1
FOOD ADVISORY COMMITTEE AND
DIETARY
SUPPLEMENTS
SUBCOMMITTEE
THE ROLE OF GLUCOSOSAMINE AND
CHONDROITIN
SULFATE IN OSTEOARTHRITIS
Monday, June 7, 2004
8:03 a.m.
Bethesda Marriott
5151 Pooks Hill Road
Bethesda, Maryland
2
P A R T I C I P A N T
S
Sanford A. Miller, Ph.D., Chair
Linda Reed, Acting Executive Secretary
Douglas L. Archer, Ph.D.
Patrick S. Callery, Ph.D.
Annette Dickinson, Ph.D.
Goulda A. Downer, Ph.D.
Johanna Dwyer, D.Sc., R.D.
Jean M. Halloran
Norman I. Krinsky, Ph.D.
Daryl B. Lund, Ph.D.
Margaret C. McBride, M.D.
Mark F. Nelson, Ph.D.
Robert M. Russell, M.D.
Carolyn I. Waslien, Ph.D., R.D.
Edward Blonz, Ph.D.
Edward D. Harris, Ph.D.
Harihara M. Mehendale, Ph.D.
Steven Zeisel, M.D., Ph.D.
Temporary Voting Members
Steven Abramson, M.D.
John J. Cush, M.D.
Luis Espinoza, M.D.
David Felson, M.D., M.P.H.
Scott A. Kale, M.D., J.D., M.S.
Nancy E. Lane, M.D.
Also Present:
Jeanne Latham, Executive Secretary,
Dietary
Supplements Subcommittee
3
C O N T E N T S
AGENDA ITEM PAGE
Call to Order, Introductions - Dr.
Miller 4
Administrative Matters and Conflict of
Interest
Statement - Ms. Reed 9
Opening Remarks, Robert E. Brackett,
Ph.D.,
Director, Center for Food Safety and
Applied
Nutrition (CFSAN) 20
Background and Questions to Committee -
Laura M.
Tarantino, Ph.D. 22
Questions and Clarifications 30
Overview of Legal Framework, Louisa Nickerson,
Office of General Counsel, FDA 33
Questions and Clarifications 38
Overview of petitions: FDA's Review Process and
Issues - Dr. Craig Rowlands, Biologist,
FDA/ONPLDS/CFSAN 42
Questions and Clarifications 57
Petitioner: Weider Nutrition International, Inc.,
Luke R. Bucci, Ph.D., Vice President of
Research,
Weider Nutrition Group 69
Questions and Clarifications 105
Petitioner: Rotta Pharmaceutical, Inc.
- Dr. Lucio C. Rovati, Executive Medical
Director,
Rotta Research Laboratory 136
- Dr. Roy D. Altman, Professor of
Medicine and
Rheumatology, University of Miami and
University of
California-Los Angeles 156
Questions and Clarifications 174
Lunch 207
Questions and Comments 250
4
C O N T E N T S
(Continued)
AGENDA ITEM PAGE
Current State of the Science on Etiology
of OA and
Modifiable Risk Factors for OA - Dr. Lee
Simon,
Harvard University 209
Questions and Clarifications 250
The Role of Animal and in vitro Models
in OA Risk
Reduction - Dr. James Witter, Center for
Drug
Evaluation and Research, FDA 256
Questions and Clarifications 287
Public Comment 291
- Jason Theodasakis, M.D. 291
- Gayle E. Lester, Ph.D. 299
- Robert Arnot, M.D. 304
- Jose Verges, M.D. 317
- Todd Henderson, D.V.M. 332
- Chuck Filburn, Ph.D. 334
Questions and Clarifications 341
Adjournment 352
5
1 P R O
C E E D I N G S
2 DR. MILLER:
Good morning. I want to take
3
this opportunity of welcoming you to this meeting
4
of the Food Advisory Committee.
Today and tomorrow
5
the committee is going to deal with two topics, one
6
dealing with the role of glucosamine and
7
chondroitin sulfate in osteoarthritis, and the
8
other having to do with furan contaminants in
9
foods.
10 For that reason, in order to expand the
11
expertise of the committee, we've invited some
12
temporary members to join the committee, several
13
dealing with the glucosamine and chondroitin
14
sulfate issue and several having to do with the
15
issues concerned with furans.
16 As always, we have much too full a
17
schedule, and as always, I'm going to insist that
18
we stick to our time. We have to
give everybody an
19
opportunity to speak and speak for the time limits
20
that they've been assigned, and we also have to
21
provide enough time for us to discuss the issues to
22
the extent that the committee needs and feels that
6
1
discussion is needed. Towards
that end, as you
2
make your presentations and you have exceeded your
3
time, I'll let you know. And I'm
not sure exactly
4
what I'll do if you continue to talk, but--
5 [Laughter.]
6 DR. MILLER:
The very least would be to
7
turn off your microphone and ask questions
8
concerning the meaning of your data.
9 To begin the meeting, I'd like to
10
introduce--or have them introduce themselves, the
11
members of the committee. This
morning we will
12
deal with the glucosamine and chondroitin sulfate
13
issues, and tomorrow we'll deal with furans.
14 I'll begin by introducing myself. My name
15
is Sandy Miller. I'm a senior
research associate
16
at the Center for Food Nutrition Policy at Virginia
17
Tech University.
18 DR. RUSSELL:
I'm Robert Russell. I'm
19
director of the USDA Human Nutrition Research
20
Center on Aging at Tufts.
21 DR. DICKINSON:
Annette Dickinson,
22
president of the Council for Responsible Nutrition.
7
1 DR. ARCHER:
I'm Doug Archer, professor,
2
Food Science and Human Nutrition at the University
3
of Florida.
4 DR. CALLERY:
Patrick Callery,
5
pharmaceutical chemist, from West Virginia
6
University.
7 DR. DOWNER:
Goulda Downer, president and
8
CEO, Metroplex Health and Nutrition Services,
9
Washington, D.C.
10 DR. McBRIDE:
Margaret McBride, child
11
neurologist at Akron Children's Hospital.
12 DR. BLONZ:
Edward Blonz, nutritional
13
biochemist, from Kensington, California.
14 DR. ABRAMSON:
Steve Abramson, Director of
15
Rheumatology at NYU and the Hospital for Joint
16
Diseases and Dean for Clinical Research at NYU.
17 DR. FELSON:
David Felson, rheumatologist,
18
from Boston University.
19 DR. ESPINOZA:
Luis Espinoza, Chief of
20
Rheumatology, LSU, New Orleans.
21 DR. KALE:
Scott Kale. I'm a
22
rheumatologist at Rush Presbyterian and St. Luke's
8
1
in Chicago.
2 DR. LANE:
Nancy Lane, rheumatologist,
3
University of California-San Francisco.
4 DR. ZEISEL:
Steve Zeisel. I'm professor
5
and Chair of the Department of Nutrition at the
6
University of North Carolina at Chapel Hill.
7 DR. MEHENDALE:
Hari Mehendale, professor
8
of toxicology at the University of Louisiana at
9
Monroe.
10 DR. HARRIS:
I'm Ed Harris, professor of
11
biochemistry and nutrition, Texas A&M University.
12 DR. NELSON:
Mark Nelson, Vice President
13
for Scientific and Regulatory Policy, Grocery
14
Manufacturers of America.
15 DR. WASLIEN:
Carol Waslien, Chair and
16
professor, Nutritional Epidemiology, University of
17
Hawaii.
18 DR. LUND:
Daryl Lund, University of
19
Wisconsin-Madison, Food Science, and Executive
20
Directors of the North Central Regional
21
Association.
22 DR. DWYER:
Johanna Dwyer, professor at
9
1
Tufts University, and Director of the Frances Stern
2
Nutrition Center and New England Medical Center,
3
and I'm spending the year in Washington.
4 DR. KRINSKY:
Norman Krinsky, emeritus
5
professor of biochemistry, Tufts University School
6
of Medicine.
7 MS. LATHAM:
Jeanne Latham, Food and Drug
8
Administration, Executive Secretary of the Dietary
9
Supplements Subcommittee.
10 MS. REED:
Linda Reed, Acting Executive
11
Secretary of the Food Advisory Committee.
12 DR. MILLER:
Next we have certain
13
administrative things that we need to go through,
14
and Linda Reed, who is the Acting Executive
15
Secretary of the Food Advisory Committee, will
16
present those rules of the road and issues
17
concerning conflict of interest.
18 MS. REED: Good
morning, everyone. As
19
you've heard, I'm Linda Reed, the Acting Executive
20
Secretary of the Food Advisory Committee. I was
21
asked to take a few minutes to refresh everyone's
22
memory about a few rules of the road, if you will,
10
1
in terms of Advisory Committee operations.
2 It is my understanding that all of the
3
committee members have been provided a copy of a
4
Committee Member Guide to FDA Advisory Committees.
5
There is a copy of the Member Guide at the
6
registration desk for anyone who may be interested
7
in looking through it. The
Committee Member Guide
8
is in need of updating, but, by and large, it does
9
provide good operational review.
10 FDA relies on Advisory Committees to
11
provide the best possible scientific advice
12
available to assist us in making complex decisions.
13
Our goal is to do that in as open and transparent a
14
manner as possible. Part of that
openness carries
15
with it a request that the members try to avoid
16
even the appearance that issues are being decided
17
or conclusions are being reached outside of the
18
meeting.
19 We understand that issues raised during
20
the meeting may well lead to conversation over
21 breaks and during a meal. In fact, we hope the
22
discussions are thought-provoking.
11
1 We have had instances where members have
2
come back from a break and said, "You know, we were
3
talking over the break, and we would like to
4
request that the FDA provide us with some
5
additional information so we can better understand
6
thus and such." That is
perfectly acceptable.
7 What we don't want is to have a situation
8
where, after the break, the members come back and
9
say, "We were talking over the break and decided
10
that an answer to a question is..." From our
11
perspective, that would be particularly troublesome
12
because neither the agency nor the public would
13
have had the benefit of listening to the entire
14
discussion, the question raised, and the responses.
15 In fact, FDA has adopted a policy that
16
only the matters can be reached by a show of hands,
17
procedure matters, for example--I read all that
18
wrong. Excuse me.
19 In fact, FDA has adopted a policy that the
20
only matters that can be decided by a show of hands
21
are procedure matters, for example, break times.
22
All other votes and comments must be placed on the
12
1
record, attributed to the member making that
2
statement. The policy goes even
further. If a
3
member has to leave the meeting early, the member
4
waives that right to vote. You
may wonder why the
5
person may lose their right to vote, but the answer
6
is fairly simple. FDA believes
that all parts of
7
the meeting and discussions are important.
8
Consequently, voting on issues without having the
9
benefit of the discussion would be premature.
10 The issue of openness is larger than what
11
transpires during the course of the meeting. I
12
would like to call your attention to the section in
13
the Member Guide titled "Member Interaction Before,
14
During, and After a Meeting."
In essence, this
15
section underscores the fact that all
16
communications with the members should be routed
17
through the committee's Executive Secretary. That
18
would be myself. No one, not
even FDA staff, with
19
the exception of the Executive Secretary, should be
20
contacting the members about upcoming meetings,
21
topics, et cetera. This same
guidance applies to
22
consultations between members prior to a meeting.
13
1 If a member receives an inappropriate
2
contact, the member should feel free to notify
3
myself and/or refer the person making the contact
4
to me. Our goal in having all
contacts routed
5
there the Exec. Sec. is to minimize any situations
6
that could be misinterpreted.
7
Appearance issues are always
difficult,
8
because, as is true of many things, appearances can
9
be deceiving. We ask that our
members, guest
10
speakers, liaisons, and everyone attending the
11
meeting be mindful of how an interaction between a
12
member--and anyone, for that matter--might be
13
perceived.
14 Please let me be clear. It is not my
15
intention to question anyone's integrity or
16
motives. But I'm very sensitive
to the issue
17
because I have--and I imagine you all have, too--seen highly
18
respected individuals become an object
19
of negative attention based on a misperception.
20
And I certainly wouldn't want anyone in this room
21
to become such a target.
22
I'm confident that everyone
here today is
14
1
sensitive to these issues and can appreciate that
2
my comments are intended as a gentle reminder.
3 Lastly, as you settle in, please take this
4
opportunity to silent any cell phones or other
5
devices that ring, beep, or play show tunes. And I
6
appreciate your attention for that statement.
7 Now I'd like to read the conflict of
8 interest statement into the record.
9 DR. MILLER:
Just to be certain that there
10
are no mistakes, does anybody need any
11
clarification?
12 [No response.]
13 DR. MILLER: If
not, why don't we go on.
14 MS. REED:
Okay. As Dr. Miller mentioned,
15
we have the pleasure of having two of our
16
subcommittees and several members of our sister
17
center Advisory Committee serving throughout the
18
meeting, and we thank you for being here.
19 And with that, I would like to read the
20
conflict of interest statement into the meeting
21
record. And as with the rules of
the road, this is
22 a
rather long one, so please bear with me.
15
1 The authority to appoint temporary voting
2
members to the Food Advisory Committee is granted
3
to the Center Director. Relying
on that authority,
4
Dr. Robert Brackett, Director, Center for Food
5
Safety and Applied Nutrition, has signed letters
6
appointing Dr. Luis Espinoza, Dr. Scott Kale, and
7
Dr. Nancy Lane as temporary voting members of the
8
Food Advisory Committee of the June 7-8, 2004,
9
committee meeting. These members
will serve on the
10
committee for the first portion of the meeting, the
11
subject of which is osteoarthritis.
12 The authority to grant permission to
13
borrow special government employees currently
14
serving on the Advisory Committee in a sister
15
center, in this case the Center for Drug Evaluation
16
and Research, is granted to the Associate
17
Commissioner for External Relations, Mr. Peter
18
Pitts. Relying on that authority,
Mr. Pitts has
19
signed a memorandum granting permission to Dr.
20
Steven Abramson, Dr. John Cush, and Dr. David
21
Felson to serve as temporary voting members on June
22
7-8, 2004, for the first portion of this meeting.
16
1
They will represent the Arthritis Drugs Advisory
2
Committee.
3 Mr. Pitts in the same memorandum also
4
granted permission for Dr. P. Joan Chesney to serve
5
as a temporary voting member for the second portion
6
of the meeting concerning furan on June 8, 2004.
7
Dr. Chesney will represent the Pediatrics Advisory
8
Subcommittee of the Anti-Infective Drug Advisory
9
Committee.
10 With that said, we have a total of seven
11
temporary voting members who will participate in
12
one of these two parts of this meeting.
13 Because of the breadth of topics to be
14
discussed at this meeting, all of the members and
15 temporary voting members have been screened for any
16
and all financial interests associated with the
17
regulated industry. Based on
this review, FDA has
18
determined, in accordance with 18 U.S.C., Section
19
208(b)(3), to grant general matters waivers to Dr.
20
Steven Abramson, Dr. Marian Allen, Dr. Douglas
21
Archer, Dr. Edward Blonz, Dr. John Cush, Dr.
22
Johanna Dwyer, Dr. Luis Espinoza, Dr. David Felson,
17
1
Dr. George Gray, Dr. Edward Harris, Dr. Scott Kale,
2
Dr. Norman Krinsky, Dr. Nancy Lane, Dr. Harihara
3
Mehendale, Dr. Margaret McBride, Dr. Sanford
4
Miller, Dr. Robert Russell, Dr. Carolyn Waslien,
5
and Dr. Steven Zeisel.
6 The granting of these waivers permits
7
individuals to participate fully in the matters
8
before this committee. Copies of
the waiver
9
statements may be obtained by submitting a written
10
request to the agency's Freedom of Information
11
Office, Room 12A-30 of the Parklawn Building.
12 In an effort to enhance consistency within
13
the FDA, the agency has recently adopted a policy
14
whereby all public commenters will be asked to
15
report any personal financial interests that could
16
be affected by the committee's deliberations. A
17
copy of the policy was provided to all individuals
18
who registered to make comments at this meeting.
19
Additional copies of the policy may be obtained
20
from the registration desk.
21 Similarly, we have asked our guest
22
speakers to complete a financial interest and
18
1
professional relationship certification for guests
2
and guest speakers to identify any potential
3
conflicts of interest. Dr. Luke
Bucci, Dr. Lucio
4
Rovati, Dr. Roy Altman, and Dr. Lee Simon will
5
speak at the first portion of the meeting. Dr.
6
Bucci has declared that he has a financial interest
7
in the Weider Nutrition Group.
Dr. Lucio Rovati
8
has declared he has a financial interest in the
9
Rotta Research Laboratorium in Monza, Italy. Dr.
10
Roy Altman has declared he has a financial
11
relationship with Rotta Pharm.
And Dr. Lee Simon
12
has indicated that he has no financial
13
relationships with dietary supplements or the
14
pharmaceutical industries.
15 Dr. Don Forsythe and Dr. Glenda Moser will
16
be guest speakers at the second portion of the
17
meeting. Both have indicated
they have no
18
financial interests in the food industry.
19 I have one final administrative announcement. We
20
have received two written submissions
21
from Nutramax Laboratories, Incorporated. The
22
submissions have been provided to our members, and
19
1
copies are available at the registration desk for
2
those attending the meeting.
3 Almost done.
Lunch will be provided today
4
and tomorrow for our members and guest speakers.
5
We hope this will avoid some of the time crunches
6
we have experienced in the past and facilitate
7
returning to the meeting in a timely fashion, as
8
this meeting is a very full one.
9 I want to thank you again for your
10
attention as I read the statement and welcome all
11
of you again. Thank you very
much for being here.
12 DR. MILLER:
Thank you, Linda.
13 As many of you know, there was a change in
14
leadership at CFSAN since the beginning of the
15
year. Dr. Robert Brackett was
named Director of
16
the Center when Joe Levitt left.
At our last
17
meeting, Dr. Brackett had an opportunity of being
18
introduced to the FAC. However,
at that time he
19
had not been--he had been named, but he hadn't
20
assumed the position of Center Director. He's with
21 us today, and he's going to make some opening
22
remarks.
20
1 Bob?
2 DR. BRACKETT:
Well, thank you, Dr.
3
Miller, and good morning to all of you. It is a
4
distinct pleasure for me to be able to provide some
5
very brief opening remarks and to welcome you to
6
this Food Advisory Committee.
7 As was mentioned, you have a very, very
8
full schedule, and so I am going to keep my
9
comments brief. But I did want
to offer the fact
10
that this is something that I support very highly,
11
the Food Advisory Committee meeting.
I think that
12
it enables FDA to enhance the expertise that we
13
have available to us; it allows for a breadth of
14
different views on some important scientific
15
issues. And the two that we've
got today and
16
tomorrow--that is, chondroitin sulfate and
17
glucosamine and then, tomorrow, furan--are two that
18
have been in front of us a lot in the last year.
19
So, you know, I myself am going to find the results
20
of the discussions quite interesting.
21 I had originally intended to stay both
22
days all day because I did want to hear some of the
21
1
scientific discussions, but I have found out that
2
my schedule has changed since I returned from
3
Europe last week, and so I will only be able to
4
stay a little bit today, and unless things change
5
tomorrow, I will not be able to be here tomorrow.
6
But I wish that I could.
7 One of the things I do want to say is in
8
supporting the Food Advisory Committee, the fact
9
that you have scientific discussion in an open,
10
transparent manner, I find that it's enhancing to
11
our experts to be able to hear what outside
12
scientists say. But as a former
member of this
13
committee before I came to FDA, I also found that
14
participating from the outside in this also helped
15
sort of give a little more depth and breadth to the
16
scientific expertise for those that come here.
17 As mentioned, we're having some extra
18
experts coming from our Center for Drugs as special
19
government employees, and that is always enriching
20
to the discussion as well.
21 I hope that things can move along on time
22
and that you will have the opportunity to give all
22
1
of the opinions that you have and all the
2
discussion that is required from this meeting.
3
It's something that, again, as I say, I am looking
4
forward to very much, and I really do want to again
5
wish you here--but I don't want to belabor the
6
point because I do know that you have a lot going.
7
And, again, thank you for coming.
Thank you for
8
participating. I know this does
take a lot of time
9
out of your professional schedules as well.
10 So good morning and welcome.
11 DR. MILLER:
Thank you, Bob.
12 Let us turn now to the basic issues of why
13
we're here. Our first speaker
from the FDA will
14
present the background and the questions the
15
committee is being asked to consider.
I would like
16
to emphasize how important it is that we listen to
17
this very carefully because if we don't stick to
18
the topics and we allow ourselves to drift and not
19
focus on what we're here for, we're not going to be
20
able to come to any conclusions by the time this
21
meeting has been completed. So
please listen to
22
this very carefully.
23
1 Thank you.
2 DR. TARANTINO:
In order to listen to it,
3
I'll have to lower the microphone dramatically.
4
But I have done so.
5 Good morning, everybody, Dr. Miller and
6
members of the committee. I am
Laura Tarantino. I
7
am not Barbara Schneeman. Dr.
Schneeman, many of
8
you may know, is the newly appointed Director of
9
the Office of Nutritional Products, Labeling, and
10 Dietary
Supplements. Unfortunately, she
couldn't
11
be here today, so on her behalf, it is my great
12
privilege and pleasure to welcome you.
And as Bob
13
Brackett did, once again, thank you for taking time
14
from what I know is a very busy schedule to come
15
here and to allow us to benefit from your expert
16
knowledge.
17 My job, as Sandy mentioned, is to outline
18
the task that we're asking you to focus on over the
19
next day and a half during the part one of this
20
two-part meeting, and perhaps to review and amplify
21
on and actually maybe translate a little bit the
22
questions that we're asking you to consider.
24
1 As you're aware from the background
2
materials that you got, the agency is evaluating
3
health claim petitions that concern glucosamine and
4
chondroitin sulfate and osteoarthritis.
In a few
5
minutes, Louisa Nickerson of FDA is going to give
6
you some brief background concerning health claims
7
to give you context and an idea of the framework in
8
which we are operating. But I
want to emphasize
9
that the questions that are in front of you
10
actually are--and the questions that we're asking
11
you to consider are not about health claims per se.
12 Furthermore, as you'll have noted from
13
your background material and the information, the
14
questions are also not about glucosamine and
15
chondroitin sulfate specifically.
Rather, what we
16
are asking you and what we're asking your help
17
about is in assessing the science needed to
18
demonstrate reduction in risk of osteoarthritis in
19
healthy people. Health claims
have to do with the
20
relationship between a substance and a disease and
21
reduction of risk of a disease in healthy people.
22 What we put in the Federal Register notice
25
1
about this meeting is actually pretty much on
2
point. In part, it reads,
"to receive advice and
3
recommendations relating to the etiology of
4
osteoarthritis, its modifiable risk factors, and
5
the relevance of scientific studies cited in the
6
petitions that substantiate the substance/disease
7
relationship."
8 Okay. Let's
see. This is this, and this
9
advances? Yes, it does. Thank you.
10 The first question--and as I say, I am
11
going to try to translate a little bit because they
12
look pretty long and involved on your piece of
13
paper, but this is identical to what you have in
14
your background. It is revised
spatially to
15
simplify it a little bit, but same words.
16 The first question really then is about
17
modifiable risk factors. That
is, are joint
18
degeneration or cartilage deterioration a valid
19
risk factor for osteoarthritis that can be
20
modified, and can be modified in this case by diet,
21 a
dietary substance, leading to a reduction in risk
22
of osteoarthritis in healthy people?
That's really
26
1
what we're asking about.
2 We recognize that there really isn't
3
complete knowledge, as you well know, about the
4
etiology and development of osteoarthritis. But in
5
this case, as is true with the other questions,
6
and, really, as is true generally in the way we do
7
business, the information that's available today is
8
what we're going to have to use to make essentially
9 a
binary decision. We recognize that our
10
conclusion could change as information changes, but
11
what we really need to ask you is your views on
12
which way does the needle point on this and the
13
other questions with the information we have in
14
front of us today.
15 The second question really gets to the
16
relevance of studies and information on patients
17
with osteoarthritis, to the questions we need to
18
answer. The petitions cite many
intervention
19
studies in patients with osteoarthritis, and this
20
question really is asking about the relevance of
21
that data, and the data and information that could
22
show that a substance treats osteoarthritis or may,
27
1
for example, slow joint degeneration or cartilage
2
deterioration in osteoarthritis patients. What is
3
the relevance of that information?
Can that
4
information be validly extrapolated to the question
5
in front of us, which is reduction of risk in
6
healthy population?
7 And the third question, (a) and (b), has
8
to do with the utility and relevance of in vitro
9
models and of animal models.
Some of the data
10
before us are from animal or in vitro models of
11
osteoarthritis. So this question
is really asking
12
what's the relevance and utility of these models
13
for assessing disease risk reduction in humans and
14
what sort of data would we really need to be able
15
to base--that we could use these particular studies
16
for, what kinds of information.
17 And later this morning, Dr. Rowlands is
18
going to talk about all of these in much more
19
detail. Furthermore, he's going
to present a
20
survey of our review of the issues raised by these
21
questions and going to present the tentative
22
conclusions from our analysis thus far.
After
28
1
that, the petitioners will present their analyses
2
and their rationale for their conclusions. And,
3
finally, you're going to hear from some additional
4
experts who will try to review the state of the
5
science on the issues raised and the questions
6
we've put before you.
7
We're certainly very interested
in hearing
8
from this committee your reaction to our and the
9
petitioners' analyses and your responses to each of
10
the questions based on the information available
11
today. Again, what we're really
looking for is,
12
based on everything you know, what you've seen in
13
the background packages, and what's there, which
14
way, again, does the needle point on each of these
15
questions.
16 Before I close, I want to make just one
17
brief aside. Some of you may
have seen a notice
18
published in the Federal Register last Thursday.
19
That notice is regarding a consumer study that the
20
agency was proposing to carry out related to
21
testing consumer reactions to various types of
22
claim language involving glucosamine and
29
1
chondroitin sulfate. In the
event any of you
2
became aware of it, I just want to make very clear
3 that the notice and the
studies described in that
4
notice are in no way relevant to today's
5
proceeding. The study that was
discussed is
6
directed at consumer perceptions, and consumer
7
perceptions is an area that the agency is very
8
interested in in terms of the whole claims area,
9
but it does not involve the scientific questions
10
that are before you today. The
notice, in fact,
11
was published in error and contains some
12
misstatements and will be corrected.
But the
13
timing was unfortunate because there was a
14
possibility that it would get confused with what we
15
are bringing before the Advisory Committee. But it
16
is quite a different issue entirely.
17 So I think I'm going to repeat what Bob
18
Brackett said. We very much look
forward to
19
today's and tomorrow's discussions on this subject.
20
I'm sure they'll be very helpful to us, as has been
21
true of other Advisory Committee meetings, in
22
reaching a solid and well-justified and well-documented
30
1
decision on these petitions.
Advisory
2
Committees in the past have helped us enormously in
3
making sure that our decisions benefit from
4
objective, public discussion and examination of
5
issues from all sides.
6 I expect your deliberations will be
7
lively, will help us greatly.
Again, welcome and
8
thank you for your attention.
9 DR. MILLER:
Thank you.
10 Before we go on, Dr. John Cush joined us.
11
Would you introduce yourself for the record?
