A Comprehensive Review of the Pharmacology of Statins and its Clinical Implications

Athiban Inbarajan ^1*, Giri GVV ², Anusha D ³, Alan Mathew Punnoose ⁴, Jasline David J ⁵, Mubeena S ⁶

The study aims to provide a detailed understanding of statins, their pharmacodynamics, and the various types involved as beneficial agents in the treatment of bone resorption and hypercholesterolemia.

Abstract

Statins are commonly prescribed medications used to lower cholesterol levels and reduce the risk of heart attacks. Recent data suggest that statins also play a role in regulating bone metabolism by stimulating the formation of new bone tissue, both in laboratory studies (in vitro) and in living organisms (in vivo). Among statins, simvastatin has emerged as particularly effective in promoting the activity of bone morphogenetic protein-2 (BMP-2), a key factor in the differentiation of osteoblasts, the cells responsible for bone formation. Furthermore, simvastatin inhibits the production of mevalonate and isoprenoids, compounds crucial for the formation of osteoclasts, the cells involved in bone resorption. This dual action of simvastatin, promoting bone formation while inhibiting bone resorption, suggests its potential as a therapeutic agent for bone regeneration, particularly in the context of dental implants and the treatment of osteoporosis. The aim of this article is to review existing literature on the effects of simvastatin, with a primary focus on its role in promoting BMP-2 activity and its effects on bone formation, especially in patients with diabetes mellitus undergoing dental implantation. An electronic search of the MEDLINE-PubMed database was conducted up to December 2008 to identify relevant in vitro studies investigating the effects of statins on BMP-2 production, as well as in vivo studies evaluating the effects of statins on bone formation and preservation. The majority of reviewed investigations focused on simvastatin as the representative statin agent. These studies generally supported the hypothesis that simvastatin possesses osteoinductive properties mediated through BMP-2 and exerts osteoprotective effects by inhibiting osteoclast activation. Overall, simvastatin shows promise as a potential therapeutic agent for inhibiting and treating bone resorption, offering potential benefits for patients requiring bone regeneration procedures such as dental implantation.

Keywords: Antiresorptive drugs, Bone regeneration, Dental Implants, Diabetes, Osseointegration, Simvastatin

References

Adams, S. P., Sekhon, S. S., & Wright, J. M. (2014: Lipid-lowering efficacy of rosuvastatin. The. Cochrane database of systematic reviews. 2014, 010254. 10.1002/14651858.CD010254.pub2.

Biondi, B., Kahaly, G. J., & Robertson, R. P. (2019: Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders. Endocrine reviews. 40:789-824. 10.1210/er.2018-00163.

Chan MH, Mak TW, Chiu, et al.: Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia. 2001, 86:4556-9. 10.1210/jcem.86.9.8001.

Chauvin B: Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. Clinical pharmacokinetics. 2013, 52:815-831. 10.1007/s40262-013-0075-4.

De Fost, M: Low HDL cholesterol levels in type I Gaucher disease do not lead to an increased risk of cardiovascular disease. Atherosclerosis. 204:267-272. 10.1016/j.atherosclerosis.2008.08.027.

Duan Y: Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Signal Transduction and Targeted Therapy. 2022, 7:265.

Elsby R, Hilgendorf C, & Fenner K: Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1. Clinical Pharmacology. 2012, 92:584-598. 10.1038/clpt.2012.163.

Fernandez, M. L., & Webb, D: The LDL to HDL cholesterol ratio as a valuable tool to evaluate coronary heart disease risk. Journal of the American College of Nutrition. 27:1-5. 10.1080/07315724.2008.10719668.

G Mundy, R Garrett, S Harris, et al.: Stimulation of bone formation in vitro and in rodents by statins. 1999, 286:1946-194. 10.1126/science.286.5446.1946.

Ho C K, & Walker, S W: Statins and their interactions with other lipid-modifying medications: safety issues in the elderly. Therapeutic advances in drug safety. 2012, 3:35-46. 10.1177/2042098611428486.

Hopewell, J. C: Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom. European heart journal. 41:3336-3342. 10.1093/eurheartj/ehaa574.

Hyyppa M. T., Kronholm E., Virtanen A., et al.: Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinology. 28:181-194. 10.1016/s0306-4530(02)00014-8

Joseph Pagkalos: Simvastatin induces osteogenic differentiation of murine embryonic stem cells. 2010. J Bone Miner Res. 2010, 25:2470-8. 10.1002/jbmr.163.

