Effects of Fluoride on Bone

FLUORIDE & BONE – SKELETAL FLUOROSIS
APPENDIX X
Excessive exposure to fluoride causes an arthrtiic bone disease called skeletal fluorosis. Skeletal fluorosis, especially in its early stages, is a difficult disease to diagnose, and can be readily confused with various forms of arthritis including osteoarthritis, and rheumatoid arthritis. In the advanced stages, fluorosis can resemble a multitude of bone/joint diseases, including: osteosclerosis, renal osteodystrophy, DISH, spondylosis, osteomalacia, osteoporosis, and secondary hyperparathyroidism. The risk of developing fluorosis, and the course the disease will take, is influenced by the presence of certain predisposing factors, including impaired kidney function; dietary deficiencies; gastric acidity; and repetitive stress. While only a limited number of studies have documented the disease in the U.S., it is almost certain that other cases of the disease have occurred but escaped detection. Fluoride & Bone - Bone Fracture: (Click for more detail) 1) The vast majority of animal studies investigating fluoride's effect on bone strength, have found fluoride to have either no effect or a negative effect on strength. Very few animal studies have found a beneficial effect. 2) Studies on human populations consuming fluoride in drinking water, have found an association between dental fluorosis and increased bone fracture in children; and between long-term consumption of fluoridated water and increased hip fracture in the elderly. 3) Carefully conducted human clinical trials - including two "double-blind trials" - have found that fluoride (at doses of 18-34 mg/day for just 1-4 years) increases the rate of bone fracture, particularly hip fracture, among osteoporosis patients. 4) Animal studies and human clinical trials indicate that fluoride can reduce bone strength before skeletal fluorosis is present. Fluoride & Bone - Research Gaps: 1) No systematic research exploring the incidence of skeletal fluorosis among susceptible subsets of the population including heavy tea-drinkers and people with kidney disease. 2) Other than 3 small, limited studies from the 1950s-1960s (Steinberg 1955, 1958; Ansell 1965), no research exploring the relationship between fluoride exposure and arthritis in the general population. 3) No comprehensive research exploring the doses of fluoride capable of producing the early stages of skeletal fluorosis, and how such doses vary based on the presence or absence of predisposing factors. 4) No research exploring how genetics may influence the risk and nature of fluoride-induced bone effects in the general population. 5) No comprehensive data in the US on the levels of fluoride in the bone and blood of individuals in fluoridated communities and the relationship of these levels to bone changes.

Fluoride & Bone - CONTENTS of DATABASE: A) Fluoride & Bone Fracture: The vast majority of animal studies investigating fluoride's effect on bone strength, have found fluoride to have either no effect or a negative effect on strength. Very few animal studies have found a beneficial effect. Studies on human populations consuming fluoride in drinking water, have found an association between dental fluorosis and increased bone fracture in children; and between long-term consumption of fluoridated water and increased hip fracture in the elderly. Carefully conducted human clinical trials - including two "double-blind trials" - have found that fluoride (at doses of 1834 mg/day for just 1-4 years) increases the rate of bone fracture, particularly hip fracture, among osteoporosis patients. Animal studies and human clinical trials indicate that fluoride can reduce bone strength before skeletal fluorosis is present. SOURCE: Danielson C, et al. (1992). Hip fractures and fluoridation in Utah's elderly population. Journal of the American Medical Association 268: 746-748. Hip fractures in Fluoridated vs Unfluoridated Areas (England) SOURCE: Cooper C, et al. (1991). Water fluoridation and hip fracture. Journal of the American Medical Association 266: 513-514. Hip fractures vs Fluoride Level in Water (China) SOURCE: SOURCE: Li Y, et al. (2001). Effect of long-term exposure to fluoride in drinking water on risks of bone fractures. Journal of Bone and Mineral Research 16:932-9. Bone fractures vs Dean dental fluorosis index SOURCE: Alarcon-Herrera MT, et al. (2001). Well Water Fluoride, Dental fluorosis, Bone Fractures in the Guadiana Valley of Mexico. Fluoride 34(2): 139-149. (See paper) Contents of Database - Fluoride & Bone Fracture: Data Compilation:

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Fluoride & Bone Strength Epidemiology on Fluoride & Bone Fracture Fluoride-Induced Bone Fractures in Human Clinical Trials Mechanisms by which fluoride may reduce bone strength

Summation - Fluoride & Bone Strength: Most animal studies investigating how fluoride effects bone strength have found a detrimental effect, or no effect. Very few animal studies have found a beneficial effect. One study that did find a beneficial effect was unable to be repeated by the authors in a later experiment (Turner 1992, 1995). There are several plausible mechanisms by which fluoride could reduce bone strength. Fluoride can reduce the strength of bone before it causes detectable skeletal fluorosis. In skeletal fluorosis, the bone becomes brittle and prone to fracture. Notable Quotes - Fluoride & Bone Strength: "Fracture risk and bone strength have been studied in animal models. The weight of evidence indicates that, although fluoride might increase bone volume, there is less strength per unit volume." SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p5. "[O]ne cannot help but be alarmed by the negative effects of fluoride on bone strength consistently demonstrated in animal models." SOURCE: Turner CH. (1996). Fluoride and the FDA: a curious case. (letter) Journal of Bone and Mineral Research 11(9):1369-71. "Several animal studies on fluoride’s effect on bone biomechanical competence have been performed... [A]n overwhelming majority of the investigations mentioned found no effect or a negative effect of fluoride on bone strength..." SOURCE: Sogaard CH, et al. (1995). Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone 16: 163-9. Excerpts from Scientific Literature - Animal Studies: "In A/J strain, we found significant decreases in stiffness with increasing fluoride dose treatment. There was a significant difference between the treatment group 0 ppm and 100 ppm... In the A/J strain, there was a decrease in ultimate load with increasing fluoride dose treatment, with significant differences between the treatment group 0 ppm and the treatment group 100 ppm (p=0.017)." SOURCE: Mousny M, et al. (2006). The genetic influence on bone susceptibility to fluoride. Bone Aug 18; [Epub ahead of print] "In group treated with NaF both the strength and stiffness were significantly decreased when compared with those in ovariectomized control." SOURCE: Czerny B, et al. (2004). The Effect of Tamoxifen and Fluoride on Bone Mineral Density, Biomechanical Properties and Blood Lipids in Ovariectomized Rats. Basic & Clinical Pharmacology & Toxicology 92:162–165. "The highest fluoride intake (50 mg/L) significantly diminished vertebral strength... This impairment of mineralization by fluoride appeared to be the primary cause of the diminished vertebral strength." SOURCE: Turner CH, et al. (2001). Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International 69: 51-57. "Bending strength of the femoral shaft decreased significantly after fluoride therapy. We conclude that high fluoride intake decreases bone quality of the femoral shaft and neck in young growing rats." SOURCE: Bohatyrewicz A. (1999). Effects of fluoride on mechanical properties of femoral bone in growing rats. Fluoride 32: 47-54. "In this study, despite the observed increased in hardness of both cancellous and cortical bone, the fracture stress and elastic modulus of vertebrae tested in compression and femora tested in three-point bending were decreased by fluoride treatment."

SOURCE: Chachra D, et al. (1999). The effect of fluoride treatment on bone mineral in rabbits. Calcified Tissue International 64:345-351. "It is likely that the bone changes induced by fluoride will lead to an impaired biomechanical competence of antlers from deer inhabitating regions with higher levels of environmental fluoride. We, therefore, would expect to find an increased incidence of antler breakage in such populations." SOURCE: Kierdorf U, et al. (1997). Fluoride content and mineralization of red deer (Cervus elaphus) antlers and pedicles from fluoride polluted and uncontaminated regions. Archives of Environmental Contamination and Toxicology 32: 222-227. "Fluoride treatment reduced all biomechanical measurements. The reductions ranged from 5% to 25%. Several of these reductions were statistically significant: the fracture force of the femoral neck was reduced by 25%, the fracture stress of the L-5 vertebra was reduced by 19%, and the bending modulus of the femur was reduced by 21%." SOURCE: Turner CH, et al. (1997). Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbits. Calcified Tissue International 61:77-83. "Fluoride concentrations of 15 and 50 ppm reduced femoral bone strength in renal-deficient animals. Femoral bone strength also was reduced in control animals given 50 ppm fluoride." SOURCE: Turner CH, et al. (1996). High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency. Bone 19:595-601. "NaF reduced the strength of cancellous bone from the L4 vertebrae, relative to the control animals, and the stiffness (resistance to deformation) of the femora." Bone strength "did not increase with bone volume, suggesting that for bones with higher volume, there was less strength per unit volume, that is, a deterioration in bone 'quality.'" SOURCE: Lafage MH, et al. (1995). Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. Journal of Clinical Investigations 95(5):2127-33. "Load corrected for ash content, which is a measure of bone quality, decreased significantly after fluoride therapy. It is concluded that the increase in bone mass during fluoride treatment does not translate into an improved bone strength and that the bone quality declines. This investigation thereby supports the hypothesis of a possible negative effect of fluoride on bone quality." SOURCE: Sogaard CH, et al. (1995). Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone 16(1): 163-9. "To date, animal studies of fluoride effects on bone have used young and healthy experimental animals exclusively. The effects of fluoride on old animals, that more closely represent people most likely to fracture, have not been studied.... In older rats receiving 50 ppm fluoride, failure stress was decreased by as much as 29%. Such dramatic losses in bone strength only have been shown previously in studies where fluoride intake was accompanied by calcium deficiency, yet, in this study, calcium intake in the older rats was no different from that in the younger rats... [I]t is possible that aging effects and fluoride incorporation in the bone act synergistically to decrease bone strength." SOURCE: Turner CH, et al. (1995). Fluoride reduces bone strength in older rats. Journal of Dental Research 74:1475-81. "[S]everal investigators - including ourselves - have shown that bone strength decreases as bone fluoride levels in the mineral phase increase to beyond about 4500 ppm." SOURCE: Turner CH, Dunipace AJ. (1993). On fluoride and bone strength (letter). Calcified Tissue International 53: 289-290. "Interfacial bonding interactions between the mineral and organic constituents of bone play an important role in the mechanical properties of cortical bone... Under a uniaxial tensile force, modification of interfacial bonding by phosphate and fluoride ions results in a reduction in the ultimate and yield stress and elastic modulus. In tension, phosphate ions effect is reversible upon removal of phosphate ions, while the fluoride ion effect is irreversible. Interestingly, when tested in compression, phosphate ion treatment results in a stiffening effect, while fluoride ions continue to lower the ultimate stress and elastic modulus." SOURCE: Walsh WR, Guzelsu N. (1993). The role of ions and mineral-organic interfacial bonding on the compressive properties of cortical bone. Bio-medical materials and engineering 3: 75-8 "The results demonstrate that water fluoride levels of 1 ppm may lead to increased bone strength, while water fluoride levels of 4 ppm would be expected to cause a decrease in bone strength."

SOURCE: Turner CH, et al. (1992). The effects of fluoridated water on bone strength. Journal of Orthopedic Research 10:581-7. (NOTE: In subsequent studies, Turner was unable to duplicate the beneficial effects on bone strength which he found at low doses in this study. As Turner noted in a more extensive, follow-up study: "the present results showed no evidence of increased bone strength resulting from fluoride levels below 16 ppm." - Ref:: J Dent Res; 1995; Vol 74: 1475-81.) "Bone quality seemed to be affected since significant decreases in bone-breaking strength and significant increases in bone mineralization were observed in fluoride-treated kestrels. When the breaking strength (LOAD) was expressed as the maximum load the bone can carry, no significant differences were detected among groups. However, when these figures are used to calculate the maximum stress the bone can resist, bone quality clearly decreased as more fluoride was added to the diet of the growing kestrels." SOURCE: Bird DM, Carriere D, Lacombe D. (1992). The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Archives of Environmental Contamination and Toxicology 22:242-6. "The reduction in interfacial bonding due to fluoride action lowers the mechanical properties of bone tissue." SOURCE: Walsh WR, Guzelsu N. (1991). Fluoride ion effect on interfacial bonding and mechanical properties of bone. Journal of Biomechanics 24: 237. "[T]he mechanical parameters for the fluorotic animals were unchanged...or decreased...It is concluded that the increased bone mass during the initial stages of fluoride treatment does not necessarily indicate an improved bone quality." SOURCE: Mosekilde L, et al. (1987). Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcified Tissue Research 40: 318-322. "The data reported herein suggested that levels of dietary F greater than 7 ppm are detrimental to bone integrity. Breaking stress and modulus of elasticity were reduced significantly at each level of added dietary F in both experiments. Similar observations have been made with nearly all species that have been subjected to F ingestion." SOURCE: Burnell TW, et al. (1986). Effect of dietary fluorine on growth, blood and bone characteristics of growingfinishing pigs. Journal of Animal Science 63(6):2053-67. "Thirty-six young rats were used to determine the effect of the fluoride on collagen synthesis in healing of fracture... Collagen synthesis of the callus was examined histochemically and histologically. In the fluoride-treated group, collagen synthesis was found to be defective, while it was normal in the controls." SOURCE: Uslu B. (1983). Effect of fluoride on collagen synthesis in the rat. Research and Experimental Medicine 182:7-12. "In the present study high levels of fluoride in the drinking water did not prevent osteoporosis, but in some experiments, by certain criteria, tended to increase it." SOURCE: Robin JC, et al. (1980). Studies on osteoporosis III. Effect of estrogens and fluoride. Journal of Medicine 11(1):1-14. "F at high levels, tended to decrease bone ash, cortical thickness, and mechanical strength parameters." SOURCE: Guggenheim K, et al. (1976). The effect of fluoride on bone of rats fed diets deficient in calcium or phosphorus. Calcified Tissue Research 22: 9-17. "The strength of osteopenic bone from calcium deprived rats, quail and roosters was significantly reduced after fluoride supplementation...This detrimental effect on bone strength must be considered in any therapeutic attempt to use fluoride ion to stimulate bone formation in osteopenic bone disorders." SOURCE: Riggins RS, et al. (1976). The effect of fluoride supplementation on the strength of osteopenic bone. Clinical Orthopedics (114):352-7. "The administration of sodium fluoride increased bone diameter, indicating stimulation of periosteal bone formation, but bone strength was reduced or not affected by fluoride ingestion." SOURCE: Riggins RS, et al. (1974). The Effects of Sodium Fluoride on Bone Breaking Strength. Calcified Tissue Research 14: 283-289. "Our observations corroborate the findings that, in general, elevated dietary fluoride results in an acceleration of bone mineralization. Uniquely, however, the increase in mineralization was accompanied by a decrease in bone strength...

the changes in bone that occur with prolonged and excessive fluoride ingestion may result in a reduction of bone strength." SOURCE: Chan MM, et al. (1973). Effect of Fluoride on Bone Formation and Strength in Japanese Quail. Journal of Nutrition 103: 1431-1440. "Femurs of fluoride-treated rats exhibited a decrease in mechanical strength as manifested by a decrease in ultimate stress to breaking as well as decrease in limit and modulus of elasticity." SOURCE: Wolinsky I, et al. (1972). Effects of fluoride on metabolism and mechanical properties of rat bone. American Journal of Physiology 223: 46-50. "In the low calcium group a similar significant increase in flexibility appeared at the 10.0 ppm dosage level as well as the 45.0 ppm, but a significant decrease in strength at the two dosage levels were observed. These were in direct relation to the amount of fluoride given." SOURCE: Beary DF. (1969). The effects of fluoride and low calcium on the physical properties of the rat femur. Anatatomical Record 164: 305-316. "[T]he heavily fluorinated bone tended to break under less stress than did bone from any other group. These findings suggest that the heavily fluorinated bone was not as strong as the bone from normal rats or from rats fed low-calcium diets without fluoride." SOURCE: Daley R, et al. (1967). The Effects of Sodium Fluoride on Osteoporotic Rats. The Journal of Bone and Joint Surgery (Abstract). 49A:796. "[T]he decrease in the mean breaking strength was significant statistically" among the fluoride-treated rats, and "is in agreement with the known fact that the breaking strength of bone decreases with increased fluoride intake." SOURCE: Gedalia I, et al. (1964). Effects of Estrogen on Bone Composition in Rats at Low and High Fluoride Intake. Endocrinology 75: 201-205. "Cristiani working with guinea pigs found that the fragility of the bones was increased about 20 per cent in the fluorized animals." SOURCE: Dean HT. (1936). Chronic endemic dental fluorosis. Journal of the American Medical Association 107: 1269-1273. Excerpts from Scientific Literature - Bone Strength in Skeletal Fluorosis: (back to top) "The bones are subject to easy fracture." SOURCE: Blood DC, Henderson JA, Radostits OM, eds. (1979). Veterinary Medicine: A Textbook of the Diseases of Cattle, Sheep, Pgs and Horses. 5th Edition. Lea & Febiger, Philadelphia. "The bone was brittle and shattered easily when cut on a bandsaw." SOURCE: Krook L, Maylin GA. (1979). Industrial fluoride pollution. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Veterinarian 69(Suppl 8): 1-70. "fluorotic specimens had a lower tensile strength and strain but a higher compressive strength and strain than the nonfluorotic ones." SOURCE: Gaynor F, et al. (1976). Mechanical properties and density of bone in a case of severe endemic fluorosis. Acta Orthopaedica Scandinavica 47: 489-495. "Lameness, pain, exostoses, emaciation, and bone fractures were symptoms associated with horses exposed to F ingestion." SOURCE: Lillie RJ. (1970). Air Pollutants Affecting the Performance of Domestic Animals: A Literature Review. U.S. Dept. of Agriculture. Agricultural Handbook No. 380. Washington D.C. "The first sign of fluorosis in cattle (and probably also in deer) is mottling, pitting, and black discoloration of the teeth. Affected teeth are soft and show abnormal wear. Later the leg and foot bones may become deformed or fractured, resulting in lameness." SOURCE: Karstad L. (1967). Fluorosis in deer (Odoceileus virginianus). Bulletin of the Wildlife Disease Association 3:42-46.

"In advanced skeletal fluorosis the bones are brittle." SOURCE: Adams PH, Jowsey J. (1965). Sodium fluoride in the treatment of osteoporosis and other bone diseases. Annals of Internal Medicine 63: 1151-1155. "In the macerated cattle specimens the bone was brittle and crumbled readily. The new bone was as fragile as chalk..." SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press (1965) 424-441. "One of the most prominent features of fluorosis in cattle in England, however, was the frequency of actue severe lameness, especially in the early summer. It resembled that described by Towers (1954) who associated it with fracture of the pedal bone (3rd phalanx)....This suggests that traumatic factors played a part in producing the lameness by causing damage to bones which were relatively fragile as a result of skeletal accumulation of fluorine..." SOURCE: Burns KN, Allcroft R. (1964). Fluorosis in Cattle. 1 - Occurrence and Effects in Industrial Areas of England and Wales 1954-57. Ministry of Agriculture, Fisheries and Food. Animal Disease Surveys Report No 2, Part I. Her Majesty's Stationery Office, London. "Increased fragility of the bones may be present, and they can be friable and crumbly." SOURCE: Kumar SP, Harper RA. (1963). Fluorosis in Aden. British Journal of Radiology 36: 497-502. "During the examination of the Achintee sheep, an unusally large number of fractures were detected; these involved ribs, mandible, and pelvis." SOURCE: Agate JN, et al. (1949). Industrial fluorosis: A study of the hazard to man and animals near Fort William, Scotland. Medical Research Council Memorandum No. 22. His Majesty's Stationery Office, London. "High fluorine levels interfere with mineral metabolism and cause abnormal growth of bone that may be structurally weak." SOURCE: Huffman WT. (1949). Effects on livestock of air contamination caused by fluoride fumes. In: Air Pollution. Proceedings of the United States Technical Conference on Air Pollution. McGraw-Hill Book Co, New York. pp. 59-63. "The bone is abnormally brittle." SOURCE: Lyth O. (1946). Endemic fluorosis in Kweichow, China. The Lancet 1: 233-235 "The osteomalacic condition (of fluorosis) to some extent varies with the species and age of the animal. Certain features are common, however... Common features are the reduced strength of the bones, the tendency to form exostoses, bone atrophy, and a deficient calcification." Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. H.K. Lewis Ltd, London. Key Findings - Fluoride-Induced Bone Fractures in Clinical Trials: 1) Due to its ability to increase bone mass, fluoride has been used as a treatment for osteoporosis. However, despite 40 years of experimentation, fluoride remains an experimental drug as of 2005, with current use mostly confined to special research clinics. 2) A well documented side-effect from fluoride therapy (doses = 20-34 mg/day) is increased bone fracture. The increased fractures observed among fluoride-treated patients have been found to occur most frequently in the appendicular skeleton region (arms, legs, and hip). 3) One of the most common sites for fluoride-induced fracture has been the hip - more specifically, the femoral neck. Several clinical trials have reported a particularly high rate of spontaneous fracture in the the femoral neck among fluoride-treated patients. 4) The high rate of spontaneous fracture among fluoride-treated patients may relate to the increase in incomplete fractures (i.e. "stress fractures") well-documented among fluoride-treated patients. 5) Other well documented side effects of fluoride treatment include: gastrointestinal disorders, 'lower-extremity pain syndrome' (which may be a result of stress fracture), and osteomalacia.

Published Data - Daily Fluoride Dose in Clinical Trials Reporting Increased Bone Fractures: Average Daily Dose (mg/day) 25 20.7 22.7 32 22.7 20.9 27.8 23.7 34.1 27*** 24.5 26.2 Average Daily Dose (mg/kg) 0.41 0.35 0.37 0.52 0.37 0.36 0.46 0.40 0.56 0.45 0.41 0.43

Trial Inkovaara 1975 Gerster 1983** Gerster 1983** Dambacher 1986 Hedlund 1989 Bayley 1990 Gutteridge 1990 Orcel 1990 Riggs 1990 Schnitzler 1990 Gutteridge 2002 AVERAGE

Age of Patients 78.4 69 78 63.5 67.7 65.3 68.2 69 68.2 63.6 70.9 68.8

Length of Treatment 8 months 11 months 21 months 3 years 2.1 years 4 years 3.4 years 17.1 months 4 years 2 years, 7 months 18 of 27 months 2 years, 6 months

Average Weight of Patients* (kg) 60 60 60 61.7 60 57.7 60 60 61 60 60.2 --

* In trials where the average weight of the patients is not given, the weight is assumed to be 60 kg, which appears to the the rough average for osteoporosis patients (comprised mostly of females). ** The data from Gerster’s two case studies are listed separately but are averaged together and treated as one trial for the overall average (bottom row). *** Schnitzler provides the fluoride dose in terms of mg/kg/day, but does not provide the average weight of the patients. The 27 mg/day figure used here is based on the assumption that the average weight of Schnitzler’s patients is 60 kg. Excerpts from the Scientific Literature - Fluoride-Induced Bone Fractures in Clinical Trials: "Vertebral fracture rates and peripheral bone density changes were surprising - and demonstrate that NaF administration is capable of increasing vertebral fracture rates and of increasing peripheral (nonspinal) bone loss. Thus our study demonstrates the potential for an anti-osteoporosis agent, under certain circumstances, to worsen a patient's clinical state." SOURCE: Gutteridge DH, et al. (2002). A randomized trial of sodium fluoride (60 mg) +/- estrogen in postmenopausal osteoporotic vertebral fractures: increased vertebral fractures and peripheral bone loss with sodium fluoride; concurrent estrogen prevents peripheral loss, but not vertebral fractures. Osteoporosis International 13:158-70. "We conducted an effectiveness meta-analysis to determine the efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures and side effects in postmenopausal women...[A]lthough fluoride has an ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. Increasing the dose of fluoride increases the risk of nonvertebral fractures and gastrointestinal side effects without any effect on the vertebral fracture rate." SOURCE: Haguenauer D, et al. (2000). Fluoride for the treatment of postmenopausal osteoporotic fractures: a metaanalysis. Osteoporosis International 11:727-38. "In this investigation, we found that after 5 years of fluoride treatment of osteoporotic patients, iliac crest trabecular bone strength was reduced by 46-56% compared with pretreatment biopsies. Also, 1 year of fluoride administration seemed to reduce bone strength by 17-30%, though this was not a significant finding... [T]he results of this study support the investigations that have found an increased rate of nonvertebral fractures, and a reduction in strength could well be a direct effect of fluoride on trabecular bone." SOURCE: Sogaard CH, et al. (1994). Marked decrease in trabecular bone quality after five years of sodium fluoride therapy--assessed by biomechanical testing of iliac crest bone biopsies in osteoporotic patients. Bone 15: 393-99. "Bone fragility during fluoride therapy for osteoporosis was observed in 24 (37.5%) of 64 patients treated with sodium fluoride, calcium, and vitamin D for 2.5 years who developed episodes of lower-limb pain during treatment. Eighteen

(28%) of these patients had clinical and roentgenographic features of 41 stress fractures and 12 new spinal fractures. There were 26 periarticular, six femoral neck, three pubic rami, three tibia and fibula, one greater trochanter, and two subtrochanteric fractures. Vertebral fractures appeared first, then periarticular, then femoral neck, and lastly longbone shaft fractures. All fractures were spontaneous in onset. The peripheral fracture rate during treatment was three times that in untreated osteoporosis." SOURCE: Schnitzler CM, et al. (1990). Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis. Clinical Orthopedics (261):268-75. Fluoride treatment was "associated with a significant three-fold increase in the incidence of nonvertebral fractures, both incomplete and complete...This increased rate of fracturing suggests that bone formed during fluoride therapy has increased fragility." SOURCE: Riggs BL, et al. (1990). Effect of Fluoride treatment on the Fracture Rates in Postmenopausal Women with Osteoporosis. New England Journal of Medicine 322:802-809. "Using all 61 fluoride-treated patients, femur fractures/patient were significantly correlated to bone fluoride (p less than 0.05) and to age (p less than 0.05)... These results suggest that fluoride therapy may be implicated in the pathogenesis of hip fractures which may occur in treated patients despite a rapid, marked increase in bone mass." SOURCE: Bayley TA, et al. (1990). Fluoride-induced fractures: relation to osteogenic effect. Journal of Bone and Mineral Research 5(Suppl 1):S217-22. "We report clinical and bone morphometric findings in 18 osteoporotic patients who experienced stress fractures during fluoride therapy... Fluoride appears to be a key factor in the pathogenesis of stress fractures, and may be associated with increased trabecular resorption in some treated patients." SOURCE: Orcel P, et al. (1990). Stress fractures of the lower limbs in osteoporotic patients treated with fluoride. Journal of Bone and Mineral Research 5(Suppl 1): S191-4. "[T]he six hip fractures occurring in patients receiving fluoride during 72.3 patient years of treatment is 10 times higher than would be expected in normal women of the same age. The probability of observing six fractures in 2 years is extremely small (0.0003). In four of the hip fracture cases, the history suggested a spontaneous fracture. These findings suggest that fluoride treatment can increase the risk of hip fracture in osteoporotic women." SOURCE: Hedlund LR, Gallagher JC. (1989). Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. Journal of Bone and Mineral Research 2:223-5. "Thirteen cases of spontaneous fissure or fracture of the lower limbs observed in 8 patients under treatment with sodium fluoride are reported... Fluor seems to be responsible for the fissures which cannot be avoided by calcium and/or vitamin D intake... When such fissures occur, fluoride therapy must be discontinued and the limb put at rest..." Orcel P, et al. (1987). [Spontaneous fissures and fractures of the legs in patients with osteoporosis treated with sodium fluoride]. Presse Med 16:571-5. "How fluoride can produce stress microfractures is unclear. That they are complications of fluoride therapy is clear, as there were no microfractures in the 101 patients in the calcium-treated group." SOURCE: O'Duffy JD, et al. (1986). Mechanism of acute lower extremity pain syndrome in fluoride-treated osteoporotic patients. American Journal of Medicine 80: 561-566. "[T]he increased number of new crush fractures of the spine during the first year of treatment raise the possibility of fluoride-induced microfractures." SOURCE: Dambacher MA, et al. (1986). Long-term fluoride therapy of postmenopausal osteoporosis. Bone 7: 199205. "Two patients with moderate renal failure sustained spontaneous bilateral hip fractures during treatment with fluoride, calcium, and vitamin D for osteoporosis....As bilateral femoral neck fractures are very rare these data suggest a causal link between fractures and fluoride in patients with renal failure. Thus fluoride should be given at a lower dosage, if at all, to patients with even mild renal failure." SOURCE: Gerster JC, et al. (1983). Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis. British Medical Journal (Clin Res Ed). 287(6394):723-5. "During treatment bone pain increased and three further vertebral compression fractures occurred." SOURCE: Compston JE, et al. (1980). Osteomalacia developing during treatment of osteoporosis with sodium fluoride and vitamin D. British Medical Journal 281: 910-911.

"Fractures and exacerbation of arthrosis were more frequent in the fluoride group...The many fractures in the fluoride group, 14 during treatment and the following month as against 6 among the controls, were surprising. Three or four of the fractures in the fluoride group appeared to be spontaneous hip fractures. In the past fractures have not been regarded as being caused by fluoride but as resulting from prolonged osteoporosis before treatment. We believe that the fluoride treatment here was probably partly responsible for the fractures in our cases." SOURCE: Inkovaara J, et al. (1975). Phophylactic fluoride treatment and aged bones. British Medical Journal 3: 7374. Key Findings: Mechanisms by which fluoride may reduce bone strength 1) There are several plausible mechanisms by which fluoride can reduce bone strength. 2) In all likelihood, the mechanisms by which fluoride reduces bone strength vary depending on the degree of fluoride exposure and/or the presence of overt skeletal fluorosis. 3) Fluoride has been found to reduce bone strength before skeletal fluorosis is detectable. Thus, several of the mechanisms discussed below likely occur before fluorosis is present. Excerpts from the Scientific Literature: 1) Reduced Cortical Bone Density 2) Damage to Mineral-Collagen interface 3) Damage to Collagen 4) Hypo-mineralization 5) Hyper-mineralization 6) Non-Uniformity of Mineralization 7) Osteocyte Damage Mechanisms: Reduced Cortical Density: It is now well acknowledged in the scientific literature that fluoride has a contradictory effect on bone density. While fluoride often increases bone density in trabecular bone (the primary bone of the axial skeleton), it often decreases bone density in cortical bone (the primary bone of the appendicular skeleton). Fluoride's ability to reduce cortical bone has been documented most extensively in human clinical trials, and in studies of humans with skeletal fluorosis. However, it has also been documented in humans living in communities in the United States with 3.8 to 4 ppm fluoride in water (Phipps 1990; Sowers 1991). Reduced cortical bone density is a particularly important risk factor for hip fracture, as one of the primary sites of hip fracture (the femoral neck) gains up to 95% of its strength from the intregity of cortical bone. Reduced cortical bone density is also important for most forms of "non-vertebral" fractures, particularly wrist fracture. It is interesting, therefore, to note that the two main forms of bone fracture associated with water fluoridation (at 1 ppm) are hip and wrist fracture - as these two bone sites are primarily dependent on the quality of cortical bone. "The strength of the femoral neck is due mainly to its shell of cortical bone. Computer analyses indicate 90%-95% of the strength of this region is from cortical rather than trabecular bone." SOURCE: Gordon SL, Corbin SB. (1992). Summary of workshop on drinking water fluoride influence on hip fracture on bone health. (National Institutes of Health, 10 April, 1991). Osteoporosis International 2:109-17. "The dramatic increase in the predominantly trabecular bone of the axial skeleton during fluoride therapy is not accompanied by a corresponding increase in the predominantly cortical bone of the appendicular skeleton...Indeed, several investigators have reported that cortical bone decreases significantly during treatment...These reports raise the possibility that fluoride therapy may protect against fractures of the vertebral bodies (which consist of predominantly trabecular bone) but may not protect the proximal femur, and could even increase the risk for fractures of this bone, which is predominantly cortical...Since hip fracture is more catastrophic than is vertebral fracture, it will be important for future studies to evaluate the effect of sodium fluoride therapy on mineral content of the proximal femur." SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: an appraisal. Bone and Mineral Research. 2: 366-393.

"The site of predilection for stress fractures, namely the metaphysis, with its thin cortex, may be determined by the decrease in cortical bone mass observed in fluoride therapy." SOURCE: Schnitzler CM, Solomon L. (1985). Trabecular stress fractures during fluoride therapy for osteoporosis. Skeletal Radioliology 14:276-9. "Because of the association between hip fracture and low femoral cortical thickness, and because of the reported decrease in cortical forearm density using Ca and NaF, it seems unwise to use NaF treatment in patients with hip fracture following minor trauma." SOURCE: Gutteridge DH, et al. (1990). Spontaneous hip fractures in fluoride-treated patients: potential causative factors. Journal of Bone and Mineral Research 5(Suppl 1):S205-15. "significant bone loss occurred by 27 months at all nonspinal sites examined. The greatest loss occurred in the lower tibia/fibula, where the loss at the shaft site was 7.3%. The lower tibia/fibula is a common site of fluoride-related stress fractures and these BMD results help to explain the mechanism of this common complication of treatment with NaF." SOURCE: Gutteridge DH, et al. (2002). A randomized trial of sodium fluoride (60 mg) +/- estrogen in postmenopausal osteoporotic vertebral fractures: increased vertebral fractures and peripheral bone loss with sodium fluoride; concurrent estrogen prevents peripheral loss, but not vertebral fractures. Osteoporosis International 13:158-70. "In four of the six hip fractures in this study, the history strongly suggested that the fracture occurred before the patient fell. The spontaneous character of the fracture in our patients, and in other reports, suggest that fluoride treatment probably increases the risk of stress fractures. This may be the result of the formation of qualitatively abnormal bone and/or the redistribution of calcium from the appendicular cortical bone to the axial skeleton." SOURCE: Hedlund LR, Gallagher JC. (1989). Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. Journal of Bone and Mineral Research 4:223-5. "We have documented a clinically relevant increase in vertebral BMD, although there was a significant reduction in cortical BMD at the radial site... In the absence of a control group it is not possible to conclude from our data whether a significant response to fluoride in trabecular or axial skeletal sites necessarily translates into higher than expected losses from cortical bone. This is of some concern, because fluoride therapy has been implicated as a cause of increased frequency of femoral neck fractures, as occurred in 2 of our patients... Although data on femoral neck BMD were not available in this study, clearly such measurements would have been of great importance." SOURCE: Hodsman AB, Drost DJ. (1989). The response of vertebral bone mineral density during the treatment of osteoporosis with sodium fluoride. Journal of Clinical Endocrinology and Metabolism 69(5):932-8. Mechanisms: Damage to Mineral-Collagen interface: (back to top) The quality and strength of bone is dependent to a large degree on the quality of bonding between its organic component (collagen) and its inorganic content (bone mineral). When this bonding is impaired, the strength of the bone is reduced, particularly the tensile strength. Several studies have found that fluoride impairs this "interfacial bonding". More importantly, studies have found that fluoride can damage this bonding in the absence of demonstrable skeletal fluorosis (Fratzl 1996; Turner 1993). "In this study, despite the observed increased in hardness of both cancellous and cortical bone, the fracture stress and elastic modulus of vertebrae tested in compression and femora tested in three-point bending were decreased by fluoride treatment. The fact that the hardness (which is dependent largely on the mineral content) increases even though the modulus (which depends on both the mineral content and the collagen) decreases suggests that there is a change in the relationship between the bone mineral and the collagen. The mechanical strength of bone is thought to derive mainly from the interface between the collagen and the mineral, so if fluoride administration alters bone mineral, it may affect this interface and therefore result in modified mechanical properties." SOURCE: Chachra D, et al. (1999). The effect of fluoride treatment on bone mineral in rabbits. Calcified Tissue International 64:345-351. "A slight increase in the average thickness of the mineral crystals as well as changes in the structure of the mineral/collagen composite were found in the case of fluoride-treated animals... These findings suggest that small changes in the structure of the mineral/collagen composite in bone may considerably affect its biomechanical properties." SOURCE: Fratzl P, et al. (1996). Effects of sodium fluoride and alendronate on the bone mineral in minipigs: a smallangle x-ray scattering and backscattered electron imaging study. Journal of Bone and Mineral Research 11: 248-253.

"The severe deterioration of the collagen/mineral compound and the nearly complete lack of normal 'old' bone suggest biomechanical incompetence and explain the pathological fractures." SOURCE: Roschger P, et al. (1995). Bone mineral structure after six years fluoride treatment investigated by backscattered electron imaging (BSEI) and small angle x-ray scattering (SAXS): a case report. Bone 16:407. "The bone strength deficit caused by fluoride accumulation in bone is not always associated with gross bone pathology (i.e. woven bone formation), but may be caused by decreased bone lipid content and calcification defects induced by decreased bonding strength at the crystal-matrix interface." SOURCE: Turner CH, et al. (1993). A mathematical model for fluoride uptake by the skeleton. Calcified Tissue International 52: 130-138. "Interfacial bonding interactions between the mineral and organic constituents of bone play an important role in the mechanical properties of cortical bone... Under a uniaxial tensile force, modification of interfacial bonding by phosphate and fluoride ions results in a reduction in the ultimate and yield stress and elastic modulus. In tension, phosphate ions effect is reversible upon removal of phosphate ions, while the fluoride ion effect is irreversible. Interestingly, when tested in compression, phosphate ion treatment results in a stiffening effect, while fluoride ions continue to lower the ultimate stress and elastic modulus." SOURCE: Walsh WR, Guzelsu N. (1993). The role of ions and mineral-organic interfacial bonding on the compressive properties of cortical bone. Bio-medical materials and engineering 3: 75-84. "The decreased bone-breaking strength caused by fluoride ingestion may result from a decreased bonding strength between the crystal material and collagen matrix of the bone. Fluoride might induce a decrease in bone lipids acting as a chemical link between the organic and inorganic phases of the bone. This would in turn produce decreased elasticity and increased brittleness." SOURCE: Bird DM, Carriere D, Lacombe D. (1992). The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Archives of Environmental Contamination and Toxicology 22:242-6. "The mechanical properties of composite material (such as bone) rely on the properties of its constituents as well as the interfacial bonding between them... This study demonstrates the importance of interfacial bonding between the mineral and organic constituents of bone through fluoride ion treatments. Fluoride ions alter interfacial bonding between the mineral and organic components of bone by exchanging with OH ions of bone mineral and creating an unfavourable electrostatic condition by a rise in pH. The reduction in interfacial bonding due to fluoride action lowers the mechanical properties of bone tissue." SOURCE: Walsh WR, Guzelsu N. (1991). Fluoride ion effect on interfacial bonding and mechanical properties of bone. Journal of Biomechanics 24: 237. "The mechanical properties of bone are influenced, principally, by the behaviour of two phase materials of the bone: the mineral substance which contributes to the compressive strength and the collagen matrix which plays a major role in tensile strength. Therefore, any alterations of physico-chemical composition or the structural changes in these materials bring about some eventual modifications on the physical properties of the bone." SOURCE: Bang S. (1978). Biophysical study of compact bone tissue in demic fluorosis. In: B Courvoisier B, et al. (1978). Fluoride and Bone; Proceedings of the Second Symposium CEMO, Nyon, Switzerland, Oct. 9-12, 1977. Hans Huber Publishers, Bern. pp. 77-81. "As suggested by Currey, bone may be looked upon as a two-phase material (hydroxyapatite crystals embedded in a collagen matrix) which can function efficiently only if there is a very firm bonding between the fibers and the matrix. The decrease in the modulus of elasticity observed by us, together with the lower limit of elasticity and increased ductility, may result from a decreased bonding strength at the crystal-matrix surface. In this context the decreased lipid content of bone of fluoride-treated animals is of interest. Perhaps, as suggested in the literature, the lipids could act as a chemical link between the mineral and the organic phases of calcified tissues." SOURCE: Wolinksy I, et al. (1972). Effects of fluoride on metabolism and mechanical properties of rat bone. American Journal of Physiology 223: 46-50. Mechanisms: Damage to Collagen: (back to top) Along with potentially altering/damaging the interface between the bone mineral and collagen matrix, fluoride may also directly damage the quantity/quality of the collagen itself. Since the collagen component of bone plays a vital role

in maintaining the tensile strength (versus compressive strength) of bone, any damage to the collagen would make the bone more prone to fracture. "Collagen synthesized and laid down during fluoride exposure is under hydroxylated and inadequately crosslinked. As a consequence, this collagen is rapidly catabolized and collagen content of the bone is decreased." SOURCE: Bird DM, Carriere D, Lacombe D. (1992). The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Archives of Environmental Contamination and Toxicology 22:242-6. "A permanently reduced bone strength might be expected if fluoride affects the bone matrix by inhibition of collagen cross-linking, changes the glycosaminoglycans, or forms fluorapatite crystals of minor biomechanical competence." SOURCE: Mosekilde L, et al. (1987). Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcified Tissue Research 40: 318-322. "As a tissue, bone is rich in collagen. When fluoride enters bone structure in toxic amounts, it modifies not only the mineral metabolism but also the collagen component of bone matrix." SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10(3-4):279-314. "In the fluoride-treated group, collagen synthesis was found to be defective, while it was normal in the controls." SOURCE: Uslu B. (1983). Effect of fluoride on collagen synthesis in the rat. Research and Experimental Medicine 182:7-12. "Electron microscopical examination of iliac crest bone biopsy specimens from four patients suggests that fluoride induces the synthesis of disarrayed collagen by the activated osteoblasts." SOURCE: Lough J, et al. (1975). Effects of fluoride on bone in chronic renal failure. Archives of Pathology 99: 484487. "We evaluated one aspect of bone quality, collagen birefringence, which is primarily determined by collagen bundle orientation... The diminished collagen birefringence observed in the present study and previously found in endemic fluorosis has also been observed in patients with renal osteodystrophy..." SOURCE: Baylink D, et al. (1970). Effects of fluoride on bone formation, mineralization, and resorption in the rat. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 37-69. "As previously suggested by Johnson decreased or abnormal collagen seemed to be present in these fluoridated zones of the bone on the basis of polarized light study of decalcified unstained sections." SOURCE: Cass RM, et al. (1966). New bone formation in osteoporosis following treatment with sodium fluoride. Archives of Internal Medicine 118: 111-116. "The collagen in a fluoride-laden skeleton also is probably abnormal; in vitro studies have shown that fluorine inhibits collagen synthesis in bone." SOURCE: Adams PH, Jowsey J. (1965). Sodium fluoride in the treatment of osteoporosis and other bone diseases. Annals of Internal Medicine 63: 1151-1155. "With well-developed mottling, portions of the osteones failed to calcify (X-ray microscopy), the calcified portions revealed an abnormal pattern of calcification, and the organic collagen matrix of the entire osteone was abnormal." SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press (1965) 424-441. Mechanisms: Hypo-mineralization: (back to top) Fluoride is well known to be able to cause a mineralization defect in bone known as "hypomineralization." Hypomineralization refers to an increase in the amount of "osteoid" tissue present in bone. Osteoid is bone tissue that is not yet mineralized. Thus, if osteoid is present in excess amounts, a bone will be more prone to fracture - as is the case with the bone disease osteomalacia (a condition of excess osteoid). While fluoride's ability to increase osteoid tissue has been most extensively documented in human clinical trials and high-dose animal experiments, it has also been observed in humans (with healthy kidney function) drinking with as little as 1.5 ppm fluoride, and in humans (with impaired kidney function) drinking water with as little as 1 ppm (Ng 2004). Thus, this form of mineralization

defect may be a relevant mechanism by which fluoride could increase bone fractures in fluoridated communities, and it is certainly a relevant mechanism for higher-dose exposures. "In contrast to calcium phosphate deficiency, high fluoride intake had no effect on trabecular bone volume, but instead increased the amount of unmineralized osteoid, particularly in older rats. This impairment of mineralization by fluoride appeared to be the primary cause of the diminshed vertebral strength." SOURCE: Turner CH, et al. (2001). Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International 69: 51-57. "The main histolological change induced by fluoride is the increase of osteoid volume... This increase in osteoid parameters was observed in our study already at fluoride concentrations above 1.5 ppm." SOURCE: Arnala I, et al. (1985). Effects of fluoride on bone in Finland. Histomorphometry of cadaver bone from low and high fluoride areas. Acta Orthopaedica Scandinavica 56:161-6. "The osteomalacic condition (of fluorosis) to some extent varies with the species and age of the animal. Certain features are common, however... Common features are the reduced strength of the bones, the tendency to form exostoses, bone atrophy, and a deficient calcification." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. H.K. Lewis Ltd, London. Mechanisms: Hyper-mineralization: (back to top) In contrast to its ability to cause hypo-mineralization (UNDER-mineralized bone), fluoride can also cause hypermineralization (OVER-mineralized bone). As with hypo-mineralized bone, hyper-mineralized bone can also weaken the integrity of bone, primarily by altering the bonding between the bone mineral and the collagen matrix. "Fluoride also affects bone strength of well-mineralized bone, possibly by altering mineral crystal size and packing. Fluoride tends to increase mineral crystal width, and may alter the electrostatic bonding between mineral crystals and the collagen matrix. Both effects may diminish the mechanical properties of the bone." SOURCE: Turner CH, et al. (1997). Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbts. Calcified Tissue International 61: 77-83. "In both cases, in which the coating was supposed to be either hypo- or hypermineralized, a loss of mechanical properties was found." SOURCE: Fratzl P, et al. (1994). Abnormal bone mineralization after fluoride treatment in osteoporosis: a small-angle x-ray-scattering study. Journal of Bone and Mineral Research 9:1541-9. "Hypermineralized fluorotic tissue has a greater true density than normal mineralized tissue. The physicochemical abnormalities of this tissue, however, again raise questions regarding a possible decrease in mechanical strength." SOURCE: Carter DR, Beaupre GS. (1990). Effects of fluoride treatment on bone strength. Journal of Bone and Mineral Research 5(Suppl 1):S177-S184. "This increased hardness is most likely due to an increased concentration of mineral or an increased mineral-tomatrix ratio... An increased number of microfractures was found frequently in fluorotic bone. They were generally located in old bone with a high mineral-to-matrix concentration ratio... More frequent and abrupt variations in this ratio were found in fluorotic bone, and this probably increased the susceptibility of areas with a high ratio to microfractures." SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85.. Mechanisms: Non-Uniformity of Mineralization: (back to top) This field study included the whole population of children aged 10–15 years (77 from a 0.19 mg/L F area; 89 from a 3.00 mg/L F area), with similar nutritional, dietary habits and similar ethnic and socioeconomic status. The fluoride concentration in the drinking water, the bone mineral content, the bone density and the degree of dental fluorosis were determined. . . . A significant increase in bone width was found with age but no differences amongst and boys and girls. R. Grobler*, A.J. Louw, U.M.E. Chikte, R.J. Rossouw and T.J. van W. Kotze The Relationships between

Two Different Drinking Water Fluoride Levels, Dental Fluorosis and Bone Mineral Density of Children The Open Dentistry Journal, 2009, 3, 48-54

Fluoride can cause both hypo-mineralization and hyper-mineralization of bone tissue. However, the entire bone is usually not impacted. Instead, there are "pockets" of mineralization disorders, in which the hypo- or hyper-mineralized bone is surrounded by normally mineralized bone. The resulting lack of homogenity in the bone tissue can decrease the strength, leaving it more prone to fracture. "One histological characteristic of fluoride-treated bone, however, tends to be the nonuniformity of the mineralized tissue. There can be regions of relatively normal bone that are adjacent to either hypo- or hypermineralized tissue. This nonuniformity can lead to even greater losses in cancellous bone strength than would be caused by homogenous changes." SOURCE: Carter DR, Beaupre GS. (1990). Effects of fluoride treatment on bone strength. Journal of Bone and Mineral Research 5(Suppl 1):S177-S184. Fluoride-induced "reduction in bone quality" has been attributed to: "nonuniformity of bone mineralization, to decreased bending strength at the crystal-matrix interface, or to inadequate crosslinks in the organic matrix.." SOURCE: Lafage MH, et al. (1995). Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs: a one year study. Journal of Clinical Investigations 95: 2127-2133. Mechanisms: Osteocyte Damage: (back to top) The osteocyte is a type of bone cell which is increasingly believed to play an important role in repairing defects that arise in bone, thereby maintaining its structural integrity. Being that osteocytes are engulfed in bone mineral, and take part in the bone resorption process, they are known to be impacted by high levels of fluoride accumulation in bone. For, when the osteocytes resorb bone with a high-fluoride content, the fluoride is liberated from the bone structure, leading to elevated and potentially toxic concentrations to the osteocytes. This, in turn, can cause osteocyte cell damage or death. Thus, to the extent that fluoride bone accumulation can damage the osteocytes, it can in turn damage the integrity of the bone. Fluoride-induced damage to osteocytes may be a particularly important factor in the pathogenesis of fluoride-induced microfractures, as microfractures are often found in areas of bone with dead or damaged osteocytes. "The co-localization of microfractures and osteocytes fits with the hypothesis that in vivo fatigue damage could be repaired by remodeling processes triggered by osteocytes." SOURCE: Muglia MA, Marotti G. (1996). Osteocyte and microfracture location in human lamellar bone. Bone 19: 155S. "The results support the sensory role of the osteocyte network as the decline in osteocyte lacunar density in human cortical bone is associated with the accumulation of microcracks and increase in porosity with age." SOURCE: Vashishth D, et al. (2000). Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26:375-80. "The impact of losing osteocytes in bone may be great. In human bone, osteocyte cell death can occur in association with age and both osteoporosis and osteoarthritis, leading to increased fragility. Such fragility may be due to increased brittleness via micropetrosis and/or loss of the ability to sense fatigue microfracture and signal to other cell types for repair." SOURCE: Noble BS, et al. (1997). Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20:273-82. "An increased number of microfractures was frequently found in fluorotic bone. In nonfluorotic and fluorotic bone, microfractures were usually located in highly mineralized areas of old bone with an increased number of dead osteocytes... [D]ead and degenerating osteocytes were found frequently in the region of microfractures, and viable osteocytes appear to be necessary for the optimum mechanical function of bone. It is possible that osteocytes are involved in the maintenance of structural integrity at an ultra-microscopic level and that impaired osteocyte function increases the tendency for small defects to become microfractures." SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85.

Excessive exposure to fluoride causes an arthritic bone disease called skeletal fluorosis. According to UNICEF, skeletal fluorosis is endemic in at least 25 countries, with millions of people impacted. Skeletal fluorosis, especially in its early stages, is a difficult disease to diagnose, and can be readily confused with various forms of arthritis including osteoarthritis and rheumatoid arthritis. In the advanced stages, fluorosis can resemble a multitude of bone/joint diseases, including: osteosclerosis, renal osteodystrophy, DISH, spondylosis, osteomalacia, osteoporosis, and secondary hyperparathyroidism. The risk of developing fluorosis, and the course the disease will take, is influenced by the presence of ceratin predisposing factors, including impaired kidney function; dietary deficiencies; gastric acidity; and repetitive stress. In individuals with kidney disease, fluoride exposure can contribute to, and/or exacerbate, renal osteodystrophy. While only a limited number of studies have documented the disease in the U.S., it is almost certain that cases of the disease have occurred but escaped detection. 'The Dose Factor' - Skeletal Fluorosis: (Click for more detail) The minimum daily doses capable of producing the various stages of fluorosis are still poorly understood. In India and China, skeletal fluorosis has repeatedly been documented in field surveys among communities with 1.0 to 1.5 ppm fluoride in water. In the U.S., there has been extremely little systematic research to assess the prevalence of fluorosis. Case reports, however, have documented fluorosis among susceptible individuals drinking water with as little as 1.7 ppm. Research Gaps - Skeletal Fluorosis: 1) No systematic research exploring the incidence of skeletal fluorosis among susceptible subsets of the population including heavy tea-drinkers and people with kidney disease. 2) Other than small, limited studies from the 1950s-1960s (Steinberg 1955, 1958; Ansell 1965), no research exploring the relationship between fluoride exposure and arthritis in the west. 3) No comprehensive research exploring the doses of fluoride capable of producing the early stages of skeletal fluorosis, and how such doses vary based on the presence or absence of predisposing factors. 4) No research exploring how genetics may influence the risk and nature of skeletal fluorosis in the general population. Skeletal fluorosis is a difficult disease to diagnose, and can be readily confused with various forms of arthritis. The joint pains of fluorosis can occur before the onset of detectable bone changes, thereby making the early stages of fluorosis difficult to differentiate from arthritis. In the advanced stages of skeletal fluorosis, the spine may closely resemble the appearance of spondylosis and DISH. Skeletal fluorosis produces a wide variety of radiological manifestations, including osteosclerosis, osteomalacia, osteoporosis, and secondary hyperparathyroidism, thus a potential for misdiangosis exists between skeletal fluorosis and these disorders. In individuals with kidney disease, fluoride exposure can exacerbate, and mimic, renal osteodystrophy.

Notable Quotes - Diagnosis of Skeletal Fluorosis: "In areas where fluorosis is endemic, skeletal fluorosis is a common mimic of seronegative arthritis and should be pursued with investigations for diagnosis of fluorosis with measurement of fluoride levels, wherever applicable." SOURCE: Gupta R, Kumar AN, Bandhu S, Gupta S. (2007) Skeletal fluorosis mimicking seronegative arthritis. Scandanavian Journal of Rheumatology 36(2):154-5. "Our case report illustrates dramatically that fluorosis can lead to severe disability while closely mimicking a wide variety of other disorders... We believe increased awareness of this unusual disease is needed to enable physicians to make the proper diagnosis." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Although skeletal fluorosis has been studied intensely in other countries for more than 40 years, virtually no research has been done in the U.S. to determine how many people are afflicted with the earlier stages of the disease, particularly the preclinical stages. Because some of the clinical symptoms mimic arthritis, the first two clinical phases of skeletal fluorosis could be easily misdiagnosed [as arthritis]... Even if a doctor is aware of the disease, the early stages are difficult to diagnose. " SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "It should also be noted that chronic fluorosis is not easily diagnosed, and that few physicians have ever seen a case. Three of the cases reported in the U.S. literature were not diagnosed until post-mortem examination revealed excessive fluoride content in the bone. It is possible that the disease may be occurring to some extent without having been recognized." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is quite possible that many cases of (skeletal fluorosis) have gone misdiagnosed and unreported over the years... The state of knowledge among practicing physicians, even those in non-fluoride areas, concerning the diagnosis of skeletal fluorosis seems to be deficient and should be more carefully assessed." SOURCE: Prival MJ. (1972). Fluorides and human health. Center for Science in the Public Interest, Washington D.C.

"Symptoms of fluoride poisoning are actually common in this country. The question not at all whether they occur, but when and how often they are produced by fluoride... It is true that reports (of skeletal fluorosis in the U.S.) are few. This is both the cause and the effect of the fact that physicians, by and large, are unaware that such a thing exists. It is hardly mentioned in the textbooks or in the medical literature. " SOURCE: Exner FB. (1957). Fallacies of the fluoridation thesis. In: J Rorty, ed. (1957). The American Fluoridation Experiment. Delvin-Adair Co, New York. pp. 29-153. is "One common feature of the three manifestations of chronic fluorine intoxication is that isolated cases may be difficult to diagnose." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd.

Preskeletal fluorosis
Key Findings - "Pre-Skeletal" Fluorosis Skeletal fluorosis may produce adverse symptoms (e.g. joint stiffness & pain) before bone changes are detectable by x-ray.

Using x-rays to diagnosis skeletal fluorosis is an unreliable method for detecting the early stages of the disease. Fluoride may reduce the strength of bone, and promote fracture, before x-ray evidence of fluorosis is present. Excerpts from the Scientific Literature - "Pre-Skeletal" Fluorosis "The radiological severity of knee osteoarthritis was greater in the endemic fluorosis group than in controls... [S]ome radiological findings such as osteosclerosis, interosseous membrane calcification, or ligament calcification, which are accepted as hallmarks of skeletal fluorosis were not found as frequently as in the literature." (NOTE from FAN: In this group of fluorosis patients, only 3.6% had radiological evidence of osteosclerosis in the spine, and only 9% had evidence of calcification in the interosseous membrane of the forearm. Hence, the exacerbation of osteoarthritis occurred in most patients before the fluorosis was detectable on x-ray.) SOURCE: Savas S, et al. (2001). Endemic fluorosis in Turkish patients: relationship with knee osteoarthritis. Rheumatology International 21: 30-5. "Radiographs of the skeleton and bone scintigraphy showed degenerative osteoarthritis... Interestingly, laboratory findings, skeletal radiographs and bone densitometry, gave no indication for abnormalities of bone metabolism or mineralization. Without bone biopsy we would have failed the correct diagnosis (of skeletal fluorosis)." SOURCE: Roschger P, et al. (1995). Bone mineral structure after six years fluoride treatment investigated by backscattered electron imaging (BSEI) and small angle x-ray scattering (SAXS): a case report. Bone 16:407. "Assessment of the fluoride-induced changes from x-ray results is often difficult, especially in the initial stages commonly encountered." SOURCE: Czerwinski E, et al. (1988). Bone and joint pathology in fluoride-exposed workers. Archives of Environmental Health 43: 340-343. "Ironically, two crucial criteria of fluorosis, i.e., osteosclerosis and bone pattern alteration, are the most questionable in the (x-ray) assessment. Perhaps this is one reason why such great discrepancies in the frequency of fluorosis are found among various authors." SOURCE: Czerwinski E, et al. (1988). Bone and joint pathology in fluoride-exposed workers. Archives of Environmental Health 43: 340-343. "A wide variety of vague, subtle symptoms occurred either prior to or simultaneously with the development of bone changes similar to those reported previously. Nonskeletal symptoms, therefore, are important for early diagnosis." SOURCE: Zhiliang Y, et al. (1987). Industrial Fluoride Pollution in the Metallurgical Industry in China. Fluoride 20: 118-125. "Arthritis of spine and small joints of hands and fingers develops early in the course of the disease with or without demonstrable radiological changes." SOURCE: Bhavsar BS, Desai VK, Mehta NR, Vashi RT, Krishnamachari KAVR. (1985). Neighborhood Fluorosis in Western India Part II: Population Study. Fluoride 18: 86-92. "Our findings demonstrate a highly significant relationship between the frequency of back and neck surgery, fractures, symptoms of musculoskeletal disease and a past history of diseases of the bones and joints. In the absence of so-called classic fluorosis, a disease complex was established which involves much more than merely the radiologic appearance of dense bone. Since more stringent regulations in many countries have resulted in reduced exposure to fluorides, it is reasonable to examine workers and watch for these findings instead of waiting for dense bone to appear which is related to massive exposure to fluoride." SOURCE: Carnow BW, Conibear SA. (1981). Industrial fluorosis. Fluoride 14: 172-181. "Similar findings of musculoskeletal changes without classical x-ray signs of fluorosis in workers exposed to high levels of fluorides have appeared in a number of other studies. Of special importance is the large prospective study by Zislin and Girskaya (1974). They followed 2738 workers from the time they first came to work in an aluminum smelter and compared them with 1700 others employed in a nonfluoride producing industry. They found that nonspecific bone changes, musculoskeletal symptoms and other findings antedate the classic x-ray changes of fluorosis in the bones by five to seven years and concluded that the changes of fluorosis described by Roholm represent the late stage of the disease." SOURCE: Carnow BW, Conibear SA. (1981). Industrial fluorosis. Fluoride 14: 172-181.

"In our opinion it is often difficult to appreciate the bone density because too many variables are involved such as radiograph penetration, influence of overlying soft tissues, etc." SOURCE: Boillat MA, et al. (1980). Radiological criteria of industrial fluorosis. Skeletal Radiology 5: 161-165. "[E]xtensive research from India has revealed severe arthritic changes and crippling neurological complications even where the fluoride concentration in water naturally is as low as 1.5 ppm...Even though extensive bone deformities may not be found on a large scale from fluoride in water at the 1 ppm concentration, some of the early signs of the disease, such as calcifications of ligaments, joint capsules, and muscle attachments, are likely to occur. Indeed these conditions are characteristic of osteoarthritis, in which the formation of microcrystals of apatite (known to be promoted by fluoride) has now been clearly demonstrated. Among the elderly, arthritis of the spine is an especially common ailment that is customarily attributed to 'aging.' Since fluoride retention in bones increases as a person grows older, how can we disregard the possibility that this 'old age' disease might be linked with fluoride intake? For example, Pinet and Pinet described in detail X-ray changes encountered in skeletal fluorosis in North Africa that are in every respect identical with those present in the arthritic spine of the elderly elsewhere." SOURCE: Waldbott GL, Burgstahler AW, and McKinney HL. (1978). Fluoridation: The Great Dilemma. Coronado Press, Inc., Lawrence, Kansas. "to our knowledge, [skeletal fluorosis] has not been described in the literature prior to the onset of the typical bone changes. This is not surprising since the intital stage, like that of many other kinds of chronic poisoning, develops slowly and insidiously with ill-defined complaints that are difficult to attribute to their cause. For instance, in lead poisoning the characteristic hallmarks are 'lead line' of gums and radial nerver paralysis; in chronic cadmium poisoning, one sees softening of bones. However, they are always precded or accompanied by a variety of subtle, inconspicuous symptoms of the kind encountered in incipient, chronic fluoride poisoning. Actually, subclinical poisoning can harm vast numbers of people before obvious clinical symptoms appear. These mulitple, hidden effects of slow poisoning pose a strong challenge to our current concepts of 'safe limits' of toxic substances in our environment." SOURCE: Waldbott GL, Lee JR. (1978). Toxicity from repeated low-grade exposure to hydrogen fluoride - Case report. Clinical Toxicology 13: 391-402. "In addition to pain in the lower spine which is associated with radiological changes, patients with negative x-ray findings also complain of pain in the lumbar-sacral area, an indication that symptoms precede changes demonstrable by x-ray." SOURCE: Czerwinski E, Lankosz W. (1977). Fluoride-induced changes in 60 retired aluminum workers. Fluoride 10: 125-136. "In early stages, fluorosis is usually associated only with stiffness, backache, and joint pains which may suggest the diagnosis of rheumatism, rheumatoid arthritis, ankylosing spondylitis and osteomalacia. At this stage the radiological findings of skeletal fluorosis may not be evident and therefore most of these cases are either misdiagnosed for other kinds of arthritis or the patients are treated symptomatically for pains of undetermined diagnosis (PUD). The majority of our patients had received treatment for rheumatoid arthritis and ankylosing spondylitis before they came under our observation." SOURCE: Teotia SPS, et al. (1976). Symposium on the Non-Skeletal Phase of Chronic Fluorosis: The Joints. Fluoride 9(1): 19-24. "we also found patients with slight radiological changes (subtle signs or O-I) who complained of intense pains in the spine and in the large joints. On the other hand, some patients whose fluorosis was radiologically distinct were almost without complaints." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. "In several patients we failed to notice evidence of typical sclerosis in the radiogram. Instead, the picture of so-called 'hypertrophic atrophy' was found... It is likely that a previously existing osteoporosis is superimposed upon fluorosis or the predominance of the fluoride-induced bone resorption in conjunction with thickening of the statically loaded bone structure may be responsible." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. "Arthritis of the spinal column develops early in the disease with or without demonstrable radiological changes." SOURCE: Waldbott GL. (1974). The pre-skeletal phase of chronic fluorine intoxication. Fluoride 7:118-122.

"In spite of this distinctive clinical picture of advanced fluorosis, the earlier stages of the disease are more difficult to recognize. The initial symptoms are quite non-specific and not obviously linked to fluoride. The onset of fluorosis leads tingling sensations in the hands and feet, pain similar to arthritic pain in the joints and the lower back, stiffness, and motor weakness. The first reliable diagnostic sign is increased bone density in X-ray examination, but in some early cases early bone changes are not radiologically detectable... The lack of a clear clinical picture of the early stages of fluorosis makes this disease easy to overlook or to misdiagnose, even in its relatively advanced stages." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It should also be noted that chronic fluorosis is not easily diagnosed, and that few physicians have ever seen a case. Three of the cases reported in the U.S. literature were not diagnosed until post-mortem examination revealed excessive fluoride content in the bone. It is possible that the disease may be occurring to some extent without having been recognized." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "This case supports the premise that some forms of arthritis are related to sub-clinical fluorosis, i.e. fluorosis which is not sufficiently advanced to show the characteristic skeletal changes radiologically." SOURCE: Cook HA. (1972). Crippling fluorosis related to fluoride intake (case report). Fluoride 5: 209-213. "Possibly some cases of pain diagnosed as rheumatism or arthritis may be due to subclinical fluorosis which is not radiologically demonstrable." SOURCE: Cook HA. (1971). Fluoride studies in a patient with arthritis. The Lancet 1: 817. "There has been very little (research) done, especially in the realm of 'borderline' or subclinical toxicity. And yet, it is precisely in this area that knowledge of most importance to man could be brought to light. To this day, many investigators still think of fluorosis exclusively in terms of osteosclerosis, whether crippling or noncrippling. This attitude is no longer valid, because osteosclerosis is only one of many skeletal abnormalities that can be induced by fluoride." SOURCE: Marier JR, Rose D. (1971). Environmental fluoride. National Research Council of Canada, Publication No. 12,226, Ottawa. "Whereas dental fluorosis is easily recognized, the skeletal involvement is not clinically obvious until the advanced stage of crippling fluorosis... Such early cases are usually in young adults whose only complaints are vague pains noted most frequently in the small joints of the hands and feet, in the knee joints and in the joints of the spine. These cases are frequent in the endemic area and may be misdiagnosed as rheumatoid or osteo arthritis." SOURCE: Singh A, Jolly SS. (1970). Fluorides and Human Health. World Health Organization. pp 239-240. "The frequent lack of increased density or derangement of trabecular structure of bone in our cases and the nonspecificity of the alterations of thie spine make both of these changes bad criteria for the diagnosis of fluorosis. The more peripheral findings of exostosis, apposition of new bone, ossification of ligaments and tendon insertions and metastatic, aberrant growth of new bone seem much more specific and constant." SOURCE: Vischer TL, et al. (1970). Industrial fluorosis. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 96-105. In the early stages of skeletal fluorosis, the "only complaints are vague pains noted most frequently in the small joints of hands and feet, the knee joints and those of the spine. Such cases are frequent in the endemic area and may be misdiagnosed as rheumatoid or osteoarthritis. Such symptoms may be present prior to the development of definite radiological signs. A study of the incidence of rheumatic disorders in areas where fluoridation has been in progress for a number of years would be of interest."

SOURCE: Singh A, et al. (1963). Endemic fluorosis. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab. Medicine 42: 229-246. "It is apparent that small grossly recognizable deposits, areas of hyperplasia and perhaps beginning exostoses can be produced in the bones of small animals without their being detected by roentgenographic methods. That this may be equally true in the case of human beings cannot be claimed, but the point seems worthy of mention because in some instances X-ray photography is the only means used to detect evidence of industrial exposure to fluorides on the part of workmen. It seems probable that changes comparable to those seen in the animals may have escaped detection. It remains to be determined whether disability or limitation of movement in certain parts of the body may also occur before bone changes are demonstrable on the X-ray plate." SOURCE: Largent EJ, Machle W, Ferneau IF. (1943). Fluoride ingestion and bone changes in experimental animals. Journal of Industrial Hygiene and Toxicology 25: 396-408. "incipient changes (1st phase) may be difficult to distinguish (via x-ray) from physiological variations." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd.

Summation - X-ray Diagnosis of Skeletal fluorosis In 1937, Kaj Roholm published his seminal study Fluorine Intoxication. Based on observations of skeletal fluorosis in fluoride-exposed workers, Roholm described three phases of bone changes detectable via x-ray. Roholm's description of the x-ray picture of skeletal fluorosis has been widely used as a diagnostic tool in detecting the disease. It is not, however, without its limitations. In 1958, the German scientist Fritz expanded on Roholm's description of the x-ray picture, by defining two additional phases ("subtle signs" & "stage O-I") of bone changes that occur prior to Roholm's 3 phases. Other researchers have called attention to a more diverse range of radiological findings, beyond the predominantly osteosclerotic form of the disease which Roholm described. In addition, others have reported that the symptoms of skeletal fluorosis can occur before the development of bone changes detectable by x-ray. This latter research has emphasized the problems of relying on x-ray analysis to diagnose fluorosis, as x-rays are bound to overlook individuals suffering from the early, "pre-skeletal" stage of fluorosis. Diagnosing Skeletal Fluorosis - Roholm's 3 Phases of Bone Changes Detectable by X-Ray: (back to top) "From the X-ray picture it is possible to differentiate between three phases of the same osteosclerotic process, each overlapping the next without any sharp boundary. 1st Phase. "The changes are observed in pelvis and columna, but are doubtful or absent elsewhere. The density of bone is very little increased. The trabeculae are rough, blurred and give deep shadows; this is often distinct in corpora of the lower lumbar vertebrae. The bone has both a more prominent and a more blurred structure at the same time, which is very characteristic when the operator is familiar with the phenomenon, but otherwise is easily overlooked. The bone contour is sharp. In some few cases there is incipient osteophyte formation on the edge of corpora of the lumbar vertebrae. The boundary against the normal bone structure is not sharp, and in an isolated case it will be difficult to decide whether the change is a normal variation or a pathological finding. In serial examinations, however, the difference is distinct. 2nd Phase. "The bone structure is blurred, the trabeculae merging together. Over often rather large areas the bone gives a diffuse, structureless shadow. At first glance the negative seems to have been underexposed, but it is difficult or

impossible to distinguish details even when the time of exposure or the tension is increased. The bone contours are uneven and somewhat blurred. The changes are most distinct in pelvis and columna, but also in the ribs and in the bones of the extremities, even if there they are less pronounced and often resemble the changes described as 1st phase. In the extremity bones the medullary cavity is usually moderately narrowed. In columna there are incipient or moderate ligament calcifications, especially caudally; they appear in the form of pointed, beaked osteophytes with an inclination to form bridges between vertebral bodies or as a diffuse blur lying posteriorly to corpora. In some cases (particularly among the younger individuals) the ligament calcifications are absent, though the bone structure is so changed that the case must be placed to the 2nd phase. 3rd Phase. "On the negative the bone presents itself as a more or less diffuse marble-white shadow, in which the details cannot be distinguished. Changes are observable in all bones but are still greatest centrally, being most conspicuous in bones with cancellous structure, pelvis, columna, ribs and sternum. In the bones of the extremities there are changes in the structure that recall the 2nd phase, or fairly often only the 1st phsase. Among the worst affected individuals changes are to be seen in the cranium, usually rather moderate in intensity. Theca is denser and gives a deeper shadow than normally, sutures and vessel grooves are indistinct, and the same applies to impressiones digitatae. The air-sinuses in the cranial bones are diminished in size. The region around sella turcica gives a deep shadow but is normal as to contour. No distinct thickening of the processus clinoidei was observed. The bone contours almost everywhere are wooly and blurred. Very often the bones or certain parts of them have a rough and slightly enlarged appearance, but otherwise the shape is not altered. On the extremity bones are irregular periosteal thicknesses, some flats, others more rough. The interosseous membrane in antibrachium and crus are calcified to a greatewr or smaller extent. The normal cristae corresponding to the muscle attachments are increased in size and resemble exostoses. On costae, especially vertebrally, there is calcification of the insertions of the intercostal muscles, which appear like "rime frost needles" or irregular shadows to both sides. There are considerable ligament calcifications, varying up to very severe, in columna, particularly in pars lumbalis and thoracalis. In columna cervicalis these changes are less pronounced, but distinct. The ligament calcifications appear partly in the form of bridge-like connections with fairly sharp borders between corpora, partly as a diffuse opacity and density round about the intervertebral and costovertebral articulations. Processus transversi and spinosi are rough and thickened; between the latter are considerable ligament calcifications with irregular borders. In the pelvis, ligamentum sacrotuberosum is sometimes calcified. The intensity of the calcification and the diffuse density of the bone usually are in conformity with each other; in some elderly workers, however, there is a density of the osseous tissue which does not attain to the extreme degree, side by side with very pronounced ligament calcification. In the extremity bones, both short and long, the medullary cavity is diminished in width and the boundary against compacta is less sharp than normally. The width of compacta is correspondingly increased. In tibia and femur the width of the medullary cavity sometimes decreases to half the normal, in metacarpals and phalanges there is sometimes a partial occlusion of the cavity. The interarticular spaces are of normal width everywhere and the contours are sharp. Limited calcifications of the capsule in hip and knee joints are seen. The intervertebral disks are not visibly changed and the calcification of the costal cartilage does not exceed the normal. If the result of the Rontgen examination is to be summarized, the first thing to emphasize is the fact that the affection is a system-disease, for it attacks all bones, though it has a predilection for certain places. The pathological process may be characterized as a diffuse osteosclerosis, in which the pathological formation of bone starts both in periosteum and in endosteum. Compacta densifies and thickens; thet spongiosa trabecula thicken and fuse together. The medullary cavity decreases in diameter. There is a considerable new-formation of bone from periosteum, and ligaments that normally do not calcify or only in advanced age undergo a considerable degree of calcification. All signs of bone destruction are absent from the picture." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. pp. 141-143

Diagnosing Skeletal Fluorosis: Two Additional Phases of Bone Changes described by Fritz (1958): (back to top)

"In addition to the well-known radiological stage classification, stage I to III according to Roholm, two prestages according to Fritz have proved to be important in our investigations: the so-called (subtle signs) and the stage O-I. Concerning the subtle signs... a condensation of the bone-structure and an enlargement of the bone trabeculae in the lumbar spine are evident. In addition, there are accompanying shadows along the tibia, fibula, radius, and ulna. At the stage O-I the structure of the thoracic spine has already increased in density, whereas in the lumbar region the normal structure of the bone begins to disappear. The periosteal apposition of new bone at the bones of the forearm and lower legs are more distinct. For better proof of the periosteal appositions on these bones, we used slightly underexposed similar to the kind of radiography employed for soft parts." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83.

Diagnosing Skeletal Fluorosis: US Public Health Service Chart (back to top)

US Public Health Service 1991
OSTEOSCLEROTIC PHASE Normal Bone Preclinical Phase asymptomatic; slight radiographically-detectable increases in bone mass Clinical Phase I sporadic pain; stiffness of joints; osteosclerosis of pelvis & vertebral column Clinical Phase II chronic joint pain; arthritic symptoms; slight calcification of ligaments; increased osteosclerosis/cancellous bones; with/without osteoporosis of long bones Phase III: Crippling Fluorosis limitation of joint movement; calcification of ligaments/neck, vert. column; crippling deformities/spine & major joints; muscle wasting; neurological defects/compression of spinal cord ASH CONCENTRATION (mg/kg) 500 - 1,000 3,500 - 5,500

6,000 - 7,000

7,500 - 9,000

> 8,400

Summation - Skeletal Fluorosis in the U.S. 1) Skeletal fluorosis is an arthritic bone disease caused by excessive, exposure to fluoride. It is a difficult disease to diagnose, and can be readily confused with various forms of arthritis. 2) While there have been several isolated case reports of skeletal fluorosis published in the U.S., there has never been a systematic study in the U.S. of skeletal fluorosis among susceptible subsets of the population (e.g. heavy tea drinkers & people with kidney disease).

3) It is all but certain that some individuals with skeletal fluorosis in the U.S. have been incorrectly diagnosed as suffering from another form of arthritis or bone disease. 4) In the 1960s & 1970s, the use of fluoridated water (1 ppm) in dialysis systems caused an increase in the rate and severity of osteomalacia (a painful bone-softening disease and a common radiological finding in skeletal fluorosis). Probability for Misdiagnosis - Skeletal Fluorosis in the U.S.: "Our case report illustrates dramatically that fluorosis can lead to severe disability while closely mimicking a wide variety of other disorders... We believe increased awareness of this unusual disease is needed to enable physicians to make the proper diagnosis." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Although skeletal fluorosis has been studied intensely in other countries for more than 40 years, virtually no research has been done in the U.S. to determine how many people are afflicted with the earlier stages of the disease, particularly the preclinical stages. Because some of the clinical symptoms mimic arthritis, the first two clinical phases of skeletal fluorosis could be easily misdiagnosed [as arthritis]... Even if a doctor is aware of the disease, the early stages are difficult to diagnose. " SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "It should also be noted that chronic fluorosis is not easily diagnosed, and that few physicians have ever seen a case. Three of the cases reported in the U.S. literature were not diagnosed until post-mortem examination revealed excessive fluoride content in the bone. It is possible that the disease may be occurring to some extent without having been recognized." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is quite possible that many cases of (skeletal fluorosis) have gone misdiagnosed and unreported over the years... The state of knowledge among practicing physicians, even those in non-fluoride areas, concerning the diagnosis of skeletal fluorosis seems to be deficient and should be more carefully assessed." SOURCE: Prival MJ. (1972). Fluorides and human health. Center for Science in the Public Interest, Washington D.C. "Symptoms of fluoride poisoning are actually common in this country. The question is not at all whether they occur, but when and how often they are produced by fluoride... It is true that reports (of skeletal fluorosis in the U.S.) are few. This is both the cause and the effect of the fact that physicians, by and large, are unaware that such a thing exists. It is hardly mentioned in the textbooks or in the medical literature. " SOURCE: Exner FB. (1957). Fallacies of the fluoridation thesis. In: J Rorty, ed. (1957). The American Fluoridation Experiment. Delvin-Adair Co, New York. pp. 29-153. Case Reports - Skeletal Fluorosis in the U.S.: "Tea drinking remains popular in the United States and increasingly is suggested to promote health. We caution that skeletal fluorosis can result from consumption of excessive amounts of instant tea because of substantial fluoride levels in some commercial preparations. A 52-year-old white woman consulted in 1998 for dense lumbar vertebras discovered after twisting her back. Spinal discomfort and stiffness for 5 years reflected “disc disease.”... Skeletal discomfort intensified during the subsequent year, and included new neck and scapular pain and elbow and knee arthralgias. Bone and joint pains, acquired axial osteosclerosis, well water, soap manufacturing, and periodontal disease suggested skeletal fluorosis... Our encounter with this patient calls for better understanding of the amounts and systemic effects of fluoride in various teas." SOURCE: Whyte MP, et al. (2005). Skeletal fluorosis and instant tea. American Journal of Medicine 118:78-82. "the fluoride concentration of water from private wells is not routinely measured. In some areas of Arizona, Colorado, Illinois, Iowa, New Mexico, Ohio, Oklahoma, and Texas, high fluoride concentration of the groundwater occurs naturally. Thus, in these areas, as exemplified by the aforementioned patient, it is possible that fluorosis may develop in individuals who obtain their drinking water from private wells."

SOURCE: Felsenfeld AJ, Roberts MA. (1991). A report of fluorosis in the United States secondary to drinking well water. Journal of the American Medical Association 265:486-8. "The cases presented demonstrate several typical features of skeletal fluorosis. By recognizing this entity early, extensive and costly studies may be avoided and the fluoride source eliminated to prevent further progression and sequelae." SOURCE: Bruns BR, Tytle T. (1988). Skeletal fluorosis: a report of two cases. Orthopedics 11: 1083-1087. "A woman with chronic pyelonephritis developed progressive muscular weakness and bone pain. For twenty years she had habitually ingested fluoride-rich soil. Osteosclerosis was found on x-ray examination, and fluorosis was confirmed by bone biopsy. Renal failure augmented skeletal retention of excessive fluoride intake which, in turn, appears to have intensified symptomatic renal osteodystrophy." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "The finding of adverse effects (skeletal fluorosis) in (kidney) patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. pp. 275-293. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. ""It is generally agreed that water fluoridation (1ppm) is safe for persons with normal kidneys. Systemic fluorosis in patients with diminished renal function, however, seems a reasonable possibility... We describe herein two patients in whom evidence of systemic fluorosis was related to three factors: (1) diminished renal function, (2) increased quantities of fluoride in drinking and cooking water (1.7-2.6 ppm), and (3) polydipsia secondary to polyuria." SOURCE: Juncos LI, Donadio JV Jr. (1972). Renal failure and fluorosis. Journal of the American Medical Association 222:783-5. "The findings of a Papago Indian with the second reported case of fluorotic radiculomyopathy in the United States are presented. Neurological deficits occurring in this entity as a manifestation of spinal cord and nerve root bony compression are decribed. This radiculomypathy is rare but it is of regional importance since fluorosis is endemic in Arizona. The lack of any potential skeletal or neurological hazards from water fluoridation programs for dental caries prevention is stressed." SOURCE: Goldman SM, et al. (1971). Radiculomyelopathy in a southwestern indian due to skeletal fluorosis. Arizona Medicine 28: 675-677. "The development of advanced fluorosis in this patient exposed to drinking water with less than 4 ppm of fluoride was unusual and was probably a consequence of his excessive water intake." SOURCE: Sauerbrunn BJ, et al. (1965). Chronic fluoride intoxication with fluorotic radiculomyelopathy. Annals of Internal Medicine 63: 1074-1078. "The diagnosis of fluoride osteosclerosis was proved by the history of a long residence in areas of endemic fluorosis (water F = 1.2 - 5.7 ppm) and by fluorine analysis of the patient's bones and teeth... Areas in the United States in which dental fluorosis exists and where the fluorine content of the drinking water is over 3 parts per million should be systematically studied by the public health authorities to determine how widespread the condition of osteosclerosis is. All patients with dental fluorosis and anemia and/or signs of renal impairment should have radiographic examinations of the skeletal systems to rule out the existence of fluoride osteosclerosis." SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484. No Systematic Studies of Patients with Kidney Disease - Skeletal Fluorosis in U.S. (back to top) "a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis... However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients

with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973.

Skeletal Fluorosis in India & Its Relevance to the West: Included below are recent newspaper articles detailing the impact of skeletal fluorosis in India. In India, the most common cause of fluorosis is fluoride-laden water derived from borewells dug deep into the earth. Of India's 32 states, 17 have been identified as "endemic" areas for fluorosis, with an estimated 25 million people impacted, and another 66 million "at risk." According to field surveys, skeletal fluorosis in India occurs when the fluoride concentration in water exceeds 1 part per million (ppm), and has been found to occur in some communities with only 0.7 parts per million. To put this in perspective, an average of 1 ppm of fluoride is added to the water in artificial fluoridation programs in the United States and other fluoridating countries (e.g. Canada, England, Ireland, Israel, New Zealand, and Australia.) While the elevated consumption of water in warm climates such as India along with the increased incidence of malnutrition make direct comparisons of the Indian experience to the "West" difficult, it is striking to observe how narrow the margin is between the doses which cause advanced fluorosis in India and the doses that people are now regularly receiving in fluoridated communities. For example: A recent, carefully conducted study from Tibet found that a daily fluoride intake of 9 to 12 mg/day was associated with a widespread incidence of advanced skeletal fluorosis (Cao 2003). In the United States, meanwhile, the Government has estimated that the daily dose of fluoride in fluoridated communities ranges from 1.6 to 6.6 mg/day (DHHS 1991). Of greatest practical importance to fluoridated communities in the west, however, are not the advanced stages of fluorosis, but the early stages of fluorosis. It is this fact which makes the proximity in doses causing advanced fluorosis in the "east" (9 - 12 mg/day) to the doses ingested in the "west" (1.6 - 6.6 mg/day) particularly troubling. For, while the advanced stages produce extreme, visibly crippling, effects on the skeleton, the earlier stages are less obvious, and extremely difficult to diagnose. Indeed, a common finding among researchers investigating fluorosis, is that the early stages are marked by symptoms (stiff and painful joints) which are frequently difficult to differentiate from various types of arthritis.

The difficulties in diagnosing the early stages of fluorosis stem from the fact that the arthritic symptoms may occur before detectable bone changes are evident. As noted by Singh and colleagues, the early symptoms: "may be misdiagnosed as rheumatoid or osteoarthritis. Such symptoms may be present prior to the development of definite radiological signs" (Singh 1963). Another difficulty in diagnosing fluorosis is that even when bone changes are apparent (e.g. osteosclerosis; ligament calcification; bone spurs), they can look strikingly similar to other bone diseases - especially to doctors unfamiliar with fluorosis. Bone diseases which fluorosis may be misdiagnosed as, include: ankylosing spondylitis; osteoarthritis; renal osteodystrophy; osteopetrosis; and diffuse idiopathic skeletal hyperostosis (DISH). According to a review of skeletal fluorosis by Chemical & Engineering News: "Although skeletal fluorosis has been studied intensely in other countries for more than 40 years, virtually no research has been done in the U.S. to determine how many people are afflicted with the earlier stages of the disease, particularly the preclinical stages. Because some of the clinical symptoms mimic arthritis, the first two clinical phases of skeletal fluorosis could be easily misdiagnosed... Even if a doctor is aware of the disease, the early stages are difficult to diagnose" (Hileman 1988).

Skeletal Fluorosis in India - Recent Newspaper Reports: (back to top) Increased threat of fluorosis in city - Times of India, June 29, 2004 NEW DELHI: With one-third of Delhi's groundwater laced with excessive fluorides, the number of people falling prey to fluoride poisoning is increasing... According to doctors, there are three forms of fluoride poisoning or fluorosis, the most common being dental fluorosis. The other two forms are skeletal and non-skeletal fluorosis. Dental fluorosis causes yellow, brown or black streaks or spots on the teeth. There is no cure for dental fluorosis. "It is this physical symptom which makes people aware, whereas skeletal fluorosis can go undetected for a long time," said Lady Hardinge Medical College's Pravesh Mehra... Executive director of Fluorosis Research and Rural Development Foundation, A K Susheela said a large number of patients are directed to the foundation since tests for fluoride were not part of the routine blood and urine tests conducted at government hospitals. Meanwhile, the non-skeletal fluorosis affects the soft tissues in the body and one may develop health problems in a very short interval. (Read more...)

Drinking water no succour for this village near Agra - Asian News International June 11, 2004 (back to top) It's no potion but plain drinking water that disables otherwise perfectly fit residents of Baroli Aheer, a village near Agra in Uttar Pradesh. And the cause of agony for the residents of this villages is an excessive fluoride content in the drinking water. Every second person-children as well as adults-are suffering from deformed limbs, cataract, and premature ageing. With the water sources drying up, only one source of water is left-a hand pump, which spews contaminated water. "All this is due to contamination of our drinking water. Everyone is suffering. More than 40-50 people of different age groups are suffering. We have tried various treatments but nothing works," said Rajkumari, a disabled girl.

Doctors attribute the problem to the excessive amounts of flouride, which is present in the drinking water. "The water is the cause of all this. Fluorosis exceeds permissible limits and this is why patients of all ages are suffering and their bones are getting deformed. Some have even turned into invalids," said D V Sharma, an orthopaedic surgeon. Independent initiatives have confirmed that fluoride content in the water is between 3.5 and 4.5 ppm, much higher than the average level. (Read more...)

Threat of Fluorosis in drought-hit Gujarat - Times of India, March 22, 2004 (back to top) GANDHINAGAR: As the dawn breaks, Nirmalaben walks a long distance, carrying water. But it is not the arduous trek for water that has cast a shadow on her face. She is worried about the water she is carrying home for her family members - it's laced with fluoride, and many in Mehsana district are already suffering from fluorosis... Past surveys suggest that the problem of fluoride content in water has been deepening. The Gujarat Ecology Commission's draft Action Environmental Programme, prepared last year, said in 1991, just 831 villages had fluoride levels in groundwater higher than permissible limit... In 1997, the figure reached 2,836. Now, the GWSSB survey says the number of such villages have nearly doubled to 4,341. (Read more...)

Fluorosis on the rise in Rajasthan - Indo-Asian News Service, January 31, 2004 (back to top) Jaipur, An alarming one fourth of the rural population in Rajasthan, India's largest state, suffers from fluorosis, a debilitating disease that damages bones and teeth, research by a voluntary body shows. "The incidence of fluorosis, caused by an excess of fluoride compounds in drinking water, has been rising at an alarming rate in the state," says Mahitosh Bagoria of Health Environment and Development Consortium. "It is estimated that around 25 percent of the rural population in the state is affected," he said... The disease was virtually crippling the victims, Bagoria told IANS. Villagers who consume non-potable water suffer from yellow, cracked teeth, joint pains and crippled limbs and also age rapidly. (Read more...)

Tribals live with fluorosis as govt turns blind eye - The Indian Express, January 12, 2004 (back to top) CHUKRU (JHARKHAND): Every family in the tribal Adivasi belt in Daltonganj has at least one person with some physical deformity. Gastro-intestinal problems are routine here and miscarriages common. And almost all of them suffer from decaying teeth. Fluorosis has spread its tentacles in this village, claiming its first victim last year. In the absence of proper drinking water facilities, these Oraon tribals have been forced to consume water contaminated with fluoride. According to Dr R.P. Singh of the Rajendra Institute of Medical Sciences, consuming water contaminated with fluoride for six months can cause flurosis. ‘‘The impact on the body varies with the extent of fluoride in the water and the genetic and dietary status,’’ he adds. (Read more...)

Fluoride rise in UP water alarming - Times of India, January 2, 2004 (back to top) LUCKNOW : Though 17 states in the country have a sizable number of people with a high fluoride content in their blood, Uttar Pradesh ranks first in this regard. A Unicef report says that 11.77 million people in the state are supposed to be having fluoride content in their blood. Fluoride, which till few years ago was found in the water in Unnao, Rae Bareilly and a few villages in Lucknow district, has spread to new areas. Now this harmful chemical is affecting 18 districts in the state. In spite of repeated appeals made by prominent social workers, the government has done nothing but to allow it to spread in Firozabad , Mathura , Agra , Rae Bareli, etc, says a survey conducted by a NGO. The survey team which collected water samples from more than 500 villages, has found that children born in those areas have been detected with low IQ, memory loss and several other kinds of debilitating problems. It may be recalled that spastic children are known to have high concentration of fluoride in their blood... In the areas considered to be hit by fluoride, cases of gastro-intestinal diseases, nausea, bloated stomach, headache, infertility, weakness of muscles, etc, were found to be on the rise, says the team. These are other than the dental, skeletal and non-skeletal symptoms. Shifting of population, where fluoride content is alarmingly high, is one of the solutions, says a social worker who had been meeting officials to take measures to save precious lives. (Read more...)

Fluoride ‘curse’ cripples Bihar village - The Telegraph, May 10, 2003 (back to top) "The sun is beating down hard amid the dusty hills but the six little devils cannot wait for the race to begin. Ears cocked for the final whistle, they fidget as they stand in line. And nervously, adjust their walking sticks. The whistle goes. Six pairs of legs, grotesquely twisted out of shape, dig their sticks into the patch of green and hobble as fast as they can to the finish line. All six are grinning: Some in shame, some in embarrassment, some with fear that they will collapse midway. Because they cannot run like other children their age — their limbs have been crippled beyond repair by fluoride poisoning. In Kachariadih village, just four km from the administrative headquarters of Rajauli subdivisional town, the children need walking sticks and the young crutches. The overdose of fluoride in drinking water — about 8 mg per litre when the permissible limit is 1.5 — has maimed them for good. ...Twenty-five-year-old Parvati Rajlakshmi agrees. Bent double and in pain, eyes fixed on the ground, she says: “I came here three years ago from a neighbouring village but after giving birth to three children, I suffered excruciating pain in the waist and my physical features got monstrously transformed.” Her children, two of who hover around her, also limp. Not a single member of the nearly 100 families in this village dominated by the Rajvanshis — who are Dalits — is unaffected." (Read more...)

Indian villagers crippled by fluoride - BBC News, April 7, 2003 (back to top) This is a story of a land where excess fluoride has turned the ground water into a slow poison, crippling at least 10,000 people and leaving hundreds of thousand of others in constant misery. This is the story of Nalgonda, one of the poorest and most drought-prone districts of Andhra Pradesh in southern India. The seriousness of the problem can be measured by the fact that the groundwater has 10 to 12 parts per million (ppm) of fluoride in contrast to a maximum permitted level of just 1.5 ppm...

People with paralysing bone diseases, stooped backs, crooked hands and legs, deformed teeth, blindness and other handicaps are a common sight. The most shocking and sad image of this suffering is Ramaswamy. At 18-yeard of age, when other youths are full of enthusiasm for life, Ramaswamy looks to be hardly five-years-old, with a physique completely devastated by the effects of fluoride. He is so weak that he cannot walk and weighs barely 15 kilogrammes (less than 34 lbs). He is blind and mentally challenged. He cannot recognise his own name and he cannot even eat by himself. "We have done all we could have done," says his father Ramalingaiah, himself a victim of fluoride in Anneparti village. (Read more...)

Andhra town under tension as fast for water goes on - Hindustan Times (India) March 11, 2003 (back to top) "...Reddy and Goud have vowed to continue their fast until the authorities start supplying potable water to 604 villages where high fluoride content in water has caused numerous problems, including bone deterioration, loss of eyesight, diabetes and retardation. Workers of the Congress, the state's main opposition party, have been organising protests all over Nalgonda district to express solidarity with the fasting leaders and to press for the supply of safe drinking water. Relay hunger strikes, road blockades and sit-ins have been a regular feature. Police are having a tough time, especially in Nalgonda town where huge crowds are thronging the fasting camp. A couple of other Congress leaders have also joined the legislator and municipal chairman in their fast." (Read more...)

Fluorosis haunts Pavagada taluk - Deccan Herald, August 22, 2002 (back to top) "I have been to all the big hospitals in Bangalore. But even the doctors have pleaded helplessness. What do I do? I have now resigned to my fate", says Channakrishna, who has been literally paralysed in the limbs due to fluorosis affliction. The situation is no different in the other households of Pavagada taluk in the district. In Thimmapura village, Naganna's four children have been immobilised by the affliction. In this village, which has about 50 households, over 30 individuals have been affected by fluorosis. As doctors say, all people in the entire taluk may become immobilised if the condition persists. The prevalence of fluorosis has caused symptoms like joint pains, irregular growth of limbs and spinal cord, formation of lumps on the body resulting in inability to even stand up in some cases. Sixty-year-old Narasappa, who had never had any health problem since childhood, today has developed bow legs and cannot even stand up. Likewise, Manjunath (8), has lost movement in the limbs since the last one year. The prevailing condition is such that a healthy child will develop abnormal growth in the limbs in a year's time and the condition worsens over the years. Treatment of fluorosis, which affects the young and the old alike, has posed a daunting task of the medical fraternity. According to a recent study undertaken in 24 villages of the taluk, about 90 per cent of the population had been affected by fluorosis. Almost all children have been affected by fluorosis of the teeth while in others, it has manifested as joint pains and deformity of the spinal cord and bones of the limbs." (Read more...)

Aging in the time of Drought - Indian Express, July 21, 2002 (back to top) The silence is the first thing to hit you in the village of Jharana Khurd, 60 km from Jaipur. Then you realise why: There are no young people in the village. Every one of the 1,200 residents, no matter if they are 50, 30 or 10, looks old, with yellow, cracked teeth and pronounced limps. Blame it on fluorosis, triggered by the flouride pumped up from the heart of the earth through the only functional tubewell. It's the story of all the 146 villages in Phagi tehsil, dominated by labourers and small farmers, a tragedy underlined by three-and-half years of drought. The failure of rains has caused groundwater levels to drop and flouride levels to concentrate alarmingly. But the flouride began making its presence felt long ago. Ask Ganga and Lachma, both in their 50s, both with hunches protruding almost at right angles from their bodies. ''We have been like this for the past 10 years,'' they say. Even 30-year-old Sarju and Sayar have yellowed teeth, bleeding gums and swollen joints. Says Sayar, ''The aches and swells in the shoulders, hips, ankles make it difficult to get out of bed in the morning. If we squat on the floor, it's painful standing up. And we all suffer from backaches.'' Adds Sayar, ''We can barely lift matkas, or even work in the fields standing up.'' The children are no luckier. The pains in her hips and legs are so bad that Roshan, 10, for instance, would rather stay at home than go to school or play. ''Over the past three years, all the 25 tubewells have dried up one by one. Now we have just one handpump. The doctor says its water is poisonous, but we have no other source of water,'' says small farmer Bhanwar Lal, 40. (Read more...)

Fluorosis playing havoc in Kolar - Times of India, June 6, 2002 (back to top) KOLAR: Barely 70 km from the hi-tech city of Bangalore lies Kolar where more than 80 per cent of the children in the age-group of 6-14 suffer from skeletal and severe dental fluorosis. Reason: The water they consume has excess fluoride which has weakened their hands and legs. Worse, in Kolar, all villages depend on ground water for their domestic and other requirements. Epidemiological survey has revealed that over 26,000 people suffer from dental and skeletal fluorosis and more than 39,000 people are prone to it. According to World Health Organisation (WHO), fluoride level in water should be within 1.5 mg/L. But the fluoride concentration in ground water in Kolar ranges from 2.8 to 4.3 mg/L, which is far above the permissible levels, according to government officials. Eleven-year-old Srikanta sits and stands with difficulty and cannot keep his feet firmly on the ground because he has severe joint pain. So is the case with 13-year-old Sahana at Nallacheravu village in Bagapalli taluk, who is irregular to school, because she suffers from severe joint pain and cannot walk. Sadly, she continues to drink the fluorideaffected water because the de-fluoridation tank in her village is defunct. According to doctors and water quality experts, fluoride affects the system slowly and accumulates in the joints and weakens it in the long run. ``It is not like cough or fever which is momentary. It degenerates the system and the ailment cannot be cured,'' said B.H. Vasudev, a quality assurance engineer who has begun an anti-fluoride campaign among children in Kolar. (Read more...)

Protected drinking water supply evades Lingagudem - Times of India, July 11, 2001 (back to top) JAGGAIAHPET (KRISHNA): People of this sleepy village have been drinking water which has a rich content of fluorine for years now. Ideally the drinking water should be free from fluorine, but the water supplied to the village contains 4.2 ppm of fluorine indicating dangerously harmful levels of flouride. Hence, almost every family in the village has one or two members suffering from arthritis. Pasupuleti Ramaiah (63), a farmer, can barely walk freely. He stopped working long ago as his limbs do not cooperate. "I suffer from body pains regularly and my legs have rendered me almost immobile," he said on Tuesday. (Read more...)

Fluorosis menace fails to move govt - Times of India, July 11, 2001 (back to top) PATNA: ...A report reaching the state headquarters here suggests that 80 per cent of the villagers suffer from fluorosis. Fluorosis, which results from the intake of excess fluoride and causes thickening of bones and destruction of nerves, has struck the village in a major way as almost every family appears to have been afflicted with the disease in varying degrees. The symptoms start with a hip pain which spreads to other parts... "This is the plight of most of the families here," remarked Haridev Yadav while stressing that they are losing their family members at a relatively young age. (Read more...)

Fluorosis makes Amreli villagers stoop - Indian Express, May 11, 2001 (back to top) Hatathigad (Amreli): Sandhiben can't sit up on the bed without an effort. She uses a rope tied to the ceiling to pull herself up and finally manages to get out of the bed with a little help from her grandson. Not many will believe that she is just 45. Fluorosis has added years to her age. Doctors say consumption of water with perilously high levels of dissolved fluorides has caused calcification of ligaments that bind her joints. As a result, Sandhiben's joints in the elbows, knees, ankles, wrists, knuckles and the spinal column have hardened, bent and become stiff. In parched Liliya, Amreli district, water is drawn from such depth that it is heavily contaminated with fluorides. Water with as low as one part per million (ppm) of fluorides is considered unfit for human consumption. According to a Dutch survey, the fluoride content here is 5ppm... "Over the years, cases of stiffened joints, extra bone formations, twisted spinal columns and spondylitis have become common among villagers of all ages. Babies are born with extra formations and children's teeth start decaying early,'' says Tomar. (Read more...)

Excess fluoride in water wreaks havoc in Jharkhand village - India Abroad News Service January 11, 2001 (back to top) Tragedy has struck many a family in the Bakhari village of Jharkhand's Daltanganj district, where excess fluoride in water has left several with severe physical deformities and even paralyzed some...Two-thirds of the villagers have reportedly developed physical deformities as all the sources of drinking water in Bakhari have excess fluoride content. Kaushalya Devi's husband, her only son and four daughters have all fallen victim to excess fluoride. Her daughter-inlaw too suffers from severe backaches. Mangaru Ram's wife, two sons and three daughters have also developed physical deformities. His 12-year-old son Tundnu Ram has been left completely paralyzed and his body is bent out of shape. (Read more... )

High-fluoride water takes toll in Assam District - India Times June 2000 (back to top) GUWAHATI: Thousands of villagers have been affected, many of them crippled for life, by drinking water containing excessive levels of fluoride, in some parts of Assam's Karbi Anglong district, a report said...

Paul said the slow poisoning caused by contaminated groundwater was spreading in remote parts of the state. Many people have been suffering from severe anaemia, stiff joints, painful and restricted movement, mottled teeth and kidney failure leading to premature death while many have been crippled for life. Fluorosis is a non-curable disease and fluoride a deadly chemical. So far, scientists claimed that the north-eastern region was safe from fluoride. (Read more...)

Villagers In Unnao Floored By Fluoride - Times of India, August 31, 1999 (back to top) High percentage of fluoride in water has wrought havoc in a cluster of villages in Unnao district, says a report prepared by the Jal Nigam. The report quotes WHO specifications which place the permissible limit at only 1 mg per litre. In these villages, however, the presence is as high as 7 mg at the highest level and 2.90 mg at the lowest. Steady consumption of fluoride water, says Arati Lalchandani, a city based doctor, affects both nerves and the bones and gradually makes movement and bending of limbs extremely difficult. In fact the situation is so bad in Siraha Khera, a village 70 kilometres from here, that angry villagers initially refused to speak to this correspondent. (Read more...)

Wells that bring nothing but ills - Manchester Guardian Weekly, August 2, 1998 (back to top) THE PUMP was installed in Shatap's village of Hirapur, in the central state of Madhya Pradesh, during the United Nations' International Water Decade of the 1980s. Its borehole was one of millions sunk throughout the world in a highly publicised race to provide the world's poor with "safe" drinking water, planned and part-funded by aid agencies such as Unicef, the UN children's fund. The underground water was indeed mostly free of the bacteria that can infest polluted surface water. But nobody ever tested the underground water for natural chemicals, such as fluoride, even though they were known to be widely present in rocks from which the water was pumped. Madhya Pradesh itself is famous for its rich mineral deposits. "The problem is enormous, unbelievable," says Andezhath Susheela of the Fluorosis Research and Rural Development Foundation in Delhi... All across Mandla, a district of a million or so people in eastern Madhya Pradesh, a steady stream of children have reported similar complaints since the late 1980s. But in this remote corner of central India, doctors had not heard of fluorosis. They instead diagnosed arthritis, polio, rickets, a genetic fault or simply a "mystery disease". The link with water was never made. Until, that is, Tapas Chakma, a young research officer at the Regional Medical Research Centre in Jabalpur came to the village of Tilaipani in 1995 and suggested that a local girl's strange disease might be fluorosis.

The Ministry of not-so-funny-walks - The Guardian (UK) - July 9, 1998 (back to top) Meet 10-year-old Shatap, with a walk straight out of Monty Python. But this diminutive figure is not playing games as he waddles up the muddy lane, his knees locked together and his stunted and misshapen lower legs splayed wide like flippers. His gait is permanent; his bones grossly deformed by fluoride in drinking water pumped from a borehole at the bottom of the lane.

Besides Shatap, there is Kamala and her bow-legged sister Krishna, both daughters of the village head. Aged 14 but looking no more than nine, Krishna was forced to abandon schooling because her deformed limbs could no longer take her to the secondary school in a neighbouring village. Many parents, including Krishna's mother, suffer painful, stiff and misshapen backs and hips, and chronic gastroenteritis. Bhaskar Raman, a local activist who brought the village's plight to the attention of doctors, says there has been an epidemic of stillbirths and involuntary abortions - all known symptoms of fluoride poisoning. All across Mandla, a district of a million or so people in eastern Madhya Pradesh, a steady stream of children have reported similar complaints since the late 1980s. But in this remote corner of central India, doctors hadn't heard of fluorosis. They instead diagnosed arthritis, polio, rickets, a genetic fault or simply a "mystery disease"... "The problem is enormous, unbelievable,' says Andezhath Susheela of the Fluorosis Research and Rural Development Foundation in Delhi. She has been unravelling the national story for a decade during which time her estimate of the people leading "a painful and crippled life" from fluorosis has risen from one million to 25 million and now to 60 million - six million of them children - spread across tens of thousands of communities. "In some villages three quarters of the population are seriously affected." (Read more... )

Skeletal Fluorosis in Other Countries - Recent Newspaper Reports: (back to top) CHINA Aid Groups Urge Action on Water-Borne Diseases Reuters, March 22, 2002 (back to top) "Bartram said there were many other "silent threats," including excessive fluoride in the water supply in China, India and the Rift Valley in Africa. In China alone, 30 million people suffer crippling skeletal fluorosis." (Read more...)

NIGER Hundreds of Children Poisoned by Tap Water - Inter Press Service, January 14, 2001 (back to top) NIGER: The children, ranging in age from 15 months to 14 years, contracted skeletal fluorosis, a disease which causes deformities of the bones, according to medical sources. The children suffer symptoms ranging from stiffness of the joints, arthritic-like symptoms and chronic joint pain, to calcification of the vertebral column, crippling spine and joint deformities, muscle wasting, and neurological defects. Mottling of the teeth is a less serious form of the disease that comes from ingesting lower levels of fluoride (dental fluorosis). According to Dr. Moussa Koini, who has written a medical dissertation on the topic, the disease is caused by drinking water containing too much fluoride. Water samples taken in Tibiri from SNE facilities show that the water contains 4.77 to 6.6 milligrams per litre, instead of the maximum 1.5 milligrams recommended by the World Health Organisation (WHO). . . Skeletal fluorosis is a very disabling disease. Hadjia Kande, a mother whose two youngest children are paralysed, says life is a daily burden. ''Look at my children. Neither one of them can even go to the toilet by himself. I need to provide them with constant attention, so I can't regularly get to my job at the cotton mill.''

One of the children, 13-year-old Salissou, expressed how sad he is. ''I'm afraid to drink water from any source, even well water. Look at the state I'm in, it's really a shame,'' he said. Although it disables both boys and girls, the disease is even worse for girls as it can have grave consequences for childbearing. Dr. Koini explained that ''if there are outgrowths around the pelvic area, girls can have difficulty giving birth and may have to have Caesarian sections because of an inability to deliver vaginally,'' he stated." (Read more...)

PAKISTAN Tainted Water Cripples Villagers - Inter Press Service, September 7, 2000 (back to top) In the last two years, more than 500 people in the four affected villages have developed serious bone disorders, which the government says is caused by excessive -- but naturally occurring -- fluoride in the drinking water. "We have identified 139 children with bone fluorosis, who will undergo corrective surgery," said Sajid Maqbool, director of the Lahore Children's Hospital... Absorption of extremely high levels of fluoride damages the bones, say medical experts. "This makes them soft, crumbly and chalky white. In later stages, this causes stiffness of joints, inability to move the spine and neurological symptoms when the spinal cord is compressed by deforming bones," said an expert from Lahore's Institute of Public Health. (Read more...) Key Findings - High Individual Variability in Skeletal Response to Fluoride: 1) People exposed to the same dose, and duration, of fluoride can exhibit markedly different effects, in both type and severity. This has been observed in areas with endemic skeletal fluorosis and in clinical trials where fluoride has used as an experimental drug to treat osteoporosis. 2) The duration of exposure necessary to produce fluorosis varies widely, even among people exposed to the same dose of fluoride. 3) In the advanced stages of skeletal fluorosis, some people can remain symptom-free, while in the early stages, some people can be mired with symptoms. 4) The concentration of fluoride in bone producing skeletal fluorosis in one individual can exist without any apparent effect in another. Excerpts from Scientific Literature - Variable Prevalence/Type of Skeletal Fluorosis at Same Exposure to Fluoride: (back to top) "It has been a consistent observation in epidemiologic studies that the clinical severity of fluoride-induced toxic effects is highly variable among persons living in the same environment and exposed to the same risk of fluoride ingestion." SOURCE: Wang Y, et al. (1994). Endemic fluorosis of the skeleton: radiographic features in 127 patients. American Journal of Roentgenology 162: 93-8. "In our study... this spectrum (of radiological features in fluorosis) was present in subjects living in the same village and sharing a water source. Obviously factors other than the amount of fluoride ingested are important in determining the type of skeletal change that occurs in fluorosis." SOURCE: Mithal A, et al. (1993). Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skeletal Radiology 22: 257-61. "Skeletal fluorosis is highly variable in its clinical severity among individuals living in the same environment and exposed to the same risk of fluoride ingestion... A number of factors govern the amount of fluoride deposited in the skeleton. Important factors include: 1) age of exposure; 2) the duration of exposure; 3) the dose of fluoride (as

reflected in the blood concentration); 4) nutritional status; 5) renal status; and 6) individual biological variation." SOURCE: Department of Health & Human Services. (U.S. DHHS) (1991). Review of Fluoride: Benefits and Risks. Report of the Ad Hoc Committee on Fluoride, Committee to Coordinate Environmental Health and Related Programs. Department of Health and Human Services, USA. "We suggest that predisposition to fluorosis (chronic toxicity) is biochemically mediated and genetically determined. This would explain the marked variation in fluorosis prevalence in areas with comparable levels of fluoride intake and the selectivity of the disease within the same area. Further studies are necessary to elucidate the complex interaction between calcium, iodine, sex hormones, vitamins and fluoride ions." SOURCE: Anand JK, Roberts JT. (1990). Chronic fluorine poisoning in man: a review of literature in English (19461989) and indications for research. Biomedicine & Pharmacotherapy 44: 417-420. "Individual differences in sensitivity to noxious fluoride seems to be important... [I]t is quite possible to be an aluminum smelter worker for 30 years or longer without showing fluoride-caused bone changes, whereas others develop symptoms of fluorosis after only 10 years..." SOURCE: Runge H, Franke J. (1989). Radiological modifications of the skeletal system among aluminum smelter workers: A 15 year retrospective study. Fluoride 22: 157-164. "[M]any problems remain unclear. For instance, the disease in many people in highly endemic areas may be very severe whereas approximately half of the local population have no obvious fluorotic symptoms or signs. Patients live in the same village and drink the same high fluorine content water but their presentations differ. In some, osteoporosis and osteomalacia are predominant while in others osteosclerosis is predominant." SOURCE: Xu JC, et al. (1987). X-ray findings and pathological basis of bone fluorosis. Chinese Medical Journal 100:8-16. "The considerable individual variability of skeletal response to excessive fluoride ingestion implies that causative factors other than total daily ingestion of fluoride exist." SOURCE: Christie DP. (1980). The spectrum of radiographic bone changes in children with fluorosis. Radiology 136:85-90. "it is an enigma that people from the same area, drinking water from the same source, have considerable variability in the degree of sclerosis, and indeed may have no roentgenographic changes at all.... The individual response to the fluorides must, for some reason, be greatly variable." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615. Excerpts from Scientific Literature - Variable Response to Fluoride Treatment for Osteoporosis: (back to top) "the bioavailability may be markedly different from one patient to another." SOURCE: Boivin G, et al. (1993). Relationship between bone fluoride content and histological evidence of calcification defects in osteoporotic women treated long term with sodium fluoride. Osteoporosis International 3:204208. "the osteogenic response (to fluroide) shows marked interpatient variation." SOURCE: Dure-Smith BA, et al. (1991). Fluoride therapy for osteoporosis: A review of dose response, duration of treatment, and skeletal sites of action. Calcified Tissue International 49(Suppl): S64-S67. "It is still not possible to determine what factors determine those patients who ultimately respond (with higher BMD) to fluoride therapy." SOURCE: Hodsman AB, Drost DJ. (1989). The response of vertebral bone mineral density during the treatment of osteoporosis with sodium fluoride. Journal of Clinical Endocrinology and Metabolism 69:932-8. "Recent data strongly suggest that individual skeletal responsiveness to fluoride therapy varies... The cause or causes of the individual variability in response are unknown." SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research 2: 366-393.

"An increase in the width of osteoid seams was noted in all the present cases of osteoporosis who were treated with NaF. Since this effect was quite variable, however, the question can be raised whether a relationship to the dose and duration of the therapy exists. Of particular interest in this respect are patients 1, 6, and 7: Despite the smallest total dose of NaF (25 to 50 mg/day NaF) for only short periods of time, an extensive effect on the bone was apparent, whereas in case number 3, who received (94.3 mg/day of NaF) within 350 days, an only minute effect was noted. This applies to case number 4, as well." SOURCE: Kuhlencordt F, et al. (1970). The histological evaluation of bone in fluoride treated osteoorosis. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 169-174. Excerpts from Scientific Literature - Variable Duration of Exposure Capable of Producing Fluorosis: (back to top) "Individual differences in sensitivity to noxious fluoride seems to be important... [I]t is quite possible to be an aluminum smelter worker for 30 years or longer without showing fluoride-caused bone changes, whereas others develop symptoms of fluorosis after only 10 years; the varying effect of fluoride has been demonstrated by therapy tests for osteoporosis." SOURCE: Runge H, Franke J. (1989). Radiological modifications of the skeletal system among aluminum smelter workers: A 15 year retrospective study. Fluoride 22: 157-164. "Cases of the 1st phase were observed after 2 5/12 years work, of the 2nd phase after 4 10/12 years, of the 3rd phase after 11 2/12 years. On the other hand the changes were slight in a certain number of the workers, even after long employment...One female worker had no bone changes, though she had been employed for 24 years with one interruption." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "As regards the bone changes... they were pronounced in one male worker who had only been in the factory 5 years, and rather severe also in two female workers who had only been there 6 years." SOURCE: Moller P, Gudjonsson SV. (1932). Massive fluorosis of bones and ligaments. Acta Radiologica 12: 269-294 Excerpts from Scientific Literature - Variable Symptoms at Same Phase of Skeletal Fluorosis: (back to top) "[W]e found patients with slight radiological changes (subtle signs or O-I) who complained of intense pains in the spine and in the large joints. On the other hand, some patients whose fluorosis was radiologically distinct were almost without complaints." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. Excerpts from Scientific Literature - Variable Degree of Skeletal Fluorosis at Same Bone Fluoride Levels: (back to top) "[A]vailable data suggest that there is wide variability in individual tolerance to toxic effects of skeletal accumulation of fluoride." "Fluoride concentrations of 200 to 6500 ppm have been reported in bones which were 'normal'... But bones from patients with severe chronic fluorosis have been found to contain 700-7000 ppm, 905-13,580 ppm, 1120-6050 ppm, and 2040-11,500 ppm. This overlap with the 'normal' range is indicative of wide variability in individual sensitivity to harm." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "Singh et al (1961) described skeletal fluorosis in individuals with F levels in bones in the 700 to 1600 ppm range. This F level in bones is far below that at which many claim fluorosis cannot occur. Data published by Call demonstrated that F content of bones does not parallel the F content in soft tissue organs. Therefore the presence or absence of ill-effect due to fluoride cannot be established on the basis of the F content of bones." SOURCE: Waldbott GL. (1968). Hydrofluorosis in the U.S.A. Fluoride 1: 94-102. "From tabulations of the present study, it is apparent that the degree of bone change does not correlate well with the amount of fluoride present in the bone." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615

"The fluoride content of bone does not appear to be the only factor contributing to the onset of fluorosis. Other metabolic factors must be considered. Concentrations of fluoride from 0.50% to 0.75% (dry, fat-free basis) have been found in ribs, sternum, and vertebrae during postmortem studies of persons with endemic fluorosis, whereas McClure et al reported fluoride values as high as 0.51% to 0.65% in various regions of the skeleton with no associated malfunction or microscopically detectable bone changes." SOURCE: Marier JR, et al. (1963). Accumulation of skeletal fluoride and its implications. Archives of Environmental Health 6: 664-671. Key Findings - Varying Susceptibility to Fluorosis: 1) The risk for developing skeletal fluorosis, and the course the disease will take, is not solely dependent on the dose of fluoride ingested. People exposed to similar doses of fluoride may experience markedly different effects. 2) The risk for developing skeletal fluorosis, and the course the disease will take, can be strongly influenced by the presence or absence of predisposing factors, which include impaired kidney function; dietary deficiencies; genetic predisposition; gastric acidity; physical/repetitive stress; age; and pregnancy/lactation. Factor increasing Susceptibility - Impaired Kidney Function: (back to top) "Individuals with kidney disease have decreased ability to excrete fluoride in urine and are at risk of developing fluorosis even at normal recommended limit of 0.7 to 1.2 mg/l." SOURCE: Bansal R, Tiwari SC. (2006). Back pain in chronic renal failure. Nephrology Dialysis Transplantation 21:2331-2332. "Persons with renal failure can have a four fold increase in skeletal fluoride content, are at more risk of spontaneous bone fractures, and akin to skeletal fluorosis even at 1.0 ppm fluoride in drinking water." SOURCE: Ayoob S, Gupta AK. (2006). Fluoride in Drinking Water: A Review on the Status and Stress Effects. Critical Reviews in Environmental Science and Technology 36:433–487. "Though fluorosis is prevalent in certain geographic parts of the world, it is likely to occur in other parts... in people with latent kidney disease even when they consume relatively lower amounts of fluoride than in endemic regions." SOURCE: Reddy DR, et al. (1993). Neuro-radiology of skeletal fluorosis. Annals of the Academy of Medicine, Singapore 22(3 Suppl):493-500. "It would not be surprising if there were some undetected cases of skeletal fluorosis in the Australian population in individuals with pathological thirst disorders and/or impaired renal function. However, the matter has not been systematically examined. This matter should be the subject of careful and systematic review." SOURCE: National Health and Medical Research Council. (1991). The effectiveness of water fluoridation. Canberra, Australia: Australian Government Publishing Service. "Impairment of renal function can prolong the plasma half-life and contribute to clinical toxicity at lower concentrations of fluoride intake." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Persons with chronic renal failures constitute a possible group at-risk with respect to the occurrence of skeletal fluorosis, because of an increased fluoride retention after oral intake. Based on the results of one study, in which the difference in retention between nephritic patients and healthy persons was quantified (average retention: 65% and 20%, respectively), a total daily intake of about 1.5 mg appears to be the maximum acceptable intake for nephritic patients. In view of the limitations of this comparative study and of the individual differences in retention and sensitivity, this figure must only be regarded as an indication." SOURCE: National Institute for Public Health and Environmental Protection. (1989). Integrated criteria document fluorides. Report No 758474010. The Netherlands. "The skeletal complication of fluoride is more common in renal disease. Because of the impairment in renal excretion of fluoride, high circulating concentrations of fluoride may be achieved in renal disease." SOURCE: Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86.

"a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis. ... However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "Fluoridation of drinking water up to 1.2 ppm apparently does not pose a potential risk to bone provided the renal function is normal... We should, however, recognize that it is difficult to give a strict value for a safe fluoride concentration in drinking water, because individual susceptibility to fluoride varies." SOURCE: Arnala I, et al. (1985). Effects of fluoride on bone in Finland. Histomorphometry of cadaver bone from low and high fluoride areas. Acta Orthopaedica Scandinavica 56(2):161-6. "Because the kidney is the main pathway of fluoride excretion, patients with chronic renal failure are especially vulnerable to osseous accumulation of ingested fluoride and to potentially deleterious effects." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "The finding of adverse effects in (kidney) patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "In the human body, the kidneys are probably the most crucial organ during the course of low-dose long-term exposure to fluoride. Healthy kidneys excrete 50 to 60% of the ingested dose (Marier and Rose 1971). Kidney malfunction can impede this excretion, thereby causing an increased deposition of fluoride into bone. Marier (1977) has reviewed data showing that, in persons with advanced bilateral pyelonephritis, the skeletal fluoride content can be 4-fold that of similarly-exposed persons with normal kidneys. Similarly, Mernagh et al. (1977) have reported a 4fold higher skeletal fluoride content in persons with the renal failure of osteodystrophy. It has also been shown (Seidenberg et al. 1976; Hanhijarvi 1975) that plasma F- levels can be 3 1/2 to 5 times higher than normal in persons with renal insufficiency. It is thus apparent that persons afflicted with some types of kidney malfunction constitute another group that is more "at risk" than is the general population." SOURCE: Marier J, Rose D. (1977). Environmental Fluoride. National Research Council of Canada. Associate Committe on Scientific Criteria for Environmental Quality. NRCC No. 16081. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973). Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is generally agreed that water fluoridation is safe for persons with normal kidneys. Systemic fluorosis in patients with diminished renal function, however, seems a reasonable possibility. In such patients, fluoride may be retained with resulting higher tissue fluoride levels than in persons with normal renal function." SOURCE: Juncos LI, Donadio JV. (1972). Renal failure and fluorosis. Journal of the American Medical Association 222:783-5. "Prolonged polydipsia (excessive thirst) may be hazardous to persons who live in areas where the levels of fluoride in drinking water are not those usually associated with significant fluorosis." SOURCE: Sauerbrunn BJ, et al. (1965). Chronic fluoride intoxication with fluorotic radiculomyelopathy. Annals of Internal Medicine 63: 1074-1078. "All patients with dental fluorosis and anemia and/or signs of renal impairment should have radiographic examinations of the skeletal system to rule out the existence of fluoride osteosclerosis... It is likely that the reason our patient retained fluorine in his bones was that he had renal damage of long standing; without this the osteosclerosis

might not have developed." SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484. Factor increasing Susceptibility - Poverty/Poor Nutrition: (back to top) "[M]alnourished individuals appear to be more prone to develop dental and skeletal fluorosis." SOURCE: Littleton J. (1999). Paleopathology of skeletal fluorosis. American Journal of Physical Anthropology 109: 465-483. "In calcium-deficient children the toxic effects of fluoride mainfest even at marginaly high (>2.5 mg/d) exposures to fluoride." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "It was also evident that the osteopenic radiological picture [of fluorosis] is more commonly found in the poorer and undernourished population of the village." SOURCE: Mithal A, et al. (1993). Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skeletal Radiology 22: 257-61. "Diets high in fat have been reported to increase deposition of fluoride in bone and, thus, to enhance toxicity." SOURCE: Department of Health & Human Services. (U.S. DHHS) (1991). Review of Fluoride: Benefits and Risks. Report of the Ad Hoc Committee on Fluoride, Committee to Coordinate Environmental Health and Related Programs. Department of Health and Human Services, USA. "As reported for dental fluorosis the modifications in bone tissue histology caused by high fluoride intake could be mitigated by the influence of dietary factors." SOURCE: Boivin G, et al. (1989). Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10:89-99. "Additional factors thought to contribute to development of endemic fluorosis include calcium deficiency and poor nutrition." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Community based studies strongly suggest that calcium status modifies the type of bone changes seen in fluorosis." SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10(3-4):279-314. "Over 90% of the persons affected with severe skeletal fluorosis, bone disease and deformities belong to the low socio-economic group of the farming community and they had generalized nutritional deficiencies." SOURCE: Teotia SPS, et al. (1984). Environmental fluoride and metabolic bone disease: an epidemiological study (fluoride and nutrient interactions). Fluoride 17: 14-22. "The occurrence of this syndrome among the poorer segments of the populations is suggestive of a detrimental role of undernutrition on fluoride-induced toxicity." SOURCE: Krishnamachari KA, Krishnaswamy K. (1973). Genu valgum and osteoporosis in an area of endemic fluorosis. The Lancet 2: 877-879. "Evidence of malnutrition in fluorosis-prone subjects has been cited by several investigators. Therefore, it is reasonable to suggest that subjects suffering from dietary deficiencies or metabolic malfunction may have an increased susceptibility to fluorosis." SOURCE: Marier JR, et al. (1963). Accumulation of skeletal fluoride and its implications. Archives of Environmental Health 664-671. "there seemed to be a definite connection between the development of joint symptoms and poverty or intercurrent infections, since the disease appeared to be much more severe in those who had the least opportunity for healthy living."

SOURCE: Kilborn LG, et al. (1950). Fluorosis with report of an advanced case. Canadian Medical Association Journal 62: 135-141. "The incidence and severity of the disease had a definite relation to the economic and nutritional status of the communities... A pronounced deficiency of the vitamin C factor in the diet was especially associated with a severe incidence of the disease." SOURCE: Pandit CG, et al. (1940). Endemic fluorosis in South India. Indian Journal of Medical Research 28: 533558. "A diet rich in Ca, P, and vitamin D has an influence on the course of the intoxication, but does not prevent its occurrence." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "In a region where there is a possibility of ingesting fluorine in toxic quantities, there will be individuals who ingest it without giving clinical symptoms of intoxication. Cristiani has applied the term latent fluorine intoxication to this condition. The manifest intoxication symptoms then develop if the fluorine intake is raised or the sensibility to fluorine increases for some reason (Ca or vitamin deficiency, etc). This explains why bones and teeth sometimes contain the same quantity of fluorine in apparently healthy individuals as in individuals with definite symptoms of intoxication." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. Factor increasing Susceptibility - Genetics: (back to top) "The results suggest that genetic factors may contribute to the variation in bone response to fluoride exposure.... The genetic influence on the efficacy and adverse effects has been demonstrated for some medications but has never been demonstrated for bone response to fluoride. The demonstration of such genetic influence on bone response to fluoride has important clinical significance. It stresses the importance to taking into account the genetic background of each individual." SOURCE: Mousny M, et al. (2006). The genetic influence on bone susceptibility to fluoride. Bone Aug 18; [Epub ahead of print] "Previous studies in mice and humans, as well as epidemiological studies, have demonstrated that severity of dental fluorosis cannot be explained simply by the amount of fluoride in the tooth structure, indicating that genetics (susceptiblity to fluoride) plays an important role in dental fluorosis severity. Based on that, one can infer that in individuals ingesting the same amount of fluoride, the DF severity will be related to and/or based on individual susceptibility to fluoride (genetics)." SOURCE: Vieira AP, et al. (2004). Tooth quality in dental fluorosis - genetic and environmental factors. Calcified Tissue International Oct 14 [Epub ahead of print]. "The phenotype frequency distributions of several classical blood genetic markers and dermatoglyphic characters were analyzed in workers of Siberian aluminum plants who had occupational fluorosis. Comparison with healthy workers revealed significant differences in frequencies of several (genetic) markers... As we have previously shown, risk of occuapational fluorosis in Siberian workers employed in aluminum industry is associated wtih several erthrocytic isoantigens and a set of particular qualitative dermatoglyphic characters." SOURCE: Lavryashina MB, et al. (2003). A study of the genetic basis of susceptibility to occupational fluorosis in aluminum industry workers of Siberia. Russian Journal of Genetics 39: 823-827. "This study helped 1) to establish the existence of genetic predisposition to fluorosis and develop criteria for estimating it, and 2) to prove that predisposition to fluorosis was associated wtih the same dermatoglyphic features in the workers of both industrial groups." SOURCE: Polzik EV, et al. (1994). A method for estimating individual predisposition to occupational fluorosis. Fluoride 27: 194-200. "We suggest that predisposition to fluorosis (chronic toxicity) is biochemically mediated and genetically determined. This would explain the marked variation in fluorosis prevalence in areas with comparable levels of fluoride intake and the selectivity of the disease within the same area. Further studies are necessary to elucidate the complex interaction between calcium, iodine, sex hormones, vitamins and fluoride ions."

SOURCE: Anand JK, Roberts JT. (1990). Chronic fluorine poisoning in man: a review of literature in English (19461989) and indications for research. Biomedicine & Pharmacotherapy 44: 417-420. Factor increasing Susceptibility - Gastric Acidity: (back to top) "We studied the relationship of gastric acid in 150 aluminnum workers to the degree of severity of fluorosis... Increase in gastric acidity was associated with greater sensitivity toward fluoride." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. Factor increasing Susceptibility - Repetitive/Physical Stress: (back to top) "it appears that the development of new fluorotic bone occurs at those sites most subjected to strain and minor trauma." SOURCE: Littleton J. (1999). Paleopathology of skeletal fluorosis. American Journal of Physical Anthropology 109: 465-483. "In man, the spine is the most common part of the skeleton to be first affected (with fluorosis) and also severely so because it is required to sustain the erect posture and has stresses and strains." Prasad VS, Reddy DR. (1994). Posttraumatic pseudomenigocoele of cervical spine in a patient with skeletal fluorosis: Case report. Paraplegia 32:627-30. "It is notable that the symptoms and radiological changes occur first in areas of greater muscular activity... Both Siddiqui and Singh et al noted... the selective effect of this halide on the joints which are most used." SOURCE: Anand JK, Roberts JT. (1990). Chronic fluorine poisoning in man: a review of literature in English (19461989) and indications for research. Biomedicine & Pharmacotherapy 44: 417-420. In "Indian basket weavers exposed to fluoride, it was observed that the much used left arm and wrist were particularly susceptible to fluorotic exostosis... [T]he areas suffering repeated or constant stress or trauma, and as a result requiring ongoing repair, may be areas of increased circulation and metabolism and, as a consequence, increased deposition of fluorides." SOURCE: Carnow BW, Conibear SA. (1981). Industrial fluorosis. Fluoride 14: 172-181. "Radiological changes in industrial fluorosis suggest that physical strain on bones, ligaments, and joints play an important role in the development of the lesions." SOURCE: Boillat MA, et al. (1980). Radiological criteria of industrial fluorosis. Skeletal Radiology 5: 161-165. "These [fluorotic] changes first appear at sites of greatest metabolic activity and stress within a given bone and in bones that are under the greatest stress from weight bearing and locomotion." SOURCE: Shupe JL, Olson AE. (1971). Cinical aspects of fluorosis in horses. Journal of the American Veterinary Association 158: 167-174. "The radiographs of our case show the typical changes of severe skeletal fluorosis. Bones subjected to greatest stress are most affected (by fluorosis), probably due to their greater calcium turnover... The severe elbow involvement in our case may have been related to his occupation as a carpenter." SOURCE: Webb-Peploe MM, Bradley WG. (1966). Endemic fluorosis with neurological complications in a Hampshire man. Journal of Neurology, Neurosurgery and Psychiatry 29:577-583. "The onset of fluorosis in humans is favored by physcial stress, affecting the skeletal regions most used by the individual. Continued surface abrasions of a bone with high fluoride and magnesium content may release relatively high levels of these ions at the crystal-solution interface, promoting crystallization of magnesium fluoride during replacement of damaged bone." SOURCE: Marier JR, et al. (1963). Accumulation of skeletal fluoride and its implications. Archives of Environmental Health 6: 664-671. "Physical strain may also contribute, because the disease was found predominantly in manual workers, who showed involvement of cervical spine and skull - a condition rarely seen by Roholm." SOURCE: Singh A, et al. (1961). Skeletal fluorosis and its neurological complications. Lancet 1: 197-200.

"The degree of osteosclerosis was found to be related to the duration of intoxication and the concentration of fluorine in the water. Physical strain was also found responsible: the greater the strain, the more pronounced were the changes observed... Pain and stiffness were more severe in the joints used most by the individual - for example, the wrists, shoulders, and neck in the females, who were mostly engaged in household work: and the lumbar spine and the joints of the lower limbs in the males working in the fields." SOURCE: Siddiqui AH. (1955). Fluorosis in Nalgonda district, Hyderabad-Deccan. British Medical Journal ii (Dec 10): 1408-1413. Factor increasing Susceptibility - Age: (back to top) "Fluoride toxicity afflicts children more severely and over a shorter period of exposure (about 6 months) as compared to adults. This is because the rapidly growing bones of children are metabolically active and more vascular and thus absorb and accumulate fluoride faster and in greater amounts than older bones, particularly at the sites of bone growth and physiological calcifications." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "To date, animal studies of fluoride effects on bone have used young and healthy experimental animals exclusively. The effects of fluoride on old animals, that more closely represent people most likely to fracture, have not been studied.... In older rats receiving 50 ppm fluoride, failure stress was decreased by as much as 29%. Such dramatic losses in bone strength only have been shown previously in studies where fluoride intake was accompanied by calcium deficiency, yet, in this study, calcium intake in the older rats was no different from that in the younger rats... [I]t is possible that aging effects and fluoride incorporation in the bone act synergistically to decrease bone strength." SOURCE: Turner CH, et al. (1995). Fluoride reduces bone strength in older rats. Journal of Dental Research 74:1475-81. "In our opinion, growing children with active bone metabolism, if exposed to high fluoride intake, are more prone to develop skeletal fluorosis than adults. As bone ages and becomes more or less stabilized in the remodelling of its Haversian systems, less fluoride may be deposited. We observed that individuals residing in an endemic area since birth develop more severe skeletal fluorosis than those who have moved into the endemic zone after 17 to 18 years of age when bone growth has created." SOURCE: Teotia M, Teotia SPS. (1973). Further observations on endemic fluoride-induced osteopathies in children. Fluoride 6: 143-151. "Mottling was the result of the action of fluoride on osteoblasts during bone formation. Young bones undergoing extensive remodeling showed extensive mottling, while old bones with scant remodeling showed little mottling." SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press (1965) 424-441. "A large calcium requirement in the organism increases the sensitivity to fluorine. Bone symptoms are produced most readily in young, growing individuals." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. Factor increasing Susceptibility - Pregnancy/Lactation: (back to top) "It appears that fluoride ingestion during lactation created a heightened state of calcium homeostatic stress. As a result, bone mineral was mobilized by resorption of the endosteal surface and by cavitation of the interior of the cortex." SOURCE: Ream LJ, et al. (1983). Fluoride ingestion during multiple pregnancies and lactations: microscopic observations on bone of the rat. Virchows Arch [Cell Pathol] 44: 35-44. "Excessive fluoride ingestion in pregnant women may possibly poison and alter enzyme and hormonal systems in the fetus causing disturbances in osteoid formation and mineralization." SOURCE: Christie DP. (1980). The spectrum of radiographic bone changes in children with fluorosis. Radiology 136:85-90.

"A large calcium requirement in the organism increases the sensitivity to fluorine. Bone symptoms are produced most readily in young, growing individuals. The toxic effect on cattle becomes visible especially in conjunction with pregnancy and lactation." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. Key Findings - Variability in Radiographic Appearance of Fluorosis: 1) Skeletal fluorosis has a variety of radiological manifestations, including osteosclerosis, osteomalacia, osteoporosis, and secondary hyperparathyroidism. 2) The reason for the variability in the appearance of skeletal fluorosis is not yet fully understood. 3) Some factors which are believed to explain some of the variability include: dose, nutrition, and area of skeleton impacted. Excerpts from the Scientific Literature - Variability in Radiographic Appearance: (back to top) "Skeletal fluorosis caused by endemic fluorine poisoning was once thought to result merely in osteosclerosis, causing marblelike changes. Later, various radiologic features were found, including osteosclerosis, osteomalacia, and osteoporosis. Although this disorder has a wide variety of appearances, little attention has been given to the spectrum of radiologic appearances... The pathogenesis of these diverse radiologic appearances remains unclear." SOURCE: Wang Y, et al. (1994). Endemic fluorosis of the skeleton: radiographic features in 127 patients. American Journal of Roentgenology 162: 93-8. "Typical descriptions of skeletal radiology in endemic fluorosis have emphasized osteosclerosis (especially of the spine), membranous and ligamentous calcification, and exostoses... Our study showed in addition a wide variety of radiological patterns: ...[T]he pelvis showed the appearance of both osteosclerosis and osteopenia. Osteosclerosis was present in the central area of the pelvis while the lateral part showed considerable osteopenia. Vertebral bodies showed an osteopenic central region bordered by a sclerotic zone at the vertebral margin." SOURCE: Mithal A, et al. (1993). Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skeletal Radiology 22: 257-61. "High F intakes have been associated wtih a wide spectrum of bone diseases including osteosclerosis, osteoporosis, osteomalacia and exostoses... The pathogenic mechanisms underlying fluorosis of the mineralizing tissues have been studied extensively, but are still a matter of controversy." SOURCE: Kragstrup J, et al. (1989). Effects of fluoride on cortical bone remodeling in the growing domestic pig. Bone 10:421-424. "We suggest that bone fluorosis be classified roentgenologically on the basis of these 3 features into 3 types: the osteosclerosis type (53 cases, 36.3%), osteoporosis type (18 cases, 12.3%), and mixed type (51 cases, 34.9%)... In mixed type fluorosis, osteosclerosis, osteoporosis and osteomalacia exist in one patient." SOURCE: Xu JC, et al. (1987). X-ray findings and pathological basis of bone fluorosis. Chinese Medical Journal 100:8-16. "A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostoses formation characterzes the bone lesions. In a proportion of cases secondary hyperparathyroidism is observed with associated characteristic bone changes." | SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10(3-4):279-314. "It is very interesting to observe that in the majority of our cases, osteosclerosis in the spine and pelvis was always combined with osteoporosis of the long bones. It might be an indication that the axial skeleton undergoes a quite different pathological process from the appendicular skeleton..." SOURCE: Lian ZC, Wu EH. (1986). Osteoporosis--an early radiographic sign of endemic fluorosis. Skeletal Radiology 15:350-3.

"Radiographic appearances varied between individuals. Conflicting changes such as both decreased and increased density, coarsened, thinned and blurred trabeculae, coexisted not only in different bones of one individual, but also in one and the same bone. Some cases showed axial osteosclerosis exclusively, others axial osteosclerosis in association with peripheral osteoporosis or osteomalacia... Combinations of various changes produced a wide sprectrum of radiological changes." SOURCE: Daijei H. (1984). Further observations on radiological changes of endemic foodborne skeletal fluorosis. Fluoride 17: 9-14. "[N]ew bone formed under the stimulus of fluoride administration may exhibit various degrees of osteosclerosis, osteoporosis, osteomalacia, and architectural disorganization. Of these manifestations, only osteosclerosis increases bone strength. When fluoride is used therapeutically, therefore, it is obvious that conditions must be carefully chosen so as to maximize the development of osteosclerosis and to minimize the undesirable manifestations of osteoporosis and osteomalacia." SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research. 2: 366-393. "The changes described did not always develop in a progressive, predictable pattern to the adult stage of osteofluorosis." SOURCE: Christie DP. (1980). The spectrum of radiographic bone changes in children with fluorosis. Radiology 136:85-90. "The considerable individual variability of skeletal response to excessive fluoride ingestion implies that causative factors other than total daily ingestion of fluoride exist." SOURCE: Christie DP. (1980). The spectrum of radiographic bone changes in children with fluorosis. Radiology 136:85-90. "The osseous changes in fluorosis have been described as osteosclerosis, exostosis, hyperostosis, osteoporosis, osteomalacia, and rickets. Many questions arise as to why sometimes one type of osteopathy is induced and another at other times. The pathogenesis of the osseous changes in fluorosis has not been uncovered. Hodge and Smith (1965) commented on the cellular mechanisms whereby the bone lesions are induced in fluorosis: 'Questions are many, and answers are few, indeed, practically non-existent.'" SOURCE: Krook L, Maylin GA. (1979). Industrial fluoride pollution. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Veterinarian 69(Suppl 8): 1-70. "The findings of osteosclerosis, osteomalacia and increased bone resorption have been confirmed in experimental fluorosis in animals. It can be seen, therefore, that fluoride bone disease could mimic renal osteodystrophy." SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202. "In the final analysis it would be surprising if the complicated effects of fluoride on bone did not reflect the versatility of fluorine, the most reactive and the most stronly electronegative of all elements." SOURCE: Faccini JM, Teotia SPS. (1974). Histopathological assessment of endemic skeletal fluorosis. Calcified Tissue Research 16: 45-57. "To this day, many investigators still think of fluorosis exclusively in terms of osteosclerosis, whether crippling or noncrippling. This attitude is no longer valid, because osteosclerosis is only one of many skeletal abnormalities that can be induced by fluoride." SOURCE: Marier JR, Rose D. (1971). Environmental fluoride. National Research Council of Canada, Publication No. 12,226, Ottawa. "The osteofluorotic lesions may be porosis, sclerosis, hyperostosis, osteophytosis, and malacia, depending on the interacting factors influencing the degree of fluorosis." SOURCE: Shupe JL, Olson AE. (1971). Cinical aspects of fluorosis in horses. Journal of the American Veterinary Association. 158: 167-174. "Skeletal fluorosis has been likened to a number of bone diseases. The dense radiographic picture of the skeleton has resulted in comparison with osteosclerosis; the presence of broad osteoid seams has suggested osteomalacia; the way in which bone formation may proceed side by side with bone destruction is reminiscent of Paget's disease and the often excessive resorption points to osteoporosis."

SOURCE: Jolly SS. (1970). Hydric fluorosis in Punjab. In: TL Vischer. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 106-121. "the findings in spontaneous and experimental fluorosis are, in part, contradictory. Human patients are usually diagnosed as having osteosclerosis whereas animals are described as having osteoporosis or 'osteomalacia'. Our radiograms might indicate that both processes are taking place, the sclerosis predominating over the greater part of most of the bones but osteoporosis being evident near the ends of some long bones." SOURCE: Kilborn LG, et al. (1950). Fluorosis with report of an advanced case. Canadian Medical Association Journal 62: 135-141. "Chronic fluorosis presented by some 10,000 inhabitants of the Argentine Republic is an anomaly of calcium metabolism involving not only the teeth but in addition the entire osseous system and characterized by generalized osteoporosis." SOURCE: Silva LL, et al. (1940). Fluorosis and tuberculosis. La Semana Medica 24: 1413-1434. "The osseous tissue displays a curious double reaction: sometimes an increased precipitation of mineral salts accompanied by stimulated growth, sometimes a reduced mineralization with mostly atrophying processes." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "It is extremely probable that fluorine acts on the metabolism in various ways and that the symptoms of chronic intoxication have a complicated genesis." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd Excerpts from the Scientific Literature - Reason for Variability Unclear: (back to top) "Although this disorder has a wide variety of appearances, little attention has been given to the spectrum of radiologic appearances... The pathogenesis of these diverse radiologic appearances remains unclear." SOURCE: Wang Y, et al. (1994). Endemic fluorosis of the skeleton: radiographic features in 127 patients. American Journal of Roentgenology 162: 93-8. "The pathogenic mechanisms underlying fluorosis of the mineralizing tissues have been studied extensively, but are still a matter of controversy." SOURCE: Kragstrup J, et al. (1989). Effects of fluoride on cortical bone remodeling in the growing domestic pig. Bone 10:421-424. "Many questions arise as to why sometimes one type of osteopathy is induced and another at other times. The pathogenesis of the osseous changes in fluorosis has not been uncovered. Hodge and Smith (1965) commented on the cellular mechanisms whereby the bone lesions are induced in fluorosis: 'Questions are many, and answers are few, indeed, practically non-existent.'" SOURCE: Krook L, Maylin GA. (1979). Industrial fluoride pollution. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Veterinarian 69(Suppl 8): 1-70. "It appears that there are some factors yet unknown which a play a part in determining the pattern of skeletal changes." SOURCE: Makhni SS, et al. (1977). Long-term effects of fluoride administration: an experimental study. Fluoride 10:82-86. "The histopathogenesis of the bone disease produced by chronic fluoride intoxication remains incompletely understood despite innumerable reports in the literature of the results of animal experimentation... In the final analysis it would be surprising if the complicated effects of fluoride on bone did not reflect the versatility of fluorine, the most reactive and the most stronly electronegative of all elements...Most probably all these factors are involved." SOURCE: Faccini JM, Teotia SPS. (1974). Histopathological assessment of endemic skeletal fluorosis. Calcified Tissue Research 16: 45-57.

"Despite the large volume of research, however, the effects of fluoride on bone are complicated and are still not fully understood." SOURCE: Faccini JM. (1969). Fluoride and bone. Calcified Tissue Research 3:1-16. Excerpts from the Scientific Literature - Common Explanations Offered for Variability: (back to top) a) Multifactorial: (back to top) "It is generally thought that several factors influence the type of bone change seen in fluoride intoxication. These include the nature, dose, and duration of fluoride exposure; nutritional status; hormonal responses; age; sex; type of bone affected (cortical or otherwise); and dietary habits... The different appearances of this disease probably represent different combinations of these variables." SOURCE: Wang Y, et al. (1994). Endemic fluorosis of the skeleton: radiographic features in 127 patients. American Journal of Roentgenology 162: 93-8. b) Dose of Fluoride: (back to top) "We found that fluoride increased cancellous bone area in the rat at the lower dose and reduced cancellous bone volume at the higher dose... Our findings suggest that the optimal concentration of fluoride that increases bone resorption is higher than the concentration that increases formation. If this is correct, the effects of fluoride on bone formation and resorption may be mediated through different mechanisms and may be dissociable." SOURCE: Turner RT, et al. (1989). The effects of fluoride on bone and implant histomorphometry in growing rats. Journal of Bone and Mineral Research 4: 477-484. "Osteosclerotic picture is evident when small doses of fluoride are ingested over a long period of time during which calcium intakes are apparently normal while osteoporotic forms are common in pediatric age group and with higher body load of the element." SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10:279-314. "Roholm (1937) realised, however, that an increase in bone growth and calcification resulted from comparatively small doses of fluorides, while large doses produced an atrophic state with a reduction in calcification." SOURCE: Faccini JM. (1969). Fluoride and bone. Calcified Tissue Research 3:1-16. "The osteoporotic stage of the disease occurs only when fluoric intoxication is very severe." SOURCE: Soriano, M. (1968). Periostitis deformans due to wine fluorosis. Fluoride 1: 56-64. "In the adult the osteosclerotic process seems to be produced by comparatively small quantities of fluorine, the osteoporotic process seems to be produced by comparatively large quantities." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. c) Nutritional Status: (back to top) "The toxic effects of fluoride were more severe and more complex and the incidence of metabolic bone disease (rickets, osteoporosis, Parathyroid Hormone bone disease) and bony leg deformities (genu valgum, genu varum, bowing, rotational and wind-swept) was greater (>90%) in children with calcium deficiency as compared to in children with adequate calcium who largely had osteoslcerotic form of skeletal fluorosis..." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "On the basis of our results, we suggest that fluoride toxicity in subjects with a reasonable calcium intake leads to typical osteosclerosis, while a calcium - (and protein-) deficient diet together with fluoride excess may be responsible for the osteopenic forms of the disease." SOURCE: Mithal A, et al. (1993). Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skeletal Radiology 22: 257-61.

"Osteosclerotic picture is evident when small doses of fluoride are ingested over a long period of time during which calcium intakes are apparently normal while osteoporotic forms are common in pediatric age group and with higher body load of the element." SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10:279-314. d) Area of Skeleton Impacted: (back to top) "In skeletal fluorosis, the spinal column is the site of election. Spinal osteosclerosis resulting from chronic fluoride intoxication may be expected to divert calcium preferentially to the spinal column at the expense of limb bones. In the presence of low dietary calcium such diversion may well result in osteoporosis of the limb bones." SOURCE: Krishnamachari KA, Krishnaswamy K. (1973). Genu valgum and osteoporosis in an area of endemic fluorosis. The Lancet 2: 877-879. Varying Individual Sensitivites to Fluoride - Variable Length of Exposure Producing Fluorosis Among Workers in Same Workplace "Individual differences in sensitivity to noxious fluoride seems to be important... [I]t is quite possible to be an aluminum smelter worker for 30 years or longer without showing fluoride-caused bone changes, whereas others develop symptoms of fluorosis after only 10 years; the varying effect of fluoride has been demonstrated by therapy tests for osteoporosis." SOURCE: Runge H, Franke J. (1989). Radiological modifications of the skeletal system among aluminum smelter workers: A 15 year retrospective study. Fluoride 22: 157-164. "Cases of the 1st phase were observed after 2 5/12 years work, of the 2nd phase after 4 10/12 years, of the 3rd phase after 11 2/12 years. On the other hand the changes were slight in a certain number of the workers, even after long employment...One female worker had no bone changes, though she had been employed for 24 years with one interruption." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "As regards the bone changes... they were pronounced in one male worker who had only been in the factory 5 years, and rather severe also in two female workers who had only been there 6 years." SOURCE: Moller P, Gudjonsson SV. (1932). Massive fluorosis of bones and ligaments. Acta Radiologica 12: 269-294 Variations in Individual Susceptibility to Fluoride: Duration of Exposure Producing Fluorosis Study Roholm 1937 Roholm 1937 Roholm 1937 Roholm 1937 Franke 1975 Franke 1975 Franke 1975 Franke 1975 Franke 1975 Runge 1989 Runge 1989 Phase of Skeletal Fluorosis No Changes Clinical Phase 1 Clinical Phase 2 Clinical Phase 3 Vague Symptoms Stage O-I Clinical Phase 1 Clinical Phase 2 Clinical Phase 3 No Changes Vague Symptoms Average Exposure (years) 8 9.3 9.7 21.1 10.71 12.15 15.7 17.6 19.5 19.9 19.2 Shortest Exposure (years) 2.8 2.4 4.8 11.2 2 5 8 11 19 5 10 Longest Exposure (years) 24 33.8 28.9 31.2 25 33 38 21 20 35 37

Runge 1989 Runge 1989 Runge 1989 Runge 1989 Runge 1989 SOURCE of DATA:

Stage O-I Clinical Phase 1 Clinical Phase 1-2 Clinical Phase 2 Clinical Phase 2-3

22.6 21.1 21.1 17.5 21.3

10 10 10 16 15

30 43 33 19 26

Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. Runge H, Franke J. (1989). Radiological modifications of the skeletal system among aluminum smelter workers: A 15 year retrospective study. Fluoride 22: 157-164.

Summation - Estimated "Threshold" Doses for Skeletal Fluorosis: For over 40 years health authorities stated that in order to develop crippling skeletal fluorosis, one would need to ingest between 20 and 80 mg of fluoride per day for at least 10 or 20 years. This belief, however, which played an instrumental role in shaping current fluoride policies, is now acknowledged by the National Academy of Sciences (NAS) and other US health authorities to be incorrect. In 1993, the NAS revised its longstanding 20-80 mg/day estimate, by stating that crippling fluorosis could be caused by doses as low as 10 and 20 mg a day. Left unaddressed, however, by the NAS and other US health authorities is the dose that could produce the earlier stages of fluorosis. Common sense would indicate that the dose which can produce the early stages of fluorosis, in which bone changes may not be detectable, would be less than the doses that can produce the crippling stages. Thus, we would expect the "threshold" dose for the early stages to be below 10 mg/day. Evidence from India (albeit limited) indicates that this is, in fact, the case. Also left unaddressed by US health authorities is the extent to which the threshold dose varies based on the existence or absence of predisposing factors in an individual (e.g. kidney disease; genetic predisposition; and nutrient deficiencies). Unfortunately, the longstanding assurances by health authorities that skeletal fluorosis could not be produced at doses below 20 mg/day, stunted scientific inquiry into the issue, and as a result, we know far less today about the range of doses that can produce fluorosis than might have otherwise been the case. Excerpts from the Scientific Literature - Uncertainty Remains/Reigns: (back to top) "There is no fixed toxic level of fluoride, since the development of fluorosis depends upon environmental factors." SOURCE: Littleton J. (1999). Paleopathology of skeletal fluorosis. American Journal of Physical Anthropology 109: 465-483. "The actual fluoride intake required to produce skeletal fluorosis is unknown." SOURCE: Cook HA. (1972). Crippling fluorosis related to fluoride intake (case report). Fluoride 5: 209-213. Excerpts from the Scientific Literature - Published Estimates of Doses Causing Fluorosis: (back to top)

"The levels of fluoride ingestion which can lead to long-term skeletal fluorosis (2-8 mg/day) appear to be exceeded in the diet of the average adult in a fluoridated community." SOURCE: Groth, E. (1973). Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "In calcium-deficient children the toxic effects of fluoride mainfest even at marginally high (>2.5 mg/d) exposures to fluoride." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "In its final report, the Surgeon General’s panel said that radiologic changes have been found in bone when fluoride exposure has been about 5 mg per day." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "The histologic features of osteofluorosis were evident in the biopsy from the patient receiving the lowest amount of fluoride (6 mg. daily for 5 months)..." SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85. "In areas of endemic fluorosis, levels of ingestion of fluoride from diet and water over 8 mg daily are common, although in certain regions in India, changes typical of skeletal fluorosis have been stated to occur at estimated lower dosages." SOURCE: Singh A, Jolly SS. (1970). Chronic toxic effects on the skeletal system. In: Fluorides & Human Health. World Health Organization, Geneva. pp. 238-249. "Singh and Jolly (1970) noted that a daily intake of 8 mg or more of fluoride is necessary to produce skeletal fluorosis. Those cases in which the disease could not be demonstrated radiologically were excluded." SOURCE: Cook HA. (1972). Crippling fluorosis related to fluoride intake (case report). Fluoride 5: 209-213. "According to our observations the prolific growth in periostitis deformans (skeletal fluorosis) continues as long as daily amounts greater than 8 to 10 mg of F are ingested no matter through what vehicle." SOURCE: Soriano, M. (1968). Periostitis deformans due to wine fluorosis. Fluoride 1: 56-64. "Only when relatively large amounts of fluoride (8-20 mg/day) are ingested for prolonged periods are generalized adverse effects encountered." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "The present paper shows that daily intakes of 9-12 mg are associated with a very high prevalence of skeletal fluorosis. (The US Institute of Medicine's) upper safe limit may need to be revised/lowered on the basis of present data." SOURCE: Cao J, et al. (2003). Brick tea fluoride as a main source of adult fluorosis. Food and Chemical Toxicology 41:535-42. "Most epidemiological research has indicated that an intake of at least 10 mg/day for 10 or more years is needed to produce clinical signs of the milder forms of the condition.” SOURCE: Institute of Medicine. (1997). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride National Academy Press, Washington D.C. pp. 307 "Osteomalacia and osteoporosis may occur in older persons who ingest excessive fluorides (over 10-25 mg/d for 1020 years)." SOURCE: Ellenhorn MJ, Barceloux DG. (1988). Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Elsevier; New York. pp. 534. Excerpts from the Scientific Literature - U.S. Health Authorities Retract 20-80 mg/day Estimate for Crippling Fluorosis: (back to top)

"Crippling skeletal fluorosis might occur in people who have ingested 10-20 mg of fluoride per day for 10-20 years." SOURCE: National Research Council. (1993). Health Effects of Ingested Fluoride. National Academy Press, Washington DC. “Most estimates indicate that crippling skeletal fluorosis occurs when 10-20 mg of fluoride have been ingested on a daily basis for at least 10 years.” SOURCE: Whitford G. (1996). The Metabolism and Toxicity of Fluoride. 2nd Revised Edition. Karger: Basel. pp. 138. "It is generally stated that a dose of 10–20 mg/day for at least 10 years is necessary for the development of crippling skeletal fluorosis, but individual variation, variation in nutritional status, and the difficulty of determining water fluoride levels in such situations make it difficult to determine the critical dose." SOURCE: Agency for Toxic Substances & Disease Registry [ATSDR]. (2003). Toxicological profile for Fluorides, Hydrogen Fluoride, and Fluorine. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. "Crippling fluorosis as an occupational disease follows exposures estimated at 10 to over 25 mg of fluoride daily during periods of 10-20 years." SOURCE: Hodge HC. (1979). The Safety of Fluoride Tablets or Drops. In: Johansen E, Taves DR, Olsen TO, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 253-274. Excerpts from the Scientific Literature - The 20-80 mg/day Error that Shaped Public Policy for 40+ Years: (back to top) "Skeletal changes are among the prominent chronic effects observed after long-continued exposures to large amounts of fluoride (20 to 80 mg per day or more). These abnormalities of the skeleton manifest themselves as osteosclerosis, osteoporosis, and exostoses of the long bones and of the vertebra, pelvis, jaw bone, and other flat bones; with somewhat smaller amounts, yet many times the 1 p.p.m. of water fluoridation, minor alterations in bone architecture, e.g., thickening of trabeculae, have been reported." SOURCE: Food & Nutrition Board. (1953). The Problem of Providing Optimum Fluoride Intake for Prevention of Dental Caries. National Academy of Sciences. Publication #294. "Crippling fluorosis occurs when men ingest or inhale 20 to 80 mg of fluoride or more daily for a period of 10 to 20 years. Since 5 gallons of fluoridated water (at 1 ppm) contain 20 mg, it is obvious that crippling fluorosis can never be produced by drinking fluoridated water." SOURCE: Hodge HC. (1956). Fluoride metabolism: its significance in water fluoridation. Journal of the American Dental Association 52:307-314. "Crippling fluorosis, a rarely described entity, may follow exposure of 10 to 20 years' duration when 20 to 80 mg. or more of fluoride are taken into the body daily." SOURCE: Hodge HC. (1960). Notes on the effects of fluoride deposition on body tissues. Archives of Industrial Health 21: 350-352. "This industrial disease identified by Roholm (1937) is described in his classic monograph Fluorine Intoxication. Danish workmen in the dusty cryolite industry became crippled and could no longer perform simple physical tasks. Exposures to 20 or 80 or more mg F/day for 10-20 years were responsible for the development of osteosclerosis, exostoses, and calcification of the ligaments. The consequent fixation of the spinal column, the 'poker back', was crippling." SOURCE: Hodge HC. (1963). Safety factors in water fluoridation based on the toxicology of fluorides. Proceedings of the Nutrition Society 22: 111-117. "Moller and Gudjonsson estimated that 20 to 80 (or more) mg F inhaled daily for 10 to 20 years will produce crippling fluorosis." (Note: Moller and Gudjonsson never produced such an estimate. Indeed, they provided no estimate at all of the dose that produced the skeletal fluorosis in the workers they studied.) Hodge HC, Smith FA. (1970). Air quality criteria for the effects of fluorides on man. Journal of the Air Pollution Control Association 20:226-232. "Crippling fluorosis as seen by Roholm is estimated to result from the daily ingestion of 20-80 mg for 10-20 years." SOURCE: NAS (1971). Fluorides. Committee on Biologic Effects of Atmospheric Pollutants, Division of Medical Sciences, National Academy of Sciences, Washington, D.C.

"The daily fluoride exposures to bring about the bony changes were roughly estimated by Moller and Gudjonsson (1932) to range from 20 to 80 mg F (or more) taken into the body daily for 10 to 20 years." (Note: Moller and Gudjonsson never produced such an estimate. Indeed, they provided no estimate at all of the dose that produced the skeletal fluorosis in the workers they studied.) SOURCE: Hodge HC, Smith FA. (1977). Occupational fluoride exposure. Journal of Occupational Medicine 19: 1239. "It is estimated that the development of crippling skeletal fluorosis, requires the daily consumption of 20 mg or more of fluoride from all sources for 20 or more years." SOURCE: Environmental Protection Agency. (1985). National primary drinking water regulations; fluoride. Federal Register May 14; 50(93): 20164-20175. Key Findings - Water Fluoride/Skeletal Fluorosis: 1) In India and China, surveys have consistently found clinical skeletal fluorosis to occur in in communities with 1.0 1.5 ppm fluoride in water, and crippling fluorosis to occur in communities wtih 3 ppm fluoride. 2) Case reports from India have documented crippling fluorosis among some individuals drinking as little as 1.2 - 1.3 ppm fluoride in water. 3) In the United States, case reports have documented skeletal fluorosis among people with kidney disease at water fluoride levels as low as 1.7 ppm, and among heavy tea drinkers, at water fluoride levels as low as 2.2 to 3.5 ppm. 4) There have been no systematic studies in the United States to assess the prevalence of skeletal fluorosis among susceptible subsets of the population. Published Data - Water Fluoride/Skeletal Fluorosis in India & China: (back to top) "Skeletal fluorosis in India and China has been reported to occur when the fluoride concentration in water exceeds 1 ppm, and has been found to occur in communities with only 0.7 ppm. The Chinese government now considers any water supply containing over 1 ppm fluoride a risk for skeletal fluorosis." SOURCE: Gupta R, Kumar AN, Bandhu S, Gupta S. (2007) Skeletal fluorosis mimicking seronegative arthritis. Scandanavian Journal of Rheumatology 36(2):154-5. "It is also generally stated that a dose of 10–20 mg/day (equivalent to 5–10 ppm in the water, for a person who ingests 2 L/day) for at least 10 years is necessary to develop crippling skeletal fluorosis. But, the research in India provides credible evidence for a striking contrast to these perceptions as most of the information relating to endemic fluorosis has originated from India where skeletal fluorosis has been associated with water-borne fluoride concentrations of 2 to 3 ppm or lower and even at 0.7 ppm. It is observed that in many populations of India, skeletal fluorosis can occur at a minimum fluoride level of 1.35 ppm and crippling form of skeletal fluorosis at or above 2.8 ppm, given the presence of predisposing factors." SOURCE: Ayoob S, Gupta AK. (2006). Fluoride in Drinking Water: A Review on the Status and Stress Effects. Critical Reviews in Environmental Science and Technology 36:433–487 "Endemic fluorosis in rural India occurs because of prolonged ingestion of water with excess fluoride (water F > l ppm) resulting in significant skeletal morbidity." SOURCE: Tiwari S, et al. (2004). Simultaneous exposure of excess fluoride and calcium deficiency alters VDR, CaR, and calbindin D 9 k mRNA levels in rat duodenal mucosa. Calcified Tissue International 75: 313-20 "High fluoride (>1.0 mg/L) in drinking water resulted in dental and skeletal fluorosis in local residents (children and pregnant women)... It has been determined that fluoride concentration in excess of 1 mg/L exposes residents to high health risks based on risk identification." SOURCE: Bo Z, et al. (2003). Distribution and risk assessment of fluoride in drinking water in the west plain region of Jilin province, China. Environmental Geochemistry and Health 25: 421-31.

"confirmed cases of human skeletal fluorosis were reported where, in 6 of 22 communities studied, the fluoride content of drinking water was between 1.2 and 1.9 ppm; whether this represents the sole source of fluoride ingested is not known." SOURCE: Marier JR, et al. (1963). Accumulation of skeletal fluoride and its implications. Archives of Environmental Health 664-671. "At this 1.5 ppm F concentration, 6.1, 6.8, and 9.5% of adults in villages of Banswara, Udaipur, and Dungarpur districts, respectively, showed evidence of skeletal fluorosis." SOURCE: Choubisa SL. (2001). Endemic fluorosis in Southern Rajasthan, India. Fluoride 34: 61-70. "The reports outside of the United States, taking everything into consideration, do get clinically observable adverse effects certainly at 4 (ppm) or above. There are plenty of papers." SOURCE: Kleerekoper M. (1983). Surgeon General's Ad Hoc Committee on 'Non-Dental Health Effects of Fluoride." Transcript of Proceedings, National Institutes of Health, Bethesda, Maryland, April 19. Water Fluoride & Skeletal Fluorosis - Inner Mongolia, CHINA SOURCE: Xu RQ, Wu DQ, Xu RY. (1997). Fluoride 30: 26-28. Skeletal Fluorosis Fluoride content of water (Villages in Inner Mongolia, China) 0.4 0.65 1.4 1.6 3.2 3.4 4.7 6.9 Individuals Examined 1,046 941 1204 889 798 866 214 834 Cases 0 2 93 109 101 132 42 166 % with Skeletal Fluorosis 0 0.21 7.72 12.26 12.66 15.24 19.63 19.9

Water Fluoride & Skeletal Fluorosis - INDIA SOURCE: Susheela AK, Kumar A, Bhatnagar M, Bahadur R. (1993). Fluoride 26: 97-104.. Skeletal Fluorosis Village Bhanakpur Sikrona Karnera Samaypur Fluoride Content of Fluoride Content of Water Water (Mean) (Range) 1 2.5 3.7 3.2 0.7 - 1.6 0.3 - 5.4 0.3 - 7 0.25 - 8 Individuals Examined 837 518 315 288 Cases 141 94 135 163 % with Skeletal fluorosis 16.8% 18% 42.8% 58.6%

Published Data - Water Fluoride/ Crippling Skeletal Fluorosis in India: (back to top) "A series of 70 cases of skeletal fluorosis with neurological manifestations was studied... The lowest F concentration in water causing skeletal fluorosis and quadriplegia was 1.35 ppm. Singh et al (1961) recorded spastic paraplegia in a 50 year old male who consumed water containing 1.2 ppm F." SOURCE: Siddiqui AH. (1970). Neurological complications of skeletal fluorosis with special reference to lesions in the cervical region. Fluoride 3:91-96. "The lowest fluoride level with skeletal fluorosis and its neurological complications has been reported at 1.2-1.35 ppm." SOURCE: Misra UK, et al. (1988). Endemic fluorosis presenting as cervical cord compression. Archives of Environmental Health 43:18-21.

"This article describes a patient with clinical and radiological features of skeletal fluorosis with neurological sequelae. His problem is of special interest because he lived in a non-tropical, non-endemic area [1-2 ppm] where cases of advanced fluorosis would not be expected." SOURCE: Maloo JC, et al. (1990). Fluorotic radiculomyelopathy in a Libyan male. Clinical Neurology and Neurosurgery 92: 63-65. "It was initially claimed that crippling fluorosis required water levels of more than 10 ppm before it occurred. More studies, however, have demonstrated that in many populations, crippling occurs above 3 ppm, and can occur at water levels of 1.35- 1.5 ppm, given the presence of predisposing factors." SOURCE: Littleton J. (1999). Paleopathology of skeletal fluorosis. American Journal of Physical Anthropology 109: 465-483. Water Fluoride & Skeletal Fluorosis/Crippling Fluorosis - Rajasthan, INDIA SOURCE: Choubisa SL. (2001). Fluoride 34: 61-70. Fluoride Content of Water (ppm) Districts & villages Banswara Isarwada Gangertalai Vassioda Mangala Borda Chhotipadel Dungarpur Mewadi Jhariyana Indora Deotalab Dad Bokedsal Udaipur Matasula Amlu Dagar Thada Bhabrana Dhamodar Jhalara 1.5 1.6 1.9 2.6 3.0 3.8 4.0 1.2-1.7 1.3-1.6 0.2-3.0 0.2-5.1 2.6-3.5 3.0-4.7 3.5-4.7 103 94 90 102 114 110 142 7 8 14 20 24 37 52 6.8% 8.5% 15.6% 19.6% 21.1% 33.6% 36.6% ----+ + + 1.6 1.8 2.4 2.8 3.1 3.2 1.1-1.8 1.7-2.0 1.1-3.1 1.5-4.1 2.8-3.9 2.9-3.5 112 104 105 98 96 102 10 20 27 39 41 40 8.9% 19.2% 25.7% 39.8% 42.7% 39.2% ---+ + + 1.6 1.9 2.6 3.3 3.5 3.7 1.2-2.1 1.2 - 3.0 2.2-2.9 2.7-4.1 2.6-4.2 2.9-4.6 108 102 122 126 120 116 7 15 23 31 36 38 6.1% 14.7% 18.9% 24.6% 30% 32.8% ---+ + + Mean Range Individuals Examined Cases (>21 yrs) Skeletal Fluorosis % with Skeletal Fluorosis Crippling Fluorosis

Water Fluoride & Skeletal Fluorosis/Crippling Fluorosis - Punjab, INDIA SOURCE: Jolly SS. (1968). Fluoride 1: 65-75. Fluoride Content of Water Village Mean Range Individuals Skeletal Fluorosis Cases % with Skeletal Crippling

Examined Gharachon Laluwala Dhapai Bhodipura Rajthai Bhikti Sanghera Ramuana/ Ganjigulab Singh Khara 1.4 2.4 3.0 3.0 3.3 3.3 3.6 5.0 8.5 9.7 0.9-2.5 1.0-5.5 1.1-5.5 1.3-5.2 0.5-6.5 1.0-5.9 1.1-5.8 1.5-11.5 3.7-14.0 6.0-16.2 82 74 107 64 160 160 154 90 56 232 2 17 21 27 16 73 51 54 33 164

Fluorosis 2.4% 23.0% 19.6% 42.2% 10% 45.6 % 33.1 % 60% 58.9% 70.7%

Fluorosis ---+ -+ + + + +

Published Data - Water Fluoride /Skeletal Fluorosis in the U.S.: (back to top) See also: Fluoridation, Dialysis, & Osteomalacia StudyFluoride Content of Water

1.2 - 5.7 2.2 - 3.5
Goldman 19711.0 - 9.2 1.7, 1.7, 1.9, 2.0Juncos 1972 Felsenfield 1991Johnson 1979 Whyte 2005 4.0 - 7.8 1.7, 2.6 7.2 - 8.2 2.8

"3 ppm wouldn't protect the individual with renal insufficiency..." SOURCE: Wallach S. (1983). Surgeon General's Ad Hoc Committee on 'Non-Dental Health Effects of Fluoride." Transcript of Proceedings, National Institutes of Health, Bethesda, Maryland, April 19. "The finding of adverse effects (skeletal fluorosis) in (kidney) patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is generally agreed that water fluoridation is safe for persons with normal kidneys. Systemic fluorosis in patients with diminished renal function, however, seems a reasonable possibility." SOURCE: Juncos LI, Donadio JV. (1972). Renal failure and fluorosis. Journal of the American Medical Association 222:783-5. "All patients with dental fluorosis and anemia and/or signs of renal impairment should have radiographic examinations of the skeletal systems to rule out the existence of fluoride osteosclerosis."

SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484; erratum 497. Research Gaps - No Systematic Studies Investigating Skeletal Fluorosis in U.S. among Susceptible Subsets: (back to top) "a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis... However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. Key Findings - Fluoridation, Dialysis, & Osteomalacia: 1) In the 1960s and 1970s, dialysis units in the U.S. and Canada did not filter out fluoride added to water via water fluoridation programs. As a result, dialysis patients received toxic doses of fluoride. 2) A series of medical reports throughout the 1970s extensively documented an increase in both the incidence and severity of osteomalacia among patients using dialysis with fluoridated water. Osteomalacia is a serious disease that softens bones, often causing incapacitating pain and fracture. 3) The doses that dialysis patients received (14-34 mg/day), and the blood fluoride levels (~1 ppm) they attained, have since been well documented to produce osteomalacia in carefully controlled clinical trials among humans without kidney disease. 4) While dialysis units now routinely filter fluoride out of the water, recent reports nonetheless suggest that the total body burden of fluoride in dialysis patients - from dietary sources and dental products - may still be provoking osteomalacia and/or other forms of bone changes in some patients. Definition - Dialysis: "The process of artificially cleansing the blood in persons whose kidneys no longer function properly." SOURCE: Kidney Transplant Program Definition - Osteomalacia: "A softening of the bones in adults caused by a failure of the normal calcification." SOURCE: HealthCentral

"The pain of osteomalacia is typically difficult to localize. All the bones are tender—especially the long ones in the legs and arms... In diagnosed cases of osteomalacia, 94% of patients complain of pain; 94% complain of muscle weakness; 88% complain of bone tenderness with pressure on touch; 24% complain of a waddling gait and muscle cramps; and, there is a higher incidence of fracture than expected for age—even in bones that test “normal” on the DEXA bone density test." SOURCE: Doctor Diet Excerpts from the Scientific Literature - Fluoridation, Dialysis, & Osteomalacia (1960s-1970s): (back to top) SEE ALSO: "New Facts on Fluoridation" - Saturday Review, March 1, 1969 "Five of the six patients exposed to fluoridated dialysate for an average of 23 months suffered bone pain and fractures, and three of these patients had incapacitating symptoms. Bone biopsy specimens from five patients exposed to fluoridated dialysate for more than 1 year were compared with those from six patients of approximately the same age, duration of azotemia, and duration of dialysis who were dialyzed using fluoride-free dialysate. The blood concentrations and ratios of bone fluoride to calcium were significantly higher in patients exposed to fluoridated dialysate. Although the severity of osteitis fibrosis was similar in the two groups, as reflected by the percentage of bone surface undergoing osteoclastic resorption, osteomalacia was significantly more severe in the fluoridated group." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "Electron microscopical examination of iliac crest bone biopsy specimens from four patients suggests that fluoride induces the synthesis of disarrayed collagen by the activated osteoblasts... In the fluoridated group, osteoid seams were more abundant and wider than in the non-fluoridated group... This study has shown that hemodialysis with fluoridated water in chronic renal failure induces the activated osteoblasts to produce excessive osteoid in which the collagen fibrils are disarrayed. The risk of severe osteomalacia is reduced with the use of fluoride-free dialysate." SOURCE: Lough J, et al. (1975). Effects of fluoride on bone in chronic renal failure. Archives of Pathology 99: 484-487. "The markedly increased incidence of osteomalacia in the fluoridated group supports previous reports that fluoride is an important factor... Since our patients in the fluoridated group were living in widely separate areas with different water supplies it seems unlikely that there was another common factor other than fluoride responsible for the higher incidence of osteomalacia. It is possible that the presence of other substances in untreated water is necessary before the toxic effects of fluoride become manifest... Forty-one patients on our chronic hemodialysis program were assessed for the degree of progression of bone disease over a period of 46 months. Four of 7 patients using fluoridated water developed florid osteomalacia, as opposed to none of the 34 patients in the non-fluoridated group... We conclude that the presence of fluoride in the dialysate, perhaps in conjunction with other substances, is associated with an increased incidence of osteomalacia. It therefore seems prudent to use non-fluoridated water in long-term hemodialysis." SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202. "within a year after starting dialysis the patient complained of chest pain and pain in the feet, and the skeletal radiologic survey showed generalized demineralization and fractures of the fifth through the eigth ribs posteriorly... In spite of a good appetite and a good intake of food, his body weight decreased by 11 kg. Because we had not seen such severe bone disease in a patient while on relatively high concentrations of dialysate calcium when fluoride-free water had been employed, we recommended in October, 1968, that a commercial mixed-bed deionizer be installed to remove the fluoride.. Bone resorption decreased and osteomalacia improved, coincident wtih the lowering of dialysate, serum and bone concentrations of fluoride... The excessive amounts of osteoid seen in the bone biopsy specimen and the decrease in osteomalacia subsequent to correcting the deionizer operation are consistent with a fluoride effect."

SOURCE: Johnson WJ, Taves DR. (1974). Exposure to excessive fluoride during hemodialysis. Kidney International 5: 451-454. "Hemodialysis with fluoridated water was associated with an elevation in serum alkaline phosphatase and an increase in renal osteodystrophy over a 2 year period, but without a control group of patients dialyzed wtih a fluoride free dialysate, it cannot be concluded that fluoride is responsible for these findings." SOURCE: Nielson E, et al. (1973). Fluoride metabolism in uremia. Transactions of the American Society of Artifical Internal Organs 19: 450-455. "All 4 patients exposed to high-fluoride dialysate showed excessive osteoid formation... Osteoid formation was 9 times greater in those exposed to high-fluoride dialysate (1 ppm) than in those exposed to lower concentrations (0.095 ppm)... The presence of increased amounts of osteoid tissue in patients exposed to high-F dialysate is consistent with the observations of DeVeber and associates... Increased osteoid is typically found in fluorosis, hence, ascribing our findings to an F effect seems reasonable. There are several possible reasons for F causing increased osteoid. In vivo, excessive F can result in increased bone production and failure of mineralization... It may be noteworthy that 4 of the 5 patients with the most disabling symptoms of bone pain, muscle weakness, wasting and multiple spontaneous fractures were exposed to high-F dialysate. This would suggest that prolonged exposure to F can contribute to the bone disease seen in long-term hemodialysis... The use of F-free dialysate decreases the risk of severe morphologic osteomalacia." SOURCE: Jowsey J, et al. (1972). Effects of dialysate calcium and fluoride on bone disease during regular hemodialysis. Journal of Laboratory and Clinical Medicine 79: 204-214. "At the Ottawa General Hospital, osteomalacia unresponsive to recommended therapy was the predominant bone lesion in our patients prior to deionization. Subsequent to deionization, no patient has developed clinical renal osteodystrophy of any type, and in particular no osteomalacia. Patients who began the program with secondary hyperparathyroidism improved with standard dialysis treatment. A patient with non-responsive osteomalacia prior to deionization responded normally following deionization by healing her fractures and calcifying her osteoid. Hence we found that we could not only prevent symptomatic osteomalacia by deionization, but could also reverse its course. This suggests that there was a factor in our tap water which prevented normal calcification of osteoid and that this is removed by deionization. We have previously reported high uptake of fluoride with an increase in the serum and bone levels of fluoride in our patients dialyzed with ordinary tap water. DeVeber and Jowsey have observed an increase in osteoid similar to ours in their dialysis patients treated with high fluoride dialysate. High fluoride concentrations have also been shown experimentally to lead to a defect in osteoid calcification. These observations suggest a role for fluoride in the osteomalacic disease in dialysis patients. Against fluoride being the only factor are reports from other centers denying the presence of osteomalacia in their patients on fluoridated dialysate. We conclude that the osteomalacia that occurs in dialysis patients is due to multiple factors that are removed by deionization. Fluoride may be one of the contributing factors." SOURCE: Posen GA, et al. (1972). Comparison of renal osteodystrophy in patients dialyzed with deionized and nondeionized water. Transactions of the American Society for Artificial Internal Organs 18: 405-411. "In our hemodialysis center, opened in April 1964, fluoridated dialysis began with the fluoridation of the city water supply in November 1965. Our subsequent therapeutic failure was completely unexpected and a possible explanation was suggested by the observation of Taves et al. that the serum fluoride levels in patients chronically hemodialyzed with fluoridated water are comparable to those that cause fluorotic bone disease. Thus, the study of fluoride levels in our patients became of particular interest because several of them had been on fluoridated dialysate for much longer periods than those patients reported by Taves et al... Clinically, radiologically, and histologically, the disease seen in thse patients was indistinguishable from uremic osteodystrophy, although the manifestations of bone disease tended to appear sooner and in more severe form in our patients maintained on fluoridated dialysate... Histologically and radiographically, these patients showed features of uremic osteodystrophy instead of the fluorosis characterized by exostoses and osteosclerosis. Nervertheless, the observed changes (osteomalacia, osteitis fibrosa and osteoporosis) were similar to those induced by high doses of fluoride in humans and experimental animals, in which widened osteoid seams have been observed, and where increased areas of resorption due to secondary hyperparathyroidism may be seen. Therefore, it seems likely that fluoride was aggravating the underlying renal osteodystrophy in our patients, and that this effect was enhanced by concomitant administration of high doses of vitamin D." SOURCE: Posen GA, et al. (1971). Renal osteodystrophy in patients on long-term hemodialysis with fluoridated water. Fluoride 4: 114-128. "The concept that osteomalacia becomes progressively worse on chronic dialysis was reinforced by the findings in the repeat bone biopsies in that 6 of the 8 patients showed a significant increase in their osteoid index... Thus, the progression of osteomalacia appears to be the main reason for the increasing incidence of bone pain and

pseudofractures which we and others have observed in patients on chronic dialysis for periods longer than 6 months. Jowsey, et al, has reported similar findings. When the patients reported by Kim, et al. are classified in the same manner as ours were, a similar higher incidence of osteomalacia and absence of severe osteitis fibrosa was observed in patients on chronic dialysis for more than 6 months... The reason(s) for the progression of osteomalacia, which we observed in our chronic dialysis patients, remain(s) unclear. Factors which could result in impaired mineralization which must be considered include fluoride, hypermagnesemia, and phosphate depletion." SOURCE: deVeber GA, et al. (1970). Changing patterns of renal osteodystrophy with chronic hemodialysis. Transactions of the American Society for Artificial Internal Organs 16: 479-486. "These data suggest that the serum fluoride values seen in these patients are likely to result in altered bone formation. Further studies will be needed to rule out the possibility that more generalized effects are occurring, particularly in the 2 patients with the highest fluoride concentrations." SOURCE: Taves DR, et al. (1968). Hemodialysis with fluoridated dialysate. Transactions of the American Society for Artificial Internal Organs 14: 412-414. Excerpts from the Scientific Literature - Fluoridation, Dialysis, & Bone Damage (1990s-Present): (back to top) "Fluoride interfered with bone mineralization and increased osteoid content, which was most evident in osteomalacia and the mixed bone disorder. In addition, fluoride may interact with aluminum to worsen the osteomalacic lesion." SOURCE: Ng AHM, et al. (2004). Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone 34: 216-224. "[B]one fluoride content was significantly higher in the entire dialysis population than in controls (0.33 + 0.04% vs 0.13 + 0.018%, P=0.04). Bone fluoride levels were increased in osteomalacic patients (0.57 + 0.1%) compared with normal controls (0.13 + 0.01%, P <0.05)... The highest values were found in patients with osteomalacia with six out of nine having values above 0.5%." SOURCE: Cohen-Solal ME, et al. (2002). Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients. Nephrology Dialysis Transplantation 17: 449–454. "Bone fluoride content was high in the osteomalacic group (1.1 + 0.3%) compared to the 25 randomly selected HPT (0.33 + 0.1%, p<0.01) and 25 randomly selected ABD group (0.21 + 0.03%, p<0.01)... Fluoride content was >0.5% in 7/11 patients. These data show that mineralisation defects observed in hemodialyzed patients are frequently associated with high bone fluoride content. Fluoride may be considered as a potential etiological factor of osteomalacic osteodystrophy." SOURCE: Cohen-Solal ME, et al. (1996). Osteomalacia is associated with high bone fluoride content in dialysis patients. Bone 19: 135S. "In the current study, concentrations of fluoride in the serum of patients with hemodialysis, for both male and female patients, were remarkably higher than those in healthy subjects... From the results obtained, it is suggested that the characteristic change of BMD in patients with hemodialysis, such as increase in BMD of the lumbar spine in spite of the decrease in that of the radius may be contributed to continuance of high concentration of fluoride in the serum. To control serum fluoride at an adequate level constantly, intake of fluoride should be controlled and also fluoride level maintenance system of the hemodialysis is desirable. Furthermore, frequent and long term monitoring of serum fluoride and BMD with hemodialysis patients are highly necessary." SOURCE: Takahashi Y. (1995). Effects of fluoride on bone metabolism in patients with hemodialysis. Bulletin of the Osaka Medical College 41: 27-35. "From these results, it was suggested that absorbed F strongly affected the metabolism of bone, especially cancellous bone in the patients with long-term hemodialysis." SOURCE: Tanimura Y. (1994). Studies on serum fluoride and bone metabolism in patients with long term hemodialysis. Bulletin of the Osaka Medical College 40: 65-72. Key Findings - Fluoride & Renal Osteodystrophy: 1) Individuals with kidney disease have a diminished ability to excrete fluoride in their urine. As a result, kidney disease results in an elevated accumulation of fluoride in the bones.

2) The spectrum of bone disorders (e.g. osteomalacia, osteoporosis, osteosclerosis, and secondary hyperparathyroidism), collectively known as renal osteodystrophy, which are found in people with advanced kidney disease can all be individually produced, or exacerbated, by elevated fluoride exposure. 3) Aluminum's impact on bone is amplified in the presence of fluoride, and vice versa. Both elements accumulate to high levels in the bones of kidney patients, and it is quite plausible that the deterimental effect of aluminum in renalosteodystrophy is enhanced by the presence of fluoride and/or the presence of aluminum-fluoride complexes. 4) No systematic studies have ever been conducted to investigate the relationship between fluoride exposure and severity of bone changes in individuals with kidney disease. Excerpts from the Scientific Literature - Kidney Patients at Increased Risk of Fluorosis: (back to top) "[A] fairly substantial body of research indicates that patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. Patients with reduced glomerular filtration rates have a decreased ability to excrete fluoride in the urine. These patients may develop skeletal fluorosis even at 1 ppm fluoride in the drinking water... The National Kidney Foundation in its ‘Position Paper on Fluoride—1980’ as well as the Kidney Health Australia express concern about fluoride retention in kidney patients. They caution physicians to monitor the fluoride intake of patients with advanced stages of kidney diseases. However, a number of reasons will account for the failure to monitor fluoride intake in patients with stages 4 and 5 of chronic kidney diseases and to detect early effects of fluoride retention on kidneys and bone. The safety margin for exposure to fluoride by renal patients is unknown, measurements of fluoride levels are not routine, the onset of skeletal fluorosis is slow and insidious, clinical symptoms of this skeletal disorder are vague, progression of renal functional decline is multifactorial and physicians are unaware of side effects of fluoride on kidneys or bone." SOURCE: Schiffl H. (2008). Fluoridation of drinking water and chronic kidney disease: absence of evidence is not evidence of absence. Nephrology Dialysis Transplantation 23:411. "Individuals with kidney disease have decreased ability to excrete fluoride in urine and are at risk of developing fluorosis even at normal recommended limit of 0.7 to 1.2 mg/l." SOURCE: Bansal R, Tiwari SC. (2006). Back pain in chronic renal failure. Nephrology Dialysis Transplantation 21:2331-2332. "In patients with reduced renal function, the potential for fluoride accumulation in the skeleton is increased. It has been known for many years that people with renal insufficiency have elevated plasma fluoride concentrations compared with normal healthy persons and are at a higher risk of developing skeletal fluorosis." SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p140. "Persons with renal failure can have a four fold increase in skeletal fluoride content, are at more risk of spontaneous bone fractures, and akin to skeletal fluorosis even at 1.0 ppm fluoride in drinking water." SOURCE: Ayoob S, Gupta AK. (2006). Fluoride in Drinking Water: A Review on the Status and Stress Effects. Critical Reviews in Environmental Science and Technology 36:433–487 "Skeletal fluorosis seems possible, especially in hot climates or with renal compromise, from drinking excessive quantities of instant or bottled teas. Our observations support the need for better understanding of the amounts and systemic effects of fluoride in teas." SOURCE: Whyte M. (2006). Fluoride levels in bottled teas. American Journal of Medicine 119:189-190. "We hypothesize that elevated serum F levels might contribute to the disturbances in mineral ion homeostasis that are observed in patients with CRI [Chronic Renal Insufficiency]. This is of particular concern since the incidence of dental fluorosis has increased due to increased F– uptake from multiple fluoridated sources. The ubiquitous presence of F in food and beverage products regardless of the degree of water fluoridation suggests that the overall F exposure in individuals with CRI may need to be more closely monitored." SOURCE: Mathias RS, et al. (2000). Increased fluoride content in the femur growth plate and cortical bone of uremic rats. Pediatric Nephrology 14:935–939 "Though (skeletal) fluorosis is prevalent in certain geographic parts of the world, it is likely to occur... in people with latent kidney disease even when they consume relatively lower amounts of fluoride than in endemic regions."

SOURCE: Reddy DR, et al. (1993). Neuro-radiology of skeletal fluorosis. Annals of the Academy of Medicine, Singapore 22(3 Suppl):493-500. "It would not be surprising if there were some undetected cases of skeletal fluorosis in the Australian population in individuals with pathological thirst disorders and/or impaired renal function. However, the matter has not been systematically examined. This matter should be the subject of careful and systematic review." SOURCE: National Health and Medical Research Council. (1991). The effectiveness of water fluoridation. Canberra, Australia: Australian Government Publishing Service. "Persons with chronic renal failures constitute a possible group at-risk with respect to the occurrence of skeletal fluorosis, because of an increased fluoride retention after oral intake. Based on the results of one study, in which the difference in retention between nephritic patients and healthy persons was quantified (average retention: 65% and 20%, respectively), a total daily intake of about 1.5 mg appears to be the maximum acceptable intake for nephritic patients. In view of the limitations of this comparative study and of the individual differences in retention and sensitivity, this figure must only be regarded as an indication." SOURCE: National Institute for Public Health and Environmental Protection. (1989). Integrated criteria document fluorides. Report No 758474010. The Netherlands. "The skeletal complication of fluoride is more common in renal disease. Because of the impairment in renal excretion of fluoride, high circulating concentrations of fluoride may be achieved in renal disease." SOURCE: Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86. "Fluoridation of drinking water up to 1.2 ppm apparently does not pose a potential risk to bone provided the renal function is normal... We should, however, recognize that it is difficult to give a strict value for a safe fluoride concentration in drinking water, because individual susceptibility to fluoride varies." SOURCE: Arnala I, 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):161-6. "Because the kidney is the main pathway of fluoride excretion, patients with chronic renal failure are especially vulnerable to osseous accumulation of ingested fluoride and to potentially deleterious effects." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "The finding of adverse effects (skeletal fluorosis) in (kidney) patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is generally agreed that water fluoridation is safe for persons with normal kidneys. Systemic fluorosis in patients with diminished renal function, however, seems a reasonable possibility. In such patients, fluoride may be retained

with resulting higher tissue fluoride levels than in persons with normal renal function." SOURCE: Juncos LI, Donadio JV. (1972). Renal failure and fluorosis. Journal of the American Medical Association 222:783-5. "Prolonged polydipsia (excessive thirst) may be hazardous to persons who live in areas where the levels of fluoride in drinking water are not those usually associated with significant fluorosis." SOURCE: Sauerbrunn BJ, et al. (1965). Chronic fluoride intoxication with fluorotic radiculomyelopathy. Annals of Internal Medicine 63: 1074-1078. "The question of the effect of water containing 1 p.p.m. upon patients with severe impairment of kidney function requires special consideration in view of the fact that radiologic evidence of chronic fluorosis has been found in two persons with severe kidney disease who died at the early ages of 22 and 23 years, respectively..." SOURCE: Heyroth F. (1952). Hearings Before the House Select Committee to Investigate the Use of Chemicals in Foods and Cosmetics, House of Representatives, 82nd Congress, Part 3, Washington D.C., Government Printing Office, p. 28. "All patients with dental fluorosis and anemia and/or signs of renal impairment should have radiographic examinations of the skeletal system to rule out the existence of fluoride osteosclerosis... It is likely that the reason our patient retained fluorine in his bones was that he had renal damage of long standing; without this the osteosclerosis might not have developed." SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484. Excerpts from the Scientific Literature - Similarities between Fluorosis & Renal Osteodystrophy: (back to top) "Fluoride is bone-seeking due to its high affinity for calcium phosphate and therefore accumulates in bone. Radiological changes can be quite similar to changes of renal osteodystrophy, and therefore the diagnosis may be missed unless specifically investigated." SOURCE: Bansal R, Tiwari SC. (2006). Back pain in chronic renal failure. Nephrology Dialysis Transplantation 21:2331-2332. "[R]enal disease and fluoride cause similar changes. This overlap makes it very difficult to assess the effect of fluoride per se in these patients." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "The findings of osteosclerosis, osteomalacia and increased bone resorption have been confirmed in experimental fluorosis in animals. It can be seen, therefore, that fluoride bone disease could mimic renal osteodystrophy." SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202. "[T]he observed changes (osteomalacia, osteitis fibrosa and osteoporosis) were similar to those induced by high doses of fluoride in humans and experimental animals, in which widened osteoid seams have been observed, and where increased areas of resorption due to secondary hyperparathyroidism may be seen." SOURCE: Posen GA, et al. (1971). Renal osteodystrophy in patients on long-term hemodialysis with fluoridated water. Fluoride 4: 114- 128. "Osteosclerosis from chronic renal disease associated with secondary hyperparathyroidism may produce similar changes (as fluorosis), and indeed may have intensified the findings (of fluorosis) in one of our patients." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615. In the fluoride-treated patients, "we observed osteoclasts resorbing bone beneath osteoid seams, and fragments of osteoid isolated in the bone marrow. This type of resorption beneath unmineralized bone matrix is often observed in osteomalacia, particularly that caused by renal abnormalities and associated secondary hyperparathyroidism." SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129.

"During our field studies our attention was drawn to the high incidence of bone disease and bony leg deformities with clinical invalidism in children exposed to high intake of endemic fluoride in drinking water. Due to variable and unusual clinical features, these children (with fluorosis) had often been mistaken for rickets, renal osteodystrophy, osteosclerosis and hereditary osteopathies etc." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "A 40-year-old American Indian woman with chronic pyelonephritis and renal failure complained of progressive muscular weakness, fatigue, and increasingly severe pain in her ribs, low back, and left hip. X-ray study of these areas showed evidence of osteosclerosis, compatible with either renal osteodystrophy or skeletal fluorosis... No other pathologic changes were apparent in the bones or ligaments..." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. Excerpts from the Scientific Literature - Fluoride as a Contributing Factor to Renal Osteodystrophy: (back to top) "Additional studies should be carried out to determine the incidence, prevalence, and severity of renal osteodystrophy in patients with renal impairments in areas where there is fluoride at up to 4 mg/L in the drinking water." SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p258. "Fluoride interfered with bone mineralization and increased osteoid content, which was most evident in osteomalacia and the mixed bone disorder. In addition, fluoride may interact with aluminum to worsen the osteomalacic lesion." SOURCE: Ng AHM, et al. (2004). Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone 34: 216-224. "fluoride-treated, aluminum-loaded rats accumulated a sevenfold larger amount of osteoid volume as compared to (the aluminum-only group) and exhibited an increase in osteoid surface of a corresponding degree...The results of our study confirm that pretreatment and concurrent administration of fluoride during aluminum loading does have a profound impact on the evolution of aluminum-induced osteodystrophy." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "It is possible that deposition of aluminum-fluoride complexes at the mineralized bone-osteoid interface disturb mineralization more effectively than aluminum itself... Exposure to fluoride will have to be considered when evaluating aluminum-related bone disease in clinical cases or in experimental models." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "Renal failure augmented skeletal retention of excessive fluoride intake which, in turn, appears to have intensified symptomatic renal osteodystrophy." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "In the present case, elimination of dietary fluoride and treatment with calcitrol was associated with improvement in the symptoms and biochemical findings of osteodystrophy, perhaps as a result of a decrease in unmineralized osteoid." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. Excerpts from the Scientific Literature - No Systematic Studies Investigating Relationship between Fluoride/Renal Osteodystrophy: (back to top) "a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis... However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42.

"In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973). Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "Information is particularly needed on fluoride plasma and bone concentrations in people with small-to-moderate changes in renal function as well as in those with serious renal deficiency." SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p 9. General Info - Renal Osteodystrophy: (back to top) "The medical term 'renal' describes things related to the kidneys. Renal osteodystrophy is a bone disease that occurs when your kidneys fail to maintain the proper levels of calcium and phosphorus in your blood. It's a common problem in people with kidney disease and affects 90 percent of dialysis patients." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK) “Osteodystrophy is a combination of bone disorders that is usually caused by chronic kidney failure (renal disease). The bone disorders affecting patients with osteodystrophy include varying combinations and degrees of osteoporosis, osteomalacia, osteitis fibrosa, and osteosclerosis.” SOURCE: MedicineNet.com "The most common presentation of renal osteodystrophy is a combination of osteomalacia, secondary hyperparathyroidism, and a varying degree of osteosclerosis." SOURCE: eMedicine.com "Renal osteodystrophy may cause osteosclerosis, soft tissue calcification, and bone resorption... Soft tissue calcifications may take the form of the large, cloudlike collections in a periarticular distribution known as tumoral calcinosis." SOURCE: AmershamHealth.com "The changes in bone seen in patients with chronic renal insufficiency are complex in that there is a spectrum of findings. At one extreme is pure osteotis fibrosis, which shows a pattern of excessive bone resorption... At the other extreme is osteomalacic bone disease that is due to a deficiency of the active vitamin D metabolites normally produced by the kidneys. Osteomalacia is recognized histologically by excessive amounts of osteoid (that is, unmineralized bone matrix)... In addition, the patients occasionally have sclerosis. Histologically, the sclerosed bone exhibits an increase in the thickness of the trabeculae, and roentgenographically, there is a coarsening of the trabecular pattern with increased opacity of the mineralized tissues. Sclerosis and increased amounts of osteoid are also features of fluorosis." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. Symptoms - Renal Osteodystrophy: (back to top)

"Renal osteodystrophy, if not treated, can lead to severe disability. Patients suffering from severe cases are often unable to walk or get out of bed without help." SOURCE: iKidney.com "The most common complication of renal osteodystrophy is fracture, which may be insufficiency fractures through osteomalacic bone or pathologic fractures through brown tumors or amyloid deposits." SOURCE: eMedicine.com "The bone changes from renal osteodystrophy can begin many years before symptoms appear in adults with kidney disease. For this reason, it's called the "silent crippler." The symptoms of renal osteodystrophy aren't usually seen in adults until they have been on dialysis for several years. Older patients and women who have gone through menopause are at greater risk for this disease because they're already vulnerable to osteoporosis, even without kidney disease. If left untreated, the bones gradually become thin and weak, and a person with renal osteodystrophy may begin to feel bone and joint pain. There's also an increased risk of bone fractures." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK) "Renal osteodystrophy is most serious in children because their bones are still growing. The condition slows growth and causes deformities. One such deformity occurs when the legs bend inward or outward (toward or away from the body); this deformity is referred to as "renal rickets." Another important consequence is short stature." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK) Frequency - Renal Osteodystrophy: (back to top) "In the US: Statistics from the Health Care Financing Administration report that more than 230,000 Americans are under treatment for end-stage renal disease (ESRD). Renal osteodystrophy rarely is seen prior to the laboratory and clinical diagnosis of renal failure." SOURCE: eMedicine.com Key Findings - Fluoride & Renal Osteodystrophy: 1) their Individuals with kidney disease have a diminished ability to excrete fluoride in urine. As a result, kidney disease results in an elevated accumulation of fluoride in the bones. The spectrum of bone disorders (e.g. osteomalacia, osteoporosis, osteosclerosis, and secondary hyperparathyroidism), collectively known as osteodystrophy, which are found in people with advanced kidney disease can be individually produced, or exacerbated, by elevated fluoride exposure. Aluminum's impact on bone is amplified in the presence of fluoride, and vice versa. Both elements accumulate to high levels in the bones of kidney patients, and it is quite plausible that the deterimental effect of aluminum in renal-osteodystrophy is enhanced by the presence of fluoride and/or the presence of aluminum-fluoride complexes. No systematic studies have ever been conducted to investigate the relationship between fluoride exposure and severity of bone changes in individuals with kidney disease.

2) renal all 3)

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Excerpts from the Scientific Literature - Kidney Patients at Increased Risk of Fluorosis: (back to top) "[A] fairly substantial body of research indicates that patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. Patients with reduced glomerular filtration rates have a decreased ability to excrete fluoride in the urine. These patients may develop skeletal fluorosis even at 1 ppm fluoride in the drinking water... The National Kidney Foundation in its ‘Position Paper on Fluoride—1980’ as well as the Kidney Health Australia express concern about fluoride retention in kidney patients. They caution physicians to monitor the fluoride intake of patients with advanced stages of kidney diseases. However, a number of reasons will account for the failure to monitor fluoride intake in patients with stages 4 and 5 of chronic kidney diseases and to detect early effects of fluoride retention on

kidneys and bone. The safety margin for exposure to fluoride by renal patients is unknown, measurements of fluoride levels are not routine, the onset of skeletal fluorosis is slow and insidious, clinical symptoms of this skeletal disorder are vague, progression of renal functional decline is multifactorial and physicians are unaware of side effects of fluoride on kidneys or bone." SOURCE: Schiffl H. (2008). Fluoridation of drinking water and chronic kidney disease: absence of evidence is not evidence of absence. Nephrology Dialysis Transplantation 23:411. "Individuals with kidney disease have decreased ability to excrete fluoride in urine and are at risk of developing fluorosis even at normal recommended limit of 0.7 to 1.2 mg/l." SOURCE: Bansal R, Tiwari SC. (2006). Back pain in chronic renal failure. Nephrology Dialysis Transplantation 21:2331-2332. "In patients with reduced renal function, the potential for fluoride accumulation in the skeleton is increased. It has been known for many years that people with renal insufficiency have elevated plasma fluoride concentrations compared with normal healthy persons and are at a higher risk of developing skeletal fluorosis." SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p140. "Persons with renal failure can have a four fold increase in skeletal fluoride content, are at more risk of spontaneous bone fractures, and akin to skeletal fluorosis even at 1.0 ppm fluoride in drinking water." SOURCE: Ayoob S, Gupta AK. (2006). Fluoride in Drinking Water: A Review on the Status and Stress Effects. Critical Reviews in Environmental Science and Technology 36:433–487 "Skeletal fluorosis seems possible, especially in hot climates or with renal compromise, from drinking excessive quantities of instant or bottled teas. Our observations support the need for better understanding of the amounts and systemic effects of fluoride in teas." SOURCE: Whyte M. (2006). Fluoride levels in bottled teas. American Journal of Medicine 119:189-190. "We hypothesize that elevated serum F levels might contribute to the disturbances in mineral ion homeostasis that are observed in patients with CRI [Chronic Renal Insufficiency]. This is of particular concern since the incidence of dental fluorosis has increased due to increased F– uptake from multiple fluoridated sources. The ubiquitous presence of F in food and beverage products regardless of the degree of water fluoridation suggests that the overall F exposure in individuals with CRI may need to be more closely monitored." SOURCE: Mathias RS, et al. (2000). Increased fluoride content in the femur growth plate and cortical bone of uremic rats. Pediatric Nephrology 14:935–939 "Though (skeletal) fluorosis is prevalent in certain geographic parts of the world, it is likely to occur... in people with latent kidney disease even when they consume relatively lower amounts of fluoride than in endemic regions." SOURCE: Reddy DR, et al. (1993). Neuro-radiology of skeletal fluorosis. Annals of the Academy of Medicine, Singapore 22(3 Suppl):493-500. "It would not be surprising if there were some undetected cases of skeletal fluorosis in the Australian population in individuals with pathological thirst disorders and/or impaired renal function. However, the matter has not been systematically examined. This matter should be the subject of careful and systematic review." SOURCE: National Health and Medical Research Council. (1991). The effectiveness of water fluoridation. Canberra, Australia: Australian Government Publishing Service. "Persons with chronic renal failures constitute a possible group at-risk with respect to the occurrence of skeletal fluorosis, because of an increased fluoride retention after oral intake. Based on the results of one study, in which the difference in retention between nephritic patients and healthy persons was quantified (average retention: 65% and 20%, respectively), a total daily intake of about 1.5 mg appears to be the maximum acceptable intake for nephritic patients. In view of the limitations of this comparative study and of the individual differences in retention and sensitivity, this figure must only be regarded as an indication." SOURCE: National Institute for Public Health and Environmental Protection. (1989). Integrated criteria document fluorides. Report No 758474010. The Netherlands. "The skeletal complication of fluoride is more common in renal disease. Because of the impairment in renal excretion of fluoride, high circulating concentrations of fluoride may be achieved in renal disease."

SOURCE: Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86. "Fluoridation of drinking water up to 1.2 ppm apparently does not pose a potential risk to bone provided the renal function is normal... We should, however, recognize that it is difficult to give a strict value for a safe fluoride concentration in drinking water, because individual susceptibility to fluoride varies." SOURCE: Arnala I, 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):161-6. "Because the kidney is the main pathway of fluoride excretion, patients with chronic renal failure are especially vulnerable to osseous accumulation of ingested fluoride and to potentially deleterious effects." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "The finding of adverse effects (skeletal fluorosis) in (kidney) patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973), Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "It is generally agreed that water fluoridation is safe for persons with normal kidneys. Systemic fluorosis in patients with diminished renal function, however, seems a reasonable possibility. In such patients, fluoride may be retained with resulting higher tissue fluoride levels than in persons with normal renal function." SOURCE: Juncos LI, Donadio JV. (1972). Renal failure and fluorosis. Journal of the American Medical Association 222:783-5. "Prolonged polydipsia (excessive thirst) may be hazardous to persons who live in areas where the levels of fluoride in drinking water are not those usually associated with significant fluorosis." SOURCE: Sauerbrunn BJ, et al. (1965). Chronic fluoride intoxication with fluorotic radiculomyelopathy. Annals of Internal Medicine 63: 1074-1078. "The question of the effect of water containing 1 p.p.m. upon patients with severe impairment of kidney function requires special consideration in view of the fact that radiologic evidence of chronic fluorosis has been found in two persons with severe kidney disease who died at the early ages of 22 and 23 years, respectively..." SOURCE: Heyroth F. (1952). Hearings Before the House Select Committee to Investigate the Use of Chemicals in Foods and Cosmetics, House of Representatives, 82nd Congress, Part 3, Washington D.C., Government Printing Office, p. 28. "All patients with dental fluorosis and anemia and/or signs of renal impairment should have radiographic examinations of the skeletal system to rule out the existence of fluoride osteosclerosis... It is likely that the reason our patient retained fluorine in his bones was that he had renal damage of long standing; without this the osteosclerosis

might not have developed." SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484. Excerpts from the Scientific Literature - Similarities between Fluorosis & Renal Osteodystrophy: (back to top) "Fluoride is bone-seeking due to its high affinity for calcium phosphate and therefore accumulates in bone. Radiological changes can be quite similar to changes of renal osteodystrophy, and therefore the diagnosis may be missed unless specifically investigated." SOURCE: Bansal R, Tiwari SC. (2006). Back pain in chronic renal failure. Nephrology Dialysis Transplantation 21:2331-2332. "[R]enal disease and fluoride cause similar changes. This overlap makes it very difficult to assess the effect of fluoride per se in these patients." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "The findings of osteosclerosis, osteomalacia and increased bone resorption have been confirmed in experimental fluorosis in animals. It can be seen, therefore, that fluoride bone disease could mimic renal osteodystrophy." SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202. "[T]he observed changes (osteomalacia, osteitis fibrosa and osteoporosis) were similar to those induced by high doses of fluoride in humans and experimental animals, in which widened osteoid seams have been observed, and where increased areas of resorption due to secondary hyperparathyroidism may be seen." SOURCE: Posen GA, et al. (1971). Renal osteodystrophy in patients on long-term hemodialysis with fluoridated water. Fluoride 4: 114- 128. "Osteosclerosis from chronic renal disease associated with secondary hyperparathyroidism may produce similar changes (as fluorosis), and indeed may have intensified the findings (of fluorosis) in one of our patients." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615. In the fluoride-treated patients, "we observed osteoclasts resorbing bone beneath osteoid seams, and fragments of osteoid isolated in the bone marrow. This type of resorption beneath unmineralized bone matrix is often observed in osteomalacia, particularly that caused by renal abnormalities and associated secondary hyperparathyroidism." SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129. "During our field studies our attention was drawn to the high incidence of bone disease and bony leg deformities with clinical invalidism in children exposed to high intake of endemic fluoride in drinking water. Due to variable and unusual clinical features, these children (with fluorosis) had often been mistaken for rickets, renal osteodystrophy, osteosclerosis and hereditary osteopathies etc." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "A 40-year-old American Indian woman with chronic pyelonephritis and renal failure complained of progressive muscular weakness, fatigue, and increasingly severe pain in her ribs, low back, and left hip. X-ray study of these areas showed evidence of osteosclerosis, compatible with either renal osteodystrophy or skeletal fluorosis... No other pathologic changes were apparent in the bones or ligaments..." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. Excerpts from the Scientific Literature - Fluoride as a Contributing Factor to Renal Osteodystrophy: (back to top) "Additional studies should be carried out to determine the incidence, prevalence, and severity of renal osteodystrophy in patients with renal impairments in areas where there is fluoride at up to 4 mg/L in the drinking water."

SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p258. "Fluoride interfered with bone mineralization and increased osteoid content, which was most evident in osteomalacia and the mixed bone disorder. In addition, fluoride may interact with aluminum to worsen the osteomalacic lesion." SOURCE: Ng AHM, et al. (2004). Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone 34: 216-224. "fluoride-treated, aluminum-loaded rats accumulated a sevenfold larger amount of osteoid volume as compared to (the aluminum-only group) and exhibited an increase in osteoid surface of a corresponding degree...The results of our study confirm that pretreatment and concurrent administration of fluoride during aluminum loading does have a profound impact on the evolution of aluminum-induced osteodystrophy." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "It is possible that deposition of aluminum-fluoride complexes at the mineralized bone-osteoid interface disturb mineralization more effectively than aluminum itself... Exposure to fluoride will have to be considered when evaluating aluminum-related bone disease in clinical cases or in experimental models." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "Renal failure augmented skeletal retention of excessive fluoride intake which, in turn, appears to have intensified symptomatic renal osteodystrophy." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. "In the present case, elimination of dietary fluoride and treatment with calcitrol was associated with improvement in the symptoms and biochemical findings of osteodystrophy, perhaps as a result of a decrease in unmineralized osteoid." SOURCE: Fisher JR, et al. (1981). Skeletal fluorosis from eating soil. Arizona Medicine 38: 833-5. Excerpts from the Scientific Literature - No Systematic Studies Investigating Relationship between Fluoride/Renal Osteodystrophy: (back to top) "a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis... However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health." SOURCE: Hileman B. (1988). Fluoridation of water.Questions about health risks and benefits remain after more than 40 years. Chemical and Engineering News August 1, 1988, 26-42. "In the United States, there have been no reported cases of skeletal fluorosis in persons who drink water containing only one part per million (ppm) of fluoride. However, since no systematic studies have been carried out in patients with renal insufficiency, this possibility cannot be excluded with certainty." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. "It seems probable that some people with severe or long-term renal disease, which might not be advanced enough to require hemodialysis, can still experience reduced fluoride excretion to an extent that can lead to fluorosis, or aggravate skeletal complications associated with kidney disease... It has been estimated that one in every 25 Americans may have some form of kidney disease; it would seem imperative that the magnitude of risk to such a large sub-segment of the population be determined through extensive and careful study. To date, however, no studies of this sort have been carried out, and none is planned." SOURCE: Groth, E. (1973). Two Issues of Science and Public Policy: Air Pollution Control in the San Francisco Bay Area, and Fluoridation of Community Water Supplies. Ph.D. Dissertation, Department of Biological Sciences, Stanford University, May 1973. "Information is particularly needed on fluoride plasma and bone concentrations in people with small-to-moderate changes in renal function as well as in those with serious renal deficiency."

SOURCE: National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press, Washington D.C. p 9. General Info - Renal Osteodystrophy: (back to top) "The medical term 'renal' describes things related to the kidneys. Renal osteodystrophy is a bone disease that occurs when your kidneys fail to maintain the proper levels of calcium and phosphorus in your blood. It's a common problem in people with kidney disease and affects 90 percent of dialysis patients." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK) “Osteodystrophy is a combination of bone disorders that is usually caused by chronic kidney failure (renal disease). The bone disorders affecting patients with osteodystrophy include varying combinations and degrees of osteoporosis, osteomalacia, osteitis fibrosa, and osteosclerosis.” SOURCE: MedicineNet.com "The most common presentation of renal osteodystrophy is a combination of osteomalacia, secondary hyperparathyroidism, and a varying degree of osteosclerosis." SOURCE: eMedicine.com "Renal osteodystrophy may cause osteosclerosis, soft tissue calcification, and bone resorption... Soft tissue calcifications may take the form of the large, cloudlike collections in a periarticular distribution known as tumoral calcinosis." SOURCE: AmershamHealth.com "The changes in bone seen in patients with chronic renal insufficiency are complex in that there is a spectrum of findings. At one extreme is pure osteotis fibrosis, which shows a pattern of excessive bone resorption... At the other extreme is osteomalacic bone disease that is due to a deficiency of the active vitamin D metabolites normally produced by the kidneys. Osteomalacia is recognized histologically by excessive amounts of osteoid (that is, unmineralized bone matrix)... In addition, the patients occasionally have sclerosis. Histologically, the sclerosed bone exhibits an increase in the thickness of the trabeculae, and roentgenographically, there is a coarsening of the trabecular pattern with increased opacity of the mineralized tissues. Sclerosis and increased amounts of osteoid are also features of fluorosis." SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293. Symptoms - Renal Osteodystrophy: (back to top) "Renal osteodystrophy, if not treated, can lead to severe disability. Patients suffering from severe cases are often unable to walk or get out of bed without help." SOURCE: iKidney.com "The most common complication of renal osteodystrophy is fracture, which may be insufficiency fractures through osteomalacic bone or pathologic fractures through brown tumors or amyloid deposits." SOURCE: eMedicine.com "The bone changes from renal osteodystrophy can begin many years before symptoms appear in adults with kidney disease. For this reason, it's called the "silent crippler." The symptoms of renal osteodystrophy aren't usually seen in adults until they have been on dialysis for several years. Older patients and women who have gone through menopause are at greater risk for this disease because they're already vulnerable to osteoporosis, even without kidney disease. If left untreated, the bones gradually become thin and weak, and a person with renal osteodystrophy may begin to feel bone and joint pain. There's also an increased risk of bone fractures." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK) "Renal osteodystrophy is most serious in children because their bones are still growing. The condition slows growth and causes deformities. One such deformity occurs when the legs bend inward or outward (toward or away from the body); this deformity is referred to as "renal rickets." Another important consequence is short stature." SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases (UK)

Frequency - Renal Osteodystrophy: (back to top) "In the US: Statistics from the Health Care Financing Administration report that more than 230,000 Americans are under treatment for end-stage renal disease (ESRD). Renal osteodystrophy rarely is seen prior to the laboratory and clinical diagnosis of renal failure." SOURCE: eMedicine.com Key Findings - Fluoride & Osteoid: 1) One of fluoride's most well-defined effects on bone tissue is it's ability to increase the osteoid (unmineralized bone) content of bone. This has been demonstrated in human clinical trials; in dialysis patients using dialysis systems which do not filter out fluoride from water; in animals exposed to high levels of fluoride; and in humans suffering from skeletal fluorosis. 2) Fluoride can increase osteoid volume to such an extent as to produce osteomalacia, a bone-softening disease marked by an excess amount of osteoid. This has been demonstrated in human clinical trials; in dialysis patients using dialysis systems which do not filter out fluoride from water; in animals exposed to high levels of fluoride; and in humans suffering from skeletal fluorosis. 3) Fluoride has been found to increase osteoid content in people (with normal kidney function) drinking water with only 1.5 ppm (Arnala 1985), and in people with impaired kidney function drinking water with 1 ppm (Ng 2004). Definition - Osteoid: "immature bone that has not yet undergone calcification." SOURCE: Amersham Health "Non-mineralised bone matrix." SOURCE: International League of Associations for Rheumatology "The protein product which becomes mineralized with calcium to form hard bones." SOURCE: International Myeloma Foundation Lowest Observed Effects - Fluoride & Osteoid: "Increase in bone fluoride was associated with increased osteoid parameters and decreased bone microhardness... Fluoride interfered with bone mineralization and increased osteoid content, which was most evident in osteomalacia and the mixed bone disorder. In addition, fluoride may interact with aluminum to worsen the osteomalacic lesion." SOURCE: Ng AHM, et al. (2004). Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone 34: 216-224. "The main histolological change induced by fluoride is the increase of osteoid volume... This increase in osteoid parameters was observed in our study already at fluoride concentrations above 1.5 ppm." SOURCE: Arnala I, et al. (1985). Effects of fluoride on bone in Finland. Histomorphometry of cadaver bone from low and high fluoride areas. Acta Orthopaedica Scandinavica 56(2):161-6. Human Clinical Trials - Fluoride & Osteoid: (back to top) "Fluoride treatment increased all osteoid values significantlly when compared with the placebo control group." SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129. "Histomorphometry revealed a bulky trabeculare architecture, high osteoblastic activity and an increased amount of osteoid... " SOURCE: Roschger P, et al. (1995). Bone mineral structure after six years fluoride treatment investigated by backscattered electron imaging (BSEI) and small angle x-ray scattering (SAXS): a case report. Bone 16:407.

"Evidence for a fluoride effect was present in seven of eight biopsies which were performed in patients on NaF, which could be evaluated qualitatively and quantitatively. This evidence consisted of a mineralization defect in all seven, increased osteiod (forming) surfaces and volume in six with (3 cases) evidence of increased osteoid thickness." SOURCE: Gutteridge DH, et al. (1990). Spontaneous hip fractures in fluoride-treated patients: potential causative factors. Journal of Bone and Mineral Research 5 Suppl 1:S205-15. "osteoid thickness was slightly but not significantly increased. Only two patients had thick osteoid seams suggesting the presence of osteomalacia." SOURCE: Orcel P, et al. (1990). Stress fractures of the lower limbs in osteoporotic patients treated with fluoride. Journal of Bone and Mineral Research 5(Suppl 1): S191-4. "the thickness of osteoid seams was slightly increased, the mineralization lag time was prolonged from 13 to 24 days, and the duration of formation increased from 78 to 110 days." SOURCE: Kragstrup J, et al. (1989). Effects of sodium fluoride, vitamin D, and calcium on cortical bone remodeling in osteoporotic patients. Calcified Tissue International 45:337-41. "When fluoride is given, especially at a high dosage without calcium, osteomalacia may develop. The newly formed matrix may be abnormal and may not undergo adequate mineralization. Thus, a typical histomorphometric picture is represented by a pronounced increase in osteoid (nonmineralized matrix) and reduced calcification front." SOURCE: Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86. "Unfortunately, fluoride-induced osteoid, although plentiful, mineralizes slowly..." SOURCE: Schnitzler CM, Solomon L. (1985). Trabecular stress fractures during fluoride therapy for osteoporosis. Skeletal Radioliology 14(4):276-9. "histomorphometric analysis of a transilica bone biopsy specimen indicated an accumulation of osteid tissue due to impairment of mineralisation." SOURCE: Gerster JC, et al. (1983). Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis. British Medical Journal (Clin Res Ed) 287(6394):723-5. "Fluoride stimulates osteoid production yet impairs its subsequent mineralization... Impaired bone mineralization producing thick osteoid seams has been a consistent histomorphometric finding in patients treated with sodium fluoride alone... The mineralization defect is less marked, and indeed, is sometimes absent when calcium supplements, with or without vitamin D, are given to patients treated with moderate doses." SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research. 2: 366-393. "An additional finding not observed in the control group was the presence in eight of ten fluoride cases of small foci of unmineralized bone or osteoid within trabecular and cortical mineralized bone. The authors termed these areas 'osteoid lakes.'" SOURCE: Vigorita VJ, Suda MK. (1983). The microscopic morphology of fluoride-induced bone. Clinical Orthopaedics and Related Research 177:274-282. "Morphologic studies of bone biopsy samples have shown that the predominant effect of fluoride therapy on the skeleton is osteoblastic stimulation. The newly formed osteoid tissue is poorly mineralized, resulting in the histologic picture of osteomalacia." SOURCE: Jowsey J, et al. (1972). Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis. American Journal of Medicine 53: 43-49. "Following therapy with NaF, all cases demonstrated a widening of the osteoid seams, although to a variable extent." SOURCE: Kuhlencordt F, et al. (1970). The histological evaluation of bone in fluoride treated osteoporosis. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 169-174. "a retardation of osteoid mineralization became obvious, showing its maximum after 40 weeks of treatment." SOURCE: Reutter FW, et al. (1970). Fluoride in osteoporosis: clinical and quantitative histological studies on bone structure and bone remodelling. Fluoride 3: 209.

"The bone tissue (formed in fluoride therapy ) was most abnormal; large areas consisted entirely of incompletely calcified bone with large, irregular lacunae surrounded by areas of low mineral density." SOURCE: Jowsey J, et al. (1968). Some results of the effect of fluoride on bone tissue in osteoporosis. Journal of Clinical Endocrinology 28:869-874. "Sodium fluoride, 100 mg (= 45 mg fluoride ion) daily for 14 months, was administered to a patient with osteoporosis associated with continuing corticosteroid therapy. New bone formation and fluoride incorporation in bone was demonstrated. After eight months, much of this new bone appeared to be in the form of uncalcified osteoid material." SOURCE: Cass RM, et al. (1966). New bone formation in osteoporosis following treatment with sodium fluoride. Archives of Internal Medicine 118: 111-116. Patients with Kidney Disease using Dialysis with Fluoridated (1 ppm) water: Fluoride & Osteomalacia: (back to top) NOTE: For more detailed information on fluoridation & diaylsis, click here "In the fluoridated group, osteoid seams were more abundant and wider than in the non-fluoridated group... This study has shown that hemodialysis with fluoridated water in chronic renal failure induces the activated osteoblasts to produce excessive osteoid in which the collagen fibrils are disarrayed. The risk of severe osteomalacia is reduced with the use of fluoride-free dialysate." SOURCE: Lough J, et al. (1975). Effects of fluoride on bone in chronic renal failure. Archives of Pathology 99: 484487. "There was a marked increase in the amount of osteoid tissue on bone biopsy in the fluoridated group." SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202. "All 4 patients exposed to high-fluoride dialysate showed excessive osteoid formation... osteoid formation was 9 times greater in those exposed to high-fluoride dialysate (1 ppm) than in those exposed to lower concentrations (0.095 ppm)... The presence of increased amounts of osteoid tissue in patients exposed to high-F dialysate is consistent with the observations of DeVeber and associates... Increased osteoid is typically found in fluorosis, hence, ascribing our findings to an F effect seems reasonable. There are several possible reasons for F causing increased osteoid. In vivo, excessive F can result in increased bone production and failure of mineralization." SOURCE: Jowsey J, et al. (1972). Effects of dialysate calcium and fluoride on bone disease during regular hemodialysis. Journal of Laboratory and Clinical Medicine 79: 204-214. "we found that we could not only prevent symptomatic osteomalacia by deionization, but could also reverse its course. This suggests that there was a factor in our tap water which prevented normal calcification of osteoid and that this is removed by deionization. We have previously reported high uptake of fluoride with an increase in the serum and bone levels of fluoride in our patients dialyzed with ordinary tap water. DeVeber and Jowsey have observed an increase in osteoid similar to ours in their dialysis patients treated with high fluoride dialysate. High fluoride concentrations have also been shown experimentally to lead to a defect in osteoid calcification. These observations suggest a role for fluoride in the osteomalacic disease in dialysis patients." SOURCE: Posen GA, et al. (1972). Comparison of renal osteodystrophy in patients dialyzed with deionized and nondeionized water. Transactions of the American Society for Artificial Internal Organs 18: 405-411. Animal Studies - Fluoride & Osteoid: (back to top) "In contrast to calcium phosphate deficiency, high fluoride intake had no effect on trabecular bone volume, but instead increased the amount of unmineralized osteoid, particularly in older rats. This impairment of mineralization by fluoride appeared to be the primary cause of the diminshed vertebral strength." SOURCE: Turner CH, et al. (2001). Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International 69: 51-57. "[O]steoid volume was increased over 20-fold in animals with renal deficiency that received 15 or 50 ppm fluoride. Increases in osteoid can result from either increased osteoid formation or impaired mineralization... The osteoid, which contributed to the bone volume, did not contribute to the bone strength." SOURCE: Turner CH, et al. (1996). High fluoride intake causes osteomalacia and diminished bone strength in rats with renal deficiency. Bone 19: 595-601.

"osteoid surface was significantly higher in the NaF groups by 48-75%... osteoid thickness was modestly increased (by 12%) in the NaF group..." SOURCE: Lafage MH, et al. (1995). Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs: a one year study. Journal of Clinical Investigations 95: 2127-2133. "fluoride-treated, aluminum-loaded rats accumulated a sevenfold larger amount of osteoid volume as compared to (the aluminum-only group) and exhibited an increase in osteoid surface of a corresponding degree. As a consequence of the severe osteoidosis, cancellous bone volume almost doubled in rats exposed to fluoride and aluminum." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "It is possible that deposition of aluminum-fluoride complexes at the mineralized bone-osteoid interface disturb mineralization more effectively than aluminum itself." SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348. "Results of this study indicated that the ingestion of fluoride produced wide osteoid seams on the periosteal surface of the femoral diaphysis within 4 weeks. The increase in osteoid appeared to be due to an increase in the number of osteoid-producing cells (osteoblasts) along with a subsequent delay in the mineralization of this tissue." SOURCE: Ream LJ. (1981). The effects of short-term fluoride ingestion on bone formation and resorption in the rat femur. Cell and Tissue Research 221: 421-430. "The effect of fluoride on bone appears to be one of increased turnover with matrix formation exceeding resorption. Mineralization of newly-formed matrix is imperfect and much of the bone appears as woven or immature bone with components of unmineralized matrix resembling osteomalacia." SOURCE: Riggins RS, et al. (1974). The effects of sodium fluoride on bone breaking strength. Calcified Tissue Research 14: 283-289. "Periosteal osteoid width was significantly more in rats treated with 100 ppm fluoride in the drinking water than in controls in experiment 1 and also in experiment 2. The increase in periosteal osteoid width was sufficiently more than the increase in periosteal matrix apposition in both experiments 1 and 2 so as to result in a prolongation of the mineralization lag time (i.e. an increase in the time between osteoid formation and the onset of mineralization)." SOURCE: Baylink D, et al. (1970). Effects of fluoride on bone formation, mineralization, and resorption in the rat. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 37-69. "By using a battery of special stains, as well as polarized, infrared, and ultraviolet light, it could be demonstrated that the changes of the collagen matrix, which normally precede calcification, had not developed, and that the osteoid was in fact uncalcifiable." SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press 424-441. "the sections from the treated animals show definite evidence of an increasing osteoid border with the higher fluorine. It thus appears that there was matrix present in bones from the fluorine animals; the fact that this matrix was devoid of calcium may mean that the osteoid produced was not capable of holding bone salts or that there was a disturbance in the system by which the bone salts were deposited." SOURCE: Comar CL, et al. (1953). Effects of fluorine on calcium metabolism and bone growth in pigs. American Journal of Anatomy 92: 361-362. Skeletal Fluorosis - Fluoride & Osteoid: (back to top) In the fluorosis patients "histopathological assessment of the undecalcified sections of iliac crest biopsies showed loops and bridges of wide osteoid seams (> 50 u)..." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. "In fluorosis one observes mineralization defects (areas of unmineralized osteiod) existing with highly mineralized areas ['mottled bone']."

SOURCE: Fratzl P, et al. (1994). Abnormal bone mineralization after fluoride treatment in osteoporosis: a small-angle x-ray-scattering study. Journal of Bone and Mineral Research 9:1541-9. "Cancellous osteoid volume and perimeter, as well as width of osteoid seams, were significantly increased in fluorotic patients... Eight patients showed a true histological osteomalacia with both a significantly increased osteoid width and a significantly decreased mineral apposition rate... Thus the hyperosteoidosis frequently noted in skeletal fluorosis was confirmed." SOURCE: Boivin G, et al. (1989). Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10:89-99. "The bone biopsy (of the fluorosis patient) was remarkable for increased osteoid and mineralized bone and was interpreted as quiescent Paget's disease or another nonneoplastic sclerotic disease." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Fluoride stimulates osteoid production yet impairs its subsequent mineralization... Impaired bone mineralization producing thick osteoid seams has been a consistent histomorphometric finding in patients treated with sodium fluoride alone... The mineralization defect is less marked, and indeed, is sometimes absent when calcium supplements, with or without vitamin D, are given to patients treated with moderate doses." SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research. 2: 366-393. "Thickening of the osteoid seams was the most striking and most consistent feature.Cancellous bone was mainly involved. It was rarely observed in cortical bone." SOURCE: Pinet A, Pinet F. (1968). Endemic fluorosis in the Sahara. Fluoride 1: 85-93. "So-called 'osteoid-seams' were prominent in places." SOURCE: Webb-Peploe MM, Bradley WG. (1966). Endemic fluorosis with neurological complications in a Hampshire man. Journal of Neurology, Neurosurgery and Psychiatry 29:577-583. "In the spongy bone, areas of osteoid tissue were found among well-formed trabeculae. Some of the irregular deposits of osteoid tissue extended into the attached muscle." SOURCE: Singh A, et al. (1963). Endemic fluorosis. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab. Medicine 42: 229-246. Summation - Fluoride & Secondary Hyperparathyroidism: A hallmark feature of renal osteodystrophy, secondary hyperthyroidism is a disorder marked by overactive parathyroid glands. Among humans with skeletal fluorosis, fluoride may cause secondary hyperthyroidism or cause bone damage resembling secondary hyperparathyroidism. General Info - Secondary Hyperparathyroidism: "The parathyroids are four glands in the neck that produce parathyroid hormone to help control calcium metabolism. Excessive production of this hormone caused by increased activity of these glands is known as hyperparathyroidism. When this occurs in response to low blood calcium caused by another condition, the condition is called secondary hyperparathyroidism. " SOURCE: National Institutes of Health "Secondary hyperparathyroidism means you have too much of a hormone (a type of signal) in your body. This signal is called parathyroid hormone (PTH). PTH is made by 4 small glands in your neck called parathyroid glands. Normally, PTH makes sure you have just enough calcium and phosphorus in your blood to keep your bones, heart, muscles, nerves, and blood vessels working well. When your kidneys aren’t working, the calcium and phosphorus balance in your body is upset. These imbalances trigger a silent alarm in your parathyroid glands to send out too much PTH to your body. This condition is called secondary hyperparathyroidism. Some people call this bone disease. But it affects more than just your bones. Because it can cause serious health problems, it is important that secondary

hyperparathyroidism is treated." SOURCE: Sensipar "leads to increased bone resorption (bone is broken down in an attempt to regulate abnormal levels of these chemicals)..." SOURCE: National Institutes of Health "The most common cause of secondary hyperparathyroidism is chronic renal disease, which is an occurrence in hemodialysis patients." SOURCE: eMedicine.com Symptoms - Secondary Hyperparathyroidism: "Secondary hyperparathyroidism can lead to a bone disease known as renal osteodystrophy. This occurs when the body draws large amounts of calcium and phosphorus from the bone. As a result, the bones become weak and brittle. Your bones may also hurt or break easily. Renal osteodystrophy, if not treated, can lead to severe disability. Patients suffering from severe cases are often unable to walk or get out of bed without help. High PTH levels can also cause itching, joint pain, heart problems, blocked blood vessels, anemia and weakness." SOURCE: iKidney.com "The clinical manifestation includes bone and joint pain and limb deformities. The radiologic features of secondary hyperparathyroidism in the skeleton are similar to those of primary hyperparathyroidism." SOURCE: eMedicine.com "Symptoms related to hyperparathyroidism may include bone pain, pathologic fractures, and nephrolithiasis." SOURCE: eMedicine.com Synonyms, keywords & related terms - Secondary Hyperparathyroidism: "osteitis fibrosa cystica, renal osteodystrophy, pronounced parathyroid gland hyperplasia, end-organ resistance to parathyroid hormone, PTH, chronic renal insufficiency, parathyroid glands" SOURCE: eMedicine.com Excerpts from the Scientific Literature - Fluoride & Secondary Hyperparathyroidism: (back to top) "The effect of fluoride on osteoclasts is less well understood than its effect on osteoblasts, and is complicated by a possible effect of fluoride-induced secondary hyperparathyroidism." SOURCE: Chachra D, et al. (1999). The effect of fluoride treatment on bone mineral in rabbits. Calcified Tissue International 64:345-351. "The toxic effects of fluoride were more severe and more complex and the incidence of metabolic bone disease (rickets, osteoporosis, parathyroid hormone bone disease) and bony leg deformities was greater (>90%) in children with calcium deficiency as compared to in children with adequate calcium who largely had osteoslcerotic form of skeletal fluorosis..." SOURCE: Teotia M, Teotia SP, Singh KP. (1998). Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000. Indian Journal of Pediatrics 65:371-81. In the fluoride-treated bone "we observed osteoclasts resorbing bone beneath osteoid seams, and fragments of osteoid isolated in the bone marrow. This type of resorption beneath unmineralized bone matrix is often observed in osteomalacia, particularly that caused by renal abnormalities and associated secondary hyperparathyroidism." SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129. "Although some authors have suggested that the resorption observed in skeletal fluorosis is due to secondary hyperparathyroidism in humans and in fluoride-treated animals, others have found no effect of fluoride on parathyroid mass or serum parathyroid levels in animal studies."

SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129. "Other diseases simulating radiographic features of fluorosis are Paget's disease, parathyroid hormone disorders, osteopetrosis, chronic renal failure, myelofibrosis, hypophosphatemic osteomalacia, and diffuse blastic metastases." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "Secondary hyperparathyroidism has been suggested as a possible mechanism by which fluoride produces changes in bone, and hyperparathyroidism has been found in some humans and experimental animals exposed to fluoride. The experimental pigs examined in the present study, however, showed no signs of hyperparathyroidism." SOURCE: Kragstrup J, et al. (1989). Effects of fluoride on cortical bone remodeling in the growing domestic pig. Bone 10:421-424. "A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostoses formation characterzes the bone lesions (of skeletal fluorosis). In a proportion of cases secondary hyperparathyroidism is observed with associated characteristic bone changes." SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10(3-4):279-314. "Metabolic bone disease occurred more frequently in residents of endemic (fluorosis) areas than in residents of nonendemic areas whose nutritional status was comparable. Common metabolic bone disorders, associated with endemic skeletal fluorosis, were osoteoporosis (bone resorption), rickets, osteomalacia, and parathyroid bone disease." SOURCE: Teotia SPS, et al. (1984). Environmental fluoride and metabolic bone disease: an epidemiological study (fluoride and nutrient interactions). Fluoride 17: 14-22. "Fluoride, by the nature of its incorporation into bone crystals and by its direct cytotoxic effect on bone resorbing cells, reduces the availability of calcium from bone. It appears that fluoride ingestion during lactation created a heightened state of calcium homeostatic stress. As a result, bone mineral was mobilized by resorption of the endosteal surface and by cavitation of the interior of the cortex. Secondary hyperparathyroidism is thought to play an integral part (in skeletal fluorosis) in an attempt to maintain calcium homeostasis." SOURCE: Ream LJ, et al. (1983). Fluoride ingestion during multiple pregnancies and lactations: microscopic observations on bone of the rat. Virchows Arch [Cell Pathol] 44: 35-44. "The inhibition of resorptive function together with the decreased level at which bone and serum calcium equilibrate after the incorporation of fluoride would lead to a fall in serum calcium and a compensatory increase in parathyroid hormone secretion. This rise in serum parathyroid hormone would stimulate the differentiation of progenitor cells into both osteoblasts and osteoclasts." SOURCE: Ream LJ. (1983). Scanning electron microscopy of the rat femur after fluoride ingestion. Fluoride 16: 169174. "unopposed fluoride may lead to hyperparathyroidism" SOURCE: Vigorita VJ, Suda MK. (1983). The microscopic morphology of fluoride-induced bone. Clinical Orthopaedics and Related Research 177:274-282. "The mechanism leading to the hyperfunction of the parathyroid glands in skeletal fluorosis is not clear. Studies on growing rabbits have suggested that fluoride, probably by producing a more stable fluorapatite, reduced the resorption of the fluoride containing bone with a resultant increase in the resorption of normal non-fluoride containing bone and that the hyperfunction of the parathyroids is, therefore, a compensatory mechanism which, probably, develops to maintain the plasma calcium and to overcome the physical effects of the more stable and less reactive fluoroapatite crystals. Jowsey et al (1972) argue that the secondary hyperparathyroidism seen in fluorosis is due to the fact that fluoride directly stimulates osteoblastic activity and that the calcium intake is insufficient to mineralise the rapidly forming new bone tissue. They cite evidence for this from the report of a decreased incidence of radiologicallyrecognised endemic fluorosis in areas with a high calcium content in the drinking water. More significantly, Jowsey and her co-workers (1972) have found that by combining vitamin D and calcium supplements with fluoride they were able to stimulate bone growth in osteoporotic patients wtihout producing a, concomitant, increase in bone resorption." SOURCE: Faccini JM, Teotia SPS. (1974). Histopathological assessment of endemic skeletal fluorosis. Calcified Tissue Research 16: 45-57.

"the increased production of (parathyroid hormone) is strongly suggested by the marked increase in the number of trabecular resorption surfaces and the pattern of tunnelling resorption observed." SOURCE: Faccini JM, Teotia SPS. (1974). Histopathological assessment of endemic skeletal fluorosis. Calcified Tissue Research 16: 45-57. "The increased bone resorption stimulated by fluoride administration may be due to excessive parathyroid activity." SOURCE: Riggins RS, et al. (1974). The effects of sodium fluoride on bone breaking strength. Calcified Tissue Research 14: 283-289. "Fluoride administration in both man and animals has been shown to stimulate new bone formation. However, the bone is poorly mineralized, and osteomalacia and secondary hyperparathyroidism frequently occur." SOURCE: Jowsey J, et al. (1972). Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis. The American Journal of Medicine 53: 43-49. "[T]here are a number of similarities between the effects of excess parathyroid hormone and the administration of fluoride on bone... In the present study secondary hyperparathyroidism would be a reasonable explanation for the observed increase in endosteal bone resorption, endosteal resorbing surface, and the linear rate of bone resorption (in the fluorotic animals)." SOURCE: Baylink D, et al. (1970). Effects of fluoride on bone formation, mineralization, and resorption in the rat. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 37-69. "The frequent description in the literature of large resorption cavities with fibrous tissue replacement suggested to me that the parathryoids were overactive in skeletal fluorosis, and this was demonstrated by an electron-microscopic study of the parathyroid glands from fluorotic sheep and a concomitant immunoassay of the amount of circulating parathyroid hormone, which was found to be as much as five times higher than resting levels and control levels." SOURCE: Faccini JM. (1969). Fluoride and bone. Calcified Tissue Research 3:1-16. "The demonstrable hyperactivity of the parathyroid glands in fluorotic rabbits and sheep in the presence of this inhibition of resorption suggests that it is a compensatory phenomenon to maintain the serum calcium at a constant level." SOURCE: Faccini JM. (1969). Fluoride and bone. Calcified Tissue Research 3:1-16. "Osteosclerosis from chronic renal disease associated with secondary hyperparathyroidism may produce similar changes (as skeletal fluorosis), and indeed may have intensified the findings (of fluorosis) in one of our patients." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615. "While some authors consider the (fluorosis) lesion to be a form of osteosclerosis, others attribute it to mineral deficiency characterized by an increase of osteoid formation. Some consider the osseous condition a response to parathyroid hyperfunction or intoxication; others have reported the aggravating effects of a calcium deficient diet. Studying young dogs, Kellner reported a gross similarity between the bony changes in fluorosis and rickets." SOURCE: Belanger LF, et al. (1958). Rachitomimetic effects of fluoride feeding on the skeletal tissues of growing pigs. American Journal of Pathology 34: 25-36. Key Findings - Fluoride & Osteopetrosis: Excessive exposure to fluoride causes a bone disease called skeletal fluorosis. One of the most common radiological findings in skeletal fluorosis is osteosclerosis - a hardening of bones with a blurring of the trabecular structure. The osteosclerotic form of fluorosis may closely resemble the appearance of osteopetrosis. Potential therefore exists for misdiagnosis between the two diseases. General Info - Osteopetrosis: “Osteopetrosis is a rare hereditary bone disease of heterogeneous pathophysiology in which failure of osteoclastic bone resorption leads to increased bone mass. However, the bone has poor mechanical properties. A German radiologist, Albers-Schönberg, first described osteopetrosis in 1904.” SOURCE: eMedicine.com

“Three distinct forms of the disease are based on age and clinical features. These are adult onset, infantile, and intermediate.” SOURCE: eMedicine.com "There is a 50 percent chance that a child of someone with adult osteopetrosis will have the disease. Many cases, however, occur without a family history." SOURCE: National Institutes of Health Symptoms - Osteopetrosis: “Many patients have bone pains. Bony defects are common and include cranial nerve entrapment neuropathies (eg, with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and might fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients.” SOURCE: eMedicine.com "Generally, patients with benign osteopetrosis are diagnosed as adults and suffer from frequent fractures, which tend to have difficulties with healing. Life expectancy is not altered with this form of the disease. Other symptoms associated with benign osteopetrosis include osteomyelitis, pain, degenerative arthritis and headache.” SOURCE: osteopetrosis.org Frequency - Osteopetrosis: “The adult form of osteopetrosis occurs in about one in 20,000 people." SOURCE: National Institutes of Health Synonyms - Osteopetrosis: "Albers-Schonberg Disease, Generalized Congenital Osteosclerosis, Ivory Bones, Marble Bones, Osteosclerosis Fragilis Generalisata." SOURCE: eMedicine.com Excerpts from the Scientific Literature - Fluoride & Osteopetrosis: (back to top) "In the differential diagnosis (of skeletal fluorosis) one must think of osteopetrosis (marble bones), metastatic cancer, and Paget's disease." SOURCE: Linsman JF, McMurray CA. (1943). Fluoride osteosclerosis from drinking water. Radiology 40: 474-484. "Other diseases simulating radiographic features of fluorosis are Paget's disease, parathyroid hormone disorders, osteopetrosis, chronic renal failure, myelofibrosis, hypophosphatemic osteomalacia, and diffuse blastic metastases." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "In addition to osteopetrosis and osteoblastic metastases, the differential diagnosis (of skeletal fluorosis) includes Paget's disease..." SOURCE: Morris JW. (1965). Skeletal fluorosis among indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615. Key Findings - Fluoride & Spinal Stenosis: 1) Excessive exposure to fluoride causes a bone disease called skeletal fluorosis. 2) In the advanced stages of skeletal fluorosis, the spine may develop extensive ligament calcifications and bone spurs (osteophytes), which in turn can produce a narrowing of the spinal canal and damage to the spinal cord (aka spinal stenosis).

3) The cervical region of the spine is the most common site for fluoride-induced stenosis. General Info - Spinal Stenosis: "Spinal stenosis is a narrowing of spaces in the spine (backbone) that results in pressure on the spinal cord and/or nerve roots... Spinal stenosis most often results from a gradual, degenerative aging process... As people age, the ligaments of the spine may thicken and calcify (harden from deposits of calcium salts). Bones and joints may also enlarge, and osteophytes (bone spurs) may form... This decreases the space (neural foramen) available for nerve roots leaving the spinal cord... If the degenerative change affects the facet joint(s) and the disk, the condition is sometimes referred to as spondylosis. This condition may be accompanied by disk degeneration, and an enlargement or overgrowth of bone that narrows the central and root canals." SOURCE: National Institutes of Health Symptoms - Spinal Stenosis: "Pain and difficulty when walking, aggravated by activity. Numbness, tingling, hot or cold feelings, weakness or a heavy and tired feeling in the legs. Clumsiness, frequent falling, or a foot-slapping gait." SOURCE: American Academy of Orthopaedic Surgeons "Spaces within the spine can narrow without producing any symptoms. However, if narrowing places pressure on the spinal cord or nerve roots, there may be a slow onset and progression of symptoms. The back itself may or may not hurt. More often, people experience numbness, weakness, cramping, or general pain in the legs that occurs during flexing the lower back while sitting." SOURCE: National Institutes of Health "People with more severe stenosis may experience abnormal bowel and bladder function and foot disorders. For example, cauda equina syndrome is a partial or complete loss of control of the bowel or bladder and sometimes sexual function; it is due to compression of the collection of spinal roots that descend from the lower part of the spinal cord and occupy the vertebral canal below the cord.." SOURCE: National Institutes of Health Frequency - Spinal Stenosis: (back to top) "Approximately 250,000-500,000 US residents have symptoms of spinal stenosis. This represents about 5 of every 1000 Americans older than 50 years." SOURCE: eMedicine.com Synonyms/Related Words - Spinal Stenosis: (back to top) "Spondylosis, spinal canal narrowing, neurogenic claudication, myopathy, focal stenosis, lateral recess syndrome, cervical spondylotic myelopathy, CSM, ligamentum flavum hypertrophy." SOURCE: eMedicine.com Excerpts from the Scientific Literature - Fluoride & Spinal Stenosis: (back to top) "Ossification of the transverse atlantal ligament (OTAL) is extremely rare and may cause upper cervical canal stenosis and spastic quadriparesis... Each of the two cases of OTAL (Ossification of the transverse atlantal ligament) presented here had been diagnosed with fluorosis. As previously discussed, the etiology of OTAL may be of multiple origins, such as injury, and acquired or congenital abnormalities. Although there have been no English articles reporting that OTAL can be caused by fluorosis, we would argue that, together with many other ligaments and membranes, the atlantal transverse ligament may be ossified (in fluorosis)." SOURCE: Wang W, et al. (2004). Ossification of the transverse atlantal ligament associated with fluorosis: a report of two cases and review of the literature. Spine 29 :E75-8. "A sizeable number of patients suffering from ossified posterior longitudinal ligament (OPLL) may have fluoride intoxication as the underlying cause." SOURCE: Reddy DR, et al. (1993). Neuro-radiology of skeletal fluorosis. Annals of the Academy of Medicine, Singapore 22(3 Suppl):493-500.

"A 70 years old farmer from Yemen was referred as a case of osteoarthritis of both knees for preoperative rehabilitation procedures. Six years before he developed skeletal stiffness. By 70 years he became dependent for ambulation and many other self-care activities. He showed quadriparesis resulting from compression of spinal cord and nerve roots at multiple levels associated with multiple joint involvement." (This patient was diagnosed by the authors as suffering from skeletal fluorosis.) SOURCE: Khamees MF, et al. (1995). An uncommon presentation of fluorosis. Electroncephalography & Clinical Neurophysiology 97: S229. "Two cases of ossification of the posterior longitudinal ligamentum with cervical myelopathy are reported. The radiologic studies determined the etiology, in the first case, it was fluorosis and the second DISH disease." SOURCE:Chaabane M, et al. (1995). [Rare causes of ossification of the posterior common vertebral ligament causing cervical compression. Apropos of 2 cases]. [Article in French] J Radiol. 76(1):43-6. "The authors report four cases of spinal cord compression (three at cervical level and one at dorsal level) due to vertebral osteosclerosis secondary to chronic fluoride intoxication. Roentgenograms showed typical diffuse densification of vertebral bodies, calcifications of bony insertions of many ligaments, discs and interosseous membranes... Spinal computed tomography showed severe cord compression due to posterior osteophytes." SOURCE: Mrabet A, et al. (1995). [Spinal cord compression in bone fluorosis. Apropos of 4 cases] [Article in French]. Rev Med Interne.16(7):533-5. "A case of skeletal fluorosis with spinal cord compression from Kekirawa following consumption of water with high fluoride content for about 20 years is described." SOURCE:Disanayake JK, et al. (1994). Skeletal fluorosis with neurological complications. Ceylon Med J. 39(1):48-50. "Plain roentgenology of the skull was normal, but of the cervical spine revealed marked fluorotic changes and a fracture of C6. Ossification of the posterior longitudinal ligament (OPLL) was seen. He was suspected of having fluorotic cervical canal stenosis with compressive myelopathy, precipitated by trauma... At operation, the characteristic changes of a fluorotic spine were observed in the form of ossified spinal ligaments and hardened bone... The spine was like a continous column of bone, typical of fluorosis... Neurological sequelae in skeletal fluorosis manifest as radiculomyelopathy, principally due to mechanical compression of the spinal cord and nerve roots... Though the disease develops slowly with relentless progression, the neurological manifestations may sometimes be precipitated by minor trauma." SOURCE: Prasad VS, Reddy DR. (1994). Posttraumatic pseudomenigocoele of cervical spine in a patient with skeletal fluorosis: Case report. Paraplegia 32:627-30. "A lumbar computer tomographic scan demonstrated severe calcification of the posterior longitudinal ligament and ligamentum flavum extending from T7 though L3 resulting in marked stenosis of the spinal canal and secondary spinal cord atrophy." SOURCE: Dhuna AK, et al. (1992). Skeletal fluorosis. An unusual cause of progressive radiculomyelopathy. Spine 17:842-4. "In advanced stages of neurofluorosis, the clinical picture is rather uniform, with complete incapacitation and the bedridden state of severe spastic paraparesis, or quadriparesis with incontinence of urine and flexor spasms... [F]luorotic changes resulted in considerable encroachment on the diameter of the intervertebral foramina and spinal canal. These changes tend to be most marked in the cervical region. This explains the clinical similarity of neurofluorosis to cervical spondylosis." SOURCE: Haimanot RT. (1990). Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy. Paraplegia 28:244-51. "A middle-aged male resident of Benghazi, northeastern Libya, with radiological features of skeletal fluorosis associated with cervical radiculomyelopathy is reported... His problem is of special interest because he lived in a nontropical, non-endemic area [1-2 ppm] where cases of advanced fluorosis would not be expected." SOURCE:Maloo JC, et al. (1990). Fluorotic radiculomyelopathy in a Libyan male. Clinical Neurology and Neurosurgery 92(1):63-5. "We report a case of spinal cord compression with paraplegia as a result of endemic skeletal fluorosis... Kyphosis of the spine was present without other apparent bone deformity... [M]yelography demonstrated partial spinal cord compression at the level of T2 and T3 vertebrae.. A radiographic skeletal survey revealed osteosclerosis of the axial skeleton with sparing of the skull and prominent calcification of the interosseous membranes and ligamentous

insertions... Magnified computed tomographic scan images of the thoracic vertebrae demonstrated marked narrowing at the T2 and T3 levels due to bony exostoses protruding into the spinal canal... Neruologic symptoms are a late occurrence and signify far advanced disease... Involvement of the peripheral and central nervous system has led to the description of neurologic manifestations as a radiculomyelopathy. Radicular features include muscle weakness with asymmetric atrophy, fasciculation, nerve root pain, and acroparesthesias. Onset of these symptoms is usually insidious. Myelopathic features are characterized by a more abrupt onset and include spastic paraplegia or quadriplegia, hyperreflexia, Babinski reflex, clonus, or a variety of sensory deficits. The course is usually progressive, and there is predilection for cervical spine involvement. Neurogenic bladder or bowel incontinence has been reported as a conequence of spinal cord involvement." SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700. "All five cases of fluorosis in this study had the clinical picture suggestive of cervical myelopathy. The diagnosis of fluorosis was based on the residence in the endemic area and the radiological features of fluorosis, which included osteosclerosis, calcification of the interosseous membrane/ligaments, periosteal bone formation, and irregular osteophytes... The spinal cord involvement is commonest in the cervical region and has been reported to constitute 56% of 136 patients of fluorosis with neruological complication. Although the lumbar vertebrae are the first to show the changes caused by fluorosis, the compression of cauda equina rarely occurs because its roots are easily accomodated." SOURCE:Misra UK, et al. (1988). Endemic fluorosis presenting as cervical cord compression. Archives of Environmental Health 43:18-21. "The mean canal body ratio was higher in fluorosis at every level of the vertebra as compared to that of normal controls. In other words, the spinal canal was narrow at every level in fluorosis as compared to normal controls." SOURCE: Kapila AK, et al. (1983). Measurement of spinal canal body ratio in fluorotic spine. Fluoride 16: 11-19. "X-ray examination revealed generalized increased bone density of the spine, ribs, and pelvis, suggestive of skeletal fluorosis. Extensive accompanying osteophytosis was present... The sagittal diameters of both the cervical and lumbar spine were below the 90 per cent tolerance levels... A diagnosis of fluorotic radiculomyopathy was made and confirmed by the consulting rheumatologist... The characteristic vertebral changes of skeletal fluorosis and severe osteophytosis were probably the basis for his neurological deficits. Although trauma may have precipitated his radiculomyopathy, the neurological symptoms are adequately explained by the marked narrowing of the sagital diameter of the spinal canal and vertebral osteophytosis secondary to fluorosis. Any trauma which might have caused edema of the spinal cord could have produced neurological damage because of the narrowed bony spinal canal. Thus, the role of trauma is equivocal since bony encroachment on the spinal cord was probable. Wolf has stated that cord compression is likely to occur when the cervical canal is 10 mm or less. The bony canal at C-4 in this patient was 9.5 mm." SOURCE: Goldman SM, et al. (1971). Radiculomyelopathy in a southwestern indian due to skeletal fluorosis. Arizona Medicine 28: 675-677. "A series of 70 cases of skeletal fluorosis with neurological manifestations was studied... The F concentration of water consumed by the patients varied between 1.2 and 11.8 ppm... In 50 cases there was evidence of involvement of the cervical cord... The lowest F concentration in water causing skeletal fluorosis and quadriplegia was 1.35 ppm. Singh et al (1961) recorded spastic paraplegia in a 50 year old male who consumed water containing 1.2 ppm F." SOURCE:Siddiqui AH. (1970). Neurological complications of skeletal fluorosis with special reference to lesions in the cervical region. Fluoride 3:91-96. "The case of a 57-year-old man with skeletal fluorosis leading to spinal cord compression is described. Myelography showed a partial block at T11, and following decompression of the lower thoracic cord there was considerable improvement in symptoms and signs. The diagnosis of fluorosis was confirmed by the radiological appearances, by the histology of the bone removed at operation, and by the raised level of the bone fluoride." SOURCE:Webb-Peploe MM, Bradley WG. (1966). Endemic fluorosis with neurological complications in a Hampshire man. Journal of Neurology, Neurosurgery and Psychiatry 29:577-583. "A 64-year-old white male was admitted to the Veterans Administration Hospital, McKinney, Tex, on May 11, 1962, because of severe respiratory distress and semicoma. He had been a complete invalid in a nursing home for a year... This case of a patient with chronic fluoride intoxication, extensive osteosclerosis, and fluorotic radiculomyelopathy is believed to be the first reported from the United States." SOURCE:Sauerbrunn BJ, et al. (1965). Chronic fluoride intoxication with fluorotic radiculomyelopathy. Annals of Internal Medicine 63: 1074-1078.

"compression of the cord (in fluorosis) is almost inevitable." SOURCE:Singh A, et al. (1963). Endemic fluorosis. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab. Medicine 42: 229-246. "The earliest symptom of spinal cord involvement, present in all cases, was weakness of both lower limbs. This usually started in one leg, with later progression to the other. In 18 cases, after a variable interval, the upper limbs became involved, producing a spastic quadriplegia... The pattern resembled in many ways that of spondylitic myelopathy...The signs of fluorotic myelopathy result chiefly from narrowing of the spinal canal or intervertebral foramina and compression may occur at a single or at multiple sites." SOURCE:Singh A, et al. (1963). Endemic fluorosis. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab. Medicine 42: 229-246. "The neurological complications of endemic fluorosis have received scant attention, and we first became interested in this aspect while investigating obscure cases of paraplegia, associated with increased density of the spine and other bones, in Punjab - a northern state of India. Almost all the patients came from a small area of Punjab and had in fact skeletal fluorosis with compression paraplegia... The neurological complications are the result of deposition of fluoride in the spine, leading to narrowing of the spinal canal and compression of the cord... It did not differ significantly from other compression paraplegias." SOURCE:Singh A, et al. (1961). Skeletal fluorosis and its neurological complications. Lancet 1: 197-200. Summation - Crippling Skeletal Fluorosis: When the US Environmental Protection Agency established its safe drinking water standard for fluoride in 1985, the only adverse health effect from fluoride which they acknowledged, and sought to prevent, was crippling skeletal fluorosis. By focusing only on crippling fluorosis, the EPA ignored the earlier stages of skeletal fluorosis which, contrary to EPA's assertions, may produce significant adverse symptoms (e.g. joint pain and stiffness), even in the absence of detectable bone changes. Excerpts from the Scientific Literature - Crippling Skeletal Fluorosis: "in fluorosis stage III we can see a complete ossification of the longitudinal ligaments of the spine which has practically stiffened to a stick." SOURCE: Franke J, et al. (1975). Industrial fluorosis. Fluoride 8: 61-83. "Due to the extreme fixation of the spine, the body moved as a single unit with each attempt to straighten any portion of it." SOURCE: Singh A, et al. (1963). Endemic fluorosis. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab. Medicine 42: 229-246. "The most striking abnormalities are those of the vertebrae, which are fused to make of the spinal column one long, rigid bone. All the intervertebral discs are completely ossified." SOURCE: Kilborn LG, et al. (1950). Fluorosis with report of an advanced case. Canadian Medical Association Journal 62: 135-141. "Thirty-five years ago she began to have pain in her shoulders and the upper part of her spine. At present her back is fixed, so that there is one complete curve from the occiput to the lumbar region. She cannot raise her head to the vertical; the only movement she can make in any part of her spine is a slight lateral rotation of the head. The knees are flexed to counteract the anterior flexion of the spine." SOURCE: Lyth O. (1946). Endemic fluorosis in Kweichow, China. The Lancet 1: 233-235. "the rigidity of the spine was a dangerous factor. He did little more than topple over from a squatting position; but, because his spine was in one piece, the weight of the head snapped it in the cervical region." SOURCE: Lyth O. (1946). Endemic fluorosis in Kweichow, China. The Lancet 1: 233-235. "Among the most severe cases, four elderly men, there was practically complete rigidity of the entire spine and a more or less pronounced restriction of the head movements."

SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "In order to look sideways he had to turn the whole body...This man was unable to pick anything up from the floor by bending the knees and could not put on his socks without aid." SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. London: H.K. Lewis Ltd. "The younger man had felt stiffness of his back coming on about six years ago, and since then it had gradually increased, until his spine has now become perfectly immovable. He complained a good deal of 'rheumatic' pain across his hips, also when lying down." SOURCE: Moller P, Gudjonsson SV. (1932). Massive fluorosis of bones and ligaments. Acta Radiologica 12: 269294.