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Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations

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Abstract

Introduction

Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where their effects on cholesterol synthesis are mediated and they undergo first pass metabolism. When given in lipid-lowering doses, these agents do not likely reach sufficient blood concentrations to reliably cause substantial increases in bone formation in humans. Moreover, statins are inactivated by cytochrome P450 enzymes, resulting in even less peripheral distribution of the biologically active moieties beyond the liver.

Method

To investigate whether an alternate method of administration might produce beneficial effects on bone formation, we administered lovastatin by dermal application to rats to circumvent the first-pass effects of the gut wall and liver.

Results

We found that the statin blood levels measured by HMG Co-A reductase activity were higher, maintained longer and less variable following transdermal application than those following oral administration. Also the increased circulating statin levels were associated with significantly enhanced biological effects on bone. After only 5 days of administration of transdermal lovastatin to rats, there was a 30–60% increase in trabecular bone volume, and 4 weeks later, we observed more than a 150% increase in bone formation rates. There was also a significant increase in serum osteocalcin, a marker of bone formation. We also found that lovastatin administered transdermally produces these profound effects at doses in the range of 1% of the oral dose, without any evidence of the hepatotoxicity or myotoxicity that can occur following oral statin administration. Several doses (0.01–5 mg kg−1 day−1) and dosage schedules were examined, and collectively the data strongly suggest a powerful anabolic effect but with an unusually flat dose-response curve.

Conclusion

These results show transdermal application of statins produces greater beneficial effects on bone formation than oral administration does.

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Abbreviations

HMG-CoA:

3-hydroxy-3-methyl-glutaryl-coenzyme A

DMSO:

Dimethyl sulfoxide

TEA:

Triethanolamine

DTT:

Dithiothreitol

BHA:

Butylated hydroxyanisole NF

HP:

Hydrophilic petrolatum

HA gel:

Hydroalcoholic gel

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

AP:

Alkaline phosphatase

LDH:

Lactic dehydrogenase

CPK:

Creatine protein kinase

OVX:

Ovariectomized

SHAM:

Sham-operated

BFR:

Bone formation rate

MAR:

Mineral apposition rate

BMD:

Bone mineral density

μCT:

Micro-computed tomography

AUC0–24h :

Area under the plasma concentration–time curve

References

  1. Mundy GR, Garrett IR, Harris SE, Chan J, Chen D, Rossini G, Boyce BF, Zhao M, Gutierrez G (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949

    Article  PubMed  CAS  Google Scholar 

  2. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H (2000) HMG-CoA reductase inhibitors and the risk of fractures. JAMA 283:3205–3210

    Article  PubMed  CAS  Google Scholar 

  3. Wang PS, Solomon DH, Mogun H, Avorn J (2000) HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 283:3211–3216

    Article  PubMed  CAS  Google Scholar 

  4. Edwards CJ, Hart DJ, Spector TD (2000) Oral statins and increased bone-mineral density in postmenopausal women. Lancet 355:2218–2219

    Article  PubMed  CAS  Google Scholar 

  5. Chan AK, Andrade SE, Boles M et al (2000) Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet 355:2185–2188

    Article  PubMed  CAS  Google Scholar 

  6. Chung YS, Lee MD, Lee SK, Kim HM, Fitzpatrick LA (2000) HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients. J Clin Endocrinol Metab 85:1137–1142

    Article  PubMed  CAS  Google Scholar 

  7. Wada Y, Nakamura Y, Koshiyama H (2000) Lack of positive correlation between statin use and bone mineral density in Japanese subjects with type 2 diabetes. Arch Intern Med 160:2865

    Article  PubMed  CAS  Google Scholar 

  8. van Staa TP, Wegman S, de Vries F, Leufkens B, Cooper C (2001) Use of statins and risk of fractures. JAMA 285:1850–1855

    Article  PubMed  Google Scholar 

  9. Bauer DC, Mundy GR, Jamal SA, Black DM, Cauley JA, Ensrud KE, van der Klift M, Pols HA (2004) Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med 26 164(2):146–152

    Article  CAS  Google Scholar 

  10. Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19:26–37

    Article  PubMed  CAS  Google Scholar 

  11. Henwood JM, Heel RC (1988) Lovastatin: a preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs 36:429–454

    PubMed  CAS  Google Scholar 

  12. Germershausen JI, Hunt VM, Bostedor RG, Bailey PJ, Karkas JD, Alberts AW (1989) Tissue selectivity of the cholesterol-lowering agents lovastatin, simvastatin and pravastatin in rats in vivo. Biochem Biophys Res Commun 158:667–675

    Article  PubMed  CAS  Google Scholar 

  13. Heller RA, Gould RG (1973) Solubilization and practical purification of hepatic 3-hydroxy-3-methylglutaryl coenzyme a reductase. Biochem Biophys Res Commun 50:859–865

    Article  PubMed  CAS  Google Scholar 

  14. Davidson MH (2000) Does differing metabolism by cytochrome P450 add clinical importance? Curr Atheroscler Rep 1:14–19

    Article  Google Scholar 

  15. Duggan DE, Vickers S (1990) Physiological disposition of HMG-CoA-reductase inhibitors. Drug Metab Rev 22:333–362

    PubMed  CAS  Google Scholar 

  16. Zhou LX, Finley DK, Hassell AE, Holtzman JL (1995) Pharmacokinetic interaction between isradipine and lovastatin in normal, female and male volunteers. J Pharmacol Exp Ther 273:121–127

