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 bisphosphonates, 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 postmenopausal 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 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 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

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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 difference between the groups in the incidence of • BISPHOSPHONATES AND OTHER DRUGS myocardial infarction, coronary heart disease 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 gene transcrip- Nonetheless, trials of idoxifene in osteoporo- tion.27 sis were stopped because of unacceptable gen- Depending on the SERM, the tissue in itourinary side effects.41 Different question, and the estrogen-dependent path- Newer SERMs include benzothiophenes SERMS have way being considered, a SERM may produce (such as LY353381), tetrahydronaphthylenes either estrogen-like effects or estrogen-block- (such as CP-336,156), and benzopyrans (such different ing effects.25 Part of the explanation for this as EM-800).42 These compounds are chemi- effects on may involve the different types of estrogen cally and pharmacologically distinct from the receptors. There are two different known triphenylethylenes, and their clinical efficacy different estrogen receptors: alpha and beta. Different and safety remain to be determined.45 organs tissues contain different ratios of alpha and beta receptors.28 SERMs bind to both types, • RALOXIFENE but differential actions through these receptors may contribute to the nature and magni- Raloxifene belongs to the benzothiophene tude of the biological response in a specific tis- class of SERMs. It has been investigated more sue to an estrogen or to a particular SERM. extensively than any other SERM for its skeletal antiresorptive effects, and it appears Tamoxifen: The first SERM to have a profile well-suited to the needs of Tamoxifen (Novaldex), a triphenylethylene postmenopausal women—ie, it has estrogen- SERM, has estrogen-like effects on the skele- like effects on the skeleton and on blood lipid ton, lipid levels, and uterus, but antiestrogen levels, but estrogen-blocking effects in the effects on the breast. breast and uterus. Tamoxifen has been used for many years to treat breast cancer.29 In 1998, it was shown Studies in animals to reduce the incidence of breast cancer in In ovariectomized rats, raloxifene preserved healthy women at high risk for developing bone mass and reduced serum cholesterol this disease.30 levels.44 In ovariectomized, cholesterol-fed

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Effect on osteoporosis in humans Raloxifene increases bone mineral density Studies in humans have also shown that raloxifene, like estrogen, protects the skeleton. In a study of calcium kinetics,50 both raloxifene and estrogen replacement reduced bone resorption in the first 4 weeks of therapy without significantly altering bone formation. With raloxifene, the rates of resorption and formation did not change significantly between the 4th week and 31st week of therapy, whereas both were lower with estrogen. In other studies, raloxifene exerted a positive effect on several biochemical markers of bone metabolism, similar to estrogen.51-52 Histomorphometry studies indicate that bone quality is normal in patients receiving raloxifene.53 Furthermore, in a study in healthy postmenopausal women,51 raloxifene 60 mg/day (approved dosage) for 2 years effectively pre- spine neck body vented bone loss, significantly increasing the bone mineral density of the lumbar spine, hip, FIGURE 1. Changes in bone mineral density in post- and total body by about 2% relative to placebo menopausal women treated with placebo or raloxifene (FIGURE I).51 This increase was somewhat less 60 mg/day for 2 years. Bone mineral density was mea- than the increases observed in studies of alen- sured by dual-energy x-ray absorptiometry and dronate and hormone replacement therapy.5'54 expressed as mean percentage change from baseline ± In the Multiple Outcomes of Raloxifene standard error of the mean (SE). Asterisks denote statis- (MORE) trial, a double-blind, placebo-con- tically significant difference from placebo, P < .05, using trolled, clinical trial that enrolled 7,705 osteo- least-squares analysis. porotic women, raloxifene treatment for 3 years

DATA FROM DELMAS ET AL.« FIGURE REPRODUCED WITH PERMISSION FROM RESCH H, CIACCIA significantly reduced the risk of new vertebral AV, DRAPER MW. SELEKTIVE ÖSTROGEN-REZEPTORMODULATOREN (SERMS): NEUE MÖGLICHKEITEN 55 DER AUFRECHTERHALTUNG DER GESUNDHEIT IN DER MENOPAUSE. J MINERALSTOFFWEC HSEL fractures by 30% to 50%, similar to the results 1999; 6(2):22-28. reported in a comparable trial with alendronate.19'20 This finding suggests that even though raloxifene's effects on bone mineral rabbits, raloxifene inhibited aortic accumula- density are less than those of some other estab- tion of cholesterol.45 On the other hand, in lished therapies, it reduces vertebral fracture ovariectomized cynomolgus monkeys ralox- rates to as great an extent as other therapy. ifene failed to reduce coronary atherosclerosis significantly when compared with conju- Effect on cardiovascular gated equine estrogen.46 However, the mon- risk factors in humans keys who received estrogen had higher-than- Raloxifene also has favorable effects on mark- expected blood levels of 17P-estradiol, the ers of cardiovascular disease. In one study, coronary plaques varied in size, and the sam- LDL cholesterol concentrations were signifi- ple number was low, and all of these may cantly decreased by about 10% after 8 weeks of have limited the ability of this model to treatment with either raloxifene 200 mg/day detect an effect of raloxifene.47 Raloxifene or conjugated equine estrogens.52 Similar antagonizes the stimulatory effects of estro- changes in serum lipid concentrations were gen in the mammary gland of mice and pre- observed in studies in which women in their vents mammary tumors induced by carcino- early years after menopause received ralox- gens in rats. In these studies, raloxifene had ifene 60 mg/day for 2 years (FIGURE 2).51 In con- little or no effect on uterine weight and his- trast to estrogen replacement therapy, ralox- tology.48.49 ifene does not increase HDL cholesterol, nor

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. does it raise triglycerides.56 However, in one study, raloxifene decreased fibrinogen levels Raloxifene improves cholesterol and LDL by 12% to 14%, whereas hormone replace- but not HDL and does not worsen triglycerides ment 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 -12.0J * raloxifene treatment.60 In contrast, in women Total LDL HDL Triglycerides taking tamoxifen, increases in endometrial cholesterol cholesterol cholesterol cancer incidence have been observed within the first 2 years of therapy.50 Continued fol- FIGURE 2. Changes in serum lipid concentrations in low-up will be needed to fully evaluate the postmenopausal women treated with placebo or effect of raloxifene on the endometrium. raloxifene, 60 mg/day for 2 years. Serum lipid data are expressed as mean percentage change from baseline ± May decrease breast cancer SE. Asterisks denote statistically significant difference from placebo, P < .05, using least-squares analysis. Women receiving raloxifene report no increased incidence of breast pain,61 a well- DATA FROM DELMAS ET Al.55 FIGURE REPRODUCED WITH PERMISSION FROM RESCH H, CIACCIA AV, DRAPER MW. SELEKTIVE OSTROGEN-REZEPTORMODULATOREN (SERMS): known side effect of estrogen replacement NEUE MÖGLICHKEITEN DER AUFRECHTERHALTUNG DER GESUNDHEIT IN DER MENOPAUSE therapy. ) MINERALSTOFFWECHSEL 1999; 6(2):22-28. In addition, in the MORE trial, the inci- maammmmmamm^mmmm^mmammmmmmmmmmmmmmm^^mm^mmmmmm dence of newly diagnosed breast cancer was approximately 75% lower in raloxifene-treat- leg cramps (TABLE 1). ed subjects than in the placebo group, through Hot flashes early in menopause were more 3 years of treatment.60 Most tumors diagnosed common in women taking raloxifene 60 during the first 3 years of this trial were prob- mg/day than in those taking placebo, but this ably present at a subclinical level at the start did not increase the discontinuation rate.61 of the trial. Thus, the reduction in breast can- The incidence of hot flashes was only statisti- cer risk currently observed with raloxifene cally significantly higher in the raloxifene may represent suppression or regression of sub- group during the first 6 months of therapy. clinical cancer.60 Postmenopausal women are more likely to Long-term trials will be required before a experience hot flashes on raloxifene therapy if definitive assessment can be made of ralox- they are younger than 55 years, have had a hys- ifene as a chemopreventive agent. In addition, terectomy, or had previously experienced hot raloxifene has not been adequately studied in flashes.62 women with active breast cancer and is not Leg cramps (mild) were reported by about indicated for the treatment of this disease. 5% of raloxifene-treated patients.61 However, no patients dropped out of raloxifene clinical Side effects of raloxifene trials because of this symptom. The reason for In clinical trials in postmenopausal women, these leg cramps remains unknown, but they raloxifene was well tolerated. Common drug- do not appear to be associated with serious related adverse events include hot flashes and complications.

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TABLE 1 events.63 The greatest risk for these events Raloxifene at a glance occurs during the first 4 months of treatment with raloxifene, and the magnitude of the risk 30 Brand name appears to be similar to that with tamoxifen Evista or estrogen replacement therapy.12 Therapeutic category Selective estrogen receptor modulator (SERM) Who should receive raloxifene? Raloxifene is indicated for the treatment and Use Treatment and prevention of osteoporosis prevention of osteoporosis in postmenopausal in postmenopausal women women, TABLE 2 gives the currently accepted Contraindications definition of osteoporosis and lists important Male gender, pregnancy, history of thromboembolic events, risk factors for this disease. prolonged immobility Why use raloxifene instead of estrogen replacement therapy? One possible reason Warnings and precautions A risk of thromboembolism exists and is greatest in the first would be if a woman refuses, stops, or cannot 4 months of therapy; discontinue raloxifene at least 72 hours take estrogen owing to: before any prolonged immobilization such as surgical recovery; • Symptomatic problems associated with the safety of raloxifene has not been extensively studied in estrogen replacement therapy (ie, breast patients with hepatic failure, premenopausal status, or tenderness, vaginal bleeding) concomitant use of systemic estrogen replacement therapy • Fear of breast cancer or endometrial cancer Adverse reactions • A family history of breast or endometrial Hot flashes, leg cramps (common); thromboembolism (rare) cancer Drug interactions • History of dysfunctional uterine bleeding. Cholestyramine reduces the absorption and metabolism of Why not use a bisphosphonate? Ralo- raloxifene; raloxifene can reduce the prothrombin time when xifene may be useful if a woman cannot com- given with warfarin; caution should be observed when ply with a complicated bisphosphonate regi- raloxifene is given with other highly protein-bound drugs such men. It also may offer a "two-for-one" benefit as dofibrate, indomethacin, naproxen, ibuprofen, diazepam, and if a woman also is at risk for cardiovascular dis- diazoxide ease, especially if she is diabetic and has ele- Pharmacokinetics and metabolism vated triglyceride Levels. (This point remains Rapidly absorbed after oral administration; highly bound to conjectural, however.) plasma proteins; undergoes extensive first-pass metabolism in Owing to the risk of thromboembolism, the liver (but not by cytochrome P450 pathways); excreted in candidates for raloxifene or estrogen replace- the feces ment therapy should be ambulatory. Dosage 60 mg/day; can be given at any time of day without regard • CONCLUSIONS to meals Patient information Among more recently developed options, cer- Patients should be advised to undertake lifestyle changes to tain SERMs may be unique in that they hold reduce the risk of osteoporosis—ie, maintain an adequate intake of calcium and vitamin D, undertake weight-bearing promise for protective effects in the skeleton exercise as tolerated, limit alcohol intake, and stop smoking and the cardiovascular system, while at the same time demonstrating antiproliferative actions in reproductive tissues. Raloxifene, a new SERM, has undergone Venous thromboembolism (deep vein extensive clinical investigation. At present it thrombosis and pulmonary embolism) is more is the only SERM approved for treating and common in raloxifene users than in nonusers, preventing osteoporosis in postmenopausal as it is with users of tamoxifen and estrogen women, as studies have found that it prevents replacement therapy. For this reason, ralox- bone resorption and maintains bone mass in ifene is contraindicated in women with active women in early postmenopause, and reduces venous thromboembolic disease or a signifi- the risk for osteoporotic vertebral fractures by cant past history of venous thromboembolic as much as 50% in women who already have

278 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. osteoporosis. TABLE 1 At the same time, raloxifene has few side Candidates effects. Because of its estrogen antagonist for raloxifene therapy action in the endometrium and breast, in clinical trials it produced no more vaginal bleed- Postmenopausal women at risk for ing or breast pain than did placebo. osteoporosis, ie, with any of the following: Although raloxifene is currently indicat- Family history of osteoporosis ed only for treating and preventing osteoporo- Evidence of rapid or extensive bone loss sis, it also shows some effects that may even- early in menopause tually make it useful in preventing cardiovas- Caucasian or Asian descent cular disease and breast cancer. It changes Slender body habitus lipid levels in directions that should reduce Smoking history cardiovascular risk, and its effect on clinical Excessive alcohol consumption cardiovascular outcomes is being evaluated. In Low calcium diet a trial in osteoporotic, postmenopausal Sedentary lifestyle women, raloxifene reduced the incidence of new cases of breast cancer by approximately Postmenopausal women with osteoporosis, 75% after 3 years.60 ie, with one or more of the following: Further research is needed to clarify its Low bone mineral density (T-score < -2.5) role in the prevention of cardiovascular dis- History or radiographic documentation of ease and breast cancer. These effects may osteoporotic fracture eventually prove to be the desired combina- Physical signs of vertebral crush fractures tion for many postmenopausal women, which (eg, height loss, dorsal kyphosis) could then result in good long-term compliance with this regimen. £3

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