12 DR. CUSH: Jack
Cush. I'm a
13
rheumatologist from Presbyterian Hospital, Dallas.
14
And I'm on the Arthritis Advisory Board.
15 DR. MILLER:
Thank you.
16 Laura, why don't you wait a minute and see
17
if there are any questions. Any
questions for
18
clarification? This is very
important that we all
19
understand what we're supposed to be doing here and
20
what we're supposed to be working on.
So if you
21
have any questions, Laura will be here, of course,
22
throughout the meeting and if questions come up--
31
1 DR. TARANTINO:
We will probably come back
2
to this a couple times, too, but yes.
3 DR. FELSON:
"Healthy people" is a hard
4
one to deal with. So if this
were to be taken or
5
if something were to be taken for people who
6
already have disease to prevent worsening of
7
disease, does that fit the criterion?
8 DR. TARANTINO:
I guess if you could
9
differentiate that from treating the disease--it's
10
not an easy distinction to make.
I'd be interested
11
to hear the discussion.
12 DR. ZEISEL:
May I ask, just to clarify,
13
because that is the crux, I think, of today's
14
discussion. There can be a stage
in which
15
cartilage degeneration or other symptoms occur in
16
which osteoarthritis is not yet diagnosed, and that
17
would be a healthy person preventing progression to
18
the point where the disease is diagnosable? Is
19 that the idea?
20 DR. TARANTINO:
Yes, if there is someone
21
who--well, either the general population without
22
symptoms, it's that population, can you show that
32
1
it would inhibit progression to disease?
2 DR. ABRAMSON:
This can go on a long time,
3
but if a person has atherosclerosis--
4 DR. TARANTINO:
Yes, I was going to say, I
5
suspect--
6 DR. MILLER:
Excuse me. Please identify
7
yourself for the record.
8 DR. ABRAMSON:
Steve Abramson. This is a
9
very subjective kind of debate, and I would only
10
have paused at this moment because the analogy of
11
someone having asymptomatic osteoarthritis is not
12
dissimilar from having asymptomatic coronary heart
13
disease, perhaps. And if a
person has coronary
14
heart disease and is asymptomatic, are they a
15
healthy person or not a healthy person?
I think
16
these are the kinds of things that we have to--not
17
make osteoarthritis a disease that's necessarily
18
different from other common diseases that we take
19
care of.
20 DR. TARANTINO:
I would agree.
21
DR. MILLER: Okay.
Thank you, Laura.
22 Next is Louisa Nickerson from the Office
33
1
of General Counsel to give us an overview of the
2
legal framework for this.
3 MS. NICKERSON:
Good morning. My name is
4
Louisa Nickerson. I'm a lawyer
for the FDA, and
5
I'm here to try to give you a little bit of legal
6
context for what you're being asked to do.
7 I am not going to even attempt to explain
8
the entire regulatory system for health claims
9
because, for one thing, we'd be here all day; and,
10
second, because it's not necessary.
As Dr.
11
Tarantino has emphasized, you're here to address
12
scientific issues.
13 Nonetheless, we thought it would be
14
helpful to tell you just a little bit about how FDA
15
regulates health claims and about how FDA defines
16
certain terms that you may have come across in the
17
background materials that were provided to you.
18 Being a lawyer, I'm going to start with a
19
disclaimer. I want to emphasize
again that your
20
role is to advise us on scientific issues, and so
21
the information that I'm going to provide is for
22
background only. You should
not--we're not asking
34
1
you to resolve any regulatory issues or to draw any
2
legal conclusions because that's the agency's role,
3
and for us to ask you to do that would not be an
4
appropriate use of the committee.
5 I want to say a little bit about
6
regulatory categories. There are
some products
7
that are drugs; there are some products that are
8
dietary supplements. Again, I'm
not going to try
9
to go into the ramifications of the full
10
definitions of those terms. But
I do want to point
11
out first that there is some overlap between those
12
categories: for products
intended to affect the
13
structure or function of the body and also for
14
products that are intended to reduce the risk of
15
disease.
16 The other point that I wanted to make is
17
that if a product is intended to treat, mitigate,
18
or cure disease, there is no overlap.
That kind of
19
product is regulated as a drug.
And that's true
20
even if it's labeled as a dietary supplement and
21
even if it otherwise qualifies as a dietary
22
supplement.
35
1 So let me give you a couple of examples in
2
the context of osteoarthritis.
The claims for
3
relief of the signs and symptoms of osteoarthritis
4
and effective arthritis pain relief, those are both
5
treatment claims that make the product a drug. In
6
fact, as many of you probably know, those are
7
actual claims that are made for osteoarthritis
8
drugs on the market.
9 I also want to talk a little bit about the
10
definition of "health claim," which I think Dr.
11
Tarantino has already mentioned.
Our definition of
12
"health claim" is not the same as the ordinary
13
English meaning of that term. I
think when a lot
14
of people hear "health claim," they think it means
15
just any claim about health, and in some contexts,
16
it certainly does mean that. But
FDA defines that
17
term in a very specific and narrower way. Our
18
definition of "health claim" is "any claim made on
19
the label or in the labeling of food, including a
20
dietary supplement, that expressly or by
21
implications...characterizes the relationship of
22
any substance to a disease or health-related
36
1
condition." And if you're
wondering the difference
2
between label and labeling, they do mean different
3
things. The label is the
immediate product label;
4
whereas, labeling is a broader term that also
5
includes other promotional material that
6
accompanies the product, such as brochures,
7
leaflets, catalogues, that sort of thing. But it
8
does not include advertising.
9 To give you a couple of examples of health
10
claims that FDA has authorized by regulation, there
11
is a claim for foods containing soy protein: "25
12
grams of soy protein a day, as part of a diet low
13
in saturated fat and cholesterol, may reduce the
14
risk of heart disease. A serving
of [name of food]
15
supplies __ grams of soy protein."
That's a type
16
of claim about a beneficial substance in food.
17 There are also claims that relate to
18
limiting the amount of substances that may be
19
harmful, that may increase the risk of disease if
20
eaten in excess. So, for
example, for low-sodium
21
foods, there's a health claim:
"Diets low in
22
sodium may reduce the risk of high blood pressure,
37
1 a
disease associated with many factors."
2 So since health claims are about the
3
effect of a food substance on a disease or a
4
health-related condition, it's important to
5
understand how FDA defines those terms.
They are
6
defined by regulation:
"Disease or health-related
7
condition" means "damage to an organ, part,
8
structure, or system of the body such that it does
9
not function properly...or a state of health
10
leading to such dysfunctioning..." except that
11
nutrient deficiency diseases, such a scurvy and
12
pellagra, are not included in the definition for
13
regulatory purposes.
14 So a couple brief examples. Diabetes
15
would be considered a disease.
Insulin resistance
16
would be considered a health-related condition,
17
that is, a state of health leading to disease.
18 It's also important to note that the scope
19
of health claims is limited.
Health claims are
20
about reducing the risk of a disease or health-related
21
condition. They're not about
treating,
22
mitigating, or curing diseases.
That is the
38
1
position that FDA took in responding to a health
2
claim petition for saw palmetto and relieving the
3
symptoms of benign prostatic hypertrophy a couple
4
years ago, and that position was upheld by a
5 federal appellate court at the beginning of
this
6
year in the case of Whitaker v. Thompson.
7 So applying that concept, an example of a
8
claim that would not be a health claim--and this is
9
actually the claim that was proposed for saw
10
palmetto--"Consumption of 320 mg daily of saw
11
palmetto extract may improve urine flow, reduce
12
nocturia and reduce voiding urgency association
13
with mild benign prostatic hyperplasia." And that
14
is not a health claim because it's about treating
15
or mitigating BPH by relieving its symptoms.
16 That's all that I wanted to cover today.
17
As I mentioned, I was not intending to provide a
18
comprehensive view of the regulatory framework, but
19
just touch on a few relevant terms and issues.
20 Are there any questions? Yes?
21 DR. HARRIS: Ed
Harris. I would like you
22
to clarify just why a nutrient deficiency, which we
39
1
know can lead to quite a bit of abnormal
2
metabolism, why is that not considered in your
3
context a health claim--or disease state?
4 MS. NICKERSON:
Because--it's not that we
5 don't
consider it a disease scientifically.
It's
6
that obviously Vitamin C is good for preventing
7
scurvy. We didn't want people to
have to go
8
through the health claim regulatory process of
9
coming to us with their data when it was obvious
10
that, you know, Vitamin C would work for that use
11
and other nutrients would solve other--would cure
12
other nutrient deficiency diseases.
13 Yes?
14 DR. DWYER: If
this example is not a
15
health claim, is it a drug claim?
16 MS. NICKERSON:
Yes. That would be a drug
17
claim.
18 Yes?
19 DR. BLONZ:
Edward Blonz. The concept of
20
functioning properly, is this an age-specific
21
dynamic definition?
22 MS. NICKERSON:
That's a scientific
40
1
question, so I'm not going to try to address that.
2
Craig, is that something that you can address
3
later?
4 DR. ROWLANDS:
[Inaudible, off
5
microphone.]
6 MS. NICKERSON:
Anyone else?
7 DR. MILLER:
Dr. Cush?
8 DR. CUSH: This
is Jack Cush. Would this
9
be a health claim if it were to stop at "improving
10
urine flow and reduce nocturia" and didn't go into
11
association with BPH? Again, it
would be being--use the
12
health claim because it improves symptoms
13
without necessarily trying to comment on
14
relatedness to disease?
15 MS. NICKERSON:
Well, I don't think it
16
matters if the disease is mentioned, as long as you
17
have characterizing symptoms of the disease. So
18
one can recognize from what conditions described
19
are that, okay, we're talking about the typical
20
symptom complex of BPH, which is what those are.
21 DR. CUSH:
Right.
22 MS. NICKERSON:
Then it doesn't make a
41
1 difference if they use the words BPH or not. It's
2
just the difference between an implied claim and an
3
express claim.
4 DR. MILLER:
Dr. Krinsky?
5 DR. KRINSKY:
Norman Krinsky. If the
6
definition of a health claim is to reduce the risk
7
of a disease, is that, therefore, limited to a
8
healthy population?
9 MS. NICKERSON:
Yes, that's our position.
10 DR. MILLER:
Dr. Zeisel?
11 DR. ZEISEL:
Again, help me understand.
12
When does a condition become a disease?
So
13
prostate being slightly larger, is that a disease?
14
Or does it have to be diagnosed as prostatic
15
hyperplasia by a physician to become a disease?
16 MS. NICKERSON:
Again, I really think
17
that's a scientific and medical question that I
18
can't address. But I will say,
you know, what a
19
healthy person is is certainly a matter of debate.
20 DR. MILLER:
This discussion reminds me
21
why I am always nervous when scientists get
22
involved in regulatory activities.
42
1 [Laughter.]
2 DR. MILLER: I
just want to remind you
3 that the questions we're being asked have
nothing
4
to do with the regulation, or to the issue of
5
regulation. The questions being
asked is whether
6
or not the science supports a relationship between
7
various biomarkers, among other things, and the
8
disease of osteoarthritis. And I
think it's been
9
too much fun trying to understand the morass of
10
regulatory language.
11 All right.
Thank you.
12 Next, Dr. Craig Rowlands from FDA will
13
give us an overview of the petitions and say
14
something about the review process.
15 DR. ROWLANDS:
I can see I already have my
16
work cut out here. I got three
questions before I
17
even got to the podium.
18
First, I just want to thank
you, Dr.
19
Miller, and thank you, members of the committee,
20
for being here. I know some of
you, perhaps all of
21
you, had to do some gymnastics with your schedules
22
to be here on such short notice, and we do
43
1
appreciate it. And what you have
to say to us is
2
very important, so we're looking forward to these
3
discussions.
4 So my goal this morning is to cover some
5
of the background you've already heard--I'll just
6
reiterate a couple of points--and then provide you
7 a
summary of the scientific evidence that was
8
submitted in the petitions, along with the relevant
9
conclusions for the questions we've asked from the
10
petitions' conclusions, provide you with our
11
evaluation of the evidence that raised the issues
12
which were the basis for the questions we gave you,
13
and then I'd like to leave you with the meeting's
14
objectives.
15 So the petitioners are Weider Nutrition
16
International, Incorporated--I'll refer to them as
17
Petitioner A--and Rotta Pharmaceutical, whom I'll
18
refer to as Petitioner B.
19 Petitioner A submitted nine independent
20
health claims based on two different substances.
21
That would be: Glucosamine may
reduce the risk of
22
osteoarthritis, may reduce the risk of joint
44
1
degeneration, and may reduce the risk of cartilage
2
deterioration. Also, chondroitin
sulfate may
3
reduce the risk of osteoarthritis, joint
4
degeneration, and cartilage deterioration. And,
5
again, the same three claims for combination
6
products of glucosamine and chondroitin sulfate.
7 Rotta Pharmaceutical, Petitioner B,
8
submitted one health claim:
Crystalline
9
glucosamine sulfate may reduce the risk of
10
osteoarthritis.
11 As Louisa has already pointed out, health
12
claims are about a substance-disease relationship.
13
They're about risk reduction in healthy
14
populations, not disease treatment or mitigation;
15
those are regulated as drugs.
Let me just go ahead
16
and point out one of the questions is what is
17
healthy, and what we look at for healthy is
18
individuals who do not have the diagnosed disease
19
that is the subject of the health claim. So they
20
would be healthy if they do not have a diagnosed
21
condition, in this case of osteoarthritis.
22 The substances, of course, are glucosamine
45
1
and chondroitin sulfate. Glucosamine
is a
2
glycoprotein and is an endogenous substance. It is
3
derived from marine exoskeletons or produced
4
synthetically for commercial markets.
