What are the long-term effects of ingesting fluoride on our bones?
Fluoride is a bioaccumulator and is toxic to bones
The results of more than five epidemiological studies indicate increased hip fractures in both naturally and artificially fluoridated areas. The incidence of hip fracture is also increasing more rapidly than can be accounted for by aging of the population. There are numerous studies which undeniably prove that fluoride's cumulative effect on bone is devastating. It is well known that chronic ingestion of fluoride can cause osteofluorosis or skeletal fluorosis (crippling bone disease). This evidence has been reported in at least nine studies from five countries (contrary to promoters' denials, this occurs even at relatively "low" water fluoride levels). Moreover, according to the World Health Organization, individuals consuming between 2.0 - 8.0 mg of fluoride/day (2-8 litres of fluoridated water), can develop the pre-clinical symptoms of skeletal fluorosis (arthritis-like symptoms). As recently reported by the U.S. PHS, many women living in fluoridated communities are now ingesting up to 6.6 mg of fluoride per day, a crippling dose for some if maintained (see fluoride.htm and skeletal.htm for more info and chart on daily fluoride intakes).
It is widely recognised that fluoride "therapy" for osteoporosis adds mass to bones but produces inferior bone -- at least seven studies found structural abnormalities or mineralization defects. In short, the biomechanical competence of the skeleton may be compromised because the tensile (elasticity) strength of bone is sacrificed. These studies not only show that fluoride may cause increased skeletal fragility (more non-vertebral fractures such as hip), but that it can lead to osteomalacia (another bone disease). The relevance to fluoridation is:
short-term high-dose fluoride studies show the same amount of fluoride accumulates in the bones of osteoporosis patients as would be found in some people who are chronically exposed to long-term "low" doses of fluoride (such as in fluoridated areas). People with renal insufficiency, for example, can incorporate four times more fluoride into bone than an average healthy individual and would therefore be more susceptible to the long-term effects of drinking "optimally" fluoridated water than the average individual (see Toxicological Profile For Fluorides, Hydrogen Fluoride, and Fluorine, by the U.S. Agency for Toxic Substances and Disease Registry).
Evidence of more bone damage is seen in a NJ Department of Health study, a U.S. National Cancer Institute study, a rodent study by the U.S. National Toxicology Program (NTP), and a Polish study which examined the bones of children with dental fluorosis using new radiographic techniques. The two epidemiological studies found increased osteosarcoma rates in young men in fluoridated areas. Osteosarcoma is a rare bone cancer which mostly originates in the growing end of bones. It is more prevalent among young males 10-19 years of age and seems to occur 1.4 times more often in males than in females. Girls are at risk at an earlier age because their adolescent growth spurt occurs before that of boys. The NTP animal study found dose-related occurrences of osteosarcomas in male rats. Polish scientists discovered bone abnormalities in male children with fluorosis. How much evidence must accumulate before authorities here acknowledge what many foreign scientists have already done years ago -- fluoride is one of the most bone-seeking elements known to man and long-term ingestion is toxic to bones even in the so-called "low" doses.
Note: see also definit.htm for more info on osteoporosis and other bone diseases.
Editorial, Official "Safe" Fluoride Intakes Based On Arithmetic Error, FLUORIDE, 1997, 30:4
Alhava EM, Olkkonen H, Kauranen P, Kari T, The effect of drinking water fluoridation on the fluoride content, strength and mineral density of human bone. Acta Orthop Scand, 1980 June, 51 (3): 413-420.
The effect of drinking water fluoridation on the fluoride content of human bone, on cancellous bone strength and on the mineral density of bone was studied by analysing 158 autopsy samples of the anterior iliac crest from persons from two different areas. In the samples from the town of Kuopio, where drinking water has been fluoridated since 1959, the fluoride concentrations were considerably higher than in samples from the surrounding area where low-fluoride drinking water is used. The fluoride content of bones from Kuopio increased significantly with age, while considerably less change with age was found in samples from outside Kuopio. The highest fluoride content in bone ash was observed in women with severe osteoporosis. Cancellous bone strength measured by a strain transducer was statistically significantly higher in women with chronic immobilizing disease from Kuopio, compared with the corresponding group from outside Kuopio. No statistically significant differences in bone strength were found in men. There were no statistically significant differences in bone mineral density, as measured by gamma ray attenuation, between the samples from the fluoridated and non-fluoridated areas.
Bayley TA, Harrison JE, Murray TM, Josse RG, Sturtridge W, Pritzker KP, Strauss A, Vieth R, Goodwin S, Fluoride-induced fractures: relation to osteogenic effect. J Bone Mineral Research, 1990 March, 5 Suppl 1: S217-S222.
The possible effects of fluoride in inducing fractures were studied in 61 patients treated with sodium fluoride (NaF), 40-60 mg daily in combination with calcium and vitamin D. Nine patients developed the fluoride-(F) related lower extremity pain syndrome. Four other patients had stress fractures associated with trauma. Seven of the 61 patients had 10 upper femur fractures of which 5 were stress fractures. The bone mineral mass of the central skeleton including the hips was measured by neutron activation and the results expressed as a calcium bone index (CaBI) which normalizes the results to that of young adults of the same body size (normal range 0.75-1.2). At the time of hip fracture, 4 patients with a minimal increase in bone mass (mean delta CaBI 0.01) had 4 femur fractures and 3 patients with a marked increase (mean delta CaBI 0.24) had 6. The 7 patients with upper femur fractures at 4 years had a significantly higher bone fluoride retention, 30 mg/g Ca compared with 23.9 mg/g Ca for the other 54 (p less than 0.02) and were older, 73.1 versus 64.2 years (p less than 0.01). 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). By partial correlation, only the correlation between hip fractures/patient and bone fluoride remained significant after controlling for the effect of 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. The lower extremity pain syndrome is not frequently associated with stress fractures in this study.
Carter DR, Beaupre GS, Effects of fluoride treatment on bone strength, J Bone Miner Res, 1990 Mar, 5:Suppl 1, S177-S184
Bone mass and architecture in appendicular and most axial sites is controlled primarily by the tissue-loading history. We introduce a conceptual framework for understanding how fluoride treatment alters this control and can cause systemic increases in bone mass. Due to possible adverse influences of fluoride on the mineralized tissue physical characteristics, however, the increase in bone mass does not necessarily result in an increase in bone strength. Using engineering analyses of bone trabeculae, we calculate the losses in trabecular strength which can be caused by the presence of hypomineralized or hypermineralized fluorotic tissue. Significant increases in bone volume fraction and bone mass may be required to overcome these strength deficits.
Cauley JA, Murphy PA, Riley T, Black D, Public Health Bonus of Water Fluoridation: Does Fluoridation Prevent Osteoporosis and Its Related Fractures?,American Journal of Epidemiology, 1991, 134, 768, (Abstract only --no study)
Fluoridation of community water supplies has been clearly established as a primary means of preventing dental caries [note: shows bias -- less than 1% of Western Continental Europe is fluoridated]. Recently, there have been renewed concerns about potential risks of fluoridation of water supplies. Documentation of additional benefits or risks is needed. Previous epidemiologic studies, most of which were ecologic studies, suggest that exposure to fluoridated water may also have beneficial effects on bone mass and fractures. To test this hypothesis in an analytical epidemiologic study, residential history and source of drinking water (public, well, cistern, spring) for 1950-1990 were obtained from 1,878 white women aged 65-93 years (mean age, 70.9 years). All of the women were participants in the Study of Osteoporotic Fractures. Thirty public water companies in southwest Pennsylvania were contacted for information on geographic service are, whether the water supply was fluoridated, and, if so, year initiated. Individual person-years of fluoride exposure was estimated. Bone mineral density was measured at three sites: distal and proximal radius and calcaneus. History of fractures (hip and wrist) after age 50 years was obtained by questionnaire. Public water constituted 73% of exposure-years. The mean years of fluoride exposure was 6.0 + or -9.24 years (range, 0-38 years). A total of 1,090 (58%) were not exposed to fluoride, while 10% were exposed for > or = 21 years. No relation was found between years of fluoride exposure and bone mineral density (r=0.005 to 0.05). Stratification by years of exposure (0-7, 8-11, 12-20, > or = 21 years) showed no relation between bone mineral density and fluoride, with or without adjustment for body mass index and age. There was also no relation with history of fracture. These data do not support a protective relation between exposure to fluoridated water and bone mineral density in this population of elderly women.
editor's note: see Lee JR, Fluoridation and Hip Fracture, Fluoride 1993, 26:4
Cauley JA, Murphy PA, Riley TJ, Buhari AM, Effects of fluoridated drinking water on bone mass and fractures: the study of osteoporotic fractures. J Bone Miner Res, 1995 July, 10 (7): 1076-1086
To determine if optimal fluoridation of public water supplies influences bone mass and fractures, we studied 2076 non-black women, all aged > or = 65 years recruited into the Study of Osteoporotic Fractures at the Pittsburgh clinic. Information on fluoride exposure was limited to community water supplies. The variable used in the analysis was years of exposure to fluoridated water in community drinking water supplies. Bone mineral density (BMD) was measured at the spine and hip using dual energy X-ray absorptiometry and at the midpoint and ultradistal radius and calcaneus using single photon absorptiometry. Prevalent and incident vertebral fractures were determined by morphometry. Incident nonspine fractures were ascertained every 4 months and confirmed by radiographic report. Exposure to residential fluoridated water had no effect on bone mass. Women exposed to fluoride for > 20 years had similar axial and appendicular bone mass to women not exposed or women exposed for ≤ 20 years. There was some suggestion that women exposed to fluoride for > 20 years had a lower relative risk of nonspine fractures (relative risk, RR, = 0.73; 95% confidence interval [CI] 0.48-1.12), osteoporotic fractures, RR = 0.74 (CI 0.46-1.19), and hip fractures, RR = 0.44 (CI 0.10-1.86), compared with women not exposed, but none of these relative risks was statistically significant. There was no association with wrist or spinal fractures. Our results do not support the findings from recent ecological studies which showed an increased risk of hip fracture among individuals exposed to fluoridated public water.
