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
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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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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