RELEASE DATE:  October 10, 2002

PA NUMBER:  PA-03-008

EXPIRATION DATE: After 11/02/2005, unless reissued. 

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
National Institute on Aging (NIA)
National Cancer Institute (NCI)
National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) 
National Institute of Dental and Craniofacial Research (NIDCR) 


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The objective of this initiative is to elicit grant submissions that focus on 
systemic hormones, local growth factors and bone-active cytokines with 
potential bone anabolic effects. The signal transduction pathways recruited 
by the receptors of these hormones and growth factors are of particular 
interest. Although the primary focus is on basic research, the long-term 
objective is to identify potential targets of therapeutic value in the 
treatment of diseases that adversely affect bone including, but not limited 
to, osteoporosis due to loss of gonadal steroids, aging, use of 
glucocorticoids and immunosuppressive drugs, hyperparathyroidism, excessive 
thyroid hormone replacement, or tumor metastasis to bone.



Bone biology has benefited over the last decade from a tremendous explosion 
of information derived from analyses of mutations affecting skeletal 
development in man and mice. Indeed, studies on bone development have 
revealed roles for signaling through peptides such as PTHrP, hedgehog, Wnt, 
FGF, and BMP / TGF-beta family members; transcription factors from the Hox, 
Pax, Forkhead, NFkB, AP-1, Runx2/Cbfa1, and Osx families; and signal 
transducing molecules such as tyrosine kinases (e.g. c-src, c-fms), serine / 
threonine kinases, TRAFs and MAP kinases involved in bone cell fate 
determination, differentiation, and formation of mature bone. For example, 
analysis of Jansen's dyschondroplasia revealed the critical role of PTHrP 
signaling in skeletal development. Additionally, genetic analysis of families 
with osteoporosis-pseudoglioma syndrome and of kindreds with autosomal 
dominant high bone density have exposed the role of LDL receptor-related 
protein 5 (LRP5) and signaling in the Wnt pathway on regulation of bone mass 
and provide a new potential therapeutic avenue to treat osteopenia, or 
thinning of the bones.  

It is clear that diseases that affect bone, such as osteoporosis and primary 
hyperparathyroidism, result in gradual net loss of bone mineral leading to 
osteopenia which is a leading cause of fractures in adults. Hormones are key 
regulators of bone mass and osteopenia may result from alterations in hormone 
action, such as loss of estrogen production in post-menopausal women or of 
androgens in older men, excessive production of parathyroid hormone (PTH) as 
in primary hyperparathyroidism, or glucocorticoid excess as a consequence of 
chronic steroid use in immunosuppressive therapy. Other imbalances in local 
growth factors and/or bone-active cytokines resulting from a variety of 
conditions (e.g. chronic inflammation, rheumatoid arthritis) may also 
contribute to osteopenia. 

Research supported by previous Program Announcements (PA-96-076 and PA-00-
017) and other initiatives revealed that growth factor signaling in 
developing and mature bone cells is key to maintaining proper mineral balance 
and peak bone mass. Results from a large clinical trial evaluating use of 
estrogen plus progestin in postmenopausal women demonstrated that the 
beneficial effects of hormone replacement therapy on bone are outweighed by 
its adverse effects on other organs (Writing group for the WHI, JAMA 
288:321). A second study concluded that women using estrogen (alone) 
replacement therapy are at increased risk of developing ovarian cancer (Lacey 
et al. JAMA 288:334). The development and use of Selective Estrogen Receptor 
Modulators (SERMs) has served to partially offset these side effects while 
giving some degree of protection against post-menopausal bone loss. It is 
critical to understand the mechanisms underlying the beneficial effects of 
estrogen on bone in order to target new therapeutic agents that promote bone 
growth and integrity. In addition, other therapeutic agents have been 
developed that alter mineral content and/or molecular structure of bone 
(e.g., bisphosphonates), or that alter physiologic hormonal balances (e.g., 
calcitonin, vitamin D). The first truly bone anabolic therapeutic agent, 
intermittently administered PTH, may enter the market in the future, although 
the mechanism of PTH action in this context remains to be further elucidated.

This initiative is designed to elicit grant application submissions that 
focus on systemic hormones, growth factors and cytokines with bone anabolic 
effects and elucidation of the signal transduction pathways recruited by 
these factors. While the primary focus is on basic research, the long-term 
emphasis should be on identifying mechanisms or processes associated with 
hormonal regulation of bone cell structure/function emphasizing signal 
transduction in bone cells and their precursors, with potential applicability 
as therapeutic agents for the treatment of diseases that adversely affect 
bone, including osteoporosis, primary hyperparathyroidism, and tumor 
metastasis to bone. Potential therapeutic agents could mimic beneficial 
effects of anabolic hormones or antagonize harmful effects of hormones that 
cause bone loss.
The major areas of interest and potential that have been identified relevant 
to this program announcement are the following:
o The mechanism(s) of action of sex steroids, selective estrogen receptor 
modulators (SERMs), partial agonists, and agents with estrogen-like activity 
in bone; androgens and androgen-like agents (SARMs) which express positive, 
anabolic effects on bone.

o The role of other members of the nuclear hormone receptor superfamily, 
including peroxisome proliferator-activated receptor (PPAR), and vitamin D in 
signaling in bone cells and their precursors.
o Parathyroid hormone (PTH) and/or parathyroid hormone-related peptide 
(PTHrP) and agonists or partial agonists that express PTH- or PTHrP-like 
anabolic effects in bone and the mechanisms of signaling in developing, 
mature and aged bone. 

