Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. Susan L. Greenspan, MD;
  2. Ronald D. Emkey, MD;
  3. Henry G. Bone III, MD;
  4. Stuart R. Weiss, MD;
  5. Norman H. Bell, MD;
  6. Robert W. Downs, Jr., MD;
  7. Clark McKeever, MD;
  8. Sam S. Miller, MD;
  9. Michael Davidson, MD;
  10. Michael A. Bolognese, MD, PC;
  11. Anthony L. Mulloy, PhD, DO;
  12. Norman Heyden, RPh, MS;
  13. Mei Wu, MS;
  14. Amarjot Kaur, PhD; and
  15. Antonio Lombardi, MD
  1. From University of Pittsburgh, Pittsburgh, and Radiant Research Reading, Wyomissing, Pennsylvania; Beth Israel Deaconess Medical Center, Boston, Massachusetts; Michigan Bone and Mineral Clinic, Detroit, Michigan; San Diego Endocrinology and Medical Clinic, San Diego, California; Medical University of South Carolina, Charleston, South Carolina; Virginia Commonwealth University, Richmond, Virginia; Research for Health, Houston, and SAM Clinical Research Center, San Antonio, Texas; Chicago Center for Clinical Research, Chicago, Illinois; Bethesda Health Research, Bethesda, Maryland; Medical College of Georgia, Augusta, Georgia; and Merck and Co., Inc., Rahway, New Jersey.

    Abstract

    Background: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly.

    Objective: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued.

    Design: Double-blind, placebo-controlled discontinuation trial.

    Setting: 18 U.S. centers.

    Patients: 244 postmenopausal, hysterectomized women 44 to 77 years of age.

    Intervention: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo.

    Measurements: Bone mineral density and biochemical markers of bone turnover.

    Results: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, −5.0% to −4.0%) and a 2.4% decrease at the trochanter (CI, −2.7% to −2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment.

    Conclusions: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.

    Article and Author Information

    • Grant Support: By a grant from Merck Research Laboratories, Rahway, New Jersey, to the individual study sites.

    • Requests for Single Reprints: Susan L. Greenspan, MD, University of Pittsburgh, Osteoporosis Prevention and Treatment Center, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213; e-mail, GriffithsD{at}msx.dept-med.pitt.edu.

    • Current Author Addresses: Dr. Greenspan: University of Pittsburgh, Osteoporosis Prevention and Treatment Center, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213.

    • Dr. McKeever: Touch Research Inc., 800 Gessner, Suite 200, Houston, TX 77024.

    • Dr. Miller: SAM Clinical Research Center, 7711 Louis Pasteur, Suite 300, San Antonio, TX 78229.

    • Dr. Weiss: San Diego Endocrine and Medical Clinic, 5920 Friars Road, Suite 208, San Diego, CA 92108.

    • Dr. Emkey: Radiant Research Reading, 1235 Penn Avenue, Suite 200, Wyomissing, PA 19610.

    • Dr. Downs: Virginia Commonwealth University, 1101 E. Marshall Street, 7-015, Richmond, VA 23298-0111.

    • Dr. Bell: Medical University of South Carolina, Strom Thurmond Building, Room 548, 114 Doughty Street, Charleston, SC 29425.

    • Dr. Bone: Michigan Bone and Mineral Clinic, 22201 Moross Road, Suite 260, Detroit, MI 48236.

    • Dr. Davidson: Chicago Center for Clinical Research, 515 North State Street, Suite 2700, Chicago, IL 60610-4324.

    • Dr. Bolognese: Bethesda Health Research, 10215 Fernwood Road, Suite 40, Bethesda, MD 20817.

    • Dr. Mulloy: Medical College of Georgia, Section of Endocrinology and Nutrition, 1467 Harper Street, HB-5025, Augusta, GA 30912-3115.

    • Mr. Heyden and Ms. Wu: Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065.

    • Dr. Kaur: Merck Research Laboratories, 126 East Lincoln Avenue, RY33-404, Rahway, NJ 07065.

    • Dr. Lombardi: Merck & Co., Inc., 126 East Lincoln Avenue, RY32-545, Rahway, NJ 07065.

    • Author Contributions: Conception and design: H.G. Bone, R.W. Downs, S.S. Miller.

    • Analysis and interpretation of the data: S.L. Greenspan, S.S. Miller, M. Wu.

    • Drafting of the article: S.L. Greenspan, S.S. Miller.

    • Critical revision of the article for important intellectual content: S.L. Greenspan.

    • Final approval of the article: S.L. Greenspan, H.G. Bone, N.H. Bell, R.W. Downs, S.S. Miller, M. Wu.

    • Provision of study materials or patients: S.L. Greenspan, R.D. Emkey, H.G. Bone, S.R. Weiss, N.H. Bell, R.W. Downs, C. McKeever, S.S. Miller, M. Davidson, M.A. Bolognese, A.L. Mulloy.

    • Statistical expertise: M. Wu.

    • Obtaining of funding: S.L. Greenspan.

    • Administrative, technical, or logistic support: N.H. Bell, N. Heyden.

    • Collection and assembly of data: S.L. Greenspan, R.D. Emkey, H.G. Bone, S.R. Weiss, N.H. Bell, C. McKeever, S.S. Miller, M. Davidson, M.A. Bolognese, N. Heyden.

    Summary for Patients

    • Summaries for Patients:Bone Loss after Stopping Estrogen or Alendronate Therapy Ann Intern Med December 3, 2002 137:I-31
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    1. Ann Intern Med December 3, 2002 vol. 137 no. 11 875-883
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