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Nature Medicine  6, 21 - 23 (2000)
doi:10.1038/71484

Statins: lower lipids and better bones?

M.J. Rogers

Bone Research Group, Dept of Medicine & Therapeutics, University of Aberdeen Medical School, Aberdeen AB25 2ZD, UK. m.j.rogers@abdn.ac.uk

Although statins are widely used as cholesterol-lowering drugs, a recent study suggests that these compounds have anabolic effects on bone and could be developed into new treatments for common metabolic bone diseases such as osteoporosis
Osteoporosis is the most common bone disease, characterized by reduced bone density and an increased risk of fractures, affecting about 30% of women and 12% of men at some point during life. Osteoporosis occurs when the amount of bone removed from the skeleton by bone-resorbing osteoclasts exceeds that laid down by osteoblasts, the cells responsible for new bone formation (Fig. 1). Restoring the imbalance between bone resorption and formation is therefore a key goal of pharmacological intervention in osteoporosis. Inhibitors of osteoclastic bone resorption, such as bisphosphonates, estrogen or selective estrogen receptor modulators, are already widely used in the treatment and prevention of osteoporosis. These agents reduce the occurrence of fractures but lack the ability to replace the substantial amounts of bone that have already been lost by the time osteoporosis has presented clinically. Drugs that stimulate new bone formation would therefore be a welcome addition to the therapeutic armamentarium in the treatment of established osteoporosis.

Figure 1. Effects of mevalonate pathway inhibition on bone metabolism.
Figure 1 thumbnail

Bone is continuously remodeled by the action of osteoclasts that excavate bone, and osteoblasts that fill in the cavity with new bone matrix that eventually mineralizes. Bisphosphonate drugs inhibit bone resorption by binding to bone mineral, followed by release from the bone surface during resorption by osteoclasts. After selective cellular uptake by osteoclasts, most bisphosphonates (shown as BP) inhibit the metabolic mevalonate pathway, causing loss of prenylated small GTPases required for osteoclast function. Simvastatin and other statins, which all inhibit the synthesis of mevalonate, stimulate the proliferation and differentiation of bone-forming osteoblasts, increasing bone formation in vitro and in rodents1. It is not known whether bisphosphonates can also directly stimulate bone formation, or whether statins also inhibit bone resorption in vivo.



Full FigureFull Figure and legend (110K)
In the 3 December issue of Science, Mundy et al. report that statins are a class of previously unknown bone anabolic agents1. Based on the observation that bone morphogenetic protein 2 (BMP-2) stimulates osteoblast differentiation, the authors linked the BMP-2 promoter to a luciferase gene reporter to develop a high-throughput screen for compounds that could stimulate osteoblast activity. From a collection of more than 30,000 natural compounds, only lovastatin (a fungal metabolite) was found to specifically activate the BMP-2 promoter, although further studies demonstrated that 1 muM to 5 muM of the compounds fluvastatin, simvastatin and mevastatin had a similar effect. These concentrations of statins also increased specifically the expression of BMP-2 mRNA and more than doubled the production of BMP-2 protein by osteoblast-like cell lines in vitro.

To determine whether these effects were relevant under more physiological conditions, Mundy et al. used organ cultures of mouse skull bones to examine the effects of statins on osteoblast proliferation and bone formation in vitro. After 3 days or more in culture, even low concentrations (0.125 muM) of statins caused a considerable increase in the number of osteoblasts and the amount of new bone formed, to an extent similar to that seen after addition of recombinant BMP-2 itself. Similar effects were seen in vivo when lovastatin or simvastatin was injected subcutaneously over the skull bones of mice. Most importantly, oral administration of simvastatin to rats increased the volume of trabecular bone and increased the rate of bone formation, even in ovariectomised (artificially post-menopausal) animals in which bone loss is accelerated.