o LRP5, its interactions with Dickkopf-1 and the Wnt signaling pathways.
o Insulin-like growth factor I (IGF-I), IGF-1 receptors, IGF-I binding 
proteins, or any other component of the IGF axis that signal in bone 
development and homeostasis. 
o Fibroblast growth factor(s) and their role(s) in bone/cartilage development 
and/or angiogenesis related to bone.
o Members of the TGF / BMP family, their receptors and signal transducers 
such as members of the SMAD family.
o Bone active cytokines including but not limited to Colony Stimulating 
Factors (e.g. CSF-1), RANKL / RANK / OPG axis, cytokine products of Th-1 and 
Th-2 T cells (e.g. interferons, TNFs, interleukins) which can modulate bone 
homeostasis, their receptors, and signaling pathways.
o Novel transcription factors, such as Osx, Runx2/Cfba1, other Hox gene 
products, and their mechanisms of signaling in bone cells and their 
o Prostaglandins with effects on bone cells.

o The roles of hormones, growth factors, cytokines or other factors and their 
receptors in craniofacial bone remodeling, damage and regeneration.

o The roles of hormones, growth factors, cytokines in modulating the bone 
microenvironment and tumor metastasis to bone. 

This is by no means a complete listing of potentially important hormones, 
growth factors, or cytokines.  The general focus should be on developing an 
understanding of the putative mechanism(s) of action of these agents with the 
goal of defining what aspect(s) of signaling in bone may be affected and how 
anabolic or other beneficial therapeutic actions may be achieved and 
sustained. Support for investigator initiated clinical trials designed to 
test the efficacy of novel anabolic factors or novel therapy regimens of 
clinically proven compounds may be sought through this initiative. 

The NIDDK, NIAMS, and NIA share the mission to provide broad fundamental and 
clinical research support for a spectrum of chronic and disabling diseases 
that affect bone, including osteoporosis, hyperparathyroidism, and other 
diseases that result in bone loss. The NIDDK has a special interest in the 
endocrinology of bone, PTH / PTHrP signaling, the mechanism of action of 
calciotropic hormones, and gene regulation by steroid / nuclear hormone 
receptors. The NCI is interested in the identification and characterization 
of factors that affect tumor cell survival, growth and metastasis to bone. 
The NIDCR has special interest in research focusing on craniofacial bone.


This PA will use the NIH R01 and R21 award mechanism(s). As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project. Applicants without extensive preliminary data or who wish 
to explore innovative high risk/ high impact ideas that are scientifically 
sound are encouraged to submit applications for this PA using the R21, 
exploratory / developmental grant mechanism.  Investigators are encouraged to 
seek continued support after completing an exploratory / developmental grant 
project through a research project grant (R01). Please see the "Submitting an 
Application" section for more details.  Applicants for the R21 must limit 
their request to $100,000 direct costs per year and are limited to two years 
of requested support.

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications. 


You may submit (an) application(s) if your institution has any of the 
following characteristics:
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Mehrdad Tondravi, Ph.D. 
Program Director for Bone & Mineral and Steroid Metabolism
Division of Diabetes, Endocrinology, and Metabolic Diseases 
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Blvd., Room 603 
Bethesda, MD  20892-5460
Telephone:  (301) 451-9871
FAX:  (301) 435-6047

Jill Carrington, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD   20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Blvd, EPN 5038
Rockville, MD 20892
Telephone:  (301) 435-1878
FAX:  (301) 480-0864

William Sharrock, Ph.D.
Bone Biology Program Director
National Institute of Arthritis and Muskuloskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD 
Telephone:  (301) 594-5055
FAX:  (301) 480-4543

Guo H. Zhang, Ph.D., M.P.H.
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
45 Center Drive, Building 45, Room 4An18B
Bethesda, MD 20892
Telephone:  (301) 594-0618
FAX:  (301) 480-8318

o Direct your questions about financial or grants management matters to:

Florence Danshes 
Senior Grants Management Specialist 
Grants Management Branch, DEA
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Blvd., 734
Bethesda, MD  20892
Telephone:  (301) 594-8861
FAX:  (301) 480-3504

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212
Bethesda, MD   20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672

Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Room 242
Rockville, MD 20892
Telephone:  (301) 496-8796
FAX:  (301) 496-8606

Melinda Nelson
Grants Management Officer
National Institute of Arthritis and Muskuloskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 801
Bethesda, MD 20892
Telephone:  (301) 594-3535
FAX:  (301) 480-5450

Robert L. Tarwater
Grants Management Specialist
Grants Management Branch
National Institute of Dental and Craniofacial Research
45 Center Drive, Building 45, Room 4AN32A
Bethesda, Maryland 20892-6402
Telephone:  (301) 594-4836
Fax:  (301) 480-8301


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at, and include February 
1, June 1, and October 1. These application deadlines are also indicated in 
the PHS 398 application kit.

outlined in the PHS 398 application kit are to be followed, with the 
following requirements for R21 applications:  

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the total 
direct costs limit of $100,000 per year. 

2. Although preliminary data are not required for an R21 application, they 
may be included.

3.  Sections a-d of the Research Plan of the R21 application may not exceed 
15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.   Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o Up to five publications, including manuscripts (submitted or accepted for 
publication), abstracts, patents, or other printed materials directly 
relevant to the project.  These may be stapled as sets.
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included within 
the 15 page limit of items a-d of the research plan

up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at The CSR will not 
accept any application in response to this PA that is essentially the same as 
one currently pending initial review unless the applicant withdraws the 
pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(; a complete 
copy of the updated Guidelines are available at 
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.  Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at 

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.847 for NIDDK, 93.866 for NIA, 93.121 for 
NIDCR, 93.396 for NCI, and 93.846 for NIAMS and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children. This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.