Drug Safety

, Volume 28, Issue 8, pp 721–730 | Cite as

Benefit-Risk Assessment of Raloxifene in Postmenopausal Osteoporosis

  • Ann Cranney
  • Jonathan D. Adachi
Review Article

Abstract

Raloxifene, a nonsteroidal benzothiophene, is a second-generation selective estrogen receptor modulator (SERM) that is an antiresorptive agent. Raloxifene is a non-hormonal agent that binds to the estrogen receptor and results in estrogen agonist effects on bone and the cardiovascular system and estrogen antagonist effects on endometrial and breast tissue. Raloxifene has diverse pharmacodynamic properties due to its differential interactions with the estrogen receptor and tissue selectivity. Raloxifene was the first SERM to be approved for the prevention and treatment of postmenopausal osteoporosis. In this review, we conducted a systematic search of the literature for trials that evaluated the following outcomes: bone density, fractures, quality of life, cardiovascular outcomes, safety and adverse events. Raloxifene at the approved dosage of 60 mg/day increased lumbar spine bone density by 2.5% relative to control after 2 years of therapy. A large fracture prevention trial confirmed that treatment with raloxifene 60 mg/day for 3 years decreased the relative risk of incident vertebral fractures by 30–50% in women with prevalent fractures or osteoporosis. Extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol levels. Assessment of the safety profile revealed that raloxifene was not associated with endometrial hyperplasia and that there was a 72% reduction in the incidence of invasive breast cancer in raloxifene-treated postmenopausal women with osteoporosis. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and an increase in the risk of hot flashes and leg cramps. In comparison to other osteoporosis therapies, raloxifene has a lesser impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, but no effect on the frequency of non-vertebral fractures. Raloxifene can be recommended for the prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.

