Fluoride: The verdict is in, but the controversy lingers

111. U N A N I M O U S vo.rt by the Metabolic Diseases Advisory T Panel of the Food and Drug Administration (FDA) to recommend approval of slow-release sodium fluoride (SRNaF) for the treatment of postmenopausal osteoporosis should be a source of great pride to Dr. Pak and his team of investigators whose diligent work and careful attention to detail brought these studies to such a successful conclusion. Regrettably, it is apparent to me and many others from private conversations and correspondence that this decision by the Advisory Panel was not universally well received. In fact it is doubtful that the carefully conducted and reported studies have moved a single pcrson from the “con” to the “pro” fluoride camp. In defense of those who remain unconvinced about either the effectiveness or safety of slowrelease fluoride, o r any other fluoride preparation, in the treatment o f osteoporosis, many valid scientific questions remain t o be answered. However, the burden of proof now rests very clearly o n the shoulders of those who remain skeptical. As with any other controversy in science, the issues must be resolved by legitimate scientific inquiry and there is n o r ~ o m for emotional appeal. A major criticism of the studies by Pak et al. is that most of them have not been validated by independent groups of investigators. The studies reporting the beneficial effect of SR-NaF o n biomechanical properties of the skeleton“’ and the lack of deleterious effect o n these properties‘’’ were, to the best of my knowledge. conducted using methods not employed in other laboratories. Even more importantly, these results wcre not validated in the investigator’s own laboratory using more conventionally applied methods of others. This lack of validation leaves open to question the whole issue o f the shortand long-term safety of SR-NaF. In ;I similar vein, the methods for detecting and reporting fractures and fracture rates have not been uniform througho u t the reporting o f these studies. The methods changed from the earlier uncontrolled studies to the reports of the controlled clinical trials. There was even a change in method from the interim‘. ’’ t o the final report of the controlled clinical trial. “’ even though thcsc publications were less than 2 years apart. Of greater concern is that insufficient individual patient information is provided in the published reports to permit reanalysis of this data in a manner that would allow more direct comparison with other clinical trials of osteoporosis in which fracture was a defined endpoint. This criticism could, of course, be leveled at all of us who have published reports of clinical trials and could extend not only to vertebral fracture as the outcome variable of interest but also to the methods of reporting bone mineral density as the major outcome variable. These issues are becoming of increasing practical importance as more drugs are approved, both in the United States and elsewhere, for the treatment of osteoporosis. For every drug that is approved there are two or three additional therapeutic agents undergoing extensive clinical trial. As these drugs bccome available, the single most important question in the minds of practitioners is, “How does this new drug compare with medications I have been prescribing for some time‘? ’’ In the United States, the FDA has a set of guidelines for the conduct of controlled clinical trials in osteoporosis, and regulatory bodies in other countries employ different guidelines. Given the international composition of the ASBMR and the several cooperative ventures of the various national osteoporosis bodies, it is probably time to convene a blue ribbon international panel to bring some order into the apparent chaos that surrounds the conduct of these clinical trials. The controlled clinical trial reported by Pak ct al. has been criticized because some o f the subjects in the study were also taking estrogen. and it is not entirely clear how these women were assigned to thc activc or placebo arm o f the trial and, more importantly, how they were assigned to the investigative ~itcs. ‘-’. ~’ I am not convinced that this is a valid criticism of the study. This issue was addressed and not fully resolved in the two NIH-sponsored fluoride trials at the Mayo Clinic‘” and Henry Ford Hospital‘”’ that began in 1981. A decision was made at that time not to include patients on estrogen, but the two studies took different approaches to this problem, with the group at thc Mayo Clinic discontinuing patients from estrogen for 6 months before enrollment while at Henry Ford Hospital