Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)

Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include (severe) bone pain, spinal cord compromise, pathological fractures, and hypercalcemia.

Zoledronic acid is a member of a class of compounds known as bisphosphonates. Bisphosphonates are effective inhibitors of osteoclastic bone resorption and have demonstrated therapeutic efficacy in the treatments of hypercalcemia of malignancy, lytic bone disease associated with multiple myeloma, and mixed lytic and blastic bone metastases associated with breast cancer. The precise mechanism by which bisphosphonates inhibit osteoclast function is not fully understood, but may include a direct toxic effect on mature osteoclasts, an inhibition of osteoclast production from precursor cells, and an impairment of osteoclast chemotaxis to sites of active bone resorption. Osteoclasts are specialized bone cells which erode mineralized bone by secreting acids and lysosomal enzymes. In normal bone remodeling, osteoclastic bone resorption is coupled to and is in equilibrium with osteoblastic bone formation. The lytic bone destruction associated with malignant bone metastases develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The osteoclastic activating factors released by tumor cells include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines. The malignant activation of osteoclasts results in a disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted toward increased bone resorption. This relative increase in osteoclastic bone resorption results in a net loss of bone. Thus, the predominant role of the osteoclast in the pathogenesis of bone destruction and the inhibitory effects of bisphosphonates on osteoclast function have formed the rationale for the use of bisphosphonates in the treatment of osteolytic bone metastases. The common role, regardless of tumor type, of the osteoclast as the mediator of bone destruction in metastatic skeletal disease is indicated by the inhibitory effects of bisphosphonates on tumor-induced osteolysis in animal models utilizing various malignant cell lines and the effectiveness of bisphosphonates in the therapy of tumor-induced hypercalcemia arising from any type of cancer. Moreover, recent studies have specifically shown that therapy with the bisphosphonate pamidronate (Aredia) combined with antineoplastic therapy significantly reduces the proportion of patients having skeletal complications due to the lytic bone disease associated with multiple myeloma and breast cancer compared to antineoplastic therapy alone.

Inclusion criteria

• Postmenopausal women with Stage I, II or IIIa breast cancer being treated with a non-steroidal Aromatase Inhibitor (AI) .Negative bone scan (no bone metastases).
• Calculated creatinine clearance > 40 ml/min
• Documented T score of less than or equal to -1.5 on Dual Energy X-ray Absorptiionmetry (DXA) scan at the lumbar spine or femoral neck within 3 months prior to screening.
• Urine NTx > 50 nano moles(nM)based on second morning void.
• Signed informed consent.
• Ambulatory patients at least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG)0-2.
• Ability to comply with trial requirements.

Exclusion criteria

• Bone Metastases.
• Any woman of child bearing potential.
• Patients with fractures occurring within three months prior to randomization. - Greater than a 2+ protein on urine dipstick without evidence of contamination or bacteriuria (may be repeated one time, at least a day apart).
• Calculated creatinine clearance less than 30 mL/min at screening.
• Serum calcium > 2.75 mmol/L (11.0 mg/dL) or < 2.00 mmol/L (8.0 mg/dL).
• Liver Function tests (LFT)> 2.0 x upper limit of normal (ULN).
• Serum alkaline phosphatase > 1.5 x ULN. History of hypersensitivity to bisphosphonates.
• Evidence of vitamin D deficiency (serum 25-(OH) D of less than 15 ng/ml).
• History of uveitis or iritis, except when secondary to trauma, and must have resolved > 2 years prior to entry.
• A history of invasive malignancy of any organ system, treated or untreated, within the past 12 months prior to screening; excluding, basal cell or squamous cell carcinoma of the skin, colonic polyps with non-invasive malignancy which have been removed, Ductal Carcinoma in-situ (DCIS) that has been surgically removed, and Carcinoma in-situ (CIS) of the uterine cervix that has been surgically removed.
• Previous major solid organ transplant recipient or on a transplant waiting list.
• Treatment with any investigational drug within 30 days prior to randomization.
• History of hyperparathyroidism, hypoparathyroidism, Osteogenesis imperfecta, Paget's disease or any metabolic bone disease other than osteoporosis.
• Any medical condition which would interfere with the action of the study drug or limit life expectancy to less than 6 months.
• Any medical or psychiatric condition which, in the opinion of the investigator, would preclude the participant from adhering to the protocol or completing the trial.
• Prior treatment with IV bisphosphonates within the last 2 years.
• Previous use of oral bisphosphonates within the past 2 years (unless used for less than 8 weeks*). *NOTE: If used less than 8 weeks, the washout period is 6 months.
• Treatment with raloxifene, calcitonin, tibolone or hormone replacement therapy. The washout period for these medications is 6 months prior to randomization.
• Any treatment with strontium ranelate, samarium, sodium fluoride or parathyroid hormone.
• Use of systemic high dose corticosteroids at an average dose of > 7.5 mg per day of oral prednisone or equivalent for a period of three months or more prior to screening.
• Known hypersensitivity to zoledronic acid or other bisphosphonates.
• Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
• Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants).