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Rapid Responses: Rapid Responses published:
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Community Water Fluoridation
- Susan Minker (11 October 2000)
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Rapid response to Phipps article
- Paul Connett (12 October 2000)
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Fluoride's Effect on Bone
- T C Schmidt (12 October 2000)
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Susan Minker
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I admit it's been a long time since I took statistics in medical school, but I cannot for the life of me understand how Phipps et al reached the conclusion that "women with continuous exposure (to fluoride)had a 31% reduction in risk of hip fracture.. and a 27% reduction in risk of vertebral fracture". Reuters News is already quoting this statistic in a quite misleading article (I saw it in the Women's Health section of Medscape). Thank you. |
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Paul Connett, Professor of Chemistry St. Lawrence University, Canton, NY 13617
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The Phipps study published in the British Medical Journal on Oct 6, 2000 (www.bmj.com/cgi/content/full/321/7265/860), is one of the studies on hip fracture which I examined as part of my invited peer review of the York report (A summary of the York report was also published in the same issue of the BMJ). The York team incorporated Kathy Phipps' data in their meta-analysis of bone fracture. Phipps' paper is one of the 18 (3 unpublished and one abstract) studies done since 1990. 10 of these studies show an assoication between increased hip fracture and fluoridation and 8 do not. Phipps is one that did not. I am glad that Phipps does not hide her enthusiasm for water fluoridation, when she declares without a supporting reference that, "the benefit of fluoridation in the prevention of dental caries has been overwhelmingly substantiated". However, the notion that fluoride protects against hip fracture, in addition to the marginal benefits to teeth it may have, is a stretch in the context of the 10 studies which conflict with Phipps' results. While it is true that her study is superior to some because she controls for 13 variables, and she uses bone mineral density as an indirect confirmation that those who had more exposure to fluoridated water have accumulated more fluoride, she still lacks the actual levels of fluoride that have accumulated in the bones. Instead she relies for her comparisons on the number of years of exposure to fluoridated water. For the study period 1971-1990, the authors give the mean age of the women examined as 74.5, 74.2 and 73.9 years in the three groups observed: no exposure, mixed exposure and continuous exposure, respectively. If this was their age in 1990, then the mean age of those exposed at the beginning of the study in 1971 was 53.9 years. Thus most of their known exposure was after menopause, which according to some authors could make a difference with respect to fluoride's impacts (Danielsen, 1992), although not all agree on this point (Kurtio, 1999). However, the most disturbing aspect of the report is how much attention is given to the DECREASE of hip fracture incidence and how little attention is given to the INCREASE in the incidence of wrist fracture in the group exposed for 20 years of water fluoridation. The ostensible reason for this is that the decrease in hip fracture incidence is deemed statistically significant while the increase in wrist fracture is deemed statistically insignificant. However, when one considers the basis of the claims of significance and insignificance the difference between the two results is very slender indeed. This is particularly important when it is recognized that the "significance" for the hip fracture decrease and the "non-significance" of the wrist fracture increase only emerges after adjustment for 12 variables. It raises the question of how accurate these adjustments were, if such fine distinctions are going to be made. Here are the details. In Table 5, after age adjustment, the authors report a relative risk of 0.85 for hip fractures for the continuously exposed group, with a 95% confidence interval (CI) of 0.63 to 1.14 and a p-value of 0.287. Translated this indicates a statistically non-significant decrease of 15% in the incidence of hip fracture. It is statistically non-significant because the CI overlaps with 1.00 and the p-value is greater than 0.05. In the same table, the authors report the relative risk for hip fracture, after adjustment for 12 more variables, as 0.69, with a CI of 0.50 to 0.96 and a p-value of 0.028. This translates to a decrease in hip fracture of 31% and it is now statistically significant because the 95% confidence interval (0.55 to 0.96) no longer overlaps with 1.00 - but only just - and the p-value is less than 0.05. If we now compare this with the wrist fracture figures we find the following. The age adjusted relative risk for wrist fracture for the women continuously exposed is 1.36 (CI: 1.07 - 1.73), p-value 0.012. This translates to a 36% increase in wrist fracture which is statistically significant, because the 95% CI does not include the value of 1.00, and the p-value is less than 0.05. After adjustment for 12 more variables, these figures become 1.32 (CI: 1.00 to 1.71) with a p-value of 0.051. This is now declared as a non-significant finding because, even though the relative risk has hardly changed, despite the consideration of 12 variables, the CI just overlaps with 1.00, in fact the lower value is actually at 1.00 and the p-value is just over 0.05 at 0.051! This is about as close as one can get to a significant result without actually calling it statistically significant. This is so close in fact, that this result must bring into question how accurately these adjustments, and the assumptions on which they were based, were performed. In this respect it is intriguing that when the York team considered these same results from Phipps et al they recorded the adjusted figure as 1.3 (1.02, 1.7) (see their appendix C8 "Bone Studies: Individual Study results") and this is the number reported in the final version of the York Review (Oct 6, 2000). This table can be examined on the web at www.york.ac.uk/inst/crd/fluores.htm. The table can be found in the appendix identified as appc8.doc. The fact that this number makes the difference between a so-called significant result and a non-significant result, raises a serious question as to why two reports published on the same day have different values - one significant the other non-significant. How did this number get changed and by whom? These issues need very careful evaluation because many news outlets and health wire services are broadcasting the "good news" that water fluoridation is good for bones. In my view this promotion is reckless based upon such slender evidence, and in the context of several important factors: a) 50% of all fluoride ingested accumulates in our bones b) water fluoridation is not the only source of fluoride we are exposed to c) high doses of fluoride used to treat patients with osteoporosis in an effort to harden their bones has led to an increase not a decrease in hip fracture d) this study also indicates an increase in wrist fracture, as close to significance as you can get and e) there are 10 studies (3 unpublished) which indicate an increase in hip fracture associated with fluoride in water and f) one of these studies shows an almost dose-response increase above 1 ppm exposure (Li et al, 1999, unpublished). All the references cited above can be found in articles I have authored or co-authored on our webpage http://www.fluoridealert.org Dr. Paul Connett,
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T C Schmidt
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Phipps et al. [BMJ 2000;321:860-4]state that "there was a trend towards fewer fractures of the humerous (P=0.387) and more fractures of the wrist (P=0.051), but the differences were not significant". As the latter was actually a 95% CI on the RR of 1.00-1.71 (clearly significant regardless of P-value) such statement simply indicates the authors' bias. What is most disturbing however, is their conclusion that "because the burden of osteoporosis is largely due to fractures of the hip" it (fluoridation) "may be one of the most cost effective methods for reducing the incidence of fractures related to osteoporosis" -- where the evidence for such reduction in hip fractures was obtained after adjusting the data for twelve factors above and beyond that of age. The factors chosen (refs 18 and 19 therein) are specific to bone mass per se., with the increase in bone mass being due to and correlated with the ingestion of fluoride. However, the FDA Guidelines for Preclinical and Clinical Evaluation of Agents Used in Prevention or Treatment of Postmenopausal Osteoporosis (1994; pub. 1997) states "the relation between increased bone mass density and reduced fracture risk has been validated for patients receiving estrogens, but not fluoride". Thus, the multifactorial analysis used, is not necessarily cogent. By comparison, the data in Figure 5 therein, for age adjustment only and continuous exposure shows the following results. The most significant result (P=0.012) is again an increase in wrist fracture, with the next most significant result (P=0.079) being a decrease in spinal fracture. Although not definitive (RR CI = 1.07-1.73 and 0.61- 1.03, respectively) they are somewhat indicative - and not unexpected. That is, it is now widely recognized that any potential benefit to the vertebra from increased bone mass density from fluoride ingestion will be at the expense of the peripheral skeleton due to a concomitant decrease in the overall bone quality. Sowers et al.