The Association between Water Fluoridation and Hip Fracture among White Women and Men Aged 65 Years and Older A National Ecologic Study Steven J. Jacobsen, MD, PhD, Jack Goldberg, and Stuart A. Lockwood, DMD, MPH

PhD, Cyrus Cooper,

MD, MRCP,

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 co 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 I. 08 (I. 06 to 1.10) for women and 1.17 (I. 13 to I. 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 need-s to be duplicated at the individual level with more precise measures ofjZuoride exposure. Ann Epidemiol 1992;2:617-626. KEY WORDS:

Hip fractures,

femoral neck fractures,

Hip fractures

constitute

years or older

(1). An estimated

fluoridation, fluorides, epidemiology.

INTRODUCTION a major

cause of morbidity

and mortality

in persons

aged 65

hip fractures

occur in the United States each

year, with an associated cost of over $7 billion (2-4).

These costs will likely increase

200,000

through the remainder of this century as the population ages. Preventive combat this problem are therefore urgently required.

strategies to

The incidence of hip fracture is known to vary markedly by age, sex, race, and geographic region. White women are at the greatest risk of fracture, followed by white men (5-9). Blacks have been noted to experience relatively low rates of fracture, whereas Hispanics and Asians appear to be at intermediate risk (9). Internationally, the highest rates of fracture are found in Scandinavia, followed by the United States, western Europe, Asia, and Africa (10-15). Within the United States there appears to be a band of increased risk in the southern states (16, 17), though this finding has not been consistent (18). Although it is likely that racial differences in hip fracture rates result from variation in Among proposed to

racial differences in bone density (19), the reason for the geographic hip fracture incidence within racial groups remains unknown. the environmental determinants of bone metabolism that have been explain geographic variation in hip fracture incidence, water fluoride

From the Medical College of Wisconsin, Milwaukee, WI. Address reprint requests to: Steven J. Jacobsen, MD, PhD, Section of Clinical Epidemiology, of Health Sciences Research, Mayo Clinic Foundation, Rochester, MN 55905. Received April 22, 1991; revised June 11, 1991. 0 1992 Elsev~erScience PublishingCo.. Inc.

Department

1047s2797/92/$05.00

618

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

content

has received much attention.

AEP Vol. 2, No. 5 September 1992: 617-626

Fluoride stimulates the function

of osteoblast-

like cells in vitro (20, 21). In humans, the administration of sodium fluoride increases bone mineral density in the axial skeleton (22, 23). However, recent trials of sodium fluoride at even higher concentrations raised the concern that the newly formed bone is structurally

weak and perhaps more fragile than normally

(24-26). The evidence for an association incidence

synthesized bone

between fluoridation of public water supplies and

of hip fracture is conflicting

(27). S ome studies suggested a protective

effect

(28, 29), others failed to demonstrate an association (30-37), and still others suggested an adverse effect (16, 38, 39). Virtually all of the epidemiologic research uses an ecologic study design with county-level indicators for fluoride exposure. To date only one study (39) used individual measurements of water consumption to quantify fluoride exposure, but this was not used in the analysis of fracture rates. A previous study from two of us (16) demonstrated a statistically significant, albeit small, relationship between the percentage of the population served with fluoridated water and hip fracture rates among white women. However, the county-level measure of fluoridation used in the previous to large The practices

report was based on the 1975 census of water fluoridation (40) and was subject amounts of random error. purpose of this study was to examine the association of water fluoridation in the United States and the incidence of hip fracture. The present analysis

focused on 323 urban counties where public water fluoridation practices were recently assessed as part of a study of cancer and fluoride (41). Incidence rates of hip fracture were calculated for these counties using data obtained from the Health Care Financing Administration (HCFA) and the Department of Veterans Affairs (VA) women and men aged 65 years or older for the period 1984 to 1987.

h4ATERIALS

AND

for white

METHODS

Identification

of Fluoridated

and Nonfluoridated

Counties

County-level fluoridation of centralized water systems was determined using a methodology developed by the National Cancer Institute (41). Briefly, this method selects only those counties that have a high probability of having a centralized water system (i.e., counties that were at least 50% urban in 1980). Those counties are then classified as fluoridated if the proportion of the population served with fluoridated water increased from less than 10% to more than 66% within a 3-year period. A county is considered to be non&or&ted (adjusted

if no more than 10% of the population received fluoridated water

or natural)

at any time through

1985.

