Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1565-1566

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Demer, L. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Demer, L. L.
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1565.)
© 2001 American Heart Association, Inc.

Editorials

Boning Up (or Down) on Statins

Linda L. Demer

From the Departments of Medicine and Physiology, University of California Los Angeles School of Medicine, Los Angeles.

Correspondence to Linda L. Demer, MD, PhD, Division of Cardiology, Box 95-167917, UCLA School of Medicine, Los Angeles, CA 90095-1679. E-mail Ldemer{at}mednet.ucla.edu


Key Words: lipids • bone • statins • osteoporosis

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mediates cholesterol biosynthesis by converting HMG-CoA to mevalonic acid. Although the focus has been on its effects on cholesterol, because mevalonic acid is also required for isoprenoid synthesis, it may also affect other important biological processes. Isoprenoids are converted by transferases to farnesyl and geranylgeranyl pyrophosphate, which are used for protein prenylation, a post-translational modification consisting of covalent addition of the isoprenoid side chains at or near the carboxyl terminus of certain proteins. Prenylation directs proteins to associate with membranes and mediates protein-protein interactions, thus contributing to a wide variety of general cell functions, particularly signal transduction. Not all the proteins that undergo prenylation have been identified.

See article, page 1636

It has been suggested that inhibitors of HMG-CoA reductase (statins), widely used for treatment of hyperlipidemia, may have pleiotropic effects through inhibition of protein prenylation. This may account for effects of statins that are independent of lipid lowering.1,2 However, there is also evidence that the mevalonate pathway is so tightly regulated that prenylation could not be significantly affected without toxic doses of statins.3

The report by Maritz et al4 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology addresses one of the possible pleiotropic effects of statins: modulation of bone metabolism. This possibility was brought to attention when Mundy et al5 reported that statins promote bone formation in rats and in calvarial fragments maintained in an organ culture. Although the exact mechanism was not determined, induction of bone morphogenetic protein-2 was observed in a human bone cell line treated with statins.

Triggered by this finding, four clinical studies soon followed.6–9 In three of these studies, fracture incidence was reduced by 50% in patients who were taking statins, based on retrospective, observational analysis. The fourth9 found that bone mineral density was significantly increased in patients receiving statin therapy.

Unfortunately, as with studies of hormone replacement therapy, initial positive findings in the observational studies were not confirmed in a subsequent randomized trial.10 A re-analysis of the LIPID study, designed to address cardiovascular outcomes in 9000 subjects, found no effect of statins on fracture risk. However, because only 17% of the subjects were women, and because adverse-event reports were used to ascertain fractures, these results may be limited by the low incidence of fractures.11 Another possibility is that the observational studies were confounded, as were the hormone replacement studies, by lifestyle effects. Patients compliant enough to be included in the statin groups (up to 13 months of consistent statin use) may have been similarly diligent in lifestyle measures, such as exercise, supplements, and medications, that prevent fractures. Nevertheless, the most recent study utilized the same observational approach and an overlapping patient population,12 but it found no significant effect of statins on fracture incidence.

Studies comparing markers of bone formation and resorption in control and statin-treated subjects have similarly variable results. An observational study of pravastatin in 30 postmenopausal women showed an increase in procollagen I amino-terminal propeptide, a marker for bone formation, in patients receiving statins. However, this effect was not detectable by a more widely used assay for bone formation, bone serum alkaline phosphatase levels.13 No effect on bone formation or resorption was found in a study of the effect of fluvastatin in 68 elderly women.14 Moreover, bone serum alkaline phosphatase decreased with statin treatment in a randomized trial of 850 patients,15 a re-analysis of a previous prospective, randomized trial addressing cardiovascular effects of statins.

