Correspondence
Effects of Raloxifene in Postmenopausal Women
N Engl J Med 1998; 338:1313-1314April 30, 1998
- Article
To the Editor:
The article by Delmas et al. (Dec. 4 issue)1 suggests that raloxifene has many of the beneficial effects of estrogen in postmenopausal women, but it contained little information on adverse events. At a public Food and Drug Administration hearing in November 1997, the manufacturer reported that raloxifene (60 mg per day) significantly increased hot flashes, leg pain, and thromboembolic events, as compared with placebo. In view of this information, an accounting of these adverse events in the trial is warranted. Furthermore, we are not told how many women were in each group at 6, 12, and 24 months. The inclusion of this information would enable readers to interpret the results better, particularly since all outcome measurements on women who dropped out of the study were carried forward to subsequent visits.
Another question is whether raloxifene prevents osteoporotic fractures. Although Delmas et al. found that raloxifene increased bone mineral density, this end point is not synonymous with fracture prevention. For example, tamoxifen and fluoride increase bone mineral density, but they also appear to increase the risk of fractures.2,3 Thus, raloxifene cannot as yet be considered to have effects on bone that are similar to those of estrogen.
3 ReferencesRebecca C. Cole, B.A.
Jodi A. Flaws, Ph.D.
Trudy L. Bush, Ph.D., M.H.S.
University of Maryland School of Medicine, Baltimore, MD 212011
Delmas PD ,Bjarnason NH ,Mitlak BH , et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-1647
Full Text | Web of Science | Medline2
Kristensen B ,Ejlertsen B ,Mouridsen HT ,Andersen KW ,Lauritzen JB . Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen. Breast Cancer Res Treat 1996;39:321-326
CrossRef | Web of Science | Medline3
Riggs BL, Hodgson SF, O'Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis.N Engl J Med 1990;322:802-9.
To the Editor:
Delmas et al. concluded that raloxifene may help prevent osteoporosis and cardiovascular disease in postmenopausal women without stimulating the endometrium. There is now evidence that estrogen maintains memory in postmenopausal women.1 It also can enhance mood.2,3 Were any tests of memory or mood done in this study?
3 ReferencesMark N. Friedman, D.O.
Pennsylvania Hospital, Philadelphia, PA 191071
Sherwin BB . Estrogen effects on cognition in menopausal women. Neurology 1997;48:Suppl 7:S21-S26
Web of Science | Medline2
Halbreich U . Role of estrogen in postmenopausal depression. Neurology 1997;48:Suppl 7:S16-S19
Web of Science | Medline3
Fink G ,Sumner BE ,Rosie R ,Grace O ,Quinn JP . Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell Mol Neurobiol 1996;16:325-344
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In response to the questions posed by Cole et al.: hot flashes were reported by 23 percent of the women in the placebo group and 26 percent of those in the group assigned to 60 mg of raloxifene per day. Leg cramps were reported by 0.7 percent and 2.6 percent, respectively. None of the women had deep-vein thrombosis or pulmonary embolism. In all placebo-controlled trials of raloxifene involving approximately 10,400 women, the relative risk of deep-vein thrombosis and pulmonary embolism combined was approximately 3.0, which is similar to that reported for postmenopausal women who were taking estrogen in observational studies1,2 and a prospective trial.3
The respective numbers of women at base line and at 6, 12, and 24 months in each group in our study were as follows: 150, 129, 127, and 119 in the placebo group and 152, 133, 127, and 119 in the group receiving 60 mg of raloxifene per day. The numbers of women in the other two raloxifene groups (30 mg per day and 150 mg per day) were similar.
With respect to the question about the effect of raloxifene on bone quality: biomechanical testing of bone from estrogen-deficient rodents4 and primates demonstrated a similar, positive relation between bone mineral density and bone strength in raloxifene-treated and estrogen-treated animals. In fluoride-treated animals, increased bone volume was not associated with increased strength.5 In the study by Kristensen et al.,6 the incidence of fractures was determined in women at high risk for recurrent breast cancer (i.e., those with axillary-lymph-node metastasis, tumors measuring more than 5 cm, or local invasion) who were treated with radiotherapy with or without tamoxifen for one year. Up to 12 years after the completion of tamoxifen therapy, there was no difference in the number of hip or femoral-neck fractures between the two groups, but there were more trochanteric fractures in the tamoxifen group.
In response to Friedman: we did not test memory or mood. There was no difference in the incidence of reported depression, insomnia, anxiety, emotional lability, or sleep disorders among the treatment groups.
6 ReferencesPierre D. Delmas, M.D., Ph.D.
Hôpital Edouard Herriot, 69437 Lyons CEDEX 03, FranceBruce H. Mitlak, M.D.
Lilly Research Laboratories, Indianapolis, IN 46285Claus Christiansen, M.D.
Center for Clinical and Basic Research, 2750 Ballerup, Denmark1
Daly E ,Vessey MP ,Hawkins MM ,Carson JL ,Gough P ,Marsh S . Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-980
CrossRef | Web of Science | Medline2
Jick H ,Derby LE ,Myers MW ,Vasilakis C ,Newton KM . Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-983
CrossRef | Web of Science | Medline3
Grady D ,Hulley SB ,Furberg C . Venous thromboembolic events associated with hormone replacement therapy. JAMA 1997;278:477-477
CrossRef | Web of Science | Medline4
Turner CH ,Sato M ,Bryant HU . Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology 1994;135:2001-2005
CrossRef | Web of Science | Medline5
Lafage M-H ,Balena R ,Battle MA , et al. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs: a one-year study. J Clin Invest 1995;95:2127-2133
CrossRef | Web of Science | Medline6
Kristensen B ,Ejlertsen B ,Mouridsen HT ,Andersen KW ,Lauritzen JB . Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen. Breast Cancer Res Treat 1996;39:321-326
CrossRef | Web of Science | Medline
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