Fragility of Evidence for the Efficacy of Anti-Fracture Medications.

Tran, N; Tran, TS; Nguyen, TV

Fragility of Evidence for the Efficacy of Anti-Fracture Medications.

Tran, N Tran, TS Nguyen, TV

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Publisher:: ENDOCRINE SOC
Publication Type:: Journal Article
Citation:: J Clin Endocrinol Metab, 2025, 111, (1), pp. e70-e82
Issue Date:: 2025-12-18

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Field	Value	Language
dc.contributor.author	Tran, N
dc.contributor.author	Tran, TS
dc.contributor.author	Nguyen, TV
dc.date.accessioned	2026-04-13T04:51:15Z
dc.date.available	2026-04-13T04:51:15Z
dc.date.issued	2025-12-18
dc.identifier.citation	J Clin Endocrinol Metab, 2025, 111, (1), pp. e70-e82
dc.identifier.issn	0021-972X
dc.identifier.issn	1945-7197
dc.identifier.uri	http://hdl.handle.net/10453/194676
dc.description.abstract	CONTEXT: A P value and statistical significance, conventionally considered for assessing an intervention's effectiveness, are usually misused and misinterpreted. OBJECTIVE: To quantify fragility of randomized controlled trial (RCT) evidence for anti-fracture efficacy. METHODS: This retrospective analysis included 27 phase 3/4 RCTs in high-impact medical journals which assessed anti-fracture efficacy, allocated participants in a 1:1 ratio to pharmacological intervention or control, and reported a statistically significant result. Fragility of the results were assessed using the Fragility Index (FI) and Fragility Quotient (FQ). FI is the minimum number of participants in a positive analysis result for whom reversing the reported status would eliminate statistical significance, while FQ is a function of FI to the sample size. RESULTS: The median FI was 9 (IQR: 4, 19), indicating that adding 9 fracture patients (∼0.51% of the study size) to the intervention group would eliminate the documented evidence of anti-fracture efficacy. Notably, the number of participants lost to follow-up exceeded the corresponding FI in 60% of analyses. The most robust evidence for anti-fracture efficacy was documented for romosozumab (FI: 19.5; IQR: 7.0, 31.5); whereas the least found for denosumab (4; 3, 17) and calcium/vitamin D supplementation (7.0; 2.3, 16.8). Anti-fracture efficacy evidence improved among the results that considered fractures the primary endpoint measure (14; 11, 33) or those with P value < .001 (26; 18, 42). CONCLUSION: The existing RCT evidence of anti-fracture efficacy is highly fragile. The FI, its comparison with loss to follow-up and FQ should be incorporated into clinical guideline development and doctor-patient risk communication.
dc.format	Print
dc.language	eng
dc.publisher	ENDOCRINE SOC
dc.relation.ispartof	J Clin Endocrinol Metab
dc.relation.isbasedon	10.1210/clinem/dgaf332
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine
dc.subject.classification	Endocrinology & Metabolism
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Randomized Controlled Trials as Topic
dc.subject.mesh	Bone Density Conservation Agents
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Fractures, Bone
dc.subject.mesh	Female
dc.subject.mesh	Osteoporotic Fractures
dc.subject.mesh	Clinical Trials, Phase III as Topic
dc.subject.mesh	Humans
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Female
dc.subject.mesh	Bone Density Conservation Agents
dc.subject.mesh	Fractures, Bone
dc.subject.mesh	Randomized Controlled Trials as Topic
dc.subject.mesh	Clinical Trials, Phase III as Topic
dc.subject.mesh	Osteoporotic Fractures
dc.subject.mesh	Humans
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Randomized Controlled Trials as Topic
dc.subject.mesh	Bone Density Conservation Agents
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Fractures, Bone
dc.subject.mesh	Female
dc.subject.mesh	Osteoporotic Fractures
dc.subject.mesh	Clinical Trials, Phase III as Topic
dc.title	Fragility of Evidence for the Efficacy of Anti-Fracture Medications.
dc.type	Journal Article
utslib.citation.volume	111
utslib.location.activity	United States
utslib.for	1103 Clinical Sciences
utslib.for	1114 Paediatrics and Reproductive Medicine
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/UTS Ageing Research Collaborative (UARC)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Wellbeing and Health
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2026-04-13T04:51:14Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	111
utslib.citation.issue	1

Abstract:

CONTEXT: A P value and statistical significance, conventionally considered for assessing an intervention's effectiveness, are usually misused and misinterpreted. OBJECTIVE: To quantify fragility of randomized controlled trial (RCT) evidence for anti-fracture efficacy. METHODS: This retrospective analysis included 27 phase 3/4 RCTs in high-impact medical journals which assessed anti-fracture efficacy, allocated participants in a 1:1 ratio to pharmacological intervention or control, and reported a statistically significant result. Fragility of the results were assessed using the Fragility Index (FI) and Fragility Quotient (FQ). FI is the minimum number of participants in a positive analysis result for whom reversing the reported status would eliminate statistical significance, while FQ is a function of FI to the sample size. RESULTS: The median FI was 9 (IQR: 4, 19), indicating that adding 9 fracture patients (∼0.51% of the study size) to the intervention group would eliminate the documented evidence of anti-fracture efficacy. Notably, the number of participants lost to follow-up exceeded the corresponding FI in 60% of analyses. The most robust evidence for anti-fracture efficacy was documented for romosozumab (FI: 19.5; IQR: 7.0, 31.5); whereas the least found for denosumab (4; 3, 17) and calcium/vitamin D supplementation (7.0; 2.3, 16.8). Anti-fracture efficacy evidence improved among the results that considered fractures the primary endpoint measure (14; 11, 33) or those with P value < .001 (26; 18, 42). CONCLUSION: The existing RCT evidence of anti-fracture efficacy is highly fragile. The FI, its comparison with loss to follow-up and FQ should be incorporated into clinical guideline development and doctor-patient risk communication.

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http://hdl.handle.net/10453/194676