Skip to main content
main-content

Tipp

Weitere Artikel dieser Ausgabe durch Wischen aufrufen

Erschienen in: Wiener klinische Wochenschrift 13-14/2014

01.07.2014 | original article

Inverse correlation of carotid intima-media thickness with raloxifene serum levels in osteoporosis

verfasst von: Tina Trdan Lušin, Aleš Mrhar, Janja Marc, Jurij Trontelj, Andrej Zavratnik, Branka Žegura, Marija Pfeifer, PhD Assist. Prof. Barbara Ostanek

Erschienen in: Wiener klinische Wochenschrift | Ausgabe 13-14/2014

Einloggen, um Zugang zu erhalten
share
TEILEN

Summary

Background

Raloxifene is a selective oestrogen receptor modulator with effects on bone and breast cancer and cardiovascular disease risk. The aim of this study was to examine the influence of raloxifene treatment on surrogate markers of atherosclerosis and the correlation of these markers with raloxifene serum concentrations.

Methods

A prospective clinical trial on 53 postmenopausal osteoporotic women treated with raloxifene was performed. Surrogate markers of atherosclerosis (flow-mediated vasodilatation, glyceryltrinitrate-induced vasodilatation of the brachial artery, carotid intima-media thickness (c-IMT), inter-cell adhesion molecule-1, vascular-cell adhesion molecule-1 and E-selectin) were measured before and after 6 months of treatment. Serum concentrations of raloxifene and raloxifene metabolites were assessed after 12 months of treatment. The tested markers were correlated with measured serum concentrations of raloxifene species.

Results

Among the tested surrogate markers of atherosclerosis c-IMT, E-selectin and ICAM changed significantly during treatment. A negative correlation of the non-metabolized raloxifene serum levels with the percentage change of c-IMT during treatment (r = − 0.315, p = 0.048) was found. Likewise, the sum of the levels of three raloxifene metabolites, raloxifene-6-b-glucuronide (M1), raloxifene-4'-b-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3) in serum showed a negative correlation with the percentage change of c-IMT during treatment (r = − 0.375, p = 0.017). For the other tested parameters, no correlation with raloxifene serum levels was found.

