Strontium signaling: Molecular mechanisms and therapeutic implications in osteoporosis

Osteoporosis is an important age-related bone disease characterized by increased bone turnover with insufficient bone formation relative to bone resorption. According to the current understanding of this disorder, anti-resorptive and anabolic drugs have been developed for therapeutic intervention. Another therapeutic approach consists of dissociating bone resorption and formation. Preclinical and clinical studies provided evidence that strontium (in the form of ranelate) induces beneficial effects on bone mass and resistance in animal models of bone loss and in osteoporotic patients. These effects are mediated in part by the pharmacological actions of strontium on bone metabolism, by reducing bone resorption and maintaining or increasing bone formation. Current pharmacological studies showed that strontium activates multiple signaling pathways in bone cells to achieve its pharmacological actions. Notably, activation of the calcium-sensing receptor by strontium in osteoclasts or osteoblasts leads to activation of phospholipase Cβ, inositol 1,4,5-triphosphate, release of intracellular Ca2+, and activation of MAPK ERK1/2 and Wnt/NFATc signaling. Strontium-mediated activation of these pathways results in the modulation of key molecules such as RANKL and OPG that control bone resorption, and to the regulation of genes promoting osteoblastic cell replication, differentiation and survival. This review focuses on the more recent knowledge of strontium signaling in bone cells and describes how the resulting pharmacological actions on bone metabolism have important therapeutic implications in the treatment of age-related bone loss and possibly other disorders.