Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.
Farr JN, Atkinson EJ, Achenbach SJ, Volkman TL, Tweed AJ, Vos SJ, Ruan M, Sfeir J, Drake MT, Saul D, Doolittle ML, Bancos I, Yu K, Tchkonia T, LeBrasseur NK, Kirkland JL, Monroe DG, Khosla S
- DOI
- 10.1038/s41591-024-03096-2
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/015a5d38-c045-43d2-aee1-870280146458 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingStudy design partially met−0.25★
- CitationsRetracted reference cited−0.25★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy claim is based on changes in bone turnover markers (CTx and P1NP) and BMD, which are surrogate endpoints for clinical outcomes like fractures. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or direct evidence of senescent cell clearance) nor cite validated evidence linking these surrogates to reduced fracture risk. The exploratory analyses show changes in biomarkers but no hard clinical outcomes.
“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... The secondary endpoint, percentage changes in the bone formation marker procollagen type 1…”
- 02Treatment effect not shown to be clinically meaningful
The reported effects are small relative to normal physiological variation and lack anchoring to clinically meaningful thresholds. For example, the primary endpoint showed no significant difference, and secondary endpoints showed modest changes (e.g., +16% P1NP) that are not established as clinically meaningful. The exploratory subgroup analysis showed a 2.7% increase in radius BMD, but this is a surrogate and not linked to fracture risk reduction.
“In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden... 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…”
- 03Cites retracted work
Retraction
“Quercetin: a flavonol with multifaceted therapeutic applications?”
Reference 38Find in source
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and transparently reported phase 2 RCT of intermittent senolytic therapy in postmenopausal women. The main methodological weakness is the open-label design, which introduces potential bias, and the lack of confidence intervals and statistical software identification are minor reporting gaps. Overall, the paper is methodologically sound and transparent.
Both reviewers independently scored all eight dimensions and agreed on all statuses; no divergence required reconciliation. The study is an interventional RCT; non-applicable sub-criteria (e.g., animal housing, cell lines) were excluded. The statistics verification checked only 1 test (consistent), so the broader statistical analysis remains unverified.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p = .611 · recomputed p = .610Reviewers 1, 2Primary endpoint CTx percentage change at 20 weeks: D+Q vs control
“median (interquartile range), D + Q −4.1% (−13.2, 2.6), control −7.7% (−20.1, 14.3); P = 0.611”
Taken as given: The p-value is from a two-sided Wilcoxon rank-sum test.; The reported p-value is exact.Method: Cannot recompute exactly without raw data; skipped.How we recomputed it: pZ(0.51)
- lowinternal contradictionThe abstract states 'n = 60 participants' but the CONSORT flow diagram may show different numbers due to withdrawals; this is expected.
“n = 60 participants”
AbstractFind in source - lowinternal contradictionExtended Data Table 1 shows adverse events percentages that may not sum to 100% for the D+Q group.
“Overall | 5 (17%) | 23 (77%) | | Headache | 16 (53%) | | Diarrhea | 7 (23%) | | Nausea | 5 (17%) | | Constipation | 3 (10%) | | Gastrointestinal reflux | 2 (7%) | | Vertigo | 2 (7%) | | Fatigue | 4 (13%) | | Body pain | 2 (7%) | 5 (17%)”
Table 1Find in source
Overstated conclusions
3 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
6 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2The skeletal response to D+Q was driven by women with high senescent cell burden (T3).Exploratory analyses support this, but the subgroup analysis is underpowered and post hoc, so the claim is partially supported.Evidence: In T3 group, P1NP increased (+34%, P=0.035), CTx decreased (-11%, P=0.049), and radius BMD increased (+2.7%, P=0.004).
“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)”
AbstractFind in source - supportedReviewer 1Intermittent D+Q did not reduce bone resorption in the overall group of postmenopausal women.The primary endpoint (CTx) did not differ between groups, supporting the claim.Evidence: Primary endpoint result: CTx percentage change at 20 weeks did not differ (P=0.611).
“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”
AbstractFind in source - supportedReviewers 1, 2D+Q increased bone formation marker P1NP at 2 and 4 weeks in the overall group.Secondary endpoint showed significant increases at 2 and 4 weeks, supporting the claim.Evidence: P1NP increased by +16% at 2 weeks (P=0.020) and +16% at 4 weeks (P=0.024).
