Effect Of Strontium Ranelate On Osteoporosis In Simulated Weightlessness Rats

Osteoporosis is a systemic disease that leads to the decrease of bone strength and increased fragility and risk of fracture characterized by the reduce of the bone mineral density (BMD) and the disruption of bone microarchitecture:bone trabecula become thiner, breaked and reduced and os integumentale become thiner with increased porosity. Weightlessness-induced osteoporosis is a secondary osteoporosis, it is a special disuse osteoporosis caused by the microgravity environment. With the space industry become flourish, it has become the prominent hampers. Weightlessness is the object shows only for the quality but not for the weight in the microgravity (10-6～10"9g). Weightlessness-induced osteoporosis is mainly caused by mechanical factors of osteoporosis.The cause of osteoporosis can be attributed to mechanical factors and biological factors of two factors, the more consideration to the endocrine factors on the mechanical environment on bone tissue of the role of inadequate attention. The weightlessness osteoporosis occurrence is mainly the bone formation decreased which leads to the bone loss. Several countermeasure strategies lack prophylactic effect under the gravity free state.At present, the main treatment options are anti-resorptive agents such as ESQ moderator of selective estrogen receptor, and calcitionin that prevent bone breakdown. Still other therapeutic agents target increasing bone formation. strontium ranelate (SR), a medication for osteoporosis marketed by Servier in 2004, is composed of an organic moiety (ranelic acid) and of two atoms of stable non-radioactive strontium. Sr ion play a role in the calcify of bone, and stimulates osteoblast activity and inhibit osteoclast resorption, improving the mechanical resistence of bone without influencing the mineralization of bone and without changing the structure of bone. ranelic acid, an organic acid with strong polar and without pharmacological activity, can form stable chelate compound with bivalence Sr ion. Strontium ranelate can not only increase the volume of trabecular bone and cortical bone, but also enhance the amount and thickness of trabecular bone after having been given to healthy rats for 2 years and the alkaline phosphatase activities in blood plasma and IGF in serum increase. In ovariectomized rats, strontium ranelate can not only prevent the reduce of bone mineral content and trabecular bone volume induced by lack of estrogen, but also can get the morphometric index of reabsorption of bone tissue back to normal. So SR had two-ways regulation by both increases bone formation and reduces bone resorption, resulting in a rebalance of bone turnover in favor of bone formation, overcomeing the one-way regulation of other drugs. Currently researches of SR focus on postmenopausal osteoporosis and senile osteoporosis far more than weightlessness induced osteoporosis. This study discussed the effects of SR on osteoporosis induced by simulated weightlessness by tail suspension in rats, through observing the change of bone metabolism markers in serum, bone density, bone biomechanics and bone histomorphometry and provide a theoretical basis on further study of SR on osteoporosis under weightlessness.Objective:To evaluate the preventive and therapeutic effect of Strontium ranelate on osteoporosis induced by tail suspension(or simulated weightlessness) in rats by means of bone metabolism markers in serum, bone density, bone biomechanics and bone histomorphometry.Method:Forty-two 3-month-old male SD rats were purchased and acclimated to condition for 1 week. The animals were randomly divided into 7 groups:group A1 is the free control group, group B1 is the tail-suspended group, one whole range free control group (group A), group B treated with SR 600mg/kg·d with the tail-suspended, group C treated with the same dose of SR after the tail-suspended, Group D treated with SR 600mg/kg·d in the whole range. After 4 weeks, group A1 and B1 were sacrificed. After 8 weeks, all remain animals were sacrificed. The femur was prepared for DEXA and bone biomechanical measurement with femoral shaft three-point bending test(after measuring BMD), the tibia was prepared for the bone histomorphometry, the lumbar vertebra was prepared for DEXA and the compression test. Blood samples were obtained before sacrifice to determine the bone turnover markers.Statistical methods:All data were reported as mean±standard error, SPSS 13.0 software was used for these analyses. Group F and group G comparisons were run using independent-samples T test, and when a significant difference was revealed (P<0.05); the remain groups assay performed were analyzed by one-way ANOVA and when significance was revealed (P<0.05).Results:1. Establishment of osteoporosis model by tail-suspended rats during simulated weightlessness:weights of rats in each group had no significant difference after 4 weeks of tail-suspendsion; Serum calcium increased but serum alkaline phosphatase and osteocalcin decreased in tail suspension group compared with the control group; Femoral bone and lumbar vertebrae mineral density, the maximum load and experimental stiffness of femur and lumbar spine compression point, bending test in Tail suspension group were lower than in control group; Bone histomorphometric study results indicate that tail-suspended rats exhibited an decreased bone mass and bone formation and an increased bone resorption activity. These showed that the tail suspension model of simulated weightlessness in rats established osteoporsis successfully.2. Determination of bone density:There are not significant differences between each group using strontium ranelate and the whole range control group, but significant differences between the SR groups and the tail suspension control group.3. Determination of bone biomechanics:There are no significant differences in the maximum load and experimental stiffness of both femur and lumbar spine compression point bending test between the whole range control group and each SR group, but significant differences ignificant differences between the SR groups and the tail suspension control group. In the maximum load and experimental stiffness of femoral bone compression point bending test.4. Observation of bone histomorphometry:Comparing tail-suspension control group with the whole range control group,percent trabecular bone area (Tb.Ar), trabecular thickness(Tb.Th) and number (Tb.N) significantly decreased while trabecular separation (Tb. Sp), showing osteopenia and bone rarefaction; Percent of labeled perimeter(%L.Pm), tissue-referent bone formation rate (BFR/TV) and mineral apposition rate (MAR) all decreased indicating reduced bone formation, osteoclast number per mm bone surface(Oc.N) increased, indicating increased bone resorption. There are no significant difference in all above-mentioned parameters between each SR groups.Comparing SR groups with tail-suspension control group, Tb.Th, Th.N and %Tb.Ar increased, and Tb.Sp ascended, showing increased bone mass;%L.Pm, BFR/TV and MAR, and Oc.N declined. There are no significant difference in static and dynamic parameters between SR groups and the whole range control groups.Conclusion:1. After simulated weightlessness by tail suspension, bone formation reduced, bone resorption increased, bone mineral density and biomechanical properties declined, bone loss, bone mass decreased, indicating that tail suspension model of simulated weightlessness in rats successfully established osteoporosis.2. SR prevented bone loss, promoted bone formation, inhibited bone resorption, increased bone mass and increased bone strength in weightlessness induced osteoporosis.3. There are no significant difference in different times of oral administraion of SR during tail suspension, before tail suspension and after tail suspension.