hexagonal, terraced hydroxyapatite crystals. Recent analysis of bone mineral indicates that a significant proportion of the hydroxyapatite crystal is a form of carbonated apatite, where carbonyl groups (CO3) replace some of the OH groups. Carbonated apatite is more soluble than hydroxyapatite at acid pH. Fluoride incorporation into the crystalline structure of bone mineral occurs with the creation of a form of apatite known as fluoroapatite (or fluorapatite). The formula for this form of the crystal is Ca10(PO4)6F2 or Ca10(PO4)6OHF. These crystals also take on a hexagonal shape and are found in terraced layers but, depending on the extent of fluoride in the crystal, may be somewhat more elongated than pure hydroxyapatite. Because fluoroapatite is less soluble in acidic solutions than hydroxyapatite, it was expected that fluoride incorporation into bone might actually make the tissue stronger. However, this has proven not to be the case in human studies (see below).

Release of fluoride from bone when it is in the form of fluoroapatite requires osteoclastic bone resorption. Acidification of the mineral matrix by the osteoclast is sufficient to solubilize the fluoroapatite and allow free exchange with extracellular fluids. Once released, the effect of fluoride on bone cells may be evident; however, the form in which fluoride has its effect remains under debate. Some investigators contend that fluoride directly affects bone cells, but others claim that the effect must be mediated by fluoride while in a complex with aluminum.

Do fluroaluminate complexes exist in biological fluids? The answer to this question depends in large part on pH, protein concentration, and cell composition. However, in general, in the acid environment of the stomach much of the aluminum and fluoride exist in a complex of AlF3 or AlF4. These forms (mostly AlF3) have been purported to cross the intestine and enter cells (Powell and Thompson 1993). Once inside a bone cell the AlFx form appears to activate a specific protein tyrosine kinase through a G protein and evoke downstream signals. A more complete discussion of this process is presented in a later section of this chapter.

The prolonged maintenance of fluoride in the bone requires that uptake of the element occurs at the same or greater rate than its clearance. This appears to be the case. (See Chapter 3 for more detailed discussion of the pharmacokinetic data on fluoride.) Turner et al. (1993) put forward a mathematical model that appears to fit the known pharmacokinetic data. This model assumes that fluoride influx into bone is a nonlinear function. This assumption is supported by pharmacokinetic data (Ekstrand et al. 1978; Kekki et al. 1982; Ekstrand and Spak 1990) and is required for the model to accurately predict fluoride movements. Another reasonable assumption is that the bulk of fluoride that moves between the skeleton and the extracellular fluid is due to bone remodeling. That is, most of the fluoride is either influxing or effluxing as a result of cellular activity. The outcome of the

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