“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)”
AbstractFind in source - supportedReviewer 1Intermittent D+Q administration was safe with no serious adverse events.No serious adverse events were reported, supporting the claim.Evidence: Safety section reports no serious or severe adverse events related to D+Q.
“No serious adverse events were observed.”
AbstractFind in source - supportedReviewer 2Intermittent D+Q treatment did not reduce bone resorption in the overall group of postmenopausal women.The primary endpoint (CTx change) was not significantly different between groups, supporting the claim.Evidence: Primary endpoint result: CTx change -4.1% vs -7.7%, P=0.611.
“Intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women.”
AbstractFind in source - supportedReviewer 2Intermittent D+Q administration was safe.No serious adverse events were reported, supporting the claim.Evidence: No serious or severe adverse events related to D+Q administration occurred.
“No serious adverse events were observed.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy claim is based on changes in bone turnover markers (CTx and P1NP) and BMD, which are surrogate endpoints for clinical outcomes like fractures. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or direct evidence of senescent cell clearance) nor cite validated evidence linking these surrogates to reduced fracture risk. The exploratory analyses show changes in biomarkers but no hard clinical outcomes.
“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... The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly... at 2 weeks and 4 weeks... but was not different from control at 20 weeks.”
- INADEQUATEEffect sizeThe reported effects are small relative to normal physiological variation and lack anchoring to clinically meaningful thresholds. For example, the primary endpoint showed no significant difference, and secondary endpoints showed modest changes (e.g., +16% P1NP) that are not established as clinically meaningful. The exploratory subgroup analysis showed a 2.7% increase in radius BMD, but this is a surrogate and not linked to fracture risk reduction.
“In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden... 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.”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Study-design details incomplete (controls, blinding, power)Assessed
The introduction cites foundational work on cellular senescence, senolytic compounds, and prior human studies, acknowledging their limitations (e.g., lack of control groups, small samples). The rationale for choosing bone metabolism as an outcome is well-argued, linking preclinical findings to the study hypothesis. Limitations of prior research are addressed by designing a controlled trial with a larger sample.
“Although representing important progress in the development of senolytic approaches to treat specific diseases, neither of these studies addressed the issue of safety or efficacy of systemic administration of senolytics to otherwise healthy individuals aged >60 years.”
“Although representing important progress in the development of senolytic approaches to treat specific diseases, neither of these studies addressed the issue of safety or efficacy of systemic administration of senolytics to otherwise healthy individuals aged >60 years.”
“Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss.”
“Although representing important progress in the development of senolytic approaches to treat specific diseases, neither of these studies addressed the issue of safety or efficacy of systemic administration of senolytics to otherwise healthy individuals aged >60 years.”
Randomization method (block randomization) and unit (participant) are reported. Blinding is explicitly not used (open-label) with a rationale (cost-prohibitive over-encapsulation). Power analysis is reported for the primary endpoint. Inclusion/exclusion criteria are detailed. Outlier handling is not explicitly described, but sensitivity analyses with imputation are mentioned. Controls are the placebo group. Independent replication is not applicable for a single trial. The open-label design and limited power for exploratory subgroups are notable weaknesses.
“Block randomization was performed by the study statistician to ensure balanced group assignments.”
“over-encapsulating all study medications to ensure double-blinding proved to be cost-prohibitive so, in this initial ‘proof-of-concept’ study, we elected to use an open-label design”
“This calculation demonstrated that 30 participants per group would provide the study with 90% power to detect a 19.8% difference in CTx between the D + Q and control groups.”
“Block randomization was performed by the study statistician to ensure balanced group assignments.”
“over-encapsulating all study medications to ensure double-blinding proved to be cost-prohibitive so, in this initial ‘proof-of-concept’ study, we elected to use an open-label design”
“This calculation demonstrated that 30 participants per group would provide the study with 90% power to detect a 19.8% difference in CTx between the D + Q and control groups.”
Sex (postmenopausal women) is reported and justified (adequate sample size). Age, weight, BMI, and health status are reported in baseline characteristics. Demographics include age, sex, and smoking status; race/ethnicity is not reported. Species/strain and housing are not applicable for a human trial.
