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The role of zoledronate localization in the induction of osteonecrosis

Award Number: R15DE025134
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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The role of zoledronate localization in the induction of osteonecrosis - ABSTRACT Anti-resorptive medications have helped millions of patients suffering from bone-wasting conditions. However, a side effect called medication-related osteonecrosis of the jaw has caused significant anxiety towards these otherwise useful medications, causing a sharp decline in prescriptions, despite the high benefit to risk ratio. Unlike other anti-resorptive medications, bisphosphonates (including zoledronate) accumulate in high concentration in the bone matrix of alveolar bone following the sessation of systemic treatment. Our preliminary results show that matrix-bound zoledronate contributed to the exclusivity of osteonecrosis to the jawbone (bisphosphonate-related osteonecrosis of the jaw; BRONJ), but was not the only factor. In human patients, certain oral bacteria were common in BRONJ lesions (for example, Fusobacterium nucleatum and Actinomyces israelii), suggesting that these bacteria may also be important for the pathogenesis of BRONJ. Our central hypothesis is that matrix-bound bisphosphonates render the oral microenvironment favorable to bacterial colonization of alveolar bone, shifting the balance of the bone regenerative response towards bone destruction rather than effective regeneration, even after stopping the systemic bisphosphonate treatment. In this proposal, we will study the interaction between predominant BRONJ-associated oral bacteria (F. nucleatum and A. israelii) with systemic and matrix-bound bisphosphonates during the pathogenesis of BRONJ. Specific Aim 1 will test whether matrix-bound ZA enhances attachment of predominant BRONJ-associated bacteria to mineralized matrix. We will examine the effects of matrix-bound ZA on the attachment mechanisms of two bacterial strains most commonly identified in necrotic alveolar bone (F. nucleatum and A. israelii), whether the effects can be reversed by chelating matrix-bound ZA using EDTA, and the effect of F. nucleatum and A. israelii on osteoclast differentiation, function, and cross-talk with osteoblast and endothelial cells with and without ZA treatment. Specific aim 2 will test whether BRONJ-associated bacteria are critical for the development of BRONJ. We will test the hypothesis that matrix-bound zoledronate render the oral microenvironment favorable to bacterial colonization, even after stopping systemic bisphosphonate treatment. Such bacterial colonization (F. nucleatum and A. israelii) of zoledronate-treated animals will induce osteonecrosis following invasive surgical procedures at extra-oral bone sites, an effect that can be ameliorated by local removal of zoledronate using EDTA. This project is based on the specific aims accomplished during the first R15 award and is an extension of the same line of research. The award also provided the sole support for 11 graduate, pre-doctoral, and undergraduate students. Successful renewal will allow the continuation of student research at the PI’s lab. 11


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1,455 )
2024	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	10/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$221
2024	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	10/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,234
														Subtotal = -$1,455

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$17,298 )
2021	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	002	2	2/28/2021	COMPETING CONTINUATION	-$39,650
2021	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	11/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$221,741
2021	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	2	11/12/2020	COMPETING CONTINUATION	-$239,039
2021	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	3	2/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$39,650
														Subtotal = -$17,298

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	001	2	2/3/2019	COMPETING CONTINUATION	$3,486
2019	2015	AUGUSTA UNIVERSITY	1120 15TH ST	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	1	2/3/2019	NEW	-$3,486
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $455,999 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	001	2	9/4/2018	COMPETING CONTINUATION	$455,999
2018	2015	AUGUSTA UNIVERSITY	1120 15TH ST	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	1	8/29/2018	NEW	$0
														Subtotal = $455,999

Issue Date FY: 2015 ( Subtotal = $449,833 )
2015	2015	Georgia Health Sciences University	1459 LANEY WALKER BLVD	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	001	1	3/6/2015	NEW	-$242
2015	2015	Georgia Health Sciences University	1459 LANEY WALKER BLVD	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	1	2/4/2015	NEW	$450,075
														Subtotal = $449,833

Grand Total All Awards = $887,079

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The role of zoledronate localization in the induction of osteonecrosis

Award Number: R15DE025134

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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