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Alendronate and Estrogen–Progestin in the Long-Term Prevention of Bone Loss: Four-Year Results from the Early Postmenopausal Intervention Cohort Study: A Randomized, Controlled Trial

Pernille Ravn, MD; Marianne Bidstrup, MD; Richard D. Wasnich, MD; James W. Davis, PhD; Michael R. McClung, MD; Ana Balske, MD, PhD; Carol Coupland, BSc; Opinder Sahota, MRCP; Amarjot Kaur, PhD; Marianne Daley, BA; Giovanni Cizza, MD, PhD, Early Postmenopausal Intervention Cohort Study Group*
[+] Article and Author Information

From Center for Clinical and Basic Research, Ballerup, Denmark; Hawaii Osteoporosis Center, Honolulu, Hawaii; Oregon Osteoporosis Center, Portland, Oregon; City Hospital, Nottingham, United Kingdom; and Merck & Co., Inc., Rahway, New Jersey.


Acknowledgment: This paper is dedicated to the memory of Dr. Anthony Lyons, who was a major contributor to the Early Postmenopausal Intervention Cohort Study.

Grant Support: In part by Merck Research Laboratories, in the form of research grants to the individual study sites.

Requests for Reprints: Pernille Ravn, MD, Center for Clinical and Basic Research, Ballerup Byvej 22, DK-2750 Ballerup, Denmark. For reprint orders in quantities exceeding 100, please contact the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints@mail.acponline.org.

Current Author Addresses: Drs. Ravn and Bidstrup: Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark.

Drs. Wasnich and Davis: Hawaii Osteoporosis Center, 401 Kamakee Street, Second Floor, Honolulu, HI 96814-4224.

Drs. McClung and Balske: Oregon Osteoporosis Center, 5050 NE Hoyt Street, Suite 651, Portland, OR 97213.

Dr. Coupland and Dr. Sahota: Bone and Mineral Unit, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom.

Dr. Kaur, Ms. Daley, and Dr. Cizza: Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, RY32-549, Rahway NJ 07065-0914.


Ann Intern Med. 1999;131(12):935-942. doi:10.7326/0003-4819-131-12-199912210-00005
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Osteoporosis is a serious disease that develops slowly over many years and results in fractures and associated health care costs (13). Available treatments increase bone mineral density and reduce the risk for fractures but do not fully restore bone mass or microarchitecture (4). Alendronate, a bisphosphonate that inhibits bone resorption but not bone mineralization (5), prevents bone loss, increases bone mineral density (610), and reduces the incidence of fractures at the spine and hip by 30% to 50% in postmenopausal women with osteoporosis (7, 1112). Because alendronate prevents bone loss, it can be used as an alternative to estrogen–progestin in the prevention of postmenopausal osteoporosis (1314). The optimal length and regimen of alendronate treatment, however, have not yet been determined. Long-term treatment is probably needed to substantially affect bone mass and achieve lasting prevention of bone loss. However, clinical trials must be done to address the continuing efficacy and safety of agents used for prevention of osteoporosis, including alendronate.

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Figures

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Figure 1.
Mean percentage change (±SE) from baseline in bone mineral density at the lumbar spine, total hip, total body, and one-third distal forearm.

Black triangles represent women who received 4 years of alendronate, 5 mg/d; black squares represent women who received 4 years of alendronate, 2.5 mg/d; white circles and dashes represent women who received 4 years of placebo; white diamonds represent women who received 4 years of estrogen-medroxyprogesterone acetate; black diamonds represent women who received 4 years of estradiol-norethisterone acetate; white triangles and dashes represent women who received 2 years of alendronate, 5 mg/d, followed by 2 years of placebo; and white squares and dashes represent women who received 2 years of alendronate, 2.5 mg, followed by 2 years of placebo. For graphical presentation, results from groups that received the same dosage of alendronate during the first 2 years of the study were pooled during this period for the two strata combined.

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Figure 2.
Cumulative percentage change and corresponding least significant difference (LSD) interval at the lumbar spine, total hip, total body, and one-third distal forearm.P

Changes from baseline to year 2 in the group that continuously received placebo are compared with changes in years 3 and 4 in the groups that did not continuously receive alendronate. Circles represent women who received 4 years of placebo; squares represent women who received 2 years of alendronate, 2.5 mg/d, followed by 2 years of placebo; and triangles represent women who received 2 years of alendronate, 5 mg/d, followed by 2 years of placebo. The LSD interval is approximately an 84% CI; overlapping LSD intervals imply that the value exceeds 0.05 for between-group tests.

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Figure 3.
Mean observed change from baseline (±SE) in urineN-telopeptide cross-links of type I collagen, serum osteocalcin, and serum bone-specific alkaline phosphatase levels.BCEN(15)(16)

Black triangles represent women who received 4 years of alendronate, 5 mg/d; black squares represent women who received 4 years of alendronate, 2.5 mg/d; white circles and dashes represent women who received 4 years of placebo; white diamonds represent women who received estrogen-medroxyprogesterone acetate; black diamonds represent women who received estradiol-norethisterone acetate; white triangles and dashes represent women who received 2 years of alendronate, 5 mg/d, followed by 2 years of placebo; and white squares and dashes represent women who received 2 years of alendronate, 2.5 mg/d, followed by 2 years of placebo. For graphical presentation, results from groups that received the same dosage of alendronate during the first 2 years of the study were pooled during this period for both strata combined. The mean premenopausal reference ranges (± SD) were 22.5 ± 9.4 nmol bone collagen equivalents ( )/mmol Cr for urine levels of -telopeptide cross-links of type I collagen and 8.8 ± 2.7 ng/mL for serum levels of bone-specific alkaline phosphatase . No premenopausal reference range was available for serum osteocalcin. To convert ng/mL to µg/L, multiply by 1.0.

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Summary for Patients

Preventing Bone Loss with Medications in Postmenopausal Women

The summary below is from the full report titled “Alendronate and estrogen–progestin in the Long-Term Prevention of Bone Loss: Four-Year Results from the Early Postmenopausal Intervention Cohort Study. A Randomized, Controlled Trial.” It is in the 12 December 1999 issue of Annals of Internal Medicine (volume 131, pages 935-942). The authors are P. Ravn, M. Bidstrup, R.D. Wasnich, J.W. Davis, M.R. McClung, A. Balske, C. Coupland, O. Sahota, A. Kaur, M. Daley, and G. Cizza, for the Early Postmenopausal Intervention Cohort Study Group.

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