And it is
5
sold as the sulfate sodium chloride, or sulfate,
6
salt, the hydrochloride salt, and N-acetyl-glucosamine.
7 Chondroitin sulfate is a very different
8
kind of substance. It's a
glucosaminoglycan, which
9
is a large molecule made of glucuronic acid and
10
galactosamine, and it is manufactured from natural
11
sources such as shark and bovine cartilage.
12 Of course, the disease is osteoarthritis,
13
and Stedman's Medical Dictionary defines this as
14
arthritis which is characterized by erosion of
15
articular cartilage, either primary or secondary to
16
trauma or other conditions, which becomes soft,
17
frayed, and thinned with eburnation of subchondral
18
bone and outgrowths of marginal osteophytes.
19
That's quite a mouthful, but basically what it
20
means is it's a disease of not just the cartilage
21
or just the bone or just the musculature. It is a
46
1
disease of the whole joint. Dr.
Lee Simon will be
2 providing
us an overview of osteoarthritis later on
3
this afternoon, where he will talk about the
4
etiology of the disease and some of its modifiable
5
risk factors.
6 The characterized risk factors include
7
genetic predisposition, trauma, anatomic/postural
8
abnormalities, and obesity.
However, our reading
9
of the petitions, the literature, and our
10
consultation with experts indicates that there are
11
no biomarkers that are valid modifiable risk
12
factors/surrogate endpoints for osteoarthritis.
13
And this is one of the major goals of the National
14
Institutes of Health's Osteoarthritis Initiative,
15
to identify cartilage and bone metabolism
16
endpoints, biochemical markers that could be
17
validated as modifiable risk factors/surrogate
18
endpoints.
19 The scientific evidence summarized in the
20
petitions include in vitro mechanistic studies,
21
animal studies, and human clinical studies in OA
22
patients. Petitioner A provided
a summary of all
47
1
three types of studies, whereas Petitioner B
2
focused on the glucosamine sulfate studies in human
3
clinical studies in osteoarthritis patients.
4 The in vitro mechanistic data were
5
conducted in human and animal primary cell
6
cultures, established cell culture models, and
7
tissue/organ cultures, and these studies reported
8 that
glucosamine and chondroitin sulfate positively
9
affected various biochemical endpoints for
10
inflammation, cartilage degradation, and immune
11
responses, as well as stimulated the production of
12
proteoglycans.
13 The animal studies for glucosamine
14
reported that it reduced kaolin- and adjuvant-induced tibio-
15
tarsal arthritis in rats; glucosamine
16
reduced cartilage degradation in rabbits; and some
17
of these studies also gave chondroitin sulfate; and
18
glucosamine was reported to enhance the rate of new
19
articular cartilage proteoglycan synthesis in mice.
20 Chondroitin sulfate prevented articular
21
cartilage degradation which was induced by
22
chymopapain in rabbits, Freund's adjuvant in mice,
48
1
and surgery in rabbits.
2 The human clinical studies were all
3
conducted in osteoarthritis patients, and these
4
studies reported that glucosamine and chondroitin
5
sulfate improved symptoms of pain and functionality
6
using things such as Lequesne index, WOMAC's index,
7
visual analog scales. And some
of these studies
8
directly compared these substances to the
9
nonsteroidal anti-inflammatory drugs, for example,
10
Ibuprofen.
11 These studies in OA patients also reported
12
that there was improvement in joint degeneration
13
and cartilage deterioration based on radiographic
14
evidence, which were X-rays of joint space
15
narrowing, and some of these studies also reported
16
biochemical evidence for bone and cartilage
17
metabolism in synovium, serum, and urine.
18 So the petitioners concluded from this
19
evidence that human clinical intervention studies
20
in OA patients support OA risk reduction in healthy
21
populations, that is, people without
22
osteoarthritis.
49
1 Joint degeneration and cartilage
2
deterioration are valid modifiable risk
3
factors/surrogate endpoints for osteoarthritis.
4
And for Petitioner A, animal and in vitro models of
5
OA are relevant to OA risk reduction in humans.
6 We evaluated the evidence and identified
7
several issues which are related to the relevance
8
of OA treatment studies to OA risk reduction in
9
healthy populations; the validity of joint
10
degeneration and cartilage deterioration as
11
modifiable risk factors/surrogate endpoints for
12
osteoarthritis; and the relevance of animal and in
13
vitro models of osteoarthritis to humans.
14 The FDA relies upon two types of outcomes
15
to determine disease risk reduction.
The strongest
16
evidence is a reduction in the incidence of
17
disease. These would be
intervention and
18
observational studies in healthy people--those
19
without OA--demonstrating that a substance reduces
20
the incidence of osteoarthritis.
21 However, all of the human clinical
22
intervention studies were conducted in OA patients.
50
1
There were no intervention or observational studies
2
in healthy people demonstrating OA risk reduction.
3 FDA also relies upon studies measuring
4
beneficial changes in valid modifiable risk
5
factors/surrogate endpoints for disease. These
6
would be intervention and observational studies in
7
healthy humans demonstrating that intake of a
8
substance produces beneficial changes in valid
9
modifiable risk factors/surrogate endpoints for
10
osteoarthritis.
11
So then what is a valid
modifiable risk
12
factor or surrogate endpoint?
This is a biological
13
entity that meets all three of the following
14
conditions: it is associated
with disease; it
15
mediates the relationship between intake in healthy
16
people and disease; and its expression is modified
17
by intake of a substance in healthy people.
18 I've tried to represent this with a
19
diagram at the bottom of the slide where the green
20
box represents healthy people, the yellow box
21
represents valid modifiable risk factors/surrogate
22
endpoints, and the red box represents disease or
51
1
health-related condition.
2
Essentially, there are
two relationships.
3
Relationship 1 is between the modifiable risk
4
factor/surrogate endpoint and the disease. And
5
Relationship 2 is between the intervention in
6
healthy subjects and the modifiable risk
7
factor/surrogate endpoint.
8 Relationship 1 must be valid if it is to
9
be relied upon in Relationship 2.
That is, there
10
must be evidence that the modifiable risk
11
factor/surrogate endpoint predicts clinical
12
outcome. Only then can
intervention studies in
13
healthy subjects rely upon the modifiable risk
14
factor/surrogate endpoint to establish disease risk
15
reduction.
16 The example given is the qualified health
17
claim for walnuts. Because it
has been established
18
that LDL cholesterol is a valid modifiable risk
19
factor/surrogate endpoint for coronary heart
20
disease, intervention studies in healthy subjects
21
that observed decreased serum LDL cholesterol were
22
relevant for demonstrating a reduced risk for
52
1
coronary heart disease.
2 So then are joint degeneration and
3
cartilage deterioration associated with
4
osteoarthritis? I think the
answer is obvious.
5
Yes, there is clearly plenty of evidence that
6
they're associated with osteoarthritis.
7 Does joint degeneration and cartilage
8
deterioration mediate the relationship between
9
intake of a substance in healthy people and
10
osteoarthritis? That is, is
there evidence that
11
changes in joint degeneration or cartilage
12
deterioration predict clinical outcome for
13
osteoarthritis? Well, the evidence
given to us in
14
the petition and our own reviewing of the
15
literature, we did not identify any intervention
16
studies of any substance in healthy individuals
17
that measured both joint degeneration or cartilage
18
deterioration and OA incidence, precisely the type
19
of evidence one would need if you're going to
20
determine whether or not these are predictive of
21
clinical outcome.
22 So then are joint degeneration and
53
1
cartilage deterioration modified by intake of a
2
substance in healthy people?
Again, all of the
3
evidence provided was in OA patients.
4 Then are joint degeneration and cartilage
5
deterioration valid modifiable risk factors/surrogate
6
endpoints for osteoarthritis. As
I said,
7
they're clearly associated with osteoarthritis.
8
However, we don't know whether they mediate the
9
relationship between intake in healthy people and
10
OA; we don't know whether their expression is
11
modified by intake of a substance in healthy
12
people.
13 So our tentative conclusion is that, no,
14
these are not valid modifiable risk factors for
15
osteoarthritis. We've given you
questions directly
16
asking this, and we're very interested to hear your
17
opinions on this matter.
18 The last issue very quickly then is: Do
19
animal and in vitro models of OA mimic human
20
osteoarthritis? Well, we know
that animals have a
21
different physiology, in vitro models are conducted
22
in an artificial environment, and when you combine
54
1 this
with the fact that the etiology of OA in
2
humans is poorly understood, it would seem to
3
indicate that animal and in vitro models of OA
4
cannot be relied upon for predicting human effects.
5
In fact, this was demonstrated a few years ago in a
6
study that reported that nonsteroidal anti-inflammatory
7
drugs inhibit OA in rodents but not in
8
humans.
9 The role of animal and in vitro models of
10
OA risk reduction will be discussed this afternoon
11
by Dr. Jim Witter, who is a rheumatologist with the
12
FDA Center for Drug Evaluation and Research.
13 So these issues served as the basis for
14
our questions. I'll go ahead and
read them into
15
the record. Is, for Question
(1a), joint
16
degeneration and, for Question (1b), cartilage
17
deterioration a state of health leading to disease,
18
that is, a modifiable risk factor/surrogate
19
endpoint for OA risk reduction?
Then we'd like to
20
know what are the strengths and limitations of the
21
scientific evidence on this issue.
This question
22
is essentially asking: Are joint
degeneration and
55
1
cartilage deterioration valid modifiable risk
2
factors/surrogate endpoints for osteoarthritis?
3 Question 2 is:
If we assume that joint
4
degeneration or cartilage deterioration is a
5
modifiable risk factor/surrogate endpoint for OA
6
risk reduction and we assume that research
7
demonstrates that a dietary substance treats,
8
mitigates, or slows joint degeneration or cartilage
9
deterioration in patients diagnosed with
10
osteoarthritis, is it scientifically valid to use
11
such research to suggest a reduced risk of OA in
12
the general healthy population--again, these would
13
be individuals without osteoarthritis--from
14
consumption of the dietary substance?
And this
15
question is essentially asking:
Is it
16
scientifically valid to use human OA treatment
17
studies to suggest a reduced risk of OA in the
18
general healthy population?
19 And the final question is: If human data
20
are absent, can the results from animal and in
21
vitro models of OA demonstrate risk reduction of OA
22
in humans? And then we have two
subparts: Subpart
56
1
(a), To the extent that animal or in vitro models
2
of OA may be useful, what animal models, or in
3
vitro models, types of evidence, and endpoints
4
should be used to assess risk reduction of OA in
5
humans? And (b) is: If limited human data are
6
available, what data should be based on human
7
studies and what data could be based on animal and
8
in vitro studies to determine whether the overall
9
data are useful in assessing a reduced risk of OA
10
in humans?
11 This question is simply asking: Are the
12
results from animal and in vitro models relevant
13
for demonstrating OA risk reduction in humans?
14 This meeting then is about the science
15
needed to demonstrate risk reduction.
It is not
16
about disease treatment or mitigation.
This
17
meeting is about osteoarthritis.
It's not about
18
glucosamine and chondroitin sulfate.
it's a
19
meeting about the etiology of osteoarthritis, its
20
valid modifiable risk factors/surrogate endpoints,
21
and the relevant models of osteoarthritis. Because
22
it's about risk reduction in osteoarthritis, we
57
1
also feel that the recommendations of this FAC can
2
apply to other substance-osteoarthritis
3
relationships.
4 Again, I thank you for being here, and I
5
look forward to the discussions over the next day
6
and a half.
7 DR. MILLER:
Thank you, Craig.
8 Any questions or comments? Dr. Cush?
9 DR. CUSH: You
several times have said
10
this is not about mitigating the disease through a
11
substance. And in Ms.
Nickerson's presentation,
12
she stated that a dietary supplement is a product
13
that is intended to treat, mitigate, or cure
14
disease--oh, it's called a drug, sorry.
So if it
15
mitigates a disease, it would then be classified as
16 a
drug.
17 DR. ROWLANDS:
That's correct.
18 DR. CUSH: Okay. I'm sorry.
19 DR. CALLERY:
Pat Callery. I understand
20
that it's not about glucosamine or chondroitin
21
sulfate, but you do mention glucosamine as a
22
glycoprotein, and I'm wondering what the rationale
58
1
is there, because we'll have much discussion later
2
about salts and makeup and the difference between
3
the particular agents or compounds.
I don't think
4
it's a glycoprotein.
5 DR. ROWLANDS:
If I made an error, I
6
apologize. I was simply quoting
the information I
7
was given. But that would
be--we'll put on the
8
record what exactly it is.
9 DR. MILLER:
Any other questions?
10 [No response.]
11 DR. MILLER:
All right. Thank you, Craig.
12 Sorry.
Johanna? Craig, just a minute.
13 DR. DWYER:
Just a quick one.
14 DR. MILLER:
Dr. Johanna Dwyer.
15
DR. DWYER: It's Slide 12, your diagram.
16
The diagram that shows healthy people, valid
17
modifiable risk factors, and you use the example of
18
walnuts, LDL cholesterol, and coronary heart
19
disease. And I'm focusing on the
arrow from
20
healthy people to valid modifiable risk. That does
21
not depend, does it, on the level of HDL
22
cholesterol? It's just that it
affects that
59
1
there's a causal chain? Is that
what your diagram
2
is saying?
3 DR. ROWLANDS:
The diagram is saying that
4
LDL cholesterol is a valid--it's a recognized valid
5
modifiable risk factor or surrogate endpoint for
6
predicting coronary heart disease.
