Probably the most practical outcome of 40 years' research on the treatment of osteoporosis with Fluoride is the recent (1999) demonstration that a safe low-dosage (20mg F as MFP) has a synergistic beneficial effect when combined with HRT (hormone replacement therapy). That is, the osteogenic-plus-antiresorptive benefits of the combination are greater than the sum of either treatment alone (P Alexandersen,BJ Riis,C Christiansen. J Clin Endocrinol Metab 84:3013-3020, 1999).
Although this study and two other recent MFP-clinicals are too small to meet the current FDA-guidelines, they are scientifically sound, as judged by peer-review required for publication (JY Reginster et al. Ann Intern Med 129:1-8, 1998; JD Ringe et al. Osteoporos Int 9:171-178, 1999). It is also reported that studies of F-combinations with other antiresorptives are in progress.
Nevertheless, sadly, it must be reported that Fluoride treatment of osteoporosis, in the U.S., in the year 2002, has reached an impasse. That conclusion is due to the U.S.-FDA's current requirement for still larger (1000-patient) clinical studies to confirm the smaller (100-patient) studies which have already statistically proved that it is safe and effective. The new U.S.-standard requires so huge a financial investment (up to $500 million) that only a few giant corporations have the necessary resources. Since the fluoride molecules which have been used are not patentable (only the dosage forms have been patented), the incentive for U.S. commercial development is thereby negated. Fluoride is, nevertheless, still marketed in several European countries, including Germany, where Novartis markets FLUORIL (MFP + Ca) under its Sandoz division. Moreover, the FDA still acknowledges that Fluoride's unique mechanism of action (stimulates new bone formation) justifies further clinicals, since the approved medications (estrogens, phosphonate, calcitonin) are basically limited to reduction of bone LOSS. Thus a combination with F could provide a two-way attack on the disease; but, in summary, a uniquely "good drug" appears to have been blocked from further development by the expanded federal standards which have, in effect, made it an "orphan drug" with no sponsors.
On March 27-29, 2000, the
NIH Consensus Conference on Osteoporosis Prevention,
Diagnosis, and Therapy was held.* "We
not come to a clear conclusion that fluoride was effective for the
of osteoporosis" (Keith Hruska, Washington U.). Robert Lindsay
evidence re: F and bone mass, but "data on fractures is more
Thus, a good drug is still without consensus-support of US experts in
field. Apparently, the antifracture data of Pak and others,
Low Dosage fluoride, requires confirmation in large-scale clinical
before the issue can be resolved.
In Osteoporosis International 9:171-178, 1999, JD Ringe et al (using MFP) confirmed the low-dosage findings of Pak in a three-year study favoring an intermittent average 11.2mg F over 20mg F per day (Therapy of Established Postmenopausal Osteoporosis with Monofluoro- phosphate plus Calcium:Dose-Related Effects on Bone Density Fracture Rate).
In the July 1, 1998 issue of Annals of Internal Medicine, Reginster (using MFP) confirmed the 1995 NaF findings of Pak. In well-controlled four-year studies, both investigator teams found vertebral antifracture effects in moderate osteoporotics, whereas Meunier's negative 1998 report involved ony two years of treatment and included more severe patients.
In September 1997, at the Annual meeting of the American Society for Bone and Mineral Research, Rubin et al, reported on their two-year confirmatory results relative to Pak's four-year low-dose, slow fluoride study, published in 1995. In addition, at the same Meeting, Reginster et al presented very favorable four-year results with MFP-Fluoride. Likewise, Alexandersen et al from Denmark reported positive findings with MFP in steroid-osteoporosis.2
A meeting of the World Congress on Osteoporosis (sponsored by the National Osteoporosis Foundation of the USA and the European Foundation for Osteoporosis) was held in Amsterdam, the Netherlands, on May 18-23, 1996. At that time a large number of clinical reports were presented on Fluoride treatment (12 studies on MFP involving a total of 777 patients; eight studies on NaF) relative to projects which had started 3-4 years earlier. Two were very well-controlled trials (FDA design) on MFP, conducted in Belgium. A third controlled study in Germany provided favorable 3-year results in male patients.
In addition, positive results were presented on the use of MFP in combination with other drugs (estrogen, phosphonate, anabolic steroid, phenytoin), as well as concomitant prednisone, to prevent glucosteroid-induced osteoporosis.
Furthermore, MFP was showed to be superior to NaF in NaF-resistant patients; slow- release MFP was better than plain-MFP in maintaining smoother F-blood levels. On the other hand, one negative collaborative report has been criticized because (1) The degree of osteoporosis was not well defined (2) The dosage is now considered to have been too high (3) The administration of large scale, long-term collaborative studies is inherently difficult to control. Finally, it is predicted that U.S. regulatory approval of Slow Fluoride (still pending) will give full recognition to Fluoride Therapy, and will open the market to general professional use, not only in the U.S. but throughout the world.
* ADA News:April 17,2000,p.22
1. "Mild-moderate" means loss up to one-third of total vertebral bone mass.
2. Some advocates who have a "crush" on Fluoride: "It's not for everyone, but maybe only one 'break' is all that's needed."