN eP2P_Apr26_Updated Video Presentation
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>> Hello.
My name is Bente Langdahl.
I'm a Professor in Endocrinology.
I work at Aarhus University Hospital,
where I see patients
with osteoporosis every week.
I'm here today to talk to you
about how to diagnose osteoporosis
and choose the optimal treatment
for your patients.
Osteoporosis is an epidemic
and it has been called,
"The Silent Epidemic."
We know that more than 200 million women
are affected by osteoporosis.
And that one in three women
and one in four men suffer fractures
due to osteoporosis.
We also know it's a silent epidemic,
but it still has a voice.
And the voice is fractures.
And although the voice is fractures,
not all of the fractures
come to our attention.
And we know that only one in three patients
with vertebral fractures
have actually noticed the fractures.
And because of
that, some of these fractures are silent,
more than 80% of patients at high risk
of future fractures do not become diagnosed,
and therefore, do not get any treatment.
So let me tell you about a patient of mine.
She's now 75 years old.
She had her first DXA in 2013.
And that DXA showed osteoporosis
with T-scores of -3.4
and -1.7 at the spine and hip.
She was prescribed Calcium and Vitamin D.
A couple of years later,
she was admitted to hospital
due to back pain.
And, they diagnosed her with a fracture
of the 12th thoracic vertebrae.
And she was hospitalized for three days,
and treated with painkillers
and physiotherapy.
She also had a DXA that also again
showed osteoporosis now with T-scores
of -3.8 and -2.2
at the spine and hip.
And she was then prescribed
Risedronate 35 mg weekly
and continued on Calcium and Vitamin D.
A little more than
one and a half year later,
she was again admitted to hospital
with severe back pain.
This time, to my hospital.
And she now had a new vertebral fracture
of lumbar vertebrae number 2.
We also repeated the DXA,
which shows stable values at the spine,
but further reduction of the BMD at the hip side.
The patient asked me:
Will I get my life back?
Meaning,
"Will I be able to work in my garden?"
"Will I be able to play
with my grandchildren?"
So let's have a look of what happened
to this patient.
She actually had a new fracture
and she also had BMD loss.
So let me ask you, what would you do now?
Would you reassure the patient,
have her continue the current treatment?
Would you change the treatment
to Zoledronic Acid or Denosumab?
Or would you change
to a bone forming treatment - Teriparatide?
Let us think a little bit more
about the fracture cascade.
It has been quite well demonstrated
that there is an imminent fracture risk
after a recent fracture,
and also that the more fractures you suffer,
the higher the risk of further fractures,
as indicated in this slide.
So do you have more,
do you have two vertebral fracture?
The risk of the third
is increased 3-fold and so on.
The other thing is that,
also, as shown in this slide,
already within the first year
of the fracture,
there's a very high risk of more fractures
especially if you have
multiple vertebral fractures.
And also, the more severe
your fractures are,
the higher the risk the patient is
at for further fractures.
As you can see in, in this slide,
where patient in the placebo group
of the big clinical trial
were divided into groups based on how severe
their baseline vertebral fractures were.
So we therefore need to examine our patients
as good as possible,
and that includes imaging of the spine.
It can be done by spinal x-rays
as you can see in this slide
where there clearly are fractures
at the lumbar spine.
But it can also be done in many DXA centers by using the VFA option of the DXA machines.
So, now we have the patient
and we have examined our patient.
We know about bone mineral density,
we know about existing fractures.
So now, our first and foremost goal
is to prevent the next fracture
because this is what is a threat to the life, and to quality of life to our patient.
And how can we do that?
Yeah, we want to improve bone mineral density
because we know that that
is an important factor
in preventing fractures.
We also want to take the best treatment
we can find to achieve
a better fracture outcome.
And finally, we want to secure our patients
that they understand why it's important to start treatment
and how they should take
the treatment and for how long.
So what options do we have?
As you all know, we have many, many antiresorptive treatments available.
In some countries,
Hormone Replacement Therapy
is still an option.
But apart from that, we have SERMs
and both of these are weaker antiresorptives,
and then we have the stronger antiresorptives which are the bisphosphonates and Denosumab.
These are all in the category
of antiresorptives.
On the other side,
we have one, bone-forming treatment
Teriparatide.
