The effects of raloxifene HCl on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene HCl, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine and total body BMD.
Effect on Bone Mineral Density
Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months ( see Table 6). The placebo groups lost approximately 1% of BMD over 24 months.
|Table 6: Raloxifene HCl- (60 mg Once Daily) Related Increases in BMD a for the Three Osteoporosis Prevention Studies Expressed as Mean Percentage Increase vs. Placebo b at 24 Months c|
|Site||NA d %||EU d %||INT d,e %|
|a Note: all BMD increases were significant (p≤0.001).|
|b All patients received calcium.|
|c Intent-to-treat analysis; last observation carried forward.|
|d Abbreviations: NA = North American, EU = European, INT = International.|
|e All women in the study had previously undergone hysterectomy.|
Raloxifene HCl also increased BMD compared with placebo in the total body by 1.3% to 2% and in Ward’s Triangle (hip) by 3.1% to 4%. The effects of raloxifene HCl on forearm BMD were inconsistent between studies. In Study EU, raloxifene HCl prevented bone loss at the ultradistal radius, whereas in Study NA, it did not ( see Figure 1).
Figure 1: Total hip bone mineral density mean percentage change from baseline
Effect on Endometrium
In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU). A total of 2978 TVU measurements were collected from 831 women in all dose groups. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the raloxifene HCl-treated women had a 0.09 mm mean increase. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding.
The effect of raloxifene HCl on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women [see Clinical Studies (14.1)] . After 4 years, raloxifene HCl, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22 to 0.67). Raloxifene HCl reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene HCl group compared with placebo. Table 7 presents efficacy and selected safety outcomes.
The effect of raloxifene HCl on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene HCl, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene HCl group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene HCl and placebo groups. Table 7 presents efficacy and selected safety outcomes.
In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene HCl, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene HCl (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene HCl group compared with placebo.
|Table 7: Raloxifene HCl (60 mg Once Daily) vs. Placebo on Outcomes in Postmenopausal Women with Osteoporosis|
|MORE 4 years||CORE a 4 years|
|Outcomes||Placebo (N=2576)||Raloxifene HCl (N=2557)||HR (95% CI) b||Placebo (N=1286)||Raloxifene HCl (N=2725)||HR (95% CI) b|
|n||IR b||n||IR b||n||IR b||n||IR b|
|Invasive c breast cancer||38||4.36||11||1.26||0.29 (0.15, 0.56) d||20||5.41||19||2.43||0.44 (0.24, 0.83) d|
|ER b,c positive||29||3.33||6||0.69||0.20 (0.08, 0.49)||15||4.05||12||1.54||0.37 (0.17, 0.79)|
|ER b,c negative||4||0.46||5||0.57||1.23 (0.33, 4.60)||3||0.81||6||0.77||0.95 (0.24, 3.79)|
|ER b,c unknown||5||0.57||0||0||N/A b||2||0.54||1||0.13||N/A b|
|Noninvasive c,e breast cancer||5||0.57||3||0.34||0.59 (0.14, 2.47)||2||0.54||5||0.64||1.18 (0.23, 6.07)|
|Clinical vertebral fractures||107||12.27||62||7.08||0.57 (0.42, 0.78)||N/A b||N/A b||N/A b||N/A b||N/A b|
|Death||36||4.13||23||2.63||0.63(0.38, 1.07)||29||7.76||47||5.99||0.77 (0.49, 1.23)|
|Death due to stroke||6||0.69||3||0.34||0.49 (0.12, 1.98)||1||0.27||6||0.76||2.87 (0.35, 23.80)|
|Stroke||5||6.42||43||4.91||0.76 (0.51, 1.14)||14||3.75||49||6.24||1.67 (0.92, 3.03)|
|Deep vein thrombosis||8||0.92||20||2.28||2.50(1.10, 5.68)||4||1.07||17||2.17||2.03 (0.68, 6.03)|
|Pulmonary embolism||4||0.46||11||1.26||2.76 (0.88, 8.67)||0||0||9||1.15||N/A b|
|Endometrial and uterine cancer f||5||0.74||5||0.74||1.01 (0.29, 3.49)||3||1.02||4||0.65||0.64 (0.14, 2.85)|
|Ovarian cancer||6||0.69||3||0.34||0.49 (0.12, 1.95)||2||0.54||2||0.25||0.47 (0.07, 3.36)|
