Let's just turn and
This is one of the newer
treatments for osteoporosis,
and its availability grew
out of new understanding
of the molecular control and
modulation of bone remodeling.
As you're aware, RANK
Ligand is a protein secreted
by osteoblasts and osteoclasts.
The action to RANK LIGAND is
necessary for the activation
and proliferation of osteoclasts.
Denosumab is a fully human
monoclonal antibody that binds
to and then activates RANK Ligand.
And as a result,
denosumab therapy inhibits
the differentiation proliferation
and activity of osteoclasts
reduces bone resorption.
As with bisphosphonates because
of a decrease number in activity
of osteoclasts, the feedback
to osteoblast is reduced,
and there is a secondary
inhibition bone formation as well.
The pharmacokinetics of denosumab,
which is given subcutaneously,
One dose of 60 milligrams
or greater reduces bone
turnover for at least six months.
In the studies that
have been performed,
denosumab therapy results in
a progressive increase in bone
mineral density over at least
the first eight years of therapy,
different and greater in
magnitude than we observe
with bisphosphonate therapy.
Because of the pharmacokinetics,
once therapy is discontinued,
there's a very rapid and complete
reversal of the effects on bone
remodeling within just
a few weeks of missing
the every six-month dose.
These are data looking at
the bone density response
to denosumab in the extension
of the pivotal FREEDOM
trial over an interval
of eight years,
showing progressive increases in
bone density in both the lumbar
spine and in the total hip
region, with changes from baseline
being more than 18% in the spine
at eight years, and more than 8%
in the total hip region
at that time point.
patterns and greater
magnitude of change
than we're seeing with
long-term bisphosphonate therapy.
In the pivotal FREEDOM
was shown to be very effective
in protecting patients
with osteoporosis from fractures.
Vertebral fracture risk was
reduced by 68%, hip fracture
by 40%, non-spine fracture by 20%.
Again, as with bisphosphonates,
the effect on fracture protection
is evident within months
of starting therapy
and continues as long as
treatment is administered.
Importantly, as we'll show in the
extension of the FREEDOM trial,
it appears that non-vertebral
fracture risk may actually
decrease with long-term therapy.
That would be an
The administration of the
drug by subcutaneous injection
every six months insures
adequate adherence to therapy,
at least between those doses.
The data from the pivotal
FREEDOM trial are shown here.
Again, simply quantifying the 68%
reduction in vertebral fracture risk,
20% reduction in
non-verterbral fracture risk,
and the 40% decrease
in hip fracture risk
in response to denosumab over the
first three years of the study.
A more detailed look at the
effect on vertebral fracture
is shown here with the
year-by-year effective therapy,
although the primary endpoint in
the study, for regulatory reasons,
was the three-year data
with a 68% reduction
in vertebral fracture risk.
Similar relative risk reductions
were observed as early as one
year after beginning treatment.
The cumulative incidence of hip
fracture in the placebo group,
as shown on top, and the treated
group, as shown in white,
is demonstrated here, with
overall a 40% reduction in risk
over the three years of the study.
But again, the two curves
appear to diverge roughly a year
in to the treatment with denosumab.
These are data from the extension
trial of the FREEDOM study,
where patients who had completed
the first three years of the study
were given the opportunity of
remaining on denosumab therapy,
and will be followed
for a total of 10 years.
These are the data from
the six-year analysis.
Shown is the incidence of non-vertebral
fracture during years four to six
of the study.
A lower incidence and was
observed during the first three
years of the study.
This is the first time there's been
a suggestion that fracture risk
reduction actually improves
with longer-term therapy
with any of our osteoporosis drugs.
The longer-term follow-up
in this extension study
will help clarify whether
that's a real finding or not.