<PAGE>

Note:  Confidential treatment requested.  Exhibit omits information that has
       been filed separately with the Securities and Exchange Commission.  


                               RESEARCH AGREEMENT

         THIS RESEARCH AGREEMENT is effective this 1st day of July, 1996, by and
between  OSTEX  INTERNATIONAL,   INC.,  a  Washington  corporation,  having  its
principal  place of business  at 2203  Airport  Way South,  Suite 400,  Seattle,
Washington  98134  ("Ostex"),  and the  UNIVERSITY  OF  WASHINGTON,  having  its
principal office at Seattle, Washington 98195 ("University").

                                    RECITALS

         A. Ostex has an ongoing  interest  in  research  technology  (including
inventions,  processes,  formulae and the like,  whether or not patentable,  and
property  eligible for  copyright  protection)  for  measuring the rate of human
tissue  resorption based on the quantitation of specific marker peptides derived
from  cross-linking  sequences  in  collagen,  entitled  "Molecular  Markers  of
Connective Tissue  Degradation," as more particularly  described in that certain
proposal attached as EXHIBIT A (the "Technology");

         B. The Technology has been assigned by the University to the Washington
Research  Foundation  ("WRF") pursuant to Section 3.3 of that certain Technology
Administration Agreement, dated January 1, 1985, between the University and WRF,
as amended (the "UW  Agreement").  Pursuant to that certain  Restated  Exclusive
License  Agreement  between Ostex and WRF,  effective  June 29, 1992, as amended
(the "Exclusive License Agreement"),  WRF granted Ostex an exclusive,  worldwide
license to make, have made, assign, sublicense, lease, develop, enhance, modify,
produce, reproduce, demonstrate, market, promote, sell, distribute, use, exploit
and otherwise commercialize and prepare derivations of the Technology;

         C.       Ostex  entered  into a  Research  Agreement  dated July 26, 
     1989 and amended  November 1, 1992  pursuant to which  initial  funding was
provided by Ostex for research with respect to the Technology;

         D.       It is in the mutual  interest of Ostex and University 
     that research be continued  with respect to the  Technology,  in accordance
with a research  program to be conducted and funded  pursuant to this  Agreement
(the "Research Program"); and

         E. Ostex is willing to fund the conduct of the Research Program, at and
through the University of Washington,  Department of Biological  Structure,  and
the University desires to obtain such funding,  all subject to and in accordance
with the terms of conditions set forth in this Agreement.

                                   AGREEMENTS

         In consideration of the covenants and promises contained herein and for
good and valuable consideration, the receipt and sufficiency of which are hereby
acknowledged, the parties hereto agree as follows:

         1.       SCOPE/SCHEDULE

         The Research Program shall be conducted in accordance with the Research
Proposal  attached  hereto as  EXHIBIT  A and made a part  hereof,  or  mutually
agreeable written  modifications  thereof. The Research Program shall be carried
out during the Program Period (as defined  below),  unless sooner  terminated or
extended as herein provided.

         2.       PROGRAM PERIOD

         The Program Period shall be from XXXXXXXXXXXXXXXXX,  and it may be 
extended
by mutual written consent of the parties not less than thirty (30) days prior to
the termination of the then current Program Period.

         3.       OSTEX'S PRINCIPAL OBLIGATIONS

         Ostex shall pay University a total of XXXXXXXXXXXXXXX to cover all 
direct and indirect costs of the Research  Program asset forth in the Budget  
included in the Research  Proposal  attached  hereto as
EXHIBIT A and incorporated herein.

         4.       PAYMENT

         Ostex  will  provide  University  funds for the  costs of the  research
performed  under this  Agreement  as  specified  in the Budget.  Ostex shall pay
University as follows upon receipt of invoices from University:

            PAYMENT                   DATE                 AMOUNT

              1                                  XXXX                  XXXX
              2                                  XXXX                  XXXX
              3                                  XXXX                  XXXX
              4                                  XXXX                  XXXX
              5                                  XXXX                  XXXX
              6                                  XXXX                  XXXX
              7                                  XXXX                  XXXX
              8                                  XXXX                  XXXX
              9                                  XXXX                  XXXX
              10                                 XXXX                  XXXX
              11                                 XXXX                  XXXX
              12                                 XXXX                  XXXX

                                                 Total                 XXXX


<PAGE>


University will submit its customary  statement of expenses  incurred under this
Agreement within thirty (30) days after the end of each six-month period.

         5.       PRINCIPAL INVESTIGATOR

         For the purpose of this  Agreement and pursuant to  University  policy,
David  R.   Eyre  is   designated   the   Principal   Investigator   ("Principal
Investigator")  who  shall be  responsible  for  direction  and  content  of the
Research Program,  including  budgeting and revisions to the Budget necessary to
accomplish the Research  Program.  Should the Principal  Investigator  leave the
University or otherwise become unavailable during the Program Period, University
may  nominate a  replacement.  If Ostex does not  accept  the  replacement,  the
Research  Program and Budget may be modified to reflect a reduced  scope of work
or  terminated  on sixty  (60)  days'  notice at the  option of Ostex  unless an
arrangement  acceptable  to Ostex can be made to  subcontract  with the departed
Principal  Investigator  or his new  institution  to  continue  the  work on the
Research Program.