And so we don't
7
have to--when we look at the evidence for whether
8
or not a substance will reduce your risk for
9
disease, we don't necessarily need--because of
10
that, we don't need necessarily incidence data in
11
populations. We can rely upon
evidence of LDL
12
cholesterol, changes in serum LDL cholesterol, a
13
reduction in this case. That was
the point of that
14
slide. Because we have evidence,
ample evidence
15
that LDL cholesterol is a valid modifiable risk
16
factor and indeed does predict your risk for
17
developing disease--and that's been established
18
with studies where you've measured the incidence of
19
heart disease, in the same group of people you're
20
measuring LDL cholesterol in response to the same
21
intervention. And so you have
that kind of
22
evidence that essentially tested whether or not it
60
1
was predictive, and, in fact, it was predictive.
2
We have plenty of evidence.
3 DR. DWYER: I
guess what I was after is:
4
Does it matter what the level of LDL is? If it's
5
outside of the 95 percentile for a population, does
6
it matter? Or is it just the
causal chain that
7
matters?
8 DR. ROWLANDS:
I'm not sure I understand
9
your question, but I can tell you that we look at
10
changes, significant changes, so statistically
11
significant changes, decreases in LDL cholesterol,
12
as being a beneficial effect, if that answers your
13
question.
14 DR. MILLER:
Dr. Russell?
15 DR. RUSSELL: A
question going back to
16
healthy population. I know you
gave us a
17
definition that they don't have diagnosed disease.
18
But I'm wondering, if a population--if a large
19
percent of a population, let's say 50 percent of
20
the population, has some degree of a disease, not
21
symptomatic, let's say hypertension or let's say
22
atrophic gastritis--there's any number that we
61
1
could pick that sort of accompany aging--are these
2
people considered healthy?
3 DR. ROWLANDS:
So what is healthy, right?
4 I
mean, everyone is--
5 DR. RUSSELL:
Yes, but I think it's an
6
important question for us to grapple with, because
7
your definition is, well, they just haven't been--they don't
8
have diagnosed disease.
9 DR. ROWLANDS:
Yes, I guess the way to
10
look at it is when we are given a body of evidence
11
and it says in the evidence that these individuals
12
have the disease, well, then, we have to assume
13
they have the disease. The
question is to the FAC:
14
Can you base risk reduction on that kind of
15
evidence? And our definition in
this case of
16
disease is they have diagnosable osteoarthritis.
17
Now, they may have other conditions.
They may be
18
unhealthy for other reasons. But
the point we're
19
trying to focus on is the disease which is the
20
subject of the claim is the most important thing we
21
want to focus on because that is what the claim is
22
about.
62
1 Now, to the extent that other things may
2
be impacting that process, the experts here can
3
fill us in. But that's
essentially our definition
4
for health claims.
5 DR.
MILLER: Dr. Cush?
6 DR. CUSH: So
soy and walnuts can be given
7
to healthy people to alter a surrogate that might
8
help someone with a disease, and that's a good
9
health claim. How would aspirin
be classified?
10
Because aspirin is given to healthy people and has
11
disease benefits downstream.
Presumably its
12
surrogate would be by having an antithrombotic
13
effect. How would aspirin be
handled?
14 DR. ROWLANDS:
Aspirin, of course, is
15
already a drug.
16 DR. CUSH:
Right.
17 DR. ROWLANDS:
And so once you already
18
have something as a drug, it cannot be a food.
19
Health claims are about foods.
But you're getting
20
into the regulations now, so there's a technical
21
regulatory reason why that wouldn't matter.
22 DR. CUSH: I
was trying an example.
63
1 DR. ZEISEL:
Just to help us, the question
2
we're being asked--Steve Zeisel.
The question
3
we're being asked today, one of them, is: Can
4
evidence in patients who already have the diagnosed
5
disease be used to predict whether something would
6
prevent the progression of the pre--the things that
7
have to occur ahead of the disease being diagnosed
8
from occurring? So joint
degeneration but not to
9
the point of diagnosable osteoarthritis,
10
progressing to that point being prevented is--and
11
the question you're asking is:
Can we use data
12
from people who already have the diagnosed disease
13
to make that prediction?
14 DR. ROWLANDS:
Yes, in a sense, that's
15
correct. I would just also point
out that risk
16
reduction and prevention, they sound the same.
17
They're a little bit different.
We're not saying
18
that we have to prevent it. It
would lower your
19
risk for getting it. So a little
bit of a nuance
20
there.
21 DR. MILLER: Dr.
Krinsky?
22 DR. KRINSKY:
Norman Krinsky. It seems to
64
1
me that you're creating a black-and-white
2
situation, whereas there is a gray area. For
3
example, I have prostate cancer, and I was
4
diagnosed with the disease. But
before I was
5
diagnosed, was I, therefore, healthy and did not
6
have prostate cancer?
7 DR. ROWLANDS:
Based on if they gave us a
8
paper and the evidence that was given to us said
9
that you were looked at by a physician and you do
10
not have prostate cancer, then we will assume you
11
do not have prostate cancer. And
I realize that is
12 a
simplistic way of looking at it, but flip it
13
around. When you have a
population that has a
14
diagnosed disease, which is all the evidence we
15
have here, what do you do with that?
16 DR. MILLER:
Dr. Cush?
17 DR. CUSH: As a
distinction between a
18
health claim and a drug claim can be difficult in
19
the kind of product you're talking about, is it
20
this committee's purview to favor one over the
21
other as opposed--or we're just here to talk about
22 the
health claim, and, for instance, there may be
65
1
not enough evidence to make the health claim, but
2
could we discuss then the use of a product as a
3
drug claim?
4 DR. ROWLANDS: This meeting is about
5
health claims, and to the extent you believe the
6
evidence supports risk reduction, that's what we
7
would like to hear about.
8 DR. MILLER:
Actually, let me interrupt.
9 The way I understood it, this meeting is not about
10 a
health claim, but is about the question of
11
whether the science supports the relationship
12
between osteoarthritis--I want to make that
13
distinction because once you get into the issue of
14
the regulation and the interpretation of the
15
regulation, that's a morass. And
I don't think we
16
have the time to get into that discussion.
17 DR. ROWLANDS:
That's correct. I guess I
18
was thinking more along the lines of Question 2,
19
which seems to be what your question is directed
20
at, whether or not you can use what we call
21
treatment studies to extrapolate to risk reduction.
22
We're not interested in whether or not there is a
66
1
therapeutic benefit for treating the symptoms of a
2
disease. That's not what our
question is about.
3 DR. MILLER:
Dr. Dickinson?
4 DR. DICKINSON:
Annette Dickinson. It's
5
typical, I think, for research studies on any given
6
substance and disease prevention or treatment to be
7
done in diseased populations because you can expect
8
with a reasonable number of subjects to get some
9
kind of a response.
10 In the case of dietary ingredients, if the
11
intervention is with a dietary ingredient, like,
12
for example, calcium or omega-3s, you may also be
13
able fairly readily to get epidemiological
14
information or observational information that
15
indicates that high intakes of that nutrient also
16
have a preventive effect in the healthy population.
17 But if you're dealing with a substance
18
like chondroitin, for example, which might not be
19
widely consumed in the general population unless
20
they're supplementing it, then there will be
21
barriers to drawing conclusions about the healthy
22
population because it's not something they're
67
1
exposed to in meaningful amounts in the regular
2
diet. And yet we can point to
many examples, like
3
with omega-3 and calcium, where intervention agents
4
are also effective prevention agents.
Are we
5
allowed to take those comparisons into account,
6
those comparative cases into account?
7 DR. ROWLANDS:
I'm not in a position to
8
tell you what you can and cannot take into account.
9
If you feel it's important, then I guess that
10
should be something you should bring into your
11
discussion.
12 DR. FELSON:
You didn't want this to be a
13
discussion of glucosamine and chondroitin, so let's
14
leave it as a discussion of osteoarthritis and
15
whether risk factors for incident disease and
16
progressive disease are the same.
There are a
17
number of studies--and probably Dr. Simon will
18
review them--that suggest very strongly that the
19
risk factors differ for incidence and progression.
20
Bone density, for example, appears to be--increased
21
bone density appears to be a risk factor for
22
incident disease, and yet data suggests that it
68
1
probably--high bone density protects against
2
progressive disease.
3 Vitamin D, what data there are suggest
4
that it protects against progressive disease and
5
has no effect on incident disease.
Okay? So I
6
think it would be beyond a scientific reasonable
7
extrapolation to suggest that anything that treats
8
this disease is likely to have an effect on
9
incidence.
10 DR. MILLER:
That was Dr. Felson.
11 Dr. Lane?
12 DR. LANE: Yes,
I was just going to
13
comment further on Dr. Felson's question. With the
14
limited data that we now have regarding risk
15
factors for incident and risk factors for--or
16
variables associated with progression of disease,
17
it's limited, but Dr. Felson brings up just about
18
everything we know.
19 DR. MILLER:
Any other comments?
20 [No response.]
21 DR. MILLER:
We're doing quite well so
22
far. I hate to think that my
role is to watch the
69
1
clock, but I guess that's what it is.
2 Dr. Bucci?
3 DR. BUCCI:
Here.
4
DR. MILLER: Are you prepared to make your
5
presentation now?
6 DR. BUCCI:
Yes, I am.
7 DR. MILLER:
Why don't we do that and then
8
we'll take our break after Dr. Bucci's presentation.
9 DR. BUCCI:
Well, good morning, ladies and
10
gentlemen, and I wish to thank the Food Advisory
11
Committee for inviting us to make this
12
presentation.
13 My role here is to do several things, and
14
really what I'm here for is to show evidence,
15
credible evidence, that glucosamine and chondroitin
16
sulfate reduces the risk of osteoarthritis, joint
17
degeneration and/or joint deterioration.
18 So what I'll do is--I don't think I'll
19
spend much time reviewing the need for reducing the
20
risk of osteoarthritis. I think
that is self-evident.
21
Also, the proposed health claims have
70
1
already been listed. What I
would like to do,
2
though, is spend a wee bit of time on reviewing the
3
roles of glucosamine and chondroitin in reducing
4
osteoarthritis risk. One of the
ways I'll do that
5
is by showing you what they do in normal cartilage
6
tissue and then get into some of what I feel is
7
credible evidence that supports these claims.
8 These are facts and figures taken from the
9
Centers for Disease Control, and arthritis is the
10
leading cause of disability in the United States.
11 I
think the numbers speak for themselves here.
12 What I find of great interest are the
13
9,500 deaths from a supposedly non-fatal disease.
14
Now, I realize some of these figures lump
15
rheumatoid arthritis with osteoarthritis, but
16
medical textbooks have said that osteoarthritis has
17
an--or if you have osteoarthritis, you have an 11-percent
18
higher death rate than the average
19
population. And this is from a
non-fatal disease.
20 So obviously there is a need to
reduce the
21
risk of osteoarthritis in the general population,
22
if for no other reason than to not have people die
71
1
needlessly.
2 But as you can see, there's a huge cost
3
associated with the treatment of osteoarthritis.
4
Its impact is enormous, and that's one of the
5
reasons that we're all here today, is to figure out
6
if we can reduce this enormous risk and burden to
7
our health care.
8 The very bottom part of this figure shows
9
the age ranges of incidence of osteoarthritis, and
10
as we all are aware, this is an age-related type of
11
condition. However, ages 18 to
44, I think people
12
in that age group would deny that they're aged, and
13
one out of five of them has diagnosed arthritis.
14
Again, some of these are rheumatoid but, still, the
15
majority is osteoarthritis since that makes up
16
about 80 percent of the total arthritis.
17 The point I'm getting at here is that
18
these people would--these are not considered aged
19
people. It is not a completely
age-related
20
disease, and this speaks to the variety of factors.
21 Okay. These
are the health claims that
22
have been proposed by Weider Nutrition.
72
1
Glucosamine and chondroitin may reduce the risk of
2 osteoarthritis,
joint degeneration, and joint
3
deterioration. I think we've
seen these already so
4
I'll proceed on in the interest of time.
5 What I'd like to do is give you some
6
visual reference points so you can put what
7
glucosamine and chondroitin do into a context and
8
mental framework.
9 Uh-oh, I hit the wrong button again. This
10
even works behind your back.
Very good.
11 This is an artist's rendition of articular
12
cartilage, and the point here is that this is a
13
different tissue than others in the body, quite
14
different, in fact. Cartilage is
thought of by
15
most people as being sort of an inert Teflon washer
16
for your joints that cushions--makes your joint
17
lubricated so they can slide easily and you can
18
have adequate movement.
Obviously, this is an
19
artist's rendition, so there are a few things out
20
of scale. But the point here is
that there's no
21
blood vessels inside of cartilage, except for some
22
in the menisci; no nerves; no lymphatics.
73
1 These chondrocytes, which are the primary
2
cell type in cartilage, rely on diffusion from
3
synovial and subchondral bone blood vessels to get
4
all their nutrients--oxygen, water, carbohydrates,
5
protein, amino acids, glucosamine, et cetera.
6 This is a little more of a closeup of
7
cartilage in a very stick-figure kind of diagram.
8
Chondrocytes are supposed to be the only cell type
9
in cartilage, and they manufacture this cartilage
10
matrix, which is a combination of Type II collagen
11
mostly, which are represented by these purple
12
girder-like structures. And in
between all the
13
very precisely laid out collagen girders are these
14
proteoglycans, commonly called--aggrecan is the
15
main one. And these are composed
of--what I'll
16
show you is mostly chondroitin sulfate.
17 As you can see in this stick figure, these
18
little yellow sticks running around randomly,
19
supposedly randomly, but in between these girders
20
represent the proteoglycans. And
we'll give you a
21
little bit better picture in a moment.
22 But, first of all, these proteoglycans
74
1
form around a hyaluronan backbone, HA, and
2
hyaluronan is a glucosaminoglycan; 50 percent of it
3
is directly derived from glucosamine.