Kapur, N. K., & Musunuru, K. (2008: Clinical efficacy and safety of statins in managing cardiovascular risk. Vascular health and risk. 4:341-353. 10.2147/vhrm.s1653.

Leslie R. Morse, Jennifer Coker, and Ricardo A: Battaglino, Statins And Bone Health: A Mini Review, Actual osteol. 2018, 14:31-35.

Liao J K, & Laufs U: Pleiotropic effects of statins. Annu. Rev. Pharmacol. 2005, 45:89-118. 10.1146/annurev.pharmtox.45.120403.095748.

Maeda T, Kawane T, Horiuchi N: Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology. 2003, 144:681-92. 10.1210/en.2002-220682.

Magan-Fernandez A, Fernández-Barbero JE, O' Valle F, Ortiz R, Galindo-Moreno P, Mesa F: Simvastatin exerts antiproliferative and differentiating effects on MG63 osteoblast-like cells: Morphological and immunocytochemical study. J Periodontal Res. 2018, 53:91-97. 10.1111/jre.12491.

Manzoni M: Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Applied microbiology and. 2002, 58:555-564. 10.1007/s00253-002-0932-9. Epub 2002 Feb 14.

Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S: Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol. 2001, 21:1636-4. 10.1161/hq1001.097781

Masahiko Mori, Tetsunari Nishikawa, Kazuya Masuno, Tomoharu Okamura, Akio Tanaka, Michio Shikimori: Statins: candidates for promoting bone formation via BMP-2, Oral Med Pathol 14.

Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Koyano K: Topical application of statin affects bone healing around implants. Clin Oral Implants Res. 2008, 19:600-5. 10.1111/j.1600-0501.2007.01508.x.

Murphy C, Deplazes E, Cranfield C G, et al.: The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. International journal of molecular sciences.2020. 21:8745. 10.3390/ijms21228745.

Neuvonen, P. J., Niemi, M., & Backman, J. T. (2006: Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clinical Pharmacology. 80:565-581. 10.1016/j.clpt.2006.09.003.

Radcliffe, K. A., & Campbell, W. W. (2008: Statin myopathy. Current neurology and neuroscience. 8:66-72. 10.1007/s11910-008-0011-4.

Ruiz-Gaspa S, Nogues X, Enjuanes A, Monllau JC, Blanch J, Carreras R: Mellibovsky L, Grinberg D, Balcells S, Díez-Perez A, Pedro-Botet J, Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cell Biochem. 2007, 15:1430-8. 10.1002/jcb.21259.

Sattar, N: Adiponectin and coronary heart disease: a prospective study and meta-analysis.Circulation.114:623  629.10.1161/CIRCULATIONAHA.106.618918.

Sirtori, C. R: The pharmacology of statins. Pharmacological research. 2014, 88:3-11. 10.1016/j.phrs.2014.03.002.

Stroes, E. S: Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. European heart journal. 36:1012-1022. 10.1093/eurheartj/ehv043.

Sugiyama M, Kodama T, Konishi K: Abe K, Asami S, Oikawa S, Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun. 200019, 271:688-92. 10.1006/bbrc.2000.2697.

Thanga Kumaran Suthanthiran, Sugumari Elavarasu, Devisree Naveen, et al.: Collagen with simvastatin promotes cell metabolism in osteoblast-like SaOS-2 cells. 2012, Journal of Pharmacy and Bioallied Sciences, Vol 4 August. 20122, - Part.:10.4103/0975-7406.100221.

Torres P. A., Helmstetter J. A., Kaye A. M., et al.: Rhabdomyolysis: pathogenesis, diagnosis, and treatment. The. Ochsner journal, 15(1), 58-69. Ochsner J. 2015, 15:58-69.

Tremblay, A. J: Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. Journal of lipid research. 50:1463-1471. 10.1194/jlr.P800061-JLR200.

Wang Y., Lammi-Keefe C. J., Hou L., et al.: Impact of low-density lipoprotein cholesterol on cardiovascular outcomes in people with type 2 diabetes: a meta-analysis of prospective cohort studies. Diabetes research. 102:65-75. 10.1016/j.diabres.2013.07.009.

Wang, H. H: Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol. European journal of clinical investigation, 43, 413-426. 10.1111/eci.12058.

Yasunori Ayukawa, Akira Okamura, Kiyoshi Koyano: Simvastatin promotes osteogenesis around titanium implants. A histological and histometrical study in rats. Clin Oral Implants Res. 2004, 15:346-50. 10.1046/j.1600-0501.2003.01015.x.