         6.       CONFIDENTIALITY

         Neither  party  shall  furnish  any  confidential   and/or  proprietary
information  of a third  party  to the  other  party  in  connection  with  this
Agreement.  Any such  information  which  either  party wishes to furnish to the
other party shall be the subject of a separate confidentiality agreement between
the parties.

         7.       DATA REPORTS AND FACILITIES

                  7.1  University   shall,   in  accordance   with   established
University practice,  keep complete,  accurate,  and authentic accounts,  notes,
data, and records of the work  performed  under this Agreement and shall provide
Ostex with semi-annual reports within thirty (30) days following the end of each
six-month period commencing on the date of this Agreement. University shall also
submit to Ostex a written  comprehensive final report within ninety (90) days of
termination of the Research Program.

                  7.2  At  the  discretion  and  convenience  of  the  Principal
Investigator, during the course of the Research Program, Ostex's representatives
and others  designated by Ostex may be present as observers while various tests,
inspections  and other  aspects of the  Research  Program  are being  conducted.
Ostex's  representatives may consult informally with the Principal  Investigator
regarding the Research Program both personally and by telephone. Further, Ostex,
at its expense,  shall have the right to send one Ostex  employee to work and be
trained  at  the  Department  of  Orthopedics  at  the  University.   University
acknowledges and agrees that the Principal Investigator may serve as a member of
the board of  directors  and/or as a  consultant  (but not an  officer) of Ostex
during the term of this Agreement.

                  7.3 From its own  resources  and  those  provided  under  this
Agreement,  University  agrees  to  make  available  laboratory  facilities  and
equipment for the Research Program.

         8.       INVENTION RIGHTS

                  8.1 University acknowledges and agrees that (i) all Technology
made,  developed or conceived on or before the date of this  Agreement  has been
assigned to WRF pursuant to Section 3.3 of the UW Agreement,  and no commitments
have been made with respect to such Technology pursuant to Section 3.2 of the UW
Agreement,  (ii) all Technology  made,  developed or conceived after the date of
this  Agreement  will be  submitted  to WRF  pursuant  to Section  3.1 of the UW
Agreement,  (iii) no  commitment  will be made pursuant to Section 3.1 of the UW
Agreement with respect to Technology made, developed or conceived after the date
of this Agreement  unless Ostex agrees to such  commitment in writing,  and (iv)
University shall not terminate, amend, waive or enforce the UW Agreement (or any
rights or  obligations  thereunder)  in any manner that could  adversely  affect
Ostex's  rights  under this  Agreement  unless  Ostex  agrees in writing to such
termination, amendment, waiver or enforcement.

                  8.2 University  shall have no right,  title or interest in any
Technology  made,  developed or conceived by employees or  consultants  of Ostex
entirely without use of University facilities.

         9.       PUBLICATION

         University  will be free to publish the  results of research  conducted
under this Agreement within a reasonable period of time. University will provide
copies of  manuscripts  to Ostex prior to their  submission  for  publication or
their presentation. In order to full protect the rights of University and Ostex,
any contemplated  publication or other  dissemination  containing  details of an
invention,   whether  or  not  patentable,  will  be  withheld  until  a  patent
application is filed or other appropriate steps to protect commercial value have
been completed.  Such withholding shall be kept to a minimum and will not exceed
six (6) months, except by mutual agreement between Ostex and University.

         10.      INDEMNIFICATION

         University  and Ostex each agree to indemnify  and to hold harmless the
other  party  from  damage to  persons  or  property  resulting  from any act or
omission on the part of itself, its employees, its agents, or its officers.

         11.      NOTICES

         Whenever  any notice is to be given  hereunder,  it shall be in writing
and shall be deemed received,  if delivered by courier on a business day, on the
day  delivered,  or on the fifth  business  day  following  mailing,  if sent by
first-class,  certified or registered mail,  postage  prepaid,  to the following
addresses:

         University:                Director, Grant and Contract Services
                                    3935 University Way N.E., JM-24
                                    Seattle, Washington  98195

         Ostex:                     Ostex International, Inc.
                                    2203 Airport Way South, Suite 301
                                    Seattle, Washington  98134

         12.      TERMINATION

                  12.1 This  Agreement  may be  terminated  by University at any
time or by Ostex at any time on or after XXXXXXXX.  Sixty (60) days' prior  
written  notice  is needed  from one  party to the  other if  either  party
determines,  in  its  discretion,   that  the  Research  Program  is  no  longer
academically,  technically or commercially feasible. Upon receipt or delivery of
such notice of termination,  University shall exert its best efforts to limit or
terminate any outstanding financial commitments for which Ostex is to be liable,
and Ostex shall reimburse University (to the extent not previously paid) for all
costs incurred by it for the Research Program,  including,  without  limitation,
all uncancellable obligations.  University shall furnish, within sixty (60) days
of the effective date of  termination,  a final report of all costs incurred and
all funds  received and shall  reimburse  Ostex for payments which may have been
advanced in excess of total costs incurred with no further obligations to Ostex.

                  12.2 Notwithstanding  paragraph 12.1, in the event that either
party shall be in default of any of its  obligations  under this  Agreement  and
shall fail to remedy such default  within thirty (30) days after written  notice
thereof,  the party not in default  shall have the  option of  terminating  this
Agreement by giving written notice of termination to the defaulting party.

