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In a 5-year observational study we have compared sodium fluoride (NaF) with different treatments commonly used in the treatment of osteoporosis: calcium, estrogens, androgens, and calcitonin, referred to as non-NaF. We have looked at the incidence of vertebral and nonvertebral fractures. At baseline, the NaF group, consisting of 125 patients (89% females) aged 65 ± 10 (X ± SE) had more crush fractures (P< 0.0001) and more months since menopause (P= 0.004) than the non-NaF group, consisting of 127 patients (90% females) aged 63 ± 10. Fractures were evaluated by X-ray. The entire follow-up of patients treated with NaF accounted for 361 person-years, of whom 43 patients suffered one or more new vertebral fractures (68 vertebral fractures in total) and 18 patients suffered one or more new nonvertebral fractures (22 complete peripheral fractures in total); follow-up of patients treated with non-NaF regimes accounted for 382 person-years, of whom 53 patients suffered one or more new vertebral fractures (69 vertebral fractures in total) and 20 patients suffered one or more new nonvertebral fractures (27 complete peripheral fractures in total). After adjusting for significant covariates at baseline, NaF proved to be a significant protector for vertebral fractures [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.2–0.9], and for peripheral fractures (OR 0.41, 95% CI 0.2–0.9). On the other hand, the probability of suffering undesired effects was much higher with NaF treatment (OR 5.04, 95% CI 2.1–11.9). We conclude that in the treatment of osteoporosis, NaF has a protective effect against vertebral and nonvertebral fractures, does not increase the risk of femoral fractures, but has a higher incidence of untoward symptomatology.