Dense BreastsPhase 2TRIDENTNCT04067726
RANKL Inhibition and Mammographic Breast Density
A Phase 2 study testing Denosumab, Calcium and Vitamin D3 in people with Dense Breasts, run by Washington University School of Medicine at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 40 years and older, women only
- Conditions the study is for
- Dense Breasts
- What is being tested?
- Denosumab, Calcium and Vitamin D3
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 210 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Aug 2019to 30 Sep 2027
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Female.
- Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a participant 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: 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.
- Conditions
- Dense Breasts
- Being tested
- Denosumab, Placebo, Calcium, Vitamin D3, Core needle biopsy
- Keywords
- Mammographic density, Breast cancer, RANKL, Denosumab, Prevention, Premenopausal
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DenosumabDrug
Also called Prolia
Denosumab is commercially available and will be provided at no cost to participants.
PlaceboDrug
Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.
CalciumDrug
-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.
Vitamin D3Drug
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.
Core needle biopsyProcedure or surgery
Baseline and 12 months
Blood drawProcedure or surgery
Baseline and 12 months
| Study group | Role | What they receive |
|---|---|---|
| Denosumab | Experimental | * 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. Receives: Drug: Denosumab; Drug: Calcium; Drug: Vitamin D3; Procedure: Core needle biopsy; Procedure: Blood draw |
| Placebo | Placebo comparator | * 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. Receives: Drug: Placebo; Drug: Calcium; Drug: Vitamin D3; Procedure: Core needle biopsy; Procedure: Blood draw |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change of Volumetric Percent Density Compared Between Baseline and 12 Months
-The investigators used volumetric percent density (VPD) as the primary mammographic breast density measure. The VPD percent change at 12 months from baseline was calculated as volumetric percent density at 12 months divided by baseline volumetric percent density minus 1*100 (i.e., unit of percentage).
Measured: At baseline and at 12 months
Secondary outcomes (2)
Percent Change of Volumetric Percent Density Compared Between Baseline and 24 Months
The VPD percent change at 12 months from baseline was calculated as volumetric percent density at 24 months divided by baseline volumetric percent density minus 1*100 (i.e., unit of percentage).
Measured: At baseline and 24 months
Percent Change of Volumetric Percent Density Compared Between Baseline and 36 Months
The VPD percent change at 12 months from baseline was calculated as volumetric percent density at 36 months divided by baseline volumetric percent density minus 1*100 (i.e., unit of percentage).
Measured: At baseline and 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2019
- Study start27 Aug 2019
- Primary completion17 Sep 2025
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Dense BreastsStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Stratified permuted block randomized design will be used to generate the randomization table where permuted block randomization will be used for each stratum by age, with a varying block size of 4 and 6.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 210 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Adetunji T Toriola, M.D., Ph.D., Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04067726
- Sponsor's protocol ID
- 201907039
- Other IDs
- R37CA235602
- Acronym
- TRIDENT
- Status last verified
- Oct 2026
- First submitted
- 16 Aug 2019
- Last updated
- 9 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified participant data used in generating tables and figures in published manuscripts.
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Clinical Trial of RANKL Inhibition With Denosumab on Mammographic Density in Premenopausal Women With Dense Breasts (TRIDENT)
- ClinicalTrials.gov ID
- NCT04067726
- Acronym / sponsor ID
- TRIDENT / 201907039
- Conditions
- Dense Breasts
- Keywords
- Mammographic density, Breast cancer, RANKL, Denosumab, Prevention, Premenopausal
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 210 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 27 Aug 2019 (actual)
- Primary completion
- 17 Sep 2025 (actual)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 26 Aug 2019 (actual)
- Results
- Posted 9 Oct 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Stratified permuted block randomized design will be used to generate the randomization table where permuted block randomization will be used for each stratum by age, with a varying block size of 4 and 6.
| Arm | Type | Receives |
|---|---|---|
| Denosumab | Experimental | Drug: Denosumab, Drug: Calcium, Drug: Vitamin D3, Procedure: Core needle biopsy, Procedure: Blood draw* 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. |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Calcium, Drug: Vitamin D3, Procedure: Core needle biopsy, Procedure: Blood draw* 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. |
Who may qualify
- Ages
- 40 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Female.
- Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a participant 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.
Key exclusion criteria (8 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DenosumabAlso: ProliaDenosumab is commercially available and will be provided at no cost to participants. | Drug | Denosumab |
| PlaceboPlacebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe. | Drug | Placebo |
| 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 | Denosumab, Placebo |
| Vitamin D3Participants 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. | Drug | Denosumab, Placebo |
| Core needle biopsyBaseline and 12 months | Procedure or surgery | Denosumab, Placebo |
| Blood drawBaseline and 12 months | Procedure or surgery | Denosumab, Placebo |
Primary outcome
Percent Change of Volumetric Percent Density Compared Between Baseline and 12 Months
Time frame: At baseline and at 12 months
-The investigators used volumetric percent density (VPD) as the primary mammographic breast density measure. The VPD percent change at 12 months from baseline was calculated as volumetric percent density at 12 months divided by baseline volumetric percent density minus 1*100 (i.e., unit of percentage).
2 secondary outcomes
Percent Change of Volumetric Percent Density Compared Between Baseline and 24 Months
Time frame: At baseline and 24 months
Percent Change of Volumetric Percent Density Compared Between Baseline and 36 Months
Time frame: At baseline and 36 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of MedicineLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified participant data used in generating tables and figures in published manuscripts.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adetunji T Toriola, M.D., Ph.D. principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Denosumab, Calcium and Vitamin D3 in people with Dense Breasts, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 9 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Change of Volumetric Percent Density Compared Between Baseline and 12 Months (time frame: At baseline and at 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2026.