                  12.3 Termination of this Agreement shall not affect the rights
and  obligations  of the parties  accrued prior to termination or the rights and
obligations set forth in Article 8.

         13.      WARRANTS AND COVENANTS BY UNIVERSITY

                  13.1  University  hereby  warrants  that it has the  right and
authority  to enter  into  this  Agreement  and that the  representatives  whose
signatures appear hereunder are duly authorized by University to enter into this
Agreement on behalf of University.

                  13.2  University  covenants  that it will not knowingly  enter
into agreements with any industrial and/or commercial  funding source other than
Ostex inconsistent with its obligations under this Agreement.

         14.      APPLICABLE LAW

         This  Agreement  shall  be  governed  by  the  laws  of  the  State  of
Washington.

         15.      ARBITRATION AND JURISDICTION

                  15.1 At the request of either party, any  controversy,  claim,
or dispute  arising out of or relating to any provision of this Agreement  shall
be  settled  by  arbitration  to  be  conducted  in  Seattle,  Washington.  Such
arbitration  shall be in  accordance  with the  rules  applied  by the  American
Arbitration  Association.  Judgment upon any award rendered through  arbitration
may be entered into any court of competent jurisdiction.

                  15.2     Ostex and University agree to submit to jurisdiction
 in Seattle, Washington.

         16.      PARTIES BOUND

         This  Agreement,  including the  indemnification  provisions,  shall be
binding upon and inure to the benefit of the parties  hereto,  their  respective
successors,  assigns,  legal  representatives  and heirs.  Ostex may assign this
Agreement  to any  successor  to  all or  substantially  all of the  assets  and
business of Ostex.  This  Agreement  shall not otherwise be assignable by either
party without the prior written consent of the other party.

         17.      NO ORAL MODIFICATION

         No  change,  modification,  extension,  termination  or  waiver of this
Agreement, or any of the provisions herein contained, shall be valid unless made
in writing and signed by duly authorized representatives of the parties hereto.

         18.      SURVIVORSHIP

         Sections 8 and 9 of this  Agreement  shall  survive any  expiration  or
termination of this Agreement.

         19.      USE OF NAMES

         Neither  party will use the name of the other party or its employees in
any  advertisement,  press release or publicity  with respect to the  Technology
without the prior written approval of the other party. University shall have the
right to acknowledge  Osteonix's  support of the research  performed  under this
Agreement in scientific publications and other scientific communications.

         IN WITNESS WHEREOF, the undersigned have entered into this Agreement as
of the date first set forth above.

UNIVERSITY:                                          OSTEX:

By   /S/ DONALD W. ALLEN                    By       ROBERT J. GLASER
     -------------------------------                 ----------------
     Donald W. Allen, Director                       Robert J. Glaser, COO
     Grant and Contract Services

Date:    11/21/96                                    Date:    10/23/96

                            University of Washington

                            Seattle, Washington 98105

To:                                 Ostex International, Inc.

Type of Support Requested: Research Grant (continuation)

Title of Project:                   Molecular Markers of Connective Tissue 
                                    Degredation

Principal Investigator:             David R. Eyre

Amount Requested:                   XXXXXX (including indirect costs)

Funding Period;                     XXXXXXXXXX

University office to be             Grant & Contract Services
contacted regarding                 3935 University Way NE, Box 355754
negotiation of award:               Seattle, Wa 98195
                                    Tel: 206-543-4043

Official authorized to

give University approval:                   /S/ DONALD W. ALLEN 
                                            -------------------------
                                            Donald W. Allen, Director

                            Grant & Contract Services

                                RESEARCH PROPOSAL

Title:                        Molecular Markers of Connective Tissue Degradation

Funding Period:               XXXXXXXXXXXXXXXXXX

PI:                                 David R. Eyre
                                    Orthopaedic Research Laboratories
                                    University of Washington

                                    Box 356500
                                    Seattle, WA 98195-6500

Sponsor:                            Ostex International, Inc.
                                    H. Raymond Cairncross
                                    Chairman and CEO
                                    2203 Airport Way South
                                    Seattle, WA 98134

SUMMARY

This is a continuation research proposal for an existing project, 
"Molecular Markers of Connective Tissue Degredation", funded from July 1, 1989 
to the present.XXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.

<PAGE>

                                                                  BUDGET
                              Molecular Markers of Connective Tissue Degradation
                                                 (continuation project, XXXX)

XXXXXXXXXXXX

Personnel                       Position        Effort     Salary  Fringe  Total
--------------          -----------             -------    ------  ------ ------
Lynne Atley, Ph.D.      Post-doctoral fellow    100%       XXX     XXX     XXX
Michael Harkey, Ph.D.   Research Associate      50%        XXX     XXX     XXX
MaryAnn Weis, B.S.      Manager-Research        25%        XXX     XXX     XXX
Ping Shao, B.S.         Res. Technologist       100%       XXX     XXX     XXX
Kristin Vosberg, B.S.   Res. Technologist       100%       XXX     XXX     XXX
Layne Norland, D.V.M.   Graduate Student        100%       XXX     XXX     XXX
                        Secretary               30%        XXX     XXX     XXX
                                                                        ------  
                                                                           XXX

