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Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial
Open accessAbstract
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 .
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“serum P1NP increased at 2 weeks in the T3 D + Q group (relative to control, +34%, P = 0.035)”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Results > Exploratory and post hoc analyses
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“the p16_variant 5 assay appeared to more effectively identify individuals likely to have a favorable skeletal response to D + Q compared with the p16_variant 1 + 5 assay.”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Results > Exploratory and post hoc analyses
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Abstract
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In the paper
“baseline SASP factors were generally higher in the T3 group versus the T1/T2 group”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Results > Assessment of SASP factors
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“changes in SASP factors did not differ between the control and D + Q groups”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Results > Assessment of SASP factors
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“in humans, senolytics (or at least, D + Q with our monthly dosing regimen) may preferentially stimulate bone formation over inhibiting bone resorption”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Discussion
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In the paper
“radius BMD at 20 weeks, which increased by 2.7% in response to D + Q relative to control (P = 0.004) in the T3 group”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Results > Exploratory and post hoc analyses
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our study represents the largest (n = 60) RCT of sustained intermittent administration of a senolytic regimen to generally healthy older women.”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Discussion
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our findings support the hypothesis that the skeletal, and perhaps nonskeletal, response to a senolytic intervention depends on the existing senescent cell burden.”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Discussion
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women.”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Abstract
Claims other papers make about this one
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In the citing paper
“a Phase 2 trial in postmenopausal women showed limited biomarker changes with subtle or no significant clinical improvements in bone mass37.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [37]
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In the paper
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Discussion
“Previous studies of systemic administration of senolytics have not included a control group, recruited only a limited number of patients with diabetes-associated chronic kidney disease (n = 9)32, idiopathic pulmonary fibrosis (n = 14)33, dementia (n = 5)11 or diabetic macular edema (n = 8)12”
§ Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial > Abstract
“a single intraocular administration of another senolytic compound, the BCL-xL inhibitor UBX1325, was safe and improved visual acuity in five of eight patients with diabetic macular edema”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
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In the paper
“D’Andrea, G. Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106, 256–271 (2015).”
Cited work 10.1016/j.fitote.2015.09.018 · retracted 2024-12-28 · notice 10.1016/j.fitote.2024.106320 · this paper published 2024-07-02
Citations
Cites
1 retracted
RETRACTED: Quercetin: A flavonol with multifaceted therapeutic applications?
D’Andrea, G. (2015) · Fitoterapia · doi:10.1016/j.fitote.2015.09.018 · Cited by 743
RetractedThe serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · cited 1×
“Cellular senescence was first described by Hayflick and Moorhead in 1961 as an in vitro phenomenon, whereby normal human fibroblasts stopped proliferating and entered a state of irreversible growth arrest 1 .”
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · cited 1×
“Moreover, the demonstration in old mice that clearing senescent cells using a genetic approach extended health span and lifespan 4,5 generated intense interest in therapeutically targeting senescent cells in humans to prevent or delay age-related comorbidities as a group 6 .”
Self-citationNaturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,876
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584 · cited 2×
“…the translation of these findings to humans was the identification of compounds (‘senolytics’) that targeted survival pathways unique to senescent cells, resulting in their selective killing and beneficial effects in old mice similar to those observed with genetic clearance of senescent cells 7,8 .”
Self-citationClearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819 · cited 1×
“…the translation of these findings to humans was the identification of compounds (‘senolytics’) that targeted survival pathways unique to senescent cells, resulting in their selective killing and beneficial effects in old mice similar to those observed with genetic clearance of senescent cells 7,8 .”
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774 · cited 2×
“…are mediated via modulation of sclerostin levels (or possibly other effects on Wnt signaling in bone), the advantage of senolytics would be their potential nonskeletal effects on frailty, metabolic dysfunction and other age-associated morbidities 16 , in addition to their skeletal actions.”
