Strontium Ranelate Improves Bone Resistance by Increasing Bone Mass and Improving Architecture in Intact Female Rats

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Abstract
Strontium ranelate given to intact rats at doses up to 900 mg/kg/day increases bone resistance, cortical and trabecular bone volume, micro-architecture, bone mass, and total ALP activity, thus indicating a bone-forming activity and an improvement of overall bone tissue quality. Introduction: Various anti-osteoporotic agents are available for clinical use; however, there is still a need for drugs able to positively influence the coupling between bone formation and bone resorption to increase bone mass and bone strength. Strontium ranelate (PROTELOS), a new chemical entity containing stable strontium (Sr), was tested for its capacity to influence bone quality and quantity. Materials and Methods: The long-term effects of strontium ranelate on bone were investigated in intact female rats treated with various doses of strontium ranelate (0, 225, 450, and 900 mg/kg/day) for 2 years. In a second series of experiments, the effects of 625 mg/kg/day were evaluated in intact male and female rats for the same period of time. Bone mineral mass and mechanical properties were evaluated at various skeletal sites (vertebra and femur), and bone tissue micro-architecture was evaluated by static histomorphometry at the tibio-fibular junction (cortical bone) and at the tibia metaphysis (trabecular bone). Plasma total alkaline phosphatase (ALP) activity and serum levels of insulin-like growth factor-I (IGF-I) were also assessed. Results: In female rats treated with strontium ranelate over 2 years, dose-dependent increases of bone strength and bone mass of the vertebral body (containing a large proportion of trabecular bone) and of the midshaft femur (containing mainly cortical bone) were detected without change in bone stiffness. Similar effects were observed in males at the level of the vertebra. This increase in mechanical properties was associated with improvements of the micro-architecture as assessed by increases of trabecular and cortical bone volumes and trabecular number and thickness. Finally, plasma total ALP activity and IGF-I were also increased in treated animals, compatible with a bone-forming activity of strontium ranelate. Conclusion: A long-term treatment with strontium ranelate in intact rats is very safe for bone and improves bone resistance by increasing bone mass and improving architecture while maintaining bone stiffness.