Selective Estrogen Receptor Modulators

Bone Effects. Selective estrogen receptor modulators (SERMs) are a structurally diverse group of compounds that interact with the estrogen receptor to elicit either an estrogen agonist or an estrogen antagonist response, depending on the target tissue and physiologic context. SERMs are compounds that can bind to and activate the estrogen receptor, but have tissue-specific effects distinct from estradiol. Raloxifene, the only SERM approved by the FDA for the prevention or treatment of osteoporosis, has a 1.5 to 2.9 times higher affinity for the estrogen receptor than estradiol.

Raloxifene specifically mimics the desirable actions of estrogen on lipids and the skeleton while acting as an antiestrogen in breast and uterine tissue. 56 Raloxifene is absorbed rapidly after oral administration. Dosing and cost information can be found Therapeutic Effects. An interim 2-year analysis of placebo-controlled osteoporosis prevention trials (N = 3300 women) showed that raloxifene is safe and well tolerated. Raloxifene increased bone density by 2 to 3 percent compared to placebo and reduced low-density lipoprotein (LDL) and total cholesterol by 10 to 12 percent.

No increased risk of myocardial infarction or stroke has been observed. These changes are similar to the beneficial changes that occur in women on ERT. In contrast to ERT, raloxifene does not appear to cause adverse changes in levels of serum triglycerides; the beneficial effects of ERT on high-density lipoprotein (HOL) cholesterol, however, are not seen with raloxifene. In a recent, double-blinded, randomized, parallel trial of 390 healthy postmenopausal women, raloxifene in doses of 60 or 120 mg/d was compared to HRT (conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg/d) or placebo to determine early lipid and coagulation parameter changes.

Raloxifene was found to favorably alter biochemical markers of cardiovascular risk by decreasing LOL cholesterol, fibrinogen, and lipoprotein (a), without raising trigylcerides. When compared to HRT, raloxifene had no effect on HOL cholesterol and plasminogen activator inhibitor-I, and less effect on lipoprotein (a). Long-term clinical trials are necessary to determine if the favorable biochemical effects are associated with cardiovascular disease protection. Raloxifene is administered without progestins because no endometrial or breast stimulation occurs. In fact, women treated with raloxifene experienced lower rates of endometrial and breast stimulation compared to placebo.

At this time, raloxifene appears to be an alternative to ERT as first-line treatment for prevention or treatment of osteoporosis. Raloxifene also offers an alternative to ERT in postmenopausal women intolerant to or who have contraindications to estrogen treatment. Information regarding cardiovascular benefits compared to ERT is not yet available. Side Effects and Cootraindkations.

The majority of adverse effects that occur during raloxifene therapy are mild and do not require discontinuation of treatment. The most common adverse effects reported were hot flashes and leg cramps (1 percent). Raloxifene does not prevent menopausal hot flashes.

In fact, hot flashes are observed more commonly during the first 6 months of therapy. Analysis of raloxifene-treated women showed an increased risk of venous thrombolic events defined as deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Risk is greatest during the first 4 months of therapy.

Similarto estrogen, raloxifene should be discontinued at least 72 h before and during prolonged immobilization (surgery recovery, prolonged bed rest). Women taking raloxifene should also be advised to avoid prolonged restriction of movement during travel. Raloxifene should be used with caution in patients with hepatic disease or impairment; however, specific dosing adjustment guidelines have not been established. Raloxifene is classified as Pregnancy Category X. It should not be administered to patients who are or may become pregnant due to risk for teratogenicity. Drug Interactions Orug-drug interactions have been identified between raloxifene and cholestyramine (60% reduction in the absorption and enterohepatic cycling of raloxifene); therefore, administration should be separated 1 hour before or 2 to 3 h after cholestyramine.

In addition, coadministration of raloxifene and warfarin results in a 10 percent decrease in prothrombin time. Monitoring of International Normalized Ratio/prothrombin time is advised when using these drugs concomitantly. Because raloxifene is 95 percent bound to plasma proteins, caution is advised when administering with other highly bound drugs like clofibrate, indomethacin, ibuprofen, diazepam, and diazoxide because increased free drug concentrations of these agents may occur, resulting in greater pharmacologic effect or toxicity. Finally, comcomitant administration of raloxifene and systemic estrogens is not recommended.

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