In an intriguing development, Maritz and colleagues4 now find in vivo evidence that statins inhibit bone formation and produce a net reduction in bone density in rats. One possible reason for these apparently disparate results is the effect of serum lipid levels on bone metabolism. Parhami et al16–18 found that high lipid levels inhibit bone (osteoblastic) cell differentiation in vitro and ex vivo, and that hyperlipidemia significantly reduces bone mineral density in mice. Clinically, LDL cholesterol levels and atherosclerotic calcification are associated with osteopenia and osteoporosis independently of age.19–22

The possibility that statins act on bone through their lipid-lowering action is supported by the finding that steroid-induced osteoporosis is inhibited equally by statins and by non-statin lipid-lowering agents.23 Two of the studies showing inhibition of fracture by statins also reported no effect of non-statin lipid-lowering agents. However, by power analysis, the numbers of subjects in this category were far too small to detect such an effect.24

The effect of lipids on bone may also explain the disparate clinical and laboratory findings. In the clinical studies of fracture risk, bone density, and bone turnover markers, results may depend on the amount of lipid lowering as well as the degree and duration of preexisting hyperlipidemia. Indeed, in the observational studies, patients with hyperlipidemia of greater severity or longer duration may have both a higher fracture risk and a greater likelihood of treatment with statins. Thus, depending on the duration of hyperlipidemia, baseline differences in bone density and fracture risk may outweigh short-term effects of statins. Such an effect may be taken into consideration by using cholesterol-year analysis25 or by matching subjects for baseline bone density. While neither cholesterol levels nor baseline bone density were determined in most of the studies cited here, lipid levels may be available for the LIPID trial subjects.

Unfortunately, baseline lipid levels and levels after statin treatment were not determined in the two animal studies.4,5 The divergent findings in these two studies may be explained if the specific types and doses of statins used in the studies had different effects on lipid levels. Even if the same doses of statins were used in both studies, differences in the fat content of the chow could significantly influence the baseline lipid levels and, thus, the lipid-lowering effect. Rats have relatively low lipid levels, and doses of up to 30 mg/kg can reduce HMG-CoA reductase activity by 50% without affecting serum cholesterol levels.1 If the fat content in the chow used for the two studies was different, then statin treatment may have resulted in cholesterol reduction in one study but not the other.

Another possible mechanism for statin effects on bone is through inhibition of isoprenoid synthesis and its effects on vitamin K metabolism. Vitamin K subclasses differ in their polyisoprenyl side chains. The form of vitamin K derived from dietary vegetables (phylloquinone) is converted to tissue menaquinone-4 by replacement of its saturated fatty acid side chain by the isoprenoid geranylgeraniol derived from mevalonate.26 Several proteins that regulate bone mineralization, such as osteocalcin, matrix Gla protein, protein S, and Gas-6 are functionally affected by gamma-carboxylation of glutamate residues by vitamin K–dependent carboxylases.27 Thus, inhibition of isoprenoid lipid synthesis by statins may influence bone mineralization indirectly not only through lipid-lowering but also through effects on vitamin K metabolism.

Overall, additional studies are needed to determine whether HMG-CoA reductase inhibitors influence bone health. If they are found to influence bone mineralization or resorption, it will be important to determine whether they act directly or indirectly through cholesterol lowering or through other mechanisms such as modifications in vitamin K metabolism. Prospective, randomized trials and laboratory studies are needed that take into consideration potential effects of lipids on bone density.

