Inclusion Criteria:

1. Patients with advanced breast cancer with radiographic confirmation of bone
metastases (minimum of one bone scan lesion must be confirmed as metastatic on plain
radiographs or CT/MR imaging)

2. Men or women aged ≥ 18 years

3. WHO (ECOG) performance status 0-2

4. Women of child-bearing potential must be using a reliable and appropriate method of
contraception

5. Urine sample taken and sent to the central laboratory for baseline Ntx analysis

6. Written informed consent.

Exclusion Criteria:

1. Bisphosphonate treatment within the 4 weeks prior to planned first study treatment

2. Abnormal renal function as evidenced by a calculated creatinine clearance < 30
ml/minute

3. Poor venous access

4. Metabolic bone disease

5. Unable to comply with study procedures, especially the reliable collection of urine
samples for bone resorption marker measurements

6. Estimated life expectancy of < 6 months

7. Treatment with systemic bone seeking radioisotopes within the 3 months prior to study
entry

8. Wide field (hemi-body) radiotherapy within the 3 months prior to study entry

9. Concomitant medication with drugs known to affect bone metabolism

10. Pregnancy or breast-feeding

11. Current active dental problems including infection of the teeth or jawbone (maxilla
or mandibular), or a current or prior diagnosis of osteonecrosis of the jaw (ONJ)

12. Recent (within 4 weeks of study entry*) or planned dental or jaw surgery