The role of fluoride in the prevention of osteoporosis.

Osteoporosis defined as low bone mass and increased susceptibility to fracture is a reflection of the sum of peak bone mass and any bone that has been lost once peak mass has been attained. Several strategies have been applied to optimize peak bone mass and to prevent bone loss. Fluoride has greatest potential as a therapy for osteoporosis once bone has been lost. It has been demonstrated both experimentally and clinically to stimulate bone formation directly and to increase bone mass in patients who already have osteoporosis. Several bone formation/stimulation therapies are under development, and some of these have reached the stage of clinical trial. None of these therapies has been as extensively studied as fluoride, and none is sufficiently advanced in development to be clinically available in the next 3 to 5 years. Fluoride therapy for osteoporosis is already performed in many countries, and approval for use in osteoporosis in the United States is pending. The first clinical trials of NaF therapy for osteoporosis were reported by Rich and Ensinck in 1961. Since then, hundreds of reports on the successes and failures of fluoride therapy have appeared in the literature. At first glance, it seems disappointing and inexplicable that, after 40 years of research, fluoride is still considered an experimental drug in the United States. One plausible explanation is that much of the early research on this drug was suboptimal, including the author's contributions. Fluoride as a naturally occurring element is difficult to patent, and this has kept major pharmaceutical companies from investing heavily in fluoride therapy despite its obvious potential. As a result, pharmacologic and pharmacokinetics studies of fluoride are limited in scope, as are phase I and phase II human toxicology and dose-finding studies. Most early studies of large doses of plain NaF were unable to demonstrate a consistent effect on fracture rate despite a consistent and dramatic effect on bone density. Once this became obvious and as new technologies for measuring bone density became available, it became equally clear that future clinical trials would have to be performed using different formulations of fluoride and lower doses. This approach has not resulted in uniformly positive clinical trials, and one must look elsewhere for answers. The most compelling explanation is that the trials have included patients with different severity of disease, suggesting that there is point in the bone loss spectrum at which even a potent bone-stimulating agent such as fluoride is ineffective. This possibility should provoke a reappraisal of the earlier negative studies: was the failure a result of the drug or of patient selection? The answer to this question is crucial, because these failures have cast a long shadow over the safety of fluoride and are contributing more to the absence of this drug from the pharmacopoeia than any other factor.