Nitrogen-containing bisphosphonates were found to inhibit farnesyl diphosphate synthase - an essential enzyme in the cholesterol biosynthesis pathway, but their effect on cholesterol synthesis per se in the central nervous system (CNS) remains unknown. The aim of the present study was to examine possible influence of a representative agent alendronate on cholesterol synthesis rates in selected parts of rat CNS and on plasma cholesterol level. Two groups of rats were orally administered either alendronate (3 mg/kg b.w. ) or vehicle for 9 days. At the end of experiment, brain (basal ganglia, frontal cortex and hippocampus) and spinal cord were isolated and cholesterol synthesis was determined using the technique of deuterium incorporation from deuterated wa ter. In the alendronate group significant reductions of choleste rol synthesis rates were detected in frontal cortex, hippocampus and spinal cord (p<0.001). However, the experimental treatment did not produce a significant alteration in the levels of plasma cholesterol. In conclusion, this study brings the first experimental evidence of the inhibition of cholesterol biosynthesis with alendronate in central nervous system., Ľ. Cibičková, R. Hyšpler, N. Cibiček, E. Čermáková, V. Palička., and Obsahuje bibliografii
In connection with the known inhibitive action of bisphosphonates on bone resorption we were interested in their possible influence on bone blood flow (BBF). We determined BBF (^Sr-microsphere uptake in the tibia, distal femur and diaphysis of femur), cardiac output, density and ash weight of the tibia, as well as 24-h incorporation of 45Ca and 3H-proline into the tibia. Pamidronate (Aredia, CIBA-Geigy, Switzerland) was administered to sham- operated or oophorectomized (OOX) female rats in doses of 0.6 mg i.p. 2 days a week for 4 weeks. ^Sr- microsphere uptake was increased after OOX in the tibia and distal femur, simultaneous pamidronate administration significantly suppressed this increase below the control level. In addition, pamidronate inhibited the 24-h incorporation of 45Ca and 3H-proline in sham-operated females and suppressed the incorporation of 3H- proline that was increased after OOX. Bone density and ash weight were significantly increased after pamidronate administration in both sham-operated and OOX rats. The results of both experiments showing a significant effect of pamidronate on BBF and incorporation of 45Ca and 3H-proline require further verification and elucidation.
In this review the authors outline traditional antiresorptive pharmaceuticals, such as bisphosphonates, monoclonal antibodies against RANKL, SERMs, as well as a drug with an anabolic effect on the skeleton, parathormone. However, there is also a focus on non-traditional strategies used in therapy for osteolytic diseases. The newest antiosteoporotic pharmaceuticals increase osteoblast differentiation via BMP signaling (harmine), or stimulate osteogenic differentiation of mesenchymal stem cells through Wnt/β-catenin (icarrin, isoflavonoid caviunin, or sulfasalazine). A certain promise in the treatment of osteoporosis is shown by molecules targeting non-coding microRNAs (which are critical for osteoclastogenesis) or those stimulating osteoblast activity via epigenetic mechanisms. Vitamin D metabolites have specific antiosteoporotic potencies, modulating the skeleton not only via mineralization, but markedly also through the direct effects on the bone microstructure., I. Zofkova, J. Blahos., and Obsahuje bibliografii