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Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial
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Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial
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Journal Article
Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial
2024
Overview
Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (
n
= 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q −4.1% (−13.2, 2.6), control −7.7% (−20.1, 14.3);
P
= 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%,
P
= 0.020) and 4 weeks (+16%,
P
= 0.024), but was not different from control at 20 weeks (−9%,
P
= 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell
p16
(also known as
CDKN2A
) mRNA levels) in which D + Q concomitantly increased P1NP (+34%,
P
= 0.035) and reduced CTx (−11%,
P
= 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%,
P
= 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier:
NCT04313634
.
In a phase 2 randomized control trial, intermittent senolytic therapy administered to postmenopausal women did not result in a reduction in the bone resorption marker, serum CTx, compared to control at 20 weeks.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aged
/ Aging
/ Biomedical and Life Sciences
/ Bone and Bones - drug effects
/ Bone Resorption - drug therapy
/ Cellular Senescence - drug effects
/ Collagen
/ Collagen Type I - metabolism
/ Cyclin-Dependent Kinase Inhibitor p16 - genetics
/ Cyclin-Dependent Kinase Inhibitor p16 - metabolism
/ Dasatinib - administration & dosage
/ Female
/ Humans
/ mRNA
/ Postmenopause - drug effects
/ Quercetin - administration & dosage
/ Radius
