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NCT Number: NCT04067726

RANKL Inhibition and Mammographic Breast Density

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.

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This study is active but is not currently recruiting participants.

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Key information

Conditions

Dense Breasts Breast Diseases Breast Neoplasms Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

40 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Denosumab

Drug

Denosumab is commercially available and will be provided at no cost to participants.

Other names: Prolia

Placebo

Drug

Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.

calcium

Drug

-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 D3

Drug

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 biopsy

Procedure

Baseline and 12 months

Blood draw

Procedure

Baseline and 12 months

Primary outcomes

  1. 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.

Secondary outcomes

  1. Change in mammographic breast density between the two arms as measured by volumetric percent density

    Time frame: From baseline to 24 months

  2. Change in mammographic breast density between the two arms as measured by volumetric percent density

    Time frame: From 12 months to 24 months

  3. Change in expression gene related to RANK in breast tissue compared between the two arms

    Time frame: Baseline and 12 months

  4. Change in expression gene related to progesterone in breast tissue compared between the two arms

    Time frame: Baseline and 12 months

  5. Change in expression gene related to metabolics in breast tissue compared between the two arms

    Time frame: Baseline and 12 months

  6. Change in expression gene related to immune in breast tissue compared between the two arms

    Time frame: Baseline and 12 months

  7. Change in expression gene related to inflammatory in breast tissue compared between the two arms

    Time frame: Baseline and 12 months

  8. Change in expression of markers of breast epithelial and stromal proliferation compared between the two arms

    Time frame: Baseline and 12 months

  9. Change in breast metabolome compared between the two arms

    Time frame: Baseline and 12 months

Sponsors and collaborators

Lead sponsor

Washington University School of Medicine

Other

Collaborators

  • National Institutes of Health (NIH)

Registry information

Official study title

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

Acronym: TRIDENT

Important dates

Study start
2019
Primary completion
2025
Study completion
2026
First posted
Aug 26, 2019
Registry last updated
Mar 31, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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