Raloxifene: A New Choice for Treating and Preventing Osteoporosis

All of the drugs currently available to prevent osteoporosis have unique advantages and disadvantages, both in their clinical action and in terms of patient compliance with therapy.

In this article we first outline the pros and cons of estrogen replacement therapy and bisphosphonates, then discuss tamoxifen, the first SERM, and its analogs. In the final section, we discuss raloxifene, the first in a new class of SERMs (the benzothiophenes), and evaluate its place in the emerging field of postmenopausal women's health.

Benefits and Limitations of Estrogen Replacement Therapy
Estrogen replacement therapy has become the standard of care for perimenopausal and postmenopausal women. It relieves perimenopausal symptoms such as hot flashes and has favorable effects on bone mineral density, bone turnover markers, and cardiovascular risk factors (1,2).

Estrogen prevents osteoporosis
Estrogen replacement is the most established treatment available for preventing and managing postmenopausal osteoporosis (3). Used prophylactically, it can maintain bone mass.

In patients with established osteoporosis, it increases bone mineral density in the lumbar spine and various other skeletal sites by 2% to 5% (5). In the elderly, it can arrest bone loss even many years after menopause (6). Observational studies suggest that estrogen therapy may reduce the risk of hip and spine fractures, although the benefit is attenuated once therapy is stopped (7,8); at present, however, data are lacking from prospective, randomized, controlled trials to confirm these findings.

Estrogen's effect on coronary artery disease is unclear
Estrogen replacement affects a variety of risk factors for coronary artery disease, lowering serum levels of cholesterol, low-density lipoprotein (LDL), and fibrinogen and raising high-density lipoprotein (HDL) (9). On the other hand, it raises serum triglyceride levels (9).

Observational studies suggest that postmenopausal women who receive estrogen replacement have lower rates of coronary artery disease than those who do not (10,11). Only one prospective, controlled, randomized trial has been performed to determine if estrogen replacement actually prevents coronary events, however, and it had negative results (12).

This recent trial was called the Heart and Estrogen/progestin Replacement Study (HERS) (12). Participants were postmenopausal women with established coronary artery disease. Treatment consisted of the combination of conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. At an average of 4.1 years of follow-up, there was no difference between the groups in the incidence of myocardial infarction, coronary heart disease death, or other cardiovascular outcomes. In fact, there were more events in the estrogen group than in the placebo group in the first year (but fewer events in years 4 and 5).

These findings apply only to the population and drug regimen studied. Studies are underway that may eventually clarify the long-term cardiovascular benefits of hormone replacement therapy in postmenopausal women.

Risks of cancer, thromboembolism: Small but significant
Estrogen replacement therapy carries a small increased risk of serious complications, and the risk increases with duration of therapy.

Endometrial cancer occurs up to four times more frequently in women with a uterus who take unopposed estrogen than in nonusers. The risk may be reduced, but not completely eliminated, by adding a progestin (13).

Breast cancer risk may increase slightly with hormone replacement. In the Nurses' Health Study, (14) the risk of death from breast cancer was 43% higher in women who had used hormones for more than 10 years than in nonusers. In a reanalysis of data from 51 epidemiological studies involving more than 150,000 breast cancer cases and controls, the relative risk for breast cancer was 1.35 for women who had used hormone replacement therapy for 5 years or more (15).

Venous thromboembolism is rare but increases with estrogen use. Observational studies report an approximately threefold increase in the incidence of venous thromboembolism in women receiving hormone replacement therapy (16,17). This finding was confirmed in the HERS clinical trial (12).

Compliance is low
Uterine bleeding, breast pain, and fear of cancer and thromboembolism probably all contribute to a low rate of compliance with hormone replacement therapy: approximately 70% of women refuse it outright or stop taking it prematurely (18). This reality diminishes the potential benefit of estrogen therapy in the postmenopausal population.