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Raloxifene: a New Choice for Treating and Preventing Osteoporosis

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Raloxifene: a New Choice for Treating and Preventing Osteoporosis OSTEOPOROSIS UPDATE ANEGLO A. LICATA, MD, EDITOR ANGELO A. LICATA, MD, PHD* ANGELINA V. CIACCIA, PHD* Department of Endocrinology, Cleveland Clinic Lilly Research Laboratories, Eli Lilly and Company, Indianapolis MAYME WONG, PHD* MICHAEL W. DRAPER, MD, PHD* Lilly Research Laboratories, Eli Lilly and Company, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis Indianapolis Raloxifene: A new choice for treating and preventing osteoporosis ABSTRACT ALOXIFENE (Evista) is one of a new gen- eration of drugs, called selective estro- Selective estrogen receptor modulators (SERMs) are a new gen receptor modulators (SERMs), with class of drugs that provide a new option for addressing the estrogen-like effects on the skeleton and car- health challenges of postmenopausal women. This review diovascular system, but antiestrogen effects discusses the proposed mechanism of action of SERMs and on the breast and endometrium. This profile describes clinical findings on raloxifene, a SERM now makes it an attractive alternative to estrogen available for treating and preventing osteoporosis. replacement for long-term therapy to treat and prevent osteoporosis in postmenopausal KEY POINTS women. All of the drugs currently available to Like estrogen, raloxifene increases bone mineral density, prevent osteoporosis have unique advantages although the magnitude of the effect is not as great. and disadvantages, both in their clinical However, raloxifene effectively prevents fractures to as action and in terms of patient compliance great a degree as has been demonstrated for any other with therapy. agent. In this arricle we first outline the pros and cons of estrogen replacement therapy and bis- phosphonates, then discuss tamoxifen, the Raloxifene is free of estrogen's side effects on the breast first SERM, and its analogs. In the final sec- and endometrium. Both drugs increase the risk of venous tion, we discuss raloxifene, the first in a new thromboembolism. Raloxifene may cause hot flashes in class of SERMs (the henzothiophenes), and some women. evaluate its place in the emerging field of post- menopausal women's health. Raloxifene lowers cholesterol, LDL, and fibrinogen levels but does not affect HDL or triglycerides. Because raloxifene • BENEFITS AND LIMITATIONS is associated with a decreased incidence of breast cancer in OF ESTROGEN REPLACEMENT THERAPY postmenopausal osteoporotic women, some patients may find it more acceptable than estrogen replacement therapy. Estrogen replacement therapy has become the standard of care for perimenopausal and post- menopausal 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 man- 5 'Disclosure: Dr. Licata has received grant support from Eli Lilly and Company, which manufactures aging postmenopausal osteoporosis. Used raloxifene; Drs. Ciatcia, Wong, and Draper are employees of Eli Lilly and Company. prophylactically, it can maintain bone mass.4 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 4 APRIL 2000 42 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. RALOXIFENE LICATA AND COLLEAGUES In patients with established osteoporosis, it Risks of cancer, thromboembolism: increases bone mineral density in the lumbar Small but significant spine and various other skeletal sites by 2% to Estrogen replacement therapy carries a small 5%.5 In the elderly, it can arrest bone loss even increased risk of serious complications, and many years after menopause.6 Observational the risk increases with duration of therapy. studies suggest that estrogen therapy may Endometrial cancer occurs up to four times reduce the risk of hip and spine fractures, more frequently in women with a uterus who although the benefit is attenuated once thera- take unopposed estrogen than in nonusers. The py is stopped7'8; at present, however, data are risk may be reduced, but not completely elimi- lacking from prospective, randomized, con- nated, by adding a progestin.13 trolled trials to confirm these findings. Breast cancer risk may increase slightly with hormone replacement. In the Nurses' Estrogen's effect Health Study,14 the risk of death from breast on coronary artery disease is unclear cancer was 43% higher in women who had Estrogen replacement affects a variety of risk used hormones for more than 10 years than in factors for coronary artery disease, lowering nonusers. In a reanalysis of data from 51 epi- serum levels of cholesterol, low-density demiological studies involving more than lipoprotein (LDL), and fibrinogen and rais- 150,000 breast cancer