This trial will evaluate two separate groups of patients with stage IIIB/IV non-small cell lung cancer. The objective of Group 1 is to investigate an FDA-approved drug in stage IIIB/IV non-small cell lung cancer patients that has spread to the bones. The objective of Group 2 is to see if a blood test can be used to predict when cancer-related bone lesions develop. This trial is seeking patients 18 years or older that have been diagnosed with Stage IIIB or Stage IV non-small cell lung cancer that cannot be treated by surgery.

Inclusion Criteria:

• Age greater than or equal to 18 years
• Histologically confirmed NSCLC (squamous cell carcinoma, adenocarcinoma, large cell carcinoma).
• Unresectable Stage IIIB with pleural effusion or stage IV NSCLC
• ECOG performance status of 0 or 1

Exclusion Criteria:

• Patients who received an IV bisphosphonate (e.g.pamidronate; zoledronic acid)
• Patients who received an oral bisphosphonate therapy in the 6 months prior to screening (alendronate; etidronate; risedronate; tiludronate; ibandronate)
• Patients who are currently receiving any investigational drugs that are suspected to have renal toxicity and/or are excreted by the kidneys
• Known clinically significant hypersensitivity to zoledronic acid or other bisphosphonates or any of the excipients in the formulation of zoledronic acid (mannitol, sodium citrate)
• Abnormal renal function or creatinine clearance
• Unstable brain metastasis
• Women of childbearing potential not using a medically recognized form of contraception, as well as women who are breastfeeding
• Patients with nonmalignant conditions which would confound the evaluation of the primary endpoint, impair tolerance of therapy, or prevent compliance to the protocol