AN UNCOUPLING AGENT CONTAINING STRONTIUM PREVENTS BONE LOSS BY DEPRESSING BONE-RESORPTION AND MAINTAINING BONE-FORMATION IN ESTROGEN-DEFICIENT RATS

Trabecular bone loss in estrogen deficiency is associated with enhance d bone resorption with a smaller increase in bone formation. We previo usly 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 (S129 11) 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 17beta-estradiol (E2, 10 mug/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Tre atment for 60 days with S12911 resulted in a dose-dependent increase i n plasma, urine, and bone strontium concentrations without any deleter ious effect on total or skeletal growth. OVX rats were osteopenic comp ared to sham rats as shown by decreased femoral dry bone weight and mi neral content measured on bone ash and by DXA. Treatment of OVX rats w ith S12911 prevented bone loss as bone ash and bone mineral content we re restored to the values in sham rats. Trabecular bone volume measure d by histomorphometry on the tibial metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 i ncreased the trabecular bone volume by 30-36%. Histomorphometric indic es of bone resorption (osteoclast surface and number) were increased i n OVX rats and were reduced by S12911 to the levels in sham rats. In c ontrast to this inhibitory effect on bone resorption, the osteoid surf ace, osteoblast surface, mineral apposition rate, and bone formation r ate were as high in OVX rats treated with S12911 as in untreated OVX r ats. In addition, plasma osteocalcin (OC) and alkaline phosphatase (AL P) levels remained elevated or were further increased in OVX rats trea ted with S12911. In contrast, treatment with E2 reduced both bone reso rption and formation and plasma ALP and OC to the levels in sham rats. The data indicate that the divalent strontium salt S12911 is acting a s an uncoupling agent that can prevent the femoral osteopenia and part ially prevent the trabecular bone loss in E2-deficient rats by inhibit ing bone resorption without reducing bone formation.