cases and controls, the ing high-density lipoprotein (HDL).9 On relative risk for breast cancer was 1.35 for the other hand, it raises serum triglyceride women who had used hormone replacement levels.9 therapy for 5 years or more.15 Observational studies suggest that post- Venous thromboembolism is rare but menopausal women who receive estrogen increases with estrogen use. Observational replacement have lower rates of coronary studies report an approximately threefold artery disease than those who do not.10'11 increase in the incidence of venous throm- Only one prospective, controlled, random- boembolism in women receiving hormone ized trial has been performed to determine if replacement therapy.16-17 This finding was The HERS study: estrogen replacement actually prevents coro- confirmed in the HERS clinical trial.12 No benefit from nary events, however, and it had negative results.12 Compliance is low estrogen in This recent trial was called the Heart Uterine bleeding, breast pain, and fear of can- coronary artery and Estrogen/progestin Replacement Study cer and thromboembolism probably all con- (HERS).12 Participants were post- tribute to a low rate of compliance with hor- disease menopausal women with established coro- mone replacement therapy: approximately nary artery disease. Treatment consisted of 70% of women refuse it outright or stop taking the combination of conjugated equine estro- it prematurely.18 This reality diminishes the gens 0.625 mg plus medroxyprogesterone potential benefit of estrogen therapy in the acetate 2.5 mg or placebo. At an average of postmenopausal population. 4-1 years of follow-up, there was no differ- ence between the groups in the incidence of • BISPHOSPHONATES AND OTHER DRUGS myocardial infarction, coronary heart dis- ease death, or other cardiovascular out- Bisphosphonates comes. In fact, there were more events in the Bisphosphonates (eg, etidronate, alendronate, estrogen group than in the placebo group in others) inhibit resorption of bone. In clinical the first year (but fewer events in years 4 and studies in women with osteoporosis, these 5). drugs increased bone mineral density and These findings apply only to the popula- reduced fractures.19-20 On the minus side, tion and drug regimen studied. Studies are alendronate can cause csophagitis, and regi- underway that may eventually clarify the mens for bisphosphonates in general are com- long-term cardiovascular benefits of hormone plex. These factors may limit long-term com- replacement therapy in postmenopausal pliance.21 Etidronate is available for osteo- women. porosis treatment in Europe and Canada.22 274 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 4 APRIL 2000 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. Calcitonin and other drugs In addition, tamoxifen prevents resorp- Calcitonin also inhibits bone resorption, may tion of bone, increasing lumbar spine bone increase bone density, and may prevent frac- mineral density in postmenopausal women.31 tures in osteoporotic women.23*24 Other It reduces serum levels of cholesterol and agents for possible use in postmenopausal LDL, but has little effect on HDL.'2 However, osteoporosis prevention are also under study.3 tamoxifen stimulates the endometrium, and Further discussion of these agents is beyond users have an increased risk of endometrial the scope of this review. cancer30'33 and thromboembolism.'4 • BENEFITS AND LIMITATIONS OF SERMS Tamoxifen analogs and other SERMs Toremifene (Fareston), droloxifene (not yet An ideal drug for long-term use in post- available), and idoxifene (not yet available) menopausal women would offer the benefits are analogs of tamoxifen. Like tamoxifen, of estrogen but not its undesirable side effects they appear to be estrogenic in the skeleton and associated cancer risks. SERMs are being and antiestrogenic in breast tissue. 55>'6 developed to address this need.25 Toremifene, which is approved for treating advanced breast cancer, also stimulates the How SERMs work endometrium,57 but an association with SERMs are a structurally diverse group of endometrial cancer has not been estab- compounds. All of them bind with high affin- lished.38 Clinical reports on the safety and ity to estrogen receptors, and all of them are efficacy of droloxifene and idoxifene in treat- believed to change the shape of the receptor ing breast cancer and postmenopausal osteo- in a unique way.26 The ligand-receptor com- porosis are limited, but preliminary findings plex combines with specific adapter proteins suggest that they may stimulate the uterus to a and interacts with target DNA sequences, lesser degree than does tamoxifen.39'40 either promoting or inhibiting
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