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Fluoride excess primarily effects dental and skeletal tissues. leading to a condition known as endemic fluorosis. The radiological and clinical features of endemic fluorosis vary in different parts of the world. The aim of this study was to investigate the clinical and radiological features of endemic fluorosis in Turkish patients. Physical examination and radiological investigations were performed in 56 patients with endemic fluorosis and 40 age- and sex-matched controls. Knee osteoarthritis (OA) was the main abnormality in both groups, both clinically and radiologically. The radiological severity of knee OA was greater in the endemic fluorosis group than in controls (P=0.01). Osteophytes at the tibial condyles and superior margin of the patellar articular surface of the femur, polyp-like osteophytes on the non-weight-bearing medial side of the femoral condyle, and popliteal loose bodies were detected more frequently in the endemic fluorosis group than in controls (P=0.0001). We suggest that the presence of atypically located osteophytes in the knees may be a feature of endemic fluorosis in Turkish patients and that endemic fluorosis may increase the severity of OA in the knees.
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ORIGINAL ARTICLE
Serpil Savas áMeltem CË etin áMehmet Akdog
Æan
Nurettin Heybeli
Endemic ¯uorosis in Turkish patients: relationship
with knee osteoarthritis
Received: 16 April 2001 / Accepted: 18 July 2001 / Published online: 10 August 2001
ÓSpringer-Verlag 2001
Abstract Fluoride excess primarily eects dental and
skeletal tissues, leading to a condition known as endemic
¯uorosis. The radiological and clinical features of en-
demic ¯uorosis vary in dierent parts of the world. The
aim of this study was to investigate the clinical and
radiological features of endemic ¯uorosis in Turkish
patients. Physical examination and radiological investi-
gations were performed in 56 patients with endemic
¯uorosis and 40 age- and sex-matched controls. Knee
osteoarthritis (OA) was the main abnormality in both
groups, both clinically and radiologically. The radio-
logical severity of knee OA was greater in the endemic
¯uorosis group than in controls (P=0.01). Osteophytes
at the tibial condyles and superior margin of the patellar
articular surface of the femur, polyp-like osteophytes on
the non-weight-bearing medial side of the femoral con-
dyle, and popliteal loose bodies were detected more
frequently in the endemic ¯uorosis group than in con-
trols (P=0.0001). We suggest that the presence of
atypically located osteophytes in the knees may be a
feature of endemic ¯uorosis in Turkish patients and that
endemic ¯uorosis may increase the severity of OA in the
knees.
Keywords Bone áCartilage áFluoride áEndemic
¯uorosis áKnee joint
Introduction
Endemic skeletal ¯uorosis is a chronic metabolic bone
and joint disease caused by ingestion of large amounts of
¯uoride either through water or rarely from foods of
endemic areas [1]. Although the prevalence of this dis-
ease has decreased considerably, it still occurs in some
parts of the world such as Isparta, an endemic ¯uorosis
area in southern Turkey. A wide range of radiological
features have been described in endemic skeletal ¯uo-
rosis [2, 3, 4, 5, 6, 7, 8]. The main radiological appear-
ances are osteosclerosis, osteopenia, membranous and
ligamentous calci®cation, exostoses, coarse trabecular
pattern, diaphyseal widening, and intermittent growth
lines. Joint pains, some crippling deformities such as
limited spinal movement, thoracic kyphosis and ¯exion
deformities at the hips and knees, bony leg deformities
(genu varum, genu valgum, bowing, wind-swept), and
spinal cord compression due to the vertebral osteoscle-
rosis have been reported as the clinical ®ndings [4, 5, 6,
7, 9, 10, 11, 12, 13, 14].
To the best of our knowledge, endemic skeletal ¯u-
orosis has not been reported previously from Turkey.
Observing a high number of female patients with dental
¯uorosis complaining of knee pain in Isparta led us to
investigate the clinical and radiological features of these
patients.
Patients and methods
Fifty-six patients with endemic ¯uorosis who attended the Su
Èley-
man Demirel University physical therapy and rehabilitation out-
patient clinic for various painful conditions were included in the
study. The clinical diagnosis of endemic ¯uorosis was modi®ed
from the criteria of Wang et al. [2]: (1) living in the endemic ¯uo-
rosis region since birth, (2) having mottled tooth enamel, indicating
dental ¯uorosis, (3) consuming water with ¯uoride levels above
Rheumatol Int (2001) 21: 30±35
DOI 10.1007/s002960100132
S. Savas (&)
Su
Èleyman Demirel University Medical School,
Physical Therapy and Rehabilitation Department,
Isparta, Turkey
M. CË etin
Su
Èleyman Demirel University Medical School,
Radiology Department, Isparta, Turkey
M. Akdog
Æan
Su
Èleyman Demirel University Medical School,
Biochemistry Department, Isparta, Turkey
N. Heybeli
Su
Èleyman Demirel University Medical School,
Orthopaedics and Traumatology Department, Isparta, Turkey
Posta Kutusu 76, 32000, Isparta, Turkey
1.2 ppm (normal 1 ppm), and (4) a urine ¯uoride level greater than
1.5 mg/l (normal <1.5 mg/l).
