Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice

It was previously shown that strontium ranelate (SR; S12911-PROTOS, Institut de Recherches Internationales Servier, Courbevoie, France) can modulate bone metabolism in rats and mice. To determine the long-term effects of SR on vertebral bone metabolism in adult mice, the compound or the vehicle was given in the diet to normal male and female mice for 104 weeks at the dose of 200, 600, or 1,800 mg/kg/d corresponding to 0.78, 2.34 or 7.01 mmol Sr(2+)/kg/d. SR dose-dependently increased plasma strontium concentration, as well as exposure to the drug. Histomorphometric analyses of indices of bone volume, bone formation, and resorption were determined in the endosteal vertebral bone. SR significantly increased the trabecular bone volume by 25% and 59% in females treated with SR 600 and 1,800 mg/kg/d, respectively. This was associated with a 27% and 62% increase in mineralized bone volume. Bone volume was also significantly increased by 17% and 38% in male mice treated with SR 200 and 1,800 mg/kg/d, respectively. In parallel, SR increased the osteoblastic surface by 131% in males. In addition to this stimulatory effect on bone formation, a 52% decrease in osteoclastic surface, and a dose-dependent decrease in osteoclastic number (30% to 47%), was observed in female mice. Finally, SR even at the highest dose tested did not alter the osteoid thickness, indicating no deleterious effect on bone mineralization. Altogether, these findings show that SR simultaneously increases bone formation and decreases bone resorption in male or female mice, which results in increased vertebral bone mass in both genders without deleterious effect on bone mineralization.