At study screening, women were asked if they had ever taken HT. Women were excluded from the study if they were experiencing clinically severe menopausal symptoms at the beginning of the study that required estrogen. Women were excluded if they had been treated with therapeutic doses of androgen, calcitonin, or estrogen (>1 cycle or 28 days) alone or with progestin (>1 cycle or 28 days) within 6 months of beginning the study. Women were permitted to have used systemic (oral or transdermal) estrogen and progestin for up to 1 cycle (28 days) during the 6 months before the study. No systemic estrogen and progestin use was allowed within 2 months before study entry. Occasional use of topical estrogens (3 times per week), and oral estriol (2 mg/d) for menopausal symptoms was permitted.
A 1-year double-blind extension phase was added to the 3-year treatment phase.10 All vertebral fracture, cardiovascular, and breast cancer endpoints that occurred over the 48-month study period were included in the present analyses.
Fracture and BMD assessment
New morphometric vertebral fractures, defined using semiquantitative assessment criteria,12 were identified by comparing spinal radiographs taken at 2, 3, and 4 years with baseline radiographs. A new vertebral fracture was defined as a vertebral fracture occurring in a vertebra that was not fractured at baseline. New clinical vertebral fractures were defined as those associated with signs or symptoms suggestive of vertebral fracture, such as back pain, reported either at an interim 6-month clinic visit or at any time between clinic visits,13 and which were subsequently corroborated with radiographs and adjudicated as previously described.10
Lumbar spine and femoral neck BMD were measured annually using dual-energy x-ray densitometry, as previously described.11
Cardiovascular event assessment
Cardiovascular events were collected as a secondary safety endpoint in the MORE trial, as previously described in detail.14 Women were asked at each clinic visit if they had had a myocardial infarction (MI), coronary bypass surgery, percutaneous coronary revascularization, or a stroke since the previous visit, and unsolicited reports of adverse cardiovascular events were recorded. All summaries of reported cardiovascular events were reviewed and adjudicated by 1 board-certified cardiologist, contracted by the sponsor, who was not associated with the trial and was blinded to treatment assignment.
Women with 4 or more risk points, assessed using the same criteria as for enrollment in the Raloxifene Use for The Heart (RUTH) trial,15 were considered to be at high risk for cardiovascular events. Coronary events included MI, unstable angina, or coronary ischemia.14 Cerebrovascular events included stroke and transient ischemic attack.14
Breast cancer assessment
Assessment of breast cancer was a prespecified secondary endpoint of the MORE trial, and was previously described in detail.16 All diagnoses of breast cancer were adjudicated by an independent oncology review board consisting of 5 physician specialists in breast cancer, and chaired by a pharmacologic scientist, none of whom were employed by the sponsor. Previous publications of the MORE breast cancer data have reported 61 cases of invasive breast cancer.16 A subsequent review of the MORE dataset found 1 fewer case of invasive breast cancer in each of the placebo and pooled raloxifene groups, so that 59 cases of invasive breast cancer were confirmed, and this number will be used in the present analysis. The change in the number of cases of invasive breast cancer was small, and had no impact on the overall interpretation of the breast cancer results from the MORE trial.
Results
Characteristics for all subjects at baseline and for women in the placebo group
Of the 7705 women enrolled, 7682 (99.7%) reported their status of previous HT use, with 2235 women (29.1%) having used HT before participating in MORE ( W1, available at www.jfponline.com). Baseline characteristics that were significantly different between women who reported prior HT use and those who reported no prior HT use included age, BMD, and the incidences of vertebral fractures, coronary angioplasty, hypertension, hyperlipidemia, and family histories of osteoporosis or breast cancer (Table W1, available at www.jfponline.com). In the subsets of women who did and who did not use HT previously, the baseline characteristics were not significantly different between the placebo and raloxifene groups, except for diabetes (placebo, 1.9%; raloxifene 60 mg/day, 3.3%; pooled raloxifene, 2.9%; P=.02).
In the placebo group, the incidence of new vertebral fractures, cardiovascular events, and breast cancer at 4 years were not significantly different in women with prior HT use compared with women without prior HT use.
Vertebral fracture events and bone mineral density
After 4 years of treatment with raloxifene 60 mg/d, women with and without prior HT use exhibited significant reductions in new vertebral fractures compared with those taking placebo ( Figure ). Vertebral fracture risk reductions between treatment groups were also statistically significant in subgroups of women with and without prevalent vertebral fractures ( Table1 ). Raloxifene 60 mg/d also reduced the risk of new clinically-apparent vertebral fractures, compared with placebo, in women with prior HT use (absolute risk reduction (ARR)=1.8%; RR=0.52 [95% CI, 0.28–0.96]), and in women without prior HT use (ARR=1.7%; RR=0.61 [95% CI, 0.43–0.87]; interaction P=.66]. The interaction P-values remained similar after adjusting for the baseline fracture risk factors (TableW1 , at www.jfponline.com) that were significantly different between women with and women without prior HT use. Women with and without prior HT use treated with raloxifene 60 mg/d had significant increases in BMD, at the lumbar spine (2.7% and 2.5%, respectively; interaction P=.54), and femoral neck (2.6% and 1.9% respectively; interaction P=.06), compared with placebo. Similar results were observed for fracture and BMD in women treated with the pooled raloxifene doses.