The purpose of this announcement is to notify the research community of areas of special interest by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), National Institute of Dental and Craniofacial Research (NIDCR), and Office of Research on Women's Health (ORWH), to enhance research on improving understanding of the mechanisms of pathophysiology and pathogenesis leading to the rare conditions of atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ) associated with bone antiresorptive medications.

Bisphosphonates (BPs) and denosumab are anti-resorptive drugs that have been used for many years to reduce the risk of osteoporotic fractures. However, their long-term use has been associated with increased risk of AFF. Reports of these rare but serious adverse events have raised questions about the safety of these anti-resorptive drugs, especially in people who use these drugs long-term. The absolute risk for AFF is low; however, public concern about AFF, along with other unanswered questions about how to appropriately treat osteoporosis patients long-term, have coincided with a significant decrease in use of osteoporosis drugs and a leveling off in what had been a promising decline in the incidence of osteoporotic fractures. This has raised concerns within the medical and scientific communities that many people who might need the drugs are either not adequately being prescribed or taking them. To date, the causative effect of long-term bisphosphonate and denosumab use on AFF has not been absolutely determined and the mechanisms of AFF development are not clear. Despite some indication that there may be genetic components to the risk and possible precursor syndromes, prediction of the occurrence of AFF is not possible. For millions of osteoporotic patients using these agents, this unpredictability presents a frightening risk.

Long-term use of antiresorptive drugs, in particular intravenous BP administration as part of cancer therapy, has likewise raised concerns due to the association of their use with increased risk of ONJ. ONJ, which is manifested in several stages of severity, is a debilitating condition affecting patient health and quality of life. Knowledge of the mechanism of action of bisphosphonates as an anti-resorptive has advanced greatly, however, less is known on the precise etiology and pathogenesis of ONJ, especially since reports that biologics such as denosumab and angiogenesis inhibitors are also associated with ONJ. Further advances in understanding of this rare systemic complication in humans, uniquely manifested in the oral cavity, will depend on unraveling complex involvement of multiple systems.

In October 2018, the National Institutes of Health convened a Pathways to Prevention (P2P) workshop on the Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention. As a follow-up to the workshop systematic evidence review and an expert panel report containing research recommendations, several NIH Institutes, Centers, and Offices and other federal agencies met to explore opportunities for collaborations and to outline research opportunities and next steps. These are summarized in the Federal Partner’ Meeting Report. NIAMS and NIA published plans for next steps following these recommendations, to be carried out in collaboration with relevant partners. These recommendations and next step actions have highlighted the need to enhance research on elucidating the mechanism and pathophysiology of both AFF and ONJ.

This Notice of Special Interest (NOSI) invites research applications that focus on improving the understanding of mechanisms of AFF and ONJ. Applications that propose to utilize existing resources including cohorts, registries, existing databases and other resources such as the NIH Common Fund's Health Care Systems (HCS) Research Collaboratory program for their studies are encouraged.

Applications on AFF should use standard case definition and specified methods for ascertainment and follow up, where appropriate, as specified by the ASBMR task force. Studies on mechanisms of pathogenesis and pathophysiology of AFF that may provide information on the potential link between prolonged bisphosphonate/denosumab therapies and AFF, prediction of AFF, treatment regimens that may reduce the risk of AFF, or potential therapies that may enhance AFF facture healing, are of special interest to this NOSI.

Examples of research topics on AFF that are of interest include, but are not limited to:

• Developing animal models that mimic the development of AFF in humans
• Identifying genetic/epigenetic factors predisposing patients to AFF
• Investigating cellular, molecular, tissue and biomechanical mechanisms for developing AFF
• Utilizing existing cohorts and large databases to study the natural history and pathophysiology of AFF and its relationship with duration of drug use and drug holidays
• Investigating measures that can decrease the risk of developing AFF
• Investigating the pathophysiology and role of different bone cells in AFF fracture repair
• Studying mechanisms of impaired local remodeling/modeling and repair processes in pathogenesis and healing of AFF and possible means of overcoming these deficits
• Testing the relationship of different biomechanical loading and bone geometry to AFF
• Investigating the function and role of prodromal reaction in the pathogenesis of AFF
• Exploring mechanism of AFF in patients without any prior exposure to osteoporosis drug treatment
• Developing biomarker or early imaging diagnosis of AFF
• Investigating the relationship between lower limb stress fractures and AFFs
• Mathematical modeling of how multiple factors, tissues and systems interact in the development and progression of AFF.

Examples of research topics on ONJ that are of interest include, but are not limited to:

• Developing new and/or improving existing animal models that represent the development of clinical medication-related ONJ under physiologically relevant doses and conditions
• Linking histological, structural and -omics findings, including single cell analysis, to determine the mechanisms leading to the different stages of ONJ
• Determining genetic/pharmacogenetic and oral environment susceptibility of jaw osteogenic cells to medications related to ONJ
• Computational modeling of how the oral mucosa, alveolar bone, immune system, microbiome, among other tissues and systems, all interact in the development and progression of ONJ
• Investigating mechanisms for how ONJ lesions heal and the processes that guide recovery of the tissues involved
• Examining behavioral and social science aspects influencing patients and providers/clinicians in decisions relating to ONJ

Institute/Center-specific considerations:

All applications to this funding opportunity announcement should fall within the mission of the Institutes listed within the NOSI. Please consult with the contacts in Section VII related to the mission of the specific Institute. The following NIH Offices may co-fund applications assigned to these Institutes.

The Office of Research on Women’s Health (ORWH) is part of the Office of the Director of NIH and works in partnership with the 27 NIH Institutes and Centers to ensure that women's health research is part of the scientific framework at the NIH, and throughout the scientific community. In general, ORWH is interested in research that considers the influence of sex and gender on health and disease, and the total health of women across the full spectrum of research. ORWH encourages interdisciplinary approaches and is interested in partnering with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other NIH institutes to support research that examines ways to integrate evidence-based practices, interventions, and policies into practice settings to improve the health of women, especially research on understanding the pathophysiology and the mechanisms leading to the rare conditions of atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) associated with osteoporosis antiresorptive medications. The Trans-NIH Strategic Plan for the Health of Women covering FY 2019 - 2023 is available on the ORWH website (https://www.nih.gov/women/strategicplan) for additional guidance.

Application and Submission Information

This notice applies to due dates on or after June 5, 2020 and subsequent receipt dates through July 18, 2023.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-19-056: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

• PA-19-053: NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AR-21-006” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Faye Chen, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: [email protected]

Lyndon Joseph, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6926
Email: [email protected]

Jason Wan, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-9898
Email: [email protected]

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-7760
Email: [email protected]

Mahasin Ingram
National Institute on Aging (NIA)
Telephone: 301-402-7736
Email: [email protected]

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]