It was not possible to classify the

fluoridation status of counties in Alaska, Hawaii, and Virginia; counties from these states were excluded from analyses. This algorithm was modified slightly due to limitations of the data available for this study. The city of St. Louis and the county of St. Louis, Missouri, were combined into a single entity as were the city of Baltimore and its surrounding county. The county of Ormsby, Nevada, was not mappable to the census data and was excluded from analysis. Using this methodology, a total of 129 counties, with a population of approximately 40 million persons, were classified as fluoridated and 194 counties, with a population of approximately 30 million persons, were classified as nonfluoridated. For those counties classified as fluoridated, it was possible to determine the year that fluoridation was initiated. Fluoridated counties were grouped to six categories on the basis of duration of fluoridation in 1985: 0 to 5 years, 6 to 10, 11 to 15, 16 to 20, 21 to 25, and more than 25 years of fluoride exposure.

AEP Vol. 2, No. 5 September 1992: 6 J7-626

Identification

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

619

of Cases of Hip Fracture

The HCFA and the VA each maintain computerized databases of inpatient hospitalizations. The HCFA compiles data on all hospital discharges for persons covered under the Medicare program (42), while the VA compiles data on all discharges from VA hospitals. The HCFA data are based on information collected with a standard billing form (HCFA Form 1450, UB-82), with each record containing a standard set of data. These records are combined annually into a derivative file known as the Medicare Provider Analysis and Review Record (MEDPAR). Records for an individual can be linked by means of an encrypted version of the Social Security number, allowing a beneficiary to be tracked through a number of years to reveal a history of all inpatient hospitalizations. The VA Patient Treatment File (VAPTF) is a computerized abstract of all discharges from VA hospitals with a structure similar to HCFA’s MEDPAR file; repeated hospitalizations can be identified by using the veteran’s Social Security numbers. Each record in MEDPAR and VAPTF includes a principal discharge diagnosis and up to four additional diagnoses, coded according to the ninth revision of the Clinical Modification of the International Classification of Diseases (ICD9CM) (43). The computerized abstract also includes age, sex, race, zip code of residence, and the dates of admission and discharge. Potential cases of hip fracture were identified in both the MEDPAR and VAPTF as any individual with an ICD9-CM code of 820.0 through 820.9 in any of the five fields provided for diagnoses. Potential cases (n = 822,384) from both files were merged by Social Security number and date of admission. In this analysis, cases were excluded if the county of residence was out of scope (n = 505,591), age was less than 65 years (n = 19,899), race was nonwhite (n = 49,463), zip code was for Puerto Rico or was missing (n = 815), the fracture was the second fracture of the hip within the follow-up period (n = 54,055), the fracture may have been secondary to metastatic or primary neoplastic disease (n = 4190), or the primary discharge diagnosis was for late effects of hip fracture or for orthopedic aftercare (n = 274). The exclusion criteria were not mutually independent and a case could be excluded for more than one reason. After exclusions, 218,951 case patients resided within the study areas and remained eligible for study.

Identification

of Population

at Risk

Denominator information was obtained from the Bureau of the Census. County estimates of the 1985 population of white men and women by 5-year age groups up to age 85, and for 85 and older, were available (44). These estimates were based on the 1980 census of the population and adjusted in subsequent years for births, deaths, immigration, and emigration (45, 46).

Statistical Analysis Age-adjusted rates were calculated for women and men separately using the direct method of age adjustment (47, 48). The entire US population aged 65 years or older served as the standard population. Age-adjusted rates were calculated for the counties aggregated on the basis of fluoridation status and duration. Poisson regression models were constructed to estimate the relative risk of hip fracture in fluoridated counties compared to the nonfluoridated counties after controlling for age (49). These models were extended to test for a trend in risk of fracture with duration of fluoridation. We adjusted the fracture rates for county-level indicators of poverty, water hard-

620

Jacobsen et al. WATER FLUORIDATION

TABLE 1

AEP Vol. 2, No. 5 Sqxember 1992: 617-626

AND HIP FRACTURE

Age-adjusted incidence of hip fracture by sex and county fluoridation status’

women Men

Fluoridated

Nonfluoridated

a.42 (8.51-8.73) 4.71 (4.59-4.83)

7.85 (7.74-7.96) 3.99 (3.88-4.10)

’ Data are the annual aged-adjusted incidence rates (per thousand) and 95% confidence intervals. Fluoridated county was defined as 250% urban, natural fluoride level ~0.3 ppm, ~10% of the population served with fluoridated water prior to change, increased to ~67% of population served with fluoridated water within a period of 3 years (129 counties). Nonfluoridated county was defined as ~50% urban, 5 10% of the population served with fluondated water, natural fluoride levels CO.3 ppm (194 counties).

ness, sunlight, urbanicity, and latitude using weighted least-squares regression. Adjustment for these variables did not substantially alter the findings and we therefore present only the age-adjusted analysis.

RESULTS For the 4-year study period, the annual age-adjusted incidence rate of hip fracture was 4.34 per thousand for men, and 8.25 per thousand for women. The age-adjusted rate for women in the fluoridated counties (Table 7.85 per thousand for those in nonfluoridated

1) was 8.62 per thousand, compared to counties. The relative risk (95% confi-

dence interval) obtained from the regression model was 1.08 ( 1.06 to 1.10) for women. For men, age-adjusted rates were 4.71 per thousand and 3.99 per thousand in fluoridated and nonfluoridated counties, respectively. The relative risk was 1.17 (1.13 to 1.22). The curves representing

the incidence of hip fracture with duration of fluoridation

display a complex pattern for both women and men (Figure 1). In women, the risk of fracture was lowest in nonfluoridated counties and highest in counties fluoridated for up to 5 years. From a peak hip fracture incidence of nearly 10 per thousand in those counties most recently fluoridated, rates generally declined to 8.38 per thousand in counties fluoridated for the longest time. A similar pattern was observed for men, with the lowest risk being in the nonfluoridated counties, the highest risk in counties most recently fluoridated, and then a gradually declining risk with duration of fluoridation. Formal tests for these patterns among men revealed a positive slope coefficient estimated from the Poisson regression model, indicating a significantly (P < 0.0001) increased coefficient

risk associated with longer durations of fluoridation. became negative

and nonsignificant

(P = 0.1123)

However,

this slope

when nonfluoridated

counties were excluded from the regression model. For women, there was a significant positive association between water fluoridation and risk of hip fracture (P < 0.0001) when nonfluoridated counties were included in the regression model. Conversely, a significant negative slope (P < 0.0001) was found when nonfluoridated counties were excluded.

DISCUSSION For the past 45 years, there surrounding the fluoridation Subcommittee on Fluoride and Related Programs at the

has been a great deal of debate regarding the health issues of public water supplies. The recent report of the Ad Hoc of the Committee to Coordinate Environmental Health Public Health Service included results of a study performed

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

AEP Vol. 2, No. 5 September1992: 617-626

”

I

I

Never

0'3

Duration

6-10

of

11-15

621

I

16-20

Fluoridation

21-25

26+

(Years)

FIGURE 1 Annual age-adjusted incidence rates of hip fracture for white men and women aged 65 years or older, by duration of county water fluoridation. The lines depict age-adjusted incidence rates in 1985. Error bars indicate 95% confidence intervals.

by investigators at the National Cancer Institute, who examined the role of fluoridation as a risk factor for the development of cancer of bone or oral-pharyngeal sites (41). Their findings were categorically negative. In the present study, using identical measures of county-level fluoridation, we found an 8 to 17% increased risk of hip fracture associated with fluoridation. This association was stronger in men and appeared to be stronger in counties that recently became fluoridated. While these associations are statistically significant, they are of relatively small magnitude and the possibility that bias and/or confounding may be responsible for these observations must be carefully examined. Our classification of county-level fluoridation is potentially subject to measurement error. With our analysis conducted at the county level, some degree of misclassification is necessarily present, as boundaries for public water systems rarely coincide with those of a given county. Further, within most counties, some households use private-well water. Fluoride levels may differ markedly from well to well, even among next-door neighbors. Even in counties where water systems are fairly homogeneous, the amount of fluoride within water supplies may vary from day to day or even hour to hour. Finally, there is probably not a true “nonexposed” population due to the fluoride content in other food sources. The hip fracture incidence rate is also subject to measurement error, arising in either the numerator or the denominator. Two studies (50,5 1) examined the sensitivity of using Medicare inpatient hospitalization data to identify hip fractures in the aged US population. These studies noted a 70 to 99% sensitivity, with considerable variability noted from state to state. To our knowledge, there have been no systematic studies examining the false-positive rate for hip fracture in the Medicare data. While the authors of the more recent study (51) suggested that the extremes in under-reporting

622

Jacobsen et al. WATER FLUORIDATION

AND HIP FRACTURE

AEP Vol. 2, No. 5 September 1992: 617426

may have been due to bills submitted for adjudication, there is clearly some degree of error built into our estimate of the injured population. The choice of an appropriate denominator is equally problematic. Fisher and others (50) noted differences between census estimates and estimates obtained through Medicare eligibility files. However, if encounters with the health care system are a route of entry into the eligibility files, census denominators may be more appropriate. These authors have also suggested the use of denominators constructed from eligibility files with persons receiving benefits through health maintenance organizations removed, citing the lack of financial incentive for reporting encounters in these capitated payment systems (52). Consequently, these investigators stated that denominators should reflect the population at risk of both experiencing a fracture and being reported to the HCFA. The most appropriate denominator is probably some combination of these. All the above factors contribute to variability in the measurement of fluoridation and fracture rates. However, only a directional bias that preferentially misclassifies a county as fluoridated or nonfluoridated on the basis of fracture rates could provide an explanation for the observed association. This seems unlikely. However, the generalization from the association observed at the county level to one at the individual level (the ecologic fallacy) is more troublesome (53, 54). We have no way of characterizing the exposure levels (duration or amount) of individuals and relating it to fracture risk using this study design. It is possible that the persons with a lower fluoride intake within counties are at the highest risk of fracture. Secondly, we were unable to measure many factors that may confound the fluoride-fracture association. For example, we cannot control for factors such as hormone replacement therapy, activity levels, prescription use, cigarette use, or calcium consumption. If any of these factors are associated with fluoridation practices, they may be responsible for artifactually inflating or deflating the magnitude of our observed association. In addition to these measurement and design issues, the lack of a clear doseresponse relationship between hip fracture risk and duration of water fluoridation is disconcerting. The highest fracture rates for women were observed in the most recently fluoridated counties. One explanation for this finding might be that of an adaptive response to fluoride exposure. Within such a model, persons would be at a higher risk of fracture on initial exposure to fluoridated water, and the increased risk would attenuate with continued exposure. However, this observation may be due to some unmeasured confounder. Previous studies of hip fracture and water fluoridation in the United States demonstrated no clear pattern of association (27). Madans and others (31) compared selfreported fracture rates (using 5 years of National Health Interview Survey data) in counties where less than 20% of the population received fluoridated water with those in counties where more than 80% of the population received fluoridated water. For men, fluoridated counties had fracture rates 10% higher than did nonfluoridated counties, whereas for women, fracture rates in fluoridated counties were 10% lower than those in nonfluoridated counties. Koms (35) compared two communities in New York State and found fracture rates for men to be 74% higher in the fluoridated community compared to the nonfluoridated community. Rates for women were 9% lower in the fluoridated community. Goggin and others (36) reported fracture rates for Elmira, New York, for the 4 years prior and 4 years following the fluoridation of public water supplies. Overall, there was a 7.4% increase in fracture rates, the difference being concentrated in persons aged 75 years or older. Avom andNiessen (33) examined long-bone fracture rates among women aged 65 years or older who were enrolled in

AEP Vol. 2, No. 5 September 1992: 617-626

623

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

Michigan’s

Medicaid program, and found them to be 22% higher in the high-fluoride-

level counties of Michigan compared to low-fluoride-level

counties. However, sampling

error could not be ruled out for any of these studies. More recently, three communities

Sowers and others

(39) reported on prevalent

fracture rates in

in Iowa. Rates of hip, wrist, or vertebral fracture in the community

with high fluoride levels were elevated compared to those of the other communities. When the data were restricted to fractures occurring within the last 10 years, there was no difference in the rates of fracture of the hip, wrist, or spine; however, there was a significant

increase in prevalence

of other fractures.

Jacobsen and colleagues (16) demonstrated a statistically significant, though small, increase in fracture rates associated with increases in the percentage of population served with fluoridated water in 1975. This study compared hip fracture rates among the 3000 counties of the United States for 1984 through 1987. Compared to the present

study, the previous

measurement

of exposure.

approach

was much

more susceptible

to error in the

All counties were included, regardless of the probability

of

having a central public water system. Further, a number of counties were misclassified due to changes

in fluoridation

practices from 1975 to 1985.

The results of ecologic studies in other countries have also been inconsistent. Two studies from Finland examined fracture rates and water fluoridation. Amala and others (32, 34) reported fracture rates in three regions with high, medium, or low levels of fluoride in the drinking water. Among men, there was a consistent

monotonic

increase

in fracture rate with increasing fluoride levels for all ages greater than 60 years. However, the data were suggestive of the opposite relationship in women. Simonen and Laitinen

(28) reported on fracture rates in a high-fluoride-level

level region

in Finland.

Fracture rates were consistently

and a low-fluoride-

higher in the low-fluoride

regions for both men and women. The inconsistency between these two studies is of concern, especially given the similar rates between men and women in the low-fluoride area of Simonen

and Laitinen’s

study. In England,

Cooper and others (37) correlated

fracture rates with fluoride levels in public water systems in 39 county districts. first report,

conducted

with an a btiori hypothesis

Their

that fluoride would be protective,

demonstrated no association between fluoride levels and fracture rates. However, analysis of the data (38) demonstrated a significant positive association.

a re-

A synthesis of these data leads to the conclusion that water fluoridation at the levels conventionally used to protect against dental caries has no protective effect against hip fracture.

Whether

fluoridation

at these levels might actually increase the

risk of fracture is a more difficult question to answer. Certainly

there are no biologic

grounds for suspecting an adverse effect at such low doses. Recent

trials of fluoride in

patients with osteoporosis reveal adverse skeletal effects at dose levels that are 10 times higher than those ingested in our drinking water (24-26). In none of the epidemiologic studies to date did the relative risks for fracture rise above 1.7. However, the highest relative risks consistently occurred among men. This is consistent with our finding of a stronger association in men. This difference in magnitude of effect across sexes may be due to the overwhelming influence of sex hormones on bone mass in women. Such a strong factor may obscure smaller effects. Furthermore, if there is only a 10 to 15% increase in risk of fracture in either sex, it is not surprising that few studies have detected statistically significant associations, especially given the a priori hypothesis that fluoride should be protective. An appropriately designed cohort study conducted at the individual level would have to enroll 415,828 persons to declare a difference at a 5% level of confidence and a power of 80%. Our analysis, nonetheless, accords with two previous ecologic studies (16, 38) in

624

Jacobsen et al. WATER FLUORIDATION

AEP Vol. 2, No. 5 September1992: 617-626

AND HIP FRACTURE

pointing toward a small positive ecologic association between fluoridation of public water supplies and incidence of hip fracture among the aged. Although these observations do not yet provide a firm platform for health policy, they are sufficiently interesting to warrant further research. In particular, the relationship observed at the county level needs to be duplicated at the individual level, with more precise measures of fluoride exposure and control for relevant potentially confounding factors.

This work was supported in part by National Institutes of Health grant ROl-AG-08709 and a grant from the National Osteoporosis Foundation. The authors would like to thank Henry Krakauer, MD, PhD, and William Stiers, PhD, for their assistance in assembling a portion of the data used for this study. The helpful insights and comments of Kenneth P. Cantor, PhD, Darrell Sanders, ChE, and John Baron, MD, MSc, were also aooreciated.

REFERENCES 1.

Cummings

and osteoporotic

SR,

Kelsey JL, Nevitt

fractures,

Epidemiol

MC,

Rev.

O’Dowd,

KJ. Epidemiology

2.

Kelsey JL, Hoffman S. Risk factors for hip fracture,

3.

Holbrook

Impact,

TL,

and Cost

Academy

Grazier

of Orthopedic

4.

Cummings

Numbers,

costs,

K, Kelsey JL,

of Musculoskeletal Surgeons;

of osteoporosis

1985;7:178-208. Stauffer

Conditions

RN.

N Engl J Med. 1987;316:404-6. The

in the United

Frequency States.

of Occurrence,

Chicago:

American

1985.

SR, Rubin SM, Black D. The future of hip fractures in the United

and

potential

effects

of postmenopausal

estrogen,

Clin

Orthop.

States: 1990;

252:163-6. 5.

Farmer ME, White

incidence, 6.

Jacobsen

incidence Health.

LR, Brody JA, Bailey KR. Race and sex differences

Am J Public Health. SJ, Goldberg

J, Miles TP,

Brody JA,

Stiers

among the old and very old: A population-based

W, Rimm AA.

study of 745,435

Hip fracture

cases, Am J Public

1990;80:871-3. 7.

Gallagher

the proximal 8.

I. Frequency

9.

Silverman

10.

Elabdien

discharge

J Bone Joint

Mayo CIin Proc.

LJ III,

WM,

Wong PCN. Fracture epidemiology

15.

Solomon

16. variation

Jacobsen

International

in senile osteoporosis:

The association of hip fracture

in

Secular

trends

in the incidence

of hip

patterns

of osteoporosis,

Clin Orthop.

in a mixed southeastern

1966;45:17-30.

Asian community

(Singa-

1966;45:55-61. L. Osteoporosis

J Bone Joint

Asians,

1988;78:1482-3.

S, Smedby B. Rising incidence

Riggs BL.

Nordin

Bantu,

of hip fracture in Hispanics,

1987;41:57-64.

14.

Orthop.

WM. Limb fractures in a defined

1984;55:284-9.

13. Clin

BEC.

Stand.

O’Fallon

Int.

of

1979;54:701-7.

data, Am J Public Health. variations

of fractures

Surg [Br]. 1970;52:667-75.

Acta Orthop

Tissue

E. Epidemiology 1980;150:163-71.

Stauffer RN, Kurland LT, O’Fallon

BSZ, Olerud S, Karlstrom

Melton Calcif

Clin Orthop.

J, Ho KC. Geographical

activity,

1965-1980,

12.

Minnesota,

and distribution,

hospital

Chalmers

11.

