Combined Effects Of Raloxifene And Estrogen On Bone And Other Target Organs In Ovariectomized Rats

【Objective】Estrogen and raloxifene have been widely used for postmenopausalosteoporosis in prevention and treatment. Each drug has its special target population:Estrogen is effective for those with menopause related symptoms while raloxifene isfor those who do not have such symptoms. In spite of almost the equal effect onosteoporosis, both drugs have their advantages and disadvantages: Long-termadministration of estrogen may induce some kind of uterine and breast tumors whileraloxifene does not stimulate uterus or breasts; raloxifene induces climactericsymptoms which estrogen is specially indicated to. In theory, combinedadministration may counteract their side effects. However, combination may alsocause counteraction or cooperation on the protecting effect on osteoporosis.Presently, combined administration is not indicated for postmenopausal osteoporosis.In this study, we established postmenopausal OP rats model and treated the rats for 3months with raloxifene combined with different doses of estradiol. The drug effectswere investigated on bones, uteri, breasts and aorta for supportive evidences ofanimals for clinically combined administration.【Methods】32 SD rats of 10-month old were ovariectomized forpostmenopausal OP models. They were randomized into 4 groups which wererespectively given intragastric administration of raloxifene of 1mg/kg/d, raloxifeneof 1mg/kg/d with estradiol valerate of 0.02mg/kg/d, raloxifene of 1mg/kg/d withestradiol valerate of 0.1mg/kg/d, raloxifene of 1mg/kg/d with estradiol valerate of0.4mg/kg/d. The treatment lasted 3 months. We measured the bone density,histomorphometry and biomechanics and made pathological observations of HEslides and immunohistochemistry slides of ER for the 4 organs stated above.【Results】1. In bones, (1) No statistical differences were found in 4 groups in BMDof the body, the vertebrae and the femurs concerning the baseline, the post-treatmentstate, the absolute changes and the percentage of changes. (2) No statistical differences were found in 4 groups concerning trabecular area, thickness, numberand separation degree. (3)As for OB number per ram, no statistical differences werefound in 4 groups. As for absorption percentage, no statistical differences were foundin femurs. But in vertebrae, raloxifene of 1mg/kg/d with estradiol valerate of0.4mg/kg/d had a significant lower value than the other 3 groups. (4)For labelingpercentage and bone formation rate, there was difference among the 4 groups.Raloxifene of 1mg/kg/d and raloxifene of 1mg/kg/d with estradiol valerate of0.1mg/kg/d groups had similarly lowest values in femurs and vertebrae. In vertebrae,raloxifene of 1mg/kg/d with estradiol valerate of 0.02mg/kg/d group and raloxifeneof 1mg/kg/d with estradiol valerate of 0.4mg/kg/d group had similarly highest values.(5) No statistical differences were found in 4 groups in bone biomechanics. (6)Neither ERa nor ERβdemonstrated statistical differences in 4 groups, but ERαhad a stronger expression than ERβ.2. In uteri: (1) No statistical differences were found in 4 groups concerning wetweight or endometrium thickness. (2) No statistical differences were found in 4groups concerning ERαand ERβexpression.3. In breasts: (1) No proliferation and dilation were observed. (2) ERαexpressionwas estrogen-dependent while ERβexpression had no statistical differences in 4groups.4. In aorta: (1) No abnormality was found in epithelium and smooth muscles. (2) ERβhad a stronger expression than ERα. ERαhad a weaker expression inraloxifene of 1mg/kg/d with estradiol valerate of 0.02mg/kg/d group than the othergroups【Conclusion】1 Raloxifene combined with different estradiol dosages hasdemonstrated the same protecting effect on bone as raloxifene alone. Combinedadministration does not decrease the protecting effect.2 Raloxifene combined with different estradiol dosages has not demonstratedstimulatory effect on uteri and breasts and has maintained normal aorta structure.Combined administration does not have any adverse effects on these organs.3 Our data only provides supportive evidence for short-term administration and further investigation is necessary of long-term effects in large animals. Whether thecombination of two drugs could counteract each other's side effects or not will onlybe answered by clinical practice.