BoneKEy-Osteovision | Perspective

Statins and their potential for osteoporosis



DOI:10.1138/2001029

The observation made several years ago that statins dramatically increase bone formation rates in rodents () has provoked a large amount of interest. Statins are natural product extracts which inhibit the enzyme HMG Co-A reductase, the rate-limiting step in hepatic cholesterol biosynthesis. As a consequence, they reduce serum cholesterol and the subsequent risk of heart attack (). These drugs are among the most widely prescribed in Western countries, with more than 3 million Americans taking a statin every day. Since there is no currently available and acceptable oral agent that stimulates formation of substantial amounts of new bone, this raises the possibility that safe oral agents such as these may be the long sought after anabolic agent for the treatment of patients with established osteoporosis.

Most of the statins exist as pro drugs (lactones) which do not inhibit HMG Co-A reductase, but are readily converted by esterases to the active form (). Although the first statins were natural product extracts, several of the more recent are synthetic, and appear to be more powerful and with different pharmacokinetic properties from the original statins. The statins were all selected for their capacity to target the liver and most are subject to metabolism by cytochrome P450 enzymes in the liver. Some of these hepatic metabolites are active and some are inactive. Most of the statins are very lipid-soluble and enter cells easily, but some of the newer synthetic statins such as pravastatin and robuvastatin are more water-soluble and probably depend on specific carrier mechanisms in hepatic cells for entry into these cells.

Pleiotropic effects of the statins

There are an increasing number of effects of statins that cannot be ascribed to cholesterol-lowering. These so-called pleiotropic effects, as well as their potential mechanisms, have received much recent attention (). They include vasodilative, antithrombotic, antioxidant, anti-inflammatory and anti-proliferative effects.

One of the best described of the pleiotropic effects of statins comes from an exciting body of work performed on their role to prevent cerebral damage following reduced blood supply. Prophylactic treatment of mice with HMG-CoA reductase inhibitors augments cerebral blood flow, reduces cerebral infarct size, and improves neurological function in normocholesterolemic mice (). These effects of statins are associated with upregulation of eNOS, which is not associated with changes in serum cholesterol levels, but is reversed by co-treatment with L-mevalonate. These beneficial effects of statins are completely absent in eNOS-deficient mice, indicating that enhanced eNOS activity caused by statins is the mechanism responsible for the beneficial effects. Treatment of human endothelial cells with statins in the presence of L-mevalonate or geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP) or low density lipoprotein, reversed the statins effects on eNOS expression (). In studies examining the mechanisms linking the mevalonate pathway with eNOS expression, Rho activity in endothelial cells was regulated by the use of Clostridium botulinum C3 transferase, or by overexpression of a dominant-negative N19 RhoA mutant, both of which increased eNOS expression (). In contrast, activation of Rho by E. coli cytotoxic necrotizing factor-1 decreased eNOS expression. These elegant studies indicate that Rho negatively regulates eNOS expression and that HMG-CoA reductase inhibitors upregulate eNOS expression by blocking Rho geranylgeranylation which is necessary for membrane-associated activity.

The Rho GTPases are members of the Ras superfamily of low molecular weight GTP binding proteins (). There are at least 14 distinct members of the family ranging in molecular weight from 20-24 kilodaltons, and these can be additionally subdivided into Rho, Rac and Cdc42. These GTPases are major substrates for posttranslational modification by isoprenylation, which targets Rho GTPases to the cell membrane. Rho proteins cycle between the active GTP-bound and the inactive GDP-bound state. The key step in the activation of Rho is the attachment of geranylgeraniol, an isoprenoid intermediate of the mevalonate pathway. This serves to translocate inactive Rho from the cytosol to the cell membrane. Statins, which block geranylgeraniol synthesis, inhibit Rho membrane translocation and activity. As noted above, this is at least part of the mechanism by which statins affect endothelial cell function and prevent ischemic stroke ().

Other mechanisms have been suggested for the pleiotropic effects of the statins on tissues unrelated for their capacity to lower cholesterol, such as the sterol regulatory element binding proteins (SREBP) (), which regulate transcription of HMG-Co reductase and other genes. These membrane bound transcription factors are released by a proteolytic mechanism which is regulated by the sterol content of the cell. This topic has been reviewed extensively ().

Mechanisms of action on osteoblasts

The mechanism by which statins cause effects on bone cell function is a central issue. Firstly, it appears that the statins mediate their effects by increasing the expression in bone of the growth factor bone morphogenetic protein-2 (BMP-2) which in turn leads to osteoblast differentiation and bone formation. They were identified as bone stimulatory agents by their effects on the BMP-2 promoter (). All of the consequences of statin action on bone in vitro can be abrogated by the addition of noggin, the naturally-occurring endogenous inhibitor of BMP-2 effects, and the effects of the statins on bone formation in vivo are impaired in transgenic mice where the transgene is the truncated 1B subunit of the BMP receptor linked to the osteocalcin promoter and which are unresponsive to BMP-2 (). These data confirm the central role of BMP-2 in mediating the effects of statins on bone. Thus, statins increase transcription of the BMP-2 gene, and this is the likely distal mechanism responsible for their effects.