Conclusions

To the best of our knowledge, this is the first study correlating raloxifene species serum concentrations with changes in the surrogate markers of atherosclerosis. A greater decrease of c-IMT in patients with higher raloxifene concentrations could contribute to a lower risk of cardiovascular events in these patients.
Literatur
2.
Zurück zum Zitat Hochner-Celnikier D. Pharmacokinetics of raloxifene and its clinical application. Eur J Obstet Gynecol Reprod Biol. 1999;85(1):23–9. PubMedCrossRef Hochner-Celnikier D. Pharmacokinetics of raloxifene and its clinical application. Eur J Obstet Gynecol Reprod Biol. 1999;85(1):23–9. PubMedCrossRef
4.
Zurück zum Zitat Dodge JA, Lugar CW, Cho S, et al. Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity. J Steroid Biochem Mol Biol. 1997;61(1–2):97–106. PubMedCrossRef Dodge JA, Lugar CW, Cho S, et al. Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity. J Steroid Biochem Mol Biol. 1997;61(1–2):97–106. PubMedCrossRef
5.
Zurück zum Zitat Bryant HU, Glasebrook AL, Yang NN, Sato M. An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999;69(1–6):37–44. PubMedCrossRef Bryant HU, Glasebrook AL, Yang NN, Sato M. An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999;69(1–6):37–44. PubMedCrossRef
6.
Zurück zum Zitat Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–45. PubMedCrossRef Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–45. PubMedCrossRef
7.
Zurück zum Zitat Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281(23):2189–97. PubMedCrossRef Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281(23):2189–97. PubMedCrossRef
8.
Zurück zum Zitat Collins P, Mosca L, Geiger MJ, et al. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation. 2009;119(7):922–30. PubMedCentralPubMedCrossRef Collins P, Mosca L, Geiger MJ, et al. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation. 2009;119(7):922–30. PubMedCentralPubMedCrossRef
9.
Zurück zum Zitat Zavratnik A, Prezelj J, Kocijancic A, Marc J. Exonic, but not intronic polymorphisms of ESR1 gene might influence the hypolipemic effect of raloxifene. J Steroid Biochem Mol Biol 2007;104(1–2):22–6. Zavratnik A, Prezelj J, Kocijancic A, Marc J. Exonic, but not intronic polymorphisms of ESR1 gene might influence the hypolipemic effect of raloxifene. J Steroid Biochem Mol Biol 2007;104(1–2):22–6.
10.
Zurück zum Zitat Walsh BW, Paul S, Wild RA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2000;85(1):214–8. PubMed Walsh BW, Paul S, Wild RA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2000;85(1):214–8. PubMed
11.
Zurück zum Zitat Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;279(18):1445–51. PubMedCrossRef Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;279(18):1445–51. PubMedCrossRef
12.
Zurück zum Zitat Oztas E, Kurtay G. Randomized, controlled study of the effects of raloxifene on high sensitivity C-reactive protein and serum lipids. Arch Gynecol Obstet. 2009;283(1):71–7. PubMedCrossRef Oztas E, Kurtay G. Randomized, controlled study of the effects of raloxifene on high sensitivity C-reactive protein and serum lipids. Arch Gynecol Obstet. 2009;283(1):71–7. PubMedCrossRef
13.
Zurück zum Zitat Colacurci N, Manzella D, Fornaro F, Carbonella M, Paolisso G. Endothelial function and menopause: effects of raloxifene administration. J Clin Endocrinol Metab. 2003;88(5):2135–40. PubMedCrossRef Colacurci N, Manzella D, Fornaro F, Carbonella M, Paolisso G. Endothelial function and menopause: effects of raloxifene administration. J Clin Endocrinol Metab. 2003;88(5):2135–40. PubMedCrossRef
14.
Zurück zum Zitat Zavratnik A, Žegura B, Marc J, Preželj J, Pfeifer M. XbaI polymorphism of the estrogen receptor alfa gene influences the effect of raloxifene on the enothelial function. Maturitas 2010;67(1):84–90. Zavratnik A, Žegura B, Marc J, Preželj J, Pfeifer M. XbaI polymorphism of the estrogen receptor alfa gene influences the effect of raloxifene on the enothelial function. Maturitas 2010;67(1):84–90.
15.
Zurück zum Zitat Sumino H, Ichikawa S, Kasama S, et al. Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women. Int Heart J. 2010;51(1):60–7. PubMedCrossRef Sumino H, Ichikawa S, Kasama S, et al. Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women. Int Heart J. 2010;51(1):60–7. PubMedCrossRef
16.
Zurück zum Zitat Colacurci N, Fornaro F, Cobellis L, et al. Raloxifene slows down the progression of intima-media thickness in postmenopausal women. Menopause. 2007;14(5):879–84. PubMedCrossRef Colacurci N, Fornaro F, Cobellis L, et al. Raloxifene slows down the progression of intima-media thickness in postmenopausal women. Menopause. 2007;14(5):879–84. PubMedCrossRef
17.
