Impact of clinically used alendronate (Fosamax) on cancer-bone metastasis and bone biology revealed by novel 3D-bone organ model systems
Alasmari, Abeer Saeed
MetadataShow full item record
OBJECTIVE: Determine the impact of clinically used anti-resorption drug alendronate (ALN) on bone cells and the capacity of bone to regenerate, and to provide insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. METHODS: Co-cultures of live mouse neonatal calvarial bone and cancer cells, PC3 prostate and breast MDA-MB-231, in a roller tube model system in the absence and presence of alendronate (ALN) and osteoprotgrin (OPG). These models were used under conditions whereby the two naturally occurring bone remodeling stages were dissociated, viz., bone resorption and formation. The used media and calvarial bones were evaluated by chemical, biochemical, histological and quantitative histomorphometric analyses. RESULTS: These studies revealed that cancer cells are unaffected to BP treatment in the presence of bone and colonize live bone irrespective to the bone remodeling stage, hence, cancer-bone metastasis/interactions are though to be ‘‘in- dependent of bone remodeling stages’’. Under resorption conditions cancer cells induce differentiation of osteoclasts and bone resorption and inclusion of alendronate (ALN) inhibited cancer-induced bone resorption at the osteoclast differentiation level. However, alendronate treated bones were adversely impacted as demonstrated by their inability to respond to stimulation for new bone formation. These data indicated that the bone stem/progenitor cells appeared non-vital after alendronate exposure. Similarly, in the formation model system the new bone formation was also limited. Mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN was consistent with the organ culture results. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminish endosteal cell population and degenerated osteocytes within the mineralized bone matrix.