Advances in Therapy

, Volume 27, Issue 12, pp 917–932 | Cite as

Lasofoxifene in osteoporosis and its place in therapy

  • Victoria J. D. Swan
  • Celeste J. Hamilton
  • Sophie A. Jamal
Review

Abstract

Selective estrogen-receptor modulators (SERMs), which have estrogen-like effects on bone and “antiestrogen effects” on other tissues, have been in development for osteoporosis prevention and treatment in postmenopausal women as a safer alternative to long-term estrogen. We conducted a literature review of the skeletal and extraskeletal effects of lasofoxifene, a new generation SERM approved by the European Commission for osteoporosis treatment. Published data on the effects of lasofoxifene are based on 23 clinical pharmacology studies with over 10,000 participants from 17 phase 2 and 3 randomized controlled trials (RCTs). In RCTs, lasofoxifene decreases bone turnover markers (BTMs), increases bone mineral density (BMD) at the spine and hip, and decreases the incidence of vertebral and nonvertebral nonhip fractures compared with placebo. Compared with raloxifene, lasofoxifene gave greater decreases in BTMs, and greater increases in lumbar spine BMD. Lasofoxifene also decreased the risk of breast cancer, major coronary heart disease events, and stroke, but—similar to raloxifene—there was an increased risk of venous thromboembolism. In one trial, endometrial hypertrophy and uterine polyps were more common with lasofoxifene than with placebo, but endometrial cancer and hyperplasia were not. Lasofoxifene is probably most appropriate for use among women in their early or middle menopausal years (age 55-65) who have, or are at risk of developing, osteoporosis and in particular vertebral fractures. At the time of publication, lasofoxifene is not approved for use by the US Food and Drug Administration, and as such is not used in North America.

