Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis.
BACKGROUND
Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis.


METHODS
Mice (n = 6-10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.2 breast cancer cells, which express green fluorescent protein (GFP) and luciferase and metastasize to bone. Zoledronic acid was given as daily, weekly, or single doses at a cumulative dose of 98-100 microg/kg body weight, equivalent to the 4-mg intravenous dose given to patients. Clodronate was given as a daily dose (530 microg/kg/day), equivalent to the daily 1600-mg oral clinical dose given to patients. Bone destruction was measured by radiography, x-ray absorptiometry or tomography, and histomorphometry (as the ratio of bone volume to tissue volume). Skeletal tumor burden was measured by histomorphometry (as the ratio of tumor burden to soft tissue volume [TB/STV]) and luciferase activity. All statistical tests were two-sided.


RESULTS
In treatment protocols, daily clodronate was less effective at decreasing the TB/STV ratio than daily (53% versus 87%, difference = 34%, 95% confidence interval [CI] = 16% to 44%, P < .001) or weekly (53% versus 90%, difference = 37%, 95% CI = 19% to 46%, P < .001) zoledronic acid-dosing regimens. Compared with vehicle, a single dose of zoledronic acid decreased tumor burden by only 16% (95% CI = 9% to 22%, P < .001). In preventive protocols, daily clodronate and daily or weekly zoledronic acid decreased the TB/STV ratio by 49% (95% CI = 40% to 57%, P = .006), 83% (95% CI = 68% to 98%, P < .001), and 66% (95% CI = 47% to 84%, P < .001), respectively, compared with vehicle, whereas a single dose of zoledronic acid decreased tumor burden by only 13% (95% CI = -2% to 28%, P = .84). Mice treated with a daily preventive regimen of clodronate or with a daily or weekly preventive regimen of zoledronic acid showed a decreased B02/GFP.2 cell tumor burden compared with vehicle, whereas a single preventive dose of zoledronic acid had no effect.


CONCLUSIONS
Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model.
Daubiné
Florence
F
INSERM Research Unit U.664, Université Claude Bernard Lyon 1, Lyon, France.
Le Gall
Céline
C
Gasser
Juerg
J
Green
Jonathan
J
Clézardin
Philippe
P
D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D017024:Chemotherapy, Adjuvant; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D010014:Osteolysis / Q000188:drug therapy; D012107:Research Design; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D049452:Green Fluorescent Proteins; D000077211:Zoledronic Acid; D008156:Luciferases