And let us have a second look
on how they work
and how they work differently.
Let me tell you about the FACT Trial.
The FACT Trial was done to investigate and compare the effect of a potent
antiresorptive Alendronate and Teriparatide,
a bone-forming agent.
So in this study, bone formation
and bone resorption markers
as well as bone mineral density was examined.
And as you can see in this slide,
on the left-hand side,
you can see how bone markers responded to treatment with Teriparatide,
and you can see the blue line
representing bone formation
here as P1NP.
You can see there's a rapid increase
in bone formation
and you can see that it stays up
for up to 12 months.
So, it's not a temporary increase
in bone formation,
it stays high through our treatment.
We can also see that there's
a secondary increase
in bone resorption here measured by NTx.
But still there's a huge difference
in the increase between bone formation and bone resorption.
On the right-hand side of the slide,
you can see how the bone turnover responds to Alendronate treatment.
There's a prominent decrease first
in bone resorption,
but secondarily in bone formation.
This has been investigated further
by looking directly on the bone surfaces using Histomorphometry.
In this study, which is a recent study called, The SHOTZ Study,
the authors compared the effect
of Teriparatide with the effect of
the very potent Bisphosphonate Zoledronic Acids.
And let me just show you pictures
because I think they tell the story quite clearly.
So here, in this slide, you see the changes in the trabecular bone.
On the left-hand side again,
you see the effect of Zoledronic acid,
and you could see there are hardly
any Tetracycline labeling,
suggesting that very little bone turnover is going on, and especially very little bone formation.
On the other side of the slide, the right-hand side,
you can see lots of activity.
Many Tetracycline labeling
suggesting large bone formation going on.
And you can see that in 6 months,
but you can also see all the lines at 24 months
suggesting that the increased bone formation continues for at least up to 24 months.
We can look at this in a bit more closer details
and you can see, here you can see
the lines laid down at six,
after 6 months of treatment
and the lines laid down
after 24 months of treatment.
And you can see the relatively big amount of bone that's been laid down in the intervening time.
And then have us look at the cortical side because that's also of course of interest
especially if you're thinking about
preventing non-vertebral fractures.
And here, you can see, again on the left-hand side,
the response to Zoledronic acid
and you can see after 6 months as well as after 24 months
that there are hardly any labeling,
suggesting that there's very little bone formation going on.
On the right-hand side of the slide,
it's the completely opposite picture
with lots of Tetracycline labeling
at the periosteal surface,
the endocortical surface
as well as intracortical surfaces.
And, if we take higher magnification,
look at this, you can see
lots of labeling, intracortical as well as both of the cortical surfaces.
So this and many other data have lead us to understand how Teriparatide works
at the remodeling level.
And this is what it's been,
what you can see in this cartoon.
So, bone resorption take place at the same rate and to the same extent as usual,
some types even increased a little bit.
And bone formation is then simulated.
So it not only fills up the remodeling cavity, but it actually overfills the remodeling cavity
so that there are much more new bone laid down
than the bone resorpts.
And this also reflected here in the BMD changes
as seen in the FACT Trial
where you can see when you measure areal BMD.
The usual way we measure BMD,
you can see there's a doubling
in the increase in BMD after 18 months
with Teriparatide compared to Alendronate.
And if you specifically investigate
trabecular bone BMD using QCT,
you can see an even bigger difference between the two treatments.
Looking at BMD changes, we have to realize that increases in BMD can come in different ways.
So here we have made a sketch of the 3 different ways
you can increase BMD.
So first of all, starting from the top,
you can increase BMD by increasing trabecular number.
You could also increase BMD
by increasing trabecular thickness.
And then of course you can increase BMD by maintaining bone volume
but building more mineral into the bone.
And that is what we call, "Secondary Mineralization".
Teriparatide, which is a bone-forming agent, uses the two upper mechanisms
for increasing bone mineral density.
Increases trabecular number
and increases trabecular thickness,
whereas antiresorptive treatments
like Bisphosphonates and Denosumab
predominantly uses the lower, the lowest cartoon way
that is increasing secondary mineralization.
So, to summarize,
what are the therapeutic choices we are facing?
that is increasing secondary mineralization.
So, to summarize,
what are the therapeutic choices we are facing?
