Effects of the selective estrogen receptor modulator, raloxifene, on the somatotropic axis and insulin-glucose homeostasis

Raloxifene is the first selective estrogen receptor modulator registered fo r the prevention and treatment of postmenopausal osteoporosis. In addition to direct effects on bone cells, estrogen and raloxifene may act indirectly via changes in hormonal homeostasis. However, the menopause-related decrea se in serum insulin-like growth factor I (IGF-I) and the increase in insuli n or glucose are not always reversed by estrogen replacement. Especially or ally administered estrogen was reported to decrease serum IGF-I levels. Und erstanding the effects of estrogens and raloxifene on the GH-IGF axis and i nsulin-glucose homeostasis are important because of their link to bone meta bolism and cardiovascular health. We investigated the effects of raloxifene on the GH-IGF-I axis and insulin- glucose homeostasis in a cross-sectional study in the third year of the Mul tiple Outcomes of Raloxifene Evaluation trial, a double blind, placebo-cont rolled, prospective study in postmenopausal women with osteoporosis (T-scor e of -2.5 or less or at least two moderate vertebral fractures). Patients w ith diabetes mellitus were excluded from this additional study. A fasting b lood sample was obtained (0 h), and women received an sc injection of 0.05 mg recombinant human GH (Humatrope)/kg BW. The second blood sample was obta ined 24 h later (24 h). GH, IGF-I, IGF-binding protein-3 (IGFBP-3), insulin , and glucose were measured. Group characteristics were tested by nonparame tric ANOVA. The dose-response to raloxifene was tested by linear regression models, with age and body mass as covariates. Seven women were taking placebo, 16 were taking raloxifene (60 mg/day), and 9 were taking raloxifene (120 mg/day). Patients from the 60 mg raloxifene group were the oldest (mean +/- sn, 64.4 +/- 4.2 vs. 69.3 +/- 6.9 and 63.3 +/- 5.9 yr for placebo, 60 mg/day raloxifene, and 120 mg/day raloxifene, re spectively; P = 0.05). Compared with placebo users, patients taking raloxif ene had higher body mass index (24.7 +/- 1.7 vs. 25.0 +/- 3.1 and 28.8 +/- 5.8 kg/m(2); P = 0.03). At 0 h, raloxifene use was associated with lower IG F-I/IGFBP-3 ratio (4.3 +/- 0.7 vs. 2.9 +/- 0.7 and 3.0 +/- 0.7 nmol/mg; P = 0.001) and insulin/glucose ratio (13.7 +/- 5.2 vs. 11.9 +/- 5.9 and 9.5 +/ - 2.3 pmol/mmol; P = 0.04). Similarly, raloxifene use was associated with l ower IGF-I/IGFBP-3 and insulin/ glucose ratios at 24 h (P = 0.01 and 0.07). Glucose, GH, and IGFBP-3 levels were similar among the groups (0.12 < P < 0.67). In conclusion, raloxifene use is associated with decreased serum IGF levels and insulin/glucose ratio before and 24 h after one rhGH injection in nond iabetic postmenopausal women with osteoporosis. Therefore, raloxifene may d ecrease liver sensitivity to GH. Other explanations are increased clearance or increased tissue sensitivity to IGF-I or insulin. The raloxifene-induce d increases in bone mineral density do not appear to be mediated by reversi ng the age- and menopause-related decreases in IGF-I levels. The results of this small cross-sectional study need confirmation by longitudinal studies .