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Skeletal  Fluorosis

- Dr. D. Raja Reddy, F.R.C.S., F.R.A.C.S. Apollo Hospital &
- Dr. Srikanth R.Deme, F.R.C.S.C.

 

 

Introduction: Fluorine, a gaseous element is a halogen which being most electronegative  and reactive of all elements does not occur in free form in nature. This element was isolated in 1886 by Nobel laureate Henri Moissan and it combines directly with most elements and indirectly with few to form fluorides. Fluorides are ubiquitous in nature and are present in rocks, soil, water, plants, foods and even air.

The relationship between fluoride and dental caries was first noted in the early part of the 20th century when it was observed that residents of certain areas of U.S.A. developed brown stains on their teeth. These stained teeth, though unsightly were highly resistant to dental decay and caries (Black and May 1916). In the 1930's it was discovered that the prevalence and severity of this type of mottled enamel was directly related to the amount of fluoride in the water (Smith et al. 1931). Subsequently it was recognized that fluoride consumption in optimal amounts in the water supply imparted protection against the development of dental caries without staining the teeth (Dean 1938).  Another benefit of fluorides is that the incidence of osteoporosis seems to occur less frequently in regions with high fluoride content in water than in those in which the inhabitants consumed little fluoride. Although, the importance of this element to normal mineralization of hard tissues and formation of caries resistant enamel has been recognized, there has been as yet no conclusive evidence proving that it is an essential element for human health (McClure 1970). Indeed, fluoride deficiency syndrome is yet to be described.  This may be due to the fact that human body requirement of this micronutrient must be small, which is met with naturally through food and water. Excessive ingestion of fluoride through water, food or dust causes acute toxicity or a debilitating disease called 'fluorosis' a term coined and first used by Cristiani and Gautier in 1925. Acute fluoride intoxication is rarely seen and results most frequently from accidental ingestion of large amounts of fluoride compounds. The acute lethal dose of fluoride for the 70 kg man is 2.5-5.0 grams. Chronic fluoride poisoning is more common and can affect animals as well as humans.  Excessive intake during pre-eruptive stage of teeth leads to dental fluorosis and further continued ingestion over years and decades causes bony or skeletal fluorosis. Lastly crippling disease produces neurological manifestations. A disease in animals called 'gaddur' believed to have arisen from fluoride intoxication caused by periodic volcanic eruptions that have been taking place since 1000 AD is mentioned in Icelandic literature (Roholm 1937). A disease of the teeth and bones of horses and cattle called 'darmous' was known to have been prevalent in North African coast for centuries and later came to be identified as one caused by fluorides (Velu 1933).

Feil first mentioned fluorosis in humans as an occupational disease in 1930. This was substantiated when the occurrence of skeletal fluorosis in cryolite miners in Denmark was reported (Moller and Gudjonsson 1932). Skeletal fluorosis was next reported as a disease endemic to an area in India (Shortt et al 1937).

Their study led to the publication of first reports of neurological manifestations of fluorosis in late stages. Subsequently cases of endemic and industrial fluorosis have been reported from various parts of India, Asia, Africa, Europe, North and South America ( Raja Reddy 1979). Endemic fluorosis is usually restricted to tropical and subtropical areas, and is frequently complicated by factors such as calcium deficiency or malnutrition. Endemic fluorosis is widely prevalent in China, India, Middle east, North Africa, Ethiopian rift valley and other parts of Africa. Sixty odd industries use fluorides and hence pollution can occur in them if proper precautions are not taken.

High incidence of endemic fluorosis in India is due to the fact that large areas of the country contain water supplies having high levels of fluoride.

All states of India except northeast reported cases of fluorosis and 25 to 30 million people are exposed to high fluoride intake and half a million suffer from skeletal fluorosis. In China 300 million people are living in endemic areas of fluorosis of whom 40 million have dental fluorosis and 3 million suffer from skeletal changes (Li and Cao 1994).

Metabolism of fluoride:
Biological effects of fluoride intoxication are related to the total amount of fluoride ingested whatever the source be it food, water or air.

Sources of fluoride:
1. Foods
: Nearly all foods contain small quantities of fluoride and the total daily intake through any average human diet is small except in endemic regions. In certain endemic regions of India the fluoride content of vegetables and food may be very high (Chari et al 1974). The contribution of food to the total daily intake of fluoride varies from region to region. Staple diets rich in Sorghum, Ragi or Bajra containing high silicon besides fluoride seem to aggravate fluoride toxicity in some endemic areas of India (Pandit et al 1940;Anasuya Das 1996).

2. Water and Beverages:
In case of natural waters, the variation in the fluoride content from region to region is dependent upon such factors as the source of water, type of geological formation and the amount of rainfall. Surface waters generally have low fluoride while ground waters may have high concentrations of fluoride as has been found in many parts of the world. The highest fluoride concentration of 28.9 PPM was reported from India (Chari et al 1974). The fluoride content of seawater varies from 0.8 to 1.4 PPM, which explains why the fluoride content of diet rises when seafoods are consumed. Among beverages tea has an exceptionally high fluoride content which varies in different brands from 122-260 PPM or more. Each cup of tea may supply 0.3-0.5 mg of fluoride. Bottled beverages, which are increasingly being consumed around the world, have a variable and some have high content of fluoride and should be considered as additional sources of fluoride.

The fluoride intake dependent upon consumption of drinking water and beverages is determined by such factors as body size, physical activity, food habits and variations in atmospheric temperature and humidity (Galagon and Vermillon 1957). That is why in tropical countries like India, the daily fluoride intake is very high. Farm laborers drink lot of water from wells and naturally have high fluoride intake and are at risk of developing fluorosis.

3. Air: The atmosphere has a very low fluoride content and in 97% of non-urban areas fluoride is hardly detectable. The fluoride content of atmosphere is seen to have risen wherever there is volcanic action or industrial activity.  Volcanic fumarole vapors have high concentration of fluoride and industrial emissions from those engaged in mining or manufacture of fluoride containing minerals may be hazardous.  Low-grade coal has high levels of fluoride and smoke may be a souce of fluoride pollution.

Total daily fluoride intake:  The fluoride contents from all the sources determine the human intake of fluoride. In majority of endemic areas around the world, the main contribution is from water and only in few areas of India and China significant amounts come from foods and rarely the polluted air is the culprit.  The estimated range of safe and adequate intake of fluorides for adults is 1.5 to 4.0 mg per day and it is less for children and those with renal disease. The daily intake of fluoride in endemic regions varies from 10 to 35 mg and can be even higher in summer months.

Absorption of fluorides: Soluble inorganic fluorides ingested through water and foods are almost completely absorbed and also those inhaled from the respiratory tract.  But absorption of less soluble inorganic and organic fluorides varies from 60-80% (Cremer and Buttner 1970). Fluorides are absorbed from the gastro-intestinal tract by a process of simple diffusion without any mechanism of active transport being involved. Various dietary components apparently influence the absorption of fluoride from the gut. It has been noticed that salts of calcium, magnesium and aluminum when added to diet reduce the quantum of fluoride absorption on account of the formation of their less soluble compounds.  This is the reason why waters with high calcium and magnesium content check the incidence of fluorosis, as indicated by epidemiological studies (Jolly et al 1969).  Therefore, it is to be expected that all other factors being equal, the incidence of skeletal fluorosis would be less where the calcium and magnesium content of drinking water is high (Raja Reddy1985).  It is noteworthy that administration of magnesium salts (serpentine and magnesium hydroxide) to patients suffering from fluorosis and experimental animals has increased the fecal and urinary excretion of fluorides. Similarly, increased absorption of fluoride from gastrointestinal tract ensues from the addition of substances like phosphates, sulphates and molybdenum to the diet and these can increase fluoride toxicity (Ericsson 1968).

Distribution of fluorides:
About 96-99% of the fluoride retained in the body combines with mineralized bones, since fluoride is the most exclusive bone seeking element on account of its affinity for calcium phosphate (Armstrong and Singer 1970). But it has been noticed that there is no significant retention of it in the body if very small quantities of fluorides are ingested (McClure et al 1945). In fact, there was no discernible retention of fluoride when upto 4-5 mg was ingested daily. But when more than 5 mg were ingested about half of it appeared to have been retained by the skeleton and rest excreted through urine. Observations show that after absorption from the gut fluoride enters the circulation, the plasma fluoride accounting for the three-fourths of the total amount of fluoride found in the whole blood and cells for the rest.  Fluoride in plasma exists in free ionic and bound forms, the latter bound to the serum albumin forming about 85% of the total amount fluoride in plasma (Taves 1968). Plasma fluoride in normal individuals in non-fluoridated areas ranges from 0.14-0.19 PPM and is higher in fluorotic patients (Singer and Armstrong 1969).  Newer methods, which only measure ionic component of plasma fluoride levels are lower and range between 0.004-0.008 PPM when drinking water contained traces of fluoride and varied from 0.1-0.02 when water was fluoridated. Plasma fluoride concentrations tend to increase slowly over the years.  It is seen that plasma levels of fluoride do not fluctuate widely despite a wide variation of fluoride levels in drinking water presumably because of the action of some regulatory mechanisms, which have not yet been clearly identified (Singer and Armstrong 1961). The sequestration of fluoride into the skeleton, urinary excretion and loss sustained through sweat help in regulation of plasma fluoride. The levels of fluoride in most soft tissues of the body are lower than 1 PPM but are higher than those of plasma. The fluoride content of brain is 0.4-0.68 PPM and the concentration in C.S.F. is 0.1 PPM, which is lower than that of plasma (Hodge and Smith 1965).

The uptake of fluoride by the skeleton is very rapid and depends upon the vascularity and the rate of its growth.  The fluoride uptake of young bones is faster than that of mature bones.  The fluoride is incorporated more readily in the active, growing and cancellous areas than in the compact regions.  It has been observed that skeletal fluoride concentration increases almost proportionately to the amount of fluoride ingested and the duration of its ingestion (Spencer et al 1975). The amount of fluoride present in various bones of same skeleton differs from bone to bone with pelvis, vertebrae registering higher fluoride content than limb bones.  Even in the limb bones amount of fluoride deposited in them depends upon the activity of muscles attached to them. In caged monkeys fluoride content of upper limb bones is more than the lower limb bones. It is this increase in the fluoride content of skeleton that provides the most reliable clue to excessive fluoride intake.  The other indicators such as urine and soft tissue levels, which manifest wide fluctuations, cannot be relied upon. Once incorporated into the hard tissues, the fluoride is retrievable, though with difficulty and entails an extremely slow process of osteoclastic resorption spread over many years.

Excretion of fluorides:
Feces: 
Fluoride present in feces results from two sources: the ingested fluoride that is not absorbed and the absorbed fluoride that is excreted into the gastrointestinal tract. About 10-25% of daily intake of fluoride is excreted in the feces.

Urinary:
The elimination of absorbed fluoride occurs almost exclusively via the kidneys. Urinary fluoride in normal individuals fluctuates widely between 0 and 1.2 PPM with an average of about 0.4 PPM when fluoride content of drinking water is 0.3PPM (Truhant and Lick 1968). Urinary levels of fluoride are higher in individuals exposed to higher intake of fluoride. The renal clearance of fluoride is directly related to urinary PH, and under some conditions, to urinary flow rate. In alkaline urine the fluoride is present in ionic form and hence its renal clearance is rapid. In the acidic urine on the other hand, fluoride is present in nonionic form (HF) and hence it is rapidly reabsorbed in renal tubules. The excretion of fluoride is much less if person concerned is suffering from chronic kidney disease resulting in renal failure, which inevitably leads to high concentrations of fluoride in serum as well as bone (Whitford and Taves 1973). In experiments on rats with renal insufficiency increased intake of fluoride caused decreased glomerular filteration rate and increased blood urea nitrogen along with increase in serum and bone concentrations of fluoride. Since disturbed renal function predisposes to excessive retention of fluoride, individuals suffering from chronic renal failure may, therefore, develop skeletal fluorosis even at a considerably low level of 1PPM of fluoride in drinking water (Waldbott 1968; Naidu et al.1986; Rao and Reddy 1988).

Sweat:  Some fluoride is also lost from the body through sweat and so appreciable amounts may be lost in situations marked by excessive sweating.  Sweat fluoride concentrations are similar to plasma.

Other routes:
The amount of fluoride in breast milk is low and same is true of saliva.

Clinicalfeatures:  Fluoride intoxication presents an extraordinary degree of uniformity in its clinical manifestations.  It occurs in humans as dental and skeletal fluorosis. They are separated by a prolonged, relatively symptom free interval, during which the skeleton does not stop accumulating fluoride.  In its advanced stages, skeletal fluorosis causes crippling deformities and neurological complications.

The effects of fluoride intoxication are related to the total amount of fluoride ingested, although, earlier, only water was taken into account presumably because the supply of fluoride by food was deemed negligible. The safest minimum daily intake of fluoride is not known (Farkas 1975). Earlier reports suggested that any daily ingestion of over 28 mg of fluoride would be harmful (Brun et al 1941). Subsequent studies cited 20 mg as the maximum safe limit (Hodge and Smith 1970). But in endemic areas where the presence of certain local factors like nutritional status etc., and prolonged exposure tend to aggravate the fluoride toxicity the safe level of fluoride intake may be even lower. Balance studies of the cases of endemic skeletal fluorosis in India revealed an average fluoride intake of 9.88 mg and it is held that any intake of more than 8 mg would be harmful (Jolly 1976). Kreptogorsky (1963) suggested 3.2 mg as the highest level of fluoride intake, which could be deemed safe. It is true that in persons with normal functioning kidneys there is wide margin of safety.

Dental fluorosis:  Dental fluorosis mainly involves enamel but severe intoxications may affect dentine as well as pulp. Enamel fluorosis occurs when fluoride concentrations in or in the vicinity of the forming enamel are excessive during its pre-eruptive development.  Mottling of teeth is one of the earliest and most easily recognizable features noticed in the first decade of life. 

Both sexes are equally affected. It is the permanent teeth that are affected and they lose their normal creamy white translucent color and become rough, opaque and chalky white.  Pitting and chipping are other marks of fluorosis. Brown or black pigment gets deposited on the defective enamel and once established tends to remain there permanently.  Incidence of dental fluorosis in endemic areas exhibits a linear relationship to the fluoride content of water but it may also vary with other factors (Jolly et al 1968). Dental fluorosis does not obviously occur, when there has been no exposure to fluoride in the first decade of life.

Pre skeletal stageThe duration of this stage may vary with the amount of fluoride daily ingested.  Reportedly, it ranges from 10 to 30 years or even longer in endemic areas and from 10 to 15 years or longer in cases of industrial fluorosis (Singh and Jolly 1970; Franke et al 1970). It is usually free of any signs or symptoms in its early stages in endemic regions. The persons concerned may occasionally complain of pains in the small joints of the limbs and back, which are often mistaken for rheumatoid arthritis or ankylosing spondylitis. However, various reports from Europe and America suggest that there would be symptoms corresponding to gastrointestinal, musculoskeletal, respiratory and visceral systems during this stage (Roholm 1937, Waldbott 1956; Petraborg 1974). The majority of these visceral symptoms may be due to allergy to fluoride in susceptible individuals or the effect of fluoride on the various target organs and these are nonspecific.

Skeletal fluorosis:  Early in the development of fluorotic changes in the skeleton, the patients often complain of a vague discomfort and paresthesiae in the limbs and the trunk. Pain and stiffness in the back appear next, especially in the lumbar region, followed by dorsal and cervical spines.  Restriction of the spine movements is the earliest clinical sign of fluorosis.

The stiffness increases steadily until the entire spine becomes one continuous column of bone manifesting a condition referred to as 'poker back'. In man the spine is most likely to be affected first and severely because of its being required to sustain the erect posture (Murray 1950).  When the condition becomes severe and chronic, various ligaments of the spine become calcified and ossified. The stiffness that first appears in the spine soon spreads to various joints in the limbs owing to the involvement of the joint capsules, the related ligaments, tendinous attachments to the bones and interosseous membranes.

The involvement of the ribs gradually reduces the movement of the chest during breathing, which finally becomes mainly abdominal. When that happens the chest assumes a barrel shape. With the increasing immobilization of the joints due to contractures, flexion deformities may develop at hips, knees and other joints, which make the patient bedridden. Bony exostoses may also appear over the limb bones, especially around the knee, the elbow and on the surface of tibia and ulna. Despite the fact that the entire bone structure has become affected, the mental faculties remain unimpaired till the last stage is reached.

The stage at which skeletal fluorosis becomes crippling usually occurs between 30 and 50 years of age in the endemic regions. Newcomers to a hyperendemic region may sometimes develop symptoms of skeletal involvement within 4 years of their arrival (Siddiqui 1955). Men suffer more than women from severe affects of the disease presumably because their work is usually more strenuous than that of women (Siddiqui 1955;Jolly et al 1968). The factors which govern the development of skeletal fluorosis are (a) the prevalence of high levels of fluoride intake,(b) continual exposure to fluoride,(c) strenuous manual labour,(d) poor nutrition and (e) impaired renal function due to disease (Pandit et al 1941;Daver 1945; Raja Reddy 1985). In regions with very high fluoride content the disease may affect younger age groups including children. The longer the exposure to fluoride higher will be its incidence. In tropical countries skeletal fluorosis occurs even while drinking low levels of fluoride. It is the farm laborers who are prone to develop fluorosis rather than those engaged in sedantary occupations. Epidemiological observations revealed that nutritional status might influence chronic fluoride toxicity.

Endemic genu valgum:

Deformities of limb bones most notably in weight bearing lower limbs in children in endemic areas of fluorosis occur in poorly nourished with low calcium intake (Krishnamachari 1976).

 

Neurological manifestations of skeletal fluorosis:
The neurological sequelae in skelatal fluorosis manifesting usually as radiculo- myelopathy arise principally because of the mechanical compression of the spinal cord and nerve roots brought about by osteophytosis and sclerosis of the vertebral column (Singh and Jolly 1961). However, it is only in later stages owing to pressure on the radicular vessels in the intervertebral foraminae that vascular complications may supervene. But the neural toxicity attributable to fluorides is yet to be established.

Neurological complications arise at a late stage of the disease in about a tenth of the total number of skeletal fluorosis cases (Jolly 1973). Shortt and his colleagues reported them from India in 1937 based on ten chronic cases with a history of 30 to 40 years intake of water containing 2-10 PPM of fluoride.

Later there were similar reports from other parts of India ( Murthi et al 1953;Rao 1955;Chuttani et al 1962;Jolly 1973). The largest number of cases with neurological manifestations were reported from two endemic belts :Punjab, Haryana, Rajasthan and adjacent Uttar Pradesh in northern India and from Andhra Pradesh in southern India. But there have been few reports of fluorosis with neurological complications from countries other than India(Lyth 1946; Webb-Peploe and Bradely 1966; Pinet and Pinet 1968; Goldman et al 1971; Lester 1974; Bruns and Tytle 1988; Haimanot 1990; Dhuna et al 1992; Disanayake et al 1994; Mrabet et al 1995).

The patients suffering from neurological manifestations varied in age from 20 to 70 years and the mean age of 74 cases reported by Jolly and his colleagues was 56 years. In the case of younger age groups these complications may be traced to higher levels of daily fluoride ingestion. It was noticed that fluorosis occured less frequently in areas having low levels of water fluoride, the lowest ranging from 1.2 to 1.35 PPM (Siddiqui 1975). The men were reported to have been affected more frequently than the women who formed only 6% of the cases reported by Jolly et al.(1974) and who numbered 18 out of 70 cases described by Siddiqui (1970). Similar findings were reported by other investigators from India (Reddy et al 1969).,except for one lone report from Rajasthan where females slightly predominated over males and they also developed fluorosis earlier than men (Tamboli et al 1982). the dorsal cord that is commonly affected by fluorosis. In the Punjab series, 70% of the cases had cervical spine involvement. Although, lumbar spine is usually the first to exhibit skeletal changes caused by fluorosis, compression of cauda equina rarely occurs because its roots are so easily accomodated that by the time they are pressed upon, other parts of the spinal cord would have been affected. Although the disease develops slowly but relentlessly, the neurological deficits may sometimes be precipitated by a minor trauma (Lyth 1946;Reddy et al 1994). Such cases present a wide spectrum of neurological deficits, which may be found manifesting either the lower motor neuron or the upper motor neuron defects  or both, which is much more common. These may be found along with those caused by skeletal fluorosis resulting in restriction of spine movements. It is to be noted that in fluorosis higher cerebral function defects or cranial nerve palsies are not normally encountered.

Myelopathy: Patients suffering from fluorosis usually experience difficulty in walking because of the progressive weakness in the lower limbs. With the spreading of this weakness to the upper limbs, neurological disabilities occur that make the patient bedridden. These disabilities are due to motor and sensory deficits, which are followed by sphincter disturbances. In such a condition motor disabilities predominate over the others and sensory defects affecting touch , vibration, position and joint sense tend to be bizarre and widespread. When this happens, acroparesthesiae may occur and sensory level is hardly ever seen. What is striking is that because of the coexistence of crippling deformities at the hips, knee and other joints it becomes difficult to decide whether the disabilities are caused by neurological lesions or by skeletal deformities. Flexor spasms appear only at late stage of the illness.

Radiculopathy: Nerve root compression leads to atrophy of various muscle groups in both upper and lower limbs. With the onset of fasciculations motor neurone disease may be mimicked. The upper limbs appear to be affected more than lower limbs which may be traced to the commoner involvement of the cervical region or even the anatomical features of the cervical spine(Reddy et al 1886). Sensory changes may not be as striking as disabilities of motor function and root pains do not usually occur. In advanced cases, marked cachexia develops on account of disuse atrophy of limb and trunk muscles.

Cranial nerve lesions: The skull is not much affected in fluorosis and basal cranial nerve foraminae are not usually encroached upon except at advanced stages of the disease (Singh et al 1963). Of the cranial nerves, the most frequently affected, in a quarter of the cases investigated, has been the eighth nerve. In all such cases calvarial changes caused by fluorosis are discernible. A progressive high frequency perceptive deafness is observed. Moreover, the bone conduction is affected more than air conduction. Neverthless, total deafness rarely occurs. It is, perhaps, the compression of the nerve in the sclerosed and narrowed auditary canal that accounts for the deafness in fluorosis (Rao and Siddiqui1962).

1Optic neuritis, however, is hardly ever seen in patients of endemic fluorosis, although administration of sodium fluoride in large doses as a therapeutic measure to the cases of osteoporosis was reported to have had a damaging effect on the optic nerve (Geall and Beillin 1964). Higher incidence of myopia and optic pallor in a small proportion of cases of endemic fluorosic village has been seen by us, which could be incidental.

Peripheral neuropathies: Exostoses, which mainly develop around the knee, elbow and ankle may press upon the median, ulnar or lateral popliteal nerves. Pain, paresthesiae followed by weakness in the limbs may be caused by such bony growths. Even meralgia paresthetica has been reported to occur in fluorosis (Chuttani et al.1962). Fluorotic patients may also manifest entrapment syndromes involving other peripheral nerves.

Cerebrovascular accidents: Involvement of vertebrobasilar circulation caused by the compression of cervical osteophytes may occasionally occur(Singh and Jolly 1970). Increased calcifications of major vessels and disturbance of lipid metabolism that has been reported in fluorosis may bring about cerebrovascular accidents.

    The occurance of certain other neurological features like headache, tetaniform convulsions, mental depression, electroencephalographic disturbances in fluorosis have also been reported (Waldbott 1962). Several other complaints have been related to fluoride intoxication without adducing irrefutable grounds for such conclusions (Schweigart 1969).

Laboratory investigations:

A) General: A mild degree of anaemia and a decrease in eryrhropoitic activity of bone marrow is found in fluorosis which may be due to associated nutritional factors or secondary to osteosclerosis and encroachment of medullary cavities. C.S.F.analysis in cases of fluorotic spinal compression reveals a moderate rise of protein and other constituents are normal. Balance studies have revealed the retention of phosphorus, magnesium, nitrogen and calcium, of which latter has been markedly positive (Srikantia and Siddiqui 1965). Evidence of impaired renal function was reported in a certain proportion of fluorotic patients (Shortt et al 1937). The abnormalities included impaired urea clearance, decreased glomerular filteration rate and increased blood urea nitrogen. Singh et al.(1963) found a generalized aminoaciduria in patients suffering from fluorosis, especially excessive tyrosine excretion but investigations made by Srikantia and Siddiqui(1965) did not bring out any abnormalities of aminoacid excretion in urine. The alkaline Phosphatase is often found to elevated in fluorotic cases, which may be due to increased turnover rather than any specific effect of fluoride on the enzyme (Rosenquist 1974). Fluorides are known to activate and inhibit enzyme systems. At low seum levels fluorides are known to stabilize and activate several enzymes and at higher levels fluoride inhibits enzymes such as adenyl cyclase, pyrophophotase etc. In endemic fluorosis regions people with poor nutrition especially those on low intake of calcium in their diets develop secondary hyperparathyroidism.

B) Electrophysiological studies: Neurophysiological experiments have revealed that sodium fluoride has anticholinesterase and anticurare like effects on muscle and nerve, although it has no effect on normal muscle membrane potentials even in the endplate region (Koketsu and Gerard 1956). There are very few electrophysiological studies of muscle and nerve in endemic skeletal fluorosis (Reddy et al 1978). Peripheral nerve conduction velocities in such cases are normal and compound action potentials are usually within normal range. These findings suggest that the nerve lesion in fluorosis is located either in the nerve roots or anterior horn cells in the spinal cord. Study of late responses, F wave and H reflex in cases of endemic fluorosis proved unequivocally that the nerve lesion is located in the root which is responsible for the muscle involvement in fluorosis (Murthy et al 1986). The nerve conduction velocities are found to be reduced to 30-35 m/sec in peripheral nerve entrapment on account of the pressure of exostoses or ligaments around the joints. In these cases both motor and sensory conduction velocities are affected, motor more than sensory.

Electromyographic studies in cases of endemic skeletal fluorosis have given unequivocal evidence of neurogenic atrophy, but no such evidence of myopathy has been furnished. The recognizable features which may be found singly or jointly in all such cases are the presence of fibrillation potentials, reduced interference pattern, increase in mean action potential amplitude and duration of surviving units. Some have shown polyphasia, which are of giant size. Other features noted in EMG studies are the upper limb muscle groups are more involved than in the lower limbs and that the proximal muscle groups are more affected than the distal musculature. These changes are perhaps, peculiar to the cases that were studied. In general, EMG findings endorsed those of clinical neurological examination. But muscle changes might sometimes be detected earlier through EMG studies rather than by clinical examination.

C) Fluoride estimations:
1Diagnosis of fluorosis depends upon the estimation of fluoride levels of urine, seum and bone. Many methods are available for the determination of fluoride and the most widely used involve colorimetry or the fluoride specific ion electrode. The latter is more popular than other methods because it offers speed. Frant and Ross(1966) introduced the selective electrode and it gives an electrochemical response that is proportional to the fluoride ion activity in the sample.

1)Urine fluoride estimation:
Urinary fluoride levels are the best indicators of fluoride intake. Since fluoride excretion is not constant throughout the day, 24-hour samples of urine are more reliable than random or morning samples for the estimation of fluoride content. In normal individuals urinary fluorides fluctuate widely between 0.1 to 2.0 PPM with an average of about 0.4 PPM when the fluoride content of drinking water is 0.3 PPM. In general urinary fluoride rises in relation to fluoride intake and it fluctuates widely from day to day and ranges from 0.5 to 4.48 PPM minimum and from 1.5 to 13.0 PPM maximum in cases of skeletal fluorosis (Reddy et al 1984).


Daily Fluoride excretion


24-hr urinary fluoride excretion in 16 patients

In some high endemic areas urinary content of fluoride could be as high as 26 PPM or more (Singh et al 1966). A study on the excretion pattern of urinary fluoride in fertilizer workers had an average of 4.2 PPM with a range of 1.5 to 7.5 PPM (Gollop1977). Urinary fluoride levels could be low in cases with renal disease. Fluoride patients on low fluoride regimen eliminate more fluoride than intake.

2) Serum fluoride estimation:
When chemical methods of estimating fluoride levels in serum and blood came to be employed by different research workers, wide divergence was noticed in their findings. But When fluoride ion electrode was used for investigation, the fluoride levels in serum were found to be considerably lower: 0.4 to 0.9 PPM in fluorotic patients and 0.19 to 0.4 PPM in normal subjects. Normal values for blood in non-endemic regions varied between 0.002 to 0.008 mg/100ml. In endemic regions blood fluoride levels ranged between 0.02 to 0.15 mg/100ml whereas patients with skeletal fluorosis they were 0.02 to0.19 mg/100 ml (Singh et al 1966). Serum fluoride levels in 500 normal healthy adults ranged between 0.03 to 0.13 PPM with a mean of 0.08   PPM and they were 0.04 to 0.28 PPM with a mean of 0.16 PPM in 17 fluorotic patients in our laboratory. The urinary levels of fluorides of these 17 fluorotic patients varied between 0.68 to 7.80 PPM with a mean of 3.28 PPM.

3)Bone fluoride estimation:
Measurement of bone fluoride content allows the determination of the extent of bone fluoride retention and is a useful complement to the bone histology for the diagnosis of skeletal fluorosis and could be used for the management of fluoride treatment of osteoporosis. Bone samples are collected and prepared for subsequent analysis using the fluoride selective electrode. Roholm's study of industrial fluorosis revealed that bone fluoride content, which varied between 6000-8400 PPM in bone ash where as normal bones, had a concentration ranging between 500-1000 PPM or mg/kg. But observations of fluoride content of bones in endemic areas are at variance with those mentioned above. For instance, the fluoride levels at which osteosclerosis was detected ranged from 700-7000 PPM of fat free dry bone in cases from Punjab (Jolly et al 1971) and from 1800-6280 PPM of fluoride in endemic areas of Sahara (Pinet and Pinet 1968). While reporting their findings these authors commented upon the lack of correlation between fluoride content of bones and the degree of osteosclerosis seen in radiographs.  Weatherell et al (1975) hold the view that the rate of intake of fluoride is much more important than the amount fluoride in the bones to the development of skeletal fluorosis. When the daily intake of fluoride is low, the skeleton may be accumulating enormous amounts of fluoride over a prolonged period without manifesting any alteration in its structure or function. When the rate of fluoride ingestion is high as in endemic areas the incidence of fluorosis is usually high.  Weatherell and his colleagues suggested that with high intake a local increase in concentration of fluoride occurs at the site of active mineralization along with high biological activity, which causes the changes that lead to fluorosis. Bone scintigraphic studies by us in endemic fluorosis cases has shown super scan appearance suggesting a very high metabolic activity in the bones (Reddy et al 1990). Electron probe microanlysis has confirmed that the newly laid bone has a higher content of fluoride than the bone existing before fluoride ingestion (Rosenquist 1974).

D) Bone Biopsy:
Histopathological changes of bone in fluorotic cases show that the Haversian system is poorly formed and there is disordered lamellar orientation in the compact bone. Osteoid tissue is found in the spongy bone, some of these irregular deposits of osteoid tissue extend into the attached muscles. In some of these cases osteoid tissue showed calcified muscular attachments. Ligaments show calcification and ossification. Crystals of fluoride material, which are described in cases of industrial fluorosis by Roholm were not seen in cases of endemic fluorosis (Reddy et al 1969). Though skeletal fluorosis involves mainly the spine, pelvis and long bones rarely it affects the small bones of hands and feet.

E) Pulmonary function tests: 

In fluorosis there is involvement of the rib cage, which causes restrictive lung disease. Vital capacity is reduced and FEV1/FVC ratio is above 85% and respiratory curve of flow- volume loop is flattened when the lungs are abnormally stiff in late stages due to restrictive ventilatory defect.

F) Scintigraphic studies:
Radionuclide bone scans by technetium labeled methylene diphophonate (99mTc-MDP) in fluorotic cases shows mostly a super scan appearance and in some cases joint abnormalities. Increased tracer activity between the forearm bones and diffuse linear tracer activity along the ligamentous attachments were seen. Concentration of tracer may be noted in the joints such as sacro-iliac, anterior iliac spine where inguinal ligament is attached. Hence bone radio-nuclide scan reveals the functional display of skeletal metabolism.

Radiology of fluorosis;
In fluorosis the radiological findings closely parallel those of gross pathological changes but there is no clear correlation between the degree of musculoskeletal changes and the osseous fluoride content. The mechanism of skeletal fluorosis has not been clearly demonstrated. It is difficult to assert that the density of bone is a result of reactive new bone formation and osteoid as a response to fluoride intoxication. All that can be said is that the density may be quantitative rather than qualitative owing to the increase in the matrix unaccompanied by any increase in mineralization. Bone continues to be formed, but the thickened trabeculae with uncalcified borders are resistant to resorption and so they thicken.

In infancy and childhood generally no definite radiological findings are normally found except the cases with malnutrition especially deficient in calcium. Radiological changes are seen manifesting usually at puberty and in adulthood. However, in some young adolescents, osteopenia of a generalized nature may be presented along with sclerotic areas at the metaphyseal ends of long bones simulating renal rickets. In such cases the epiphyses are also dense. The vertebral bodies may be prone to sclerosis of the end plates. Fluorotic poisoning does not materially affect growth but the marks of fluorosis are discernable as growth lines at the metaphyses of long bones.        In adults, the radiological findings could be set forth in three stages, each overlapping the preceding one (Roholm 1937;Chawla et al 1964).

1) The findings are mainly confined to the axial skeleton. The primary trabeculae appear slightly rough due to sclerosis. This is clearly revealed in the iliac wings and the thoracolumbar vertebral bodies. In the secondary trabeculae however, these are not prominent. The bones assume a ground glass appearance, an earlier manifestation.

2) In the next stage, the thick primary trabeculae merge with the secondary trabeculae to make the bone homogenously dense. The bone contours become uneven, due to subperiosteal new bone apposition, which is prominently present in the ribs, pelvis and vertebral column. The skull demonstrates minimal changes in the base. The appendicular skeleton however, is less affected, but the long bones of the limbs may show encroachment of the medullary cavities with endosteal new bone. The spongiosa bone manifests trabecular prominence and sclerosis. It may be noted that ligamentous calcification begins most frequently in the paraspinous, sacrospinous and sacrotuberous ligaments.

3) In the final stage, the bones of the axial skeleton demonstrate characteristic radiological features. The bones appear chalk like with ill-defined trabecular pattern. With the loss of cortical and trabecular definition the bone appears wooly. The cortices of long bones are dense and thick due to amorphous subperiosteal new bone formation. The medullary cavities are encroached upon by endosteal new bone. In such cases calcification in the paraarticular ligaments is pronounced. Calcification is marked at the insertion of the tendon and muscles and is seen in the interosseous membrane.

The articular ends of bones are less affected but in advanced cases the condyles of long bones are prominent with irregularity of cortical bones. Osteophyte formation in the vertebral column is frequent. These osteophytes may encroach upon the intervertebral foramina, spinal canal and foramen magnum. The ribs are slightly enlarged with needle like projections, which point to the advance of calcification into the intercostal muscles and membranes. There is extensive calcification of the costal cartilages.  Subperosteal resorption of bone and osteomalaciais found in some cases.                                                                                                                       

The skull shows minimal changes in the calvarial bones. Sclerosis of bone at the sutural lines is one of the minor manifestations. However, the bones at the base show marked thickening. The petroclinoid ligaments show dense calcification. The occipital protuberance is very prominent and exostoses may be occasionally noted. Small osteophytes may encroach upon the foramina and produce cranial nerve palsies, as for instance, the 8th nerve. A tendency toward calcification may be noted in the falx cerebri. Hypercementosis of the roots of the teeth is also encountered in some cases.

Bony excrescencies are presented at the iliac crest, ischial tuberosities, condyles of long bones and other protuberances of bones. In such cases there is possibility of large calcareous spurs developing and bones of hands and feet show cortical thickening. Calcification of interspinous and intervertebral ligaments is noteworthy.

In the differential diagnosis of radiological findings of fluorosis, several 'entities' should be taken into consideration. Paget's disease, which prevails in certain geographical areas and races, may produce diffuse sclerosis of bones and may closely mimick fluorosis. However, the enlargement of affected bones and the lack of calcification at the musculotendinous insertion and interosseous membranes and para-articular ligaments provide a clue, which should enable one to differentiate it from fluorosis.

Diffuse osteosclerotic lesions such as myelofibrosis, osteoblastic metastases, myeloma, hypoparathyroidism and renal osteodystrophy may pose a similar problem.  However, a skeletal survey should help in differentiating them from fluorosis. Osteopetrosis, melorheostosis and similar congenital forms of diffuse sclerotic bone lesions should identified and distinguished from skeletal fluorosis. Differentiation is also called for in the case of a high degree of metal intoxication such as phosphorus, vitamin D and radium. However, in most of these cases, clinical history would be of great help in arriving at a proper diagnosis. Mastocytosis, tuberous sclerosis and occasionally syphylis, yaws and other infective lesions have to be differentiated from one another. To this long list may be added unusual lesions of Gauchers disease, sickle cell anemia and idiopathic osteosclerosis as well as other esoteric lesions caused by familial hypophosphatemia, vitamin D resistant osteomalacia , Wilson syndrome etc.

Osteosclerosis is a well-known effect of chronic fluoride intoxication, which can also cause osteoporosis and osteomalacia. It was Roholm (1937) who describing bone changes in industrial fluorosis suggested that in certain cases osteoporosis could occur.  Soriano (1968) while giving an account of 'wine fluorosis' made a mention of the development of osteoporotic and osteomalacic changes in the skeleton of individuals concerned. He pointed out that smaller doses of fluoride stimulated osteogenesis and new bone formation, while severe intoxication led to increased bone resorption and defective matrix formation. A significant observation in this regard has been that at high levels of fluoride intake there is a reduced collagen synthesis in humans (Nichols and Flanagan1966).

Osteoporotic changes in leg bones in endemic skeletal fluorosis have been reported as Kenhardt bone disease from South Africa (Jackson 1962). This usually affects children whose limb bones revealed demineralization accompanied by thinning of cortex and widening of medullary cavities. The adult population of the area showed classical osteosclerotic changes of the skeleton. Cases similar to those of Africa were reported from various endemic regions of India and China. These changes in the appendicular skeleton of young individuals seem to be due to poor nutrition especially low in calcium (Krishnamachari and Krishnaswamy 1973; Wang et al. 1994).  Lian and Wu(1986) describing the radiological features of endemic skeletal fluorosis from China concluded that osteoporosis towards the ends of long bones is an early radiographic sign in individuals under the age of 40 years even among those with a good nutritional status. In high endemic regions with a very high intake of fluoride and diets being deficient in calcium there is a secondary hyperparathyroidism, which also adds to the radiological changes. Hence the radiological changes in endemic regions with poor nutrition a variety of radiological appearances are seen (Teotia et al 1974).

Computed tomography:
Computed tomography is the best imaging modality for visualization of bony pathology and it provides more details than plain skiagrams. Besides proper appreciation of the morphological anatomy, density of the various parts of the vertebra, it shows the exact location and direction of the osteophytes compressing the various neural elements and thus helps in proper surgical planning. Spinal canal and root canal stenosis are also better appreciated with CT scan.

The calcified ligaments are visualized with much more clarity and earlier than by plain roentgenology, so are the indentations of the epidural space and the alterations in the spinal canal. By reconstruction, CT provides exact dimensions of the ossified intraspinal ligaments such as posterior longitudinal ligament and yellow ligaments. The anterior osteophytes are seen to be most prominent in the thoraco-lumbar region. The facetal joints show significant hypertrophy occasionally in fluorosis. In delineation of ossification of the forearm interosseous membrane and ligaments of pelvis in early cases of fluorosis, CT is extremely sensitive.

Magnetic resonance imaging:
MR imaging being noninvasive obviates the difficulties in performing myelography and on the other hand, delineates the anatomy of the soft tissue structures and the spinal cord changes.  It also demonstrates associated abnormalities like pseudomeningocoele and cord changes due to prolonged compression and secondary vascular compromise.  It is useful to take imaging of the entire spine, which may demonstrate incidental and interesting pathological lesions peculiar to fluorosis. Fluorotic vertebrae are seen to be hypointense in both T1 and T2 weighted images. 

The localized areas of hypertrophy and ossifications of ligaments are visualized clearly and these give a clue to the surgical approach.  However, the differential diagnosis of cervical disc herniation, spondylosis and segmental OPLL is often difficult and plain radiography, tomography or CT can be complimentary in this regard. MRI is superior to CT in the evaluation of cervical and upper dorsal area because of shoulder girdle artifact on CT image, but in demonstration of minute ossification of ligaments and spinal canal stenosis, CT is more useful.

As for spinal cord morphology, there is no better imaging modality than MRI. Evidence of chronic cord compression producing pathological changes like myelomalacia, cavitation and necrosis is seen as high intensity signal in spinal cord in T2 weighted images. This is frequent in cases of continuous OPLL since this type of ossification causes severe cord compression. Apart from these chronic changes, pathology of acute cord injury and its sequelae are visualized with clarity.

Myelography:
At advanced stages of skeletal fluorosis, lumbar and even cisternal punctures become difficult for obvious reasons, hindering the undertaking of myelographic studies. What is observable in early stages, is the localized epidural type of block, which is extensively found in later stages. For finer details, water-soluble contrast myelography coupled with computed tomography is far superior. However, following the advent of noninvasive MRI imaging, myelography is now seldom performed.

Pathology of fluorosis:

A) Gross changes in the skeleton:
Skeletal changes involving overall increase in bone mass, 2-3 times the normal is a characteristic feature of fluorosis (Weatherell and Weidmann 1959; Singh et al 1962; Reddy et al 1969). The changes will be first noticed in the vertebral column and pelvis and thereafter in the rib cage and limb bones. The bones become whitish and occasionally mottled like the teeth.

A clear indication of chronic fluorosis is the calcification and ossification of ligaments and interosseous fasciae occuring along with periosteal new bone formation and development of exostoses on long bones and osteophytes in the spine. It is in the muscular attachments and tendinous insertions that new bone formation occurs, as a result of which there is a thickening of the cortex and narrowing of the medullary cavity. The effect on the vertebral column is seen in roughening of pedicles, laminae, spinous and transverse processes. The osteophytes projecting into the spinal canal and intervetebral foraminae may press upon the cord and spinal roots and thus account for the  radiculomyelopathic features in chronic fluorosis. The spine is converted into a single rigid bone as a result of ossification of spinal ligaments and fusion of the adjacent bony structures. The bones of pelvis exhibit changes essentially similar to those found in the spine. The skull is rarely involved, although there may be thickening of the calvaria and a roughening  of the outlines of the foramen magnum. Other foraminae at the base of the skull are rarely affected, which is the reason why the cranial nerve defects do not appear in fluorosis.

B) Histopathology of bones:
There have been few reports on the pathology of fluorotic bones and they present a confusing picture.  These reports are unhelpful in that they are silent about the histogenesis and the mechanisms that bring about changes in bones. Johnson et al (1965) work on osteofluorosis, indeed outstanding because it spells out the mechanisms underlying the development of skeletal changes caused by fluorosis in animals and man.  It was they who set forth three successive stages of development of fluorosis in bones, viz., fluoridation, mottling and abnormality. Bone fluoridation or chemical fluorosis is indicated if the fluoride content is less than 2500 PPM- a stage at which no gross or microscopic abnormalities occur in the bones. Bone mottling is seen at fluoride levels ranging between 2500-5000 PPM. When this condition is reached, gross inspection and radiological examination will not reveal any abnormality, but when subjected to microscopic study changes such as mottled osteone are seen. The mottled osteone is signified by brownish discoloration and increase in the number of osteocytes found in a tangled mass on its periphery synchronizing with a reduction of osteocytes in the rest of the osteone. What is further noticeable is the failure of these abnormal osteones to calcify, although in the other parts abnormality is marked in calcification and also in the formation of collagen matrix. Similar changes are also observable in the periosteal new bone. Indeed, mottling may be said to result from the action of fluoride on osteoblasts. The final stage is reached when the fluoride levels exceed 5000-6000 PPM, a stage at which even the naked eye could detect abnormality in the formation of the bone. These changes cause impairment of mechanical properties of bones.

C) Muscle pathology:
Neurological manifestations in skeletal fluorosis are secondary to compressive myelopathy. Franke (1973,1976) suggested that there could a direct toxic effect of fluoride on spinal cord as well as on muscle based on a lone report of a study in a patient of industrial fluorosis who died due to glioblastoma multiforme. Similar myopathic changes were also reported in experimental studies made by Kaul and Susheela (1974,1976). Similar cardiac muscle changes have been reported in cases of experimental animals and these might have been caused by the administration of very large doses of fluorides to these animals (Okushi 1971). Our own detailed histochemical and histological studies on muscle in 22 patients suffering from endemic skeletal fluorosis have not revealed any muscle involvement due to toxic affect but muscle changes were characteristic of denervating muscle pathology (Raja Reddy et al 1997).

D) Nerve pathology:
Nural nerve biopsies were performed in 13 patients suffering from endemic skeletal fluorosis and processed for the study of a) myelinated fiber densities and diameter frequency distribution, b) internodal lengths and diameter on teased fiber preparations and c) histological changes. Myelinated fiber densities were reduced indicating a dropout, probably due to axonal degeneration or demyelination or both. It is however unusual that there was relative sparing of larger fibers, which is not the case in compression neuropathies. The data suggests that there is a selective damage to small myelinated fibers or their neurons with intact larger and fast conducting fibers. Hence there was no significant reduction in conduction velocities in electrophysiological studies in fluorosis.

E) Spinal cord studies:
There has been no report of spinal cord examination having been made in cases of fluorotic spinal compression. In a few of these cases in which autopsy was performed, the bones were macerated for studying the changes in the vertebral column, but no attention was paid to spinal cord and spinal nerves. Franke (1976) reported anterior horn cell damage in spinal cord without there being compression of cord or nerves and it was attributed to the direct action of fluoride on these tissues. We studied spinal cord changes in fluorotic dogs from endemic regions without myelographic evidence of compression. Spinal cords revealed no abnormality histologically to suggest anterior horn cell disease.

Differential diagnosis:

In areas of known endemicity, the diagnosis of dental and skeletal fluorosis does not present any problem. In industries, where fluoride intoxication is a known hazard, skeletal fluorosis marked by restriction of spine movements can easily be diagnosed. In early stages of skeletal fluorosis patients complain of arthritic symptoms, which have to be differentiated from those caused by such diseases as rheumatoid and ankylosing spondylitis. This is all the more important in the case of children residing in endemic regions in which these symptoms need to be differentiated from those of rheumatic arthritis (Teotia et al1976). Diseases that are known to produce osteosclerosis in skiagrams should be taken into account while undertaking a diagnosis.  In children and young adults genu valgum deformities have to be distinguished from those brought about by rickets and sometimes by osteodystrophies.  When sclerosis of vertebral column is not marked, calcification of the interosseous membrane in the forearm bones clearly indicates the incidence of fluorosis, which indeed, is a very suggestive radiographic sign (Singh et al.1965).  Pre-skeletal stage of fluoride intoxication poses problems for diagnosis. In these cases radiographs of the skeleton do not show sclerosis or calcification of the ligaments, nor will urinary levels of fluoride be found significantly elevated. Moreover, the symptoms that are manifested are so varied that they may be identifiable with those of various system diseases.

Freitag and colleagues (1970) state that for early diagnosis of skeletal fluorosis, microradiographic techniques are more helpful than conventional skiagrams. In doubtful cases a bone biopsy and estimation of its fluoride content may have to be undertaken (Franke 1972). Mild trauma producing major neurological deficit is a known complication of skeletal fluorosis and in such situations in non-endemic regions one might overlook the diagnosis of fluorosis. MRI scans of spine showing hypodensity of vertebrae in both T1 and T2 weighted images suggests that underlying pathology as one caused by fluoride intoxication (Reddy et al.1994).

Treatment of fluorosis:

Prevention: In all cases of skeletal fluorosis prevention is the aim, since no cure is possible through medical or surgical therapy, especially if it is allowed to develop to the stage when it becomes a crippling disease.

Prevention of endemic fluorosis: In India, which is highly endemic for fluorosis, over 50% of ground water sources have excess of fluoride for a tropical country and it affects more than 150000 villages. The supply of water with permissible levels of fluoride though desirable cannot obviously be made available to the vast numbers of people nor they can be shifted. That is why water purifying or defluoridation plants should be pressed into service in those areas. The plane of nutrition appears to play a crucial role in the incidence and severity of fluorosis and hence a balanced diet having adequate calcium and vitamins reduces the toxicity of fluoride.

Prevention of industrial fluorosis: Workers in industries and mining exposed to fluorides should be monitored and it should be ensured that their fluoride content of urine is below 5 PPM (Zsogon 1989). It is said that skeletal fluorosis would not develop in well-nourished individuals, unless fluoride content of bones exceeds 5000PPM (McClure et al 1958). If the workers are found to be suffering from skeletal fluorosis, they should be removed at once from exposure to fluoride. If this is affected, their condition over the years will improve even though their urine may continue to excrete large amouts of fluoride. There is every possibility of osteosclerosis returning to normalcy and morphology of bone improving.

Medical therapy: It is noteworthy that patients suffering from skeletal fluorosis, when kept off fluoride intake, register a negative fluoride balance while continuing to excrete large amounts of fluorides for years (Brun et al 1941; Siddiqui 1955; Jolly 1976). It should be obvious that excretion of fluorides mobilized from the skeleton through urine and feces is a very slow and prolonged process lasting for many months or even years (Spencer et al. 1975). Attempts have been made to study the effect of various drugs on the binding of fluoride in in-vivo studies and excretion of fluoride in in-vivo experiments performed in animals and human beings. In-vitro studies revealed that bone meal, serpentine, dowex, and magnesium compounds etc could be effective in the reduction of the fluoride levels of water having a high fluoride content (Rao et al 1975;Teotia et al 1976). In-vivo experiments with animals showed that salts of calcium, magnesium and aluminum acted as a check on fluoride absorption and also increased its excretion from the body (Venkatraman and Krishnaswamy 1949; Allcroft and Burns 1969). The use of serpentine resorted to in recent times for increasing the excretion of fluoride in human fluorosis cases has been successful for clear reasons (Rao et al 1975). This naturally occuring mineral, which is chemically a magnesium metasilicate, seems to have an enormous capacity for absorbing fluoride at a wide range of PH and that is why it seems to hasten the excretion of fluoride from the body by mobilizing it from bones. It has been observed during the administration serpentine that urine becomes markedly alkaline, which probably has the effect of increasing the fluoride excretion from the body- an observation which tallies with the findings of physiological experiments of Whitford et al.(1976) and which suggests that fluoride renal clearance is a PH dependent event. Since serpentine is an impure and represents a group of minerals which comprise of chrysotile, antigorite, lizardite and a number of subgroups such as orthochrysotile etc having traces of many elements including fluorine, the use of active ingredients of serpentine, namely magnesium oxide and magnesium hydroxide, has been tried and found effective in animal fluorosis as well as in humans (Reddy et al 1974,1977). Magnesium hydroxide has been more effective than serpentine in both in-vivo and in in-vitro studies of both animals and human beings (Reddy et al 1974; Quader et al 1974). But long-term studies have to be undertaken for guaging the effectiveness of these drugs in human fluorosis cases. Experiments conducted by Marier(1969) and Odell et al (1973) found a similarity between magnesium deficiency symptoms and those of fluoride intoxication, which made them suggest that higher intakes of magnesium might prove beneficial to endemic fluorosis cases. Our own clinical and experimental studies confirm their observations and lend support to the view that physiologically magnesium ion has a peculiar affinity for fluoride.

Surgical management of skeletal fluorosis with neurological manifestations:
Neurological manifestations of fluorosis are mainly mechanical in nature although at advanced stages secondary vascular changes may supervene. Surgery obviously can be of little help to the alleviation of neurological deficits in view of the extensive prevalence of the disease. Surgical decompression is only possible in such of those early cases in which the compression is confined to a small segment of the vertebral column. But management of even these cases bristles with problems because of the marked fixity of the spine and rigidity of the thoracic cage. Moreover, the markedly reduced expansion of the chest and the vital capacity of the lungs tend to create postoperative chest complications. Furthermore, the intubation of the trachea during anesthesia becomes problematic because of the rigidity of the cervical spine and what is more because of the difficulty experienced even in positioning of the spine during surgery. That is why laminectomy, which has to be extensive in view of the disease being widespread, becomes difficult and burholes have to be used for removing laminae (Aggarwal and Singh 1964; Webb-Peploe and Bradely1966; Lester 1974; Reddy et al 1974; Naidu et al.1994). However, the results of surgical decompression of the spine undertaken in a select group of cases were found to be encouraging in the case of cervical region, but discouraging in that of dorsal region (Reddy et al 1974) which might be attributed to the pecularities of the anatomical features of these regions. Lumbar compression rarely necessitates surgical decompression as the roots get accommodated easily and by the time they are pressed upon, other parts of the spine become affected precluding surgery. It is on account of all these reasons that the attitudes towards the use of surgery in the case of spinal compression vary from those of cautious optimism to those of pessimism. In recent years with accurate localization of the compression, its extent in both vertical and axial planes by the MRI, fiber optic intubation and rigid fixation, better illumination and instrumentation during surgery for drilling and removal hard fluorotic bone and postoperative ventilatory support made surgery safer and effective in alleviation of mechanical compression in fluorosis.

In recent years surgical approach to certain types of lesions of the cervical spine in fluorosis has changed. Ossification of the posterior longitudinal ligament which could be continuous or segmental is tackled through anterior approach where as it was operated by posterior route alone in the past, with better results. Even when posterior approach is undertaken in such cases newer methods are followed such as canal expansive laminaplasty which obviates the complication of anterior approach which immobilizes the spine and destabilizing problems following extensive laminectomy. It is also not known what happens to these patients after they go back to their endemic areas and again ingest high fluoride containing water and food.

Fluoride administration in osteoporosis::
Sodium fluoride was used in the treatment of osteoporosis by Rich and Ensinck (1961) which improved the mineralization of bone but did not reduce the number of fractures. The studies of Bernstein et al (1966) of osteoporosis in high and low fluoride regions of North Dakota suggest that fluoride consumption might be able to prevent the occurrence of osteoporosis. It is this suggestion which has led to the widespread use of fluoride in the cases of osteoporosis and various other demineralized skeletal disorders such as Pagets, multiple myeloma etc. Fluoride has the potential to increase the skeletal mass to a greater extent than any other pharmacological agent does by affecting the quality of bone matrix (Kleerekoper 1996). Fluoride in large doses also induces osteomalacia, which can be counteracted by simultaneous treatment with calcium supplements. Vitamin D is also needed in proven cases of osteomalacia. By supplementing the diet with appropriate doses of calcium and Vitamin D the mineralization of newly formed bone can be improved upon but there is always the possibility of bone fluorosis and secondary hyperparathyroidism developing. This bone, though not as satisfactory as a normal one, is preferable to a demineralized bone. Long term controlled clinical trials do not bear out the promise that fluoride showed being helpful to the control of osteoporosis. Recent experimental studies suggest that intermittent therapy to be preferred than continuous release sodium fluoride in osteoporosis (Schnitzier 1997).

The fluoridation controversy:
Fluoridation of water supplies is one public health issue, which has generated and continues to generate enormous amount of controversy. Fluoridation was undertaken after careful clinical studies, backed by epidemiological surveys and supplemented by experimental work, which proved beyond doubt that fluoride ingestion through water in optimum levels is beneficial for oral hygiene by reducing the caries incidence and has no proven deleterious effects in human beings. It is also very cost effective. But proponents of fluoridation overlook one aspect i.e. the people with renal disease especially those who are on dialysis since these people run the risk contracting skeletal fluorosis. Hence provision must be made so that dialysate does not contain excess fluoride by improving dialysis membrane and people with kidney disease should be warned about their total daily intake of fluoride and to keep off those foods and beverages, which are rich in fluorides.

The opponents of fluoridation seem to be a vocal intellectual group who consider that fluoride is a poison and attribute all kinds of ailments starting from congenital anomalies, allergic illnesses, repetitive bone injury and fractures, degenerative diseases like Alzeimer to even cancers and their list is endless. If allergy to fluoride present in drinking water is true, it should have been found in billions of people around the world drinking fluoride rich beverage, tea. If it is true of claims of cancers caused by fluorides, such a happening would not have gone unnoticed in millions of people living in endemic regions in India, China etc. Any major carcinogenic effect of heavy fluoride exposure would be very unlikely in humans as well as in animals (Grandjean et al 1985; Shupe et al.1980). In support of some of their claims, Opponents of fluoridation produce experimental evidence in animals, which were given massive doses of fluoride. Rabbits weighing about a kg were fed 50mg/kg for weeks and months while adult humans in the endemic regions do not consume more than 20 mg of fluoride a day. Hence the effects of fluorides causing myopathy and cardiac damage are untenable. It is true that there is a need to reduce water fluoride concentration to 0.2-0.4 PPM because of overall increase  in intake of fluoride in recent years related to increase of fluoride in food chain, the unintentional use of fluoride containing dental health products and consumption of beverages rich in fluorides.

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