References

  1. Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000; 80: 1095–1100.[Medline] [Order article via Infotrieve]
  2. Martin G, Duez H, Blanquart C, Berezowsky V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B. Statin-induced inhibition of the Rho-signaling pathway activates PPAR alpha and induces HDL apoA-I. J Clin Invest. 2001; 107: 1423–1432.[Medline] [Order article via Infotrieve]
  3. Sinensky M. Recent advances in the study of prenylated proteins. Biochim Biophys Acta. 2000; 1484: 93–106.[Medline] [Order article via Infotrieve]
  4. Maritz FJ, Conradi MM, Hulley PA, Gopal R, Hough FS. The effect of statins on bone mineral density and bone histomorphometry. Arterioscler Thromb Vasc Biol. 2001; 21: 1636–1641.[Abstract/Free Full Text]
  5. Mundy G, Garrett R, Harris S, Chang J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999; 286: 1946–1949.[Abstract/Free Full Text]
  6. Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, Goodman MJ, Gurwitz JH, LaCroix AZ, Platt R. Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet. 2000; 355: 2185–2188.[Medline] [Order article via Infotrieve]
  7. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000; 283: 3205–3210.[Abstract/Free Full Text]
  8. Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA. 2000; 283: 3211–3216.[Abstract/Free Full Text]
  9. Edwards CJ, Hart DJ, Spector TD. Oral statins and increased bone-mineral density in postmenopausal women. Lancet. 2000; 355; 2218–9.[Medline] [Order article via Infotrieve]
  10. Reid IR, Hague W, Emberson J, Baker J, Tonkin A, Hunt D, MacMahon S, Sharpe N. LIPID Study Group. Effect of pravastatin on frequency of fracture in the LIPID study. Lancet. 2001; 357: 509–512.[Medline] [Order article via Infotrieve]
  11. Hennessy S, Strom BL. Statins and fracture risk. JAMA. 2001; 285: 1888–9.[Free Full Text]
  12. van Staa TP, Wegman S, deVries F, Leufkens B, Cooper C. Use of statins and risk of fractures. JAMA. 2001; 285: 1850–1855.[Abstract/Free Full Text]
  13. Mostaza JM, DelaPiedra C, Curiel MD, Pena R, Lahoz C. Pravastatin therapy increases procollagen I N-terminal propeptide, a marker of bone formation, in post-menopausal women. Clin Chim Acta. 2001; 308: 133–137.[Medline] [Order article via Infotrieve]
  14. Bjarnason NH, Riis BJ, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int. 2000; 12: 380–384.
  15. Stein EA, Farnier M, Waldstreicher J, Mercuri M. Simvastatin./Atorvastatin Study Group: effects of statins on biomarkers of bone metabolism—a randomized trial. Nutr Metab Cardiovasc Dis. 2001; 11: 84–87.[Medline] [Order article via Infotrieve]
  16. Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation: a possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol. 1997; 17: 680–687.[Abstract/Free Full Text]
  17. Parhami F, Jackson SM, Tintut Y, Le V, Balucan JP, Territo M, Demer LL. Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells. J Bone Miner Res. 1999; 14: 2067–2078.[Medline] [Order article via Infotrieve]
  18. Parhami F, Tintut Y, Beamer WG, Gharavi N, Goodman W, Demer LL. Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res. 2001; 16: 182–188.[Medline] [Order article via Infotrieve]
  19. Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calcif Tissue Int. 1996; 59: 352–356.[Medline] [Order article via Infotrieve]
  20. Barengolts EI, Berman M, Kukreja SC, Kouznetsoya T, Lin C, Chomka EV. Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women. Calcif Tissue Int. 1998; 62: 209–213.[Medline] [Order article via Infotrieve]
  21. Hak AE, Pols HA, vanHemert AM, Hofman A, Witteman JC. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol. 2000; 20: 1926–1931.[Abstract/Free Full Text]
  22. Stulc T, Ceska R, Horinek A, Stepan J. Hyperlipoproteinemia, the apo-E genotype and bone density. Cas Lek Cesk. 2000; 139: 267–271.[Medline] [Order article via Infotrieve]
  23. Wang GH, Chung KC, Shen WJ. Lipid clearing agents in steroid-induced osteoporosis. J Formos Med Assoc. 1995; 94: 589–592.[Medline] [Order article via Infotrieve]
  24. Parhami F, Garfinkel A, Demer LL. Role of lipids in osteoporosis. Arterioscler Thromb Vasc Biol. 2000; 20; 2346–2348.[Abstract/Free Full Text]
  25. Schmidt HH, Hill S, Makarion EV, Fenersein IM, Dugi KA, Hoeg JM. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Am J Cardiol. 1996; 77: 575–580.[Medline] [Order article via Infotrieve]
  26. Thijssen HH, Drittij-Reijnders MJ, Fischer MA. Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone organ concentrations. J Nutr. 1996; 126: 537–543.
  27. Berkner KL. The vitamin K-dependent carboxylase. J Nutr. 2000; 130: 1877–1880.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Arch Intern MedHome page
D. C. Bauer, G. R. Mundy, S. A. Jamal, D. M. Black, J. A. Cauley, K. E. Ensrud, M. van der Klift, and H. A. P. Pols
Use of Statins and Fracture: Results of 4 Prospective Studies and Cumulative Meta-analysis of Observational Studies and Controlled Trials
Arch Intern Med, January 26, 2004; 164(2): 146 - 152.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Demer, L. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Demer, L. L.

ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.