(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Osteoporosis

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Topics: Animals; Atorvastatin; Bone and Bones; Clinical Trials as Topic; Drug Delivery Systems; Fatty Acids, Monounsaturated; Fluorobenzenes; Fluvastatin; Fractures, Bone; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Lovastatin; Osteogenesis; Osteoporosis; Pharmacokinetics; Pravastatin; Pyridines; Pyrimidines; Pyrroles; Quinolines; Rosuvastatin Calcium; Simvastatin; Sulfonamides

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Lovastatin; Mevalonic Acid; Osteogenesis; Osteoporosis; Stimulation, Chemical; Transforming Growth Factor beta

The objective of present study was to develop hydrogel based nanoemulsion (NE) drug delivery system for transdermal delivery and evaluate its potential in in vivo anti-osteoporotic activity. NE was prepared using aqueous phase titration method and characterized for droplet size, zeta potential and morphology. It was then formulated into hydrogel based NE gel using carbopol 940 as gelling agent. NE gel was evaluated for pH, viscosity, in vitro/ex vivo permeation studies and in vivo anti-osteoporotic activity. The results indicated formation of spherical, nano sized globules of NE ranging from 11.17 ± 0.24 to 128.8 ± 0.16 nm with polydispersity of <0.5. In vitro and ex vivo permeation studies showed significantly higher permeation of NE as well as NE gel in comparison to fluvastatin solution indicating that NE gel can effectively penetrate through skin layers. In vivo anti-osteoporotic results demonstrated formation of new bone in trabecular region of osteoporotic rat femurs through micro-CT scanning radiographs. Biomechanical strength testing demonstrated greater load bearing capacity of rat femurs in the treated animals in comparison with the osteoporotic group. Thus, developed NE gel formulation of fluvastatin demonstrated greater potential for transdermal delivery and in the treatment of osteoporosis.

Topics: Acrylic Resins; Administration, Cutaneous; Animals; Drug Carriers; Drug Delivery Systems; Emulsions; Fluvastatin; Gels; Nanoparticles; Nanotechnology; Osteoporosis; Particle Size; Rats; Skin; Skin Absorption; Viscosity

This study aimed to investigate the effects of fluvastatin on the differentiation of bone marrow stromal cells (BMSCs) into osteoblasts in senescence-accelerated mouse prone 6 (SAMP6) compared with that in the normal senescence-accelerated-resistant mouse (SAMR1) model. SAMP strains arose spontaneously from the AKR/J background and display shortened life span and an array of signs of accelerated aging, compared with control SAMR strains. The dose effects of fluvastatin were also evaluated. BMSCs were cultured with/without fluvastatin (0 μM, 0.1 μM, 0.5 μM, and 1.0 μM). WST-1-based colorimetry was performed to evaluate cell proliferation. To evaluate cell differentiation, gene expression levels of bmp2 and runx2 were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and protein expression levels were determined using enzyme-linked immunosorbent assay (BMP2) and immunofluorescence staining (BMP2 and Runx2). Alkaline phosphatase (ALP) activity assay and histochemical detection were determined; the effect of noggin, a BMP-specific antagonist, was examined using ALP histochemical detection. To assess for mature osteogenic marker, gene expression levels of bglap2 were determined by qRT-PCR and mineralization was determined by alizarin red staining. RhoA activity was also examined by Western blotting. In SAMP6, BMP2, Runx2 and Bglap2 mRNA and protein expressions were significantly increased by fluvastatin, and ALP activity was increased by BMP2 action. RhoA activity was also inhibited by fluvastatin. The concentration of fluvastatin sufficient to increase BMP2 and Runx2 expression and ALP activity was 0.5 μM in SAMP6 and 0.1 μM in SAMR1. In conclusion, the present study revealed that fluvastatin promoted BMSC differentiation into osteoblasts by RhoA-BMP2 pathway in SAMP6. BMSCs of SAMP6 are less sensitive to the osteogenic effects of fluvastatin than SAMR1.

Topics: Alkaline Phosphatase; Animals; Bone Morphogenetic Protein 2; Calcification, Physiologic; Cell Differentiation; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fluvastatin; Gene Expression Regulation; Male; Mesenchymal Stem Cells; Mice; Osteoblasts; Osteogenesis; Osteoporosis; rhoA GTP-Binding Protein; RNA, Messenger

Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.

Topics: Animals; Animals, Newborn; Antioxidants; Cell Differentiation; Cells, Cultured; Diet; Down-Regulation; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Female; Fluvastatin; Fructose; Indoles; Insulin Resistance; Mevalonic Acid; Osteoclasts; Osteoporosis; Rabbits; Rats; Rats, Wistar; Signal Transduction

To explore the effect of fluvastatin on vascular endothelial growth factor (VEGF) in rats with osteoporosis in the process of fracture healing.. Fractures at the intermediate piece of the femur were made on 72 Sprague Dawley (SD) rats (weighing initially 290-340 g and aged 6 months) with osteoporosis after ovariectomy for three months, then these rats were divided randomly into the medication administration group (the experimental group) and the control group, 36 rats each. In the experimental group, the rats received fluvastatin lavage (10 mg/kg per day) since the next day of operation lasting for 6 weeks, and the rats in the control group received placebo. Then the expression of VEGF and VEGF mRNA in bony callus of the two groups was measured respectively with immunohistochemistry and in situ hybridization on days of 3rd, 7th, 14th, 21st, 28th, and 42nd, and image analysis was made with real-color image analysis machine.. No difference was found in the cellular localization of VEGF and VEGF mRNA gene expression between the experimental group and the control group in process of fracture healing and their expression modes were almost similar. On the 14th day postoperatively, the positive extent of positive cells in the experimental group was higher than that of the control group (P < 0.05).. Fluvastatin can promote the VEGF level in rats with osteoporosis in process of fracture healing.

Topics: Animals; Fatty Acids, Monounsaturated; Fluvastatin; Fracture Healing; Immunohistochemistry; In Situ Hybridization; Indoles; Osteoporosis; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A