EQUIPMENT
Micro-titer plate washer, XXXX; water baths, XXXX; Microcentrifuge, XXXX;
Pulsed power supply, XXXX; Controlled environment shaker XXXX; Gel
electophoresis system XXXX; Purchase of HPLC system for peptide 
fractionation, XXXX                                                        XXXX

SUPPLIES
XXXXXXXXXXXXXXXX
XXXXXXXXXXX and supplies
XXXXXXXXXXX and supplies
General chemicals and biochemicals
Plasticware, glassware and disposable                                      XXXX

TRAVEL
Investigators to acedemic scientific meetings                              XXXX

DISCRETIONARY BUDGET(64 series, separate account)
To sponsor research seminars, conferences, meals, travel and
entertainment expenses for visiting scientists, seminar speakers
and visitors to the University on Ostex-related business                   XXXX

OTHER
XXXXXXXXXXXX
XXXXXXXXXXXX. Shared
Costs of service contracts on major equipment, equipment
repairs and replacement, photographic services, publication
costs, computer charges, copying, postage, courier services
and telephone charges.                                                     XXXX
                                                                          ------
                                                           Total Direct    XXXX
                  (XX of modified total direct costs)    UW indirect costs XXXX
                                                                        --------
                                                           XXX Total       XXXX
<PAGE>

                                BUDGET FOR ENTIRE PROPOSED PROJECT-PERIOD

                                                     XXXX     XXXX      XXXX
                                                     XXXX     XXXX      XXXX
                                                     XXXX     XXXX      XXXX
                                                     XXXX     XXXX      XXXX
                                                   --------   -----   ---------
Salaries (+fringe benefits)                          XXXX     XXXX      XXXX
Equipment                                            XXXX     XXXX      XXXX
Supplies                                             XXXX     XXXX      XXXX
Travel                                               XXXX     XXXX      XXXX
Discretionary                                        XXXX     XXXX      XXXX
Other                                                XXXX     XXXX      XXXX
                                                   --------  ------   ---------
Total direct costs                                   XXXX     XXXX      XXXX
UW indirect costs                                    XXXX     XXXX      XXXX
 (XX of MTDC)                                     ---------  ------    ---------
           Total                                     XXXX     XXXX      XXXX

<PAGE>

BUDGET JUSTIFICATION

The  principal  investigator,  David  Eyre,  Ph.D.,  will  direct  the work
scientifically.  Lynne  Atley,  who spent 6 months with us in 1994 as a visiting
scholar,  will  complete  her Ph.D.  requirements  in Melbourne  (University  of
Melbourne)  by April 1996 and join us as a  post-doctoral  fellow.  She  trained
under Drs. John Wark and Peter Ebeling with her thesis research on bone turnover
markers,  and is keen to expand her knowledge of collagen  biochemistry and work
on novel  markers of skeletal  metabolism.  Working  100% on this  project,  her
efforts will focus on XXXXXXXXXXXXXXXXXXXXXas well as the application of the new
collagen-based  markers (types II and III) in clinical XXXXXXX.  Michael Harkey,
Ph.D.  is a molecular  biologist  studying the  XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.
MaryAnn Weis, B.S. the laboratory's chief technician and research manager,  runs
the gas-phase  protein  sequencer (a core resource for all the scientific  aims)
and also has taken over project duties on O-CSF from Patricia  Woods,  B.S., who
left the laboratory in December 1995.  Ping Shao,  B.S., has worked full time on
the  project  for  over  four  years.   She  has   considerable   experience  in
XXXXXXXXXXXXX and in the running of immunoassays,  including  responsibility for
all NTx assays that we run in  collaboration  with  outside  investigators.  Her
responsibility  going  forward will be the  XXXXXXXXXXXXXXXX.  Kristin  Vosberg,
B.S., has worked full time on the project for over two years.  Her experience is
in preparing antisera,  running immunoassays  including Western blots and in the
preparation and analysis of XXXXXXXXX.  Her responsibility going forward will be
the  development  and  XXXXXXXXXXXX.  Layne Norland,  D.V.M.,  is studying for a
Masters degree in the Dept. of Comparative  Medicine.  His research project is a
collaboration with our laboratory, to investigate whether XXXXXXXXXXXXXXXXX.

<PAGE>

A. SPECIFIC AIMS

The primary focus of this project will continue to be... 

One Page Redacted
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XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.

B. PROGRESS REPORT

The aims for the last three years in summary were to:

One half page redacted
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.

PROGRESS

Two pages redacted
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.

C.  RESEARCH PLAN

The scientific strategy is to ...

Four and one half pages redacted
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX.

<PAGE>

D.   PUBLICATIONS

The following papers and abstracts of meeting  presentations from the Orthopedic
Research Laboratories have resulted from or are related to this project.