Such effects of statins are very intriguing, as these compounds are potent, competitive inhibitors of HMG-CoA reductase, which catalyzes the synthesis of mevalonate and is the rate-limiting enzyme of the mevalonate pathway (ref. 2) (Fig. 1). Because mevalonate is the precursor of cholesterol as well as a variety of isoprenoid-containing compounds, statins such as lovastatin have become front-line cholesterol-lowering drugs for the treatment of hypercholesterolemia. Their pharmacological efficacy and safety is mainly due to their selective localization to liver, the chief site of cholesterol biosynthesis, and less than 5% of a given dose reaches the systemic circulation3. Although statins can inhibit cholesterol biosynthesis, their ability to lower plasma cholesterol is more complicated and involves upregulation of LDL receptors on hepatocytes. As the mevalonate pathway is also the source of isoprenoid precursors necessary for the post-translational lipid modification (prenylation) and hence function of Ras and other small GTPases (ref. 4), the ability of statins to inhibit the mevalonate pathway has also attracted attention as a potential means of disrupting the localization and signaling function of oncogenic forms of Ras. Although statins are anti-proliferative, inducing apoptosis of tumor cell lines in vitro, and have some anti-tumor activity in animal models, the usefulness of statins as anti-tumor agents is limited by their selective hepatic uptake and low systemic availability.

The observations by Mundy et al. emphasize the hitherto unknown role of the mevalonate pathway in the regulation of bone formation. Although the exact molecular mechanism by which statins increase bone formation remains to be identified, one possibility is that small GTPases, prenylated by-products of the mevalonate pathway, negatively regulate expression of BMP-2. By inhibiting the mevalonate pathway and preventing the prenylation and function of small GTPases, BMP-2 expression may be stimulated, causing increased osteoblast proliferation and differentiation and, consequently, enhanced bone formation. This hypothesis is supported by the preliminary report from the same group that the anabolic effect of statins can be overcome by the addition of isoprenoid substrates required for protein prenylation5.

The importance of the mevalonate pathway in bone cells also became evident recently after the discovery that the potent, nitrogen-containing class of anti-resorptive bisphosphonate drugs inhibit bone resorption by inhibiting one or more enzymes downstream of HMG-CoA reductase in the mevalonate pathway in osteoclasts. This prevents the synthesis of isoprenoids required for the prenylation of small GTPases such as Rho and Rac, necessary for osteoclast function6, 7, 8. Therefore, the discovery that inhibition of the mevalonate pathway in bone cells can both stimulate bone formation (with statins) and inhibit bone resorption (with bisphosphonates) raises some intriguing questions. Can bisphosphonate drugs stimulate bone formation as well as inhibit bone resorption? Some bisphosphonates seem to stimulate osteoblast proliferation in vitro and may even inhibit osteoblast apoptosis9, although the low concentrations required (<1 muM) suggest a mechanism other than inhibition of the mevalonate pathway. Furthermore, current evidence suggests that bisphosphonates are selectively targeted to osteoclasts rather than other bone cells in vivo.

Another interesting question is whether bisphosphonates lower serum cholesterol. The answer is most likely not, as bisphosphonates have high affinity for bone mineral and lack the hepatic targeting property of statins. Alternatively, do statins inhibit bone resorption as well as stimulate bone formation? Studies have recently shown that concentrations of statins similar to those used by Mundy et al. (1−10 muM) effectively cause osteoclast apoptosis and inhibit bone resorption in vitro6, 7. Indeed, as reported by Mundy et al., decreased numbers of osteoclasts were found on bone surfaces after statin treatment in vivo. Hence, an anti-resorptive effect as well as an anabolic effect of statins cannot be ruled out. Although statins do not have the selective bone-targeting property of bisphosphonates in vivo, a recent retrospective study showed a tantalizing trend towards decreased fracture risk and increased bone mineral density in statin-treated women10. However, as Mundy et al. point out, even though oral administration of simvastatin seemed to be effective in rats, the statins now available are probably unsuitable as bone anabolic agents in humans, owing to their low systemic availability1. Furthermore, the dosages tested on rats, when adjusted for humans, were much higher than the standard dose in patients and would risk myalgia and other side effects.

An agent capable of lowering cholesterol levels, inhibiting bone resorption and stimulating bone formation would, after all, be a physician's dream come true. Nevertheless, it has become clear that modulation of the mevalonate pathway in bone cells could be a new approach to the treatment of common metabolic bone diseases such as osteoporosis, and a statin or other prenylation inhibitor with bone selectivity is now eagerly awaited.

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  8. van Beek, E. et al. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem. Biophys. Res. Commun. 264, 108–111 (1999). | Article | PubMed  | ISI | ChemPort |
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  10. Bauer, D.C. et al. Statin use, bone mass and fracture: an analysis of two prospective studies. J. Bone Miner. Res. 14, S179 (abstract) (1999). | PubMed  | ChemPort |
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