[editor's note: only 9.2% of women had exposure to fluoridated water > 20 years. Among these women, the average number of exposure years was 12.7 years. Moreover, most of the exposure to fluoride was recent (from 1980-1990). In other words, not many had significant fluoride exposure before menopause. Bone turnover rate is relatively rapid before menopause and slow after. Fluoride's major effect on bone is thus most likely to occur before menopause (before age 45-50). See Lee JR, Fluoridation and Hip Fracture for more info
Caverzasio J, Imai T, Ammann P, Burgener D, Bonjour JP, Aluminum potentiates the effect of fluoride on tyrosine phosphorylation and osteoblast replication in vitro and bone mass in vivo, J Bone Miner Res 1996 Jan;11(1):46-55
Osteosclerosis in workers exposed to fluoride (F) and aluminum (Al) (industrial fluorosis) led to the use of F as a treatment to increase bone mass in osteoporosis patients. Because the influence of traces of Al on the effects of F on bone formation is heretofore unknown, we have investigated this issue both in vitro and in vivo. We have found that minute amounts of Al (≤ 10(-5) M) potentiate the effects of F in vitro such that osteoblast proliferation increased by 15 ± 2.7% at 50 microM (p < 0.001) and by 117.6 ± 5.1% at 750 microM (p < 0.001), concentrations of F with no mitogenic effect alone. F + Al time-dependently modulated a growth factor signaling pathway(s) associated with enhanced tyrosine phosphorylation (TyrP) of several proteins (p90 [2.9x], p77 [4.9x], p68 [9.6x], and mitogen activated protein kinases [3x]). TyrP was only slightly or not at all changed by F and Al alone, respectively. The effects of F + Al on TyrP and cell proliferation were markedly reduced by 100 microM tyrphostin-51, a tyrosine kinase inhibitor. Protein kinase A (PKA) and protein kinase C (PKC) pathways were not involved in this response. In vivo, F + Al administered for 8 months, at doses that had no effect when the minerals were administered individually, significantly enhanced proximal tibia bone mineral density (BMD) by 6.3 ± 1% compared with initial values and by 2-fold compared with control ovariectomized rats (p < 0.0001). These effects are consistent with a crucial role of Al in osteosclerosis observed in industrial fluorosis. The results suggest that the combination of F + Al modulates a growth factor-dependent TyrP pathway enhancing mitogen-activated protein kinase and osteoblastic proliferation and bone mass.
[editor's note: for info on aluminum-fluoride interactions, see brain.htm. For related article, see Czerwinski E, et al., and Xiao B, et al., below.
Chlebna-Sokól D, Czerwinski E, Bone Structure Assessment On Radiographs Of Distal Radial Metaphysis In Children With Dental Fluorosis, Fluoride, 1993 Jan, 26:1, 37-44
Cooper C, Wickham AAC, Barker D, Water Fluoridation and Hip Fracture, JAMA, 1991 July 24/31, 266:4, letters 513
In a recent article in The Journal, Jacobsen et al demonstrated a positive ecologic association between hip fracture discharge rates in the United States and fluoride content in water supplies. In a similar study, we recently reported the ecological association of discharge rates for hip fracture and water fluoride levels in 39 county districts in England. Our study was performed in response to the suggestion that fluoridation of water might serve to stem the rising tide of hip fracture in western populations. Such a strategy was supported by laboratory evidence that fluoride was a potent inducer of bone formation, and by epidemiologic studies from Finland [see note] and the United States demonstrating lower rates of hip fractures associated with higher water fluoride levels. Our analysis demonstrated no significant association between discharge rate and total fluoride concentration (r=.16, P=.34). This lack of association was found for both men and women, as well as in a restricted analysis eliminating the smaller counties. However, the results from the recent US study prompted us to reexamine our data.
[editor's note: the original Finland study was flawed -- more on this to follow. After a subsequent study there, Finland discontinued artificial water fluoridation]
Our original statistical methods did not adequately account for differences in precision of the county-specific rate estimate. We reanalyzed the data using a weighted least-squares technique (weighting each county by the size of the population aged 45 years and older) to allow for these differences. We found a significant positive correlation between fluoride levels and discharge rates for hip fracture (r=.41, P=.009, Figure). This relationship persisted for both women (r=.39, P=.014) and men (r=.42, P=.007). The respective regression coefficients and their standard errors were 0.46 (0.17) (discharges per thousand/milligrams per liter of fluoride) for total rate, 0.65 (0.25) for women, and 0.23 (0.08) for men.
We present these data for two purposes. First, given the widespread use of fluoridated water in public water supplies for the prevention of dental caries, any risk or benefit associated with this practice will affect extremely large numbers of persons. Using an appropriately weighted regression model, there appears to be a positive ecologic association between fluoride levels of county water supplies and fracture discharge rates. This ecologic association is consistent with a recently published study and others currently in progress. Of course, this approach remains hampered by the problems common to all ecologic studies. The relationship observed may be spurious due to the confounding of some other factor that has not been accounted for in our analysis. Furthermore, an adverse impact of such low levels of fluoride appears biologically implausible [not so -- fluoride is cumulative], despite the recent trials suggesting such a consequence at much higher doses than in our study. Nevertheless, this positive association demands further investigation at the individual level. Our second purpose is to stress the methodologic issue of weighting in this type of analysis. The precision with which each county-specific rate is estimated is directly related to the size of the population. Analyses that fail to adequately account for this variation in precision give inappropriate emphasis to counties in which there is greater error in measurement of the rate. These data provide a striking example of such a bias obscuring the detection of potentially important associations. [comments added]
Czerwinski E, Friedlein J, Kukielka RT, Evaluation of bone mineral density in the distal radius of former workers employed at the Aluminum Works, Przegl Lek 1997;54(4):269-271 (Article in Polish)
Fluoride causes an increase in bone mass by stimulation of osteogenetic process. This effect is used in treatment of osteoporosis. Chronic exposure to fluoride in aluminium works can cause an industrial fluorosis, which is characterised by increased mineral content in bone tissue. It is well known that after cessation of fluoride is gradually eliminated from the bone. Probably this same process can exist in patients with osteoporosis after stopping of osteoporosis treatment, so we decided to estimate bone mineral density in former workers of aluminium works. For investigation a group of 169 of men in mean age of 50.0 years, all of whom had worked for at least five years (average 12.9 yrs) in Skawina aluminium works before their closure in 1981, was selected. The control group was 29 men in the same age not exposed for fluoride. In all patient bone densitometry in distal and ultradistal region were evaluated. Decreased bone mineral density was found in workers of aluminium workers, compared to the control group, particularly in age groups of 40-44 and 50-54 years. Differences were bigger in measurements of trabecular bone.
[editor's note: for related articles, see below and Caverzasio J, et al., and Xiao B, et al. For info on fluoride-aluminum interactions, see brain.htm
Czerwinski E, et al., Bone and Joint Pathology in Fluoride-Exposed Workers, Archives of Environmental Health, 1988, 43:5
Danielson C, Lyon JL, Egger M, Goodenough GK, Hip fractures and fluoridation in Utah's elderly population, JAMA, 1992 August 12, 268:6, 746-748
OBJECTIVE--To test the effect of water fluoridated to 1 ppm on the incidence of hip fractures in the elderly. The incidence of femoral neck fractures in patients 65 years of age or older was compared in three communities in Utah, one with and two without water fluoridated to 1 ppm. PATIENTS--All patients with hip fractures who were 65 years of age and older over a 7-year period in the three communities, excluding (1) those with revisions of hip fractures, (2) those in whom the hip fracture was anything but a first diagnosis, (3) those in whom metastatic disease was present, or (4) those in whom the fracture was a second fracture (n = 246). The relative risk for hip fracture for women in the fluoridated area was 1.27 (95% confidence interval [CI] = 1.08 to 1.46) and for men was 1.41 (95% CI = 1.00 to 1.81) relative to the nonfluoridated areas. We found a small but significant increase in the risk of hip fracture in both men and women exposed to artificial fluoridation at 1 ppm, suggesting that low levels of fluoride may increase the risk of hip fracture in the elderly.
Dequeker J, Declerck K, Fluor in the treatment of osteoporosis. An overview of thirty years clinical research. Schweizerische Medizinische Wochenschrift, Journal Suisse de Medecine, 1993 Nov 27, 123(47):2228-34.
It has long been known that fluoride "hardens" mineralized tissues. Fluoride ingestion through drinking water in areas naturally rich in fluoride leads to osteosclerosis, known as endemic fluorosis. The first suggestion that fluoride be used in the treatment of osteoporosis was made in 1964. However, despite 30 years of research, the treatment remains controversial. Fluoride has a dual effect on osteoblasts. On the one hand, it increases the birthrate of osteoblasts at tissue level by a mitogenic effect on precursors of osteoblasts, while on the other hand it has a toxic effect on the individual cell with mineralization impairment and reduced apposition rate resembling osteomalacia. Fluoride has a positive effect on axial bone density, but the axial bone gain is not matched by similar changes in cortical bone. Furthermore, approximately one third of patients are non-responders. The effect of the addition of fluoride to the drinking water on fracture rate is not clear. It probably only has a small relative impact on total hip fracture rates. In two controlled fluoride therapy studies the incidence of vertebral fractures decreased, while in two other studies it increased. Experience teaches that denser bones are not necessarily better bones. The major side effects of fluor therapy are skeletal fluorosis, gastrointestinal intolerance, and painful lower extremity syndrome. Fluoride is the single most effective agent for increasing axial bone volume in the osteoporotic skeleton; however, its therapeutic window is narrow. The best candidates for fluoride therapy are patients with axial osteoporosis but with good peripheral bone density. They should have a good renal function and vitamin D status. (Abstract truncated)
Dure-Smith BA, Farley SM, Linkhart SG, Farley JR, Baylink DJ, Calcium deficiency in fluoride-treated osteoporotic patients despite calcium supplementation, J Clin Endocrinol Metab, 1996 Jan, 81(1), 269-275
To test the hypothesis that the osteogenic response to fluoride can increase the skeletal requirement for calcium, resulting in a general state of calcium deficiency and secondary hyperparathyroidism, we assessed calcium deficiency, spinal bone density, by quantitative computed tomography, and serum PTH in three groups of osteoporotic subjects. Two of the three groups had been treated with fluoride and calcium (at least 1500 mg/day) for 32 ± 19 months. Group 1 consisted of 16 fluoride-treated subjects who had shown rapid increases in spinal bone density (+ 3.8 ± 2.6 mg/cm2 month), group II consisted of 10 fluoride-treated subjects who had shown decreases or only slow increases in spinal bone density (-0.05 ± 0.6 mg/cm3 month), and group III consisted of 10 age-matched untreated osteoporotic controls. Calcium deficiency was assessed by measurement of calcium retention after calcium infusion. The results of our studies showed that 1) 94% of the subjects in Group I were calcium deficient compared with only 30% in groups II and III (P < 0.01 for each); 2) the subjects in group I retained more calcium (79%) than the subjects in group II (60%, P < 0.001) or the subjects in group III (64%, P < 0.005); 3) calcium retention was proportional to serum PTH (r = 0.37, n = 36, P < 0.03); and 4) calcium retention was proportional to the (previous) fluoride-dependent increase in quantitative computed tomography spinal bone density (in groups I and II, r = 0.48, n = 26, P < 0.02). To test the hypothesis that the calcium deficiency and the secondary hyperparathyroidism that were associated with the positive response to fluoride would respond to concomitant calcitriol treatment, a subgroup of 7 calcium-deficient subjects were selected from group I and treated with calcitriol (plus fluoride and calcium) for an average of 7 months. The calcitriol therapy reduced the calcium deficit in all 7 subjects, decreasing calcium retention from 80% to 62% (P < 0.02), and decreasing PTH from 50 to 28 pg/mL (P < 0.02). Together, these data indicate that fluoride-treated osteoporotic subjects may develop calcium deficiency in proportion to the effect of fluoride to increase bone formation, and this calcium deficit is responsive to calcitriol therapy.
