What a great privilege and honor to give you 15 minutes about osteoporosis.
When Steve called me, he said the good news is you're going to give
a little talk about osteoporosis.
The bad news, you only have 15 minutes.
That's impossible for me.
So I immediately scurried to call my colleagues and I want to acknowledge some people who
contributed slides, some of which I put in, some of which we had to leave out, but Steve
Teitelbaum, Sundeep Khosla and Steve Cummins and Eric
Orwoll who sent slides and contributed to this talk, thank
you very much.
It's really a pleasure to tell you that we've made great progress as Francis said, in both
understanding the pathophysiology and the treatment of osteoporosis.
These last 25 years have been exciting.
Osteoporosis is a devastating disease that affects about 40 million individuals and costs
our healthcare estimates at $19 billion.
And most of this is related to this tremendous impairment in mobility, the difficulty with
quality of life, and, of course, the presence of hip fractures
which can subsequently lead to not only confinement in
nursing homes, but also into individuals dying from coincidental morbidities.
What is osteoporosis?
We do have a strong definition.
It is a disease associated with microarchitectural deterioration which
leads to impaired bone strength and fractures, frequently with very minimal trauma.
One of the great contributions to the field was started back when NIAMS was started and
Francis alluded to those.
This is the study of osteoporotic fractures.
This cohort continues 25 years later with almost 6,000 women; it started with over 9,700
women over the age of 65, funded by NIAMS and the National
Institute on Aging.
With over 2,500 citations in 375 papers, their seminal work contributed by many investigators
in defining risks for osteoporosis.
And as Francis said, we're now able to successfully identify those people at greatest risk, not
only by bone density, but also by the number of risk
factors.
This is incorporated into clinical practice in what
we call the FRAX database so practitioners can dial in risk factors in bone density and
produce risk to define who is at greatest risk and who we
should be treating.
Not only is it a disease of women, but also a disease of men.
Back in 1999 NIAMS, along with NIA, supported the study of osteoporotic fractures in men,
subsequently called Mr. OS.
This study is now in its 11th year and has over 113 publications and nearly 6,000 men
they are following longitudinally.
Two major discoveries from that group out of many, many, are that number one, obese
individuals, especially obese men, tend to have the greatest
risk of fracture, which is somewhat of a surprise, but is
an emerging area of investigation.
Two, rib fractures are an early indicator in men of subsequent osteoporotic fracture
risk.
These are items we hadn't considered previously when studying cohorts such as Mr. OS.
The other area, Francis alluded to it and Steve and Joan have been a big supporter of
this, is our area of understanding microstructure and of imaging
the skeleton.
These are some images using extreme CT which we can look now at the inner trabeculae of
the skeleton.
This happens to be in the tibia.
You can see the difference between a 24-year-old female and a 71-year-old female, particularly
the thinning of the cortex, this thick area that
lines the outside of bone as well as the trabecular disarchitecture that occurs with osteoporosis
and with aging.
And through lots of studies at different sites, particularly the Mayo Clinic, but UCSF and
Columbia, we’ve begun to understand that age-related bone
loss begins early in life, not just at menopause, not just at
the magical age of 65, and that this loss is incessant and related to many factors not
which is hormone related.
Some areas we have spent more time and got started a little later on is the genetics
of osteoporosis.
And we now know, it's been established for a while that genes contribute 60% to 70% of
your peak bone density, which you gain between the ages 10
and 20 years of age.
This big black box was really untapped for a long time.
The theory was that if we could identify genes, we might be able to start very early in the
process, particularly with environmental interactions,
such as calcium and vitamin D, to modify subsequent risk.
As it turns out, the secret was really unlocked through some surreptitious studies and some
very hard work looking at diseases, rare diseases that
occurred.
This is work from the Warman laboratory at the Cleveland Clinic-- at Case Western and
they discovered that in osteoporosis pseudo glioma, which
is a disease of one in 2 million individual children get severe
osteoporosis and a inflammatory retinitis that leads to blindness.
They were able to map this disease to a region on chromosome 11.
At about the same time Bob Recker and his group at the Creighton, identified just the
opposite.
A group of individuals with very high bone mass and resistance to fracture.
And those individuals were also mapped to a region on chromosome 11.
As it turns out, in of the most seminal discoveries by many investigators, some of whom are in
the room, it was discovered that both the mutation that
caused osteoporosis pseudo glioma occurred on an extra
cellular receptor, the LRP-5 receptor in propeller 1, blade 4, and that the gene for high bone
mass was also identified on the same extra cellular
receptor, LRP-5 receptor, which had a high bone density and
was related to those pictures that you saw.
It was exciting not only because we identified the cause of a rare disease or two rare syndromes,
but also because it opened the way for our understanding
of a major cellular pathway for the formation of
new bone, and that is through the Wnt LRP-5 signaling pathway.
This discovery had led to thousands of publications and more work both at a basic level, but also
at a translational level, trying to design drugs
that might be bone-specific to stimulate new bone formation,
without changing the activity in other tissues.
So this has been work ongoing by a number of different investigators.
You heard a little bit about the genome study and work from what Francis talked about.
When we came to trying to identify genes that were related to osteoporosis or bone density,
we started with mice, but at the same time, there was
a huge effort in humans.
This slide from Doug Kiel emphasizes the importance of the inter-institute interdigitation that
occurs in bringing large cohorts together to try to
get power to identify common disease, gene polymorphisms.
Not only is the United States looking at the cardiovascular study in the Framingham heart
study for skeletal genes that affect fracture and bone
density, but GFAS, a European and international collaboration is bringing together the significant
power we needed to identify genes related to bone
density.
And in this slide, you can see that not only was LRP-5 very important in the gene for OPPG
and the high bone mass phenotype, but it also turns out
to be a very important gene in which polymorphisms are
related to bone mineral density.
So that we have the entire extreme of low to middle to high bone density related to
a single gene that was discovered from rare disorders sponsored
in focus from the NIH.
Not only does NIH support pathophysiology and basic research, but also clinical studies
looking at new treatment options.
This is work published in the New England Journal of Medicine from Dennis Black
and colleagues showing that parathyroid hormone alone was as good or better than combining
parathyroid hormone with this phosphonate, in this case alendronate.
And this set the standard for clinical treatment in osteoporosis by people around the world.
Not only that, the NIH is interested and NIAMS is particularly interested in innovative new
approaches to treatment.
So this is work from Clint Rubin and his group at State University of New York, at Stony
Brook.
He started vibrating turkey wings back in the late '80s, and then graduated to sheep.
And through low amplitude high frequency sound waves, he was able to show that you could
protect the sheep from overly ectimized induced bone
loss.
This was a very impressive response that was duplicated in mice, as well.
This has led to a clinical trial, several small clinical trials, but a very large trial
sponsored by NIA looking at the role of high frequency low amplitude
vibration on protecting bone density in the elderly and
possibly reducing fractures.
Finally, Clint noticed, and several of us have noticed that there is this relationship
between obesity and osteoporosis, and seminal work from Gerard
Karsenty and Tom Clemons and others have shown that
bone is more than just a structure that holds up our protoplasm, but also is an endocrine
secretor and that the hormone osteocalcin, which is bone
specific, has a major effect on energy expenditure, insulin
secretion, insulin sensitivity, and, most recently, in testosterone production.
In summary, I have given you a very brief tour thanks to a lot of investigators that
contributed to this work, and it highlights what NIH and particularly
NIAMS have led the way in osteoporosis research.
This has occurred through a multi-faceted approach funding investigators from bench
all the way to bedside.
And our future discoveries will continue to span this basic work in clinical trials, and
comparative effectiveness.
So thank you very much.