    PubMed  CAS  Google Scholar 

  17. Parfitt AM (1988) Bone histomorphometry: standardization of nomenclature, symbols and units. Summary of proposed system. J Bone Miner Res 4:1–5

    CAS  Google Scholar 

  18. Maeda T, Matsunuma A, Kawane T, Horiuchi N (2001) Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 280:874–877

    Article  PubMed  CAS  Google Scholar 

  19. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ (1985) Midazolam: pharmacology and uses. Anesthesiology 62:310–324

    Article  PubMed  CAS  Google Scholar 

  20. Love JN (1994) Beta-blocker toxicity: a clinical diagnosis. Am J Emerg Med 12:356–357

    Article  PubMed  CAS  Google Scholar 

  21. Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S (2001) Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol 21:1636

    Article  PubMed  CAS  Google Scholar 

  22. Oxlund H, Dalstra M, Andreassen TT (2001) Statin given perorally to adult rats increases cancellous bone mass and compressive strength. Calcif Tissue Int 69:299–304

    Article  PubMed  CAS  Google Scholar 

  23. Oxlund H, Andreassen TT (2004) Simvastatin treatment partially prevents ovariectomy-induced bone loss while increasing cortical bone formation. Bone 34:609–618

    Article  PubMed  CAS  Google Scholar 

  24. Wang RW, Kari PH, Lu AYH, Thomas PE, Guengerich FP, Vyas KP (1991) Biotransformation of lovastatin: IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 290:355–361

    Article  PubMed  CAS  Google Scholar 

  25. Halpin RA, Ulm EH, Till AE, Kari PH, Vyas KP, Hunninghake DB, Duggan DE (1993) Biotransformation of lovastatin: V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human. Drug Metab Dispos 21:1003–1011

    PubMed  CAS  Google Scholar 

  26. Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth I, Benet LZ, Sewing KF, Christians U (1999) Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 27:173–179

    PubMed  CAS  Google Scholar 

  27. Chen HS, Gross JF (1980) Intra-arterial infusion of anticancer drugs: theoretic aspects of drug delivery and review of responses. Cancer Treat Rep 64:31–40

    PubMed  CAS  Google Scholar 

  28. Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG, Wersinger EM, Lemmon D, Beer TM (2005) Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer 103:717–723

    Article  PubMed  CAS  Google Scholar 

  29. Utian WH (1987) Transdermal estradiol overall safety profile. Am J Obstet Gynecol 156:1335–1338

    PubMed  CAS  Google Scholar 

  30. Wemme H, Pohlenz J, Schonberger W (1995) Effect of oestrogen/gestagen replacement therapy on liver enzymes in patients with Ullrich-Turner syndrome. Eur J Pediatr 154:807–810

    Article  PubMed  CAS  Google Scholar 

  31. Arnaud CD (2001) Two years of parathyroid hormone 1–34 and estrogen produce dramatic bone density increases in postmenopausal osteoporotic women that dissipate only slightly during a third year of treatment with estrogen alone: results from a placebo- controlled randomized trial. Bone 28:S77

    Google Scholar 

  32. Inkovaara J et al (1975) Prophylactic fluoride treatment and aged bones. Br Med J 3:73–74

    PubMed  CAS  Google Scholar 

  33. Gerster JC et al (1983) Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis. Br Med J 287(6394):723–725

    Article  CAS  Google Scholar 

  34. Dambacher MA et al (1986) Long-term fluoride therapy of postmenopausal osteoporosis. Bone 7:199–205

    Article  PubMed  CAS  Google Scholar 

  35. Wozney JM, Rosen V(1998) Bone morphogenetic proteins. In: Mundy JR, Martin TJ (eds) Physiology and pharmacology of bone. Springer-Verlag, Berlin Heidelberg New York, p 725–748

    Google Scholar 

  36. Tam CS, Heersche JN, Murray TM, Parsons JA (1982) Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology 10:506–512

    Article  Google Scholar 

  37. Vyas KP, Kari PH, Prakash SR, Duggan DE (1990) Biotransformation of lovastatin. II. In vitro metabolism by rat and mouse liver microsomes and involvement of cytochrome P-450 in dehydrogenation of lovastatin. Drug Metab Dispos 18:218–222

    PubMed  CAS  Google Scholar 

  38. Ping Fang, Lei Dong, Jin-Yan Luo, Xiao-Long Wan, Ke-Xin Du, Ning-Li Chai (2004) Effects of motilin and ursodeoxycholic acid on gastrointestinal myoelectric activity of different origins in fasted rats. World J Gastroenterol 10:2509–2513

    Google Scholar 

  39. Chiang JY, Kimmel R, Stroup D (2001) Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 10(262):257–265

    Article  Google Scholar 

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Acknowledgement

Supported by grants from the NIH to G.R.M. (R01 AR 048801) and a Veterans Affairs Merit Review.

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Correspondence to G. E. Gutierrez.

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GE Gutierrez, IR Garrett, G Rossini and GR Mundy are all employees of and hold stock in OsteoScreen Ltd.

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Gutierrez, G.E., Lalka, D., Garrett, I.R. et al. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos Int 17, 1033–1042 (2006). https://doi.org/10.1007/s00198-006-0079-0

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  • DOI: https://doi.org/10.1007/s00198-006-0079-0

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