Fluorides Effects on Bone as read from Dr. John Lee's Site

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Fluoride's Effects on Bone as read from Dr. John Lee's Site

 

 

 

 

 

http://www.johnleemd.net/breaking_news/fluoridation_02.html

 

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----------Fluoride's Effect on BONE - and some related considerations

T.C. Schmidt – 12 March 2000

Foreword. Except for the introductory sentence (from a textbook); one

CDC document; two FDA documents; and the NIOSH RTECS (as referenced

in the text per se.) the technical basis for this review has been

LIMITED on purpose ONLY to those citations which are retrievable on-

line from the National Library of Medicine (PubMed MEDLINE and/or

Internet Grateful Med TOXLINE).

 

Introduction

 

Bone tissue has long been recognized as a key accumulation site for

some toxic substances – " bones also serve a detoxicating function,

elements such as lead, radium, fluorine and arsenic being removed

from circulation and deposited into bones and teeth " (The

Physiological Basis of Medical Practice, 1961). That is, fluoride

accumulates in skeletal tissue, concentrating in the surface layers

of the lacunae and canaliculae -- thus helping to clarify the

pathogenesis of the osseous lesions seen in skeletal fluorosis

(Smith, 1985a). Bone samples from cadavers show that fluoride content

of trabecular bone correlates with that of the drinking water -- with

histomorphic bone changes becoming markedly increased when water

fluoride content exceeds 1.5-ppm (Alrnala, et al. 1985). Thus, daily

intake of fluoride that is deemed beneficial to developing teeth, if

ingested throughout adult life, may lead to skeletal fluorosis of

varying degrees, plus certain disorders that are now becoming common

in both the middle-aged and elderly (Smith, 1985b). This was more

recently substantiated in a review (Diesendorf, et al. 1997) --

showing " a consistent pattern of evidence " . Osteoporosis in the long

bones may provide the earliest radiographic indicator of fluorosis

(Lian and Wu, 1986); with clinical radiological aspects including

calcification and/or ossification of the attachments of the soft-

tissue structures to bone, osteosclerosis, osteopenia, growth lines,

and metaphyseal osteomalactic zones (Wang, et al. 1994). More subtle

changes as stained section and microradiograph include interstitial

mineralization defects and mottled eperiosteocytic lacunae (Boivin,

et al. 1989) and CT/MR imaging are very helpful in early diagnosis

(Reddy, et al. 1993).

 

Lessons-Learned from Therapy

 

Water fluoridation proponents like to tout that fluoride is used as

a " treatment " for osteoporosis. Despite more than several decades of

research, the efficacy " remains controversial " (Kopp and Roby, 1990;

inter-alia); and it has NOT been approved as a treatment by FDA. Even

adherents now recommend restricting prospective clinical trials to

axial skeleton only -- provided that the patient has good peripheral

bone density, renal function and vitamin-D status (Dequeker and

Declerck, 1993). However, unless the patients receiving fluoride are

also closely monitored for the onset of osteo-fluorosis, there are

examples (Tollefsen, et al. 1995; Mrabet, et al. 1995)

contraindicating this treatment approach, even for such very select

cases. Side effects include gastro-intestinal problems and " painful

lower extremity syndrome " -- and " experience has taught that denser

bones are not necessarily better bones " (ibid, 1995).

 

This is consistent with earlier findings (Stein and Granik, 1980)

that although increased bulk might offset the reduced static

compressive strength of vertebral bone which presented as a function

of the fluoride content, it may also become more brittle, thus

rendering it more likely to fracture on impact. Similarly, based on

small-angle x-ray scattering and backscattered electron imaging of

the vertebrae of mini-pigs treated with fluoride (Fratzl, et al.

1996) changes in the mineral/collagen composite were evident, which

helped explain the reduction in the bio-mechanical properties due to

fluoride treatment that were found in earlier studies. These

reductions were comparable to the vertebral bone strength results

found in rats after fluoride treatment (Sogaard, et al. 1995a), which

concluded " the increase in bone mass during fluoride treatment does

not translate into an improved bone strength -- rather, bone quality

declines " . Not only does this approach not exhibit any efficacy for

the axial skeleton based on vertebral fracture incidence (Hillier, et

al. 1996) but to make matters worse this is " achieved at the expense

of bone-mineral in the peripheral cortical skeleton " . That is, in

prospective clinical trials comparing fluoride treatment vs a

placebo, not only was there was no decrease in vertebral fracture

rate, but there was an increase in non-vertebral (hip) fractures

(Riggs, et al. 1990; Riggs, et al. 1994). Per FDA Consumer (April,

1991) that study included the use of calcium and resulted in a 35%

increase in bone mass but " the new bone was weak and structurally

abnormal " . Indeed, the difference in rate of hip fractures for

fluoride treated patients vs non-treated is ten-times higher than

would normally be expected (Hedlund and Gallagher, 1989).

 

Likewise, fluoride treatment was found to result in a nine-fold

increase in definitive osteomalacia (Lundy, et al. 1995) which was

attributed to a prolonged mineralization lag time, as well as a

resultant relative calcium deficiency. Although the latter might be

expected to be ameliorated by incorporating calcium supplements, such

a double-blind clinical trial (Kleerekoper, et al. 1991) showed this

to be no more effective than placebo in retarding the progression of

spinal osteoporosis. Similarly, fluoride with both calcium and

vitamin-D, is no more effective than calcium and vitamin-D alone

(Meunier, et al. 1998). That fluoride cannot be recommended as a

prophylactic agent for the fractures that are the primary adverse

health outcome of osteoporosis (Melton, 1990) is supported by patient

bone biopsies (Sogaard, et al. 1994; Sogaard, et al. 1995b) in which

bone fluoride level increased significantly after 1-year and 5-years -

- however, after 5-years of " treatment " decreases in trabecular bone

strength and quality were 45% and 58%, respectively.

 

Whereas bone mass and architecture in all appendicular and most axial

sites is normally controlled by loading history, the new bone formed

as a result of artificially stimulated bone remodeling using fluoride

is exclusively appositional, with no creation of new trabeculae

(Balena, et al. 1998). It has an " abnormal texture " that is less

strong (Lips, 1998), and the loss in trabecular strength due to the

adverse influence of fluoride treatment altering the normal control

has been calculated (Carter and Beaupre, 1990). Although the

increased fragility has been attributed to both hypo- and hyper-

mineralization, the net result is " identical to that of heavy

fluorosis " (Fratzl, et al. 1994) -- characterized by the presence of

additional large crystals, located outside the collagen fibrils.

These large crystals (calcium-fluoride) which are not present in

either controls or osteoporotic bone before the fluoride treatment

contribute to increased mineral density with no improvement in

mechanical properties (ibid, 1994). Again, even for the select case

of axial vertebral fracture, U.S. randomized double-blind study shows

no beneficial effect (Zeigler, 1991) -- such that the subsequent FDA

Guidelines for Preclinical and Clinical Evaluation of Agents Used in

the Prevention of Treatment of Postmenopausal Osteoporosis (1994;

pub. 1997) states " the relation between increased bone mass density

and reduced fracture risk has been validated for patients receiving

estrogens, but not fluoride " . Yet, the fluoride proponents still keep

on trying (e.g., Gitomer, et al. 2000) to show what does NOT exist --

an efficacious balance between increased bone mass and deterioration

of the bone material properties. Similarly, an issue of Journal of

Dental Research (Turner, et al. 1995) states that fluoride affects

bone strength more severely in older animals – but the " responsible

mechanism " is unknown.

 

Etiology

 

Although it had been suggested that there may be a physiological

mechanism which homeostatically regulates plasma fluoride

concentrations resulting from ingestion, an extensive investigation

(Whitford and Williams, 1986) using four different methods (including

concentration in femur epiphyses) verified that plasma fluoride level

does NOT influence either the rate or degree of fluroide absorption

from the gut. During prolonged exposure of adult bone to fluoride,

the early uptake is variable and depends on the remodeling activity.

Regardless of whether or not the rate of uptake into bone stabilizes

at a maximum level following an initial period of increasing rapidity

(Boivin, et al. 1988), the effect is as follows. While simple in-

vitro soaking reduces rigidity with a 45% decrease in torsional

strength (Silva and Ulrich, 2000), the remodeling process is changed

by altering the normal balance between resorption and formation,

accompanied by a retardation of subsequent mineralization (Ream,

1981; Grynpas, 1990; Mohr, 1990; Dequeker and Declereck, 1993;

Kleerekoper, 1996). That the net result is reduced strength per unit

of bone has been confirmed based on fracture stress and x-ray

diffraction, even if no fluorosis or osteomalacia is observed

histologically (Turner, et al. 1997). That bone uptake as calcium-

fluoride in-vitro (Okazaki, et al. 1985) occurs in-vivo with a

concomitant reduction in strength has been confirmed (Kotha, et. al.

1998). And, the premise that this calcium-fluoride may effect the

interface bonding between the bone mineral and the organic matrix of

the bone tissue (ibid, 1998) is basically the same as the contention

(Walsh, et al. 1994) that the reduction in both the tensile and

compressive properties is attributable to " a constituent interfacial

de-bonding mechanism " . That is, after initial octacalcium-phosphate

nucleation (Bodier-Houlle, et al. 1998), a cartilaginous type matrix

results from abnormal mineralization during the matrix maturation

(Susheela and Jha, 1983), most likely due to the effects on

glycosaminoglycan and proteoglycan synthesis (Waddington and Langley,

1998).

 

Epidemiology

 

Fluoride is a cumulative toxin, adversely affecting the homeostasis

of bone mineral metabolism. Total ingested fluoride is the most

important factor determining the clinical course of osteo-fluorosis,

which is on the increase world-wide (Krishnamachari, 1986). A level

of 4-10 ppm in drinking water causes progressive ankylosis of various

joints and crippling deformities irrespective of other variables – as

evidenced by skeletal radiology and scintigraphy, cross-correlated

with urinary and serum fluoride levels (Gupta, et al. 1993). At

greater than 4-ppm for longer than 10-years (Haimanot, 1990) there is

generalized osteophytosis and sclerosis with reduction in diameter of

inter-vertebral foramina and spinal clonal. Animal studies (Turner,

et al. 1996) showed fluoridated water equivalent to only 3-ppm in

humans results in reduced bone strength after 6-months -- when

accompanied by renal deficiency. Similarly, comparison of a control

community having a fluoride content of 1-ppm and that of another with

a 4-ppm level (Sowers, et al. 1991) showed a 95% confidence-interval

(CI) for the 5-year relative risk (RR) for women of any fracture of

1.0-4.4 -- and for wrist, spine or hip it was 1.1-4.7. That such

increase in risk correlates with fluoride accumulation was

corroborated based on a study of toenail fluoride concentration in

more than 64,000 women (Feskanich, et al. 1998) -- comparing the

highest quartile against the lowest quartile provided a 95% CI 0.2-

4.0 for hip fracture RR, and 0.8-3.1 for forearm fracture. That

detrimental accumulation occurs due to water fluoridation at

the " public health goal " was shown by comparing fluoridated and non-

fluoridated areas (Alhava, et al. 1980) with the highest

accumulations being in women with severe osteoporosis. That reduction

in bone strength presents clinically at the " public health goal " --

the 95% CI RR for hip fracture of fluoridated vs non-fluoridated

(Jacobsen, et al. 1992) was 1.06-1.10 for women and 1.13-1.22 for

men. Similarly, for femoral neck fracture the 95% CI of RR was 1.08-

1.46 for women and 1.00-1.81 for men (Danielson, et al. 1992) -- and

a study (Kurttio, et. al. 1999) showed a 95% CI for hip fracture

among younger women of 1.16-3.76.

 

Related Considerations

 

During treatment with fluoride for spinal osteoporosis, some patients

suffered spontaneous bilateral hip fractures (Gerster, et al. 1983)

with histological examination revealing severe osteo-fluorosis --

attributed to excessive retention of fluoride due to renal

insufficiency. Fluoride is nephrotoxic, causing lesions of kidney

tubule (Kassabi, et al. 1981). Acute renal failure results from

accidental industrial exposure to fluoride (Usada, et al. 1998); with

the nephrotoxic effects related to serum fluoride level. Not only

does this result in aluminum deposition into bone (Ittel, et al.

1992); as fluoride elimination is via the kidney (Kono, 1994) and

decreased kidney function results in increasing serum fluoride, a

vicious cycle is not unlikely (Marumo and Li; 1996). Elevated PTH is

not uncommon in fluorosis (Srivastava, et al. 1989) and is a uremic

toxin playing a major role in nervous system dysfunction

(Smogorzewski and Massry, 1995) and development of hypertension

(Uchimoto, et al. 1995). Also, there is evidence that detrimental

effects on kidney function may occur at fluoride levels associated

with the " misuse " of fluoridated dentifrice by children (Borke and

Whitford; 1999). Finally, while CDC calls for a normal control range

for school fluoridation systems of up to 6.5-ppm (Water Fluoridation:

A manual for water plant operators; 1994) the following relate the

deleterious renal and other effects caused by a bottled mineral water

at 8.5-ppm (Alexandra, et al. 1984; Arlaud, et al. 1984; Noel, et al.

1985; Camous, et al. 1986; Boivin, et al. 1986; Lantz, et al. 1987;

Welsch, et al. 1990; Haettich, et al. 1991; Nicolay, et al. 1997 and

1999).

 

Some epidemiological studies indicate that men may have a greater

susceptibility to the detrimental effects of fluoride on bone

strength (Karagas, et al. 1996; inter-alia); a comparison of

fluoridated and non-fluoridated areas revealed a significant increase

in osteosarcoma among males under 30-years of age (Mahoney, et al.

1991); the animal model also produces male osteosarcomas (Bucher, et

al. 1991); and a gender-specific physiologically based pharmokinetic

model has been developed to describe the absorption, distribution and

elimination of fluoride (Rao, et al. 1995). Testosterone deficiency

is a major risk factor for male osteoporosis (Katznelson, 1998); and

fluoride correlates with decreased testosterone levels (Susheela and

Jethanandani, 1996), as well as reduced sperm count and motility

(Narayana and Chinoy, 1994). In most likelihood, this is the

causative factor for reduced fertility rate in areas of the U.S.

having fluoride levels of at least 3-ppm (Freni, 1994). That is,

based on the deleterious testicular effects in three different animal

models (Chinoy and Sequeira, 1989; Sushella and Kumar, 1991;

Krasowski and Wlostowski, 1992; Kumar and Sushella, 1994 and 1995)

this decrease in the total fertility rate due to ingested fluoride is

paternal in nature. As CDC now " celebrates " the fifty-years of water

fluoridation as being one of the greatest public health advances of

the century, the following have documented very significant

(approximately 50%) decrease in human semen quality (both seminal

volume and mean sperm density) concomitant with a very significant

(300-400%) increase in testicular cancer over the past fifty-years –

(Carlsen, et al. 1992; Giwercman, et al. 1993; Carlsen, et al. 1995;

Skakkebaek, et al. 1998; Medras and Jankowska, 1999; Sinclair, 2000).

While those references assert that this must be due to some (albeit

undetermined) environmental pollutant, the previous mentioned study

showing decreased total fertility rate in the areas of the U.S. with

water fluoride levels of at least 3-ppm (ibid, 1994) has a consensus

p-value of 0.0002 - 0.0004.

 

In addition to being a " reproductive effector " (due to both paternal

and maternal effects) the compound descriptors for sodium-fluoride in

the NIOSH Registry of Toxic Effects of Chemical Substances (RTECS)

also include " tumorigen " and " mutagen " . The latter is based on more

than 40 positive results including the following -- unscheduled DNA

synthesis and DNA inhibition of human fibroblast; cytogenic analysis

of human fibroblast, human lymphocyte, and other human cells;

mutation in human lymphocyte; and DNA inhibition in human lung.

Similarly, another review of genetic toxicity (Zeiger, et al. 1993)

states that gene mutations in human cells were produced in the

majority of cases, and " the weight of the evidence leads to the

conclusion that fluoride does result in increased chromosome

aberrations " .

 

The " painful lower extremity syndrome " from fluoride treatment has

been attributed (O'Duffy, et al. 1986) to stress fractures. An

associated fibromyalgia however, should not be dismissed out of hand.

It is associated with " chronic fatigue syndrome " , and there is a

relationship between chronic fatigue and pineal gland calcification

(Sandyk and Awerbuch, 1994) with the latter consisting of apatite

crystals similar in size and structure to dentin and bone (Nakamura,

et al. 1995). Thus, fluorides potential to acerbate soft-tissue

pathologies in general, deserves further consideration. Similarly,

the cognitive difficulties that result from exposure to fluoride

(Spittle, 1994) are accompanied by general malaise and fatigue;

intolerance to low levels of environmental chemicals is a

polysymptomatic sequela of chronic fatigue, fibromyalgia, etc.

resulting from an immunological and/or a neurogenic triggering of

somatic symptoms and inflammation (Bell, et al. 1998); and the

earliest subjective symptoms of osteo-fluorosis are arthritic in

nature.

 

Side-effects of fluoride treatment also include gastro-intestinal

problems simply referred to as -- " symptoms " (Riggs, et al.

1990); " intolerance " (Dequeker and Declerick, 1993); and " complaints "

(Lips, 1998). In two separate studies, the comparative results

between patients receiving fluoride treatment for 3-12 months (Das,

et al. 1994) and those having documented osteo-fluorosis (Dasarathy,

et al. 1996) were identical - 70% endoscopic abnormalities, 70-90%

histologic chronic atrophic gastritis; and 100% microscopic

abnormalities such as loss of microvilli. Moreover, these affects

were also qualitatively similar to a study (Gupta, et al. 1992) that

correlated non-ulcer dyspepsia with ingested fluoride level. As

expected, symptoms occurring at the (RTECS) human acute TDLo dosage

of only 214 ug/kg are gastrointestinal.

 

Similar to curing osteoporosis, fluoride has been proposed as a

preventive measure (sic) against Alzheimer's Disease (AD) based on

the presumption that by direct competition in the gut, fluoride would

decrease aluminum uptake (Kraus and Forbes, 1992). Rather, such

antagonism (Li, et al. 1990) is due to the formation of aluminum-

fluoride complex (Li, et al. 1991). That fluoride potentiates neuro-

toxicity of aluminum has been substantiated (van der Voet, et.al.

1999) -- consisting of interference with neuronal cytoskeleton

metabolism. Aluminum accumulations have been found in nuclei of the

paired-helical filament (PHF) containing neurons in the brains of

both AD patients and elderly normal controls (Shore and Wyatt, 1983)

but as no elevations of aluminum were found in serum or cerebrospinal

fluid of AD patients, aluminum alone is not the cause – rather,

aluminum in PHF bearing neurons is simply a " marker " . Fluoride had

been deemed to be a potent stimulator of bone formation (Farley, et

al. 1983), but most recent work indicates that the mitogenic effect

on osteoblasts is due to fluoro-aluminate (Caverzasio, et al. 1997;

Susa, et al. 1997) -- while another model claims the mitogenic action

is non-specific (Lau and Baylink,1998). In the animal model, 0.5-ppm

aluminum-fluoride for one-year resulted in decreased neuronal density

and " necrotic-like " brain-cells (Varner, et al. 1998). Also, fluoride

decreases protein content of brain tissue (Shashi, et al. 1994) with

7-months of 30-ppm fluoride resulting in a 10% decrease in total

brain phospholipid content (Guan, et.al. 1998) – as well as

(biphasic) changes in brain levels of coenzyme-Q (Wang, et al. 1997).

Osteo-fluorosis is endemic in certain regions of China (Dasheng and

Cutress, 1996) with detrimental effects of fluoride on the IQ of

children now being documented (Yang, et al. 1994; Li, et al. 1995).

 

Just as ingested fluoride has a deleterious effect on bone, the same

is true for developing teeth. Dental fluorosis (enamel hypoplasia) is

a form of lesion (Limeback, 1994; Fejerskov, et al. 1994) now having

an incidence (Clark, 1994) of 35-60% in fluoridated areas of N.

America. Most studies (Wiktorsson, et al. 1991; Kobayashi, et al.

1992; Frencken, et al. 1992; Ismail, et al. 1993; Vignarajah, 1993;

Hartshorne, et al. 1994; Cisternas, et al. 1994; Akpata, et al. 1997;

Ibrahim, et al. 1997; Wang and Riordan, 1999; Angelillo, et al. 1999)

show no statistically significant decrease in the incidence of dental

caries from ingested fluoride. Indeed, caries in permanent dentition

increase with increasing dental fluorosis (Mann, et al. 1990); the

odds ratio for developing dental fluorosis increases with decreasing

age of exposure (Ismail and Messer, 1996); caries decrease after

cessations of water fluoridation (Seppa, et al. 1998; Kunzel and

Fischer, 1997 and 2000); and incidence correlates with elevated blood

lead levels (Moss, et al. 1999) with the heavily fluoridated North-

Eastern U.S. having a greater incidence than the less fluoridated

Western portions. As the caries decrease over the past 50-years is

NOT due to water fluoridation (Miyazaki and Morimoto, 1996; Evans, et

al. 1996; Einarsdottir and Bratthall, 1996; de Liefde, 1998) general

consensus attributes it to fluoridated dentifrice. The extent of that

is now being questioned however (Nadanovsky and Sheiham, 1995;

Haugejorden, 1996); with speculation as to the actual cause including

changes in oral microbial flora (Einarsdottir and Bratthall, 1996)

and antibiotics (de Liefde, 1998).

 

Peer Review Journal References Cited in the Text – with more than 80%

of them being published within the past ten-years

 

Akapa, et al. (1997). Dental fluorosis in 12-15-year-ol rural

children exposed to fluorides from well drinking water in the Hail

region of Saudi Arabia. Community Dent Oral Epidemiol; 25(4): 324-327.

 

Alexandre, et al. (1984). Fluoride poisoning caused by Vichy Saint-

Yorre water. [title only; article in French]. Presse Med; 13(16);

1009.

 

Alhava, et al. (1980). The effect of drinking water fluoridation on

the fluoride content, strength and mineral density of human bone.

Acta Orthop Scand; 51(3): 413-420.

 

Angelillo, et al. (1999). Caries and fluorosis prevalence in

communities with different concentrations of fluoride in the water.

Caries Res; 33(2):114-122.

 

Arlaud, et al. (1984). Osteomalacia disclosing bone fluorosis caused

by regular consumption of Vichy Saint-Yorre mineral water. [title

only; article in French]. Presse Med; 13(39); 2393-2394.

 

Arnala, et al. (1985). Effects of fluoride on bone in Finland:

histomorphometry of cadaver bone from low and high fluoride areas.

Acta Orthop Scand; 56(2): 161-166.

 

Balena, et al. (1998). Effect of different regimens of sodium

fluoride treatment for osteoporosis on the structure, remodeling and

mineralization of bone. Osteoporos Int: 8(5): 428-435.

 

Bell, et al. (1998). Serum neopterin and somatization in women with

chemical intolerance. Neuropsychobiology; 38(1): 13-18.

 

Bodier-Houlle, et al. (1998). First experimental evidence for human

dentin crystal formation involving conversion of octacalcium

phosphate to hydroxyapitite. Acta Crystallogr D Biol Crystallogr; 54

(2 – Pt 6): 1377-1381.

 

Boivin, et al. (1986). Histophometric profile of bone fluorosis

induced by prolonged ingestion of Vichy Saint-Yorre water. Comparison

with bone fluorine levels. Pathol Biol; 43(1): 33-39.

 

Boivin, et al. (1988). Fluoride content in human iliac bone: results

in controls, patients with fluorosis, and osteoporotic patients

treated with fluoride. J Bone Miner Res; 3(5): 497-502.

 

Boivin, et al. (1989). Skeletal fluorosis: histomorphometric analysis

of bone changes and fluoride content in 29 patients. Bone; 10(2): 89-

99.

 

Borke and Whitford (1999). Chronic fluoride ingestion decreases 45Ca

uptake by rat kidney membranes. J Nutr; 129(6): 1209-1213.

 

Bucher, et al. (1991). Results and conclusions of the National

Toxicology Program's rodent carcinogenicity studies with sodium

fluoride. Int J Cancer; 48(5): 733-737.

 

Camous, et al. (1986). [title only; article in French]. Hypokalemia

with severe rhythm disorders induced by Vichy water. Presse Med; 15

(44): 2212-2213.

 

Carlsen, et al. (1992). Evidence for decreasing quality of semen

during past 50 yrs. BMJ; 305(6854): 609-613.

 

Carlsen, et al. (1995). Declining semen quality and increasing

incidence of testicular cancer: is there a common cause? Environ

Health Perspect; 103 (Suppl 7): 137-139.

 

Carter and Beaupre (1990). Effects of fluoride treatment on bone

strength. J Bone Miner Res; 5(suppl 1): 177-184.

 

Caverzasio, et al. (1997). Mechanism of the mitogenic effect of

fluoride on osteoblast-like cells: evidences for G protein-dependent

tyrosine phosphorylation process. J Bone Miner Res; 12(12): 1975-1983.

 

Chinoy and Sequeiera (1989). Effects of fluoride on histoarchitecture

and reproductive organs in male mouse. Reprod Toxicol; 3(4): 261-267.

 

Clark (1994). Trends in prevalence of dental fluorosis in North

America. Community Dent Oral Epidemiol; 22(3): 148-152.

 

Cisternas, et al. (1994). Dietary ingestion of fluoride and caries

prevalence in preschool and school children in cities with different

fluoride content in the drinking water and diet. Rev Med Chil; 122

(4): 459-464.

 

Danielson, et al. (1992). Hip fractures and fluoridation in Utah's

elderly population. JAMA; 268(6): 746-748.

 

Das, et al. (1994). Toxic effects of chronic fluoride ingestion on

the upper gastrointestinal tract. J Clin Gastroenterol; 18(3): 194-

199.

 

Dasarathy, et al. (1996). Gastroduodenal manifestations in patients

with skeletal fluorosis. J Gastroenterol; 31(3): 333-337.

 

Dasheng and Cutress (1996). Endemic fluorosis in Guizhou Province,

China. World Health Forum; 17(2): 173-174.

 

de Liefde (1998). The decline of caries in New Zealand over the past

40 years. N Z Dent J; 94(417): 109-113.

 

Dequeker and Declerick (1993). Fluor in the treatment of

osteoporosis: an overview of thirty years of clinical research.

Schweiz Med Wochenschr; 123(47): 2228-2234.

 

Diesendorf, et al. (1997). New evidence on fluoridation. Aust N Z J

Public Health; 21(2): 187-190.

 

Einarsdottir and Bratthall (1996). Restoring oral health. On the rise

and fall of dental caries in Iceland. Eur J oral Sci; 104(4 Pt 2):

459-469.

 

Evans, et al. (1996). The effect of fluoridation and social class on

caries experience in 5-year-old Newcastle children in 1994 compared

with results over the previous 18 years. Community Dent Health; 13

(1): 5-10.

 

Farley, et al. (1983). Fluoride directly stimulates proliferation and

alkaline phosphatase activity of bone-forming cells. Science; 222

(4621): 330-332.

 

Fejerskov, et al. (1994). Dental tissue effects of fluoride. Adv Dent

Res; 8)1): 15-31.

 

Feskanich, et al. (1998). Use of toenail fluoride levels as an

indicator for the risk of hip and forearm fractures in women.

Epidemiology: 9(4): 412-416.

 

Fratzl, et al. (1994). Abnormal bone mineralization after fluoride

treatment in osteoporosis: a small-angle x-ray-scattering study. J

Bone Miner Res; 9(10): 1541-1549.

 

Fratzl, et al. (1996). Effects of Na-F and alendronate on the bone

mineral in minipigs: small-angle x-ray scattering and backscattered

electron imaging study. J Bone Miner Res; 11(2): 248-253.

 

Frencken, et al. (1992). Exposure to low levels of fluoride and

dental caries in deciduous molars of Tanzanian children. Caries Res;

26(5): 379-383.

 

Freni (1994). Exposure to high fluoride concentrations in drinking

water is associated with decreased birth rates. J Toxicol Environ

Health; 42(1): 109-121.

 

Gerstner, et al. (1983). Bilateral fractures of femoral neck in

patients with moderate renal failure receiving fluoride for spinal

osteoporosis. Br Med J (Clin Res Ed); 287(6394): 723-725.

 

Gitomer, et al. (2000). A comparison of fluoride bioavailability from

a sustained-release NaF preparation (Neosten) and other fluoride

preparations. J Clin Pharmacol; 40(2): 138-141.

 

Giwercman, et al. (1993). Evidence for increasing incidence of

abnormalities of the human testis: a review. Environ Health Perspect;

101(Suppl 2): 65-71.

 

Grynpas (1990). Fluoride effects on bone crystals. J Bone Miner Res; 5

(suppl 1): 169-175.

 

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