Inclusion Criteria:

1. Patients with metastatic breast cancer with radiologically confirmed bone
metastases.

2. On intravenous bone-targeted therapy (bisphosphonate or subcutaneous (SC) denosumab)
for at least 3 months.

3. ECOG ≤ 2

4. Life expectancy >3 months.

5. No changes in the type of systemic chemotherapy, endocrine therapy or biological
therapy (i.e. trastuzumab, lapatinib) treatment in the 4 weeks prior to study entry
or anticipated changes in the 4 weeks after entering the study. (Markers of bone
formation can be affected by a change in systemic therapies).

6. Ability to provide informed consent and complete study evaluations.

Exclusion Criteria:

1. Prior hypersensitivity to either IV bisphosphonate therapy or SC denosumab,
doxycycline or tetracyclines.

2. Patients with myasthenia gravis

3. Patients taking hepatic enzymes inducers such as phenytoin, barbiturates and
carbamazepine

4. Patients with rapidly progressive non-bone metastases for whom delaying a change in
systemic anti-cancer treatment in the first 4 weeks of the study could have a
detrimental impact on patient outcome.

5. Women of child bearing potential who are unwilling to use acceptable methods of
contraception while on study.

6. Pregnancy or lactation.

7. Clotting disorder that would preclude bone marrow aspirate and trephine biopsy.
(Patients on Fragmin or Daltaperin are allowed on study)