Vitamin K2 Monotherapy And Cotherapy With Sexual Hormone On Bone Loss And Other Target Organs In Ovariectomized Rats

【Objective】Osteoporosis has become a life threatening disorder with the world gradually entering an aged society, especially for menopausal women whose fracture risk rises with rapid bone loss caused by estrogen deficiency and subsequent increased bone turnover. The mostly applied drugs for osteoporosis includes ant]absorptive substances and bone formation stimulators, such as hormone therapy, diphosphonate, SERM, calcitonin and PTH. The effect of these drugs are satisfacted, but still have some limit on the use. Meanwhile, new effective drugs with satisfactory safety have been being investigated. In the last forty years, vitamin K(VK) was revealed new pharmacological functions including promoting bone formation and surpressing bone absorption in addition to its coagulation effects. Therefore, it has ever since been extended to the prevention and treatment of osteoporosis, especially cothrapy with other drugs to enhance the effects. Furthermore, it was pointed out that VK2 may prevent from vessel calcification and decrease the incidence of cardiovascular disease.It may also reduce the level of plasmal cholesterol, indicating this drug benefits for the aged not only with osteoporosis but also with cardiovascular diseases. In addition, few side effects have been observed concerning its coagulatory properties under the dosage for osteoporosis. Vitamin K2 combined with sexual hormone may improve the effect of anti-osteoporosis one side, and relieve the menopausal symptoms on the other side.This study is designed to investigate the effects of VK2 and cotherapy with sexual hormone on ovariectomized rats concerning prevention of osteoporosis as well as vessel calcification, blood lipid metabolism and coagulation. The results will serve as evidences guiding clinical application of VK2 in postmenopausal osteoporosis. of 10 months old were randomized into 5 groups according to weight: Sham(8), OVX(8), OVX+VK2(7), OVX+HT(7) and OVX+VK2+HT(7). Gastric infusion of corresponding drugs was performed 2 weeks alter operation. VK2: 30mg/kg/d; HT: Premarin 0.07mg/kg/d with Depogeston 0.2mg/kg/d; Sham and OVX: purified water 2.5ml/kg/d. Variables were evaluated 14 weeks later including bone density, bone turnover parameters, bone histomorphometry, bone biomechanics, blood lipids, coagulatory parameters and aorta calcification.【Results】Effects on bone: (1) turnover parameters: BALP and uDPYD in OVX group are much increased than those in Sham group, indicating an increased bone turnover rate. VK2 group presents a higher uDPYD and uCa/uCr compared with OVX group, but the BALP are not statistical different in the two groups. The above three parameters are all apparently deceased in the HT group. In the VK2+HT group, both BALP and uDPYD are decreased and uCa/uCr not significantly changed. VK2 group demonstrates an apparent increase in uDPYD rather than others comparing with the Sham group.The results declare the interaction between VK2 and HT on uDPYD and BALP. (2)BMD: For lumbar BMD, whatever adjusted by the body weight, OVX group is lower than Sham group, and VK2 group is higher than OVX group, and no difference is observed in the HT group as well as the combined administrated groups. No difference is found between the groups concerning BMD of the femurs. However, the significant decrease of femoral BMD is observed in OVX group compared with Sham group, alter adjusted by the body weight. But the interaction between VK2 and HT is showed on lumbar BMD. (3) bone morphometry: a, parameters of bone content and structure: Compared with the Sham group, the OVX group present no statistical different ,but shows a trends of downgrading of BV/TV, Tb.N and Tb.Th and upgrading of Tb.Sp. The administered groups present same changes as the OVX group, b, formation parameters: The OVX group is higher than Sham group, among which BFR/Bs and % O.Pm are statistically different. No difference is observed between the administered groups and the OVX group, except that VK2+HT group demonstrate a significant declining in MLT and BFR. c, absorbtion parameters: No difference between the groups. The interaction between VK2 and HT lies on the BFR,TbN,TbSp and O.Pm. (4) biomechanics: No difference for all parameters is observed between OVX group and Sham group. As for maximum strain and Young's modulus, all the administered groups present no difference from the Sham and OVX group. However, for maximum load, VK2+HT group is significantly lower than any other group.(5)serum Ca²⁺: no difference between the groups is observed.Effects on other systems: (1) prothrombin time: no difference between the groups. (2)serum lipids: VK2 presents an significant increase of LDL compared with OVX groups. The LDL, HDL and TC in HT group are higher than those in OVX group. The result didn't show the effect of VK2+HT group on serum lipids,but the significant decrease of TC, HDL and LDL compared with HT group. It may be The interaction of VK2 and HT is found on TC, HDL and LDL. (3)aorta: thoracic aorta calcification is observed in one case in HT group as well as Sham group and 3 cases in OVX group. No calcification is found in VK2 group and VK2+HT group.【Conclusion】(1) Administration of VK2 alone will increase the BMD of ovariectomized rats with unidentifying mechanism. A dosage of 30mg/kgBW adds no risk to coagulation function in rats and is beneficial for preventing vessel calcification. VK2 has no advantages on serum lipids. (2) For older ovariectomized rats, the bodies react insensitive to short-term low-dosage estrogen therapy. (3) VK2 cotherapy with HT almostly produce interaction on some different organs.The study does not find an advantage for bone if VK2 is combined with HT. However, no apparent effect is observed on coagulation and serum lipid and there might be a preventing action on vessel calcification.