Articles

1.  Niyibizi C, Bonadio J, Byers PH, Eyre DR.  Incorporation  of type I collagen
molecules that contain a mutant a2(l) chain  (Gly580-greater than Asp) into 
bone matrix in a  lethal case of osteogenesis imperfecta. J ' Bioi. 
Chem. 267:23108-23112,1992.
2.  Bogaert R,  Tiller GE,  Weis MA,  Gruber HE,  Rimoin DL,  Cohn DH,  Eyre DR.
Substitution  of glutamate for glycine 853 of the triple  helical domain of type
11 collagen produces hypochondrogenesis.  J. Biol. Chem. 267:22522-22526,  1992.
3.  Harris  ST,  Gertz BJ,  Eyre DR,  Genant HK,  Chesnut CH Ill.  The effect of
short-term  treatment with  alendronate  upon vertebral  density and biochemical
markers of bone remodeling. J. Clin. Endocrinol. Meth. 76:1399-1407, 1993.
4. Ezzat S, Melmed S, Endrew D, Eyre DR,  Singer FR.  Biochemical  assessment of
bone  formation  and  resorption  in  acromegaly.  J. Clin.  Endocrinol.  Metab.
76:1452-  1457,  1993. 
5. Bolien AM, Eyre DR. Direct  extraction of  gelatinases
from rat bone. Connect. Tiss. Res. 29:223-230, 1993.
6.  Gerstenfeld  LC, Riva A, Hodgens K, Eyre DR,  Landis WJ.  Post-translational
control of collagen  fibrillogenesis  in a mineralizing chick osteoblast culture
system. Bone Miner. Res. 8:1031-1043, 1993.
7. Gertz BJ, Shao P, Hanson DA,  Quan H, Harris ST,  Genant HK,  Chesnut CH 111,
Eyre  DR.  Monitoring  bone  resorption  in  early  postmenopausal  women  by an
immunoassay  for  cross-linked  collagen  peptides in urine.  J. Bone Miner Res.
9:135- 142, 1994.
8. Eyre, DR. New Molecular Markers of Bone Metabolism. Ther. Res. 15:1 00-1 1 1,
1994.
9.  Bollen A-M,  Eyre DR. Bone  resorption  rates in children  monitored  by the
urinary assay of collagen type I cross-linked peptides. Bone 15:31-34, 1994.
10. Bell NH,  Hollis BW,  Shary J, Eyre DR,  Eastell R,  Colwell A, Russell GRG.
Diclofenac  sodium is as effective as premarin in inhibiting bone resorption in
postmenopausal women. Am. J. Med. 96:349-353, 1994.
11.  Brenner  RE,  Vetter U,  Bollen  A-M,  Mike M, Eyre DR.  Bone  resorption
assessed by immunoassay of urinary  cross-linked  collagen  peptides in patients
with osteogenesis imperfecta. J. Bone Miner. Res. 9:933-937, 1994.
12.  Blumsohn A, Herrington K, Hannon RA, Shao P, Eyre DR, Eastell R. The effect
of calcium supplementation on the circadian rhythm of bone collagen degradation.
J. Clin. Endocrinol. Metab. 79:730-735, 1994.
13. Niyibizi C, Eyre DR. Structural  characteristics  of cross-linking  sites in
type V collagen of bone:  Chain  specificity's  and heterotypic  links to type I
collagen. Eur. J. Biochem. 224:934-950, 1994.
14.  Bogaert R,  Wilkin D,  Wilcox WR,  Lachman R,  Rimoin D, Cohn DH,  Eyre DR.
Expression  in cartilage of a 7-amino acid deletion in type 11 collagen from two
unrelated  individuals with Kniest dysplasia.  Am. J. Hum. Genet.  55:1128-1136,
1994.
15.  Bockman RS,  Wilhelm F, Siris E, Singer F,  Chausmer A, Sitton R, Kotier J,
Bosco BJ, Eyre DR, Levenson D. A multicenter  trial of low-dose  gallium nitrate
in patients with advanced Paget's disease of bone. J. Clin.  Endocrincl.  Metab-
80:595-602, 1995.

<PAGE>

16. Eyre DR, Wu J-J.  Collagen  structure and  cartilage  matrix  integrity.  J.
Rheumatol. 22(Suppl. 43):82-85, 1995.
17.  Eyre DR. The  specificity  of collagen  cross-links  as markers of bone and
connective tissue degradation. Acta Orthop. Scand. 66(Suppi. 266):166-170, 1995.
18. Key Jr. LL, Rodriguez RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, Cure JK,
Griffin PP, Ries WL. Long term treatment of osteopetrosis with recombinant human
interferon   gamma:   An  18  month   clinical   trial.   N.   Engl.   J.   Med.
332(24):1594-1599, 1995.
19. Wu J-J, Eyre DR. Structural  analysis of cross-linking  domains in cartilage
type  Xi   collagen:   Insights   on   polymeric   assembly.   J.  Biol.   Chem.
270(32):18865-18870, 1995.
20.  Tiller GE,  Polumbo PA, Weis MA,  Lachman RS, Cohn DH,  Rimoin DL, Eyre DR.
Dominant   mutations   in  the   type  11   collagen   gene   (COL2Al)   produce
spondyloepimetaphyseal   dysplasia   (SEMD),   Strudwick  type.   Nature  Genet.
11(l):87-89, 1995.
21.  Steinmann  B,  Eyre  DR,  Shao  P.  Urinary  pyridincline   cross-links  in
Ehlers-Danlos Syndrome type VI. Am. J. Hum. Genet. 1995; 57:1505-1508.
22. Bolien A-M,  Martin MD, Leroux BG, Eyre DR.  Circadian  variation in urinary
excretion of bone collagen cross-links.  J. Bone Miner. Res. 1995;  10(12):1885-
1890.
23. Diab M, Wu J-J, Eyre DR. Collagen type IX from human cartilage: A structural
profile of intermolecular cross-linking sites. Biochem. J. 3 14:327-332, 1996.

