5. Fluorine (F)

According to some researchers, fluorine is a microelement needed for proper development. However, in the case of this element, it is important to determine its concentration in
the human body, because the difference between the tolerated dose and the toxic dose is very small [110].

Fluorides (F-), the ionic form of fluorine, in trace amounts are essential for the proper development of the bones and the teeth [111]. They stimulate the proliferation of osteoblasts
and inhibit the activity of osteoclasts, thus leading to an increase in bone mass [112]. Therefore, fluorine compounds are used in the treatment of osteoporosis. It has been observed that in the course of steroid therapy, the administration of low doses of F- and 1,25(OH)2 D3 reduces the risk of vertebral fractures and protects against bone loss in these patients [113]. It has been found that F, especially in drugs with a slow release of a fluoride anion, in daily doses of 10–20 mg, may increase trabecular bone density [114].

Fluorine directly affects the bones by two main mechanisms. In mineralized tissues, F is incorporated into apatite crystals in the process of ion exchange, which leads to the formation of fluorapatite [111]. Such conversion results in changes in crystallinity and a reduction in mechanical properties [115]. Fluorapatite is more stable and less soluble in acids, which may result in a higher resistance to bone resorption by osteoclasts. It turns out, however, that its accretion is perpendicular to the collagen fibers, unlike hydroxyapatite. It is also less conducive to binding with proteins. Fluorine also stimulates bone formation by inducing proliferation and activity of osteoblasts. No direct effect of F on osteoclasts has been reported [116]. The ionic form of F stimulates the proliferation of bone cells by directly inhibiting the phosphotyrosyl protein phosphatase activity. This increases total cellular tyrosyl phosphorylation, thus leading to the stimulation of bone cell proliferation [117]. Fluoride also increases the level of bone cell growth factor, such as insulin-like growth factor–1 (IGF-1) and osteoblastic transforming growth factor-1 (TGF-1) [118]. The osteogenic action of F- has been suggested to involve the activation of the mitogen-activated protein kinase (MAPK) [111,119]. The administration of F- in rats increased expression of mRNA of collagen type I alpha 1 chain (COL1A1), alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), which could be blocked by Dickkopf-related protein 2 (DKK-2), an inhibitor of the Wnt/-catenin receptor. Thus, fluoride stimulates osteoblastogenesis by the canonical Wnt pathway [120,121].

Excessive fluoride intake causes skeletal fluorosis—a condition characterized by radiographic bone changes ranging from osteoporosis to osteosclerosis [122].

Histomorphometric examinations in fluorosis revealed an increase in the number of osteoblasts, in the density of the spongy bone, in the thickness of the trabeculae, and in the volume of the osteoid.

The typical features of bone under the influence of fluoride are macular osteocytic sinuses, resulting from a delay in mineralization.

There is also a widening of and an increase in the porosity of the cortical layer, and increased periosteal activity [123].

Excessive fluoride intake may disturb bone turnover, thus affecting the differentiation of osteoblasts and osteoclasts, and induce the development of bone changes [124,125]. This ultimately results in an imbalance between bone formation and bone resorption [111,126,127].

It is suggested that the detrimental effect of fluoride on the skeleton is caused by an overproduction of PTH and activated bone resorption [128,129]. Exposure to F may also modulate PTH secretion, and thereby changes in Ca levels. Zierold and Chauviere [130] documented decreased serum Ca levels after acute hydrofluoric acid inhalation.

In the human body, 93-97% of fluorine is stored in hard tissues, and the rest is accumulated in the organs, including the liver and the kidneys [131].

The highest F levels are observed on the bone surface. The concentration of F in trabecular bone is approximately two to three times higher than in cortical bone. As for cortical bone, the highest F levels are usually found on its surface [127]. The spongy bone was found to be more resistant to the effect of F than the compact bone.

In children, F retention in bones is greater than in adults [132].

It has been found that children and adults exposed to low doses of F compounds accumulate approximately 50% and 10% of the F taken, respectively, in the bone tissue [133].

The half-life of F in hard tissues ranges from several to even 20 years [134].

There are a few studies concerning F concentration in the bones. The accumulation of F in bones is determined, among others, by the duration of exposure, age, sex, as well as bone diseases [135,136].

Higher F is accumulated in female than in male bones [137].

Fluoride gradually accumulates in the bone through life.

Higher levels of F were found in patients over 60 years old than below 60 years of age [137–140]. Based on the available data presented in Table 4, the F concentration in the bones is related to contact with fluoridated water supply or preparations containing F.

Based on the analysis of the concentration of F- in different types on bones, it was noticed that F- levels were highest in the vertebrae (>500 mg kg?1 dw), ribs (100–500 mg kg?1 dw) and the femur (100–450 mg kg?1 dw), and lower in the long bones (100–300 mg kg?1 dw) and the other bones (>120 mg kg?1 dw) [136], (Table 4). Physiological F levels in bones were found to be <550 mg kg?1 dw. The reference value of F accumulated in bones should be kept below 0.4–0.5% bone ash [141].

Table 4 presents the literature data concerning F levels.

---