References

  1. 1.
    Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fractures in the year following a fracture. JAMA 2001; 285: 320–3PubMedCrossRefGoogle Scholar
  2. 2.
    Papaioannou A, Wiktorowicz M, Adachi JD, et al. Mortality, independence in living, and re-fracture, one year following hip fracture in Canadians. J Soc Obstet Gynecol Can 2000; 22: 591–7Google Scholar
  3. 3.
    Tosteson ANA, Grove MR, Hammond CS, et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003; 115: 209–16PubMedCrossRefGoogle Scholar
  4. 4.
    Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002; 288: 321–33Google Scholar
  5. 5.
    Evista [product monograph]. Ontario: Eli Lilly Canada Inc., 2000Google Scholar
  6. 6.
    Center for Drug Evaluation and Research. Food and Drug Administration Division of Metabolic and Endocrine Products. Medical review, supplemental NDA for raloxifene hydrochloride, 1999Google Scholar
  7. 7.
    US FDA. Adverse events/raloxifene. Medwatch [online]. Available from URL: http://www.fda.gov/medwatch [Accessed 2004 Nov 1]Google Scholar
  8. 8.
    Bryant HU. Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulator. Rev Endocr Metab Disord 2001; 2: 129–38PubMedCrossRefGoogle Scholar
  9. 9.
    Jensen EV, Jordan VC. The estrogen receptor: a model for molecular medicine. Clin Cancer Res 2003; 9: 1980–9PubMedGoogle Scholar
  10. 10.
    Yang NN, Venugopalan M, Hardikar S, et al. Identification of an estrogen response element activated by metabolites of 17beta estradiol and raloxifene. Science 1996; 273: 1222–5PubMedCrossRefGoogle Scholar
  11. 11.
    Riggs BL, Hartmann LC. Selective estrogen-receptor modulators: mechanisms of action and application to clinical practice. N Engl J Med 2003; 348: 618–29PubMedCrossRefGoogle Scholar
  12. 12.
    Meunier PJ, Vignot E, Gernero P, et al. Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Osteoporos Int 1999; 10: 330–6PubMedCrossRefGoogle Scholar
  13. 13.
    Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282: 637–45PubMedCrossRefGoogle Scholar
  14. 14.
    Bjarnason NH, Sarkar D, Duong T, et al. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk after 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int 2001; 12: 922–30PubMedCrossRefGoogle Scholar
  15. 15.
    Gluck O, Maricic M. Raloxifene: recent information on skeletal and non-skeletal effects. Curr Opin Rheumatol 2002; 14: 429–32PubMedCrossRefGoogle Scholar
  16. 16.
    Morello KC, Wurz GT, DeGregorio MW. Pharmacokinetics of selective estrogen receptor modulators. Clin Pharmacokinet 2003; 42: 361–72PubMedCrossRefGoogle Scholar
  17. 17.
    Heringa M. Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther 2003; 41: 331–45PubMedGoogle Scholar
  18. 18.
    Miller JW, Skerjanec A, Knadler MP, et al. Divergent effects of raloxifene HCl on the pharmacokinetics and pharmacodynamics of warfarin. Pharm Res 2001; 18: 1024–8PubMedCrossRefGoogle Scholar
  19. 19.
    Siraj ES, Gupta MK, Reddy SSK. Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 2003; 163: 1367–70PubMedCrossRefGoogle Scholar
  20. 20.
    Johnell O, Scheele W, Lu Y, et al. Additive effects of raloxifene (RLX), alendronate (ALN) and RLX + ALN on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002; 87: 985–92PubMedCrossRefGoogle Scholar
  21. 21.
    Pavo I, Masanauskaite D, Rojinskaya L, et al. Effects of raloxifene versus placebo on bone mineral density in postmenopausal women in the absence of calcium supplementation [abstract]. J Bone Miner Res 1999; 14: S410Google Scholar
  22. 22.
    Lufkin EG, Whitaker MD, Nickelesen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998; 13: 1747–54PubMedCrossRefGoogle Scholar
  23. 23.
    Reid IR, Eastell R, Fogelman I, et al. A comparison of raloxifene with estrogen replacement therapy in normal postmenopausal women. Arch Intern Med 2004; 164: 871–9PubMedCrossRefGoogle Scholar
  24. 24.
    Delmas PD, Bjarnson NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: 1641–7PubMedCrossRefGoogle Scholar
  25. 25.
    Johnston CC. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med 2000; 160: 3444–50PubMedCrossRefGoogle Scholar
  26. 26.
    National Institute for Clinical Excellence. Appraisal consultation document: technologies for the prevention and treatment of osteoporosis and prevention of osteoporotic fractures in postmenopausal women [online]. Available from URL: www.nice.org [Accessed 2004 Dec 1]Google Scholar