So we can choose a bone-forming agent like Teriparatide
and we will see new bone formation
because the drug stimulates osteoblast activity.
We have some secondary osteoclast activity increase as well.
We have increase of bone turnover.
We have new bone formation,
and that leads to increased skeletal mass and increased bone volume.
Then the opposite, antiresorptive treatment, we have decrease in bone resorption
due to a decrease in osteoclast activity.
With secondary leads also
to a decrease in osteoblast activity,
that leads to decreased bone turnover.
And that leads to a filling on of the remodeling space
and increased mineralization of the existing bone.
But there's no effect on bone volume.
So let's have a look of how well these drug work in real life in clinical trials.
So first of all, let me just remind you
of the pivotal fracture trial
investigating the effect on preventing
fractures of Teriparatide.
It was a study with two different dosages used.
The 20 microgram we use in the clinic today but also 40 micrograms
and it was compared with placebo.
And as you probably recall,
there was a very prominent
84% reduction in new, vertebral fractures
in patients treated with Teriparatide
compared to placebo.
There was also a 50% reduction
in new, non-vertebral fractures.
So, very prominent antifracture efficacy in this placebo-controlled trial.
Bone biopsies will also taken in that trial and you can just see from these reconstructions
how bone is changed from the baseline where it's characterized by thin cortices
and a rock-like structure of the trabecular bone to thicker cortices
and a more plate-like structure of the trabecular bone, a structure that we know
confers much more strength to the bone.
Bone mineral density by areal DXA was also measured.
And you can see again a very prominent increase in bone mineral density here at the lumbar spine.
So this is nothing new, but why did I choose to show this picture?
Anyway, it's because it's interesting to see what happens after Teriparatide.
Because in the pivotal fracture study,
treatment was ended
after approximately 20 months of treatment.
And in this slide, you can see,
on the right part of the slide,
you can see what happens
after ending Teriparatide treatment.
And you can see the patients
that go on an antiresorptive treat
and they have further increases
in bone mineral density.
And why is that?
That is because all the new bone that is filled up
during the Teriparatide treatment are now being mineralized
and the antiresorptive also prevents osteoclasts
from breaking down the new bone.
So you have a further increase
when you go from Teriparatide
to an antiresorptive treatment.
There were also, of course,
observation of adverse events in that study.
And the things that were more common in patients treated with Teriparatide compared to placebo
were dizziness and also leg cramps,
and there were cases of mild hypercalcaemia
But they were not very frequent and I think we've all known, learned how to deal with these in clinical practice.
And of course, many colleagues ask me, but do we know that this drug work in clinical practice?
And that's been done a number of observational studies and I'll just show you one slide from one of those.
The European Observational Study,
called the "EFOS Study",
where women who were chosen by clinicians to receive treatment with Teriparatide
could be enrolled and monitored.
And we just monitored fracture
frequency in these patients.
And as you can see,
the study was done at a time
where Teriparatide
were only approved
for 18 months of treatment.
So we only have 18 months of observation on Teriparatide treatment.
But you can see how
in every 6 months interval
the incident of new, vertebral fracture
is reducing over time.
And what is also important is to see
that their reduction in new fractures
continues when the patients
go from Teriparatide
to an antiresorptive treatment.
Then, of course, many clinicians wondered,
"Is this drug better than an antiresorptive?"
Can I really advise my patients
to go on Teriparatide,
or would they do equally well
on a strong Antiresorptive treatment?
So, I'm happy to present to you
with the outcome of the VERO trial.
The VERO trial was a randomized,
active-controlled, double dummy study
assessing the outcome of fractures,
comparing Teriparatide with Risedronate.
The study was a two-year study
and included postmenopausal women
with severe osteoporosis
that would be existing vertebral fractures.
So, a little bit about the patients
who went into the study.
So they were, on average, 72 years old.
They had osteoporosis.
100% of the patients in both groups
had existing vertebral fractures.
They had BMD in the osteopenic range
which is not a surprise,
as 60% of the patients
have previously been treated
with a Bisphosphonate.
We can also see that almost 50%
of the patient
had had a previous non-vertebral fracture.
And this is the main outcome.
The primary endpoint
was new, vertebral fractures
and this was what the study
was powered to investigate.