Abstracts

1 . Diab M, Shapiro F, Eyre DR.  Abnormality  of type IX collagen in diastrophic
dysplasia. Trans. Ortho. Res. Cos. (San Francisco (1 8)S 1): 1 20, 1993.
2.  Caulfield MP, Morgan C, Carlton E, Brickman AS, Clemens JD, Eyre DR, Pandian
MR. Comparison of an immunoassay for cross-linked N-telopeptide of bone collagen
with HPLC detection of pyridinolines. The Endocrine Society, 1993.
3. Dickson IR, Arora MK,  Coombes RC, Shao P, Eyre D.  Pyridinolines  and cross-
linked type 1 collagen  N-telopeptides  as markers of bone  metastases in breast
cancer. J. Bone Miner. Res. 8(Sl):S288, 1993.
4. Lee MY, Woods PE,  Lottsfeldt  JL, Ramesh N, Osborne WRA, Eyre DR.  Isolation
and molecular  characterization of a murine osteoclast colony stimulating factor
(0- CSF). J. Bone Miner. Res. 8(Sl):Sl44, 1993.
5. Blumsohn A,  Al-Dehaimi AW,  Herrington K, Shao P, Eyre DR, Eastell R. Effect
of timing of calcium  supplementation  on the circadian  rhythm of bone collagen
degradation. J. Bone Miner. Res. 8(Sl):Sl58, 1993.
6.  Rodriguez  RR,  Ries WL, Eyre DR, Key LL.  Type I collagen  cross-linked  N-
telopeptide excretion by osteopetrotic patients during interferon gamma therapy:
A correlation with bone biochemical and  densitometric  markers.  J. Bone Miner.
Res. 8(Sl):S291, 1993.
7. Ebeling PR, Atley LM, Eyre DR, Guthrie J, Dennerstein L, Wark JD. Sensitivity
of type I collagen  N-telopeptide  cross-links  in  detecting  early  menopausal
changes in bone tumover. Proc. ANZ Bone Miner. Soc. A2, 1993.

<PAGE>

8.  Ebeling PR, Atley LM, Eyre DR, Shao P,  Guthrie J,  Dennerstein  L, Wark JD.
Sensitivity of collagen  N-telopeptide  cross-links and osteocalcin in detecting
early  menopausal  changes  in  bone  tumover.  Abstract  presented  at the  4th
lntemational symposoium on Osteoporosis in Hong Kong, March 1993.
9. Fiedelius C, Eyre DR, Christiansen C. Urinary type I collagen cross-linked N-
telopetides:  A new  marker for bone  resorption.  Poster  presented  at the 4th
International Symposium on Osteoporosis in Hong Kong, March 1993.
10. Eyre DR,  Bogaert R, Diab M, Hanson D, Knigge P, Niyibizi C, Weis MA, Wu ii.
Studies  on the  molecular  structure  of  collagen  heteropolymers  in bone and
cartilage.  Presented  at  the  5th  International  Conference  on  Osteogenesis
Imperfecta, September 27-30, 1993, Oxford, England.
11.  Kanthawatana  S, Eyre DR,  Hendeles  L. The effect of short  course of oral
prednisone  on a  biochemical  marker  of bone  resorption.  Xllth  Intemational
Congress of Pharmacology. Montr6al, Qu6bec, July 1994.
12. Apone S, Fevold K, Lee M, Eyre D. A rapid method for quantifying  osteoclast
activity in vitro. J. Bone Miner. Res. 9(Sl):Al2O, p. S178, 1994.
13. Clemens JD,  Herrick- M, Singer FR, Rosen HN, Shao P, Eyre DR.  Cross-linked
N-  telopeptides  of type I collagen in human serum as a  biochemical  marker of
bone resorption. J. Bone Miner. Res. 9(Sl):A5-72, p. S228, 1994.
14.  Prior JC,  Eyre Dr,  Ebeling  PR,  Wark,  JD.  Trabecular  bone loss  after
premenopausal   oophorectomy   is  not  prevented  by  con'ugated   estrogen  or
medroxyprogesterone--a  double-blind,  randomized  1-year study.  J. Bone Miner.
Res. 9(Sl):C294, p. S394, 1994.
15. Key LL,  Rodriguez RM,  Hatcher H, Eyre DR, Ries WL. Long term  treatment of
osteopetrotic  patients with interferon gamma. J. Bone Miner. Res. 9(Sl):72,  p.
S138, 1994.
16. Sowers M-F, Eyre, D, Hollis,  BW.  Changes in bone tumover  markers and bone
density with lactation. J. Bone Miner. Res. g(Sl):A512, p. S2p7, 1994.
17.  Jackson G,  Hollis BW, Eyre DR,  Baylink  DJ, Bell NH.  Effects of race and
calcium  intake on bone  markers and calcium  metabolism  in young adult men. J.
Bone Miner. Res. 9(S 1):Al 78, p. S 1 85, 1994.
18.  Ebeling PR, Eyre DR,  Gurthrie J,  Dennerstein  L, Wark JDF.  Prediction of
early menopausal bone loss by biochemical  markers of bone turnover.  Amer. Soc.
Bone Miner. Res., Kansas City, MO, September 1994.
19. Wu JJ, Murray J, Eyre DR.  Evidence foi  copolymeric  cross-linking  between
types 11 and Ill collagens in human articular cartilage. ORS, Atlanta, 1996.
20. lchimura S, Wu JJ, Eyre DR. A sensitive method for collagen type IX peptide-
mapping in human cartilage. ORS, Atlanta, 1996.
21. Wang C, Eyre DR, Clark R,  Kleinberg D,  lranmanesh  A, Dudley RE, Berman N,
Swerdloff RS. Sublingual testosterone  replacement decreases bone resorption and
increase  bone  formation   markers  in  hypogonadal   men.  Int.   Congress  of
Endocrinol., 1996.