“We randomized 60 eligible postmenopausal women (follicle-stimulating hormone >20 IU l −1 ; sex/gender based on self-reporting) aged 60–90 years”
“Age (years) | 74.4 (69.7, 79.2) | 71.2 (69.3, 74.8) | 0.117”
“Smoker (n, %) | 12 (40%) | 10 (33.3%) | 0.592”
“We randomized 60 eligible postmenopausal women (follicle-stimulating hormone >20 IU l −1 ; sex/gender based on self-reporting) aged 60–90 years”
“Age (years) | 74.4 (69.7, 79.2) | 71.2 (69.3, 74.8) | 0.117”
The study reports IRB approval (protocol no. 18–010546) and IND number. Written informed consent is described. Regulatory compliance is implied through IRB approval and adherence to ethical principles. The study is registered on ClinicalTrials.gov.
“All studies were performed at the Mayo Clinic outpatient Clinic Research and Trials Unit (CRTU) following IRB approval (protocol no. 18–010546; IND no. 145558).”
“After obtaining written informed consent and following comprehensive screening studies”
“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT04313634”
“All studies were performed at the Mayo Clinic outpatient Clinic Research and Trials Unit (CRTU) following IRB approval (protocol no. 18–010546; IND no. 145558).”
“After obtaining written informed consent and following comprehensive screening studies”
The investigational products (D and Q) are identified with brand names and manufacturers. Assays (P1NP, CTx, SASP) are described with manufacturers and coefficients of variation. Software (Encore v.12.2) is identified. Antibodies, cell lines, and mycoplasma testing are not applicable. Primer sequences are provided in Extended Data Table 4.
“D (100 mg per day for two consecutive days; Sprycel, Bristol Myers Squibb) plus Q (250 mg four times a day (1,000 mg per day) for three consecutive days; Quercetin Phytosome, Thorne Research).”
“P1NP by radioimmunoassay (Orion Diagnostica, coefficient of variation <9%); and CTx by one-step ELISA (Nordic Bioscience Diagnostics, coefficient of variation <8%).”
“using the Lunar iDXA (GE Medical Systems; Encore software v.12.2)”
“D (100 mg per day for two consecutive days; Sprycel, Bristol Myers Squibb) plus Q (250 mg four times a day (1,000 mg per day) for three consecutive days; Quercetin Phytosome, Thorne Research).”
“P1NP by radioimmunoassay (Orion Diagnostica, coefficient of variation <9%); and CTx by one-step ELISA (Nordic Bioscience Diagnostics, coefficient of variation <8%).”
“using the Lunar iDXA (GE Medical Systems; Encore software v.12.2)”
Statistical tests are named (Wilcoxon rank-sum, chi-squared, Spearman). Assumptions are not explicitly verified but standard non-parametric tests are used. Exact p-values are reported for primary and secondary endpoints. Effect sizes are reported as percentage differences with p-values; confidence intervals are not consistently provided. Software is not explicitly identified for statistical analysis. Data presentation includes medians with IQR and per-group n. Mathematical plausibility checks were not performed due to continuous data.
“Comparisons between the control and D + Q groups were made using the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables”
“it was significantly higher (relative to control) in the D + Q group at 2 weeks (difference from control, +16%, P = 0.020)”
“Comparisons between the control and D + Q groups were made using the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables”
“it was significantly higher (relative to control) in the D + Q group at 2 weeks (difference from control, +16%, P = 0.020)”
The data availability statement provides a concrete route: individual deidentified participant data are available as an Excel file in the supplementary material, with no restrictions. The study protocol is also available. No code was used, so code sharing is not applicable.
“Individual deidentified participant data that underlie the results reported in this article (text, tables, figures) are available as an Excel file in the . The study protocol, which includes the statistical analysis plan, is also available in the . No restrictions are placed on the availability of this data.”
“No code was used in the analyses.”
“Individual deidentified participant data that underlie the results reported in this article (text, tables, figures) are available as an Excel file in the . The study protocol, which includes the statistical analysis plan, is also available in the . No restrictions are placed on the availability of this data.”
Methods are detailed enough for replication. Trial registration is provided. CONSORT flow diagram is referenced. All outcomes are reported, including negative results. Limitations are extensively discussed. Conclusions are appropriately cautious, acknowledging exploratory nature. Funding and competing interests are disclosed.
