Raloxifene improves spine bone mineral density (BMD), and its ability to reduce vertebral fractures by 40–50% suggests that it increases vertebral strength. Positive effects on hip BMD suggest a similar strengthening of the hip, but dimensional ambiguities in BMD by dual energy x-ray absorptiometry (DXA) make it difficult to infer strength effects directly. Hip fractures may be too infrequent to evaluate in practical clinical trials; even the Multiple Outcomes of Raloxifene Evaluation (MORE) study with 7,705 subjects was insufficiently powered to show a comparable reduction in hip fractures.

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced the risk of vertebral fracture. However, a systematic analysis of the anti-vertebral fracture efficacy of raloxifene, which includes the results of newly reported studies, has not been performed. A meta-analysis was carried out using all randomized, double-blind, placebo-controlled trials to determine whether the reduction in the risk for vertebral fracture, reported with raloxifene, was consistent among studies, and to define more accurately the point estimate of the odds ratio. Three prevention studies, two arms of the MORE trial, and three additional treatment studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (MedLine, EMBASE) confirmed that no studies with raloxifene had been excluded from this analysis. The effects of raloxifene 60 mg/day (RLX60) and 120 mg/day pooled with 150 mg/day (RLX120/150) were analyzed by intention to treat. There was no significant heterogeneity among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.60 (0.49, 0.74) for RLX60 and 0.51 (0.41, 0.64) for RLX120/150. From these data we infer that raloxifene consistently reduces the risk of vertebral fracture in postmenopausal women.

We would like to thank Dr. Palomba and colleagues for their interest on our article (1Jirecek S Lee A Pavo I Crans G Eppel W Wenzl R Raloxifene prevents the growth of uterine leiomyomas in premenopausal women.Fertil Steril. 2004; 81: 132-136Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar) and their commentary regarding the conflicting results of the two exploratory studies. The aim of both studies was to investigate the effect of raloxifene monotherapy on the growth of leiomyomas in premenopausal women (1Jirecek S Lee A Pavo I Crans G Eppel W Wenzl R Raloxifene prevents the growth of uterine leiomyomas in premenopausal women.Fertil Steril. 2004; 81: 132-136Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 2Palomba S Orio Jr, F Morelli M Russo T Pellicano M Zupi E et al.Raloxifene administration in premenopausal women with uterine leiomyomas a pilot study.J Clin Endocrinol Metab. 2002; 87: 3603-3608Crossref PubMed Scopus (67) Google Scholar). Dr. Palomba and colleagues also discuss the differences between the study designs and to what extent these might have impacted the outcome. The adequately designed, double-blinded, placebo-controlled study of Palomba et al. (2Palomba S Orio Jr, F Morelli M Russo T Pellicano M Zupi E et al.Raloxifene administration in premenopausal women with uterine leiomyomas a pilot study.J Clin Endocrinol Metab. 2002; 87: 3603-3608Crossref PubMed Scopus (67) Google Scholar) concluded that the effect of 6-month raloxifene treatment with doses as high as 180 mg/day was not different from placebo in influencing the growth of the leiomyomas. In contrast, our data suggested an inhibitory effect on leiomyoma growth after 3 months of treatment with the same dose (180 mg/day) of raloxifene. It is important to note that despite the overall negative conclusions of the authors, the Palomba study resulted in interesting information. There was a significant, approximately 11%–13% volumetric growth of leiomyomas after 6 months with both placebo and raloxifene 60 mg/day; there was no volumetric increase, however, in leiomyomas treated with raloxifene 180 mg/day. Obviously, the study was not designed to detect 10% change differences between raloxifene and placebo treatment. We are in agreement with the opinion that the potential inhibitory effect of raloxifene on leiomyomas might be inversely related to the presence of estrogen. Raloxifene is an estrogen antagonist in the uterus: however, because of the higher circulating levels of E2 in younger, premenopausal women, the potential inhibitory effect of raloxifene could be demonstrated only if the “raloxifene/estrogen ratio” is high. Raloxifene might thus be more effective in women with lower circulating levels of E2, such as older premenopausal women (as in our study), in perimenopausal women (no data available yet) and postmenopausal women (3Palomba S Sammartino A Affinito P Di Carlo C Zullo F Nappi C Effect of raloxifene treatment on uterine leiomyomas in postmenopausal women.Fertil Steril. 2001; 76: 38-43Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), or in women with pharmacologically suppressed E2 levels (4Palomba S Russo T Orio Jr, F Tauchmananovà L Zupi E Benedetti Panici P.G et al.Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas a prospective, randomized, single-blind, placebo-controlled clinical trial.Hum Reprod. 2002; 17: 3213-3219Crossref PubMed Scopus (74) Google Scholar). We would like also to provide some further details regarding our study design, as requested. All study participants had a regular menstrual cycle and had single leiomyoma at study entry. In addition to the percent of volumetric changes of the leiomyomas reported, the responder analysis also suggests an inhibitory effect of raloxifene in our study. Compared with baseline, after 1 month, eight patients (73%) taking raloxifene and three (25%) in the control arm (P=.022) experienced regression in tumor size and after 3 months eight (73%) and four (33%, P=.059), respectively. The size of the leiomyomas either increased or remained unchanged in the remainder of the patients. We reported one patient who developed a persistent ovarian follicle during raloxifene treatment. After finishing the study, the follicle spontaneously disappeared. The leiomyoma of this 22-year-old patient increased during the course of the study, from 3.22 mL at baseline to 3.86 and 4.57 mL after 1 month and 3 months of raloxifene administration, respectively. The measurement of hormones in our study served safety purposes only, and blood sampling was not performed at specific times within the menstrual cycle. At study design, we considered the results of another study that examined the effect of 100 and 200 mg/day raloxifene on circulating FSH and E2 levels in premenopausal women. This study showed a moderate increase in FSH and E2 levels through the entire menstrual cycle (5Baker V Draper M Paul S Allerheiligen S Glant M Shifren J et al.Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles.J Clin Endocrinol Metabol. 1998; 83: 6-13Crossref PubMed Scopus (98) Google Scholar). We believe that the results of the two published studies could provide important information for the design of a larger study to evaluate the effect of raloxifene on leiomyomas in premenopausal women. We agree with Dr. Palomba and colleagues that such a study would be needed to determine a final conclusion. It is important to note, however, that raloxifene is not indicated for any use in premenopausal women, and the only approved dose for prevention and treatment of postmenopausal osteoporosis is 60 mg/day.

OBJECTIVE:Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN:The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS:Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS:Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1-1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.