Forty patients living in a nonendemic region who attended the
same outpatient clinic and had nontraumatic knee pain were ran-
domly selected as controls. The patients and controls were all ur-
ban dwellers and housewives. The medical histories and the main
complaint of the groups were recorded. Patients with metabolic
bone disease or in¯ammatory disease in their medical histories were
excluded. Physical examination was performed in all groups. The
patients' body weight and height were recorded. Body mass index
(BMI) was calculated for each patient as weight (kg)/height (m)
2
.
Diagnosis of genu varum or valgum deformity was made using the
femorotibial angle. This angle is formed by the intersection at the
knee joint of the long axes of the femur and tibia, represented by
appropriate lines drawn on the radiograph. Measurements of 175°,
or 5°valgus, were accepted as normal [15].
Biochemical investigations
Serum samples were analyzed for calcium, inorganic phosphorus,
total alkaline phosphatase, total proteins, albumin, creatinine, and
blood urea nitrogen by standard biochemical methods. Patients
and controls were asked to bring tap water from their houses in
plastic containers. Water, serum, and urine samples were estimated
by using an ion-speci®c electrode (Orion F 94±09).
Radiology
The patients with endemic ¯uorosis had anteroposterior (AP) ra-
diographs made of the forearm, hands, pelvis with the upper end of
the femur, thoracic spine, lumbar spine, knees (anteroposterior, or
AP, and lateral views), and tibia and ®bula (AP and lateral views).
Controls had AP and lateral views of the tibia and ®bula only. All
radiographs were analyzed by two radiologists who were blinded to
each other's ®ndings.
Radiological changes were classi®ed as: (1) existence of radio-
logical knee abnormalities based on the worse knee consisting of
femorotibial osteoarthritis (OA) graded according to the Kellgren
method using a 5-point scale (0±4), osteophyte formation at the
superior and inferior margins of patella, osteophytes on the ante-
rior and posterior parts of the tibial condyles and at the superior
margin of the patellar articular surface of the femur, and popliteal
loose bodies, (2) osteosclerosis, an overall increase in bone density
with thickening of the cortex, and (3) ossi®cation of ligaments,
tendons, and interosseous membranes. De®nite OA was de®ned as
that with a Kellgren score of 2 [16]. Maximum patellar osteophyte
size (grade 3) was determined by measuring with a ruler. Grades
2 were calculated as two-thirds and one-third reductions in the area
of grade 3 [17].
Statistical analysis
Results were given as meanSD. Statistical signi®cance was set at
the 0.05 level. Comparison of the groups was performed using
Student's-ttest in parametric values and the chi-squared test in
nonparametric values. Correlation analysis was performed to assess
the relation between some radiological and the clinical features.
Results
Demographic and clinical features
The endemic ¯uorosis group consisted of 51 female and
®ve male patients and the control group included 34
females and six males. There was no dierence in sex
distribution between the groups (P=0.36). The mean
age of the endemic ¯uorosis group and controls was
54.911.6 years and 57.459.76 years, respectively
(P=0.26). The BMI of both groups were 29.755.08
and 29.364.31, respectively. (P=0.69). The mean
numbers of years since menopause were 12.16.3 in
endemic ¯uorosis patients and 11.356.7 in controls.
There was no dierence between the groups in the
number of mean years since menopause (P=0.5).
The most common complaint of the patients with
endemic ¯uorosis was knee pain (37 patients, 66.1%).
The distribution of complaints of the patients with
endemic ¯uorosis is shown in Table 1.
Table 1 The prevalence of symptoms in the 56 patients with
endemic ¯uorosis
Location N
Knee 37 (66.1%)
Hip 2 (3.6%)
Feet 2 (3.6%)
Low back 3 (5.4%)
Low back and knee 5 (8.9%)
Generalised pain 4 (7.1%)
Shoulder 2 (3.6%)
Neck 1(1.8%)
Fig. 1 Radiograph of knee showing osteophytes on the anterior
and posterior parts of the tibial condyles (thin arrows) and at the
superior margin of the patellar articular surface of the femur
31
None of the patients had thoracal kyphosis, ®xed
knee, or hip ¯exion deformities. Seventeen patients
(30.4%) with endemic ¯uorosis and ®ve controls
(12.5%) had genu varum deformity (P=0.05). The mean
femorotibial angle was 184.63.9°in the right knee and
184.44.2°in the left knee in the endemic ¯uorosis
patients with genu varum deformity. In controls with
genu varum deformity, the mean femorotibial angle of
the right knee was 183.62.6°, and the mean femorot-
ibial angle of the left knee was 183.81.3°. Genu varum
deformity correlated to age (P=0.0001, r=0.48) but not
to BMI (P=0.32, r=0.13) in our patients with endemic
¯uorosis. In controls, genu varum deformity correlated
to BMI (P=0.01, r=0.38) but not to age (P=0.07,
r=0.28). None of the patients in either group had genu
valgum deformity.