Self-citationDasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
Kantarjian, H. M., Shah, N. P., Hochhaus, A., Cortes, J. E., Shah, S. A., Ayala, M., Moiraghi, B., Shen, Z., Mayer, J., Pasqüini, R., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1002315 · Cited by 1,572
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.069 · Cited by 1,383 · cited 1×
“…senolytics have not included a control group, recruited only a limited number of patients with diabetes-associated chronic kidney disease ( n = 9) 32 , idiopathic pulmonary fibrosis ( n = 14) 33 , dementia ( n = 5) 11 or diabetic macular edema ( n = 8) 12 and were focused primarily on safety or…”
Self-citation
Cited by
Sorted by citations
From geroscience to precision geromedicine: Understanding and managing aging
Kroemer, G., Maier, A. B., Cuervo, A. M., Gladyshev, V. N., Ferrucci, L., Gorbunova, V., Kennedy, B. K., Rando, T. A., Seluanov, A., Sierra, F., et al. (2025) · Cell · doi:10.1016/j.cell.2025.03.011 · Cited by 395
Emerging insights in senescence: pathways from preclinical models to therapeutic innovations
Mansfield, L., Ramponi, V., Gupta, K., Stevenson, T., Mathew, A. B., Barinda, A. J., Herbstein, F., & Morsli, S. (2024) · npj Aging · doi:10.1038/s41514-024-00181-1 · Cited by 88
Millar, C. L., Iloputaife, I., Baldyga, K., Norling, A. M., Boulougoura, A., Vichos, T., Tchkonia, T., Deisinger, A., Pirtskhalava, T., Kirkland, J. L., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105612 · Cited by 88
“14,27,28 To date, four human studies administering DQ as a combination senolytic therapy have been completed in various populations, including idiopathic pulmonary fi brosis, 29 diabetic kidney disease, 30 age-related osteoporosis, 31 and Alzheimer ’ s disease.”
Self-citationMacrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics
Peng, M., Li, N., Wang, H., Li, Y., Liu, H., Luo, Y., Lang, B., Zhang, W., Li, S., Tian, L., et al. (2025) · MedComm · doi:10.1002/mco2.70304 · Cited by 98
“In a study assessing the effects of intermittent D + Q on bone metabolism in postmenopausal women, no significant reduction in overall bone resorption was observed (NCT04313634) [387], highlighting the need for optimized dosing regimens.”
Advances in the management of osteoporosis
Hoong, C. W. S., Saul, D., Khosla, S., & Sfeir, J. G. (2025) · BMJ · doi:10.1136/bmj-2024-081250 · Cited by 77
“P1NP increases rapidly within two weeks and peaks within one month, and it is coupled with suppression of CTX maintained over 12 months.”
InfluentialSelf-citation
Metadata
- Authors
- Farr, J. N., Atkinson, E. J., Achenbach, S. J., Volkman, T. L., Tweed, A. J., Vos, S. J., Ruan, M., Sfeir, J., Drake, M. T., Saul, D., Doolittle, M. L., Bancos, I., Yu, K., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Monroe, D. G., & Khosla, S.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Farr, Joshua N.
- Khosla, Sundeep
- ORCID
- Venue
- Nature Medicine
- Published
- 2024-07-02
- Volume
- 30
- Issue
- 9
- Pages
- 2605-2612
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC11705617
- OpenAlex
- W4400248879
- Semantic Scholar
- 0e53cd07806a2b8dfab4ce0f5781c7d52dcac991
- Cited by
- 127
- References
- 39
- Citations by year
- 2026: 67 · 2025: 55 · 2024: 5
- FWCI
- 35.85
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21 AG065868, R01 AG076515, R01 AG055529, R37 AG13925, R33 AG61456, P01 AG062413, R01 AG 062413)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128552)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- senolytics, intermittent dosing, dasatinib, quercetin, bone metabolism, postmenopausal women, bone loss, bone resorption, bone formation, C-terminal telopeptide of type I collagen, P1NP, CDKN2A, bone mineral density, aging
- MeSH terms
- Dasatinib, Senotherapeutics, Aged, Bone and Bones, Bone Resorption, Female, Humans, Middle Aged, Peptide Fragments, Peptides, Procollagen, Quercetin, Biomarkers, Bone Density, Cellular Senescence, Postmenopause, Cyclin-Dependent Kinase Inhibitor p16, Collagen Type I
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