  27. 27.
    Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone 2003; 33: 293–300PubMedCrossRefGoogle Scholar
  28. 28.
    Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four year results from a randomized clinical trial. J Clin Endocrinol Metab 2003; 87: 3609–17CrossRefGoogle Scholar
  29. 29.
    Maricic M, Adachi JD, Sarkar S, et al. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002; 162: 1140–3PubMedCrossRefGoogle Scholar
  30. 30.
    Delmas PD, Genant HK, Crans GC, et al. Severity of prevalent fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone 2003; 33: 522–32PubMedCrossRefGoogle Scholar
  31. 31.
    Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002; 2002: 1–10Google Scholar
  32. 32.
    Weinstein RS, Parfitt AM, Marcus R, et al. Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women. Osteoporos Int 2003; 14: 814–22PubMedCrossRefGoogle Scholar
  33. 33.
    Cranney A, Tugwell P, Krolicki N, et al. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev 2002; 23: 524–8PubMedCrossRefGoogle Scholar
  34. 34.
    Palomba S, Orio F, Morelli M, et al. Roloxifene administration in women treated with gonadotropin-releasing hormone agonist for uterine leiomyomas: effects on bone metabolism. J Clin Endocrinol Metab 2004; 87: 4476–81CrossRefGoogle Scholar
  35. 35.
    Nevitt MC, Thompson DE, Black DM, et al. Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures: Fracture Intervention Trial Research Group. Ann Intern Med 1998; 128: 793–800PubMedGoogle Scholar
  36. 36.
    Silverman SL, Minshall ME, Shen W, et al. The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum 2001; 44: 2611–9PubMedCrossRefGoogle Scholar
  37. 37.
    Strickler R, Stovall DW, Merritt D, et al. Raloxifene and estrogen effects on quality of life in healthy postmenopausal women: a placebo-controlled randomized trial. Obstet Gynecol 2000; 96: 359–65PubMedCrossRefGoogle Scholar
  38. 38.
    Utian WH, Janata JW, Barbier S, et al. Effect on quality of life: a prospective study using the Utian Quality of Life (UQOL) scale. Menopause 2004; 11: 275–80PubMedCrossRefGoogle Scholar
  39. 39.
    Modugno F, Ness R, Ewing S, et al. Effect of raloxifene on sexual function in older postmenopausal women with osteoporosis. Obstet Gynecol 2003; 101: 353–61PubMedCrossRefGoogle Scholar
  40. 40.
    Nickelsen T, Lufkin EG, Riggs BL, et al. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 1999; 24: 115–28PubMedCrossRefGoogle Scholar
  41. 41.
    Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 2001; 344: 1207–13PubMedCrossRefGoogle Scholar
  42. 42.
    Barrett Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002; 287: 847–57PubMedCrossRefGoogle Scholar
  43. 43.
    Barrett-Connor E, Ensrud KE, Harper K, et al. Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes. Clin Ther 2003; 25: 919–30PubMedCrossRefGoogle Scholar
  44. 44.
    Mosca L, Barrett-Connor E, Wenger NK, et al. Design and methods of the Raloxifene Use for The Heart study (RUTH). Am J Cardiol 2001; 88: 392–5PubMedCrossRefGoogle Scholar
  45. 45.
    Jolly EE. Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause 2003; 10: 337–44PubMedCrossRefGoogle Scholar
  46. 46.
    Cohen FJ, Watts S, Shah A, et al. Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol 2000; 95: 104–10PubMedCrossRefGoogle Scholar
  47. 47.
    Neven P, Lunde T, Benedetti-Panici P, et al. A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate: Euralox 1 Study Group. BJOG 2003; 110: 157–67PubMedCrossRefGoogle Scholar
  48. 48.
    Maia Jr H, Maltez A, Oliveira M, et al. Growth of an endometrial polyp in a postmenopausal patient using raloxifene. Gynecological Endoscopy 2000; 9: 117–21CrossRefGoogle Scholar
  49. 49.
    Davies GC, Huster WJ, Lu Y, et al. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 1999; 93: 558–65PubMedCrossRefGoogle Scholar
  50. 50.
    Cummings SR, Eckert S, Krueger KA. The effects of raloxifene on risk of breast cancer in postmenopausal women treated with raloxifene: results from the MORE randomized trial. JAMA 1999; 281: 2189–97PubMedCrossRefGoogle Scholar
  51. 51.
    Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4 year results from the MORE trial. Multiple Outcomes of Raloxifene Evaluation. Breast Cancer Res Treat 2001; 65: 125–34PubMedCrossRefGoogle Scholar