Biochemical parameters and ¯uoride levels
Serum total calcium, inorganic phosphorus, and alkaline
phosphatase concentrations were normal in all patients.
The mean ¯uoride level in the drinking water was
signi®cantly higher in patients with ¯uorosis
(2.740.85 mg/l) than in controls (0.710.06 mg/l)
(P<0.0001). Serum and urine ¯uoride levels were
0.100.04 mg/l and 1.960.37 mg/l, respectively, in the
patients with endemic ¯uorosis. These values were sig-
ni®cantly higher than in controls, whose mean serum
and urine ¯uoride levels were 0.030.01 mg/l and
0.370.16 mg/l, respectively (P=0.0001).
Radiology
The main radiological features of the patients with en-
demic ¯uorosis were degenerative changes including
mainly the medial femorotibial and patellofemoral
compartments. Twelve patients (21.4%) with endemic
¯uorosis and eight control patients (20%) had grade 2
OA, 16 patients (28.6%) with endemic ¯uorosis and
three control patients (7.5%) had grade 3 OA, and six
patients (10.7%) with endemic ¯uorosis and one control
patient (2.5%) had grade 4 OA. The OA severity was
greater in the endemic ¯uorosis group (P<0.01).
Osteophytes at the anterior and posterior parts of the
tibial condyles, osteophytes at the superior margin of the
patellar articular surface of the femur (Fig. 1), and
popliteal loose bodies (Fig. 2) were detected more fre-
quently in the endemic ¯uorosis group than in controls.
Fig. 2 Popliteal loose bodies
Fig. 3 Large osteophytes located at the superior and inferior parts
of the patella
32
There was no dierence between groups in the existence
of osteophytes at superior and inferior margins of the
patella (P=0.67). However, these osteophytes were
larger in endemic ¯uorosis patients than in controls
(P=0.001) (Fig. 3).
Twenty-®ve (44.6%) patients with endemic ¯uorosis
had polyp-like osteophytes at the medial non-weight-
bearing margin of the femoral condyle (Fig. 4). This
kind of osteophyte was not detected in controls. Com-
parison of the radiological features of the groups are
summarized in Table 2.
Two patients (3.6%) with endemic ¯uorosis had axial
osteosclerosis (Fig. 5), and ®ve (8.9%) had interosseous
membrane calci®cation on the forearm (Fig. 6). None of
the patients with endemic ¯uorosis had cartilage calci-
®cation or bowing of the tibia or ®bula.
Discussion
In our patients with endemic ¯uorosis, the knee joint
was the most commonly involved joint, both radiologi-
cally and clinically. In skeletal ¯uorosis, involvement of
the axial skeleton is characteristic, and changes are most
marked in the spine, pelvis, and forearm [5, 6, 10, 18,
19]. Knee involvement in endemic ¯uorosis has been
clinically described mainly in children and adolescents as
¯exion deformities [6, 19] and genu varum or valgum
deformities due to the bowing of long bones caused by
osteomalacia, secondary hyperparathyroidism, and
rickets [4, 9, 10, 11]. Not much is known about the ra-
diological features of the knee involvement in endemic
¯uorosis.
Table 2 Comparison of knee radiographs of the patients with endemic ¯uorosis and controls
Fluorosis Controls P
Grades 2 and 3 osteophytes at the superior and inferior margins of the patella 21 (37.5%) 3 (7.5%) 0.001
Osteophyte at the anterior part of the tibial condyle 29 (51.8%) 3 (7.5%) 0.000
Osteophyte at the posterior part of the tibial condyle 27 (48.2%) 2 (5%) 0.001
Osteophyte at the superior margin of the patellar articular surface of the femur 25 (44.6%) 8 (20%) 0.013
Popliteal loose bodies 20 (35.7%) 4 (10%) 0.004
Fig. 4 Polyp-like osteophytes on the medial non-weight-bearing
margin of femoral condyle Fig. 5 Osteosclerosis of the spine
33
It was surprising to see female dominance in an en-
demic region. As OA is particularly common in middle-
aged/elderly females in this geographic region, it is
possible that femorotibial OA was the main problem in
both groups; however, the severity of OA was greater in
patients with endemic ¯uorosis than controls, both
clinically and radiologically. We thought that endemic
¯uorosis might be responsible for the increased severity
of degenerative features. Some of the osteophytes seen in
endemic ¯uorosis patients were located in unusual sites
for OA such as the tibial condyles. Some of the osteo-
phytes were polyp-like and located at the non-weight-
bearing medial side of the medial femoral condyle,
which is atypical for OA. The osteophytes at the supe-
rior and inferior margins of the patella were larger than
the patellar osteophytes seen in controls. These atypical
osteophytes were not seen in the patients with endemic
¯uorosis without knee pain, so we decided that they were
not incidental ®ndings.
