Osteoporosis SERMs

It has been shown that in postmenopausal women habitually high intakes of dietary isoflavones are associated with higher bone mineral density (BMD) values at both the spine and hip region (Mei et al, 2001). It is conceivable that an isoflavone-rich diet may help to reverse the state of secondary hyperparathyroidism associated with estrogen withdrawal and hence lower the rate of bone turnover in postmenopausal women, thus reducing the risk of osteoporosis (Valtuena et al, 2003). Phytoestrogens could be used as natural SERMs (Brzezinski and Debi, 1999) and some studies (Setchell, 2001 and refs therein) support such an idea since the molecular targets of... 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

The second group of SERMs includes drugs such as raloxifene (previously named keoxifene), arzoxifene (Fig. 2.2), and LY-117018. Raloxifene was initially designed as a drug to treat breast cancer, but its clinical development was later focused on prevention and treatment of postmenopausal osteoporosis,... 

In addition to lasofoxifene and arzoxifene, bazedoxifene (TSE-424, WAY-140424) is one of the newer SERMs in advanced Phase III clinical development for the prevention and treatment of postmenopausal osteoporosis. In pre-... 

Raloxifene is a SERM devoid of stimulating effects on the uterus as is known from the initial studies (Delmas et al. 1997). Eliminating one of the major concerns raised by the experience gained with tamoxifen studies, both in prevention and adjuvant treatments, puts raloxifene in a place of privilege to be a rational alternative agent. At the same time it improves bone density, prevents osteoporosis and vertebral fracture, and reduces cardiovascular events in a subset of high-risk patients (Silverman et al. 2004). The evidences on the effects of raloxifene on the uterus are explained in detail in Chap. 10 of this book. 

Prevention of osteoporosis and fracture can be achieved through limiting the resorption-remodeling process. Four main families of products can be effective in controlling bone resorption estrogens, SERMs, bisphosphonates, and calcitonin. Large, prospective randomized trials have proven the effectiveness... 

This is a proposal to help the clinician to counsel individual women. This process of individualization is crucial and is the best guarantee of a wise use of the different alternatives presently available for an efficient management of the postmenopausal period. Guidelines are only indications of the best choice for a majority of women, but, as health agents of our patients, we have the responsibility of determining how suitable they are for a given woman and introduce the appropriate corrections. In this context SERMs are an early alternative for osteoporosis prevention and treatment that provide an additive protective effect on the breast and are neutral on cardiovascular risk. 

The novel SERMs, which include bazedoxifene and ospemifene (also known as deaminohydroxy-toremifene), are being investigated for the prevention and treatment of osteoporosis in post-menopausal women in phase III clinical trials [151,165]. The non-steroidal SERM lasofoxifene (CP-336156) [151], currently under consideration by the Food and Drug Administration for both prevention of osteoporosis and urogenital atrophy, may have potential for... 

Raloxifene (Evista) is a new SERM approved for use in the treatment and prevention of osteoporosis because it has estrogenic activity in bone. Raloxifene is an estrogen antagonist in both breast and endometrial tissues. The estrogenhke properties of raloxifene result in the maintenance of a favorable serum Upid profile (decreased low-density lipoprotein levels with no change in either high-density lipoproteins or triglycerides). Raloxifene is 95% bound to plasma proteins. Absorption of raloxifene is impaired by cholestyramine. 

The chief therapeutic uses of estrogens and progestins are as oral contraceptives and hormone replacement therapy. Progestins and SERMs are also important agents in the treatment of osteoporosis, breast cancer, endometrial cancer, and infertility. 

Raloxifene has been studied for its ability to reduce bone loss in postmenopausal women (4). Some specialized SERMs could reduce the risk of osteoporosis after the menopause without having other troublesome hormonal effects (5), but much more work is needed to determine whether they will fulfill this hope. 

Albertazzi P, Purdie DW. Oestrogen and selective oestrogen receptor modulators (SERMs) current roles in the prevention and treatment of osteoporosis. Best Pract Res Clin Rheumatol 2001 15(3) 451-68. 

More recently, another SERM, known as raloxifene (Evista), was developed. Raloxifene is similar to tamoxifen except that it blocks estrogen receptors on breast and uterine tissues and may therefore produce beneficial effects (inhibiting breast cancer, improving bone and cardiovascular function) without increasing the risk of endometrial cancers.30,51,57 Raloxifene is currently approved for treating osteoporosis, and the use of this drug is associated with increased vertebral bone density and a reduced risk of vertebral fractures.30,77... 

Osteoporosis Generalized bone demineralization often associated with effects of aging and hormonal changes in postmenopausal women Calcium supplements, vitamin D, calcitonin, bisphosphonates, intermittent parathyroid hormone, estrogen, or SERMs (raloxifene] (see Chapter 30]... 

---