Raloxifene: Risk Factors in Humans

Effect on cardiovascular risk factors in humans
Raloxifene also has favorable effects on markers of cardiovascular disease. In one study, LDL cholesterol concentrations were significantly decreased by about 10% after 8 weeks of treatment with either raloxifene 200 mg/day or conjugated equine estrogens (52). Similar changes in serum lipid concentrations were observed in studies in which women in their early years after menopause received raloxifene 60 mg/day for 2 years (51). In contrast to estrogen replacement therapy, raloxifene does not increase HDL cholesterol, nor does it raise triglycerides (56). However, in one study, raloxifene decreased fibrinogen levels by 12% to 14%, whereas hormone replacement therapy had no significant effect on this cardiovascular risk factor (56).

The potential cardioprotective effects of raloxifene are being evaluated in the Raloxifene Use for the Heart (RUTH) trial, which will enroll 10,000 postmenopausal women. The primary endpoint will be the combination of coronary death and nonfatal myocardial infarction (57).

Little or no effect on endometrium
Unlike estrogen, raloxifene does not stimulate the endometrium (58,59). Results from the MORE trial suggest that the risk for endometrial cancer is not increased after 3 years of raloxifene treatment (60). In contrast, in women taking tamoxifen, increases in endometrial cancer incidence have been observed within the first 2 years of therapy (30). Continued follow-up will be needed to fully evaluate the effect of raloxifene on the endometrium.

May decrease breast cancer
Women receiving raloxifene report no increased incidence of breast pain,(61) a well-known side effect of estrogen replacement therapy.

In addition, in the MORE trial, the incidence of newly diagnosed breast cancer was approximately 75% lower in raloxifene-treated subjects than in the placebo group, through 3 years of treatment (60). Most tumors diagnosed during the first 3 years of this trial were probably present at a subclinical level at the start of the trial. Thus, the reduction in breast cancer risk currently observed with raloxifene may represent suppression or regression of subclinical cancer (60).

Long-term trials will be required before a definitive assessment can be made of raloxifene as a chemopreventive agent. In addition, raloxifene has not been adequately studied in women with active breast cancer and is not indicated for the treatment of this disease.

Side effects of raloxifene
In clinical trials in postmenopausal women, raloxifene was well tolerated. Common drug-related adverse events include hot flashes and leg cramps (Table 1).

Hot flashes early in menopause were more common in women taking raloxifene 60 mg/day than in those taking placebo, but this did not increase the discontinuation rate (61). The incidence of hot flashes was only statistically significantly higher in the raloxifene group during the first 6 months of therapy. Postmenopausal women are more likely to experience hot flashes on raloxifene therapy if they are younger than 55 years, have had a hysterectomy, or had previously experienced hot flashes (62).

Leg cramps (mild) were reported by about 5% of raloxifene-treated patients (61). However, no patients dropped out of raloxifene clinical trials because of this symptom. The reason for these leg cramps remains unknown, but they do not appear to be associated with serious complications (23).

Venous thromboembolism (deep vein thrombosis and pulmonary embolism) is more common in raloxifene users than in nonusers, as it is with users of tamoxifen and estrogen replacement therapy. For this reason, raloxifene is contraindicated in women with active venous thromboembolic disease or a significant past history of venous thromboembolic events (63). The greatest risk for these events occurs during the first 4 months of treatment with raloxifene, and the magnitude of the risk appears to be similar to that with tamoxifen (30) or estrogen replacement therapy (12).

---------------------------
Table 1
Raloxifene at a glance

Brand name: Evista

Therapeutic category: Selective estrogen receptor modulator (SERM)

Use:
Treatment and prevention of osteoporosis in postmenopausal women

Contraindications:
Male gender, pregnancy, history of thromboembolic events, prolonged immobility

Warnings and precautions:
A risk of thromboembolism exists and is greatest in the first 4 months of therapy; discontinue raloxifene at least 72 hours before any prolonged immobilization such as surgical recovery; the safety of raloxifene has not been extensively studied in patients with hepatic failure, premenopausal status, or concomitant use of systemic estrogen replacement therapy

Adverse reactions:
Hot flashes, leg cramps (common); thromboembolism (rare)

Drug interactions:
Cholestyramine reduces the absorption and metabolism of raloxifene; raloxifene can reduce the prothrombin time when given with warfarin; caution should be observed when raloxifene is given with other highly protein-bound drugs such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide

Pharmacokinetics and metabolism:
Rapidly absorbed after oral administration; highly bound to plasma proteins; undergoes extensive first-pass metabolism in the liver (but not by cytochrome P450 pathways); excreted in the feces

Dosage:
60 mg/day; can be given at any time of day without regard to meals

Patient information:
Patients should be advised to undertake lifestyle changes to reduce the risk of osteoporosis-ie, maintain an adequate intake of calcium and vitamin D, undertake weight-bearing exercise as tolerated, limit alcohol intake, and stop smoking
---------------------------

 

Who should receive raloxifene?
Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. Table 2 gives the currently accepted definition of osteoporosis and lists important risk factors for this disease.

Why use raloxifene instead of estrogen replacement therapy? One possible reason would be if a woman refuses, stops, or cannot take estrogen owing to:

•Symptomatic problems associated with estrogen replacement therapy (ie, breast tenderness, vaginal bleeding)

•Fear of breast cancer or endometrial cancer

•A family history of breast or endometrial cancer

•History of dysfunctional uterine bleeding.

----------------------
Table 2
Candidates for raloxifene therapy

Postmenopausal women at risk for osteoporosis, i.e., with any of the following:

•Family history of osteoporosis
• Evidence of rapid or extensive bone loss early in menopause
• Caucasian or Asian descent
• Slender body habitus
• Smoking history
• Excessive alcohol consumption
• Low calcium diet
• Sedentary lifestyle

Postmenopausal women with osteoporosis, i.e., with one or more of the following:

•Low bone mineral density (T-score 2-2.5)
• History or radiographic documentation of osteoporotic fracture
• Physical signs of vertebral crush fractures (eg, height loss, dorsal kyphosis)
----------------------

Why not use a bisphosphonate? Raloxifene may be useful if a woman cannot comply with a complicated bisphosphonate regimen. It also may offer a "two-for-one" benefit if a woman also is at risk for cardiovascular disease, especially if she is diabetic and has elevated triglyceride levels. (This point remains conjectural, however.)

Owing to the risk of thromboembolism, candidates for raloxifene or estrogen replacement therapy should be ambulatory.