<PAGE>


                University of Washington Hazardous Materials Use

                             Complete and Return to

                      Environmental Health and Safety GS-05

A.  Principal Investigator:         David R. Eyre. Ph.D.
B.  Department:            Orthopaedics

C.  Building:              Health Sciences           Room #:           BB1052
D.  Phone No.:             543-4700

E.  Mail Stop:             Box 356500

F. Co-investigator(s)      _________________________ ______________________

                           ========================= ======================
G  Title of Project or Proposal.
Molecular Markers of Connective Tissue Degradation
<TABLE>
<CAPTION>

                                                                                        Yes      No
<S>                                                                                     <C>      <C>           
1.  Will Hazardous Materials be used or stored in your laboratory?                      x
2.  Have you and your employees received Hazard Communication training?                 x
3.  Will your research include the use of substances of high acute toxicity,            x
reproductive toxins, carcinogens, mutagens, or teratogens?
4.  Is there a chemical inventory available for your laboratory?                                 x
5.  Do you have access to a computer that is in or near your laboratory for the
purpose of accessing networked safety information?                                      x
6.  Are you familiar with the UW's Hazardous Waste Disposal Guidelines?                 x
7.  Doe your laboratory contain the following?
</TABLE>

         A.       X        FIRE EXTINGUISHERS?
         B.       X        FLAMMABLE LIQUID STORAGE CABINETS?
         C.       X        BIOLOGICAL SAFETY CABINETS?
         D.       X        FUME HOODS (ANY TYPE)?
         E.       _        RESPIRATORS AND REPLACEMENT CARTRIDGES?
         F.       X        PROTECTIVE GLOVES (LATEX, NITRILE, VINYL, ETC.)?
         G.       X        COMPRESSED GASES?

         H.       X        EYE WASHES?

         I.       X        EMERGENCY SHOWER WITHIN 100 FT. OF THE LAB?
         J.       X        ROOM WINDOWS THAT OPEN?

8.  Please  list on the back of this form any  special  hazards  or  precautions
associated with the use of chemicals in your research?


<PAGE>


               University of Washington Biohazard Activity Review

                             Complete and Return to

                    Environmental Heath and Safety Box 354400

A.  Principal Investigator:         David R. Eyre. Ph.D.
B.  Department:            Orthopaedics

C.  Building:              Health Sciences   LAB Room #:   BB1052, 1054, 1032
D.  Phone No.:             543-4700
E.  Box:                   356500                  E-Mail:  ntx@u.washington.edu
F. Co-investigator(s)      _________________________ ______________________

                           ========================= ======================
G  Title of Project or Proposal.
Molecular Markers of Connective Tissue Degradation

__ Check here if project is non-competitive renewal and skip to Section M

                                                                     Yes      No

H.  Is your lab engaged in the following areas of biohazard activity?

1.  Activities involving non-human primates, including blood, tissues and/or 
body fluids from non-human primates.                                 __       x

2.  Activities involving other animals or animal blood and tissues:

         Animal Type: XXXXXX

         a.       Commercially raised laboratory animals.         x        __
         b.       Feral (wild caught) animals.                    __       x

3.   Activities involving human blood, tissues, body fluids and excreta.
         a.       Have all personnel received Hepatitis B vaccinations?

                  (See UW Exposure Control Plan or call 543-7278 for

                  more information.)                                x        __
         b.       Does the laboratory have an exposure control plan?
                  (if yes,  answer  Section  I. below.)             x        __

4.   Activities involving contact with cultures or specimens which may contain
microorganisms (including viruses). Culture Type:  ___________      __       x

5.   Activities involving recombinant DNA. (All projects involving recombinant
DNA must be registered with the UW  Recombinant  DNA  Committee,
regardless of  containment level.  See Section III., pages 2-5 of the 
"University
Biohazard Safety Manual" or call EH&S at 543-7278 regarding non-competitive
grant renewals.)                                                     __       x

I.  Does your laboratory exposure control plan cover:
         1.       Procedures on use of personal protective equipment and

                  clothing?                                          x        __
         2.       Procedures for handling hypodermic needles, glass, pipettes
                  and biological wastes?                             x        __
         3.       Immunization and medical surveillance program(s)?  x        __
         4.       Personnel training?                                x        __

If the answer to any or part of section H. is "Yes" , please complete the next 
page.


<PAGE>


University of Washington
Biohazard Activity Review

Page 2 of  2

                                                                       Another

J.  Does this project require the use of?                   In Lab*    Location
         1.       Laminar flow biological safety cabinets.   x             __
         2.       Centrifuge                                 x             __
         3.       Autoclave                                  x             __
         4.       Sonication Equipment                       x             __

*equipment located in rooms listed on first page.

