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Beta1-selective blockade for prevention of postmenopausal bone loss: A randomized controlled trial

Award Number: R01AG065154
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Beta1-selective blockade for prevention of postmenopausal bone loss: A randomized controlled trial - Osteoporosis is a disease of aging that leads to ~2 million fractures and ~$17 billion in healthcare costs annually. Although several drugs are FDA-approved for the treatment of osteoporosis, the potential for serious side effects (e.g., osteonecrosis of the jaw, atypical femur fractures) has led most physicians to use these drugs only for the treatment, but not the prevention, of osteoporosis. This has led to the current situation where most postmenopausal women must wait until they develop frank osteoporosis (i.e., fractures, or sufficiently high fracture risk) to begin drug therapy. As such, there is a compelling need for novel, relatively low-risk and low-cost pharmacological approaches to prevent osteoporosis. The current proposal aims to translate evidence from rodent studies showing that the sympathetic nervous system (SNS) is an important regulator of bone metabolism to a simple, cost-effective, and safe approach for osteoporosis prevention. In key Preliminary Data, we obtained multiple lines of evidence to establish clearly the role of the SNS in regulating human bone metabolism. A critical component of these data was a “proof-of- concept” interventional study demonstrating that β1-selective blockers (atenolol, nebivolol), but not a non- selective β-AR blocker (propranolol), have favorable effects on bone turnover and bone mineral density (BMD) in postmenopausal women. Based on these data, we will perform a randomized, double-blind, placebo- controlled 2 year clinical trial addressing the following Specific Aims: (1) Test the hypothesis that treatment with a widely used, inexpensive, and relatively β1-selective blocker (atenolol) will prevent bone loss at the lumbar spine and femur neck as assessed by dual-energy X-ray absorptiometry in 420 postmenopausal women without pre-existing osteoporosis (Aim 1a); and evaluate the tolerability and safety of atenolol when used for the prevention of bone loss (Aim 1b). (2) Evaluate the effects of atenolol on trabecular and cortical bone microarchitecture using high resolution-peripheral quantitative computed tomography (Aim 2a), on bone turnover markers (Aim 2b), and test whether baseline measures of bone turnover or of sympathetic activity (resting heart rate, plasma catecholamine levels) are predictive of the BMD response to atenolol over 2 years (Aim 2c). (3) In a subset of patients, explore the underlying molecular and cellular mechanisms for the effects of β1-selective blockade on bone in humans using analyses of osteoblast populations isolated from bone biopsies as well as tissue-level bone formation rates on quadruple-labelled bone biopsies (Aim 3). The proposed studies will rigorously test whether atenolol is efficacious and safe for the prevention of osteoporosis in postmenopausal women and also further define the mechanisms of SNS effects on bone in humans. If our proposed clinical trial demonstrates protection from bone loss in postmenopausal women by atenolol, this would fill a crucial clinical need, as these women currently have virtually no pharmacological options for osteoporosis prevention.


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: 2026 ( Subtotal = $0 )
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	11/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $2,330,081 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	5	7/23/2025	NON-COMPETING CONTINUATION	$190,211
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	11/15/2024	NON-COMPETING CONTINUATION	$2,139,870
														Subtotal = $2,330,081

Issue Date FY: 2024 ( Subtotal = $2,489,289 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	4	6/4/2024	NON-COMPETING CONTINUATION	$248,930
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	4	2/7/2024	NON-COMPETING CONTINUATION	$2,240,359
														Subtotal = $2,489,289

Issue Date FY: 2023 ( Subtotal = $2,456,365 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	3	1/13/2023	NON-COMPETING CONTINUATION	$2,456,365
														Subtotal = $2,456,365

Issue Date FY: 2022 ( Subtotal = $2,405,613 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	2	4/26/2022	NON-COMPETING CONTINUATION	$240,561
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	2	1/21/2022	NON-COMPETING CONTINUATION	$2,165,052
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	10/27/2021	NEW	$0
														Subtotal = $2,405,613

Issue Date FY: 2021 ( Subtotal = $2,347,808 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	12/24/2020	NEW	$2,347,808
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	1	1/21/2021	NEW	$0
														Subtotal = $2,347,808

Grand Total All Awards = $12,029,156

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Beta1-selective blockade for prevention of postmenopausal bone loss: A randomized controlled trial

Award Number: R01AG065154

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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