Correlations between bone metabolism biomarkers and fluoride exposure in adults and children.

Endemic fluorosis is a major global public health concern, still affecting approximately 200 million individuals in 25 countries in the 21st century [1]. It can be classified into three types based on the source of fluoride intake: drinking water, brick tea, or coal-fired pollution [2]. In China, drinking-water-associated fluorosis is the most common type, affecting a large proportion of the population in numerous provinces [3]. Fluorine is an essential trace element in the human body, with dual effects on bone formation and absorption. Fluorine can enhance osteoblast activity and cause bone sclerosis while inducing osteoporosis by increasing bone resorption [4]. Hydroxyl ions in outer layer of tooth enamel can be replaced by F^? through moderate fluoride intake (0.5–1.0 mg/L) [5]. This conversion transforms hydroxyapatite into fluorapatite, effectively preventing dental caries and treating osteoporosis [6]. However, excessive fluoride intake can alter bone and teeth mineralization, leading to diseases characterized by dental fluorosis and skeletal fluorosis as the main clinical features [7], [8]. These changes in mineralization are associated with the risk of osteoporosis and osteosclerosis [9], reducing bone density and joint mobility [10]. Monitoring fluoride levels and exploring changes in bone metabolism associated with fluoride in the body are crucial due to the close proximity of the toxic dose of fluoride exposure to the safe dose [11].

Serum alkaline phosphatase (ALP) is mainly produced by osteoblasts and transported to the liver through the blood. ALP levels are commonly used to monitor liver and bone disorders [12]. During osteogenesis, bone ALP (BALP) hydrolyzes phosphate esters to produce the phosphoric acid necessary for hydroxyapatite deposition, thereby promoting bone formation and mineralization. Since BALP is secreted by osteoblasts, serum BALP levels can be used to monitor skeletal disorders [13]. Osteocalcin (OCN) is a non-collagenous protein consisting of 49–50 amino acids secreted by osteoblasts. Monitoring serum OCN levels is essential for the diagnosis of osteoporosis [14]. Calcitonin (CT) reduces the serum Ca²⁺ concentration by inhibiting the flow of Ca²⁺ from the bones to the blood, thereby enhancing bone strength [15]. CT is clinically used for treating hypercalcemia, osteoporosis, and other bone metabolic disorders [16]. Parathyroid hormone (PTH) is secreted by the parathyroid glands. Its production and secretion are regulated by the hypothalamic–pituitary–thyroid axis. B-CrossLaps (?-CTX) are fragments released into the blood during bone remodeling when collagen degrades, indicating the degree of bone resorption and loss [17].

Despite various biomarkers being reported in previous studies, the associations between fluoride and bone metabolism indicators are still controversial. A study on animals found that mice and sheep showed an increase in serum OCN levels under the same fluoride exposure, while dogs exhibited a decrease [18], [19]. Similarly, an epidemiological study on postmenopausal women revealed that continuous fluoride exposure led to increased serum OCN levels [20]. ALP, as the important marker of bone metabolism, has also been attracting widespread attention from researchers. An experiment in vitro demonstrated that exposure to 10 mg/L of fluoride resulted in an increase in ALP secretion. However, when the fluoride concentration reached 400 mg/L, there was a significant decrease in ALP concentration [21]. Another animal experimental study found that the highest proliferation of osteoclasts occurred at a fluoride concentration of 50 mg/L, while the highest serum ALP concentration was observed at a fluoride exposure concentration of 100 mg/L [22], which suggests that ALP can serve as a sensitive indicator of fluoride-induced bone metabolism. Another epidemiological study found that both lower and higher UF concentrations corresponded to lower serum ALP concentrations [23]. We therefore believe that there may be a complex nonlinear dose-effect relationship between ALP and UF concentrations. Similar issues also exist with other bone metabolism indicators [24], [25], [26].

To address this issue, we conducted an epidemiological study using urinary fluoride (UF) concentration as an indicator of fluoride exposure levels in the population [27], [28] to explore the relationship between fluoride exposure and bone metabolism. In addition, we also included a wide range of clinical classical bone metabolism indicators and controlled the living areas of participants to make our results more convincing.