LJ III, Riggs BL, Bergstraith

SL, Madison RE. Decreased incidence

California

with physical

fracture,

Melton

Garraway WM,

and blacks:

Uppsala,

JC,

femur in Rochester,

population:

pore),

in hip fracture

1984;74:1374-80.

and fracture

of the femoral

neck

in the South

African

Surg [Br]. 1968;50:2-13. SJ,

Goldberg

in the incidence

J, Miles

of hip fracture:

TP,

Brody JA,

Stiers

W,

Rimm

AA.

Regional

US white women aged 65 years and older, JAMA.

1990;264:500-2. 17.

Stroup

hospitalization

NE,

Freni-Titulaer

rates for fracture

WJ,

Schwartz

JJ.

of the hip, J Bone Joint

Unexpected

geographic

Surg [Am].

1990;72:

variation

1294-8.

in

AEP Vol. 2, No. 5 September 1992: 617426

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

625

18. Bacon WE, Smith GS, Baker SP. Geographic variation in the occurrence of hip fractures among the elderly white U.S. population, Am J Public Health. 1989;79:1556-8. 19. Trotter M, Broman GE, Peterson RR. Densities ofbones ofwhite and negro skeletons, J Bone Joint Surg [Am]. 1960;42:50-8. 20. Farley JR, Wergedal JE, Baylink DJ. Fl uoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells, Science. 1983;222:330-2. 2 1. Hall BK. Sodium fluoride as an initiator of osteogenesis from embryonic mesenchyme in vitro, Bone. 1986;B:ll l-6. 22. Farley SM, Libanati CR, Mariano-Menez MR, Tudtud-Hans LA, Schulz EE, Baylink DJ. Fluoride therapy for osteoporosis promotes a progressive increase in spinal bone density, J Bone Miner Res. 1990;5(suppl 1):537-42. 23. Harrison JE, Bayley TA, Josse RG, et al. The relationship between fluoride effects on bone histology and on bone mass in patients with postmenopausal osteoporosis, Bone Miner. 1986;1:321-33. 24. Riggs BL, Hodgson SF, O’Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis, N Engl J Med. 1990;322:802-9. 25. Kleerekoper M, Peterson E, Phillips E, Nelson D, Tilley B, Parfitt AM. Continuous sodium fluoride does not reduce vertebral fracture rate in postmenopausal osteoporosis, J Bone Miner Res. 1989;4(suppl l):S376. 26. Riggs BL, Baylink DJ, Kleerekoper M, Lane JM, Melton LJ 111. Incidence of hip fractures in osteoporotic women treated with sodium fluoride, J Bone Miner Res. 1987;2: 123-6. 27. Melton LJ III. Fluoride in the prevention of osteoporosis and fractures, J Bone Miner Res. 1990;5(suppl l):S163-7. 28. Simonen 0, Laitinen 0. Does fluoridation of drinking water prevent bone fragility and osteoporosis?, Lancet 1985;2:432-4. 29. Bernstein DS, Sadowsky N, Hegsted DM, Guri CD, Stare FJ. Prevalence of osteoporosis in high- and low-fluoride area in North Dakota, JAMA. 1966;198:499-504. 30. Alffram PA, Hernborg J, Nilsson BER. The influence of a high fluoride content in the drinking water on the bone mineral mass in man, Acta Orthop Stand. 1969;40:137-42. 31. Madans J, Kleinman JC, Comoni-Huntley J. The relationship between hip fracture and water fluoridation: An analysis of national data, Am J Public Health. 1983;73:296-8. 32. Arnala I, Alhava EM, Kivivuori R, Kauranen P. Hip fracture incidence not affected by fluoridation: Osteofluorosis studied in Finland, Acta Orthop Stand. 1986;57:344-8. 33. Avom J, Niessen LC. Relationship between long bone fractures and water fluoridation, Gerodontics. 1986;2:175-9. 34. Amala 1. Fluoridation and hip fractures (letter), Med J Aust. 1987;146:451. 35. Korns RF. Relationship of water fluoridation to bone density in two N.Y. towns, Public Health Rep. 1969;84:815-25. 36. Goggin JE, Haddon W Jr, Hambly GS, Hoveland JR. Incidence of femoral fractures in postmenopausal women, Public Health Rep. 1965;80:1005-11. 37. Cooper C, Wickham C, Lacey RF, Barker DJP. Water fluoride concentration and fracture of the proximal femur, J Epidemiol Community Health. 1990;44: 17-9. 38. Cooper C, Jacobsen SJ, Wickham CAC, Barker DJP. Water fluoridation and hip fracture (letter), JAMA. 1991;266:513-4. 39. Sowers MFR, Clark MK, Jannausch ML, Wallace RB. A prospective study of bone mineral content and fracture in communities with differential exposures, Am J Epidemiol. 1991;133:649-60. 40. Fluoridation Census. Washington, DC: Dental Disease Prevention Activity, Bureau of State Services, Center for Disease Control, Public Health Service, US Department of Health, Education, and Welfare; 1975. 41. Hoover RN, Devesa SS, Cantor KP, Lubin JH, Fraumeni JF Jr. Fluoridation of Drinking Water and Subsequent Cancer Incidence and Mortality. In: Review of Fluoride Benefits and Risks. Washington, DC: Ad Hoc Subcommittee on Fluoride, Committee to Coordinate Environmental Health and Related Programs, Public Health Service, Department of Health and Human Services; 1991.

