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Cost-Effective Use of Bisphosphonates in Metastatic Bone Disease - A Comparison of Bone Marker Directed Zoledronic Acid Therapy to a Standard Schedule

18 Years
Open (Enrolling)
Breast Cancer, Hypercalcemia of Malignancy, Metastatic Cancer, Musculoskeletal Complications, Pain

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Trial Information

Cost-Effective Use of Bisphosphonates in Metastatic Bone Disease - A Comparison of Bone Marker Directed Zoledronic Acid Therapy to a Standard Schedule



- Compare the frequency and timing of serious related events (e.g., fractures,
radiotherapy to bone, hypercalcemia of malignancy, orthopedic surgery, and spinal cord
compression) in patients with advanced breast cancer metastatic to the bone treated
with bone marker-directed schedule vs standard schedule zoledronic acid.


- Compare the quality of life of patients treated with these regimens.

- Compare the clinical burden of skeletal complications in these patients.

- Compare pain, performance status, and analgesic use (PPA score) in these patients.

- Compare the incidence of new bone metastases in these patients.

- Compare overall survival of these patients.

- Compare bisphosphonate use and expenditure on administration in these patients.

OUTLINE: This is an open-label, randomized, controlled, parallel-group, multicenter study.
Patients are stratified according to treatment center, gender, type of concurrent systemic
therapy at study entry (endocrine therapy [with or without trastuzumab (Herceptin^®)] vs
chemotherapy [with or without trastuzumab] vs trastuzumab alone vs chemotherapy and
endocrine therapy [with or without trastuzumab] vs no systemic anticancer treatment), prior
skeletal-related event (yes vs no), duration of bisphosphonate use for metastatic disease
prior to study entry (4-6 months vs 6-12 months), type of metastases present at study entry
(bone only vs bone and soft tissue vs bone and visceral metastases vs bone, soft tissue, and
visceral metastases). Patients are randomized to 1 of 2 treatment arms.

- Arm I (standard schedule): Patients receive zoledronic acid IV over 15 minutes once
every 3-4 weeks for 24 months.

- Arm II (bone marker-directed schedule): Patients receive zoledronic acid IV over 15
minutes once every 3-4, 8-9, or 15-16 weeks (based on serum N-telopeptide:creatinine
ratio) for 24 months.

Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months.

After completion of study therapy, patients are followed periodically for up to 3 years.

PROJECTED ACCRUAL: A total of 1,500 patients will be accrued for this study.

Inclusion Criteria


- Histologically confirmed primary breast cancer

- Advanced disease

- Radiographic confirmation of bone metastases (≥ 1 bone scan lesion must be confirmed
as metastatic by plain radiographs or CT scan/MRI)

- Must have received zoledronic acid to treat metastatic bone disease (i.e., ≥ 4
or 5 zoledronic acid treatments prior to study entry for patients receiving 4-
or 3-weekly infusions, respectively) for ≥ 4 months prior to study entry

- Any bisphosphonate to treat metastatic bone disease allowed provided it was not
given for more than 12 months prior to study entry

- No metabolic bone disease (e.g., Paget's disease of bone)

- Osteoporosis allowed

- No brain metastases

- Hormone receptor status not specified


- Male or female

- Menopausal status not specified

- WHO or ECOG performance status 0-2

- Life expectancy ≥ 6 months

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- AST and ALT ≤ 3 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- Creatinine clearance ≥ 30 mL/min

- No poor venous access

- No concurrent active dental problems, including infection of the teeth or jawbone
(maxilla or mandibular)

- No prior or current diagnosis of osteonecrosis of the jaw

- No other cancer within the past 5 years except nonmelanomatous skin cancer, carcinoma
in situ of the uterine cervix, or superficial bladder cancer treated with curative


- See Disease Characteristics

- No other prior bisphosphonate treatment within the past 3 weeks

- No treatment with systemic bone-seeking radioisotopes (e.g., strontium chloride Sr
89, samarium Sm 153 lexidronam pentasodium) within the past 3 months

- No wide-field (hemibody) radiotherapy within the past 3 months

- Recent standard-field, localized radiotherapy allowed

- No dental or jaw surgery (e.g., extractions, implants) within the past 4 weeks

- No other concurrent bisphosphonates

- No concurrent medication with drugs known to affect bone metabolism (e.g., calcitonin
or high-dose systemic corticosteroids [> 10 mg prednisolone/day or equivalent])

- Systemic or oral corticosteroids allowed for clearly indicated conditions (e.g.,
chemotherapy-induced emesis, brain metastases, compression syndromes)

- Concurrent chemotherapy, biological therapy, or endocrine therapy allowed

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:


Principal Investigator

Robert E. Coleman, MD, FRCP

Investigator Role:

Study Chair

Investigator Affiliation:

Cancer Research Centre at Weston Park Hospital



Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Breast Cancer
  • Hypercalcemia of Malignancy
  • Metastatic Cancer
  • Musculoskeletal Complications
  • Pain
  • hypercalcemia of malignancy
  • musculoskeletal complications
  • pain
  • stage IV breast cancer
  • male breast cancer
  • recurrent breast cancer
  • bone metastases
  • Breast Neoplasms
  • Neoplasms
  • Hypercalcemia
  • Neoplasm Metastasis
  • Neoplasms, Second Primary