And we have
4
these proteoglycan subunits that are attached to
5
the hyaluronan over and over and over again,
6
hundreds per hyaluronan. These
proteoglycan
7
subunits are relatively large molecular structures.
8
They have a couple hundred, on the average,
9
chondroitin sulfate chains attached to each core
10
protein, and you have several hundred of these
11
proteoglycan--which I've abbreviated here as PG--subunits
12
per aggrecan or proteoglycan molecule.
13 Now, I think something that's extremely
14
important for everyone here to realize and remember
15
is that the life span of aggrecan proteoglycan in
16
adult human cartilage is 600 to 1,000 days, two to
17
three years. Keep that time
frame in mind. I
18
think it's important for interpretation of the
19
results of human studies.
20 In other words, cartilage is a very slow
21
tissue, and it responds to stimuli in a very slow
22
and simple manner.
75
1 This is another artist's picture that
2
gives you a little bit better idea of how space-filling the
3
proteoglycans are. The
chondroitin
4
sulfates have a relatively large amount of sulfate
5
groups that are charged and attract water, and they
6
fill up all the space between the collagen girders
7
that make up the shape and the structural integrity
8
of cartilage. Various insults
can physically
9
damage and degrade the structures of cartilage,
10
specifically the chondroitin sulfate, the collagen,
11
as well as the hyaluronan backbone of
12
proteoglycans. These insults are
constant,
13
ongoing, and inescapable. Free
radicals are
14
probably one of the primary insults, and any type
15
of other risk factor eventually leads to generation
16
of free radicals that do actually physically damage
17
and break off small pieces of cartilage, including
18
chondroitin sulfate, hyaluronan, and Type II
19
collagen. Some of these pieces
are actually being
20
looked at surrogate endpoints or biomarkers for
21
cartilage damage.
22
So what I'm trying to do
here is give you,
76
1
again, a context or a perspective of what
2
glucosamine and chondroitin are.
I hit the wrong
3
button again, but here we go.
4 One thing I didn't mention previously is
5
that glucosamine is the major precursor for
6
chondroitin sulfate. We'll look
at that in a
7
moment. I'd like to cover some
of the human
8
supplementation studies that have used glucosamine
9
and chondroitin sulfate and their applicability to
10
risk reduction of osteoarthritis and joint
11
degeneration and deterioration.
12 Again, I want to reiterate the fact that
13
cartilage turnover, normal maintenance and repair,
14
is constant and ongoing. Your
cartilage is not an
15
inert Teflon washer. Although
kind of slow and
16
best by problems of nutrient diffusion compared to
17
other perfuse tissues, cartilage does maintain
18
itself all the time as we go through life. The
19
half-life of the major structural components--aggrecan,
20
proteoglycan, and collagen--is about one
21
to two years. Remember the life
span was two to
22
three years. And as I've already
mentioned, normal
77
1
wear and tear in healthy people--everybody, for
2
that matter--produces these degraded fragments
3
constantly.
4 Another cause is shear stress, and this is
5
where things like trauma and injuries can enter
6
into play. In other words, just
the shear stress
7
of overload of mechanical forces can literally
8
break off pieces.
9 Cartilage does respond via the
10
chondrocytes in the synovial lining to the
11
molecular pieces of the most exposed macromolecular
12
constituent. That's pretty much
obvious, and these
13
constituents being hyaluronan in synovial fluid and
14
chondroitin sulfate in cartilage itself, since they
15
are the space-filling macromolecules that anything
16
that would be at a molecular level would encounter
17
first in synovial fluid and collagen.
So it kind
18
of makes sense that these chondrocytes which are
19
trapped in their matrix respond to pieces of the
20
structure. In other words, the
analogy, very
21
simple analogy, would be that if you start to see
22
bricks falling around outside your house, you know
78
1
you have a problem with the structural integrity of
2
your house and you need to start patching up your
3
brickwork again. It's a very
simplistic analogy,
4
but there are receptors on chondrocytes and
5
synovial lining cells and, indeed, cells throughout
6
the body that recognize both intact and various
7
sizes and fragments of both hyaluronan and
8
chondroitin sulfate.
9 So all these things are happening all the
10
time, whether somebody is five years old, 50 years
11
old, 90 years old, whether they walk with a limp or
12
can run marathons.
13 Supplementation trials also have these
14
other factors going on. Joint
tissues can only
15
maintain themselves and, thus, resist degradation,
16
resist deterioration, and remain normal by
17
biosynthesis of more matrix.
This is a brick-and-mortar-
18
type of idea I'm trying to get across.
if
19
the bricks and mortar start to fall apart, you have
20
to add more brick and mortar. So
the only way that
21
joint tissues can make more matrix is to start off
22
with glucosamine and convert that into chondroitin
79
1
and proteoglycans, and that sets the stage for
2
collagen production on top of that.
There must be
3 a
combination of collagen production and
4
proteoglycan production to produce cartilage. It's
5 a
relatively simple tissue structurally.
And
6
biosynthesis of chondroitin is essential to the
7
maintenance of cartilage and, thus, to the
8
prevention of joint deterioration.
9 I took this quote from a textbook in 1986
10 called
"Articular Cartilage Biochemistry," and I'll
11
read it for the record.
"The integrity of this
12
matrix is critical for the unique biochemical
13
properties of hyaline cartilage and depends on a
14
maintenance of the quantity and quality of the
15
matrix components. Such
maintenance must be the
16
result of a balance between synthetic and
17
degradative processes within the tissue. Thus, any
18
loss of, for example, proteoglycan from the
19
cartilage matrix due to physiologic or pathologic
20
processes must be balanced by de novo synthesis of
21
proteoglycans by the chondrocytes."
22 So, in other words, if there's anything
80
1
going on with the cartilage in terms of structural
2
damage or loss of any components, the only way to
3
fix that is to actually make more.
And the only
4
way to make more is to use glucosamine to
5
manufacture chondroitin, et cetera, et cetera.
6 Also, a review of the available
7
literature, which is, of course, quite extensive,
8
shows that the same biochemical signals, the same
9
regulatory, cellular, biosynthetic, anabolic,
10
catabolic, and metabolic mechanisms that operate in
11
cartilage in normal health are also operating
12
during the process of diagnosed osteoarthritis. So
13
what I'm trying to say here is that I believe that
14
normal cartilage is acting the same way that
15
cartilage does in osteoarthritis to a very large
16
extent.
17 Maintenance of cartilage consists of the
18
same processes and events that occur during normal
19
wear and tear, that also occur during normal aging,
20 and also in persons diagnosed with
osteoarthritis.
21
In other words, all three of these situations
22
involve use of glucosamine and chondroitin to make
81
1
more matrix.
2 In other words, the chondrocyte doesn't
3
know if you've been labeled osteoarthritic or
4
elderly or young and growing. It
just does what it
5
has to do, and that's make more matrix.
6 Also, I think one thing that's been
7
alluded to extensively is surrogate markers or
8
endpoints of progression of disease.
And I think
9
it's pretty clear from looking at textbooks over
10
the last five decades that there is an unbroken
11
continuum of events in cartilage from health to
12
degenerative disease. Notice
that the official
13
definition of osteoarthritis from Stedman's Medical
14
Dictionary really identified a very late stage,
15
such as eburnation. That's the
progression that
16
we're trying to stop, that we're trying not to get
17
to, is losing cartilage and getting bone on bone.
18
That is what we are trying to reduce the risk of
19
getting to.
20 So, therefore, there's no agreed-upon
21
threshold or marker that clearly defines the onset
22
of osteoarthritis. I think Dr.
Krinsky's point
82
1
about when does diagnosis occur and when are you
2
considered or diseased is very applicable here. In
3
other words, if someone walks into a doctor's
4
office and gets diagnosed with osteoarthritis that
5
day, what were they the day before?
They would
6
have been considered healthy unless they had, of
7
course, been looked at and determined to be
8
osteoarthritic. So that is, I
think, the question,
9
but I think the answer is that there's really not
10
much difference. It is a
continuum. If you're
11
going to say, well, you right there, you're
12
osteoarthritic, and the next person that you look
13
at and evaluate whether they're osteoarthritic or
14
not has similar findings but no symptoms, well, is
15
that the same thing or not?
They'd be considered
16
healthy. So there is a
continuum.
17 There's also considerable overlap of these
18
biochemical markers as well as the appearance of
19
cartilage from various diagnostic imaging
20
techniques between healthy controls and
21
osteoarthritic subjects. I think
this is well
22
borne out in the literature. You
look at the
83
1
reference ranges for some of these biomarkers in
2
normal persons and persons with diagnosed
3
osteoarthritis, and by normal people I mean persons
4
that have no or very little signs of joint
5
degeneration or damage visually by diagnostic
6
imaging techniques, and there is considerable
7
overlap.
8
In other words, I think that
speaks to the
9
fact that chondrocytes are doing the same thing in
10
each condition. All they know
how to do is make
11
more matrix. They don't care if
they're healthy;
12
they don't care if they're hurting.
So I'm arguing
13
that the same type and extent of imbalance between
14
matrix component synthesis and degradation is seen
15
in both healthy and osteoarthritic subjects. If
16
you're going to start segmenting arbitrarily,
17
you're going to knock out a significant proportion
18
of the population.
19 I'm a Ph.D., not a rheumatologist, but
20
maybe you can help clarify this for the audience
21
later on today, but osteoarthritis diagnosis is
22
based on the clinical signs, subjective clinical
84
1
signs of the individual, pain and stiffness in
2
joints, as well as X-ray evidence of structural
3
changes in joints.
4
The staging is relatively
arbitrary and
5
subjective. In other words,
there's no lab test
6
you can send off to a laboratory for it and it
7
comes back and says, yes, you have osteoarthritis.
8
This has to be determined by physicians and by the
9
signs and symptoms given to them subjectively by
10
the patient as well as diagnostic imaging.
11 Human studies with osteoarthritic subjects
12
have examined a portion of that continuum of joint
13
health. They represent one
window on that
14
continuum.
15 Pre-diagnostic joint damage, therefore,
16
must exist in greater incidence than diagnosed
17
osteoarthritis. And since
diagnosis is roughly
18
about 20 percent of the population over age 50
19
right now, it's an enormous number.
There are
20
obviously many more people than that that perhaps
21
would be diagnosed with osteoarthritis that are
22
considered healthy right now--again, blurring the
85
1
distinction between disease and health.
2 Just looking at the situation of normal
3
aging shows that a loss of chondroitin in cartilage
4
and/or hyaluronan in synovial fluid occurs all the
5
time. It happens as we age. Normal aging
6
specifically shows decreased length or size of
7
chondroitin and, thus, the aggrecan proteoglycans
8
that are synthesized routinely for maintenance and
9
upkeep. Obviously, if you live
to be 80 years old,
10
you've gone through 20 to 40 or so cycles of new
11
cartilage or of turning over cartilage.
And as
12
those cycles keep going, the macromolecular
13
components start to get a little bit smaller.
14
Thus, with less chondroitin around, cartilage holds
15 a
little bit less water and actually reduces in
16
size. I think a lot of us
realize that we lose
17
height as we age, and a lot of that is from the
18
actual diminishing size of intervertebral disks,
19
whether or not--it is completely unrelated to loss
20
of bone in the spinal column, but one or two inches
21
can be lost simply from normal aging, losing the
22
size of cartilage because of the loss of size of
86
1
chondroitin. And that's
considered normal.
2 So osteoarthritis obviously results from
3
an imbalance of normal anabolic and catabolic
4
activities in cartilage, and this is alluded to in
5
textbooks over and over.
Therefore, osteoarthritis
6
is a deficiency of normal regulation of cartilage
7
maintenance. And I think the
data from the human
8
studies and also from the animal and in vitro
9
studies shows that both glucosamine and chondroitin
10
sulfate help to regulate towards normal cartilage
11
maintenance. Maintenance of the
normal balance of
12
anabolic and catabolic actions leads to a return to
13
health and obviously reduces the risk of
14
osteoarthritis. So a relatively
simplistic concept
15
here because cartilage is a relatively simplistic
16
tissue. It only knows how to
make more matrix.
17 Let's take a closer look at some of the
18
clinical studies on glucosamine itself.
19 Again, much work has gone into finding
20
that the availability of glucosamine is a key rate-limiting
21
step for synthesis of connective tissue
22
macromolecules. This is true not
only for
87
1
cartilage but other connective tissues as well.
2
Normally, glucosamine is manufactured from glucose,
3
which, of course, is readily available all over our
4 bodies. But if you supply
the synthetic cells with
5
glucosamine itself, they like it, a lot better than
6
having to make it themselves. In
other words, it
7
bypasses several chemical enzymatic steps, and it
8
kind of--I play Monopoly--does go directly to go--you bypass
9
the jail and go directly to go, and
10
straight into synthesis of GAGs or glycosaminoglycans, the
11
major one being chondroitin sulfate.
12 So, in other words, glucosamine is a
13
preferred substrate for repair, maintenance, and
14
upkeep of cartilage, and also of hyaluronan and
15
synovial fluid.
16 I've put together a list of the types of
17
published evidence in glucosamine.
There's
18
consensus statements and review articles I've
19
lumped as independent expert opinions.
There are
20
14 meta-analyses that I've identified on
21
glucosamine, all of them supportive.
Large, well-designed
22
human clinical trials are at least 80
88
1
total subjects, and several of those have been
2
reported more than one time, but the majority of
3
those do support some benefit for administration of
4
glucosamine for persons with osteoarthritis.
5 There are smaller, well-designed human
6
clinical trials. Again, the
evidence is credible
7
in that there is much more supportive than non-supportive.
