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.
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.
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 M
to 5 M 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 M)
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 M) 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 M) 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.
Mundy, G. et al. Stimulation of bone formation in vitro and in rodents by statins. Science286, 1946–1949 (1999). | Article | PubMed | ISI | ChemPort |
Alberts, A.W. et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA77, 3957–3961 (1980). | PubMed | ChemPort |
Hamelin, B.A. & Turgeon, J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci.19, 26–37 (1998). | Article | PubMed | ISI | ChemPort |
Zhang, F.L. & Casey, P.J. Protein prenylation: molecular mechanisms and functional consequences. Ann. Rev. Biochem.65, 241–269 (1996). | Article | PubMed | ISI | ChemPort |
Garrett, I.R., Escobedo, A. & Mundy, G.R. N2-containing bisphosphonates risedronate and ibandronate stimulate bone formation in organ culture. J. Bone Miner. Res.14 S525 (abstract) (1999). | PubMed |
Luckman, S.P. et al. J. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res.13, 58–589 (1998).
Fisher, J.E. et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activation in vitro. Proc. Natl. Acad. Sci. USA96, 133–138 (1999). | Article | PubMed | ChemPort |
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 |
Plotkin, L.I. et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J. Clin. Invest.104, 1363–1374 (1999). | PubMed | ISI | ChemPort |
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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