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Dose-Response Relationships for Alendronate Treatment in Osteoporotic Elderly Women¹

Bone and Mineral Division, Henry Ford Hospital (H.G.B.), Detroit, Michigan 48202; the Endocrine Division, Medical College of Virginia (R.W.D.), Richmond, Virginia 23298; the Endocrine Division, Roger Williams Medical Center (J.R.T.), Providence, Rhode Island 02908; Osteoporosis Programs, University of California (S.T.H.), San Francisco, California 94117; Center for Osteoporosis and Metabolic Bone Disease, University of Arkansas for Medical Sciences (R.S.W.), Little Rock, Arkansas 72205, Osteoporosis/Metabolic Bone Disease Unit, Cleveland Clinic Foundation (A.A.L.), Cleveland, Ohio 44195; Osteoporosis Research Center (M.R.M.), Portland, Oregon 97213; Center for Hard Tissue Research, Creighton University (D.B.K.), Omaha, Nebraska 68131; and Merck Research Laboratories (B.J.G., E.H., W.J.P.), Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Henry G. Bone, M.D., Bone and Mineral Division K-15, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women.

This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60–69 yr and 224 aged 70–85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr.

This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment.

We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0–5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

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