Fluoride is a cumulative poison that increases meta-
bolic turnover of the bone in favor of bone formation
[1]. It stimulates bone cell proliferation by directly in-
hibiting osteoblastic acid phosphatase activity [20] and
by prolonging or enhancing the mitogenic signals of
growth factors [21, 22]. Histopathological studies of
bone in ¯uorosis have shown osteoid tissue deposited
irregularly on the trabeculae and cortex, with extension
into muscle attachments [6]. This osteoblastic activity
causes a marked increase in bone formation at the organ
level, causing the production of exostoses, calci®cation
of tendons and ligaments, and osteosclerosis [22]. The
other explanation for the degenerative changes in
the knees of our patients with endemic ¯uorosis may
be the chondrotoxic eect of ¯uoride. Fluoride mainly
aects bone metabolism [21]. However, cartilage is one
of its deposition areas [22, 23]. In an animal study [9], it
was shown that excessive ¯uoride ingestion caused
necrosis of articular chondrocytes, ulcer formation, and
articular calci®cation, which causes a mushroom-like
appearance.
Radiological changes in industrial ¯uorosis suggest
that physical strain on bones, ligaments, and joints plays
an important role in the development of the lesions [24,
25]. The reason for the selective knee involvement in our
patients may be ¯uoride's selectivity for the most stres-
sed joints [26, 27]. Sitting habits like hyper¯exion sitting
and ritual worship in our population may stress the
knees and cause vulnerability to ¯uorotic damage.
In our study, some radiological ®ndings such as
osteosclerosis, interosseous membrane calci®cation, or
ligament calci®cation, which were accepted as hallmarks
of skeletal ¯uorosis, were not found as frequently as in
the literature [1, 10, 22]. We also did not observe severe
crippling deformities. The causes for the clinical and
radiological dierences may be due to several factors
such as the nature, dose, duration of ¯uoride exposure,
age, sex, dietary habits, or their combination [1, 3, 6, 10,
18]. The mean ¯uoride level in the drinking water of our
region was 2.7 ppm. Osteosclerosis and interosseous
membrane calci®cation have usually been reported in
levels over 4 ppm [6, 10]. The total quantity of ingested
¯uoride is reported as the single most important factor
determining the clinical course of this disease, which is
characterized by immobilization of joints of the axial
skeleton and of major joints of the extremities [1, 6].
Jolly [10] suggested that crippling deformities are usually
associated with drinking water with a 10 ppm level for
10 to 20 years. However, the concentration of ¯uoride
alone was not found to be responsible for the incidence
of skeletal ¯uorosis. In dierent areas with similar ¯u-
oride content in the drinking water [10, 28] and even in
the same endemic area where the source of drinking
water was the same, the incidence of the disease and
extent of bone changes diered, and X-ray ®ndings of
bone ¯uorosis were signi®cantly dierent [7, 10]. Arnala
suggests the variability of individual susceptibility to
¯uoride [29]. Another important cause is nutritional
status. It is accepted that poor nutrition and low calcium
intake enhance the deleterious eects of ¯uoride [3, 4,
14, 18]. As we did not assess the nutritional status of the
patients, we cannot clearly state that poor nutrition is
responsible for the abnormal radiological ®ndings in our
patients with endemic ¯uorosis.
We suggest that atypically located osteophytes in the
knees may be a feature of endemic skeletal ¯uorosis in
Fig. 6 Ossi®cation of interosseous membrane
34
Turkish patients. We also suggest that endemic ¯uorosis
may increase the severity of knee OA. Further studies
are needed in order to understand the exact mechanism
of bone and cartilage changes in the knees of patients
with endemic ¯uorosis.
Acknowledgement We are grateful to Dr. Tayfun Turgut for his
expert opinion on X-rays.
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... and even worsen OA's symptoms [18,19]. Several studies have provided clues to a probable link between fluoride and OA. ...
... Additionally, another ecological study in which 56 endemic fluorosis patients were matched in age and sex to 40 non-endemic control patients suggested that endemic fluorosis may increase the severity of knee OA and cause OA before SF is obvious. And the radiological severity of knee OA and osteophytes sign were significantly higher in endemic fluorosis group than in control group [19]. In conversely, US health authorities still assume that fluoride does not cause arthritis symptoms before the traditional bone changes (osteosclerosis) of fluorosis are evident on X-ray [24]. ...
... For all the 618 consenting participants, a single standing, anteroposterior radiograph of both the knee and elbow was performed in the Baicheng central hospital. The knee and elbow OA subtypes were selected in this study because both joints sites are the most frequently reported in the endemic area [19,29]. Also, knee OA is the most frequent in normal situation and again with severe complications [30,31]. ...
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Fluoride is an environmental chemical that has adverse effects on articular cartilage, probably increasing osteoarthritis (OA) risk. However, this association still needs more epidemiological evidence to clarify. The aim of this study was to determine the relationships between chronic fluoride exposure and OA risk among the residents living in Tongyu County, China, 2019, with a frequency-matched case–control study (186 OA patients and 186 healthy participants). The results showed that urinary fluoride (UF) (2.73 ± 1.18 mg/L) was significantly higher in OA patients compared to the controls (2.35 ± 1.24 mg/L) (p < 0.002). After adjustment, the odds ratios (ORs) with 95% confidence intervals (95% CIs) between the OA risk and fluoride were calculated by the unconditional logistic regression. In full sample analysis, a 1 mg/L increase in UF level was associated with a 27% higher risk of OA (1.06–1.52, p = 0.008), and 4th quarter’s participants were associated with higher risk when compared to 1st quarter (OR: 2.46, 95% CI: 1.34–4.57, p = 0.003). In stratified analysis, compared to 1st quarter, 4th quarter’s participants were 4 times more likely to have OA (1.86–8.82, p < 0.001) in the non-obese group and 7.7 times more likely to have OA (2.58–25.05, p < 0.001) among adults ≤ 60 years. In conclusion, excessive exposure of water fluoride may increase OA risk, and could have more impact on the specific population such as non-obese, and adult aged ≤ 60 years.
... and even worsen OA's symptoms [18,19]. Several studies have provided clues to a probable link between fluoride and OA. ...
... Additionally, another ecological study in which 56 endemic fluorosis patients were matched in age and sex to 40 non-endemic control patients suggested that endemic fluorosis may increase the severity of knee OA and cause OA before SF is obvious. And the radiological severity of knee OA and osteophytes sign were significantly higher in endemic fluorosis group than in control group [19]. In conversely, US health authorities still assume that fluoride does not cause arthritis symptoms before the traditional bone changes (osteosclerosis) of fluorosis are evident on X-ray [24]. ...
... For all the 618 consenting participants, a single standing, anteroposterior radiograph of both the knee and elbow was performed in the Baicheng central hospital. The knee and elbow OA subtypes were selected in this study because both joints sites are the most frequently reported in the endemic area [19,29]. Also, knee OA is the most frequent in normal situation and again with severe complications [30,31]. ...
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DNA methylation is an epigenetic modification of genome that is involved in many human diseases. Recent studies revealed DNA methylation may be associated with fluorosis. This study was aimed to evaluate the dose-response effect of fluoride on DNA methylation in human and rat blood. A commercial ELISA kit was employed to evaluate 5-methylcytosine (5-mC) level of genome in human and rat blood. A total of 281 subjects were enrolled in this study and divided into four equal-size groups by the quartile of fluoride in drinking water. The difference of 5-mC among the four groups was significant. The U-shaped relationship was found between fluoride and 5-mC in the population. The U-shaped curve was also observed in the rats with three months of fluoride treatments. Taken together, these results clue the disruption of DNA methylation in mammals may has a certain association with fluoride in natural exposures.
... The scholars in India, Turkey and China conducted the smaller sample size of ecological studies to explore the link between fluoride and OA. In 2001, Turkish scholars reported that endemic fluorosis may increase the severity of KOA in an ecological study with 56 endemic fluorosis patients and 40 non-endemic control patients (Savas et al., 2001). An ecological study conducted in Gaomi City, China, in 2006 found that the more frequency of OA symptoms was reported in the population living in the areas with higher water fluoride (Ge et al., 2006). ...
... The above statistical results are consistent with the previous investigation results of our research group, that is, fluoride in drinking water can increase the risk of KOA (Sowanou et al., 2022). The same findings were found in a case-control study conducted in Turkey (Savas et al., 2001), which, more notably, found strong evidence of an association between fluoride and OA in individuals without signs of skeletal fluorosis. In our study, the proportion of patients with skeletal fluorosis is relatively small, and the confounding influence of skeletal fluorosis is basically excluded. ...
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Previous studies indicate that fluoride in drinking water has a toxic effect on cartilage and skeleton, which triggers osteoarthritis (OA) of which the most frequent is knee OA (KOA). A cross-sectional study was conducted to assess the association between fluoride exposure and KOA among 1128 subjects. Water fluoride (WF) and urinary fluoride (UF) were chosen as external exposure (internal exposure) of fluoride. Logistic regression analysis showed that an increased fluoride exposure was a risk factor for KOA (WF: OR = 1.318, 95% CI 1.162–1.495, p < 0.001; UF: OR = 1.210, 95% CI 1.119–1.310, p < 0.001). After adjusting for covariates, the risk of KOA in the 4th quartile (Q) of WF was twice that of the 1st Q (OR = 2.079, 95% CI 1.448–2.986, p < 0.001). The risks of KOA in the 2nd Q, 3rd Q and 4th Q of UF were 1.6, 1.5, and 2.9 times higher than in the 1stQ (OR = 1.597, 95% CI 1.066–2.393, p = 0.023; OR = 1.560, 95% CI 1.043–2.333, p = 0.030; OR = 2.897, 95% CI 1.957–4.288, p < 0.001). The population aged < 60 exposed to the 4th Q of WF (or UF) had a higher risk than the population exposed to the 1st Q of WF (or UF) (ORWF = 1.958, 95% CI 1.249–3.070, p = 0.003; ORUF = 2.923, 95% CI 1.814–4.711, p < 0.001). With increasing UF by Q, the male had a risk of KOA. In conclusion, excessive fluoride dose in drinking water could increase the risk of KOA. Especially, the population with aged < 60, male and obesity more likely to having KOA when they exposed to same higher fluoride.
... Ha precursors are octacalcium phosphate (OCP) and in the case of long-term high F − exposure, the F − ion will be accumulated into bone and teeth by the formation of fluorapatite (FaP) (Ca 5 (PO 4 ) 3 F) instead of Ha. 55,56 Fluorine can in certain endemic areas reach toxic levels in drinking water resulting in severe growth deformities in children (Figure 6a and 6b). in adults, fluorine causes 'marble bone disease' with severe secondary osteoarthritis (Figure 6c and 6d). 57,58 The consumption of drinking water with a fluoride concentration higher than the world Health Organization's (wHO) recommended limit of 1.5 mg/l 59 is a health concern for more than 250 million people today worldwide and an endemic causing serious disability in, for example, india. 60 in many industrial countries, although controversial, 61 fluorine is added to drinking water. ...
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Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health. Cite this article: Bone Joint Res 2020;9(10):709–718.
... Tartatovskaya concluded that fluoride exposure could exacerbate the degenerative effect of physical stress on joints, with or without the presence of radiologically detectable skeletal fluorosis 8 . Savas et al in 2001 found strong evidence of a fluoride-osteoarthritis link in individuals who did not have tell-tale sign of skeletal fluorosis 9 . Hileman reported that because the clinical symptoms mimic arthritis, the early clinical phases of skeletal fluorosis is easily misdiagnosed 10 . ...
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Introduction: Fluorosis has been associated with an increased risk of degenerative changes in the knee. Multiple studies have found an association between arthritis and elevated fluoride levels. We aim to delineate if elevated fluoride level has any direct correlation with the degree of radiological grading and clinical symptoms in knee arthritis. Materials and methods: A cross-sectional study of 80 knee arthritis patients was conducted from February 2017 to April 2018. Serum fluoride levels were measured and patient's pain scores, WOMAC scores and radiological grading were correlated with the elevated fluoride levels. Results: In our study, 30 out of 80 patients had increased serum fluoride level. Statistically significant differences were noted in VAS score, WOMAC score and Kellgren and Lawrence radiological grades between patients with normal serum fluoride level and those with elevated fluoride level. Conclusion: There is an increased risk of knee arthritis in patients with elevated blood fluoride levels and patients with increased fluoride levels are associated with more severe symptoms and radiographic disease.
... In its early stages, symptoms may resemble those of arthritis (CDC 2006). Endemic fluorosis may increase the severity of osteoarthritis of the knees, (Savas, 2001) increased brittleness of bones with increased fluoride exposure (Turner, 1997). According to the National Toxicology Program, "the preponderance of evidence" from laboratory `invitro' studies indicates that fluoride is an mutagen, and it can cause genetic damage. ...
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Fluoride is anion F " , the reduced form of fluorine. Inorganic fluorine containing compounds are called fluorides. Fluoride, like other halides, is a monovalent ion. Concentration of fluoride in water can be detected by SPADNS method. Samples collected from some areas of Kanpur city, like Jajmau, Juhi and Anwarganj, were analysed for fluoride by this method. Observed value of fluoride from Anwarganj area ranged between 1.0 mg/L to 1.08 mg/L. In some samples of Jajmau area ,fluoride concentration was 0.1mg/L to 0.3 mg/L that can create the problem of dental carries (i.e tooth decay). Fluoride concentration was observed 0.58 mg/L in some areas of Juhi. Although in most samples of these areas, fluoride concentration was almost in the safe limit but fluoridation may be needed in those areas where fluoride concentration was below the permissible or acceptable limit prescribed by WHO as well as Indian standards (i.e, 1.5mg/L).
Article
The prevalence of osteoarthritis (OA) in Tibetans is higher than that in Han, while Tibetans have a habit of drinking brick tea with high fluoride. A cross-sectional study was conducted to explore the association between fluoride exposure in drinking brick tea and OA. All subjects were divided into four groups by the quartiles (Q) of tea fluoride (TF) and urine fluoride (UF). ROC was plotted and OR were obtained using logistic regression model. The prevalence of OA in the Q3 and Q4 group of TF were 2.2 and 2.7 times higher than in the Q1 group, and the prevalence of OA in the Q2, Q3 and Q4 group of UF were 3.2, 3.5, and 4.1 times higher than in the Q1 group. ROC analysis showed the cutoff values were 4.523 mg/day (TF) and 1.666 mg/L (UF). In conclusion, excessive fluoride in drinking brick tea could be a risk factor for developing OA.
Chapter
In low concentration, fluoride is considered a necessary compound for human health. Long-term exposure to excessive content of fluoride is the reason for a disease called fluorosis. In more than 25 countries and regions in the world, the excessive fluoride content in the environment has led to the occurrence of chronic endemic fluorosis. Fluorosis not only damages bones and teeth, but also causes extensive pathological damage to human organs/systems. The pathogenesis of endemic fluorosis has not been fully elucidated. Many studies have shown that the mechanism of chronic fluorosis causing extensive pathological damage in the body may be oxidative stress induced by accumulation of fluoride. As an essential intermediate process that causes inflammation, it is such oxidative stress causes extensive damage to the body’s tissues. At present, there are few reports about the pathological role of inflammation in the pathogenesis of endemic fluorosis. Therefore, this section outlines the pathological role of inflammation in the pathogenesis of endemic fluorosis and focuses on the effects of inflammation on organs/systems (such as kidney, thyroid, cardiovascular, brain, and reproductive system) during fluoride exposure, together with its possible mechanism of injury.
Chapter
References: Brickley, M.B. Ives, R. & Mays, S. (2020). The Bioarchaeology of Metabolic Bone Disease, Second Edition
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This summarizes current knowledge of the benefits and risks of fluoride ingestion. The preponderance of evidence indicates that fluoride can reduce the incidence of dental caries and that fluoridation of drinking water can provide such protection. Due to the ubiquitous nature of exposures to fluoride sources other than drinking water, it is currently impossible to draw firm conclusions regarding the independent effect of fluoride in drinking water on caries prevalence using an ecologic study design. Moderate dental fluorosis occurs in 1 to 2% of the population exposed to fluoride at 1 mg/l in drinking water and in about 10% of the population at 2 mg/l; moderate/severe fluorosis occurs in variable percentages ranging up to 33% of the population exposed to fluoride at 2.4 to 4.1 mg/l in drinking water. The issue of whether moderate or severe dental fluorosis represents an adverse health effect is still controversial. There is no evidence of skeletal fluorosis among the general U.S. population exposed to drinking water fluoride concentrations lower than 4 mg/l. Radiographically detected osteosclerosis after chronic exposure to fluoride in drinking water at 8 mg/l was not associated with clinical symptoms. Reports of crippling skeletal fluorosis associated with low concentrations of fluoride in drinking water in tropical countries have been attributed to other dietary factors. The available data suggest that some individuals may experience hypersensitivity to fluoride-containing agents. Further studies on hypersensitivity are required. There is no evidence of increased incidence of renal disease or renal dysfunction in humans exposed to up to 8 mg fluoride per liter in drinking water. Structural changes in kidneys of experimental animals have been detected at doses exceeding 1 to 5 mg fluoride per kilogram per day. Based on four case reports, individuals with renal insufficiency who consume large volumes of naturally fluoridated water at 2 to 8 mg/l are possibly at increased risk of developing skeletal fluorosis. Studies on the effects of fluoride in individuals with renal insufficiency are needed. There is no evidence that chronic exposure to concentrations of fluoride reported to be greater than 2 mg/l in drinking water increases human cancer mortality or incidence. A study of lifetime exposure to fluoride on cancer incidence in rats and mice has been completed, but assessment for cancer has not been completed. There is no evidence that fluoride is genotoxic except in some in vitro assays at cytotoxic concentrations. There is no in vivo evidence that fluoride affects human cellular enzyme activities.(ABSTRACT TRUNCATED AT 400 WORDS)
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The results of surveys carried out between 1976 and 1985 in the fluorosis-endemic area of the Ethiopian Rift Valley is summarised, with emphasis on the neurological complications resulting from the crippling osteofluorosis. The neurological manifestations in the forms of myelopathy with and without radiculopathy (respectively 72% and 28%) occurred after exposure to high fluoride (greater than 4 ppm) for longer than 10 years. These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal. Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence. The dilemma of these medical problems in relation to the agro-industrial economic developments of the Ethiopian Rift Valley is discussed.
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A middle-aged male resident of Benghazi, northeastern Libya, with radiological features of skeletal fluorosis associated with cervical radiculomyelopathy is reported. This is believed to be the first documentation of such a disorder from this non-tropical, non-endemic region.
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Fluoride (F) is a potent inhibitor of osteoblastic acid phosphatase activity with an apparent Ki value (10 to 100 mumol/L) that corresponds to F concentrations that increase bone cell proliferation and bone formation in vivo and in vitro. This high sensitivity of acid phosphatase to F inhibition appeared to be specific for skeletal tissues. Mitogenic concentrations of F did not increase cellular cAMP levels but significantly stimulated net protein phosphorylation in intact calvarial cells and in isolated calvarial membranes. These concentrations of F also stimulated net membrane-mediated phosphorylation of angiotensin II (which contains tyrosyl but no seryl or threonyl residues), suggesting that some of the F-stimulated protein phosphorylations could occur on tyrosyl residues. F had no apparent effect on thiophosphorylation of membrane proteins, suggesting that the F-stimulated net protein phosphorylation in bone cells was probably not mediated via activation of protein kinases. Orthovanadate or molybdate at concentrations that inhibit bone acid phosphatase activity also stimulated bone cell proliferation, supporting the idea that inhibition of bone acid phosphatase would lead to stimulation of bone cell proliferation. Mitogenic concentrations of F potentiated the mitogenic activities of insulin, EGF, and IGF-1 (ie, growth factors the receptors of which are tyrosyl kinases) to a greater extent than they potentiated the action of basic FGF (a growth factor that does not appear to stimulate tyrosyl protein phosphorylation). Based on these findings, a model is proposed for the biochemical mechanism of the osteogenic action of F in which F stimulates bone cell proliferation by a direct inhibition of an osteoblastic acid phosphatase/phosphotyrosyl protein phosphatase activity, which in turn increases overall cellular tyrosyl phosphorylation, resulting in a subsequent stimulation of bone cell proliferation.
Article
Bone fluoride content (BFC) was measured and histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores from 29 patients (16 men, 13 women, aged 51 +/- 17 years) suffering from skeletal fluorosis due to chronic exposure to fluoride. The origin of the exposure, known in 20 patients, was either hydric (endemic or sporadic) or industrial, or in a few cases iatrogenic. Measured on calcined bone using a specific ion electrode, BFC was significantly high in each specimen (mean +/- SD; 0.79 +/- 0.36% on bone ash). The radiologically evident osteosclerosis observed in each patient was confirmed by a significant increase in cancellous bone volume (40.1 +/- 11.2% vs. 19.0 +/- 2.8% in controls, p less than 0.0001). There were significant increases in cortical width (1292 +/- 395 mcm vs. 934 +/- 173 mcm, p less than 0.0001) and porosity (14.4 +/- 6.4% vs. 6.5 +/- 1.7%, p less than 0.002), but without reduction of cortical bone mass. Cancellous osteoid volume and perimeter, as well as width of osteoid seams, were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost three-fold greater than that noted in cancellous eroded perimeter. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, mineralization lag time was significantly increased. The fluorotic group had a greater number of osteoblasts than controls with a very high proportion of flat osteoblasts. The ultrastructural characteristics reflecting the activity of the bone cells were clearly visible on electron microscopy. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. On stained sections and microradiographs, bone tissue showed typical modifications for skeletal fluorosis (linear formation defects, mottled bone). The volume of cancellous interstitial mineralization defects and the proportion of mottled periosteocytic lacunae were markedly increased in skeletal fluorosis. These two parameters were significantly correlated together but neither of these was significantly correlated with BFC. Renal function did not significantly influence the changes in BFC and histomorphometry of fluorotic patients. Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and a great number of osteoblasts with a high proportion of flat osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
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We report a case of spinal cord compression in a Mexican immigrant due to vertebral osteosclerosis from chronic fluoride intoxication. Endemic fluorosis is acquired through drinking water. Groundwater sources with high fluoride content occur worldwide. The epidemiology, metabolism, and clinical features of fluorosis are reviewed. Greater physician awareness of this entity is important to identify correctly patients with this unusual and potentially devastating clinical disorder.