“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT04313634”
“shows the CONSORT flow diagram for the study.”
“We recognize several limitations of our study, many of which have been discussed above.”
“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT04313634”
“shows the CONSORT flow diagram for the study.”
“We recognize several limitations of our study, many of which have been discussed above.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
1 finding · worst highReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
- Cites retracted workRecomputed
Checked 40 references by DOI: 38 verified — 1 retracted, 1 no DOI (shown, not verified).
- RETRACTED10.1016/j.fitote.2015.09.018Quercetin: a flavonol with multifaceted therapeutic applications?Reason: Retraction
- NO DOISenolytics: a major anti-aging advanceNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://doi.org/10.1038/s41591-024-03096-2LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORconsistencyAbstract“n = 60 participants”→ Use consistent notation for sample size throughout.Minor inconsistency in notation.
- MINORclarityMethods, Study design“over-encapsulating all study medications to ensure double-blinding proved to be cost-prohibitive”→ Clarify that over-encapsulation was considered but not implemented.Sentence is slightly awkward.
- MINORconsistencyAbstract“n = 60 participants”→ Consider using 'n = 60' consistently throughout.Minor inconsistency in notation.
- MINORclarityMethods, Study design“over-encapsulating all study medications to ensure double-blinding proved to be cost-prohibitive”→ Consider rephrasing for clarity: 'Double-blinding was not feasible due to the cost of over-encapsulating all study medications.'Awkward phrasing.
- MINORtypoExtended Data Table 1“5 (17%) | 23 (77%)”→ Check if the percentages sum correctly; may be a typo.Potential arithmetic inconsistency in adverse events table.
The published work is robust and transparent, but an informed reader should weigh the open-label design and the lack of confidence intervals for secondary endpoints. No erratum is warranted for the minor reporting gaps, but the retracted citation should be corrected. The paper is suitable for its proof-of-concept purpose.
- 1.HIGHotherRemove or replace the retracted reference 'Quercetin: a flavonol with multifaceted therapeutic applications?' (DOI 10.1016/j.fitote.2015.09.018) with a non-retracted source.Citing a retracted paper undermines the integrity of the reference list and may mislead readers.
- 2.HIGHreportingAdd confidence intervals for the reported effect sizes (e.g., the +16% P1NP difference) in the Results section.Confidence intervals provide precision and are expected for secondary endpoints in clinical trials.
- 3.HIGHreportingState the statistical software used for analyses (e.g., SAS, R) in the Methods, Statistical analyses section.Identifying the software is a standard reporting requirement and aids reproducibility.
- 4.MEDIUMreportingExplicitly describe how outliers were handled in the statistical analysis, or state that none were excluded.Outlier handling is a key methodological detail that is currently unclear.
- 5.MEDIUMreportingAdd a statement in the Discussion acknowledging the potential for bias due to the open-label design and the lack of blinding.The open-label design is a known limitation that should be explicitly discussed to inform readers.
- 6.MEDIUMreportingReport race/ethnicity in the baseline demographics table (Table 1) to improve generalizability.Race/ethnicity is a standard demographic variable and its absence limits assessment of external validity.
- 7.MEDIUMstatisticsAcknowledge the multiple comparisons issue in the exploratory analyses and state that p-values are exploratory or adjust them.Multiple testing can inflate false positives; transparency about this is important.
- 8.MEDIUMdata codeDeposit the deidentified participant data in a recognized repository with a DOI for long-term access.A permanent repository link is more robust than a supplementary Excel file and ensures data availability.
- 9.LOWcopyeditFix the potential arithmetic inconsistency in Extended Data Table 1 where percentages (5 (17%) | 23 (77%)) do not sum to 100%.Inconsistent percentages may indicate a typo and could confuse readers.
- 10.LOWcopyeditUse consistent notation for sample size (e.g., 'n = 60') throughout the Abstract and main text.Consistent notation improves clarity and professionalism.
- 11.LOWcopyeditRephrase the sentence about over-encapsulation in Methods, Study design for clarity: 'Double-blinding was not feasible due to the cost of over-encapsulating all study medications.'The current phrasing is awkward and could be clearer.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.