Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.
Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma. 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks, all animals had a paraprotein. Animals were treated with zoledronic acid (120 microg/kg, subcutaneously, twice weekly) or vehicle, from the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks, respectively. All animals injected with tumor cells developed osteolytic lesions, a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a decrease in bone mineral density. Zoledronic acid prevented the formation of lesions, prevented cancellous bone loss and loss of bone mineral density, and reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. In separate experiments, Kaplan-Meier analysis demonstrated a significant increase in survival after treatment with zoledronic acid when compared with control (47 vs. 35 days). A single dose of zoledronic acid was also shown to be effective in preventing the development of osteolytic bone disease. These data show that zoledronic acid is able to prevent the development of osteolytic bone disease, decrease tumor burden in bone, and increase survival in a model of established myeloma.
Croucher
Peter I
PI
Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Headington, Oxford, United Kingdom. peter.croucher@ndos.ox.ac.uk
De Hendrik
Raeve
R
Perry
Mark J
MJ
Hijzen
Anja
A
Shipman
Claire M
CM
Lippitt
Jennifer
J
Green
Jonathan
J
Van Marck
Eric
E
Van Camp
Ben
B
Vanderkerken
Karin
K
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D018572:Disease-Free Survival; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid