ReviewRationale for using raloxifene to prevent both osteoporosis and breast cancer in postmenopausal women
Introduction
Menopause is a biological process that occurs as part of aging in women, and the key factor of the menopause is estrogen deficiency [1]. Estrogen and its receptors, ERα and ERβ [2], mediate the modulation of bone density [3]. Estrogen deficiency is the main cause of postmenopausal osteoporosis [4], and its occurrence after menopause leads to an increase in bone remodeling, resulting in an imbalance between bone resorption and formation. This is reflected in a decrease in bone mineral density (BMD) and an increase in fracture risk. Osteoporotic fractures lead to morbidity and mortality [5]. The incidence of osteoporosis and the associated economic burden will rise as the population ages [5]. Due to the close relationship between estrogen deficiency and osteoporosis, the use of estrogen therapy (ET) or a combination of estrogen and progestogen (EPT) after menopause, has been well accepted for decades. However, the prolonged use of either single ET or EPT (for example, in the Women's Health Initiative [WHI] trial) may be associated with a slightly, but definitely, increased risk of breast cancer [6], [7]. The weight of evidence indicates that exposure to estrogen is an important determinant of the risk of breast cancer [8]. Therefore, pure estrogens may not be a good choice in the management of postmenopausal women with osteoporosis. If agents could function like estrogen in terms of bone, but without estrogen's stimulation of the breast, they might be a better choice. Recently, selective estrogen receptor (ER) modulators (SERMs) have represented a major therapeutic advance for clinical practice [9]. Unlike estrogens, which are uniformly agonists, and anti-estrogens, which are uniformly antagonists, the SERMs exert selective agonist or antagonist effects on various estrogen target tissues [9]. The unique properties of SERMs lie in their bulky side-chain. This blocking effect in turn prevents key coregulator proteins (known as coactivators) from interacting with the receptor, and thus prevents activation [10], [11]. The mechanisms of the tissue-selective, mixed agonist–antagonist action of SERMs, although still only partly understood, are gradually becoming clearer [9]. Most of the unique pharmacology of SERMs can be explained by three interactive mechanisms: differential ER expression in a given target tissue, differential ER conformation on ligand binding, and differential expression and binding to the ER of coregulator proteins [9].
Many different types of SERMs have undergone large clinical trials. Among them, raloxifene may be the most attractive agent, because at least three large trials, including the Multiple Outcomes of Raloxifene Evaluation (MORE) [12], [13], [14], Continuing Outcomes Relevant to Evista (CORE) [15], [16], and Raloxifene Use for the Heart (RUTH) [17], have shown practical and promising results when using raloxifene for the prevention and management of postmenopausal women with osteoporosis or osteopenia. In these trials, raloxifene not only decreased the incidence of osteoporosis-associated complications, such as vertebral fractures and possible non-vertebral fractures, but also offered benefits for breast cancer prevention, with a dramatic decrease in the incidence of all breast cancers. In addition, two other trials have demonstrated raloxifene to be a potential candidate and choice for menopausal women: the Study of Tamoxifen and Raloxifene (STAR) [18], [19], and Evista Versus Alendronate (EVA) [5]. The STAR trial further confirmed the efficacy of raloxifene in preventing breast cancer, and showed it to be similar to the well-known anti-breast cancer drug tamoxifen. The EVA trial used the frequently prescribed anti-osteoporosis drug alendronate as a comparison, and the results showed equal efficacy in preventing osteoporosis-related fractures. These definitive clinical studies have highlighted the opportunities for innovation in the selective modulation of estrogen target tissues, especially raloxifene for the prevention and treatment of estrogen deficiency-related osteoporosis and possibly for estrogen-related breast cancers.
Since raloxifene has shown the above benefits, the aims of this report will be to offer data to support the rationale for using raloxifene in postmenopausal women, especially in a given population. We will review the emerging evidence of the efficacy of raloxifene in relation to both major health problems – osteoporosis and breast cancer – in postmenopausal women, summarize the results, and place in perspective their therapeutic uses for women having either a high risk of osteoporosis or a high risk of breast cancer.
Section snippets
MORE, CORE, and RUTH studies
At least three large clinical trials have studied the value, benefits, and risks of raloxifene in the management of postmenopausal women. The first one was the MORE study, a multicenter, randomized, double-blind trial, in which women taking raloxifene at 60 or 120 mg/day (5129 women) or a placebo (2576 women) were followed up [12], [13], [14]. A total of 7705 postmenopausal women (mainly in the United States and Europe), younger than 81 years (mean age, 66.5), and with osteoporosis as defined by
The anti-fracture efficacy of raloxifene: bone markers and BMD
As shown above, raloxifene was effective in preventing postmenopausal bone loss over a 3-year period in the MORE trial [12]. The BMD gains after 3 years were 2.1% in the spine and 2.6% in the femur. Concomitantly, significant decreases were noted for osteocalcin (−26.3% versus −8.6% in the placebo group) and urinary cross-linked N-telopeptides of type I collagen (NTX) (−34% versus −8.1% in the placebo group). BMD gains after 4 years were 2.6% in the spine and 2.1% in the femur. BMD increases
The anti-fracture efficacy of raloxifene: vertebral fracture and non-vertebral fracture
The anti-fracture efficacy of raloxifene has also been well established by the MORE trial [12], [14]. Raloxifene was efficacious (with a vertebral fracture reduction of 30% in women with and 55% in women without prevalent fractures over 3 years) [12], sustainable (with a 50% reduction in the fourth year versus a 55% reduction in years 0–3) [14], fast-acting (with 68% reduction, p = 0.01, in a 1-year post hoc analysis, and 90% reduction, p = 0.01, in a 6-month post hoc analysis) [28], [29], and very
Raloxifene and the prevention of breast cancer (Table 3)
An increase in mammographic density should be regarded as an unwanted side effect of HT, because increased breast density can impair the interpretation of mammograms, thus increasing the failure rate of breast cancer screening programs [35]. In fact, the WHI report showed that combination HT did indeed increase the risk of the incidence of breast cancers. Therefore, since raloxifene can reduce mammographic breast density [36] and breast cancer proliferative indices [37], it may play a
Discussion
Although the anti-osteoporosis and anti-osteoporosis-related fracture efficacy of raloxifene has been proven in large clinical trials, such as the MORE, CORE, and RUTH studies, one may question why there are so many anti-osteoporosis-related fracture agents currently available for prevention and/or treatment of postmenopausal osteoporosis. Bisphosphonates (alendronate, etidronate, pamidronate, zoledronic acid, risedronate, and ibandronate), calcitonin, calcium, vitamin D, estrogen, parathyroid
Areas of potential development
Since the publication of the WHI [6], the prescription of hormone therapy (HT) in the management of menopausal women has become controversial. Major efforts have been made to identify alternatives to hormone therapy. Compounds suggested have included SERMs, which represent a class of a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favorable estrogenic
Conclusion
Based on these observations (the MORE, CORE, and RUTH trials), the efficacy of raloxifene in the prevention and management of osteoporosis, the decreased incidence of fracture, and the decreased incidence of invasive breast cancer has been proved. The potential risk of thromboembolism has also been emphasized. A recent meta-analysis to evaluate the effect of raloxifene on the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) showed that therapy with raloxifene was associated with a
Acknowledgements
This work was supported in part by grants from the Taipei Veterans General Hospital – National Taiwan University Hospital Joint Research Program (96VN-008 and 97VN-012), and the National Science Council (NSC-96-2629-B-010-001 and NSC-96-2314-B-010-018-MY3), Taiwan.
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