Sponsor Deadline
Posted: 11/1/2022

Notice of Special Interest: Promoting Research on Mechanisms of Pathogenesis and Pathophysiology of Atypical Femoral Fracture (AFF) and Osteonecrosis of the Jaw (ONJ)

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.

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

If interested in this opportunity, Duke investigators should contact:

Cinthia E. Sanchez, Ph.D. (cinthia.sanchez@duke.edu), CTSA Program Director, Duke Clinical & Translational Science Institute (CTSI) 


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