Keywords

lasofoxifene osteoporosis postmenopausal women selective estrogenreceptor modulators 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Riggs BL, Khosla S, III LJM. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998;13:763–773.CrossRefPubMedGoogle Scholar
  2. 2.
    Lindsay R, Pack S, Li Z. Longitudinal progression of fracture prevalence through a population of postmenopausal women with osteoporosis. Osteoporosis Int. 2005;16:306–312.CrossRefGoogle Scholar
  3. 3.
    McDonnell DP. Mining the complexities of the estrogen signaling pathways for novel therapeutics. Endocrinology. 2003;144:4237–4240.CrossRefPubMedGoogle Scholar
  4. 4.
    Delmas PD, Bjarnason 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;337:1641–1647.CrossRefPubMedGoogle Scholar
  5. 5.
    Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637–645.CrossRefPubMedGoogle Scholar
  6. 6.
    Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281:2189–2197.CrossRefPubMedGoogle Scholar
  7. 7.
    Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–137.CrossRefPubMedGoogle Scholar
  8. 8.
    Ladva S. Horizon scanning: EU approves lasofoxifene (Fablyn™) for the treatment of osteoporosis in post-menopausal women. NHS National electronic Library for Medicines. Available at: www.nelm.nhs.uk/en/NeLM-Area/News/2009—March/25/Horizon-scanning-EUapproves-lasofoxifene-Fablyn-for-the-treatmentof-osteoporosis-in-post-menopausal-women/. Accessed March 25, 2009.
  9. 9.
    PfizerInc. FABLYN® (lasofoxifene tartrate) 0.5 mg tablets. NDA 22-242 Briefing Document prepared for The Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Division of Reproductive and Urologic Products. Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4381b1-02-Pfizer.pdf. Accessed September 8, 2008.
  10. 10.
    Pocock N. FDA requests further data prior to considering approval of lasofoxifene for osteoporosis. NHS National electronic Library for Medicines. Available at: http://www.nelm.nhs.uk/en/NeLM-Area/News/2009.January/19/FDA-requests-further-data-prior-to-consideringapproval-of-lasofoxifene-for-osteoporosis/. Accessed January 16, 2009.
  11. 11.
    Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. 2002;112:281–289.CrossRefPubMedGoogle Scholar
  12. 12.
    Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone. 2004;34:599–604.CrossRefPubMedGoogle Scholar
  13. 13.
    Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res2002;17:1–10.Google Scholar
  14. 14.
    Kuiper GGJM, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology. 1997;138:863–870.CrossRefPubMedGoogle Scholar
  15. 15.
    Harris HA, Katzenellenbogen JA, Katzenellenbogen BS. Characterization of the biological roles of the estrogen receptors, ER α and ER β, in estrogen target tissues in vivo through the use of an ER α-selective ligand. Endocrinology. 2002;143:4172–4177.CrossRefPubMedGoogle Scholar
  16. 16.
    Paige LA, Christensen DJ, Gron H, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ER α and ER β. Proc Natl Acad Sci U S A. 1999;96:3999–4004.CrossRefPubMedGoogle Scholar
  17. 17.
    Riggs BL, Hartmann LC. Selective estrogen-receptor modulators - mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618–629.CrossRefPubMedGoogle Scholar
  18. 18.
    McDonnell DP. The molecular pharmacology of SERMs. Trends Endocrinol Metabol. 1999;10:301–311.CrossRefGoogle Scholar
  19. 19.
    Rosati RL, Da Silva Jardine P, Cameron KO, et al. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem. 1998;41:2928–2931.CrossRefPubMedGoogle Scholar
  20. 20.
    Ke H, Brown T, Thompson D. Lasofoxifene (CP- 336,156), a novel selective estrogen receptor modulator, in preclinical studies. J Am Aging Assoc. 2002;25:87–99.Google Scholar
  21. 21.
    Gardner M, Taylor A, Wei G, Calcagni A, Duncan B, Milton A. Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women. J Clin Pharmacol. 2006;46:52–58.CrossRefPubMedGoogle Scholar
  22. 22.
    Fountaine RJ, Nishizawa Y, Wei G, Dogolo L, Calcagni A, Gardner MJ. Clinical pharmacology of lasofoxifene in Japanese and white postmenopausal women. J Clin Pharmacol. 2006;46:693–699.CrossRefPubMedGoogle Scholar
  23. 23.
    Bramson C, Ouellet D, Roman D, Randinitis E, Gardner MJ. A single-dose pharmacokinetic study of lasofoxifene in healthy volunteers and subjects with mild and moderate hepatic impairment. J Clin Pharmacol. 2006;46:29–36.CrossRefPubMedGoogle Scholar
  24. 24.
    Roman D, Bramson C, Ouellet D, Randinitis E, Gardner M. Effect of lasofoxifene on the pharmacokinetics of digoxin in healthy postmenopausal women. J Clin Pharmacol. 2005;45:1407–1412.CrossRefPubMedGoogle Scholar
  25. 25.
    Ouellet D, Bramson C, Roman D, et al. Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene. Br J Clin Pharmacol. 2007;63:59–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Ouellet D, Bramson C, Carvajal-Gonzalez S, et al. Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin. Br J Clin Pharmacol. 2006;61:741–745.CrossRefPubMedGoogle Scholar
  27. 27.
    Moller RA, Fisher JM, Taylor AE, et al. Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism. Ann Pharmacother. 2006;40:32–37.PubMedGoogle Scholar
  28. 28.
    Rogers A, Glover S, Eastell R. A randomised, doubleblinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy. Bone. 2009;45:1044–1052.CrossRefPubMedGoogle Scholar
  29. 29.
    McClung M, Siris E, Cummings S, et al. Lasofoxifene increased BMD of the spine and hip and decreased bone turnover markers in postmenopausal women with low or normal BMD. J Bone Miner Res. 2005;S97.Google Scholar
  30. 30.
    Davidson M, Moffett A, Welty F, et al. Extraskeletal effects of lasofoxifene on postmenopausal women. J Bone Miner Res. 2005;20:S173.Google Scholar
  31. 31.
    Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362:686–696.CrossRefPubMedGoogle Scholar
  32. 32.
    Moffett A, Ettinger M, Bolognese M, et al. Lasofoxifene, a next generation SERM, is effective in preventing loss of BMD and reducing LDL-C in postmenopausal women. J Bone Miner Res. 2004;19(Suppl. 1):F426.Google Scholar
  33. 33.
    Bachmann G, Gass M, Kagan R, Moffett A, Barcomb L, Symons J. Lasofoxifene (LASO), a next generation selective estrogen response modulator (SERM) improves dyspareunia in postmenopausal women with vaginal atrophy (VA). Menopause. 2005;12:238.CrossRefGoogle Scholar
  34. 34.
    McClung MR, Siris E, Cummings S, et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause. 2006;13:377–386.CrossRefPubMedGoogle Scholar
  35. 35.
    Eastell R, Reid D, Vukicevic S, Thompson D, Cummings S, Delmas P. The effects of lasofoxifene on bone turnover markers: the PEARL trial. J Bone Miner Res. 2008;23:S81.CrossRefGoogle Scholar
  36. 36.
    Riggs BL, Melton LJ. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res. 2002;17:11–14.CrossRefPubMedGoogle Scholar
  37. 37.
    Dempster D, Lian J, Goldring S. Anatomy and functions of the adult skeleton. In: Favus M, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Washington DC: American Society for Bone and Mineral Research;2006:7–11.Google Scholar
  38. 38.
    Melton LJ, Crowson CS, O’Fallon WM. Fracture incidence in Olmsted County, Minnesota: comparison of urban with rural rates and changes in urban rates over time. Osteoporos Int. 1999;9:29–37.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Healthcare 2010

Authors and Affiliations

  • Victoria J. D. Swan
    • 1
  • Celeste J. Hamilton
    • 1
    • 2
  • Sophie A. Jamal
    • 1
    • 3
  1. 1.Osteoporosis Research ProgramWomen’s College HospitalTorontoCanada
  2. 2.Faculty of Physical Education and Health, Graduate Department of Exercise ScienceThe University of TorontoTorontoCanada
  3. 3.Department of Medicine, Division of Endocrinology and MetabolismThe University of TorontoTorontoCanada

Personalised recommendations