Statins and bone metabolism
Ohu University, Hukusima, Fukushima, Japan Oral Diseases
(Impact Factor: 2.43).
04/2006; 12(2):85-101. DOI: 10.1111/j.1601-0825.2005.01172.x
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are potent inhibitors of cholesterol biosynthesis. Cholesterol-lowering therapy using statins significantly reduces the risk of coronary heart disease. However, extensive use of statins leads to increases of other undesirable as well as beneficial effects, so-called pleiotropic effects. With respect to these effects, statins augment the expression of bone morphogenetic protein-2, a potent simulator of osteoblast differentiation and its activity, and promote mineralization by cultured osteoblasts, indicating that statins have an anabolic effect on bone. Chronic administration of statins in ovariectomized (OVX) rats modestly increases bone mineral density (BMD) of cancellous bone but not of compact bone. In clinical studies, there are conflicting results regarding the clinical benefits of this therapy for the treatment of osteoporosis. Observational studies suggest an association between statin use and reduction in fracture risk. Clinical trials reported no effect of statin treatment on BMD in hip and spine, and on bone turnover. Statins also may influence oral osseous tissues. Administration of statins in combination with osteoporosis therapy appears to improve alveolar bone architecture in the mandibles of OVX rats with maxillary molar extraction. Statins continue to be considered as potential therapeutic agents for patients with osteoporosis and possibly with periodontal disease. Development of new statins that are more specific and potent for bone metabolism will greatly increase the usefulness of these drugs for the treatment of bone diseases.
Available from: sciencedirect.com
- "Statins are commonly prescribed lipid-lowering agents, which have been shown to exhibit favourable effects on bone in high oral doses but not in lipid lowering doses in experimental studies  . The biological effects of statins are expressed via the inhibition of mevalonate pathway . Postmenopausal women are susceptible to both cardiovascular diseases and osteoporosis . "
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ABSTRACT: Statins are competitive inhibitors of HMGCoA reductase and are commonly used as antihypercholesterolemic agents. Experimental studies clearly demonstrate the beneficial effects of statins on bone. Tocotrienols have also been shown to have anti-osteoporotic effects on the skeletal system. This study was conducted to observe the effect of a combination of delta-tocotrienol and lovastatin on structural bone histomorphometry and bone biomechanical strength in a postmenopausal rat model at clinically tolerable doses, and to compare it with the effect of delta-tocotrienol or lovastatin.
Forty-eight female Sprague Dawley rats were randomly divided into six groups: baseline control; sham-operated control; ovariectomised control; ovariectomised+11mg/kg lovastatin; ovariectomised+60mg/kg delta-tocotrienol and ovariectomised+60mg/kg delta-tocotrienol+11mg/kg lovastatin. These treatments were given via oral gavage daily for eight weeks. After sacrificing the rats, the left and right femurs were dissected and processed for bone histomorphometric analysis and a bone biomechanical test, respectively.
Delta-tocotrienol in combination with lovastatin significantly improved the trabecular volume, trabecular number, trabecular thickness and trabecular separation; and it significantly increased bone strength in oestrogen-deficient rats. Delta-tocotrienol alone enhanced bone formation and maintained bone strength in ovariectomised rats. Delta-tocotrienol plus lovastatin treatment promoted better trabecular volume and trabecular number and received higher load than delta-tocotrienol alone. Lovastatin alone was not effective.
Thus, combination of delta-tocotrienol and lovastatin has the potential to be used for anti-osteoporotic therapy in postmenopausal women.
Copyright © 2014. Published by Elsevier Inc.
Available from: Tzu-Ming Pan
- "Many drugs currently used to treat osteoporosis, including bisphosphonates, estrogen, selective estrogen receptor modulators , and statins, act as antiresorptive agents in the prevention of bone loss (Delmas 2002; Keen 2007). Many studies have found that statins, specific competitive inhibitors of the 3-hydroxy-3- methylglutaryl coenzyme A reductase enzyme, increase bone formation and bone mass in rodents (Horiuchi and Maeda 2006), suggesting that they could be an important treatment option for osteoporosis, particularly when significant amounts of trabecular bone have been lost (Garrett and Mundy 2002; Mundy et al. 1999). The class of statin drugs includes mevastatin , lovastatin, simvastatin, and pravastatin, which are all naturally occurring statins derived by fermentation. "
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ABSTRACT: Phytoestrogens are a class of bioactive compounds derived from plants and exert various estrogenic and antiestrogenic effects. Estrogen deficiency osteoporosis has become a serious problem in elderly women. The use of ovariectomized (OVX) rat or mice models to simulate the postmenopausal condition is well established. This review aimed to clarify the sources, biochemistry, absorption, metabolism, and mode of action of phytoestrogens on bone health in intervention studies. In vitro, phytoestrogens promote protein synthesis, osteoprotegerin/receptor activation of nuclear factor-kappa B ligand ratio, and mineralization by osteoblast-like cells (MC3T3-E1). In the OVX murine model, administration of phytoestrogens can inhibit differentiation and activation of osteoclasts, expression of tartrate-resistant acid phosphatase, and secretion of pyridinoline compound. Phytoestrogens also enhance bone formation and increase bone mineral density and levels of alkaline phosphatase, osteocalcin, osteopontin, and α1(I) collagen. Results of mechanistic studies have indicated that phytoestrogens suppress the rate of bone resorption and enhance the rate of bone formation.
Available from: Takayuki K Nemoto
- "Metabolism of mevalonic acid pathway in C2C12 cells. The metabolic pathway of mevalonic acid is schematically illustrated, as shown previously [Horiuchi and Maeda 2006]. The major metabolic route in C2C12 cells revealed in the present study is represented by the bold arrows. "
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ABSTRACT: Statins, which are known as cholesterol-lowering drugs, have several additional effects including the enhancement of bone formation and the stimulation of smooth muscle cell proliferation. In this study, we investigated the signal pathway of simvastatin operating in C2C12 myoblast cells. Myotube formation of C2C12 cells was efficiently blocked by 1 muM simvastatin, and mevalonic acid was able to cancel this effect. Geranylgeranyl pyrophosphate restored the myotube formation, whereas farnesyl pyrophosphate did not. These findings demonstrate that the Rho family, such as Rho, Rac and Cdc42, occurring downstream of geranylgeranyl pyrophosphate in the mevalonic acid pathway, was involved in the simvastatin-mediated blockage of myotube formation. An inhibitor of Rho kinase did not influence the myotube formation; whereas an inhibitor of Rac blocked this process. Taken together, we conclude that the differentiation of C2C12 cells into myotubes was blocked by simvastatin through the pathway mediated by Rac, not by Rho.
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