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Lasofoxifene in Postmenopausal Women with Osteoporosis
Steven R. Cummings, M.D., Kristine Ensrud, M.D., Pierre D. Delmas, M.D., Ph.D.,* Andrea Z. LaCroix, Ph.D., Slobodan Vukicevic, M.D., Ph.D., David M. Reid, M.B., Ch.B., M.D., Steven Goldstein, M.D., Ph.D., Usha Sriram, M.D., Andy Lee, M.A., John Thompson,Ph.D., Roisin A. Armstrong, Ph.D., David D. Thompson, Ph.D., Trevor Powles, M.D., Jose Zanchetta, M.D., David Kendler, M.D., Patrick Neven, M.D., Ph.D., and Richard Eastell, M.D., for the PEARL Study Investigators†
A bs t r ac t
From the San Francisco Coordinating Center, California Pacific Medical Center Research Institute, and University of California, San Francisco, San Francisco(S.R.C.); University of Minnesota and Veterans Affairs Medical Center, Minneapolis (K.E.); Université de Lyon and INSERM Research Unit 831, Lyon, France (P.D.D.); Fred Hutchinson Cancer Research Center, Seattle (A.Z.L.); Laboratory for Mineralized Tissue, School of Medicine, University of Zagreb, Zagreb, Croatia (S.V.); Division of Applied Medicine, University of Aberdeen, Aberdeen (D.M.R.),Parkside Oncology Clinic, Wimbledon, London (T.P.), and Academic Unit of Bone Metabolism, University of Sheffield, Sheffield (R.E.) — all in the United Kingdom; New York University School of Medicine, New York (S.G.); Associates in Clinical Endocrinology, Education and Research, Chennai, India (U.S.); Pfizer Global Research and Development, New London, CT (A.L., J.T., R.A.A., D.D.T.); Instituto deInvestigaciones Metabólicas and El Salvador University School of Medicine, Buenos Aires (J.Z.); St. Paul’s Hospital, Vancouver, BC, Canada (D.K.); and University of Leuven, Leuven, Belgium (P.N.). Address reprint requests to Dr. Cummings at 185 Berry St., Lobby 4, Suite 5700, San Francisco, CA 94107, or at scummings@sfcc-cpmc .net. *Deceased. †Investigators in the Postmenopausal Evaluation andRisk-Reduction with Lasofoxifene (PEARL) Study are listed in the Appendix. N Engl J Med 2010;362:686-96.
Copyright © 2010 Massachusetts Medical Society.
The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.
In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density Tscore of –2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)–positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.
Lasofoxifene at a dose of 0.5 mg per day,as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95%CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years;hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60],...