And, as you can see,
already after 12 months,
there was a 50% reduction
of new, vertebral fractures
in patients treated with Teriparatide,
in comparison with not placebo,
but a very strong antiresorptive agent
Risedronate
And their difference
in new, vertebral fractures
was maintained throughout
the second year of the study
and we are 12% in the Risedronate
who have suffered new, vertebral fractures
compared to only 5.4%
in the Teriparatide-treated group.
Secondary endpoint were multiple,
vertebral fractures
and where there also was a 54% reduction
which, if you remember,
is very similar to what was seen
in the near study, the pivotal fracture study.
But again, we have to remember
that this time,
it's against an active treatment
Risedronate
And also, clinical vertebral fractures were significantly reduced in this study
with the P value of 0.002.
Coming to clinical fractures,
that would be clinical vertebral fractures
and non-vertebral fractures.
You can see that there is a rapid difference between the two groups.
After 6 months, the curves start to diverse
and after 24 months, there's a prominent,
almost 50% difference
between the two groups.
Finally, non-vertebral fractures
didn't reach a significant difference.
There was a reduction but as I said, none,
not significantly different.
And then, also, major non-vertebral
fractures were investigated.
And why specifically this group?
This is because this
is the group IMEA
identified as the group
of non-vertebral fractures
that's especially important.
And as you can see, it almost reads
a significance with the P value of 0.06.
And we have to remember
that the study was not powered
to look for non-vertebral fractures.
But, despite of that,
it almost made a significant reduction.
This slide is very busy.
But to summarize,
it's the outcome of the VERO study.
You can see that there was a prominent
and significant reduction
in new, vertebral fracture.
In new or worsening of vertebral fractures in clinical fractures.
And then there was a borderline trend for non-vertebral fractures
as well as major, non-vertebral fractures.
What about adverse events?
Are there some things
we need to consider here?
You can see overall
the ballot, it was very well balanced
between the two groups.
There were a few, adverse events
that were more common among patients treated with Teriparatide.
That would be dizziness
and hypoglycemia as we know it.
But also pain in hands and feet,
and pain in general.
And that is also a very well-known symptom in patients treated with Teriparatide,
and it has been demonstrated
that it is related
to the increase in bone turnover
that we see in these patients.
But again, these adverse events
that were more common
in the Teriparatide-treated patients
were still not very common.
So to sum up, I hope you agree
that in postmenopausal women
with established osteoporosis
who are at high risk for fracture,
FORSTEO significantly reduced vertebral
and clinical fractures
compared with Risedronate.
FORSTEO is better at preventing fractures in patients with severe osteoporosis
and confirm previous data
from clinical trials of Teriparatide
or FORSTEO versus Bisphosphonates with fracture as secondary outcome.
Clinicians should consider FORSTEO for optimal management of patients
with osteoporosis who have prevalent vertebral fractures.
Coming back to my patient.
This 75-year-old woman
who now has 2 vertebral fractures.
She has a new one,
and she also has a loss of BMD.
What would you do now
with all these new data in mind?
Would you reassure the patient,
have here continue on her current treatment?
Would you change the treatment
to Zoledronic Acid or Denosumab?
Or would you change to a bone-forming treatment - Teriparatide?
So here's my answer:
I started my patient on FORSTEO
because I think it's the best choice
in patients with existing vertebral fractures and low BMD.
So, to summarize, patients with osteoporosis
have decreased bone strength which leads to increased risk of fracture.
The first osteoporotic fracture
leads to a considerable risk
of subsequent fractures
and the fracture cascade can start.
So clinicians like you and me
should consider FORSTEO
for optimal treatment of osteoporosis
who have prevalent vertebral fractures.
And why should we do that?
Because the benefits of Teriparatide
or FORSTEO therapy include
it that it stimulates the osteoblasts
and that is what we want.
We want new bone.
We want more bone.
We want a better structure of the bone.
We know it reduces fracture risk.
We know it improves BMD.
And we know that the effect of Teriparatide
is observed very early on
in the treatment of the patients.
And, it has now been demonstrated
in the VERO trial
that it's better at preventing
fractures in patients
with severe osteoporosis
compared to a Bisphosphonate.
Thank you very much for your attention,
and I'm happy to take
any questions you may have.