Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790.
Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain-related behavior and decreased the spinal expression of glial fibrillary acidic protein, whereas NE-10790 had no effect on these parameters. Furthermore, risedronate but not NE-10790 induced dose-dependent toxicity in NCTC-2472 cells in vitro. Furthermore, the direct toxic effect of risedronate on tumor cells observed in vitro opens the possibility that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis and pain, and merits further study.
Hald
Andreas
A
Department of Pharmacology and Pharmacotherapy, University of Copenhagen, Denmark.
Hansen
Rikke R
RR
Thomsen
Mette W
MW
Ding
Ming
M
Croucher
Peter I
PI
Gallagher
Orla
O
Ebetino
Frank H
FH
Kassem
Moustapha
M
Heegaard
Anne-Marie
AM
D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D001522:Behavior, Animal; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001862:Bone Resorption / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004164:Diphosphonates / Q000627:therapeutic use*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010146:Pain / Q000188:drug therapy*; D011725:Pyridines / Q000627:therapeutic use*; D000068296:Risedronic Acid; D000071681:Tartrate-Resistant Acid Phosphatase; D023041:Xenograft Model Antitumor Assays
C410028:2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D011725:Pyridines; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D000068296:Risedronic Acid; D012968:Etidronic Acid