8
And instead of saying uncontrolled, I
9 think
I should have said unblinded human clinical
10
trials. Many of these trials did
have control
11
groups but were open. And the
animal intervention
12
studies, giving glucosamine and then inducing
13
arthritis, and in vitro studies, they are all very
14
supportive, providing credible evidence that
15
glucosamine has benefits for joint health. And
16
this is kind of across the board, anything you can
17
find. So 180 original studies,
and I was very
18
light on the animal and in vitro studies since I
19
obviously, being a trained scientist, also feel
20
that they have slightly less merit than the human
21
clinical studies. So I didn't go
crazy with those.
22 I
just listed a few of them. There's a lot
more
89
1
than that out there.
2 These are some of what I call--let's just
3
call them biomarkers that are affected by
4
glucosamine. The biosynthesis of
hyaluronan,
5
glycosaminoglycans, collagen.
It's relatively
6
obvious this is textbook stuff.
Glucosamine is the
7
major precursor. Also, not only
being a building
8
block, but glucosamine does have regulatory effects
9
and has been called a biological response modifier.
10
It does enhance gene expression of the enzymatic
11
machinery that produces chondroitin and other
12
glycosaminoglycans as well as collagen.
13 Also, glucosamine is added to collagen,
14
and I think that's where the glycoprotein confusion
15
might have arisen from glucosamine being called
16
glycoprotein. Obviously,
glucosamine is not a
17
glycoprotein. It's an amino
sugar. But it does
18
get added to quite a few proteins, and especially
19
Type II collagen. Also,
glucosamine is converted
20
into other sugars that are then glycosylating
21
proteins throughout cartilage.
22 Also, glucosamine has been shown to
90
1
inhibit cartilage breakdown.
There have been two
2
large, three-year human clinical studies, and I'm
3
sure that my compatriots from Rotta will address
4
those. They both showed the
prevention of joint
5
space loss in knee osteoarthritis in humans.
6 One interesting point that I think has
7
been overlooked in the second of these studies by
8
Pavelka from 2002 is that when you do these types
9
of studies, you pretty much focus on one knee that
10
has definite signs of osteoarthritis and is causing
11
all the symptoms. Well, what
about the other knee?
12
They actually stated that the contralateral or non-
13
osteoarthritic knees looked better, and actually
14
people reported that they felt better.
And those
15
weren't the knees that were diagnosed with
16
osteoarthritis. So I propose
that that's a
17
definition of normalcy and that glucosamine in a
18
long-term study has been documented to benefit a
19
normal joint.
20 Also, there have been correlations with
21
some of the molecular biomarkers associated with
22
joint damage. Osteocalcium,
which I didn't list on
91
1
this slide, and the chondroitin sulfate 3B3
2
epitope, which is one of those fragments of
3
chondroitin that are produced from damage, have
4
correlated with the radiological images in humans.
5
There is one case report of an intervertebral disk
6
actually regenerating after six months of
7
glucosamine and chondroitin sulfate, verified by
8
MRIs. And one of the earlier
studies from Italy by
9
Drovanti in 1980 actually looked at cartilage
10
biopsies after the study in a couple of people
11
given glucosamine sulfate and found that the
12
surfaces were smooth and almost normal.
But they
13
also looked at a couple biopsies of cartilage from
14
normal subjects to compare it to.
They chose a
15
couple of people from the placebo group that were
16
happening to have surgery, looked at their
17
cartilage biopsies, and they showed the typical
18
surface fibrillation and damage associated with
19
osteoarthritis.
20 So, therefore, there are indications in
21
the literature that giving glucosamine does affect
22
the structure of cartilage. It
brings it more back
92
1
to normal.
2 I think the cases of joint degeneration in
3
healthy animals that are induced to become
4
osteoarthritic being prevented by glucosamine is
5
relevant. It shows that
glucosamine does have the
6
ability, if it is present before any joint damage,
7
to actually slow down, delay, and prevent the
8
progression or incident of osteoarthritis once
9
osteoarthritis is definitely administered. And
10
obviously from in vitro studies, glucosamine can be
11
added, and, again, that data supports glucosamine
12
improving cartilage by inhibiting breakdown.
13 One interesting study by Braham in 2003,
14
published in the British Journal of Sports
15
Medicine, looked at people with knee pain. They
16
said they specifically did not include people with
17
osteoarthritis diagnosis. They
just had knee pain
18
and decreased function. After
2000 mg per day for
19
12 weeks, these subjects noted less pain and
20
improved function. Most of these
people were
21
younger and had sports injuries.
In fact, I think
22
that this mirrors the continuum of joint health to
93
1
disease, that some of these people may probably
2
have become osteoarthritic in the future. Injuries
3
to joints are obviously a etiological cause of
4
osteoarthritis. So, again, more
evidence that
5
glucosamine can help prevent the progression of
6
joint damage and deterioration.
7 Okay. I need
to move along. I will just
8
kind of quickly go through some of the other
9
mechanisms of glucosamine. There
are anti-inflammatory
10
effects that actually are not so
11
immediate. They work via
regulation, not direct
12
inhibition of inflammatory events.
So, in other
13
words, glucosamine is not an aspirin, it's not an
14
NSAID. It doesn't work like
that. It works by
15
regulating the cells to stop doing all those
16
things, is the simplest way I can put it. And in
17
human studies, giving glucosamine with NSAIDs has
18
shown a synergy in the effects of the NSAIDs.
19
Downregulation of inducible nitric oxide in joints,
20
in cartilage; some antioxidant protective effects,
21
perhaps by being converted into hyaluronan; and
22
other immune modulation effects have been
94
1
demonstrated as well. Yes, these
are animal and in
2
vitro studies, but they speak to the mechanism of
3
how glucosamine can accomplish the findings seen in
4
the human studies.
5 Now on to chondroitin sulfate. Again, a
6
list of the various types of published evidence
7
shows, again, an overwhelming amount of credible
8
evidence in favor of chondroitin supporting joint
9
health. Eight meta-analyses, all
in one form or
10
another expressed that there were benefits derived
11 from
chondroitin sulfate administration to people
12
with osteoarthritis or joint damage.
13 Again, the large, well-designed human
14
clinical trials, of which there are a pretty good
15
number here, were unanimous.
Again, similar for
16
glucosamine, chondroitin shows a high preponderance
17
of beneficial evidence.
18 And as I mentioned for glucosamine, I was
19
very partial in listing animal and in vitro
20
studies. This is but a sampling
of the many
21
studies that are available.
Chondroitin has been
22
around for a long time, has been widely studied for
95
1
other health conditions as well.
But I'm limiting
2
these to joint health.
3 Let me back up one second. On the
4
consensus statements, one of those is from the
5
Arthritis Foundation in which they said that for
6
both glucosamine and chondroitin, it does reduce
7
the signs and symptoms of osteoarthritis. So for
8
someone as conservative as the Arthritis Foundation
9
to make that statement in their public writings and
10
also to allow sponsorship of dietary supplements
11
containing glucosamine and chondroitin by allowing
12
placement of their logo on approved products I
13
think speaks very highly that there is a consensus
14
of medical experts somewhere that glucosamine and
15
chondroitin do affect osteoarthritis and in a very
16
positive manner.
17 One of the other consensus statement is
18
from EULAR, the European Union League Against
19
Rheumatism, where they list glucosamine and also
20
chondroitin sulfate as part of the primary
21
treatment of osteoarthritis, as part of a multi-modality
22
approach. So, in other words, it
is
96
1
considered standard therapy in certain countries.
2 Again, chondroitin can be--in other words,
3
how does it work? Obviously it
is a building
4
block, and, again, it's also a regulatory building
5
block. More chondroitin means
more stimulation.
6
And it actually works on gene expression of the
7
enzymes involved in chondroitin sulfate and, thus,
8
cartilage production.
9 A lot of work has focused on the
10
inhibition of cartilage breakdown.
One study in
11
particular from 1986 in France looked at sports
12
overuse injuries. It used
kneecap cartilage
13
biopsies, and after 16 weeks of 1500 mg per day of
14
chondroitin sulfate, they noticed thicker, smoother
15
cartilage appearance from these kneecap cartilage
16
biopsies. So these were in
people with sports
17
overuse injuries.
18 This type of finding was also mirrored by
19
glucosamine sulfate in an open-label study from
20
Germany in the early 1980s in people around 20
21
years old or so that their chondropathia also
22
improved after a few months of glucosamine.
97
1 There were at least four studies showing
2
the prevention of new lesions in finger
3
osteoarthritis. Okay. There it is. Two of these
4
studies were two years in length; one of the
5
studies was three years in length.
And erosive
6
finger osteoarthritis has a large genetic
7
component. Causes are presumed
to be genetically
8
mediated, which means that it may be impossible to
9
stop it. But if the
progression--in other words,
10
the progression to erosion can be prevented, then I
11
would say that's reducing the risk of
12
osteoarthritis. And that's been
shown in these
13
two- and three-year studies by Rovetta and
14
VerBruggen.
15 Likewise, there have been at least eight
16
studies of preventing joint space loss in knee
17
osteoarthritis from chondroitin sulfate. These
18
studies range from one to two years in length, and,
19
again, with eight studies showing the same thing,
20
the magnitude of joint space protection was about
21
0.3 millimeters after a one- to two-year period.
22
In other words, the magnitude of preservation of
98
1
joint space was virtually identical to that seen by
2
the glucosamine studies. So we
are seeing that
3
glucosamine and chondroitin both prevent the loss
4
of joint cartilage during mild to moderate
5
osteoarthritis. And I think
another interesting
6
point is that most of the investigators stated that
7
the people with earlier stages and, thus, more
8
towards normal stages appeared to have better
9 results.
Again, this speaks directly to reducing
10
the risk of osteoarthritis and in my mind makes
11
this more relevant to "normal" or healthy
12
population that may have joint damage already
13
ongoing and just being diagnosed.
14 Again, the biomarkers of cartilage
loss
15
were shown to correlate some of the time--not all
16
of the time, but some of the time to the diagnostic
17
imaging pictures. In other
words, less signs of
18
joint damage and degeneration, such as cartilage
19
oligomeric protein, keratan sulfate, urine
20
pyridinoline/creatinine ratios, and the
21
deoxypyridinoline/creatine ratios.
Those are
22
markers of collagen damage and destruction. These
99
1
were reduced as the joint space loss was halted.
2
So although I'm not going to sit here and say that
3
glucosamine and chondroitin will rebuild cartilage,
4 I
think stopping the progression seen over a
5
several-year period is pretty close to the same
6
thing.
7 Likewise, with chondroitin, prevention of
8
osteoarthritis in animal models being induced to
9
have arthritis showed that it could prevent the
10
signs of damage, degeneration, and deterioration.
11 There are some other interesting human
12
studies on chondroitin sulfate.
After
13
administering 800 mg for five or ten days, the
14
levels and the size of hyaluronan and synovial
15
fluid were increased in subjects with knee
16
osteoarthritis. Also, the
elastase inhibitor
17
complex levels were reduced, which means that
18
chondroitin had a direct inhibition of degradative
19
enzymes, as was the collagenase activity and N-acetyl-
20
glucosaminidase activity levels.
And
21
there's at least three human studies looking at
22
joint fluid to show direct inhibition of enzyme
100
1
activity with typical oral dosages, and that's over
2 a
short term.
3 Now, if you can extrapolate the effects of
4
doing that over and over and over and over and over
5
again for years, I think that can easily explain
6 the cessation of loss of cartilage. If you're
7
stopping the inhibition and improving the
8
synthesis, what else can happen?
9 How much more time do I have? I want to
10
make sure not to run over. Okay,
thank you.
11 I also wanted to mention other
biomarkers
12
affected by chondroitin, one of which is mechanostructural
13
or tensegrity for tension integrity.
14
Chondroitin being a highly charged molecule and
15
accounting for a lot of the structural integrity of
16
cartilage itself, when it is lost, that structural
17
integrity is lost, more mechanical forces are
18
transmitted to chondrocytes.
They do have mechano-receptors
19
as part of what their cytoskeleton is
20
there for. So when cartilage is
lost, chondrocytes
21
have another way to determine that.
They don't
22
need the fragments. They can
just see the overall
101
1
structure or mechanical load, and that also
2
influences the synthesis of chondroitin. More
3
load, more synthesis.
4 Other immune modulation effects for
5
chondroitin in human, animal, and in vitro studies,
6
downregulation of inducible nitric oxide antitoxin
7
effects, and, again, some nonsteroidal type of
8
anti-inflammatory effects, but not like
9
nonsteroidal anti-inflammatory drugs.
10 Chondroitin and glucosamine are working on
11
the cells to stop making these signals that
12
maintain and exacerbate the catabolic cascade
13
rather than actually knocking out a cytooxygenase
14
enzyme, for example.
15 So I'd like to summarize as quickly as I
16
can. I did want to mention that
the oral
17
bioavailability of each of these two ingredients
18
has been well worked out. The
chondroitin
19
especially has been an issue because it's a
20
macromolecule and, thus, how can it get in. Well,
21
it does get in. A lot of
fragments are absorbed
22
into the bloodstream. A lot of
them are partially
102
1
desulfated, and this is expected to account for
2
some of its actions. Again,
these are similar to
3
what is seen by the chondrocytes.
Since
4
chondrocytes get plasma effusions, they see these
5
fragments. And both glucosamine
and chondroitin,
6
after oral administration, have been shown to be
7
incorporated into large macromolecular structures
8
of cartilage in healthy animals, healthy humans, as
9
well as osteoarthritic animals and osteoarthritic
10
humans. That I think is
important to show that the
11
same processes occur in normal people and
12
osteoarthritic people. Giving
them glucosamine and
13
chondroitin does get to the joints, and it does
14
what chondrocytes and cartilage do, which is make
15
matrix in both conditions. So
that's why I think
16
this continuum is just that, a continuum. And that
17
is why I feel that normal people would be benefited
18
from this.
