Medical scientists often tend to neglect certain pharmaceutical considerations related to drug research. In the case of Fluoride, this has resulted in some confusing and conflicting reports regarding safety and efficacy. For example, it should have been noted that the "actual" or "real" (bioavailable) dosage of Fluoride depends on four variables:
That is, the total amount of Fluoride absorbed into the bloodstream and accumulated in the bone relates to:
In reviews of the Pak studies, however the dosage cited is 25 mg NaF bid (50 mg NaF or 22.6 mg F/d). However, because of the slow-release formulation employed and the use of Calcium citrate, the actual absorbed dosage (7 mg F/d)* was only about one- third of the administered dosage.
Hence, the failure to recognize that a very low dosage can be both safe and effective. One investigator, however, has crossed over from the medical to the pharmaceutical field. Dr. Wolfgang Ritschel, Ph.D., MD has published extensively on the bioavailability of drugs, including MFP. Unfortunately, he has only published in Pharmaceutical Science journals, which are generally not read by medical clinicians. The NIH, however, has recognized the importance of Ritschel's contributions by awarding him a very large long-term grant to establish a Pharmaceutical Science Center at the University of Cincinnati.
Dose-Response (Biphasic): At very low, slow, long-term biodosages, starting at about 5-10 mg F per day, Fluoride (combined with Calcium) has been found to be safe and effective in reducing vertebral fracture rates (VFR) in mild-moderate osteoporosis (35% or less bone loss). At much higher dosages, however, the VFR reaches a nadir, beyond which there is a reversal of both efficacy and safety (see graph, Nagant 1996). Unfortunately, certain "safety studies" in animals have been conducted at excessively high dosages (10-100 times higher than Pak's) and have showed mineralization defects and loss of bone strength. This discrepancy between clinical and animal dosing-levels has caused considerable problems of interpretation in the review literature, which, in turn, has hindered the general acceptance of Fluoride therapy.
However, the most recent clinical study report by Rubin (1997) has now confirmed earlier results by Pak on the safety and efficacy of Fluoride at the same low dosage level. Furthermore, additional confirmatory studies (1997), at somewhat higher dosages of MFP, by Reginster and by Ringe in Europe, support the favorable U.S. results. Still, the latest report by Meunier in France is disappointingly inconsistent with his previous positive results. This latest study, however, appears to involve a more severely osteoporotic patient population and several small treatment groups, resulting in low statistical power.
*Equivalent to approximately 0.1mg F/kg/d (7mg F/d).
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The 1996 self-reanalysis and reassessment of Mayo's 1990 data has revealed that their negative results of
Fluoride therapy were due to excessive overdosing (Riggs 1996). When toxic-dosed patients
were excluded (serum level 8.0 micromole per liter or higher) there was a
fourfold decrease in VFR between the lowest and highest values for
LS-BMD. (See their figure 1 to the right.)
Similarly, in an animal study, Turner, Akhter, and Heaney (J Orthop Res 10:581-587,1992) found a biphasic effect of bone-F content on bone strength, increasing in strength up to about 1000 ppm F in bone mineral, but then decreasing at higher F-levels (Fig 4 p.585). |