Inverse correlation of carotid intima-media thickness with raloxifene serum levels in osteoporosis.
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.
Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
Tina Trdan
TT
Lušin
Aleš
A
Mrhar
Janja
J
Marc
Jurij
J
Trontelj
Andrej
A
Zavratnik
Branka
B
Zegura
Marija
M
Pfeifer
Barbara
B
Ostanek
D000328:Adult; D000368:Aged; D015415:Biomarkers; D002340:Carotid Artery Diseases / Q000097:blood* / Q000139:chemically induced*; D019040:E-Selectin / Q000097:blood; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008875:Middle Aged; D010024:Osteoporosis / Q000097:blood* / Q000188:drug therapy*; D011446:Prospective Studies; D020849:Raloxifene Hydrochloride / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017524:Slovenia; D013223:Statistics as Topic; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*; D017540:Tunica Media / Q000187:drug effects* / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D015415:Biomarkers; D019040:E-Selectin; D020845:Selective Estrogen Receptor Modulators; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D020849:Raloxifene Hydrochloride