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Treatment of Postmenopausal Osteoporosis with Slow-Release Sodium Fluoride: Final Report of a Randomized Controlled Trial

Charles Y.C. Pak, MD; Khashayar Sakhaee, MD; Beverley Adams-Huet, MS; Veronica Piziak, MD, PhD; Roy D. Peterson, RN; and John R. Poindexter, BS
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From the University of Texas Southwestern Medical Center, Dallas, Texas, and the Scott and White Clinic, Temple, Texas. Note: Slow Fluoride is an investigational drug study under the Food and Drug Administration's investigational new drug application number 20 612. The University of Texas Southwestern Medical Center, the sponsor of the investigational new drug application, holds all rights to this drug. The Mission Pharmacal Company, the manufacturer of Slow Fluoride, has provided the drug free of charge for this trial but has not offered other research support. Dr. Pak is the principal investigator of the investigational new drug application. None of the investigators has equity in, receives direct compensation from, or serves on the Board of the Mission Pharmacal Company. Grant Support: In part by grants R01-AR-16061 and M01-RR00633 from the United States Public Health Service, and by institutional funds. Requests for Reprints: Charles Y.C. Pak, MD, University of Texas South-western Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8885. Current Author Addresses: Drs. Pak and Sakhaee, Ms. Adams-Huet, Mr. Peterson, and Mr. Poindexter: Center for Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8885.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(6):401-408. doi:10.7326/0003-4819-123-6-199509150-00001
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Objective: To test whether slow-release sodium fluoride inhibits spinal fractures and is safe to use.

Design: Placebo-controlled randomized trial.

Interventions: Slow-release sodium fluoride, 25 mg twice daily, in four 14-month cycles (12 months receiving sodium fluoride followed by 2 months not receiving it) compared with placebo. Calcium citrate, 400 mg calcium twice daily, continuously in both groups.

Patients: 48 of 54 patients who received sodium fluoride and 51 of 56 patients who received placebo completed at least 1 year of the study. All patients had postmenopausal osteoporosis.

Results: Compared with the placebo group, the fluoride group had a lower individual vertebral fracture rate (0.064 ± 0.182 per patient-year compared with 0.205 ± 0.297 per patient-year; P = 0.002), a higher unadjusted fracture-free rate (85.4% compared with 56.9%; P = 0.001), and a greater survival estimate (relative risk, 0.3 [95% CI, 0.12 to 0.76]) for new fractures. The recurrent spinal fracture rate did not differ between the two groups. The fluoride group had a substantial increase in L2-L4 bone mass of 4% to 5% per year for 4 years, a mean increase in femoral neck bone density of 2.38% ± 3.33% per year, and no change in radial shaft bone density. The frequency with which minor side effects and appendicular fractures occurred was similar in the two groups; no patients developed microfractures or gastric ulcers.

Conclusion: Slow-release sodium fluoride and calcium citrate administered for 4 years inhibits new vertebral fractures (but not recurrent fractures), augments spinal and femoral neck bone mass, and is safe to use.

Figures

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Figure 1.
Proportion of patients without new spinal fractures during 4 years of treatment in the groups receiving slow-release sodium fluoride and placebo.
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Figure 2.
Dependence of individual vertebral fracture rate (IVFR) on baseline L2-L4 bone density (BD) in the groups receiving slow-release sodium fluoride (SR-NaF) and placebo.Top.Bottom.

All patients had radiologic evidence of osteopenia. However, six patients (three in each group) had baseline L2-L4 bone density greater than 95% that of a normal 30-year-old woman (mean). Values were probably falsely high because of severe scoliosis in three patients and compression fracture in one patient (which yielded a subnormal vertebral area) and reactive degenerative arthritis and aortic calcification, respectively, in two patients (which added extraskeletal mass). Dependence of individual vertebral fracture rate on baseline L2-L4 bone density in the group receiving sodium fluoride. Dependence of individual vertebral fracture rate on baseline L2-L4 bone density in the group receiving placebo.

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Figure 3.
Effect of treatment on the L2-L4 bone mineral content (BMC) and on the bone density (BD) of the femoral neck and radial shaft.PPP

For each year, the percentage change of the value from the preceding year or from baseline was calculated. Thus, a year-to-year change, rather than a cumulative change, is shown. Symbols above the bars indicate a significant change from zero, whereas symbols above the brackets show significant changes between the group receiving placebo and the group receiving slow-release sodium fluoride (SR-NaF). * < 0.05; ** < 0.01; † < 0.001.

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Figure 4.
Effect of treatment on the mean fasting serum fluoride level.P

Dashed horizontal lines indicate therapeutic window. In each study period (of 14 months), slow-release sodium fluoride (SR-NaF) or placebo was received during the first 12 months. Significant differences between the two groups at corresponding time periods are shown by †, which indicates < 0.0001. Values are presented as mean ± SE.

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