Sodium fluoride has for more than 2 decades been a commonly used therapeutic agent for established osteoporosis because of a repeatedly documented anabolic effect on trabecular bone mass. Recently, however, three controlled trials have failed to demonstrate any therapeutic advantage of NaF over placebo with respect to vertebral fracture rate. Also, there have been several reports of an increased incidence of nonvertebral fractures during fluoride administration. Thus, the efficacy of fluoride therapy remains a controversial issue. The aim of this longitudinal study was to investigate the effect of sodium fluoride (40-60 mg per day), calcium (45 mmol), and vitamin D2 (18,000 IU) on trabecular bone strength, assessed before and after 1 or 5 years of treatment for osteoporosis. Iliac crest biopsies were taken before and after 1 year of treatment in 12 patients, and before and after 5 years of treatment in 14 patients. Measurements were made of biomechanical competence, ash content, and bone fluoride content, and bone strength parameters were normalized for ash content, thereby obtaining a measure of trabecular bone quality. Bone fluoride content was significantly increased after both 1 and 5 years of treatment, indicating that the administered fluoride had been ingested. After 1 year of treatment, no difference was observed in iliac crest trabecular bone ash content. A general trend for decreased bone strength and bone quality was observed, but this was insignificant. After 5 years of fluoride treatment, an insignificant decrease in iliac crest trabecular bone ash content was observed. A significant reduction of 45% was found in trabecular bone strength (p < 0.05), and an even more pronounced reduction of 58% was found in trabecular bone quality (p < 0.01). The results of this study indicate that long-term administration of sodium fluoride may be detrimental to bone quality, at least as measured in nonloaded iliac crest trabecular bone.