Strontium ranelate: New insights into its dual mode of action

Abstract

Strontium ranelate is a newly developed drug that acts as an effective antiosteoporotic therapy in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate induces opposite effects on bone resorption and formation. Preclinical studies showed that this dual effect results in increased bone mass and improved bone microarchitecture and strength in intact rodents, and in prevention of bone loss in osteopenic animals. Histomorphometric analysis of unpaired iliac crest bone biopsies in postmenopausal osteoporotic patients treated with strontium ranelate for 3 years showed that the drug increased bone formation, assessed by both the mineralization rate and osteoblast surface, and tended to decrease the osteoclast surface, compared with the placebo group. Three-dimensional micro-computed tomography analysis of the bone biopsies consistently showed a higher number of trabeculae, decreased trabecular separation, and an increase in cortical thickness, which provides evidence for a better trabecular and cortical bone microarchitecture in treated patients compared with the placebo group. Some mechanisms that underlie the beneficial effects of strontium ranelate on bone metabolism and strength have now been identified. In vitro analyses showed that strontium activates the calcium-sensing receptor. We, however, showed that strontium ranelate activates cell replication and downstream ERK1/2 signaling in osteoblasts from calcium-sensing receptor-null mice, indicating that, in addition to the calcium-sensing receptor, another receptor could mediate the effect of strontium ranelate on osteoblastic cell replication. Other in vitro studies showed that strontium ranelate can activate the osteogenic differentiation of bone marrow stromal cells by activating cyclo-oxygenase 2 (COX-2)-mediated prostaglandin E 2 production. Finally, recent data indicate that strontium ranelate can upregulate osteoprotegerin (OPG) and decrease receptor activator of nuclear factor kappa B (RANK) ligand expression in human osteoblastic cells, suggesting that strontium ranelate may reduce bone resorption by modulating the RANK/RANK-ligand/OPG system, which is essential for osteoclastogenesis. These recent data provide new insights into the mechanism of action of strontium ranelate and give biochemical support to cell physiology which explain the opposite effects of strontium ranelate on bone formation and resorption.