Zurück zum Zitat Sarrel PM, Nawaz H, Chan W, Fuchs M, Katz DL. Raloxifene and endothelial function in healthy postmenopausal women. Am J Obstet Gynecol. 2003;188(2):304–9. PubMedCrossRef Sarrel PM, Nawaz H, Chan W, Fuchs M, Katz DL. Raloxifene and endothelial function in healthy postmenopausal women. Am J Obstet Gynecol. 2003;188(2):304–9. PubMedCrossRef
18.
Zurück zum Zitat Sanne AEP. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart. 2012;98:177–84. CrossRef Sanne AEP. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart. 2012;98:177–84. CrossRef
19.
Zurück zum Zitat Hope SA, Meredith IT. Cellular adhesion molecules and cardiovascular disease. Part II. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction. Intern Med J. 2003;33(9–10):450–62. PubMedCrossRef Hope SA, Meredith IT. Cellular adhesion molecules and cardiovascular disease. Part II. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction. Intern Med J. 2003;33(9–10):450–62. PubMedCrossRef
20.
Zurück zum Zitat Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24(2):471–6. PubMedCrossRef Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24(2):471–6. PubMedCrossRef
21.
Zurück zum Zitat Trontelj J, Bogataj M, Marc J, Mrhar A. Development and validation of a liquid chromatography-tandem mass spectrometry assay for determination of raloxifene and its metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007;855(2):220–7. Trontelj J, Bogataj M, Marc J, Mrhar A. Development and validation of a liquid chromatography-tandem mass spectrometry assay for determination of raloxifene and its metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007;855(2):220–7.
22.
Zurück zum Zitat Trdan Lušin T, Stieger B, Marc J, et al. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene. J Transl Med 2012;10(1):76. Trdan Lušin T, Stieger B, Marc J, et al. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene. J Transl Med 2012;10(1):76.
23.
Zurück zum Zitat Trdan Lušin T, Mrhar A, Stieger B, et al. Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res 2012;160(4):298–308. Trdan Lušin T, Mrhar A, Stieger B, et al. Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res 2012;160(4):298–308.
24.
Zurück zum Zitat Cobble M, Bale B. Carotid intima-media thickness: knowledge and application to everyday practice. Postgrad Med. 2010;122(1):10–8. PubMedCrossRef Cobble M, Bale B. Carotid intima-media thickness: knowledge and application to everyday practice. Postgrad Med. 2010;122(1):10–8. PubMedCrossRef
25.
Zurück zum Zitat O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14–22. PubMedCrossRef O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14–22. PubMedCrossRef
26.
Zurück zum Zitat Coll B, Feinstein SB. Carotid intima-media thickness measurements: techniques and clinical relevance. Curr Atheroscler Rep. 2008;10(5):444–50. PubMedCrossRef Coll B, Feinstein SB. Carotid intima-media thickness measurements: techniques and clinical relevance. Curr Atheroscler Rep. 2008;10(5):444–50. PubMedCrossRef
27.
Zurück zum Zitat Dubey RK, Gillespie DG, Jackson EK, Keller PJ. 17Beta-estradiol, its metabolites, and progesterone inhibit cardiac fibroblast growth. Hypertension. 1998;31(1 Pt 2):522–8. PubMedCrossRef Dubey RK, Gillespie DG, Jackson EK, Keller PJ. 17Beta-estradiol, its metabolites, and progesterone inhibit cardiac fibroblast growth. Hypertension. 1998;31(1 Pt 2):522–8. PubMedCrossRef
28.
Zurück zum Zitat Fischer GM, Swain ML. Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas. Atherosclerosis. 1985;54(2):177–85. PubMedCrossRef Fischer GM, Swain ML. Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas. Atherosclerosis. 1985;54(2):177–85. PubMedCrossRef
29.
Zurück zum Zitat Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287(7):847–57. PubMedCrossRef Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287(7):847–57. PubMedCrossRef
30.
Zurück zum Zitat Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb Haemost. 2008;99(2):338–42. PubMed Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb Haemost. 2008;99(2):338–42. PubMed
31.
Zurück zum Zitat Mosca L, Grady D, Barrett-Connor E, et al. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke. 2009;40(1):147–55. PubMedCentralPubMedCrossRef Mosca L, Grady D, Barrett-Connor E, et al. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke. 2009;40(1):147–55. PubMedCentralPubMedCrossRef
Metadaten
Titel
Inverse correlation of carotid intima-media thickness with raloxifene serum levels in osteoporosis
verfasst von
Tina Trdan Lušin
Aleš Mrhar
Janja Marc
Jurij Trontelj
Andrej Zavratnik
Branka Žegura
Marija Pfeifer
PhD Assist. Prof. Barbara Ostanek
Publikationsdatum
01.07.2014
Verlag
Springer Vienna
Erschienen in
Wiener klinische Wochenschrift / Ausgabe 13-14/2014
Print ISSN: 0043-5325
Elektronische ISSN: 1613-7671
DOI
https://doi.org/10.1007/s00508-014-0551-3