Perhaps as a consequence of these actions of the statins on bone to enhance BMP-2 expression, the statins produce prolonged biological effects after short exposure. Therefore, when they are used in vitro, a mere 6 hours exposure to a statin leads to a prolonged effect on bone formation in bone organ cultures which is apparent even after 14 days of continuous culture (). These results are astounding, and suggest that an initial induction of BMP-2 triggers a cascade of factors that are responsible for the subsequent effects on bone formation. Similar results have been found in vivo in rats, where statin administration to the skin for 5 days is associated with a 150% increase in bone formation rates 35 days later (). Again, this suggests that transient exposure to the drug leads to a prolonged effect.

It is important to note that the effects of statins on bone do not parallel the effects of statins on the liver. Some statins are very effective in the liver, for example pravastatin, but have no effect at all on bone. The almost certain reason for this is the low uptake of the more water soluble statins by bone cells and their poor distribution beyond the liver to the periphery where they can be active in bone. Most statins are extracted by the liver and are subject to first-pass metabolism, and this impairs their bioavailability considerably to non-hepatic sites. Moreover, the effects of some of the newer statins, and particularly cerivastatin () and atorvastatin, appear to be much more powerful on bone than the earlier agents such as lovastatin.

Bisphosphonates and the mevalonate pathway

Independent of our studies on statin effects on bone, but occurring at the same time, Rogers and colleagues () have shown that the N2-containing bisphosphonates decrease osteoclast activity by effects on more distal enzymes in the cholesterol biosynthesis pathway. They have proposed that this causes osteoclasts to undergo apoptosis, an effect of bisphosphonates we described several years earlier (). They and others () have shown this effect is due to inhibition of farnesyl pyrophosphate synthase activity, a distal enzyme in the mevalonate pathway, although it has been questioned whether osteoclast apoptosis is important ().

These results are intriguing, particularly when considered in light of our studies on the effects of statins on bone formation. The interesting point is that bisphosphonates, drugs that inhibit osteoclastic bone resorption, and statins, compounds that enhance bone formation, both have targets in the same metabolic pathway. We have examined the effects of the more potent N2-containing bisphosphonates on bone formation in vitro, and found that in high concentrations there is an effect on bone formation (). However, the major action of these drugs is on bone resorption. Conversely, we and others have shown that statins can inhibit osteoclast function (), although our data show that the major effect of statins is on bone formation. Bisphosphonates are localized to osteoclasts and taken up by them, which may explain why their effects on the mevalonate pathway are more apparent in osteoclasts (). An alternative explanation is that there are many side pathways branching from the main mevalonate pathway, and different components are responsible for the effects we see on osteoblasts and osteoclasts by inhibiting different enzymes in the pathway. Perhaps the most important point is that these results point to the importance of the mevalonate pathway in bone formation. They suggest that there may be other molecular targets within this pathway that could be useful targets for drug discovery. This important concept will await further testing and investigation.

Effects of statins on bone in humans

However, a lot of questions have been raised as a consequence of the animal studies. The key immediate issue is whether these findings have relevance to mankind. A number of investigators have now looked retrospectively at the large available databases to determine if there is existing evidence for the effects of statins on the human skeleton. Bauer and Cummings examined their large databases at UCSF to determine if there was any previously unrecognized association between statin usage and skeletal status. They found in the SOF and FIT databases that there was indeed a possible relationship between statin use, bone mineral density and subsequent fractures, and presented this work on the oral program of the ASBMR annual scientific meeting in December 1999 (). Since that time, there have been 5 published reports of observational studies suggesting a beneficial effect on fracture rates and bone mineral density (,,,,). On the other hand, several abstracts were presented at ASBMR 2000 (one from the same data base as a positive published report) suggesting no effect (), and the data of Van Staa et al have recently been published (). The significance of these findings at the present time is difficult to determine. Most of these databases comprise a majority of patients who have used lovastatin, the earliest of the statins, and probably one of the least effective on bone when given orally. The results are also diluted by the use of pravastatin, which has very little effect on bone. As a consequence, it is not clear that these results provide meaningful information on the issue of whether statins benefit bone mass in humans. The recently published study of Van Staa et al, () was accompanied by a thoughtful editorial reviewing the published clinical data (), which concluded “the available evidence seems consistent with a protective effect of statins on risk of hip fracture, but this finding also could have been caused by an uncontrolled confounding”. The only way in which this issue can be addressed definitively is by randomized controlled trials in patients using appropriate doses and agents.


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