RANKL Inhibition and Mammographic Breast Density (TRIDENT)

March 25, 2026 updated by: Washington University School of Medicine

Randomized Clinical Trial of RANKL Inhibition With Denosumab on Mammographic Density in Premenopausal Women With Dense Breasts (TRIDENT)

Data supporting a role for RANKL signaling in mammographic density and breast cancer development has begun to emerge, but clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in primary breast cancer prevention are not yet available. The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts. To address this, the investigators have developed this clinical trial to quantify the impact of RANKL inhibition on mammographic density in high-risk premenopausal women with dense breasts and to determine the effect of RANKL inhibition on markers of proliferation and biomarkers of breast cancer risk. Successful demonstration that RANKL inhibition reduces mammographic density could open up additional approaches to primary breast cancer prevention in high-risk premenopausal women, who do not have dominant genetic predisposition.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
210

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • Name: Adetunji T Toriola, M.D., Ph.D. MPH
  • Phone Number: 314-286-2668
  • Email: a.toriola@wustl.edu

Study Contact Backup

Study Locations

  • United States
    • Missouri
      • St Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Female.
  • Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a partcipant is premenopausal)
  • At least 40 years of age.
  • Dense breasts on routine mammogram (BI-RADS Category C and D)
  • Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria:

  • History of breast or any other invasive cancer except for DCIS (ductal carcinoma in situ) who received only lumpectomy, LCIS (lobular carcinoma in situ), atypical hyperplasia, non-melanoma skin cancer, carcinoma in situ of the cervix.
  • Current use of tamoxifen, aromatase inhibitors, or bisphosphonates, or RANKL inhibitors
  • Concurrent participation in another cancer chemoprevention trial (unless no longer receiving the intervention).
  • Pregnant, lactating, or planning to get pregnant while the trial is ongoing.
  • Recent history of invasive dental procedure (e.g. tooth extraction, dental implant, oral surgery).
  • Unhealed and/or planned dental/oral surgery.
  • History of osteonecrosis/osteomyelitis of the jaw.
  • History of osteoporosis or severe osteopenia.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Denosumab
  • Subcutaneous injection of denosumab at a dose of 60 mg at two time points: baseline and 6 months
  • Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12-month mammographic breast density examination.
  • Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36-month optional assessment may also occur.
  • Biopsies and blood draws will occur for research purposes at baseline and 12 months.
Drug: Denosumab
Denosumab is commercially available and will be provided at no cost to participants.
Other Names:
  • Prolia
Procedure: Core needle biopsy
Baseline and 12 months
Procedure: Blood draw
Baseline and 12 months
Drug: Calcium
-Participants will be instructed to take calcium (at least 500 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.
Drug: Vitamin D3
Participants will be instructed to take vitamin D3 (at least 400 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.
Placebo Comparator: Placebo
  • Subcutaneous injection of the placebo at a dose of 60 mg at two time points: baseline and 6 months
  • Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12 month mammographic breast density examination
  • Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36 month optional assessment may also occur.
  • Biopsies and blood draws will occur for research purposes at baseline and 12 months.
Procedure: Core needle biopsy
Baseline and 12 months
Procedure: Blood draw
Baseline and 12 months
Drug: Placebo
Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.
Drug: Calcium
-Participants will be instructed to take calcium (at least 500 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.
Drug: Vitamin D3
Participants will be instructed to take vitamin D3 (at least 400 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in mammographic breast density between the two arms as measured by volumetric percent density
Time Frame: From baseline to 12 months
-The investigators will use volumetric percent density (VPD) as the primary mammographic breast density measure.
From baseline to 12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Change in mammographic breast density between the two arms as measured by volumetric percent density
Time Frame: From baseline to 24 months
From baseline to 24 months
Change in mammographic breast density between the two arms as measured by volumetric percent density
Time Frame: From 12 months to 24 months
From 12 months to 24 months
Change in expression gene related to RANK in breast tissue compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression gene related to progesterone in breast tissue compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression gene related to metabolics in breast tissue compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression gene related to immune in breast tissue compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression gene related to inflammatory in breast tissue compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of markers of breast epithelial and stromal proliferation compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in breast metabolome compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Time Frame
Change in expression of RANKL pathway genes compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of progesterone receptor and progesterone-regulated pathway genes compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of markers of epithelial proliferation compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of markers of stromal proliferation and growth factors compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of immune markers compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Change in expression of inflammatory markers compared between the two arms
Time Frame: Baseline and 12 months
Baseline and 12 months
Correlations between gene expression within the breast tissue and within the blood
Time Frame: Baseline
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institutes of Health (NIH)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Adetunji T Toriola, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 27, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 17, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 16, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 21, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 26, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 31, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 25, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 201907039

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified participant data used in generating tables and figures in published manuscripts.

IPD Sharing Time Frame

IPD will be shared beginning 12 months, and ending 24 months following article publication.

IPD Sharing Access Criteria

IPD will be shared with investigators who propose a methodologically sound proposal. These proposals should have been reviewed and approved by independent review committees, including institutional review boards. Proposals should be directed to the Principal Investigator, who will review the request with other co-Investigators. Proposals may also be subject to further review by the Protocol Review Monitoring Committee and Institutional Review Board at Principal Investigator's institution. Requestors will need to sign an institutional data access agreement to gain access to the data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Dense Breasts

Clinical Trials on Denosumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings