Raloxifene is used for the prevention and treatment of osteoporosis in postmenopausal women. Safety and efficacy in premenopausal women have not been established.
Osteoporosis, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with consequent increased bone fragility and susceptibility to fracture, is observed in a large proportion of postmenopausal women. Adult women have less bone mass than men at all ages, and decreased production of estrogen at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years, during which time skeletal mass loss averages 3% per year. While the risk of postmenopausal osteoporosis cannot be quantified by a single clinical finding or test result, many risk factors have been identified, with the probability of developing osteoporosis increasing with multiple risk factors. Risk factors include premature ovarian failure; a family history of osteoporosis; a small, slim body frame; endocrine disorders such as thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, and insulin-dependent diabetes mellitus (type 1, IDDM); cigarette smoking; drinking excessive amounts of alcohol; a sedentary life-style and/or lack of physical exercise; low body weight; and low dietary calcium intake. White or Asian women, particularly those who are thin or small and have a positive family history of osteoporosis, are at a higher risk for the disease than are black women. Increased bone turnover as manifested by increased serum and urine markers of bone turnover and low bone mineral density (BMD) (e.g., at least 1 standard deviation below the premenopausal mean) as determined by densitometric techniques also are risk factors. Premature ovarian failure (surgical or nonsurgical) hastens the onset of osteoporosis, and estrogen deficiency in premenopausal women (e.g., secondary to anorexia nervosa- or exercise-induced amenorrhea, or to hyperprolactinemia) induces bone loss and may reduce peak bone mass.
Osteoporosis may be confirmed by the finding of a low bone mass (e.g., at least 2 or 2.5 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture.
Prevention in Postmenopausal Women
Raloxifene is used for the prevention of osteoporosis in postmenopausal women; supplemental calcium and/or vitamin D should be used concomitantly if daily dietary intake is considered inadequate. The goal of preventive therapy is preservation of bone mass and a resultant decrease in fracture risk. Unlike estrogens, raloxifene is not effective in relieving vasomotor symptoms (hot flushes [ flashes]) associated with estrogen deficiency.
(See Cautions: Cardiovascular Effects.)The efficacy of raloxifene in preventing other forms of osteoporosis (e.g., drug [ such as corticosteroid]-induced) remains to be established.
Raloxifene has been evaluated for the prevention of osteoporosis in postmenopausal women in 3 multinational (North American trial, European trial, International trial), randomized, placebo-controlled, double-blind studies that included 1764 women (median age: 54 years; median time since menopause: 5 years; 93.5% white; all women in the International trial had undergone hysterectomy; 12 or 19% of women in the European or North American trials, respectively, had undergone hysterectomy) with normal or low (osteopenia) BMD values (mean lumbar spine BMD value 0.74-1 standard deviations below the premenopausal mean). All women received 400-600 mg of elemental calcium daily in addition to their usual dietary calcium intake. In these studies, therapy with raloxifene hydrochloride 60 mg daily increased BMD, as determined by dual-energy radiographic absorption (DXA) measurements, in the lumbar spine, hip, and total body. While women receiving placebo (i.e., calcium) lost approximately 1% of BMD at 24 months, substantial increases in BMD were apparent at 12 months following initiation of raloxifene therapy and were maintained at 24 months. Increases in total body BMD of 1.3-2% compared with placebo (i.e., calcium) have been reported in raloxifene-treated women. In North American or European postmenopausal women receiving raloxifene hydrochloride 60 mg daily for 24 months, the increase in BMD (expressed as mean % increase versus placebo) was 2-2.4% for total hip, 2.1-2.5% for femoral neck, 2.2-2.7% for trochanter, 2.3-2.4% for intertrochanter, and 2-2.4% for lumbar spine. In women receiving raloxifene hydrochloride 60 mg daily who had undergone hysterectomy (the International trial), the increase in BMD (expressed as mean % increase versus placebo) was 1.3% for total hip, trochanter, and intertrochanter; 1.6% for femoral neck; and 1.8% for lumbar spine. The effect of raloxifene therapy for longer than 2 years is being investigated in ongoing studies. Whether increases in BMD are maintained following withdrawal of raloxifene has not been established. The effect of raloxifene therapy on forearm BMD remains to be determined. While raloxifene prevented bone loss at the ultradistal radius in one study (European trial), a protective effect at this site was not documented in another study (North American trial).
The effect of raloxifene on BMD versus estrogens or alendronate has been evaluated in several clinical studies. In one comparative study, therapy with conjugated estrogens 0.625 mg daily for 6 months was associated with substantially greater increases in BMD than therapy with raloxifene. Based on historical comparisons, the effect of raloxifene on hip BMD appears to be slightly less than that of estrogen/progestin or alendronate, and the effect of raloxifene on lumbar spine BMD appears to be about half that of estrogen/progestin or alendronate. In osteoporosis prevention studies that evaluated raloxifene (European trial), various estrogen/progestin combinations (HRT) (Early Postmenopausal Intervention Cohort Study), or alendronate therapy (Early Postmenopausal Intervention Cohort Study) for 24 months, raloxifene hydrochloride therapy (60 mg daily) was associated with 1.6% increases in hip BMD compared with baseline, HRT was associated with 1.8-3.2% increases, and alendronate (5 mg daily) therapy was associated with 1.3-1.9% increases. In these studies, raloxifene, HRT, or alendronate was associated with increases in BMD of lumbar spine of 1.6%, 4-5.1%, or 2.9-3.5%, respectively, compared with baseline. In a limited number of healthy postmenopausal women, administration of tamoxifen 20 mg daily for 24 months was associated with an increase in lumbar spine BMD compared with baseline of 1.4%.
While the exact role of raloxifene in the prevention of osteoporosis relative to other available agents (e.g., estrogens, alendronate, risedronate) remains to be clearly determined, advantages of raloxifene include a better adverse effect profile than that of estrogens (with or without progestin). In addition, raloxifene may be especially useful in patients who are unable or unwilling to comply with the recommended regimen for oral administration of alendronate. While estrogen replacement therapy is effective for the prevention of osteoporosis in women, such therapy is associated with a number of adverse effects and the proportion of postmenopausal women who take estrogens for prolonged periods of time is low. Because raloxifene appears to have a more favorable adverse effect profile than estrogen or estrogen/progestin therapy, long-term compliance with raloxifene may be better than that with estrogens. However, clinical experience with raloxifene is limited compared with estrogen replacement therapy, and the effect of raloxifene on fracture rates has not been established. The role of raloxifene versus alendronate also has not been established. The choice of alendronate, estrogen, raloxifene, or risedronate for the prevention of postmenopausal osteoporosis should be individualized, taking into account differences in tolerability and safety, and individual preference.
The optimal timing for initiation of preventive therapy for osteoporosis, including that with raloxifene, and the optimal duration of such therapy remain to be established. Although raloxifene preventive therapy was initiated at a median of 5 years postmenopause in clinical trials, experience with estrogen replacement therapy suggests that the protective effect may be greatest if the drug is initiated soon after menopause and continued into late life or indefinitely. If preventive therapy is not initiated soon after menopause, some benefit also may be likely with delayed initiation. In general, exercise and adequate calcium and vitamin D intake should be encouraged for all women. Whether additional preventive therapy generally should be offered to all women or just recommended for selected women at highest risk of developing osteoporosis remains to be established.
Treatment in Postmenopausal Women
Raloxifene is used for the treatment of osteoporosis in postmenopausal women. Estrogen replacement therapy is effective for the treatment of osteoporosis in postmenopausal women and has been recommended as first-line therapy for women with osteoporosis. However, because results of a recent controlled study indicate that estrogen/progestin therapy is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism, recommendations on the appropriate use of such therapy are being revised. Other therapeutic modalities for the treatment of osteoporosis include alendronate, calcitonin, calcium, risedronate, and vitamin D.Therapy with alendronate reduces spine and nonspine fracture rates in women with osteoporosis. While recent evidence indicates that raloxifene reduces the risk of vertebral fracture in women with osteoporosis, experience with the drug is limited and efficacy of raloxifene in the treatment of osteoporosis compared with that of estrogens or alendronate remains to be determined. The role of raloxifene in the treatment of osteoporosis may be determined by the effect of the drug on breast cancer.
(See Breast Cancer: Reduction in the Incidence of Breast Cancer in Women with Osteoporosis, in Uses.)
The effects of raloxifene on BMD and fracture incidence have been evaluated in a 3-year, multinational, randomized, double-blind study that included 7705 postmenopausal women (median age: 67 years; median time since menopause: 19 years) with osteoporosis (vertebral or hip BMD values at least 2.5 standard deviations below premenopausal mean values without baseline vertebral fractures or one or more vertebral fractures). All women received 500 mg of elemental calcium daily and 10-15 mcg (400-600 units) of cholecalciferol daily in addition to their usual calcium and vitamin D intake. In this study, therapy with raloxifene increased BMD (as determined by dual-energy radiographic absorption [DXA] measurements) of the spine, hip, and total body, and reduced the risk of vertebral fracture (as determined radiographically).
In women receiving raloxifene 60 mg daily for 24 months, the increase in BMD (expressed as a mean percent increase versus placebo) was 2.2% for ultradistal radius, 0.9% for distal radius, and 1.1% for total body. In women receiving raloxifene 60 mg daily for 36 months, the increase in BMD was 2.6% for lumbar spine and 2.1% for femoral neck. In this study, women receiving raloxifene had fewer new vertebral fractures regardless of vertebral fracture status at the beginning of the study. In women without baseline vertebral fractures, radiographic evaluation at study completion revealed one or more new vertebral fractures in 4.3% of placebo-treated women and in 1.9% of raloxifene-treated women (relative risk reduction 55%). In women with one or more baseline fractures, radiographic evaluation at study completion revealed one or more new fractures in 20.2% of placebo-treated women and in 14.1% of women receiving raloxifene hydrochloride 60 mg daily (relative risk reduction 30%). In women with one or more baseline fractures, the incidence of new fractures was 10.7% in women receiving raloxifene hydrochloride 120 mg daily. Fewer raloxifene-treated women (1.8%) experienced one or more new symptomatic vertebral fractures than placebo-treated women (3.1%). Differences in the reduction in vertebral fracture risk associated with raloxifene therapy based on age, baseline femoral neck or lumbar spine BMD, prior hormone replacement therapy, or prior hysterectomy have not been observed in this study. A reduction in nonspinal fractures was not observed in raloxifene-treated women at month 36.
Use in Premenopausal Women
Safety and efficacy of raloxifene in premenopausal women have not been established, and the role, if any, of the drug in the prevention or treatment of osteoporosis in such women remains to be determined.
Corticosteroid-induced Hypogonadism and Osteoporosis
Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the ovaries and testes, and such hypogonadism may be associated with bone loss. Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present. Hormone replacement therapy (HRT, combined estrogen and progestin therapy) has been effective in increasing bone mass density (BMD) in postmenopausal women with asthma or rheumatoid arthritis who were receiving chronic corticosteroid therapy. Although the efficacy of raloxifene for the prevention or treatment of corticosteroid-induced bone loss remains to be established, some experts (e.g., the American College of Rheumatology) currently state that raloxifene theoretically should be effective in preventing such bone loss and therefore can be offered to selected postmenopausal corticosteroid-treated women who refuse HRT therapy or other antiresorptive agents (e.g., bisphosphonates, calcitonin) or in whom such therapies are contraindicated.
Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for developing invasive breast cancer. Raloxifene should not be used to reduce the risk of breast cancer in premenopausal women.
Raloxifene is not indicated for the treatment of breast cancer or to reduce the risk of recurrence of breast cancer. Raloxifene is not indicated for reduction in the risk of noninvasive breast cancer.
Reduction in the Incidence of Breast Cancer in Women with Osteoporosis
Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women with osteoporosis. Findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, a double-blind study that evaluated effects of raloxifene on fracture incidence (primary end point) and incidence of breast cancer (secondary end point) in postmenopausal women with osteoporosis, provided the first evidence of possible breast cancer risk reduction effects of raloxifene. Results from the 4-year MORE study showed a 72 and 84% reduction in the incidence of newly diagnosed invasive breast cancer and estrogen receptor (ER)-positive breast cancer, respectively, in women receiving raloxifene compared with those receiving placebo. The Continuing Outcomes Relevant to Evista (CORE) study investigated the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in a subset of the MORE cohort who agreed to continue therapy. During the 8 years of the MORE and CORE study, the incidence of invasive breast cancer and ER-positive positive breast cancer was reduced by 66 and 76%, respectively, in those receiving raloxifene compared with those receiving placebo. The incidence of noninvasive breast cancer in women receiving raloxifene was similar to that in women receiving placebo.
Reduction in the Incidence of Breast Cancer in Women at High Risk
Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women at high risk for developing the disease.
Experts consider use of raloxifene an option in postmenopausal women 35 years of age or older who are considered high risk for developing breast cancer (i.e., a 5-year projected risk of 1.67% or greater based on the calculated score derived from the Gail risk model) to reduce the risk of invasive breast cancer. Additionally, experts consider use of raloxifene an option to reduce the risk of invasive breast cancer in postmenopausal women 35 years of age or older with a history of lobular carcinoma in situ (LCIS), since these women are at increased risk for developing invasive breast cancer in both the affected and contralateral breast.
The effects of raloxifene versus tamoxifen on reducing the incidence of breast cancer was evaluated in a clinical trial known as STAR (Study of Tamoxifen and Raloxifene). This study enrolled postmenopausal women at least 35 years of age who were at high risk for developing breast cancer. Breast cancer risk was determined using the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool based on a statistical model (the Gail model). High risk was defined as a 5-year projected breast cancer risk score of 1.67% or greater, calculated using the NCI (or Gail) assessment tool. Additionally, postmenopausal women 35 years of age or older with a history of LCIS, whose only prior treatment included local excision, were eligible to participate in the study. Patients enrolled in the STAR study were randomized to receive either tamoxifen (20 mg daily) or raloxifene (60 mg daily) for a maximum of 5 years. Results from the STAR study showed that raloxifene and tamoxifen were equivalent in efficacy in lowering the risk of invasive breast cancer (4.3 per 1000 in the tamoxifen group versus 4.41 per 1000 in the raloxifene group). There were fewer cases of noninvasive breast cancer in women receiving tamoxifen than in those receiving raloxifene (1.51 per 1000 in the tamoxifen group versus 2.11 per 1000 in the raloxifene group); the clinical importance of this finding remains to be determined. Use of raloxifene was associated with a lower risk of thromboembolic events than use of tamoxifen; there was no difference in the rates of myocardial infarction, severe angina, or acute ischemic syndrome between the tamoxifen and raloxifene groups. Rates of fracture were essentially identical in the raloxifene and tamoxifen groups. There were fewer cataracts in the raloxifene group than in the tamoxifen group.
Based on patient reported symptoms and quality of life assessments performed during the STAR study, there were no differences in overall physical, mental health, or depressive symptoms among women receiving either raloxifene or tamoxifen. However, women receiving raloxifene reported more musculoskeletal problems, dyspareunia (painful intercourse), and weight gain; women receiving tamoxifen reported more bladder-control (e.g., urinary incontinence) problems, gynecologic problems, and leg cramps. Fewer cases of endometrial cancer were reported in women receiving raloxifene compared with tamoxifen, but the difference was not statistically significant.
(See Cautions: Genitourinary Effects.)
The effect of raloxifene on the reduction in breast cancer incidence in women with BRCA1 or BRCA2 genetic mutations has not been established. Additionally, the effect of raloxifene (or tamoxifen) has not been studied in women with a history of exposure to thoracic radiation, which is considered a possible risk factor for breast cancer.
Reduction in the Incidence of Breast Cancer in Women at Increased Risk of Coronary Events
The effect of raloxifene on the incidence of coronary events and invasive breast cancer was evaluated in postmenopausal women with coronary heart disease or increased risk for coronary heart disease (Raloxifene Use for the Heart; RUTH). Results from the 5-year RUTH study showed a 44 and 55% reduction in the incidence of newly diagnosed invasive breast cancer and estrogen receptor (ER)-positive breast cancer, respectively, in women receiving raloxifene compared with those receiving placebo. Treatment with raloxifene did not affect the risk of coronary events; an increased risk of venous thromboembolic events and fatal stroke was observed in women receiving raloxifene. (See
Cautions: Cardiovascular Effectsand Cautions: Precautions and Contraindications.)