INTERNATIONAL FLUORIDE INFORMATION NETWORK.

IFIN BULLETIN #202: More on fluoride and bones.

Dec. 19, 2000

Dear All,

Below we have reprinted an abstract of a recent update on a Conchrane
Review of fluoride treatment for osteoporosis, but first some background.

When toxicologists probe the toxicity of a new chemical they usually start
by testing animals with large doses. They have to use large doses, because
if they used small doses they would have to use a huge number of animals to
see any effect, which is very expensive. Once data has been collected for
high doses, researchers then have the problem of trying to extrapolate from
these high animal doses to predict the effect of low doses on humans. This
extrapolation is often controversial. Toxicologists also probe the effect
of dosing for a short time to test for acute effects and for long time to
test for chronic effects.

In the case of fluoride and its impact on bones, we have the advantage of
having had both "natural" experience and man-designed experiments with
humans. In the former case we know that literally millions of people in
India, China and other countries with regions with moderate to high
background levels of fluoride in the drinking water, have suffered serious
and crippling bone damage from fluoride exposure. This  condition is called
"skeletal fluorosis". In some instances in the Punjab in India, the levels
of fluoride in the drinking water which cause this condition are not that
elevated (2.25 -9.94 ppm, Jolly, 1971 and Waldbott et al, 1978) and
commentators have suggested that the impacts at these very low levels is
caused by a combination of fluoride and malnutrition. What is not in doubt
is that doses not so very much higher than that which would be delivered by
consumption of an average quantity of fluoridated drinking water can damage
our bones over a lifetime of exposure. Gordon and Corbin (1992) estimated
that at 4 ppm in the drinking water, fluoride concentrations in the bone
would reach as high as 6,400 ppm. According to the Department of Health and
Human Services (DHSS,1991)) such levels are associated with the first
clinical phase of skeletal fluorosis. The symptoms for this phase are
described as sporadic pain, joint stiffness and osteosclerosis of the
pelvis.

In 1985, Arnalla et al measured the accumulation of fluoride in bones in
Finland. According to their abstract "Bone samples were taken from cadavers
from a low-fluoride area (fluoride concentration under 0.3 ppm), an area
with fluoridated drinking water (1.0-1.2 ppm) and a high-fluoride area
(over 1.5 ppm). The fluoride content in trabecular bone was greatly
increased in the high-fluoride area, and it was also higher in the
fluoridated-water area than in the low-fluoride area. Histomorphometric
bone changes were markedly increased when the fluoride content in water
exceeded 1.5 ppm."

Because it is known that fluoride increases bone mineral density (hardens
the bones - i.e. osteosclerosis) some medical researchers thought that
fluoride might actually help patients (particularly postmenopausal women)
suffering from osteoporosis - a condition in which the bones lose their
mineral density. It was hoped that such treatment would not only harden the
bones but reduce the incidence of fracture. However, studies by Hedlund and
Gallagher (1989) and Riggs et al (1990) showed that fluoride treatment
actually led to an increase in hip fracture. Others have argued that
treatment with lower doses or with slow release treatments are effective in
reducing bone fractures (Pak, 1997). Whether this is true or not, doses of
50-75 mg of fluoride per day clearly makes bones more brittle and more
likely to break, particularly those subjected to torsional stress (e.g the
femoral neck of the hip bone). Thus we don't have to extrapolate from high
dose animal experiments: we have clear results from high dose human
experiments that fluoride can damage our bones. But what about low doses?

In an effort to probe the question of long term exposure to lower doses of
fluoride (as opposed to shorter term exposure to high doses) a number of
epidemiological studies have been performed which have compared hip
fracture rates among the elderly in fluoridated and non-fluoridated
communities. Since 1990, there have been 18 of these studies (3
unpublished, see references below). Of these, 10 show an association and 8
do not. Many of these studies suffer from the weakness that we do not know
the doses of fluoride that individuals experienced in these communities.
However, one study (li et al, 1999), which is still unpublished, is more
convincing. The authors examined the hip fracture rates in 6 Chinese
villages and found an approximate linear increase in hip fractures as
levels rose above 1 ppm (in the drinking water). At levels over 2 ppm, the
rate doubled and over 4 ppm it tripled.

Putting all these results together, we can say the following. There is peer
reviewed and published evidence in the literature that at 1 ppm the
fluoride content in the trabecular bone (i.e. the spongelike interior of
the bone) is increased. At 1.5 ppm histomorphometric changes (i.e. changes
in structure) can be observed. At 1- 2 ppm hip fracture rates are
increased. At 4 ppm (or lower if exposure is coupled with malnutrition) the
first clinical phase of skeletal fluorosis can be observed. Clearly, all
these situations could be made worse if water consumption is above average
and/or exposure to other sources of fluoride also occurs. Finally, shorter
time exposure to higher doses (1 - 4 years at 50- 75 mg per day) increases
the rate of hip fracture in osteoporotic patients.

Recently the treatment of osteoporosis with fluoride has been subjected to
a Cochrane Review. Thanks to Cory Mermer for sending us a summary of that
review, which we have printed below along with references to all the
studies sited above.

Paul Connett.


Fluoride for treating osteoporosis (Cochrane Review)

D Haguenauer, V Welch, B Shea, P Tugwell, G Wells

ABSTRACT


A substantive amendment to this systematic review was last made on 30
August 2000. Cochrane reviews are regularly checked and updated if
necessary.

Objectives: To assess the efficacy of fluoride therapy on bone loss,
vertebral and non-vertebral fractures and side effects in postmenopausal
women.

Search strategy: We searched Medline, Current Contents and the Cochrane
Controlled Trial Registry up to December 1998.

Selection criteria: Two independent reviewers selected RCTs which met
predetermined inclusion criteria.

Data collection and analysis: Two reviewers independently extracted data
using predetermined forms and assessed the methodological quality of the
trials using a validated scale. For dichotomous outcomes, relative risks
(RR) were calculated and for continuous outcomes, weighted mean differences
(WMD) of percentage change from baseline were calculated. Where
heterogeneity existed (determined by a chi-square test) a random effects
model was used.

Main results: Eleven studies (1429 subjects) met the inclusion criteria.
The increase in lumbar spine bone mineral density (BMD) was found to be
higher in the treatment group than in the control group with a WMD 8.1%
(95%CI: 7.15,9.09) after two years of treatment and 16.1%(95%CI:
14.65,17.5) after four years. The RR for new vertebral fractures was not
significant at two years [0.87 (95%CI: 0.51,1.46)] or at four years
[0.9(95%CI: 0.71,1.14)]. The RR for new non-vertebral fractures was not
significant at two years 1.2(95%CI: 0.68,2.1) but was increased at four
years in the treated group 1.85(95%CI: 1.36,2.5), especially if used at
high doses and in a non slow  release form. The RR for gastrointestinal
side effects was not significant at two years 2.18(95%CI: 0.86,1.21) but
was increased at four years in the treated group 2.18(95%CI: 1.69,4.57)
especially if fluoride was used at high doses and in a non slow release
form. The number of withdrawals and dropouts was not different between
treated and control groups at two and four years.

Reviewers' conclusions: Although fluoride has an ability to increase BMD at
lumbar spine, it does not result in a reduction of vertebral fractures. In
increasing the dose of fluoride, one increases the risk of non-vertebral
fracture and gastrointestinal side effects without any effect on the
vertebral    fracture rate.


Citation: D Haguenauer, V Welch, B Shea, P Tugwell, G Wells. Fluoride for
treating osteoporosis (Cochrane Review). In: The Cochrane Library, 4, 2000.
Oxford: Update Software.

This is an abstract of a regularly updated, systematic review prepared and
maintained by the Cochrane Collaboration. The full text of the review is
available in The Cochrane Library (ISSN 1464-780X).

The Cochrane Library is prepared and published by Update Software Ltd. All
rights reserved.

See www.update-software.com or contact Update Software, info@update.co.uk,
for information on subscribing to The Cochrane Library in your area.

Update Software Ltd, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK
(Tel:+44 1865 513902; Fax:+44 1865 516918)

File Reference: ab002825-20004


REFERENCES for IFIN #202.

Arnala I, Alhava EM, Kauranen P (1985) Effects of fluoride on bone in
Finland. Histomorphometry of cadaver bone from low and high fluoride areas.
Acta Orthop Scand 56(2):161-6

DHHS (1991). Review of Fluoride: Benefits and Risks, Report of the Ad
Hoc Committee on Fluoride of the Committee to Coordinate Environmental
Health and Related Programs. Department of Health and Human Services, USA.

Gordon, S.L. and Corbin, S.B. (1992). Summary of Workshop on Drinking
Water Fluoride Influence on Hip Fracture on Bone Health. Osteoporosis
International 2, 109-117.

Hedlund, L.R. and Gallagher, J.C. (1989). Increased incidence of hip
frature in osteoprotic women treated with sodium fluoride. J. Bone Min.
Res. 4, 223-225.

Jolly, S.S. et al (1971). Human intoxication in Punjab. Fluoride, 4(2)
64-79.

Pak, C.Y.C. et al (1997). Susatained-release sodium fluoride in the
management of established postmenopausal osteoporosis. Ann. J. Med. Sci.
313, 23-32.

Riggs, B.L. et al (1990). Effect of Fluoride treatment on the Fracture
Rates in Postmenopausal Women with Osteoporosis. N. Eng. J. Med., 322,
802-809.

Waldbott, G.L., Burgstahler, A.W. and McKinney, H.L. Fluoridation: The
Great Dilemma. Coronado Press, Inc., Lawrence, Kansas, 1978.


THE 18 STUDIES ON THE POSSIBLE ASSOCIATION OF HIP FRACTURE AND FLUORIDE
EXPOSURE.


1. Cauley, J., P. Murphy, et al. (1995). "Effects of fluoridated drinking
water on bone mass and fractures: the study of osteoporotic fractures." J
Bone Min Res 10(7): 1076-86.

2. a) Cooper, C., C. Wickham, et al. (1991). "Water fluoridation and hip
fracture." JAMA 266: 513-514 (letter, a reanalysis of data presented in
1990 paper).

2. b) Cooper, C., C. Wickham, et al. (1990). "Water fluoride concentration
and fracture of the proximal femur." J Epidemiol Community Health 44: 17-19.

3. Danielson, C., J. L. Lyon, et al. (1992). "Hip fractures and
fluoridation in Utah's elderly population." Jama 268(6): 746-748.

4. Hegmann, K.T. et al (2000) the Effects of Fluoridation on Degenerative
Joint Disease (DJD) and Hip Fractures.Abstract #71, of the 33rd Annual
Meeting of the Society For Epidemiological research, June 15-17, 2000.
Published in a Supplement of Am. J. Epid.

5. Hillier, S., C. Copper, et al. (2000). "Fluoride in drinking water and
risk of hip fracture in the UK: a case control study." The Lancet 335:
265-269.

6. Jacobsen, S., J. Goldberg, et al. (1992). "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 2: 617-626.

7. Jacobsen, S., J. Goldberg, et al. (1990). "Regional variation in the
incidence of hip fracture: US white women aged 65 years and olders." J Am
Med Assoc 264(4): 500-2.

8. Jacobsen, S.J. et al  (1993). Hip Fracture Incidence Before and After
the Fluoridation of the Public Water Supply, Rochester, Minnesota. American
Journal of Public Health, 83, 743-745.

9. a) Jacqmin-Gadda, H. (1995). "Fluorine concentration in drinking water
and fractures in the elderly." JAMA 273: 775-776 (letter).

9 b) Jacqmin-Gadda, H., A. Fourrier, et al. (1998). "Risk factors for
fractures in the elderly." Epidemiology 9(4): 417-423. (An elaboration of
the 1995 study referred to in the JAMA letter).

10. Karagas,M.R. et al (1996). "Patterns of Fracture among the United
States Elderly: Geographic and Fluoride Effects". Ann. Epidemiol. 6 (3),
209-216.

11. Keller, C. (1991) Fluorides in drinking water. Unpublished results.
Discussed in Gordon, S.L. and Corbin, S.B,(1992) Summary of Workshop on
Drinking Water Fluoride Influence on Hip Fracture on Bone Health.
Osteoporosis Int. 2, 109-117.

12. Kurttio, P., N. Gustavsson, et al. (1999). "Exposure to natural
fluoride in well water and hip fracture: A cohort analysis in Finland."
American Journal of Epidemiology 150(8): 817-824.

13. Lehmann R. et al (1998). Drinking Water Fluoridation: Bone Mineral
Density and Hip Fracture Incidence. Bone, 22, 273-278.

14. Li, Y., C. Liang, et al. (1999). "Effect of Long-Term Exposure to
Fluoride in Drinking Water on Risks of Bone Fractures." Submitted for
publication. Contact details: Dr. Yiming Li, Loma Linda School of
Dentistry, Loma Linda, California, Phone 1-909-558-8069, Fax 1-909-558-0328
and e-mail, Yli@sd.llu.edu

15. May, D.S. and Wilson, M.G. Hip fractures in relation to water
fluoridation: an ecologic analysis. Unpublished data, discussed in Gordon,
S.L. and Corbin S.B.,(1992), Summary of Workshop on Drinking Water Fluoride
Inflruenbce on Hip Fracture on Bone Health. Osteoporosis Int. 2, 109-117.

16. Phipps, K. R. (1999). Community water fluoridation, bone mineral
density and fractures. R01DE10814-02. HSR/96101800. USA, Oregon Health
Sciences University, 611 SW Campus Dr, Portland, OR 97201, IR: (503)
494-8895,. 199309: National Institute of Dental Research (NIDR) - Grant:
Noncompeting Continuation (5). To be published in the British Medical
Journal.

17. Sowers, M., M. Clark, et al. (1991). "A prospective study of bone
mineral content and fracture in communities with differential fluoride
exposure." American Journal of Epidemiology 133: 649-660.

18. Suarez-Almazor, M., G. Flowerdew, et al. (1993). "The fluoridation of
drinking water and hip fracture hospitalization rates in two Canadian
connunities." Am J Public Health 83: 689-693.