Bisphosphonates and Other Drugs

Bisphosphonates
Bisphosphonates (e.g., etidronate, alendronate, others) inhibit resorption of bone. In clinical studies in women with osteoporosis, these drugs increased bone mineral density and reduced fractures (19,20). On the minus side, alendronate can cause esophagitis, and regimens for bisphosphonates in general are complex. These factors may limit long-term compliance (21). Etidronate is available for osteoporosis treatment in Europe and Canada (22).

Calcitonin and other drugs
Calcitonin also inhibits bone resorption, may increase bone density, and may prevent fractures in osteoporotic women (23,24). Other agents for possible use in postmenopausal osteoporosis prevention are also under study (3). Further discussion of these agents is beyond the scope of this review.

Benefits and Limitations of SERMS

An ideal drug for long-term use in postmenopausal women would offer the benefits of estrogen but not its undesirable side effects and associated cancer risks. SERMs are being developed to address this need (25).

How SERMs work
SERMs are a structurally diverse group of compounds. All of them bind with high affinity to estrogen receptors, and all of them are believed to change the shape of the receptor in a unique way (26). The ligand-receptor complex combines with specific adapter proteins and interacts with target DNA sequences, either promoting or inhibiting gene transcription (27).

Depending on the SERM, the tissue in question, and the estrogen-dependent pathway being considered, a SERM may produce either estrogen-like effects or estrogen-blocking effects (25). Part of the explanation for this may involve the different types of estrogen receptors. There are two different known estrogen receptors: alpha and beta. Different tissues contain different ratios of alpha and beta receptors (28). SERMs bind to both types, but differential actions through these receptors may contribute to the nature and magnitude of the biological response in a specific tissue to an estrogen or to a particular SERM.

Tamoxifen: The first SERM
Tamoxifen (Novaldex), a triphenylethylene SERM, has estrogen-like effects on the skeleton, lipid levels, and uterus, but antiestrogen effects on the breast.

Tamoxifen has been used for many years to treat breast cancer (29). In 1998, it was shown to reduce the incidence of breast cancer in healthy women at high risk for developing this disease (30).

In addition, tamoxifen prevents resorption of bone, increasing lumbar spine bone mineral density in postmenopausal women (31). It reduces serum levels of cholesterol and LDL, but has little effect on HDL (32). However, tamoxifen stimulates the endometrium, and users have an increased risk of endometrial cancer (30,33) and thromboembolism (34).

Tamoxifen analogs and other SERMs
Toremifene (Fareston), droloxifene (not yet available), and idoxifene (not yet available) are analogs of tamoxifen. Like tamoxifen, they appear to be estrogenic in the skeleton and antiestrogenic in breast tissue (35,36). Toremifene, which is approved for treating advanced breast cancer, also stimulates the endometrium, (37) but an association with endometrial cancer has not been established (38). Clinical reports on the safety and efficacy of droloxifene and idoxifene in treating breast cancer and postmenopausal osteoporosis are limited, but preliminary findings suggest that they may stimulate the uterus to a lesser degree than does tamoxifen (39,40). Nonetheless, trials of idoxifene in osteoporosis were stopped because of unacceptable genitourinary side effects (41).

Newer SERMs include benzothiophenes (such as LY353381), tetrahydronaphthylenes (such as CP-336,156), and benzopyrans (such as EM-800) (42). These compounds are chemically and pharmacologically distinct from the triphenylethylenes, and their clinical efficacy and safety remain to be determined (43).

Raloxifene

Raloxifene belongs to the benzothiophene class of SERMs. It has been investigated more extensively than any other SERM for its skeletal antiresorptive effects, and it appears to have a profile well-suited to the needs of postmenopausal women-i.e., it has estrogenlike effects on the skeleton and on blood lipid levels, but estrogen-blocking effects in the breast and uterus.

Studies in animals
In ovariectomized rats, raloxifene preserved bone mass and reduced serum cholesterol levels (44). In ovariectomized, cholesterol-fed rabbits, raloxifene inhibited aortic accumulation of cholesterol (45). On the other hand, in ovariectomized cynomolgus monkeys raloxifene failed to reduce coronary atherosclerosis significantly when compared with conjugated equine estrogen (46). However, the monkeys who received estrogen had higher-thanexpected blood levels of 17ß-estradiol, the coronary plaques varied in size, and the sample number was low, and all of these may have limited the ability of this model to detect an effect of raloxifene (47). Raloxifene antagonizes the stimulatory effects of estrogen in the mammary gland of mice and prevents mammary tumors induced by carcinogens in rats. In these studies, raloxifene had little or no effect on uterine weight and histology (48,49).

Effect on osteoporosis in humans
Studies in humans have also shown that raloxifene, like estrogen, protects the skeleton.

In a study of calcium kinetics, (50) both raloxifene and estrogen replacement reduced bone resorption in the first 4 weeks of therapy without significantly altering bone formation. With raloxifene, the rates of resorption and formation did not change significantly between the 4th week and 31st week of therapy, whereas both were lower with estrogen. In other studies, raloxifene exerted a positive effect on several biochemical markers of bone metabolism, similar to estrogen (51,52). Histomorphometry studies indicate that bone quality is normal in patients receiving raloxifene (53).

Furthermore, in a study in healthy postmenopausal women, (51) raloxifene 60 mg/day (approved dosage) for 2 years effectively prevented bone loss, significantly increasing the bone mineral density of the lumbar spine, hip, and total body by about 2% relative to placebo (51). This increase was somewhat less than the increases observed in studies of alendronate and hormone replacement therapy (5,54)

In the Multiple Outcomes of Raloxifene (MORE) trial, a double-blind, placebo-controlled, clinical trial that enrolled 7,705 osteoporotic women, raloxifene treatment for 3 years significantly reduced the risk of new vertebral fractures by 30% to 50%, (55) similar to the results reported in a comparable trial with alendronate (19,20). This finding suggests that even though raloxifene's effects on bone mineral density are less than those of some other established therapies, it reduces vertebral fracture rates to as great an extent as other therapy.