Fratzl P, Roschger P, Eschberger J, Abendroth B, Klaushofer K, Abnormal bone mineralization after fluoride treatment in osteoporosis: a small-angle x-ray-scattering study. J Bone Miner Res, 1994 October 9 (10): 1541-1549.
Sodium fluoride treatment of osteoporosis is known to stimulate bone formation and to increase bone mass, but recent clinical trials failed to prove its antifracture effectiveness. The formation of bone with abnormal structure and, therefore, increased fragility is discussed as a possible explanation. Until now, however, exact information on the mineral structure of osteoporotic bone after fluoride treatment has been lacking. Bone biopsies were taken from three patients with postmenopausal osteoporosis before and after fluoride treatment (60 mg NaF/day for 1-2 years), from one patient with iatrogenic fluorosis, as well as from three normal controls. The mineral in these samples was investigated by a combination of backscattered electron imaging and small-angle x-ray scattering. Depending on the total dose of fluoride, an increasing amount of new bone is laid down on the surface of preexisting trabeculae. Its mineral structure is identical to that of heavy fluorosis and is characterized by the presence of additional large crystals, presumably located outside the collagen fibrils. These large crystals, which are not present in the controls or in osteoporotic bone before fluoride treatment, contribute to increase the mineral density without significantly improving the biomechanical properties of the bone. The possible success of fluoride treatment depends not only on the amount of newly formed bone but also on the rate of bone turnover. Indeed, as soon as significant amounts of fluoride are present, bone turnover leads to the replacement of old (normal) bone by new (pathologically mineralized) bone.
Grynpas MD, Fluoride effects on bone crystals, J Bone Miner Res, 1990 Mar, 5:Suppl 1, S169-S175
Fluoride is known to have biological effects on bone cells as well as physicochemical effects on bone crystals. This review concentrates on the latter. Fluoride increases the stability of the apatite lattice and decreases the solubility of the apatite crystals. In bone mineral, this ion has been shown to affect bone crystal structure by increasing crystallinity and reducing specific surface area. These changes in turn lead to changes in the chemistry of bone mineral. Bone mineral deposition is delayed by fluoride. This ion does not diffuse into bone already formed, but is incorporated during mineralization. Subsequently fluoride tends to accumulate in the most highly mineralized bone. Bone treated with fluoride has been shown to be more resistant to acid dissolution than normal bone, which would explain the reduced rate of resorption of fluoridated bone. The distribution of fluoride in bone is not uniform, but its net effect is to increase bone mineral density probably by an increased packing of bone crystals. Finally, there is a debate as to whether fluoride produces a bone of different quality. Whether these changes in the quality of bone will prove to be helpful or harmful remain to be determined. [if fluoride leads to increased fractures, it's highly unlikely that "stability" is enhanced]
Gutteridge DH, Price RI, Kent GN, Prince RL, Michell PA, Spontaneous hip fractures in fluoride-treated patients: potential causative factors, Spontaneous hip fractures in fluoride-treated patients: potential causative factors, J Bone Miner Res, 1990 Mar 5, Suppl 1, S205-S215
Spontaneous fractures were reported to be rare (less than 1%) in 1664 hospital admissions for hip fracture in the 1950s in Sweden. We report 11 fluoride-treated postmenopausal patients who developed spontaneous fractures of the femoral necks, all subcapital initially. In 7 patients who continued treatment there were later femoral neck or shaft fractures; in 6, these were bilateral (one followed a fall). In all there were 19 spontaneous fractures: 5 were asymptomatic, including 2 with deformity; 12 fractures required surgery. Five were incomplete (stress) fractures. All were treated with supplementary calcium 1 g daily; 10 had vitamin D supplementation. In all patients where the timing was known, the initial and subsequent fractures were preceded by, or associated with increased bone turnover as measured by plasma alkaline phosphatase (pAlP) (i.e., they were all "good responders"). Two had pretreatment hip fractures following falls. We compared these 11 (Group 1) and another identically treated group of 14 patients (Group 2), without spontaneous femoral fractures and not different in mean age, pretreatment vertebral fractures, years since menopause, fluoride dosage, and plasma creatinine. Group 1 had a lower (p less than 0.05) index of cortical bone in the femoral neck, as assessed by the ratio "calcar width/femoral neck minimum width." The 6 biopsied fluorotic patients from Group 1 had a higher (p less than 0.05) bone fluoride content than the 4 biopsied fluorotic patients from Group 2. Furthermore, histological cortical features of thinning, increased porosity, and advanced tunneling resorption characterized Group 1 posttreatment biopsies. There were no significant differences in peak pAlP responses in the two groups. Mild asymptomatic vitamin D excess may have been a contributing factor in three Group 1 patients. Two further treatment groups have been studied more recently by forearm single-photon absorptiometry (SPA) at two sites; a cyclic NaF group (Group 3) and a calcium ± vitamin D group (Group 4). Neither showed significant changes in forearm cortical bone density on treatment for 2 and 1.5 years, respectively, but Group 3 showed a significant increase in density at an ultradistal (60% trabecular) site. The pAlP response in Group 3 was significantly less than in Group 1. Spontaneous femoral neck or shaft fractures did not occur in either Groups 3 or 4. Therefore, we recommend: (1) Avoidance of sodium fluoride (NaF) treatment if pretreatment femoral fracture or thin femoral neck cortices exist.
Gutteridge DH, Kent GN, Prince RL, Nicholson GC, Stewart GO, Jones CE, Bhagat CI, Stuckey BG, Retallack RW, Fluoride treatment of osteoporosis: cyclical non-blinded or continuous blinded studies?, Osteoporos Int, 1993, 3:Suppl 1, 215-217
The future of sodium fluoride (NaF), the most potent osteoblast stimulator known to man, is in the balance. Of three recent randomized trials of continuous NaF only one found a significant in vertebral fractures in the NaF group. When data from the first year were excluded, two of the studies (those with the largest numbers)showed a significantly reduced risk of vertebral fracture on NaF. The effect of NaF on cortical bone is poorly documented. Two studies have shown reduced forearm cortical bone density with continuous NaF. A further two (histomorphometric) studies have shown the development of increased cortical porosity on continuous NaF treatment. In one, this was selectively at the external cortex and was linearly correlated with cancellous volume increase. Our pilot study using NaF administered cyclically has shown an encouraging (though non-significant) reduction in vertebral fracture rates (excluding year 1) and no fall in forearm cortical density. Another (US) cyclical study has shown no increase in cortical porosity. A current W. Australian randomized study of 50 patients is described where NaF dosage is varied proportional to the osteoblast response, and duration is dependent on densitometric and radiographic response. The future of NaF should involve cyclical administration, in cautious initial dosage (50-60 mg/day) of enteric-coated NaF, in conjunction with a potent inhibitor of resorption such as hormone replacement, bisphosphonates or calcitonin. [emphasis added]
[editor's note: one U.S. cyclical study used lower dose timed-release NaF and did not run long enough to show the cumulative toxic effects of fluoride. See review by Lee JR]
Harrison JE, Bayley TA, Josse RG, Murray TM, Sturtridge W, Williams C, Goodwin S, Tam C, Fornasier V, The relationship between fluoride effects on bone histology and on bone mass in patients with postmenopausal osteoporosis, Bone Mineral, 1986 September, 1 (4): 321-33.
Twenty-one patients with postmenopausal osteoporosis were studied for 4 years after initiation with sodium fluoride (NaF), 20-25 mg b.i.d., elemental calcium, 1.0 g/day, and vitamin D2, 50,000-100,000 I.U. weekly. Histomorphometry was carried out on bone biopsies taken prior to and while on NaF treatment. The total bone mineral mass of the central third of the skeleton was measured by neutron activation analysis at 0.5-1.0 year intervals, and the result expressed as the Calcium Bone Index (CaBI), which normalizes the mineral mass to values for normal subjects of the same size. Twelve patients (57%) who developed, within the first 2 years of treatment, histological effects of fluoride (F) (increased bone formation surfaces together with thickened osteoid seams or hyperosteoidosis) increased their CaBI significantly (P less than 0.01) over the 4 year period, from 0.64 ± 0.02 to 0.78 ± 0.03 (or 21.0 ± 2.9%). No other agent is known to stimulate bone growth to this degree. The remaining nine patients showed no histological evidence of F stimulation and no increase in CaBI (from 0.67 ± 0.03 to 0.66 ± 0.03 over 4 years). The results suggest that the histological findings of hyperosteoidosis are prerequisite for the increases in bone mass of osteoporotic patients. Although serum and bone F levels were higher in patients with F response compared to those without response, there was considerable overlap in values between the two groups so that these parameters of F retention were not reliable for predicting F response. Histological evidence of hyperosteoidosis appears to be a more reliable predictor of subsequent increase in bone mass. The effect on fracture prevention of the hyperosteoidosis associated with the increases in bone mass remains to be shown.
Hedlund LR, Gallagher JC, Increased Incidence of Hip Fracture in Osteoporotic Women Treated with Sodium Fluoride, J. Bone Mineral Res, 1989 April, 4:2, 223-225.
There has been controversy as to whether fluoride therapy increases the risk of fracture in the appendicular skeleton. In the present study we compared the incidence of hip fracture in four groups of osteoporotic women: 22 treated with placebo, 17 with fluoride and calcium, 18 treated with fluoride and calcitriol, and 21 with calcitriol alone. Four hip fractures occurred in 3 patients on fluoride and calcitriol, and two hip fractures occurred in 2 patients on fluoride and calcium. No hip fractures occurred in patients receiving either calcitriol alone or placebo. The difference in fracture rates for fluoride versus nonfluoride treatment is significant (p = 0.006). Moreover, the 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. [emphasis added]
Sharon Hillier, Cyrus Cooper, Sam Kellingray, Graham Russell, Herbert Hughes, David Coggon, Fluoride in drinking water and risk of hip fracture in the UK: a case-control study, Lancet Jan/2000, Vol 355, No 9200.
Background: Although the benefits of water fluoridation for dental health are widely accepted, concerns remain about possible adverse effects, particularly effects on bone. Several investigators have suggested increased rates of hip fracture in places with high concentrations of fluoride in drinking water, but this finding has not been consistent, possibly because of unrecognised confounding effects.
Methods: We did a case-control study of men and women aged 50 years and older from the English county of Cleveland, and compared patients with hip fracture with community controls. Current addresses were ascertained for all participants; for those who agreed to an interview and who passed a mental test, more detailed information was obtained about lifetime residential history and exposure to other known and suspected risk factors for hip fracture. Exposures to fluoride in water were estimated from the residential histories and from information provided by water suppliers. Analysis was by logistic regression.
Findings 914 cases and 1196 controls were identified, of whom 514 and 527, respectively, were interviewed. Among those interviewed, hip fracture was strongly associated with low body-mass index (p for trend <0.001) and physical inactivity (p for trend <0.001). Estimated average lifetime exposure to fluoride in drinking water ranged from 0.15 to 1.79 ppm. Current residence in Hartlepool was a good indicator for high lifetime exposure to fluoride. After adjustment for potential confounders, the odds ratio associated with an average lifetime exposure to fluoride 0.9 ppm was 1.0 [95% CI 0.7-1.5].
Interpretation There is a low risk of hip fracture for people ingesting fluoride in drinking water at concentrations of about 1 ppm. This low risk should not be a reason for withholding fluoridation of water supplies.
Medical Research Council, Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, SO16 6YD, UK (S Hillier PhD, C Cooper DM, S Kellingray MSc, Prof D Coggon DM); and Department of Human Metabolism and Clinical Biochemistry, Sheffield University Medical School (G Russell DM, H Hughes PhD), UK. Correspondence to: Prof David Coggon (e-mail: email@example.com)
[editor's note: see Lee JR, Fluoride in drinking water and risk of hip fracture in the UK]
Jacobsen SJ, Goldberg J, Cooper C, Lockwood SA, The association between water fluoridation and hip fracture among white women and men aged 65 years and older. A national ecologic study, Annals of Epidemiology, 1992 September, (2:5): 617-626
For the past 45 years, there has been a great deal of debate regarding the health issues surrounding the fluoridation of public water supplies. In order to assess the association between fluoridation and hip fracture, we identified 129 counties across the United States considered to be exposed to public water fluoridation and 194 counties without exposure. Data from the Health Care Financing Administration and the Department of Veterans Affairs were used to calculate the incidence of hip fracture among white persons, aged 65 years or older, in fluoridated and nonfluoridated counties. There was a small statistically significant positive association between fracture rates and fluoridation. The relative risk (95% confidence interval) of fracture in fluoridated counties compared to nonfluoridated counties was 1.08 (1.06 to 1.10) for women and 1.17 (1.13 to 1.22) for men. As comparisons were made at the grouped level, it may be inappropriate at this time to draw inferences at the individual level. The relationship observed at the county level needs to be duplicated at the individual level with more precise measures of fluoride exposure. [emphasis added-note the higher rate for men]
Jacobsen SJ, O'Fallon WM, Melton LJ 3d, Hip fracture incidence before and after the fluoridation of the public water supply, Rochester, Minnesota, Am J Public Health, May, 1993, 83:5, 743-5.
Recent ecological comparison studies have suggested a positive association between fluoridation and hip fracture. Using data from the Rochester Epidemiology Project, we found the incidence of hip fracture for the 10 years before the fluoridation of the Rochester, Minn, public water supply was 484 per 100,000, compared with 450 per 100,000 in the following 10 years. When the effects of calendar time and age were controlled for, the relative risk associated with fluoridation was 0.63. These ecologic trend data suggest that the fluoridation of public water supplies is not associated with an immediate increase in rates of hip fracture. Further studies of this association at the individual level are clearly required before public policy decisions can be made.
[editor's note: see Lee JR, Fluoridation and Hip Fracture]
Jacobsen SJ, Goldberg J, Miles TP, Brody JA, Stiers W, Rimm AA Regional Variation in the Incidence of Hip Fracture, JAMA, 264:4, 1990 Jul, 500-502.
[excerpt] There is a weak positive association between the percent of county residents who receive fluoridated water and hip fracture incidence in the unadjusted analysis that is strengthened after adjustment
Jacqmin-Gadda H, Commenges D, Dartigues JF, Commenges D, Dartigues JF, Fluorine concentration in drinking water and fractures in the elderly [letter]. JAMA, 1995 Mar 8, 273:10, 775-6.
...We report results of a population-based study of the relationship between concentrations of fluorine and calcium in drinking water and risk of hip fractures or fractures at any site. Results reported herein are based on the sample of the Paquid study of normal and pathological aging, which comprised 3777 subjects aged 65 years or older living at home in 75 civil parishes of southwestern France. The mean time that individuals in the sample had remained in the same parishes was 41 years. Data about fractures were available for 3578 subjects, 503 (14.1%) indicated they had at least one fracture at any site during the previous 10 years and 70 (1.95%) had at least one hip fracture. Calcium and fluorine concentrations were measured in water from each parish; data from two measurements surveys performed in 1991 and data collected routinely since 1991 were used. All analyses were performed using a multiple logistic regression Five personal characteristics were studied: age, sex, Quetelet index (weight in kilograms divided by the square of height in meters), smoking status, and sport activity. Only age (odds ratio [OR], 2.5 for 10 years; 95% confidence interval [CI], 1.7 to 3.6), sex (OR, 2.3 for women vs men; 95% CI, 1.2 to 4.3), and Quetelet index (OR, 0.90; 95% CI, 0.84 to 0.97) were significantly associated with the risk of hip fractures, and only age (OR, 1.2; 95% CI, 1.1 to 1.4) and sex (OR, 2.0; 95% CI, 1.6 to 2.4) were significantly associated with the risk of any fractures These variables were used as adjustment variables in the subsequent analyses.
Two classes of fluorine and calcium concentration were defined, using the median of the distribution among parishes as the cut off point. The main results are shown in the Table. The risk of hip fractures was significantly higher when water fluorine concentration was higher than 0.11 mg/L (P=.04), and this result persisted when using a mixed-effect logistic regression for taking into account the grouping of the subjects in parishes. No association was found between hip fractures and water calcium (P=.30) and between fractures at any site and water fluorine (P=.88) or water calcium (P=.50). Thus, adjusting for major individual risk factors, this study suggests a deleterious effect of fluorine in drinking water on the risk of hip fractures, even for moderate concentrations of fluorine, and no effect on other kinds of fractures. [emphasis added]
Jiang Y, Zhao J, Van Audekercke R, Dequeker J, Geusens P, Effects of low-dose long-term sodium fluoride preventive treatment on rat bone mass and biomechanical properties. Calcif Tissue Int, 1996 January, 58 (1): 30-39.
Effects of fluoride on bone strength and cortical bone mass remain controversial. We compared 9-month, low-dose sodium fluoride (NaF) treatment with estrogen replacement therapy. Female Wistar rats 4.5 months old were divided into baseline, sham-operated (sham), sham-treated with NaF at 0.5 mg NaF/kg/day in drinking water, and ovariectomy (OVX), OVX treated with NaF and with estrogen. Bone mass was measured by dual X-ray absorptiometry (DXA) in vitro. Dimensions of the first lumbar vertebral body (L1) were determined by radiogrammetry. The right femur was processed undecalcified to obtain a midshaft cross-section to determine cross-sectional moments of inertia (CSMIs). L1 compressive test and left femoral torsional test were performed. OVX induced significant bone loss in L1 and femoral midshaft. Bone mass was increased to a greater extent in NaF-treated rats than in rats receiving estrogen replacement therapy. Femoral CSMIs in OVX rats, both L1 sizes and femoral CSMIs in NaF-treated rats, were significantly increased. Estrogen treatment had the least dimension expansion. OVX significantly decreased L1 compressive variables. There was no statistical difference in compressive parameters between NaF-treated groups and controls. OVX significantly increased femoral torsional strength but NaF treatment did not. Bone fluoride content was significantly increased after treatment with NaF. No significant difference in bone mineralization degree (ash and calcium) was found between treated and control rats. The discrepancy that an increase in bone mass and geometric properties in both trabecular and cortical bones by low-dose, long-term NaF treatment did not increase vertebral strength nor proportionally improve femoral strength indicated that the bone intrinsic biomechanical properties could be changed by NaF treatment.
Kanis JA, Treatment of symptomatic osteoporosis with fluoride, Am J of Medicine, 1993 Nov 30, 95(5A), 53S-61S
Fluoride has been used for > 30 years in the management of osteoporosis. It is one of the few agents that has marked anabolic effects on the skeleton. Indeed, treatment results in continued increments in cancellous bone volume so that cancellous bone volume can be restored to normal in patients with advanced osteoporosis. Despite its long history, both the efficacy and risks of fluoride regimens continue to be the subject of controversy. One of its problems is its age, and much of the early work undertaken utilized methodology and proofs that are today unacceptable. A further problem is that sodium fluoride as a treatment is cheap and not patented (although some formulations are), so that it has been difficult for investigators or industry to make the investments required to provide a modern program of evaluation.
Karagas MR, Baron JA, Barrett JA, Jacobsen SJ, Patterns of fracture among the United States elderly: geographic and fluoride effects, Ann Epidemiol, 1996 May, 6(3), 209-216
The purpose of this study was to examine whether geographic area or water fluoride were related to the occurrence of fractures among the elderly in the United States. We used a 5% sample of the white U.S. Medicare population, aged 65 to 89 years during the period 1986-1990, to identify fractures of the hip, proximal humerus, distal forearm, and ankle. The association of geographic region and fluoridation status with fracture rates was assessed using Poisson regression. We found that rates of hip fracture were generally lower in the northern regions of the United States and higher in the southern regions. For fractures of the distal forearm and proximal humerus, lower rates were found in the Western states, and higher rates in the East. No discernible geographic pattern was found for ankle fractures. Adjustment for water fluoridation did not influence these results. Independent of geographic effects, men in fluoridated areas had modestly higher rates of fractures of the distal forearm and proximal humerus than did men in nonfluoridated areas; no such differences were observed among women, nor for fractures of the hip or ankle among either men or women. In conclusion, our data suggest that fractures of the distal forearm and proximal humerus have etiologic determinants distinct from those of fractures of the hip or ankle [emphasis added].
Kleerekoper M, Non-dental tissue effects of fluoride, Advances in Dental Research, 1994 Jun, 8(1), 32-8
The anti-caries effects of water fluoridation are well-established. The non-dental tissue effects of fluoride in drinking water, either naturally occurring or as an additive, have been too poorly studied to permit definitive conclusions to be drawn. Claims have been made that fluoride results in an increased occurrence of malignancies, particularly osteogenic sarcoma. Experimental rat data have not resolved this issue, and epidemiologic studies are equally unclear. Initial claims that fluoride offers protection against atherosclerosis remain viable, but here too, much more directed research is needed. Early studies suggested that a water fluoride content greater than 1 ppm resulted in a lower prevalence of osteoporotic fractures. Recent epidemiologic data seriously question this conclusion and raise the possibility that even this relatively low level may increase the prevalence of osteoporotic hip fractures. Other elements, including calcium and magnesium, also vary in amount as water fluoride content varies, and it has proved difficult to distinguish the independent effects of the various nutrients in water from each other. Therapeutic use of fluoride has been largely restricted to studies of its effect on the osteoporotic study, this important issue remains unresolved. This review provides an overview of these issues, focusing on the uncertainties alluded to, and attempting to develop strategies for future research. [emphasis added]
Kleerekoper M, Fluoride and the skeleton, Crit Rev Clin Lab Sci 1996 Apr, 33:2, 139-161
Fluoride has the potential to increase skeletal mass to a greater extent than any other pharmacologic agent, yet it has proven difficult to translate this into therapeutic benefit for patients with low bone mass in diseases such as osteoporosis. This apparent paradox can be explained in part by toxic actions of the ion on skeletal mineralization, impairment of the normal processes of bone resorption, and fluoride-induced decreases in strength per unit of bone (mass or volume). In part, the paradox can be explained by the late stage of osteoporosis in most patients enrolled in controlled clinical trials of fluoride, with alterations in skeletal microarchitecture beyond which restoration of mechanical integrity is not likely. Exposure of calcified tissues to environmental fluoride (water supply, dentifrices) also offers paradoxes. The anticaries effects are well documented as are the deleterious skeletal effects of endemic fluorosis when environmental exposure is too high. More controversial is the effect of seemingly nontoxic levels of exposure on the prevalence of osteoporotic fractures of the hip. This review attempts to provide a balanced overview of the conflicting literature concerning therapeutic and environmental effects of fluoride on the skeleton [emphasis added].
[editor's note: it cannot be emphasized enough that fluoride is cumulative and the toxic effects of "seemingly" small doses depend on length of time exposed, dietary factors (inadequate calcium/magnesium intake, etc), state of health (whether diabetic, with kidney disease, etc), and total fluoride intake from all sources]
Krishnamachari KA, Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease, Prog Food Nutr Sci, 1986, 10 (3-4): 279-314.
Endemic skeletal fluorosis is a chronic metabolic bone and joint disease caused by ingesting large amounts of fluoride either through water or rarely from foods of endemic areas. Fluoride is a cumulative toxin which can alter accretion and resorption of bone tissue. It also affects the homeostasis of bone mineral metabolism. The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities. A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostosis formation characterizes the bone lesions. In a proportion of cases secondary hyperparathyroidism is observed with associated characteristic bone changes. Contrary to earlier thinking, severe crippling forms of skeletal fluorosis are seen in paediatric age group too. Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity. 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 paediatric age group and with higher body load of the element. Alterations in hormones concerned with bone mineral metabolism are seen in fluorosis. Kidney is the primary organ of excretion for fluorides. Age, sex, calcium intake in the diet, dose and duration of fluoride intake and renal efficiency in fluoride handling are the factors which influence the outcome. Serum parameters rarely help in the diagnosis. Elevated urinary fluoride and increased bone fluoride content are indicators of fluoride toxicity. Fluorosis is a preventable crippling disease. No effective therapeutic agent is available which can cure fluorosis. Industrial fluorosis is on the increase on a global basis. Bone density measurement is a tool for early diagnosis.
Kurttio P, Gustavsson N, Vartiainen T, Pekkanen J, Exposure to natural fluoride in well water and hip fracture: a cohort analysis in Finland. Am J Epidemiol 1999 Oct 15;150(8):817-24 (National Public Health Institute, Unit of Environmental Epidemiology, Kuopio, Finland).
In the retrospective cohort study based on record linkage, the authors studied a cohort of persons born in 1900-1930 (n = 144,627), who had lived in the same rural location at least from 1967 to 1980. Estimates for fluoride concentrations (median, 0.1 mg/liter; maximum, 2.4 mg/liter) in well water in each member of the cohort were obtained by a weighted median smoothing method based on ground water measurements. Information on hip fractures was obtained from the Hospital Discharge Registry for 1981-1994. No association was observed between hip fractures and estimated fluoride concentration in the well water in either men or women when all age groups were analyzed together. However, the association was modified by age and sex so that among younger women, those aged 50-64 years, higher fluoride levels increased the risk of hip fractures. Among older men and women and younger men, no consistent association was seen. The adjusted rate ratio was 2.09 (95% confidence interval: 1.16, 3.76) for younger women who were the most exposed (>1.5 mg/liter) when compared with those who were the least exposed (< or =0.1 mg/liter). The results suggest that fluoride increases the risk of hip fractures only among women.
Lafage MH, Balena R, Battle MA, Shea M, Seedor JG, Klein H, Hayes WC, Rodan GA, Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. J Clin Invest, 1995 May, 95 (5): 2127-2133.
Fluoride stimulates trabecular bone formation, whereas bisphosphonates reduce bone resorption and turnover. Fracture prevention has not been convincingly demonstrated for either treatment so far. We compared the effects of 1-yr treatment of 9-mo-old minipigs with sodium fluoride (NaF, 2 mg/kg/d p.o.) or alendronate (ALN, 4 amino-1-hydroxybutylidene bisphosphonate monosodium, 1 mg/kg/d p.o.) on the biomechanical and histomorphometric properties of pig bones. As expected, NaF increased and ALN decreased bone turnover, but in these normal animals neither changed mean bone volume. NaF reduced the strength of cancellous bone from the L4 vertebra, relative to control animals, and the stiffness (resistance to deformation) of the femora, relative to the ALN group. In the ALN-treated animals, there was a strong positive correlation between bone strength and L5 cancellous bone volume, but no such correlation was observed in the NaF group. Furthermore, the modulus (resistance to deformation of the tissue) was inversely related to NaF content and there was a relative decrease in bone strength above 0.25 mg NaF/g bone. Moreover, within the range of changes measured in this study, there was an inverse correlation between bone turnover, estimated as the percentage of osteoid surface, and modulus. These findings have relevant implications regarding the use of these agents for osteoporosis therapy.
Lantz O, et al., Fluoride-induced chronic renal failure, Fluoride-induced chronic renal failure, Am J Kidney Dis, 1987 Aug, 10:2, 136-9
Lee JR, Fluoride in drinking water and risk of hip fracture in the UK: a case-control study (A critique of the study appearing in Lancet 22 January 2000; 355:265-269 by Hillier S, Cooper C, Kellingray S, et al).
Lee JR, Slow-Release Sodium Fluoride In The Management Of Postmenopausal Osteoporosis, Fluoride 1994 October, 27:4 227-228 (critical review -- CYC Pak et al, Annals of Internal Medicine 120 625-632 1994).
Lee JR, Fluoridation and Hip Fracture, Fluoride 1993 Oct, 26:4 274-277, review -- National Research Council Report: "Health Effects of Ingested Fluoride"
Lee JR, Fluoridation and Osteoporosis '92, Fluoride,1992, 25:3,162-164 [a response to the "knee-jerk" claims of some fluoridation promoters]
Lehmann R, Wapniarz M, Hofmann B, Pieper B, Haubitz I, Allolio B, Drinking water fluoridation: bone mineral density and hip fracture incidence. Bone 1998 Mar;22(3):273-278, Medizinische Universitatsklinik Wurzburg, Germany.
The role of drinking water fluoride content for prevention of osteoporosis remains controversial. Therefore, we analyzed the influence of drinking water fluoridation on the incidence of osteoporotic hip fractures and bone mineral density (BMD) in two different communities in eastern Germany: in Chemnitz, drinking water was fluoridated (1 mg/L) over a period of 30 years; in Halle, the water was not fluoridated. BMD was measured in healthy hospital employees aged 20-60 years (Halle: 214 women, 98 men; Chemnitz: 201 women, 43 men, respectively) using dual-energy X-ray absorptiometry. Hip fractures in patients > or = 35 years admitted to the local hospitals in the years 1987-1989 were collected from the clinic registers. There was no difference in age, anthropometric, hormonal, or lifestyle variables between the two groups. Mean fluoride exposure in Chemnitz was 25.2 ± 7.3 years. No correlation was found between fluoride exposure and age-adjusted BMD. We found no significant difference in spinal or femoral BMD between subjects living in Halle and Chemnitz [lumbar spine: 0.997 ± 0.129 (g/cm2) vs. 1.045 + 0.171 (g/cm2), p = 0.08, for men; 1.055 ± 0.112 (g/cm2) vs. 1.046 ± 0.117 (g/cm2), p = 0.47, for women]. The fracture incidence showed an exponential increase with aging in men and women with an incidence about 3.5 times higher for women. In Chemnitz, we calculated an age-adjusted annual incidence of 142.2 per 100,000 for women and 72.5 per 100,000 for men, respectively. In Halle, the incidences were 178.5 per 100,000 for women and 89.2 per 100,000 for men. There was a lower hip fracture incidence after the age of 85 in women in Chemnitz (1391 per 100,000 in Chemnitz vs. 1957 per 100,000) in Halle, p = 0.006). Using the age-adjusted incidences, significantly fewer hip fractures occurred in Chemnitz in both men and women. In conclusion, our study suggests that optimal drinking water fluoridation (1 mg/L), which is advocated for prevention of dental caries, does not influence peak bone density but may reduce the incidence of osteoporotic hip fractures in the very old.
[editor's note: two of the most important short-comings in this study is that it found a statistically significant "benefit" only for women over age 85, not for any other age group or men; and, the study covers only TWO years of fracture incidence, 1987-1989. The Germans are usually pretty good at keeping data. The question which comes to mind is: why these two years and why only two? Hip fracture incidence can vary significantly from year-to-year. Moreover, the older women were post-menopausal when fluoridation started in their city. Fluoride uptake into bone is reduced compared to the more important pre-menopausal years when bone remodelling is active. See Lee JR, Fluoridation and Hip Fracture, Fluoride 1993.
Li J, Nakagaki H, Kato K, Ishiguro K, Ohno N, Kameyama Y, Mukai M, Ikeda M, Weatherell J, Robinson C, Distribution profiles of fluoride in three different kinds of rat bones. Bone, 1993 Nov, 14 (6): 835-841
The study was performed to reveal the detailed distribution profiles of fluoride in three different kinds of rat bone--humerus, vertebral arch, and parietal bone--and to compare this with the histological appearance of each bone type. Two groups of Wistar rats were provided water ad libitum containing 0 and 100 ppm fluoride, respectively, for 24 weeks. The fluoride distribution profiles across the bone of the three different bones from the outer to the inner surface were determined by means of an abrasive micro-sampling technique. In control animals, both humerus and parietal bones showed higher concentrations at the periosteal and endosteal surfaces, while the vertebral arch showed additional high levels in the middle (containing trabecular bone) of the tissue. In exposed animals, fluoride levels increased greatly in all three bone types. The vertebral and parietal fluoride distribution profiles were relatively unchanged, although humerus fluoride increased from periosteum to endosteum. The differences in fluoride distribution profiles were apparently related to the histological appearances of these bones. The surface area of bone available and the extent of vascularity appear to affect fluoride uptake.
Lundy MW, Stauffer M, Wergedal JE, Baylink DJ, Featherstone JD, Hodgson SF, Riggs BL, Histomorphometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporos Int, 1995 March, 5 (2): 115-129
In a 4-year controlled, prospective trial, histomorphometric analysis was used to compare the tissue-level skeletal effects of fluoride therapy in 43 postmenopausal women (75 mg NaF/day) with those of 35 matching placebo subjects; all subjects received 1500 mg/day elemental calcium supplement. In addition to an initial, baseline biopsy, a second biopsy was obtained after 6, 18, 30 or 48 months. Measurements were made on a third biopsy obtained from 8 subjects following at least 72 months of fluoride therapy. The change in cancellous bone volume or trabecular thickness in fluoride-treated subjects was not different from a change in placebo-treated subjects. However, paired analysis in the fluoride-treated subjects indicated that bone volume was increased between the first and second biopsies (p < 0.005). Both osteoid length and width were significantly increased in fluoride compared with placebo subjects; however, only the osteoid surface increased linearly (r = 0.63, p < 0.001). The mineral apposition rate and relative tetracycline-covered bone surface were not different between fluoride and placebo treatment, although they were decreased in both groups in the second biopsy. The tetracycline-covered bone surface returned to normal in the third biopsy. Definitive evidence for osteomalacia is a prolonged mineralization lag time, which following fluoride treatment was found to be increased 9-fold in the second biopsy and 4-fold in the third biopsy. Further evidence for osteomalacia was increased osteoid thickness by 6 months, evidence of focal areas of interstitial mineralization defects, and broad tetracycline labels of low fluorescence intensity. In the third biopsies, osteoclastic resorption was observed beneath osteoid seams. Fluoride therapy increased the cortical width compared with placebo treatment (p < 0.02), and increased the osteoid surface in Haversian canals, but did not change the osteoid width, resorption surface or cortical porosity. After an initial rise, serum fluoride levels remained constant, and the urine values fell slightly. The bone fluoride concentration rose throughout the treatment period, and was correlated with the change in osteoid-covered bone surface (r = 0.56, p < 0.001). Although we found definitive evidence for osteomalacia, the cause of the osteomalacia was not determined in this study. On the other hand, the presence of bone resorption beneath unmineralized osteoid and of osteocyte halos is suggestive of hyperparathyroidism. Thus, it is possible that the strong stimulus for bone formation brought about by fluoride therapy resulted in relative calcium deficiency.
Maylin GA, Eckerlin RH, Krook L, Fluoride intoxication in dairy calves, Cornell Vet, 1987 Jan, 77:1, 84-98
Chronic fluoride intoxication in dairy cattle, caused by feeding fluoride contaminated commercial feed, was previously described in a dairy herd. Dental fluorosis and a catastrophic decrease in milk yield were the foremost findings. In calves born to the fluoride intoxicated cows, congenital fluorosis was manifested by brown discoloration of enamel, enamel hypoplasia, brown mottling of bone, severe retardation of cartilage cell differentiation, atrophy of osteoblasts, osteopenia, atrophy of bone marrow cells, serious atrophy of bone marrow fat and severely stunted growth.
Patel S, Chan JK, Hosking DJ, Fluoride pharmacokinetics and changes in lumbar spine and hip bone mineral density, Bone, 1996 Dec, 19(6), 651-655
Debate about the use of fluoride for the treatment of vertebral osteoporosis has centered not only on whether fluoride treatment decreases vertebral fractures, but also the interindividual vertebral bone mineral density (BMD) response, the potential for nonvertebral fractures, as well as side effects and tolerability. These effects may be dose dependent and, in this study, we examine the pharmacokinetics of sodium monofluorophosphate (MFP) in osteoporotic patients and relate this to changes in BMD. Plasma fluoride absorption curves were measured from 0 to 6 h after ingestion of MFP at baseline and during long-term dosing in 21 patients with vertebral osteoporosis (T scores ≤ 2). BMD was measured at baseline and at 12 months at the lumbar spine (LS), femoral neck (FN), trochanter, and Ward's triangle. We found that fluoride elimination was inversely related to creatinine clearance. LS BMD increased from a median of 0.77 g/cm2 (range 0.69 to 0.99) at baseline to 0.88 g/cm2 (0.75 to 1.13) (p < 0.001) after 12 months. This equates to a median increase of 12% (range -1.2 to 37). Median femoral neck BMD decreased from 0.75 g/cm2 (0.62 to 0.94) at baseline to 0.69 g/cm2 (0.62 to 0.92) (p = 0.13) after 12 months. This equates to a decrease of -2% (-19 to 10). BMD at the other hip sites also decreased slightly. Changes in LS and FN BMD were not significantly related (r = 0.28, p = 0.29). The various pharmacokinetic parameters measured were not related to changes in LS BMD; however, there was an inverse relationship between trough fluoride concentration during long-term dosing and change in FN BMD. Further studies are required to see if this relationship can be used to monitor osteoporotic patients treated with fluoride and prevent significant decreases in FN BMD and possibly fractures at this site.
Phipps KR, Burt BA, Water-borne fluoride and cortical bone mass: a comparison of two communities. J Dental Research, 1990 June, 69 (6):1256-1260 School of Public Health, University of Michigan, Ann Arbor 48109-2029.
This study investigated the relationship between cortical bone mass in an older female population and their ingestion of fluoride from community water supplies. The study was conducted among lifelong female residents in Lordsburg (3.5 ppm fluoride) and Deming (0.7 ppm fluoride), NM. A total of 151 postmenopausal women ranging in age from 39 to 87 years took part; 69 were residents of the optimal-fluoride community, while the remaining 82 were residents of the high-fluoride community. Although bivariate analyses showed no difference in cortical bone mass between women in the two communities, with multiple regression analyses, significant predictors of bone mass (p less than 0.05) were weight, years since menopause, current estrogen supplementation, diabetes, and fluoride exposure status. Based on a model containing all of these variables, women living in the high-fluoride community had a bone mass ranging from 0.004 to 0.039 g/cm2 less than that of similar women living in the optimum-fluoride community. These results suggest that lifelong ingestion of water containing 3.5 ppm fluoride, compared with water containing 0.7 ppm fluoride, does not increase cortical bone mass in women of similar age, weight, and menopausal status. Under the conditions of this study, cortical bone mass might be reduced in a high-fluoride area.
Razumov VV, Klitsenko OA, Rykov VA, Danilov IP, Morphogenesis of occupational fluoride osteopathy, Med Tr Prom Ekol, 1997, 4, 18-23. [Article in Russian].
Fluor osteopathy, as the authors suppose, is a morphologic repetition of phylogenesis early stages in osteogenesis. Thus, osteosclerosis and osteoporosis demonstrated by X-ray should be considered as manifestation of bone fluorosis. Fluor-induced changes of bone tissue could not be adequately termed as "osteoporosis" and "osteosclerosis", so is defined as "fluor osteopathy".
Richards A, Fejerskov O, Ekstrand J, Fluoride pharmacokinetics in the domestic pig, J Dent Res 1982 Sep, 61(9), 1099-1102
Plasma fluoride concentrations were studied in 11 pigs following single oral or intravenous doses of fluoride. The results showed a less-than-20% bioavailability of fluoride when administered with calcium-rich food. Pharmacokinetic analyses showed that the plasma half-life varied from 0.6 to 1.4 h, depending on diet and route of fluoride administration. These data are comparable to those reported for man, and thus illustrate the suitability of the pig for studies of effects of fluoride on hard tissues.
[editor's note: as discussed elsewhere, those people on inadequate diets, will incorporate more fluoride into their bones and teeth increasing the risk of developing dental and skeletal fluorosis. The subsection of the population most at risk are the lower socio-economic groups]
Riggs BL, et al., Effect of Fluoride Treatment on the Fracture Rate in Postmenopausal Women with Osteoporosis, New England J. of Medicine, 1990 March, 322:12, 802-9
Although fluoride increases bone mass, the newly formed bone may have reduced strength. To assess the effect of fluoride treatment on the fracture rate in osteoporosis, we conducted a four-year prospective clinical trial in 202 postmenopausal women with osteoporosis and vertebral fractures who were randomly assigned to receive sodium fluoride (75 mg per day) or placebo. All received a calcium supplement (1500 mg per day). Sixty six women in the fluoride group and 69 women in the placebo group completed the trial. As compared with the placebo group, the treatment group had increases in median bone mineral density of 35 percent (P<0.0001) in the lumbar spine (predominantly cancellous bone), 12 percent (P<0.0001) in the femoral neck, and 10 percent (P<0.0001) in the femoral trochanter (sites of mixed cortical and cancellous bone), but the bone mineral density decreased by 4 percent (P<0.02) in the shaft of the radius (predominantly cortical bone). The number of new vertebral fractures was similar in the treatment and placebo groups (163 and 136, respectively; P not significant), but the number of nonvertebral fractures was higher in the treatment group (72 vs. 24; P<0.01). Fifty-four women in the fluoride group and 24 in the placebo group had side effects sufficiently severe. to warrant dose reduction; the major side effects were gastrointestinal symptoms and lower-extremity pain.We conclude that fluoride therapy increases cancellous but decreases cortical bone mineral density and increases skeletal fragility. Thus, under the conditions of this study, the fluoride-calcium regimen was not effective treatment for postmenopausal osteoporosis. [emphasis added]
Riggs BL, O'Fallon WM, Lane A, Hodgson SF, Wahner HW, Muhs J, Chao E, Melton LJ 3rd, Clinical trial of fluoride therapy in postmenopausal osteoporotic women: extended observations and additional analysis, J Bone Miner Res, 1994 Feb, 9:2, 265-275
[excerpt from the paper] Because NaF treatment results in losses of cortical bone, the effect on fracture occurrence may be more adverse at sites that contain substantial amounts of cortical bone, such as the hip, than at sites than contain large amounts of cancellous bone, such as the vertebral bodies. Because of the severity of the consequences of hip fracture, a treatment that decreases the incidence of vertebral fractures would be deemed to be worthwhile only if it does not concomitantly increase the risk of hip fracture. In this regard, it is of concern that in our study there was a threefold, but nonsignificant, increase in the incidence of hip fracture in the NaF group and that another randomized controlled trial using only 50 mg NaF per day there was a twofold, statistically significant increase in hip fracture occurrence. [emphasis added]
Riggs BL, Melton LJ 3rd, O'Fallon WM, Drug therapy for vertebral fractures in osteoporosis: evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy, Bone, 1996 Mar, 18(3 Suppl), 197S-201S
The conventional belief is that osteopenia is the major cause of vertebral fractures and that drug therapy must induce a substantial increase in vertebral bone mineral density (BMD) before the vertebral fracture rate (VFR) is decreased. We hypothesized that the increased bone turnover in osteoporosis also is a major cause of vertebral fractures because of its adverse effects on the microarchitecture of the vertebrae and, thus, that normalization of bone turnover by antiresorptive drug therapy will decrease VFR substantially. This hypothesis is supported by our reanalysis of data from previous clinical trials with fluoride and with estrogen therapy in postmenopausal osteoporotic women. As evident from computer-generated three-dimensional graphic plots of data from osteoporotic women treated with placebo, VFR increased as bone turnover increased or as vertebral BMD decreased. Estrogen therapy decreased the bone turnover rate to normal and eliminated the relationship between VFR and bone turnover, whereas the inverse relationship with vertebral BMD persisted. In osteoporotic women treated with fluoride, VFR decreased as vertebral BMD increased, provided that patients with high (toxic) serum fluoride levels were not included in the comparison. Over the range of values in the data set, increased vertebral BMD and decreased bone turnover had approximately equal effects in decreasing VFR. Thus, both formation-stimulating and resorption-inhibiting drugs can substantially decrease VFR but do so by different mechanisms.
Shi J, Dai G, Zhang Z, Relationship between bone fluoride content, pathological change in bone of aborted fetuses and maternal fluoride level, Chung Hua Yu Fang I Hsueh Tsa Chih, 1995 Mar;29(2):103-105 (Article in Chinese)
Relationship between bone fluoride content, pathological change in bone of aborted fetuses and maternal fluoride level was studied in 46 pregnant women and their inducedly-aborted fetuses. Results showed fluoride content in fetal femur averaged 368.2 micrograms/g, and 41.4% of the bone with pathological change. Fluoride levels in maternal urine and amniotic fluid and fluoride content in fetal femur and pathological change in fetal femur appeared a positive correlation between them. Femur fluoride content and pathological change of bone in fetuses born to mothers with mottling teeth were significantly greater than to those without them. Pathological change in fetal femur presented dose-response relationship with their bone fluoride content. When the latter reached greater than 500 micrograms/g, pathological changes occurred in 90% of the bone.
Søgaard CH, et al., Marked Decrease in Trabecular Bone Quality After Five Years of Sodium Fluoride Therapy -- Assessed by Biomechanical Testing of Iliac Crest Bonce Biopsies in Osteoporotic Patients, Bone, 1994, 15:4, 393-399
In order to evaluate the effect of sodium fluoride (NaF) on bone biomechanical competence, iliac crest biopsies were taken before and after one year of treatment in 12 osteoporotic patients, and before and after five years of treatment in 14 patients. Bone fluoride content had increased significantly after both one and five years of treatment, indicating that the administered fluoride had been ingested. After one year of treatment, no difference was observed in iliac crest trabecular bone ash content. A general trend for decreased bone strength and bone quality was observed, but this was insignificant. After five years of fluoride treatment, an insignificant decrease in iliac crest trabecular bone ash content was observed. A significant reduction of 45% was found in trabecular bone strength (p < 0.05), and an even more pronounced reduction of 58% was found in trabecular bone quality (p < 0.01). The results of this study indicate that long-term administration of sodium fluoride may be detrimental to bone quality, at least as measured in non-loaded iliac crest trabecular bone.
Søgaard CH, Mosekilde L, Schwartz W, Leidig G, Minne HW, Ziegler R, Effects of fluoride on rat vertebral body biomechanical competence and bone mass, Bone, 1995 January, 16:1, 163-169.
For more than 30 years, sodium fluoride has been a commonly used therapeutic agent for established osteoporosis because of its repeatedly documented anabolic effect on trabecular bone mass. Recent clinical and experimental studies have, however, indicated a possible detrimental effect of fluoride on bone strength. Thus, the efficacy of fluoride therapy remains a controversial issue. The aim of this study was to investigate the effect of fluoride on both vertebral bone mass and quality in rats. Twenty-nine 3-month-old, female rats were randomized into three groups. One group served as a control group, and the other two groups received fluoridated water at different doses (100 ppm and 150 ppm). The rats were followed for 90 days. Three lumbar vertebrae were obtained from each rat, and changes in bone fluoride content, bone mass and biomechanical competence were assessed. The results revealed a significant increase in bone fluoride content, ash density and trabecular bone volume after fluoride treatment. Directly obtained load values and load corrected for cross-sectional area were constant. 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.
Sowers MR, Clark MK, Jannausch ML,Wallace RB, A Prospective Study of Bone Mineral Content and Fracture in Communities with Differential Fluoride Exposure, Am J. of Epidemiology, 1991, 133:7, 649-660
In 1983/1984, a study of bone mass and fractures was begun in 827 women aged 20-80 years in three rural Iowa communities selected for the fluoride and calcium content of their community water supplies. The control community's water had a calcium content of 67 mg/liter and a fluoride content of 1 mg/liter. The higher-calcium community had water with a calcium content of 375 mg/liter and a fluoride content of 1 mg/llter. The higher-fluoride community's water had 15 mg/liter of calcium and 4 mgl liter of fluoride naturally occurring. In 1988/1989, a follow-up study characterized the 684 women still living and available for study. Residence in the higher-fluoride community was associated with a significantly lower radial bone mass in premenopausal and postmenopausal women, an increased rate of radial bone mass loss in premenopausal women, and significantly more fractures among postmenopausal women. There was no difference In the 5-year relative risk of any fracture in the higher-calcium community versus the control community; however, the relative risk was 2.1 (95% confidence interval (CI) 1.0-4.4) in women in the higher-fluoride community compared with women in the control community. There was no difference In the 5-year risk of wrist, spine, or hip fracture In the higher-calcium community versus the control community; however, the 5-year relative risk for women in the higher-fluoride community, compared with women in the control community, was 2.2 (95% CI 1.1-4.7). Estimates of risk were adjusted for age and body size. [emphasis added]Sowers MR, Wallace RB, Lemke JH, The relationship of bone mass and fracture history to fluoride and calcium intake: a study of three communities. Am J Clinical Nutrition, 1986 Dec, 44 (6): 889-898.
Stimulated by the suggestion that water fluoride greater than 1 mg/L may protect against osteoporosis, we studied bone mass of women in three rural communities with differing mineral content of the water supply. Mean fluoride and calcium of community drinking waters were 4 mg/L and 16 mg/L, respectively, high fluoride community; 1 mg/L and 375 mg/L, respectively, high calcium community; and 1 mg/L and 65 mg/L, respectively, low calcium community. Bone mass was measured by single photon absorptiometry, and women were interviewed about fracture history, dietary intake, and other important covariates. We observed no protective effect with higher fluoride intake. Bone mass was lower in older women from the high fluoride community though not statistically so; these women reported significantly more fractures. There was no observed community difference in young women's bone mass or fracture history. Young women in the high fluoride community consuming calcium and vitamin D in excess of 800 mg/day and 400 IU/day, respectively, had significantly better bone mass (p less than 0.05) than their peers. [emphasis added]
Suarez-Almazor ME, Flowerdew G, Saunders DL, Soskolne CL, Russell A, The Fluoridation of Drinking Water and Hip Fracture Hospitalization Rates in Two Canadian Communities, Am J. Public Health, 1993 May, 83, 689-693
OBJECTIVES. The purpose of this study was to compare hip fracture hospitalization rates between a fluoridated and a non-fluoridated community in Alberta, Canada: Edmonton, which has had fluoridated drinking water since 1967, and Calgary, which considered fluoridation in 1991 but is currently revising this decision. METHODS. Case subjects were all individuals aged 45 years or older residing in Edmonton or Calgary who were admitted to hospitals in Alberta between January 1, 1981, and December 31, 1987, and who had a discharge diagnosis of hip fracture. Edmonton rates were compared with Calgary rates, with adjustment for age and sex using the Edmonton population as a standard. RESULTS. The hip fracture hospitalization rate for Edmonton from 1981 through 1987 was 2.77 per 1000 person-years. The age-sex standardized rate for Calgary was 2.78 per 1000 person-years. No statistically significant difference was observed in the overall rate, and only minor differences were observed within age and sex subgroups, with the Edmonton rates being higher in males. CONCLUSIONS. These findings suggest that fluoridation of drinking water has no impact, neither beneficial nor deleterious, on the risk of hip fracture [emphasis added]
[editor's note: ALL men (aged 45+ and the subgroup of men aged 65+) in fluoridated Edmonton had a statistically significant higher rate of hip fracture admissions than did unfluoridated Calgary men. Possible confounding estrogen use which might reduce hip fractures in women was not addressed. There are several points which need to be emphasized as this study does not mean that fluoridation has "no impact" on fracture rates.
One would expect to see more fracture rates in women than in men. Should the finding of increased fractures in men be a "red-flag"? Moreover, fluoride is a cumulative element and Edmonton was fluoridated for less than 20 years when records of fracture hospitilization rates were checked. What will the increased risk be 20 years from now? Do we dare wait and see? Some other points:
Are we ignoring the red-flags?]
Turner CH, Garetto LP, Dunipace AJ, Zhang W, Wilson ME, Grynpas MD, Chachra D, McClintock R, Peacock M, Stookey GK, Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbits, Calcif Tissue Int, 1997 July, 61:1, 77-83.
We hypothesized that fluoride partly acts by changing the levels of circulating calcium-regulating hormones and skeletal growth factors. The effects of oral fluoride on 24 female, Dutch-Belted, young adult rabbits were studied. The rabbits were divided into two study groups, one control and the other receiving about 16 mg fluoride/rabbit/day in their drinking water. After 6 months of fluoride dosing, all rabbits were euthanized and bone and blood samples were taken for analyses. Fluoride treatment increased serum and bone fluoride levels by over an order of magnitude (P < 0.001), but did not affect body weight or the following serum biochemical variables: urea, creatinine, phosphorus, total protein, albumin, bilirubin, SGOT, or total alkaline phosphatase. No skeletal fluorosis or osteomalacia was observed histologically, nor did fluoride affect serum PTH or Vitamin D metabolites (P > 0.4). BAP was increased 37% (P < 0.05) by fluoride; serum TRAP was increased 42% (P < 0.05); serum IGF-1 was increased 40% (P < 0.05). Fluoride increased the vertebral BV/TV by 35% (P < 0.05) and tibial ash weight by 10% (P < 0.05). However, the increases in bone mass and bone formation were not reflected in improved bone strength. Fluoride decreased bone strength by about 19% in the L5 vertebra (P < 0.01) and 25% in the femoral neck (P < 0. 05). X-ray diffraction showed altered mineral crystal thickness in fluoride-treated bones (P < 0.001), and there was a negative association between crystal width and fracture stress of the femur (P < 0.02). In conclusion, fluoride's effects on bone mass and bone turnover were not mediated by PTH. IGF-1 was increased by fluoride and was associated with increased bone turnover, but was not correlated with bone formation markers. High-dose fluoride treatment did not improve, but decreased, bone strength in rabbits, even in the absence of impaired mineralization.
Turner CH, Takano Y, Hirano T, Reductions in bone strength after fluoride treatment are not reflected in tissue-level acoustic measurements, Bone, December, 1996, 19:6, 603-607.
Acoustic velocity measurements are used to estimate tissue-level bone strength after fluoride therapy for osteoporosis. However, acoustic measurements provide information about elasticity, not strength, and bone elasticity does not necessarily correlate with bone strength at a tissue level. The current study was undertaken to evaluate the effects of fluoride treatment on tissue-level acoustic velocities, and to determine the relationship between acoustic velocity and bone strength measured in the femur, femoral neck, and spine. Young adult rabbits were treated with either 0 or 100 parts per million of fluoride in their drinking water for six months. After treatment, the bones were harvested for measurement of tissue fluoride, bone strength, and acoustic properties. Acoustic velocities were measured in the femoral midshaft using an acoustic microscope with a 50 MHz transducer. Both longitudinal and transverse velocities were measured. After the initial acoustic measurements the bone specimens were treated to remove either the organic matrix or mineral, and the acoustic measurements were repeated. Fluoride treatment increased bone fluoride levels 7-8 fold and reduced all biomechanical parameters. Most notably the fracture force of the femoral neck was reduced by 25% (p < 0.005), and the fracture stress of the L-5 vertebra was reduced by 19% (p < 0.05). Fluoride treatment had no significant effect on any of the measured acoustic velocities. The elastic anisotropy of the bone was decreased by demineralization (p < 0.0001) and increased by removal of the organic matrix (p < 0.0001), but unaffected by fluoride treatment. Acoustic measurements were not correlated with bone strength in the femoral neck or femoral midshaft. There was a positive correlation between the longitudinal velocity measured in the femur and the vertebral fracture stress, but this was the only positive association between acoustic velocities and strength measurements. These data cast doubt on the utility of high frequency (>2 MHz) acoustic measurements for evaluating the efficacy of fluoride therapy, especially in the hip.
Turner CH, Owan I, Brizendine EJ, Zhang W, Wilson ME, Dunipace AJ, High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency, Bone, 1996 December, 19 (6): 595-601.
Renal insufficiency is known to increase plasma fluoride levels, which may increase the risk of fluorosis and osteomalacia. The purpose of this study was to determine the effects of fluoride on skeletal fragility and mineralization in renal-deficient animals. We evaluated the skeleton of rats with surgically induced renal deficiency (4/5 nephrectomy) that were chronically exposed to fluoridated water at concentrations of 0, 5, 15, and 50 ppm for a period of 6 months. The chosen fluoride doses caused plasma fluoride levels equivalent to those in humans consuming fluoridated water levels of 0, 1, 3, and 10 ppm, respectively. Animals with renal deficiency drank about 60% more water and excreted 85% more urine than control animals. Glomerular filtration rate (GFR) was decreased 68% and plasma BUN was increased fourfold in rats with renal deficiency. Plasma fluoride was strongly correlated with 1/GFR and was greatly increased by renal deficiency in all animals consuming fluoridated water. There was a strong positive, nonlinear relationship between plasma fluoride and bone fluoride levels, suggesting nonlinear binding characteristics of fluoride to bone. The amount of unmineralized osteoid in the vertebral bone was related to the plasma fluoride levels. Vertebral osteoid volume was increased over 20-fold in animals with renal deficiency that received 15 or 50 ppm fluoride, suggesting osteomalacia. Should osteomalacia be defined as a tenfold increase in osteoid volume, there appeared to be a threshold plasma fluoride level of about 20 micromol/L, above which osteomalacia was observed consistently. This plasma fluoride level was not achieved in control rats regardless of fluoride intake, nor was it achieved in renal-deficient rats receiving 0 or 5 ppm fluoride. A fluoride concentration of 50 ppm reduced femoral bone strength by 11% in control rats and by 31% in renal-deficient rats. Vertebral strength also was decreased significantly in renal-deficient rats given 50 ppm fluoride. In conclusion, fluoridated water in concentrations equivalent to 3 and 10 ppm in humans, caused osteomalacia and reduced bone strength in rats with surgically-induced renal deficiency.
Turner CH, Hasegawa K, Zhang W, Wilson M, Li Y, Dunipace AJ, Fluoride reduces bone strength in older rats, J Dent Research, 74 (8): 1995 August, 1475-1481.
In response to recent concerns about the effect of water fluoridation on hip fracture rates, we studied the influence of fluoride intake on bone strength. Four groups of rats were fed a low-fluoride diet ad libitum and received 0, 5, 15, or 50 ppm of fluoride in their drinking water. Animals were euthanized after 3, 6, 12, or 18 months of treatment. Mechanical strength of the right femur was measured by three-point bending. Fluoride content for the left femur was measured, and static histomorphometric measurements were made on a lumbar vertebra. Femoral failure load was not significantly decreased in rats treated for 3 and 6 months, but was decreased as much as 23% in rats treated 12 and 18 months at 50 ppm fluoride. Extrapolation from regression equations predicted that older rats lose 36% of femoral bone strength when bone fluoride content is increased from 0 to 10,000 ppm, while younger rats will lose only 15%. Thus, the decreased strength appeared to be due to the combined effects of fluoride intake and age on bone tissue and was not associated with a decrease in bone density or mineralization defects. There were only small effects of fluoride on bone histomorphometry. Fluoride intake at high levels had no negative effects on bone mineralization. Fluoride intake was associated with slight increases in trabecular bone volume and trabecular thickness, but these effects could not be demonstrated consistently. The mechanism by which large amounts of fluoride affect bone strength more severely in older animals is unknown.
Turner CH, Boivin G, Meunier PJ, A mathematical model for fluoride uptake by the skeleton, Calcif Tissue Int, 1993 February, 52 (2): 130-138.
A mathematical model was developed that predicts fluoride accumulation and clearance from the skeleton based upon fluoride bioavailability, bone remodeling rate, and the fluoride binding characteristics of bone. It was assumed that fluoride binds to bone in a nonlinear fashion such that a smaller percentage of fluoride is bound to bone if fluoride intake is increased to high levels. Bone resorption rate was assumed to be proportional to the solubility of hydroxyfluoroapatite which is inversely related to bone fluoride content. The predictions made by the model compared favorably with experimental results from fluoride uptake and clearance studies. Parametric studies done using the model showed the following: (1) fluoride can be cleared from the skeleton by bone remodeling, but fluoride clearance takes over four times longer than does fluoride uptake; and (2) fluoride uptake by the skeleton was positively associated with bone remodeling rate. However, the concentration of fluoride in newly formed bone does not decrease with reduced remodeling rates and surpasses 10,000 ppm for intakes of fluoride greater than 9 mg/day. For osteoporosis, daily dose and duration of fluoride treatment should be selected to avoid reaching a toxic cumulative bone fluoride content.
Turner CH, Akhter MP, Heaney RP, The effects of fluoridated water on bone strength, J Orthop Research, 1992 July 10 (4): 581-587.
Fluoride from fluoridated water accumulates not only in the enamel of teeth but also in the skeleton. The effects of fluoridated water on the skeleton are not well understood, yet there is some evidence that fluoridated water consumption increases the incidence of fractures. In the present study, femoral bending strength was measured in rats on fluoride intakes that ranged from low levels to levels well above natural high fluoride drinking water. Bone strength followed a biphasic relationship with bone fluoride content. Fluoride had a positive effect on bone strength for lower fluoride intakes and a negative influence on bone strength for higher fluoride intakes. The vertebral fluoride content at which femoral strength was maximum was between 1,100 and 1,500 ppm. The increase in femoral strength at this fluoride level was not accompanied by an increase in femoral bone density. The optimal fluoride content is within the range of bone fluoride contents found in persons living in regions with fluoridated water (1 ppm) for greater than 10 years.
Turner RT, Francis R, Brown D, Garand J, Hannon KS, Bell NH, The effects of fluoride on bone and implant histomorphometry in growing rats, J Bone Miner Res, 4 (4): 477-484 (Aug 1989).
The effects of fluoride at concentrations of 2.0 and 4.5 mM in drinking water on growth rate, vitamin D, water and mineral metabolism, bone histomorphometry, and osteoinduction of demineralized allogenic bone matrix (DABM) were compared in the rat. Whereas fluoride did not influence fluid intake or growth rate at the lower concentration, it increased fluid intake and inhibited growth rate at the higher concentration. Fluoride produced dose-related increases in serum fluoride and alkaline phosphatase but did not alter serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D. Serum calcium and phosphate were reduced by fluoride at concentrations of 2.0 mM but not 4.5 mM. Cancellous bone fractional area was increased by fluoride at 2.0 mM and was reduced by fluoride at 4.5 mM. Fluoride had no effect on cancellous bone surface length or the percentage surface lined by osteoblasts and osteoclasts. Fluoride increased medullary area and decreased the endosteal bone formation rate. Fluoride increased periosteal bone formation and apposition rates at concentrations of 2.0 mM but not 4.5 mM. Fluoride inhibited mineralization in DABM implants, and at the higher concentration, fluoride increased the formation of new bone matrix. These results indicate that in the rat, fluoride increases cortical and trabecular bone at therapeutic doses and reduces trabecular bone at toxic doses. The serum concentration of fluoride at therapeutic doses in the rat is similar to that in patients with osteoporosis who are on treatment with fluoride. In the rat, there is a narrow range between toxic and therapeutic doses.
Waldbott GL, The Preskeletal Phase of Chronic Fluoride Intoxication, Fluoride, 1998, 31:1, 13-20
Wei XY, Study on determinationing the bone mineral content as diagnostic value for occupational fluorosis, Chung Hua Yu Fang I Hsueh Tsa Chih 1993 Mar;27(2):88-90 (Article in Chinese)
The results of determination of the bone density of 194 workers exposed to fluorine by SPA-III type osteodensimeter were compared with people unexposed to fluorine, and with the results of diagnosing the fluorosis by X-ray.
Xiao B, Dong Q, Li S, Li D, Zhan C, Aluminum and fluorine in blood and bone of rats fed on diet mixed with various contents of aluminum, fluoride or their mixture, Hua Hsi I Ko Ta Hsueh Hsueh Pao, 1992 Jun, 23:2, 185-189
Wistar rats were divided into 8 groups: control, 300 ppm F, 130 ppm F, 300 ppm Al, 1200 ppm Al, 130 ppm Al + 130 ppm F. 300 ppm Al + 300 ppm F and 1200 ppm Al + 300 ppm F. The chemicals were mixed into the standard diet. The animals were fed on the diets for 12 weeks. Contents of F, Al, Ca and P in the blood (or serum) and humerus were determined at the end of 12 weeks. The results showed that the level of F in the blood and bone in the unadulterated F group was increased, especially F in the bone reached a level more than 10 times that of the control. In the 3 mixture groups, blood F and bone F were lowered, while blood F was restored to normal level, but bone F was not nevertheless, the results showed that Al was in antagonism to the absorption of F. In the unadulterated Al groups, blood and bone Al did not parallel with the amount of Al administered. The level of Al in the median Al group was higher than that of the high Al group. Taking the level of blood and bone Al as a measure, when different doses of Al were administered with F, in the low and median dosage of Al, F was in antagonism to Al absorption, but in case of high dosage of Al, F was in potentiation to Al absorption. In all the experimental groups serum P was elevated, but serum Ca was not disturbed. Bone Ca and P were decreased only in the 3 groups with unadulterated F as well as unadulterated and adulterated high dosage of Al. Mechanism of the nonlinearity of Al absorption vs Al dosage, as well as the dual effect of F on the absorption of Al was proposed.
[editor's note: for related articles, see Czerwinski E, et al. and Caverzasio J, et al. For info on fluoride-aluminum interactions see brain.htm]
Zhang Y, Li H, Yang C, Zheng Z, Chen X, Histopathologic and bone histomorphometric studies of pigs' phalanges in an endemic fluorosis area, Hua Hsi I Ko Ta Hsueh Hsueh Pao, 1994 Mar, 25(1):74-77 (Article in Chinese)
This paper presents the histopathologic changes and bone histomorphometry of ten pigs' phalanges in an endemic fluorosis area. Ten pigs from nonendemic area served as control. Results showed that the fluoride contents of blood, urine and bone were markedly increased and the calcium contents of blood were markedly decreased in endemic pigs than those in nonendemic ones. Histopathologic and bone morphometric studies of the phalangeal bones of pigs from endemic area indicate that osteoporosis is the predominant change.