19 The economic impact, as we have all seen
20
the billions of dollars of cost and burden. In
21
France, they've looked at 11,000 subjects using
22
chondroitin, and because of their decreased NSAID
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1
use and, thus, also feeling better and less other
2
therapies, they actually came out, if not equal,
3
ahead in the price game. So, in
other words, for
4
socialized medicine such as they have in France,
5
this is a boon. They get to
safely treat people,
6
prevent long-term problems with the drugs and with
7
the illness itself. That argues
very strongly to
8
me that you are reducing the risk, if not of the
9
disease, then of the economic burden.
10 Now, there's also a similar study in
11
Russia, but I haven't translated it yet, so I can't
12
give any details. But their
abstract reported that
13
they did have more efficient economy of treatment
14
of osteoarthritis.
15 So to kind of wrap this up, both
16
glucosamine and chondroitin have been shown to
17
prevent the loss of cartilage over time. Remember
18
the turnover time of cartilage, one to three years.
19
Look at the length of studies that have shown this,
20
one to three years. Earlier
stages of
21
osteoarthritis showed larger effects at reducing
22
the cartilage loss, indicating prevention of
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1
progression over versus simply treating symptoms.
2
And the effects were long-lasting after cessation.
3
In other words, stop taking glucosamine or
4
chondroitin, and the symptoms are--the reduction of
5
symptoms and the improvement in the structure are
6
maintained for months. This is
not just a quick-time, rapid
7
action type of nutrient. These
are
8
actually affecting the structural integrity.
9 There are the biomarkers that are
10
affected. These biomarkers have
been correlated
11
with the signs and symptoms of joint degeneration
12
and deterioration.
13
I'm going to skip over the
animal and in
14
vitro models. They do support
the human clinical
15
findings, but I would like to again reiterate that
16
data from various types of publications for
17
glucosamine and for chondroitin are very
18
reproducible and very consistent for benefits that
19
do support preventing joint degeneration. I feel
20
the result is inescapable.
There's not any other
21
conclusion.
22 The time course of the findings in humans,
105
1
both symptomatic and structural, do fit the
2
mechanisms of ingredients that work on the
3
regulation of anabolic and catabolic properties.
4 We've seen how glucosamine can prevent
5
progression of joint deterioration in human studies
6
as well as chondroitin, and that's echoed by animal
7
studies as well, which can be actually more
8
controlled to answer the question than human
9
studies can.
10 So glucosamine and chondroitin have the
11
ability to prevent joint deterioration and joint
12
degeneration by all the lines of evidence that are
13
out there and, thus, reduce the risk of
14
osteoarthritis, which has been defined as the
15
progression of joint deterioration and degeneration
16
to eburnation.
17 Thank you very much.
18 DR. MILLER:
Thank you, Dr. Bucci.
19 Comments or questions? Dr. Archer?
20 DR. ARCHER: I'm trying to get clear.
21
You've thrown a lot of information at us. But are
22
you saying is joint degeneration a surrogate for
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1
osteoarthritis or does it define osteoarthritis?
2 Dr. BUCCI: How
about both? I mean, I
3
hate to make it a bivalent answer, but how can you
4
have osteoarthritis without joint degeneration or
5
joint deterioration? The
endpoint is eburnation
6
and loss of cartilage, and joint degeneration and
7
deterioration I think is loss of cartilage at one
8
point or another. So I guess
that's why I'm saying
9
yes to both. Also, that's one of
the
10
characteristics of the radiological staging.
11 DR. MILLER:
Dr. Krinsky?
12 DR. KRINSKY:
Norman Krinsky. I would
13
assume that in the normal joint, if one exists, the
14
anabolic and catabolic processes are in
15
equilibrium. And under those
circumstances, if you
16
treat that with glucosamine or glucosamine and
17
chondroitin sulfate and you increase the anabolic
18
processes and decrease the catabolic processes,
19
does that, therefore, lead to an increase in
20
cartilage? And what are the
implications of that
21
in a normal joint?
22 DR. BUCCI:
Right, that's an excellent
107
1
question because I am--one of my answers is, Have
2 you seen people with
cartilage just pouring out of
3 a
joint? No. Even in acromegaly, which is really
4 a
regulatory problem with growth hormone, you do
5
see extra cartilage, but not otherwise.
And, in
6
fact, if you give glucosamine and chondroitin into
7
normal cultures, unless there's a need for
8
synthesis, you don't make extra cartilage. You
9
might synthesize a few more precursors, but they're
10
not let outside the cell to make matrix. That's
11 why
I was trying to stress these are regulatory
12
molecules. If you don't need
them, they won't
13
overdo it, so to speak. If you
need them, they fit
14
right in and help restore matrix.
15 DR. MILLER:
Dr. McBride?
16
Dr. McBRIDE: You've mentioned that
17
there's evidence that chondroitin sulfate and
18
glucosamine are absorbed into joints.
Is there
19
evidence that they're absorbed into healthy joints,
20
not inflamed joints?
21 DR. BUCCI:
Yes. In fact, most of the
22
evidence is in healthy animals and healthy humans
108
1
as well.
2 DR. McBRIDE:
These are marker studies or--
3
DR. BUCCI: Yes, these are radiolabeled
4
glucosamine, radiolabeled chondroitin.
Labels on
5
the sulfate for chondroitin and also the hydrogens
6
on the sugar ring for both glucosamine and
7
chondroitin; also tech-(?) 99
labeling of
8
chondroitin as well.
9 DR. McBRIDE:
Are there any comparison
10
studies of absorption into inflamed joints or those
11
that might truly have osteoarthritis and those that
12
would be precursors, probably less inflamed?
13 DR. BUCCI: I
know that there have been
14
studies in osteoarthritic animals and even, I
15
think, one or two in people that have looked at
16
uptake into joints. I'm afraid I
can't recall if
17
there's any direct comparison.
18 DR. McBRIDE:
But those would be
19
osteoarthritic joints.
20 DR. BUCCI:
Yes, so we do know that they
21
can get into osteoarthritic joints and become
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1
incorporated into macromolecules, also the same for
2
healthy tissues.
3 Now, the rates of incorporation, I don't
4
know if that has been quantified.
If it I has, I
5
just have not picked that up in the literature.
6
There is obviously a lot here to remember. But I
7
know that that has been looked at in animal
8
studies, and the normal maintenance that is
9
constantly ongoing is enough to label cartilage
10
with glucosamine and chondroitin in a normal
11
setting, if that helps answer your question..
12 DR. MILLER:
Dr. Russell?
13 DR. RUSSELL:
Yes, I was interested in the
14
two studies that may have something to do with
15
primary prevention of osteoarthritis.
One was the
16
finger osteoarthritis. You said
that treatment
17
prevented new finger osteoarthritis.
Does that
18
mean joints that were previously uninvolved that
19
remain uninvolved? And
presumably in the untreated
20 group that there were some new finger lesions? And
21
were those statistically significant differences
22
or--I don't know the detail of the study.
110
1 DR. BUCCI:
Okay. To clarify that, some
2
of the studies did show a prevention of new
3
lesions; in other words, no arthritic lesions in a
4
finger joint, there was less appearance of new
5
lesions in the chondroitin-treated group versus the
6
placebo group. Some studies did
not find it and
7
others did. But pretty much all
the studies did
8
find that the prevention to the severe erosive
9
stage from moderate-mild damage was prevented. I
10
think that was near universal in each of those
11
studies. And the effects were
obviously larger and
12
significant as time went on.
Some studies did not
13
see it at one year, but at two or three years they
14
did see it.
15 DR. RUSSELL:
And I wonder if you could
16
clarify just a little bit on the knee study that
17
you mentioned, that the non-osteoarthritic knees in
18
this 2002 study were improved.
Again, was this--not
19
improved, but were not involved.
Was this
20
statistically significant from the non-treated
21
group?
22 DR. BUCCI: I
don't think that they looked
111
1
at this in a statistical manner because it wasn't
2
one of the enterprises of measurement.
I think it
3
was an observation in the discussions.
I think
4
that my colleagues can speak to that, too.
5 DR. MILLER:
Dr. Abramson?
6 DR. ABRAMSON:
That was a very clear
7
presentation, and I always need to have those fern-like
8
molecules pointed out to me again.
But I want
9
to just discuss whether one can sometimes overly
10
simplify very complicated tissue and talk about the
11
chondrocyte as making and creating proteoglycans
12
and collagen, because I think apropos the fact that
13
this may be a different disease once established
14
versus early on, these kinds of metabolic changes
15
may be difficult to extrapolate over.
16 So, for example, if early OA, we know, is
17 a
proliferative hypertrophic disease where
18
proteoglycan actually is increased in its
19
production and not decreased, then it's not clear
20
that in early disease, at least just playing the
21 hypothetical here, that a decrease in
proteoglycan
22
synthesis should necessarily be corrected by the
112
1
addition of exogenous substrates like glucosamine.
2
And then the changes occur, you know, through
3
hypertrophy and the catabolic changes, and then you
4
get this very complicated disease which is not just
5
in and out of proteoglycan and collagen, but
6
there's bone and there's synovial cells and there's
7
interleukin-1. And at that
point, the in vitro
8
evidence I think is very intriguing that
9
glucosamine and chondroitin, as you showed, can
10
reverse some of these catabolic events.
And that
11
case is consistent with whatever kind of clinical
12
evidence we may have that this is a beneficial
13
treatment.
14 But I think going back on the table today
15
of health claims, it's not clear that those
16
effects, were they true in vivo, in patients, are
17
necessarily applicable to these early changes. And
18 I
just--so that's a long statement. Do
you want to
19
comment on the actual complexity of this biology?
20 DR. BUCCI:
Yes, I'd love to, and I'll try
21
to keep it brief, obviously.
But, no, that's a
22
consideration I've thought about quite a bit,
113
1
obviously. Of course, there is a
difference
2
between osteoarthritis and just normal non-damaged
3
tissue, and it does get more complex.
But, again,
4
the reason I made my whole presentation simplistic
5
on purpose is because, no matter how complex it
6
became, no matter what biomarkers you were looking
7
at, no matter what pathways you were looking at, no
8
matter what disease state, no matter what the state
9
of cartilage was, whether it's in the increased
10
production of proteoglycans in the early stages or
11
the decreased production in later stages, they all
12
go back to the same point, which is making more
13
matrix. Sooner or later,
everything points to
14
that. It's almost a unified
field area or unified
15
matrix area, if I can coin a term, that regardless
16
of which stage--normal, early, middle late
17
osteoarthritis, damage with no signs and symptoms--sooner or
18
later it's a problem with making the
19
matrix. And glucosamine is
intimately involved not
20
only in making the matrix but in regulating it.
21
And for whatever reason, the catabolic signals
22
overwhelm the limited ability to increase the
114
1
anabolism. I think that the
ability of
2
chondrocytes to generate more matrix, they can only
3
increase proteoglycan production from normal upkeep
4
about 250 percent. I think
that's from human and
5
animal studies in general.
6 So, in other words, cartilage has a very
7
slow, limited response to any of these complex
8
stimuli. But that's the response
to all of these.
9 DR. ABRAMSON:
So I would just--I
10
understand. I would just point
out that there are
11
two mechanisms of glucosamine and chondroitin that
12
you're talking about. One is
it's acting as a
13
substrate to a building block for more
14
proteoglycan. The other is a
pharmacological
15
action, which is somehow through receptors it
16
inhibits the activation of chondrocytes in response
17
to IL-1, and that probably is via a different
18
mechanism, or one could possibly--that's two
19
separate mechanisms: one is the
available
20
substrate, and the other is what it's doing to
21
signaling that we really don't understand, except
22
it does seem to do that, and what happens in
115
1
clearly established disease, and separating the
2
relative importance of that I think is an
3
interesting question that I think needs more
4
understanding.
5 DR. BUCCI: I
agree. But, conceptually, I
6
would say that these are physiological roles and
7
events, and these regulatory roles are trying to
8 get
tissue back to normal. That's obviously
what
9
our bodies try to do in every tissue.
This is the
10
way chondrocytes do it. They use
glucosamine and
11
chondroitin to try to return to normal, keep
12
normalcy. If there is anything abnormal,
then they
13
are there to try to restore normality.
And that
14
really is what I think reducing risk and prevention
15
of a disease is all about. How
can you prevent
16
disease if it's not there? Well,
by these
17
mechanisms you just described.
18 DR. MILLER:
Dr. Felson?
19 DR. FELSON: I
guess, once again, sort of
20 a
lovely, comprehensive discussion of many, many
21
issues. Unfortunately, perhaps
oversimplifying
22
some difficult ones, which probably if there were a
116
1
variety of other osteoarthritis scientists in the
2
room would take a week to discuss and not resolve.
3 One of them is I think you sort of
4
presented the clinical data in a couple of ways
5
that I think the rest of the audience sort of needs
6
to comprehend a little bit, which is that my
7
reading of the clinical data are not that
8
convincing. And the reason for
that is that there
9
have been--all of the studies that you commented
10
on, many of them--all of them, I think, the
11
positive ones, are industry-supported.
There have
12
been three publicly supported trials of
13
glucosamine, and all have been null, one of which
14
is a very nice Canadian multi-center withdrawal
15
trial. And that's one of the
reasons why the NIH
16
is now spending millions of our tax dollars on a
17
trial to try to definitely determine whether
18
glucosamine and chondroitin are efficacious. I
19
think the jury is still out as far as treatment
20
goes. I'm not sure how to
interpret all the data
21
that you described, and I don't disagree with you
22
that the preponderance of it is supportive.
117
1 The other issue that you were--you used a
2 p