|Hot flashes||151||17.31||237||27.06||1.61 (1.31, 1.97)||11||2.94||26||3.31||1.12 (0.55, 2.27)|
|Peripheral edema||134||15.36||164||18.73||1.23 (0.98, 1.54)||30||8.03||61||7.77||0.96 (0.62, 1.49)|
|Cholelithiasis||45||5.16||53||6.05||1.18 (0.79, 1.75)||12||3.21||35||4.46||1.39 (0.72, 2.67)|
|a CORE was a follow-up study conducted in a subset of 4011 postmenopausal women who originally enrolled in MORE. Women were not re-randomized; the treatment assignment from MORE was carried forward to this study. At CORE enrollment, the raloxifene HCl group included 2725 total patients with 1355 patients who were originally assigned to raloxifene 60 mg once daily and 1370 patients who were originally assigned to raloxifene 120 mg at MORE randomization.|
|b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women; N/A = not applicable.|
|c Included 1274 patients in placebo and 2716 patients in raloxifene HCl who were not diagnosed with breast cancer prior to CORE enrollment.|
|d p<0.05, obtained from the log-rank test and not adjusted for multiple comparisons in MORE.|
|e All cases were ductal carcinoma in situ.|
|f Only patients with an intact uterus were included (MORE: placebo = 1999, Raloxifene HCl = 1950; CORE: placebo = 1008, Raloxifene HCl = 2138).|
The effect of raloxifene HCl on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Women in this study had a median age of 67.6 years (range 55 to 92) and were followed for a median of 5.6 years (range 0.01 to 7.1). Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer and 41.4% of the women had a 5-year predicted risk of invasive breast cancer >1.66%, based on the modified Gail model.
Raloxifene HCl, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo [absolute risk reduction (ARR) 1.2 per 1000 women-years]; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene HCl group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer. Table 8 presents efficacy and selected safety outcomes.
|Table 8: Raloxifene HCl (60 mg Once Daily) vs. Placebo on Outcomes in Postmenopausal Women at Increased Risk for Major Coronary Events|
|Placebo a (N=5057)||Raloxifene HCl a (N=5044)||HR (95% CI) b|
|Outcomes||n||IR b||n||IR b|
|Invasive breast cancer||70||2.66||40||1.50||0.56 (0.38, 0.83) c|
|ER b positive||55||2.09||25||0.94||0.45 (0.28, 0.72)|
|ER b negative||9||0.34||13||0.49||1.44 (0.61, 3.36)|
|ER b unknown||6||0.23||2||0.07||0.33 (0.07, 1.63)|
|Noninvasive d breast cancer||5||0.19||11||0.41||2.17 (0.75, 6.24)|
|Clinical vertebral fractures||97||3.70||64||2.40||0.65 (0.47, 0.89)|
|Death||595||22.45||554||20.68||0.92 (0.82, 1.03)|
|Death due to stroke||39||1.47||59||2.20||1.49 (1, 2.24)|
|Stroke||224||8.60||249||9.46||1.10 (0.92, 1.32)|
|Deep vein thrombosis||47||1.78||65||2.44||1.37 (0.94, 1.99)|
|Pulmonary embolism||24||0.91||36||1.35||1.49 (0.89, 2.49)|
|Endometrial and uterine cancer e||17||0.83||21||1.01||1.21 (0.64 to 2.30)|
|Ovarian cancer f||10||0.41||17||0.70||1.69 (0.78, 3.70)|
|Hot flashes||241||9.09||397||14.82||1.68 (1.43, 1.97)|
|Peripheral edema||583||22||706||26.36||1.22 (1.09, 1.36)|
|Cholelithiasis g||131||6.20||168||7.83||1.26 (1.01, 1.59)|
|a Note: There were a total of 76 breast cancer cases in the placebo group and 52 in the raloxifene HCl group. For two cases, one in each treatment group, invasive status was unknown.|
|b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women.|
|c p<0.05, obtained from the log-rank test, after adjusting for the co-primary endpoint of major coronary events.|
|d All cases were ductal carcinoma in situ.|
|e Only patients with an intact uterus were included (placebo = 3882, raloxifene HCl = 3900).|
|f Only patients with at least one ovary were included (placebo = 4606, raloxifene HCl = 4559).|
|g Only patients with an intact gallbladder at baseline were included (placebo = 4111, raloxifene HCl = 4144).|
The effect of raloxifene HCl in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model <1.66%, or ≥1.66%.
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