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Pathophysiologic mechanisms during initiation of medication related osteonecrosis of the jaws

Award Number: R01DE019465
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Antiresorptive medications, particularly bisphosphonates (BPs) and denosumab are potent inhibitors of osteoclast function and are used to manage skeletal diseases such as bone malignancy or osteoporosis. Although clinically important, these medications are associated with medication related osteonecrosis of the jaw (MRONJ), a rare but serious side effect, that can cause debilitating pain and morbidity. Moreover, the fear of developing MRONJ has contributed to a progressive decline in patient compliance with antiresorptive use, and a looming crisis in osteoporosis. Improving MRONJ prevention, diagnosis and treatment would have a great impact in health care of patients with skeletal diseases. From studies supported by the parent grant, our well-established, interdisciplinary team of clinician-scientists has made important contributions to the pathophysiology, diagnosis and management of MRONJ. Collectively, our studies have provided significant insight into MRONJ pathogenesis. In control animals with dental disease, bone resorbs away from the inflammatory nidus. In contrast, osteoclast inhibition leads to bone being exposed to inflammation, and to osteonecrosis adjacent to inflammatory foci. Epithelial migration occurs in both control and antiresorptive treated animals. However, with inhibition of bone resorption, the epithelium descends towards the alveolar crest, and eventually rims the necrotic bone, resulting in bone exposure. Extraction of teeth with dental disease, results in conspicuous MRONJ. In contrast, after extraction of healthy teeth in animals on antiresorptives mucosal and socket healing is achieved. Through our studies, we have developed and characterized animal models of MRONJ by inducing experimental periodontal or periapical disease and treating with high-dose antiresorptives, in the absence of tooth extraction. These models capture early tissue changes during MRONJ initiation. Based on our published and preliminary findings, we hypothesize that initiation of the pathophysiologic framework that eventually leads to clinically exposed bone involves an interplay among dying osteocytes, challenged soft tissue homeostasis, and a distorted immune response. Our objective is to determine the early pathophysiologic mechanisms of MRONJ initiation and progression and to pursue effective therapeutic interventions. To meet our objective and test our hypothesis, we propose three Specific Aims. Aim 1: Determine the extent to which HMGB1 released from necrosing osteocytes contributes to MRONJ initiation and progression Aim 2: Delineate macrophage involvement in MRONJ initiation and progression. Aim 3: Define the role of macrophage and osteocyte heme-oxygenase-1 (HO-1) in MRONJ initiation and progression.


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 = $354,033 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	14	8/9/2024	NON-COMPETING CONTINUATION	$354,033
														Subtotal = $354,033

Issue Date FY: 2023 ( Subtotal = $361,258 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	13	8/16/2023	NON-COMPETING CONTINUATION	$361,258
2023	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	12	8/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,258

Issue Date FY: 2022 ( Subtotal = $357,646 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	12	8/18/2022	NON-COMPETING CONTINUATION	$357,646
														Subtotal = $357,646

Issue Date FY: 2021 ( Subtotal = $361,258 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	11	8/10/2021	NON-COMPETING CONTINUATION	$361,258
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	10	5/21/2021	COMPETING CONTINUATION	$146,225
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	10	2/2/2021	COMPETING CONTINUATION	$0
2021	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	9	5/21/2021	NON-COMPETING CONTINUATION	-$146,225
														Subtotal = $361,258

Issue Date FY: 2020 ( Subtotal = $361,258 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	10	9/16/2020	COMPETING CONTINUATION	$361,258
2020	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	9	9/15/2020	NON-COMPETING CONTINUATION	$0
2020	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	6/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,258

Issue Date FY: 2018 ( Subtotal = $377,237 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	7/25/2018	NON-COMPETING CONTINUATION	$377,237
														Subtotal = $377,237

Issue Date FY: 2017 ( Subtotal = $377,237 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	8	8/1/2017	NON-COMPETING CONTINUATION	$377,237
														Subtotal = $377,237

Issue Date FY: 2016 ( Subtotal = $378,281 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	7	8/4/2016	NON-COMPETING CONTINUATION	$378,281
														Subtotal = $378,281

Issue Date FY: 2015 ( Subtotal = $383,681 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	6	7/24/2015	NON-COMPETING CONTINUATION	$383,681
														Subtotal = $383,681

Issue Date FY: 2014 ( Subtotal = $383,074 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	7/17/2014	COMPETING CONTINUATION	$383,074
														Subtotal = $383,074

Issue Date FY: 2012 ( Subtotal = $528,592 )
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	5/4/2012	NON-COMPETING CONTINUATION	$371,888
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	4	9/25/2012	NON-COMPETING CONTINUATION	$46,684
2012	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	7/10/2012	NON-COMPETING CONTINUATION	$110,020
														Subtotal = $528,592

Issue Date FY: 2011 ( Subtotal = $364,375 )
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	6/2/2011	NON-COMPETING CONTINUATION	$364,375
														Subtotal = $364,375

Issue Date FY: 2010 ( Subtotal = $441,756 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	2	8/10/2010	SUPPLEMENT FOR EXPANSION	$66,112
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	5/21/2010	NON-COMPETING CONTINUATION	$375,644
														Subtotal = $441,756

Issue Date FY: 2009 ( Subtotal = $379,439 )
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	9/3/2009	NEW	$379,439
														Subtotal = $379,439

Grand Total All Awards = $5,409,125

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Pathophysiologic mechanisms during initiation of medication related osteonecrosis of the jaws

Award Number: R01DE019465

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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