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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
The primary objective of this study is to establish if once a year 5mg dosing of zoledronic acid is sufficient to suppress and maintain urine NTx within normal range at 12 months post-dosing in postmenopausal early breast cancer patients.
Allan Lipton, MD
Milton S. Hershey Medical Center
United States: Food and Drug Administration
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