Effects Of Simvastatin On Experimental Osteoporosis And Its Mechanism

Osteoporosis is a systemic and metabolic skeleton disease characterized as low bone mineral density and micro-architectural deterioration, resulting in increased bone fragility and fracture risk. It is estimated that over200million people worldwide suffer from osteoporosis and its incidence has become the seventh common diseases according to the report from World Health Organization (WHO). And its prevalence is continuing to elevate with the increasing of elder population. Although current drugs such as bisphosphonates, estrogen replacement treatment, and selective estrogen receptor modulators, had been used to treat osteoporosis in clinical, they are not the ideal ones due to their insufficient curative effects and adverse side effects. It is urgent to develop the new drugs with good curative effect, less side effect and high safety. Recently, simvastatin are used to treat osteoporosis more frequently. Howerer, its clinical effect and treatment mechanism is still unknown.In present study, the bilateral ovariectomy of rabbits was duplicated to construct osteoporosis model. The effect of simvastatin in vivo was determined, and its treatment mechanism was studied in vitro after the curative effect was explored.Firstly, female New Zealand white rabbits underwent bilateral ovariectomy and bone mineral density was measured since120d after the operation. We found that bone mineral density of whole body and spine of OVX group was significantly lower than the sham group at150d of ovariectomy. To confirm the osteoporotic rabbit model, serum biochemical parameters, mechanical properties and micro-architecture of the lumbar vertebra were measured. We found that:compared with the Sham group, the levels of bone turnover biomarkers such as BALP, TRAP5b and NTX of OVX group were significantly higher, the biomechanical parameters of OVX group such as maximum load, displacement, stiffness and energy absorbing capacity were significantly lower, the micro-architecture parameters of OVX group such as TB.N, Tb.Th, BV/TV were significantly lower and Tb.Sp, BS/BV were significantly higher, which indicated that it was succeed in the duplication of osteoporotic rabbit model150d after ovariectomy. Then, simvastatin was administered orally to the osteoporotic rabbit model once every day at a dose of5mg/kg. After treated for60d and120d respectively, serum biochemical parameters test, MicroCT analysis, bone biomechanical test and histopathological evaluation were conducted. We found that simvastatin could significantly decrease the level of bone turnover biomarkers such as BALP, TRAP5b and NTX, increase the mechanical parameters such as maximum load, stiffness and energy absorbing capacity, increase the micro-architecture parameters such as TB.N, Tb.Th, BV/TV and decrease the micro-architecture parameters such as Tb.Sp, BS/BV, and improve the micro-architecture, which indicated that simvastatin was effective for treating experimental osteoporosis.At last, to observe the effects of serum contaning simvastatin on cell proliferation and the expression of BMP-2, Cbfal, OPG and RANKL gene, we used the serum contaning simvastatin which was separated when treated for60d and120d respectively to intervene the preosteoblast cell line, MC3T3-E1. We found that:(1) Serum contaning simvastatin could promote cell proliferation significantly, the best effect was obtained at final concentration of10%, and the effect was better of serum contaning simvastatin of two month than that of four month;(2) Compared with the serum of model group, the serum of simvastatin group at final concentration of10%could elevate the expression of BMP-2and Cbfal, and the effect was better of serum of two month than that of four month;(3) The serum of simvastatin group of any month at final concentration of10%has no effect on the expression of OPG and RANKL. The above results indicated that the anti-osteoporosis activity of simvastatin may due to the promotion of proliferation and differentiation of ostelblast.The present research confirmed the treatment effectiveness of simvastatin on experimental osteoporosis and preliminary explored its treatment mechanisms, which provide necessary experimental evidence to the clinical application.