An Uncoupling Agent Containing Strontium Prevents Bone Loss by Depressing Bone Resorption and Maintaining Bone Formation in Estrogen-Deficient Rats

Abstract

Trabecular bone loss in estrogen deficiency is associated with enhanced bone resorption with a smaller increase in bone formation. We previously reported that low doses of strontium can increase trabecular bone volume in rodents by affecting bone resorption and formation. In this study we determined the effect of a new divalent strontium salt (S12911) on bone loss induced by E2 deficiency. Sprague-Dawley female rats (230 g, n = 15-25 per group) were sham operated or ovariectomized (OVX) and treated with 170-estradiol (E2, 10 pg/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Treatment for 60 days with S12911 resulted in a dose-dependent increase in plasma, urine, and bone strontium concentrations without any deleterious effect on total or skeletal growth. OVX rats were osteopenic compared to sham rats as shown by decreased femoral dry bone weight and mineral content measured on bone ash and by DXA. Treatment of OVX rats with S12911 prevented bone loss as bone ash and bone mineral content were restored to the values in sham rats. Trabecular bone volume measured by histomorphometry on the tibia1 metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 increased the trabecular bone volume by 30-36%. Histomorphometric indices of bone resorption (osteoclast surface and number) were increased in OVX rats and were reduced by S12911 to the levels in sham rats. In contrast to this inhibitory effect on bone resorption, the osteoid surface, osteoblast surface, mineral apposition rate, and bone formation rate were as high in OVX rats treated with S12911 as in untreated OVX rats. In addition, plasma osteocalcin (OC) and alkaline phosphatase (ALP) levels remained elevated or were further increased in OVX rats treated with S12911. In contrast, treatment with E2 reduced both bone resorption and formation and plasma ALP and OC to the levels in sham rats. The data indicate that the divalent strontium salt S12911 is acting as an uncoupling agent that can prevent the femoral osteopenia and partially prevent the trabecular bone loss in E2-deficient rats by inhibiting bone resorption without reducing bone formation.

In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells

“…4 In animals, Sr prevents bone loss in OVX rats 7,8 and increases bone mass in intact rats 16 and monkeys. 17 However, information of the anabolic effect of Sr on trabecular bone is limited, especially at the structural and tissue level.…”

“…4 In OVX rats, SR treatment prevented bone loss by increasing the bone formation maker and decreasing the bone resorption marker. 7,8 The cellular and molecular mechanism of the anabolic effect of strontium (Sr) on bone remains poorly understood. In vitro studies suggest that Sr can promote osteoblast proliferation and differentiation.…”

A review on strontium ranelate long-term antifracture efficacy in the treatment of postmenopausal osteoporosis

“…Studies in rats have demonstrated that in addition to the increase in bone mass, there is an increase in cortical thickness and an improvement in trabecular and cortical microarchitecture, leading to an increased bone quality and strength [Ammann et al 2004[Ammann et al , 2007. In ovariectomized rats, an established animal model for postmenopausal osteoporosis, strontium ranelate was able to prevent bone loss by decreasing bone resorption while maintaining bone formation not only in the short term [Marie et al 1993], but also in the long term [Bain et al 2009]. In this latter study, the ovariectomy-induced decline in bone mass, volume and strength was prevented by achieving a plasma concentration of strontium ranelate similar to that obtained in women with osteoporosis treated with the therapeutic daily dose of 2 g.…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…Strontium ranelate acts on both bone formation indices and bone resorption indicators. Indeed, strontium ranelate prevents trabecular bone loss, decreases bone resorption and increases or maintains bone formation in the ovariectomised rat model or in rats subjected to hindlimb immobilisation [133,134]. Strontium ranelate also reduces bone resorption and enhances bone mass and strength in mice, rats and monkeys [135][136][137].…”