The goal of this clinical research study is to learn if Xofigo® (also called Ra-223 dichloride) combined with hormone therapy and denosumab can help to control breast cancer that has spread to the bones and/or bone marrow. The safety of this study drug combination will also be studied.

This is an investigational study. Denosumab and the hormone therapies used in this study are FDA-approved and commercially available for the treatment of metastatic breast cancer. Ra-223 dichloride is FDA-approved and commercially available for the treatment of bone metastases. It is considered investigational to use the combination of Ra-223 dichloride, hormone therapy and denosumab to treat patients with bone cancer that has spread to the bones.

The study doctor can explain how the study drugs are designed to work.

Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive Ra-223 dichloride by vein over no more than 1 minute on Day 1 of each 28-day study cycle.

You will also receive denosumab as an injection under the skin on Day 1 of Cycles 1- 6.

You will also receive hormone therapy while on study. Your doctor will discuss with you what type of hormone therapy you will have, how it will be given, and its risks.

Study Visits:

On Day 1 of Cycle 1, blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2-5:

• You will have a physical exam.
• Blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycle 6:

• Blood (about 2 teaspoons) and urine will be collected for routine tests.
• Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic biomarkers.
• Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic testing.
• You will have a PET-CT scan and a bone scan to check the status of the disease. If the doctor thinks it is needed, you will also have an MRI.

Length of Study Participation:

You may continue taking the study drugs for up to 6 cycles. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation will be over after the end-of-study visit.

End-of-Study Visit:

After your last dose of study drug:

• You will have a physical exam.
• Blood (about 2 teaspoons) and urine will be collected for routine tests.
• Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic biomarkers.
• Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic testing.
• You will have a PET-CT scan and either a bone scan or a CT scan to check the status of the disease. If the doctor thinks it is needed, you will also have an MRI.
• If the doctor thinks it is needed, you will have a bone marrow aspiration/biopsy to check the status of the disease.

Inclusion Criteria:

1. Stage IV breast cancer with metastases to the bone and/or bone marrow.
2. Pathological or radiographically confirmation of metastases to the bone and/or bone marrow. (The definition of radiologic diagnosis of bone metastasis is based on typical and highly reliable imaging findings in studies such as bone scan (new or multiple TC99m positive lesions), PET/CT (new or multiple FRG positive lesions), and MRI (typical T1w replacement, T2w positive and T1 plus contrast media positive) for bone metastasis with 2 or more lesions. If the bone metastasis is highly suspected or not well defined by imaging, bone biopsy is necessary for confirmation.)
3. Visible uptake in at least one lesion on bone scanning prior to radium therapy.
4. No limit in number of prior hormonal agents in metastatic breast cancer; only one prior chemotherapy is allowed in metastatic setting. Anti-HER2 targeting therapy, CDK4/6 inhibitor, other targeted therapy (e.g., mTOR or PI3K inhibitor) in combination with hormonal treatment will be counted as one hormonal agent. Any anti-HER2 targeting therapy in combination with chemotherapy will not be counted as one additional treatment.
5. Breast tumors with hormone receptor positive disease (ER+/PR+, ER+/PR- regardless of HER2 status).
6. ECOG performance score of 0, 1.
7. Age =/> 18 years.
8. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF).
9. Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 6 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.
10. Acceptable hematology and serum biochemistry screening values: White Blood Cell Count (WBC) =/> 3,000/mm3 Absolute Neutrophil Count (ANC) =/> 1,500/mm3 Platelet (PLT) count =/> 100,000/mm3 Hemoglobin (HGB) =/> 10 g/dl Total bilirubin level </=2.0 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3.0 x ULN Creatinine </= 1.5 x ULN
11. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.

Exclusion Criteria:

1. Following breast cancer disease conditions are not eligible: A) Single Bone Lesion. B)Two or more visceral metastasis C) Single visceral lesion < 2cm without any laboratory changes or clinical symptoms due to the metastatic lesion is permitted. D)Presence of brain metastases E) Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). T F) Impending fracture, spinal cord compression, and/or potentially unstable compression fracture of vertebral body with possibility of cord compression. G) Life expectancy severely limited by concomitant illness (less than 12 months). H) Concurrent external beam radiation therapy to non target lesion is permitted.
2. Following prior treatments are not eligible. A) Use of any investigational agent within 30 days preceding enrollment. B) Treatment with cytotoxic chemotherapy within previous 4 weeks C) Failure to achieve </= Grade 2 AE resolution from cytotoxic chemotherapy administered more than 4 weeks previous (however, ongoing neuropathy is permitted). D) Received systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188, or Ra-223 dichloride) for the treatment of bony metastases.
3. Following medical conditions are not eligible. A) Other malignancy treated within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer or cervical dysplasia) B) Any other serious illness or medical condition, such as but not limited to: Any infection =/> National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade 2. C) Cardiac failure New York Heart Association (NYHA) III or IV. D) Crohn's disease or ulcerative colitis-Bone marrow dysplasia or Myelodysplastic syndrome.
4. Women who are pregnant or breast-feeding. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test.
5. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
6. Major surgery within 30 days prior to start of study drug.
7. Excluded therapies and medications, previous and concomitant: A) Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, biologic therapy, anti-HER 2 targeting therapies, or tumor embolization) other than Ra 223 dichloride. Concurrent external beam radiation therapy is permitted.B) Prior use of Ra-223 dichloride. C) Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry (signing of the informed consent form).