K.  Submit the following with this form.

         1 .      A copy of the GC-1 form.

         2.       An assessment of the possible risks from biohazards and a 
                  brief summary of the biosafety
                  precautions followed.

         3.       Any comments received from departmental review of the project.

         4.       A summary of the proposed project written in lay terms and/or
                  a copy of the application
                  being submitted for grant support

L. If Class III agents* are involved submit the following additional information
 with this form:

         1.       A resume of the training and experience of each person who
 will participate in the  project

         2.       A description  of laboratory  facilities  available  including
                  containment equipment such as biological safety cabinets, etc.
                  Include  a  statement  by   Environmental   Heath  and  Safety
                  assessing the adequacy of containment facilities.

         +        Consult UW Biosafety Manual for classification of agents.

Note:    Work with Class IV agents will not be approved at the
         University of Washington as appropriate facilities are not

         available.

M.  If this is a non-competitive renewal of funded grant and there are no 
significant changes in the project from
the original submittal, submit the following:

a.       A copy of the new GC-1 form.

b.       a brief summary of the new year's proposed activity.

                          For more information contact

                      EH&S Biosafety Specialist at 543-7278


<PAGE>
Form HS SR-1 trev
BOX FOR COMMITTEE USE ONLY

                                                       MASTER        ___
                                                       COMMITTEE     ___
                                                       REVIEWER      ___
                                                       INVESTIGATOR   X

25-763-E
APPLICATION NUMBER


UNIVERSITY OF WASHINGTON
HUMAN SUBJECTS DIVISION BOX 355752

STATUS REPORT:  Application no. 24-112-E
__      DO NOT RENEW.  Complete items 1-6 of Status Report and return form.
XX      RENEW WITH MINOR OR NO CHANGES.  Complete items 1-10 of Status Report;
--      submit one original plus three (3) copies of this form.
        RENEW WITH CHANGES IN PROCEDURES, POPULATION, OR PURPOSE:  Complete 
        and submit nine (9) copies of a new HSRC application (UW 13-11) and 
        this Status Report (items 1-10).

Investigator's name, position, division and department, mail stop and telephone
 number:
David R. Eyre, Ph.D., Professor, Dept. of Orthopaedics, Box 356500, 543-4700
Title of Human Subjects Application:
Connective Tissue Research   XXXXXXXXXXXXXXXXXXXXXXXXXXXX
Brief summary of findings to date (add sheets if necessary):
SEE ATTACHED
4.      Number and types of adverse events. complaints, and withdrawals and 
how they were handled (add sheets if necessary):
        NONE.
5. No. of subjects enrolled in study to date:                     
   XX Normals/Controls XX Patients/Cases
6. No. of subjects added during past year of approval:             
   XX Normals/Controls XX Patients/Cases
7. No. of subjects continuing participation:  N/A See attached.    
   XX Normals/Controls XX Patients/Cases
8. How many new subjects will join the study over the next year?   
   XX Normals/Controls XX Patients/Cases
9. Do you propose any minor changes in this study or consent form?  
   X  No.  ___  Yes.  If yes, describe (add sheets if necessary).  
   Submit 4 copies of revised consent form and other materials, if appropriate.
10. Provide information for all funding, awarded or proposed for this activity 
(add sheets if necessary).
Type:  XX research grant, __ contract, __ fellowship, __training grant, 
       __ other, explain:
Name of principal investigator:  David R. Eyre, Ph.D.
Name of agency:  SEE ATTACHED.          Agency's no. (if assigned):
Title of proposal:  SEE ATTACHED                SEE ATTACHED
Inclusive dates:  from SEE ATTACHED, through ________________
Submitted through Grant and Contract Services? __ No  XX Yes  __ VAMC  __Other:
HSRC Chair's signature:  ____________________  Date June 08, 1995  Approve XX 
Disapprove __
Subject to the following conditions:


Period of approval is one year, from 06-08-95 through 06-07-96.
* VALID ONLY AS LONG AS APPROVED PROCEDURES ARE FOLLOWED *

<PAGE>

 Washington, Comparative Medic                                 01/30/1996
- Protocol Description
Eyre, David R.                  BOX 356500

PROTOCOL:  2547-03                                   Last Update:  01/30/1996
Immunoassay Assessment of Type I and Type II Collagen Degradation in the
Received:  11/15/1995   Approved:  11/16/1995   Sig. Chg.:  01/25/1996
   Expires:  11/15/1996 Vet Appr.:  01/25/1996
Funding sources:  Ostex International

PI:  Eyre, David R.           Mail:  BOX 356500   S/D:  / Orthopaedics
Contacts:                     Function                Phone           Emergency
  Norlund, Layne              C                       543-0474/       685-8932

Species:  11    XXXXXXXXXXX             Strain:  XXXXXXX
Vivarium:  01                   Lab Room:  01 G609,D604         Oper. Room:
                     1  2       3       4       Total
Approved:            X  X       X       X       XXX
Ordered:        XXX     X       X       X       XXX
Adjusted:          XX   X       X       X          XX
Remaining:         XX   X       X       X          XX

        Y-Drug administration   Y-Blood sampling                Y-Euthanasia
        Y-Collection of tissue          Y-Withhold meds

NO CONDITIONS

Protocol Summary:
        21.  XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX