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5 Musculoskeletal Effects
Pages 131-180

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From page 131...
... , on the developing growth plate, and on articular cartilage as it may relate to arthritic changes. New data on the effects of fluoride on skeletal architecture, bone quality, and bone fracture are also considered.
From page 132...
... Acidification of the mineral matrix by the osteoclast is sufficient to solubilize the fluoroapatite and allow free exchange with extracellular fluids. Once released, the effect of fluoride on bone cells may be evident; however, the form in which fluoride has its effect remains under debate.
From page 133...
... It has been known for many years that fluoride exposure can change bone quality. Franke et al.
From page 134...
... This has raised concerns that fluoride exposure might be an independent risk factor for new osteosarcomas (see Chapter 10 for the committee's assessment)
From page 135...
... Two hypotheses in the literature describe the effect of fluoride. Both state that the concentration of tyrosine phosphorylated signal pathway intermediates is elevated after fluoride exposure.
From page 136...
... have mean fluoride content in bone ash (from iliac crest samples) ranging from 0.06% to 0.10% (600 to 1,000 mg/kg)
From page 137...
... Some well-controlled animal studies document a decrease in osteoclast (as well as odontoclast) activity.
From page 138...
... Because these data were derived from intact in vivo animal models, the investigators could not conclude that the effects of fluoride on osteoclastic bone resorption were direct. It is interesting that only a single report has appeared that links fluoride exposure to the receptor activator of NF kappaB (RANK)
From page 139...
... exceeds that for people drinking water with fluoride at 4 mg/L (4 to 8 mg/ day for 1 to 2 L/day) , the latter may be exposed much longer, leading to comparable or higher cumulative doses and bone fluoride concentrations (see discussion later in this chapter.)
From page 140...
... . Assuming that the blood fluoride concentrations decline between each episode of water consumption of 8 oz or less, such exposures may not achieve a concentration of fluoride in the extracellular fluids sufficient to affect bone cells.
From page 141...
... An examination of the curves in Figure 5-1 indicates that the fluoride concentration around a site of bone resorption can be quite high immediately adjacent to the osteoclast. The theoretical maximum concentration at 20 µm from the site (at the surface of the osteoclast)
From page 142...
... The predominant effect in the older animals clustered around bone fluoride concentrations of 6,000 to 8,000 mg/kg (Turner et al.
From page 143...
... Epidemiology Data The committee reviewed epidemiologic data on the relationship between fluoride exposure and fractures from two sources: observational studies of exposure to fluoride in water and randomized clinical trials of the use of fluoride in treating osteoporosis. Table 5-1 summarizes studies of bone fracture in populations exposed to fluoride in drinking water.
From page 144...
... hip fracture in counties Nonfluoridated throughout the USA (n = (concentrations not specified)
From page 145...
... No significant et al. 1995 association was found between fluoride exposure and wrist, spinal, nonspinal, osteoporotic, or hip fractures.
From page 146...
... <15% of the population receives fluoridated water Ecologic Canada Patients (ages 45 to 64, 0.3 mg/L 65+) with hip fracture in 1 mg/L two cities Case-control United Patients with hip fractures <0.9 mg/L (artificial)
From page 147...
... . 1991 Subsequent reanalysis of the data using a weighted least-squares technique showed a positive correlation between fluoride concentrations and hip fracture (r = 0.41, P = 0.009)
From page 148...
... various concentrations of 1.00 to 1.06 mg/L (natural) fluoride in drinking water 1.45 to 2.19 mg/L (natural)
From page 149...
... Arnala Osteofluorosis was found in 22% of the high exposure group. Fluoride content et al.
From page 150...
... Although difficult to measure in epidemiology studies, bone fluoride concentrations are positively associated with the amount of fluoride exposure, length of exposure, age, and certain diseases such as chronic renal insufficiency (see Chapter 3 for discussion of pharmacokinetic factors that affect fluoride uptake by bone)
From page 151...
... Studies Releant to Assessing Risks at 4 mg/L Observational Studies. The committee is aware of five published observational studies of fractures in subjects exposed to drinking water containing fluoride at 4 mg/L or higher (Sowers et al.
From page 152...
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From page 153...
... 13 ) 1002(latearerreH-nócralA ydutskae W latnedsusreverutcarffosisylanaevitsegguS liatedtneicfifusnitubsisoroufl 5002.latesrewoS level-laudividnidnacigolocehtobhtiwtrohocevitcepsorP serusaemerusopxe ydutsreilraesaawoIfosaeraeerhtemaS )
From page 154...
... 14 erutcarfcitoropoetso) 70.0= ediroufl laromefrof31.0= 5002.latesrewoS P(ksirdesaercnidlof-55.2:cigolocE tonnwodkaerbega(nemowllarof L/gm1susrev L/gm4ta foytisnedlarenimenobgnidulcni(tnemtsujdaretfa)
From page 155...
... Fasting serum fluoride concentrations are considered a good (although not necessarily perfect) measure of long-term exposure and of bone fluoride concentrations (Ericsson et al.
From page 156...
... The dose-response curve for all fractures is plausible: some, but not all, animal studies suggest a biphasic relationship between bone fluoride
From page 157...
... Whereas the trend for fractures appears to increase from 1.00 to 4.00 mg/L, it must be appreciated that the fracture rate in the 1.00 to 1.06 mg/L category was lower than the rate in the category with the lowest intake. Estimated fluoride exposure in the Li study is higher than for the Sowers studies (see Table 5-4 later in this chapter)
From page 158...
... (1999) is pertinent to the issue of fracture risk at 4 mg/L, even though relatively few wells in that study had drinking water with fluoride concentrations that high.
From page 159...
... Despite the methodological strengths of the randomized clinical trials, their use in this review has limitations. In particular, fluoride exposures in the trials were higher in magnitude (20 to 34 mg/day)
From page 160...
... On the other hand, the committee assumes that bone fluoride concentration is the most appropriate measure of exposure for examining fracture risk. Data permitting, it could be possible to compare the bone fluoride concentrations reached in the randomized clinical trials with those in the observational studies.
From page 161...
... Since the regression model does not take water consumption rates into account, it should underpredict bone fluoride concentrations for people with high water consumption. The bone fluoride estimates for Li et al.
From page 162...
... 162 dnaslairTlacinilCdezimodnaRnisksiRerutcarFenoBdnasnoitartnecnoCediroulFenoBdetamitsE a) RO(soitaRsddOro)
From page 163...
... 163 detamitserednuebyamseiduts.S.UrofsnoitartnecnocenoB.erusopxelatotnodesab) 3retpahC(slairtlacinilcrofledomnoissergergnisudetamitsE tuobaerasnoitartnecnocenob .edirouflfo .sraey4rofdesopxetesbusaniderusaemnoitartnecnocenobetamixorppA .)
From page 164...
... In this instance, the type of physiological effect of fluoride on bone "quality" and the fractures observed in animal studies are consistent with the effects found in the observational studies. Furthermore, the results of the randomized clinical trials are consistent with an increased risk of nonvertebral fractures at fluoride concentrations in bone that may be reached by lifetime exposure to water at 4 mg/L.
From page 165...
... It focused primarily on evaluating fluoride content and the histomorphometry of bone samples taken from the iliac crest of hip fracture patients and had the advantage of providing data on bone fluoride concentrations. Mean fluoride concentrations (± standard deviation)
From page 166...
... . fluoride content of drinking water Two exposure categories: 0.05 to in different communities 0.11 mg/L and 0.11 to 1.83 mg/L Communities with fluoride at <0.3 mg/L, 1.0 to 1.2 mg/L, and >1.5 mg/L Outcomes Hip fractures among men and Hip fractures women combined, for age 50+.
From page 167...
... concentration was assigned to each region Fluoride concentrations estimated for as a weighted mean. each residence by using weighted medians, Avezanno (0.05 mg/L; range 0.040 to 0.058 smoothed interpolations.
From page 168...
... to histomorphology and bone and did not have sufficient detail to fluoride concentrations in iliac assess the distribution of fluoride crest. The results of that portion exposure with the higher category; of the study are summarized in the lacked information on age subgroups accompanying text insofar as they and on genders; inability to assess bear on the incidence part of the cumulative exposure; referent group paper.
From page 169...
... Weak Strong Serious design and analysis limitations. No Suggestive of hip fracture risk, with data that would inform an assessment of continuous gradient from lowest to highest a gradient.
From page 170...
... One region had fluoride concentrations in drinking water of 0.05 mg/L and the second region had fluoride at 1.45 mg/L. A significantly greater rate of fracture incidence, particularly femur fractures, were found in the low-exposure community.
From page 171...
... , with average monthly fluoride concentrations of 0.98-2.13 mg/L over the 18-month period referred to by Leone et al.
From page 172...
... . It has been known for many years that people with renal insufficiency have elevated plasma fluoride concentrations compared with normal healthy persons (Hanhijärvi et al.
From page 173...
... has reported that patients with preclinical skeletal fluorosis have fluoride concentrations between 3,500 and 5,500 mg/kg by ash weight. Clinical stage I patients have concentrations in the range of 6,000 to 7,000 mg/kg, stage II patients range from 7,500 to 9,000 mg/kg, and stage III patients have fluoride concentrations of 8,400 mg/kg and greater.3 However, a broader review of the literature on bone fluoride concentrations in patients with skeletal fluorosis revealed wider and overlapping ranges associated with different stages of the condition.
From page 174...
... 1984 Stage 3 Third phase 7,600 to 13,100 1 Roholm 1937 Stage 3 6,300 1 Singh and Jolly 1961 Stage III 11,500 1 Franke and Auermann 1972 Crippling 4,200 1 Teotia and Teotia fluorosis 1973 Stage III 8,400 1 Schlegel 1974 Stage III >10,000 Authors' Franke et al. 1975 summary
From page 175...
... bTibia or iliac crest; includes 1 case of stage III fluorosis listed separately above. cIndicates mean and standard deviation.
From page 176...
... 15 Schlegel 1974 Stage 2 Moderate 7,680 1 Sankaran and Gadekar 1964 Stage I to II 4,300 1 Franke and Auermann 1972 Stage II 4,100 and 4,600 2 Franke and Auermann 1972 Stage II 3,000 (mean) 18 Schlegel 1974 Stage 3 Skeletal fluorosis 8,600 1 Sankaran and Gadekar 1964 Advanced 8,800 and 9,680 2 Sankaran and Gadekar 1964 Stage III 3,600 (mean)
From page 177...
... appear to influence fluorosis severity at different concentrations of bone fluoride. Overall, the committee finds that the predicted bone fluoride concentrations that can be achieved from lifetime exposure to fluoride at 4 mg/L (10,000 to 12,000 mg/kg bone ash)
From page 178...
... The veterinary literature also contains a report indicating that, in 21 dairy herds consuming fluoride-containing feed and water, of the 100 cows examined and determined to have arthritic changes, the bone fluoride concentrations ranged from 2,000 to 8,000 mg/kg (Griffith-Jones 1977)
From page 179...
... Although a small set of epidemiologic studies were useful for evaluating bone fracture risks from exposure to fluoride at 4 mg/L in drinking water, there was consistency among studies using ecologic exposure measures to suggest the potential for an increased risk. The one study using serum fluoride concentrations found no appreciable relationship to fractures.
From page 180...
... These studies should use a quantitative measure of fracture such as radiological assessment of vertebral body collapse rather than self-reported fractures or hospital records. Moreover, if possible, bone fluoride concentrations should be measured in long-term residents.


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