[Am J Epidemiol 1991; 133(7):649- 60] found a statistically significant increase in wrist fracture when comparing 1 mg/l vs 4 mg/l in drinking water. And fluoride treatment proponents now recommend that prospective clinical trials be restricted to the axial skeleton only -- provided that the patient has good peripheral bone density, renal function, and vitamin-D status [key factors which were not included in the multifactorial analysis of Phipps et al.]. Finally, the next most significant result for continuous exposure with age adjustement only was hip fracture -- with the result (P=0.287) being quite ambiguous. Contrary to the authors' conclusions, per Melton [J Bone Miner Res 1990; Suppl 1:S163-7] "epidemiologic data provide little support for the notion that exposure to fluoride reduces hip fracture incidence" and "fluoride cannot be recommended as a prophylactic agent for the fractures that are the primary adverse health outcome of osteoporosis". With the exception that it will become greater following any onset of chronic renal insufficiency [Mathias, et al. Pediar Nephrol 2000; 14(10-11); 953-9], the total fluoride accumulation will be directly proportional to total lifetime ingestion. Thus, the cumulative total effects over an entire lifetime [vs the 20-years evaluated by Phipps, et al.] may be reflected by the effects due to shorter durations of "therapy", and the effects on bone tissue per se. (including the animal model). For example, per Hedlund and Gallagher [J Bone Miner Res 1989; 4(2): 223-25] the difference in rate of hip fractures for fluoride treated patients is ten-times higher than would be expected -- which is substantiated by the patient bone biopsies of Soggard et al. [Bone 1994; 15(4): 393-9 and Ugeskr Laeger 1995; 157(14): 2002-8]. That is, after five years of treatment, decreases in trabecular bone strength and quality were 45% and 58%, respectively. Similarly, in prospective clinical trials comparing fluoride treatment vs a placebo (Riggs, et al. N Engl J Med 1990; 322(12):802-9 and J Bone Miner Res 1994; 9(2):265-75] not only was there no decrease in vertebral fracture rate, but there was an increase in non-vertebral fractures. Indeed, per FDA Consumer (April, 1991) trials including the use of calcium resulted in a 35% increase in bone mass, but "the new bone was weak and structurally abnormal". What is happening is best elucidated as follows. Whereas bone mass and architecture in all appendicular and most axial sites is normally controlled by loading history, the remodeling process is changed by altering the normal balance between resorption and formation. [Per Phipps, et al. this osteogenic effect occurs at plasma fluoride levels as low as 1 umol/l, compared to the 0.7-2.4 umol/l for fluoridated areas]. Regardless, the new bone that is formed as a result of this artificially stimulated remodeling is exclusively appositional -- with no creation of new trabeculae [Balena, et al. Osteoporos Int 1998; 8(5):428-35]. The subsequent mineralization appears to be characterized by the presence of additional large crystals, located outside the collagen fibrils [Fratzel, et al. J Bone Miner Res 1994; 9(10); 1541-9] and these large crystals are what contribute to the increased bone mineral density. That the result is reduced strength per unit of bone has been confirmed based on both fracture stress and x-ray diffraction, even if no fluorosis or osteomalacia is observed histologically [Turner, et al. Calcif Tissue Int 1997; 61(1):77-83]. And the premise that calcium-fluoride reduces the structurally effective bone mineral content, and may effect the interface bonding between the bone mineral and the organic matrix of the bone tissue [Kotha, et al. Biomed Mater Eng 1998; 8(5-6):321-34] is essentially the same as the contention [Walsh, et al. Ann Biomed Eng 1994; 22(4):404-15] that the reduction in the mechanical properties is attributable to "a consituent interfacial de-bonding mechanism". As stated by Phipps, et al., "it is reasonable to expect the concentrations of fluoride at 1-ppm may have discernable skeletal effects after 20-years of exposure". Indeed, samples from cadavers [Arnala, et al., Acta Orthop Scand 1985; 56(2): 161-66] show that the fluoride content of trabecular bone correlates with that of the drinking water with histomorphic bone changes becoming markedly increased when water fluoride content exceeds 1.5-ppm. Thus, the increase in bone density reported by Phipps, et al. due to exposure to public water fluoridation should be viewed with some concern (vs applause). As they state "fluoride is ubiquitious and is found in food, water, air, and dental products". Indeed, it is now many times more ubiquitious than the levels seen by the cadavers of Arnala, et al., and per Dequeker and Declerck [Schweiz Med Wochenschr 1993; 123(47):2228-34]- "experience has taught that denser bones are not necessarily better bones". respectfully submitted, T.C. Schmidt
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