Raloxifene

Selective estrogen receptor modulators, or SERMs have estrogen agonist activity in some tissues and antagonist or minimal agonism in other tissues. For the treatment of postmenopausal estrogen deficiency, SERMs have been referred to as "designer drugs" because they are specifically designed to mimic the favorable effect of estrogens without bringing about undesirable changes in the breast or uterus.

Tamoxifen is the prototype for this class, and has been used to treat breast cancer due to its estrogen antagonist activity in breast tissue. Tamoxifen was also found to have beneficial estrogen agonist-like (antiresorptive) effects on bone and serum cholesterol. However, uterine stimulatory (estrogen agonist) effects are also found with this agent.⁴⁷

Raloxifene ^{46, 47} a second-generation SERM is now approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. Studies are ongoing to determine its effects on heart disease and breast cancer.

Indications

• Osteoporosis treatment: 60 mg PO once daily

• Osteoporosis prevention: 60 mg PO once daily

Effects on BMD and Fractures

The Multiple Outcomes of Raloxifene Evaluation (MORE) ⁴⁸ is double-blind, placebo-controlled, randomized trial examining the effects of raloxifene on the incidence of new vertebral and non-vertebral fractures. The study included a total of 7,705 postmenopausal women (aged 31-80 years) with osteoporosis who were randomized to receive placebo or raloxifene 60 mg/day or 120 mg/day. In addition, all women received supplemental calcium (500 mg/day) and vitamin D (400-600 IU/day). At 36 months, at least 1 new vertebral fracture was evident radiographically in 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene. Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly. Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg)at P<0.001 for all comparisons. Women receiving raloxifene had a three fold increased risk of venous thromboembolism compared to placebo. Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.

In summary, raloxifene 60 mg or 120 mg daily plus calcium and vitamin D increased BMD in the spine and femoral neck, and reduced the risk of vertebral fractures by 35% in postmenopausal women.

Investigators analyzed the results of raloxifene on the risk of invasive breast cancer from the MORE trial.⁴⁹ and concluded that among postmenopausal women with osteoporosis, the risk of invasive breast cancer decreased by 76% during three years of treatment with raloxifene.

Side-Effects 46, 47

Common adverse effects reported in clinical trials are hot flashes and leg cramps. Raloxifene is not effective in reducing hot flashes associated with estrogen deficiency and may precipitate hot flashes in asymptomatic patients upon initiation of therapy. Unlike ERT/HRT, raloxifene is not associated with breast pain or vaginal bleeding.

Concomitant use of raloxifene with ERT has not been evaluated and is not recommended at the present time.

Due to the increased risk of thromboembolic events, raloxifene is contraindicated in patients with an active or past history of deep vein thrombosis, pulmonary embolism, or retinal vein thrombosis and in patients that are sedentary.

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