FOOD ADVISORY COMMITTEE AND DIETARY
THE ROLE OF GLUCOSOSAMINE AND CHONDROITIN
SULFATE IN OSTEOARTHRITIS
Monday, June 7, 2004
5151 Pooks Hill Road
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.
Jeanne Latham, Executive Secretary, Dietary
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,
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
Questions and Comments 250
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
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
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
the extent that the committee needs and feels that
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--
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,
president of the Council for Responsible Nutrition.
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
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
rheumatologist at Rush Presbyterian and St. Luke's
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
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
18 DR. LUND: Daryl Lund, University of
19 Wisconsin-Madison, Food Science, and Executive
20 Directors of the North Central Regional
22 DR. DWYER:
Johanna Dwyer, professor at
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
memory about a few rules of the road, if you will,
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
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
discussions are thought-provoking.
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.
All other votes and comments must be placed on the
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
consultations between members prior to a meeting.
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
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.
I'm confident that everyone
here today is
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
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
rather long one, so please bear with me.
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
7-8, 2004, for the first portion of this meeting.
1 They will represent the Arthritis Drugs Advisory
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
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.
Johanna Dwyer, Dr. Luis Espinoza, Dr. David Felson,
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
speakers to complete a financial interest and
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
submissions have been provided to our members, and
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
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
days all day because I did want to hear some of the
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
and that you will have the opportunity to give all
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
this very carefully.
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
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
questions that we're asking you to consider.
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
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
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
of osteoarthritis in healthy people?
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
show that a substance treats osteoarthritis or may,
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
conclusions from our analysis thus far.
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
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
claim language involving glucosamine and
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
reaching a solid and well-justified and well-documented
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,
throughout the meeting and if questions come up--
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
symptoms, it's that population, can you show that
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
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
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
background only. You should
not--we're not asking
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
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
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
any substance to a disease or health-related
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
sodium may reduce the risk of high blood pressure,
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,
mitigating, or curing diseases.
That is the
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
to clarify just why a nutrient deficiency, which we
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.
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
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
1 question, so I'm not going to try to address that.
2 Craig, is that something that you can address
4 DR. ROWLANDS: [Inaudible, off
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
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
involved in regulatory activities.
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
to be here on such short notice, and we do
1 appreciate it. And what you have to say to us is
2 very important, so we're looking forward to these
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
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
osteoarthritis, may reduce the risk of joint
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
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
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
or just the bone or just the musculature. It is a
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
19 The scientific evidence summarized in the
20 petitions include in vitro mechanistic studies,
21 animal studies, and human clinical studies in OA
patients. Petitioner A provided
a summary of all
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
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
chymopapain in rabbits, Freund's adjuvant in mice,
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,
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
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
intervention studies were conducted in OA patients.
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
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
endpoints, and the red box represents disease or
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
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
relevant for demonstrating a reduced risk for
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
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
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
in an artificial environment, and when you combine
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
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
is essentially asking: Are joint
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
in humans? And then we have two
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
it's about risk reduction in osteoarthritis, we
1 also feel that the recommendations of this FAC can
2 apply to other substance-osteoarthritis
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
glycoprotein, and I'm wondering what the rationale
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
cholesterol? It's just that it
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
evidence that essentially tested whether or not it
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
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
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
atrophic gastritis--there's any number that we
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
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.
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
21 DR. MILLER: Dr. Krinsky?
22 DR. KRINSKY:
Norman Krinsky. It seems to
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
health claim, and, for instance, there may be
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.
We're not interested in whether or not there is a
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
population because it's not something they're
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
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
incident disease, and yet data suggests that it
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
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
far. I hate to think that my
role is to watch the
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
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.
Also, the proposed health claims have
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,
if for no other reason than to not have people die
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
have been proposed by Weider Nutrition.
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
in the menisci; no nerves; no lymphatics.
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
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
and simple manner.
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.
So what I'm trying to do
here is give you,
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
three years. And as I've already
1 wear and tear in healthy people--everybody, for
2 that matter--produces these degraded fragments
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
bricks falling around outside your house, you know
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
with glucosamine and convert that into chondroitin
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
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
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
involve use of glucosamine and chondroitin to make
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
of osteoarthritis. I think Dr.
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
borne out in the literature. You
look at the
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
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
based on the clinical signs, subjective clinical
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
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
considered healthy right now--again, blurring the
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
size of cartilage because of the loss of size of
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
macromolecules. This is true not
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
human clinical trials are at least 80
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.
just listed a few of them. There's a lot
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
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
joint damage. Osteocalcium,
which I didn't list on
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
20 So, therefore, there are indications in
21 the literature that giving glucosamine does affect
the structure of cartilage. It
brings it more back
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
that this mirrors the continuum of joint health to
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
other immune modulation effects have been
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
around for a long time, has been widely studied for
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
approach. So, in other words, it
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
improved after a few months of glucosamine.
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
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.
In other words, the magnitude of preservation of
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
markers of collagen damage and destruction. These
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
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
joint fluid to show direct inhibition of enzyme
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
need the fragments. They can
just see the overall
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
into the bloodstream. A lot of
them are partially
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
chondroitin, and because of their decreased NSAID
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
the cartilage loss, indicating prevention of
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
22 The time course of the findings in humans,
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
you saying is joint degeneration a surrogate for
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
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
evidence is in healthy animals and healthy humans
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
can get into osteoarthritic joints and become
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
or--I don't know the detail of the study.
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
22 DR. BUCCI: I
don't think that they looked
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
synthesis should necessarily be corrected by the
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
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
consideration I've thought about quite a bit,
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
overwhelm the limited ability to increase the
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
it does seem to do that, and what happens in
1 clearly established disease, and separating the
2 relative importance of that I think is an
3 interesting question that I think needs more
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
some difficult ones, which probably if there were a
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
that the preponderance of it is supportive.
1 The other issue that you were--you used a