Drug Evaluation Raloxifene for the treatment of postmenopausal osteoporosis

Estrogen is a potent inhibitor of osteoclastic bone resorption. After menopause, osteoclastic resorption is accelerated due to the decrease in endogenous estradiol levels. Hormone replacement can prevent bone loss and reduce risk of fractures [1–3]. However, use of estradiol and conjugated estrogens alone (estrogen therapy [ET]) or combined with progestins (estrogen progestin therapy [EPT]) may have serious side effects, including an increased risk of breast cancer [4], myocardial infarction [4], stroke [4,5] and venous thromboembolism [4,6]. For these reasons use of ET or EPT after menopause is discouraged except for short-term treatment (<2 years) of symptoms of meno pause [101] (i.e., not for treating or preventing postmenopausal osteoporosis) [7]. Some of these side effects may perhaps be linked to the progestin compound as (e.g., an increased risk of cardiovascular disease (CVD) may be seen with EPT as conjugated estrogen plus progestin) [4], but not with pure conjugated estrogen (ET) [5]. However, ET may only be used in hysterectomized women [5]. The differential effects of estrogens on bone and breast stems from the effects on the estrogen receptor subtypes. The positive effects on bone stems from effects on estrogen receptor-b, and the negative effects on breast tissue stems from effects on estrogen receptor-a [8–10]. For these reasons, selective estrogen receptor modulators (SERMs) have been developed. These have agonist effects on bone and antagonistic effects on breast tissue. The SERMs consist of raloxifene, bazedoxifene [11–13], lasofoxifene, arzoxifene [8,14], ospemifene [15] and toremifene [16]. Other drugs, such as tamoxifen, are also by nature SERMs [17] although tamoxifen is primarily used for the treatment of breast cancer [18,19]. This article will focus on the effects on bone and fracture risk with raloxifene and the side effects on breast tissue, endometrium and the cardiovascular system (risk of stroke, coronary events and deep venous thromboembolism [DVT]).