  52. 52.
    Cuzick J, Powles T, Veronesi U, et al. Overview of main outcomes in the breast cancer prevention trials. Lancet 2003; 361: 296–300PubMedCrossRefGoogle Scholar
  53. 53.
    Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004; 96: 1751–61PubMedCrossRefGoogle Scholar
  54. 54.
    Vogel VG, Constantino JP, Wickerham DL, et al. The study of tamoxifen and raloxifene: preliminary enrollment data from a randomized breast cancer risk reduction trial. Clin Breast Cancer 2002; 3: 153–9PubMedCrossRefGoogle Scholar
  55. 55.
    Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: The Heart and Estrogen/Progestin Replacement study. Ann Intern Med 2000; 132: 689–96PubMedGoogle Scholar
  56. 56.
    Azevedo GD, Franco RF, Baggio MS, et al. Effects of raloxifene therapy on the anticoagulant system in postmenopausal women. Climacteric 2003; 6: 140–5PubMedGoogle Scholar
  57. 57.
    Layton D, Clarke A, Wilton L, et al. Safety profile of raloxifene as used in general practice in England: results of a prescription-event monitoring study. Osteoporosis Int 2005; 11: 490–500CrossRefGoogle Scholar
  58. 58.
    Vilches AR, Perez V, Sucheck DE. Raloxifene associated hepatitis. Lancet 1998; 352: 1524–5PubMedCrossRefGoogle Scholar
  59. 59.
    Grady D, Ettinger B, Moscarelli E, et al. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol 2004; 104: 837–44PubMedCrossRefGoogle Scholar
  60. 60.
    Christodoulakos GE, Lambrinoudaki IV, Vourtsi AD, et al. Mammographic changes associated wtih raloxifene and tibolone therapy in postmenopausal women: a prospective study. Menopause 2002; 9: 110–6PubMedCrossRefGoogle Scholar
  61. 61.
    Lee CC, Kasa-Vubu JZ, Supiano MA. Differential effects of raloxifene and estrogen on insulin sensitivity in postmenopausal women. J Am Geriatr Soc 2003; 51: 683–8PubMedCrossRefGoogle Scholar
  62. 62.
    Cranney A, Guyatt G, Griffith L, et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002; 23: 570–8PubMedCrossRefGoogle Scholar
  63. 63.
    Luckey M, Kagan R, Greenspan S, et al. Once-weekly alendronate 70mg and raloxifene 60mg daily in the treatment of postmenopausal osteoporosis. Menopause 2004; 11: 405–15PubMedCrossRefGoogle Scholar
  64. 64.
    Sambrook PN, Geusens P, Ribot C, et al. Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone mineral density: result of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med 2004; 255: 503–11PubMedCrossRefGoogle Scholar
  65. 65.
    Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–41PubMedCrossRefGoogle Scholar
  66. 66.
    Cranney A, Guyatt G, Willan A, et al. A meta-analysis of alendronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002; 23: 508–16PubMedCrossRefGoogle Scholar
  67. 67.
    Sharpe M, Noble S, Spencer CM. Alendronate: an update of its use in osteoporosis. Drugs 2001; 61: 999–1039PubMedCrossRefGoogle Scholar
  68. 68.
    Lanza F, Schwartz H, Sahba B, et al. An endoscopic comparison of the effects of alendronate and risedronate on upper gastrointestinal mucosae. Am J Gastroenterol 2000; 95: 3112–7PubMedCrossRefGoogle Scholar
  69. 69.
    Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535–41PubMedCrossRefGoogle Scholar
  70. 70.
    Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoprosis: a randomized controlled trial. JAMA 1999; 282: 1344–52PubMedCrossRefGoogle Scholar
  71. 71.
    McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344: 333–40PubMedCrossRefGoogle Scholar
  72. 72.
    Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal safety profile of alendronate: the fracture prevention trial. Arch Intern Med 2000; 160: 517–25PubMedCrossRefGoogle Scholar
  73. 73.
    Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002; 77: 262–70PubMedCrossRefGoogle Scholar
  74. 74.
    Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: Scientific Advisory Council of the Osteoporosis Society of Canada. CMAJ 2002; 167: S1–S34PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Ann Cranney
    • 1
  • Jonathan D. Adachi
    • 2
  1. 1.Department of Medicine, C402, Clinical Epidemiology Program, Ottawa Hospital Civic CampusUniversity of OttawaOttawaCanada
  2. 2.Department of MedicineMcMaster UniversityHamiltonCanada

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