626

Jacobsen et al. WATER FLUORIDATION AND HIP FRACTURE

42.

Health

Medicare

Care Financing

Statistical

AEP Vol. 2, No. 5 September 1992: 6 17-626

Administration,

Files Manual.

Bureau of Data Management

Baltimore,

MD:

Health

Care

Financing

and Strategy. Administration;

1990. 43. tion.

Breslow L. The International

v. 1-3.

Service,

Health

44.

Printing

US Office;

Population

County

Reports,

DC: US Government Fleiss JL. Statistical

Printing

Methods

Breslow NE, Day NE. Statistical

Analysis

of Cohort

Agency

for Research

KJ. Modem Studies.

Population

by Age,

Printing

Sex,

and Race:

DC: US Government

Estimates

Reports,

of the Population

series P-23,

no. 103.

1985.

for Rates and Proportions. Boston:

Methods

2nd ed. New York: John

Scientific

Little,

Brown;

Ray WA,

Publications

v. II. The Design and

no. 82. Lyon, France:

International

1987.

data for epidemiologic

research,

0 vercoming

Am J Public Health.

Griffin MR, Fought R, Adams ML. Identification

potential

pitfalls

1990;80:1487-90.

of fractures from compu-

files, J Clin Epidemiol.

Fisher ES, Baron JA,

Hip fracture

1986.

in Cancer Research.

Fisher ES, Baron JA, Malenka DJ, Barrett J, BubolzTA.

terized Medicare

54.

Estimates

for Experimental

Office;

Epidemiology.

IARC

in Cancer;

in the use of Medicare

53.

by Age, Sex,

DC: US Government

1981:244-7. Rothman

Health.

Intercensal

Methodology

48.

52.

no. (PHS)BO-1260.

(Experimental)

series P-23, no. 139. Washington,

49.

51.

Washington,

by Age and Sex: July 1, 1975. Current

Washington,

50.

publication

Estimates

Modifica-

Public Health

1985.

US Bureau of the Census.

of Counties, 47.

documentation.

9th rev. Clinical

and Human Services,

1980. DHHS

County Population

Bureau of the Census.

Current

46.

Wiley;

Administration;

Technical

of Diseases.

of Health

1989.

45. 1970-80.

Care Financing

1980-1985.

Classification

MD: US Department

US Bureau of the Census.

and Race: Office;

Hyattsville,

incidence

Morgenstem

Malenka

and mortality

DJ, B arrett JA,

in New England,

H. Uses of ecologic

analysis

Bubolz TA,

Epidemiology. in epidemiologic

Kriff WD,

Whaley

FS.

1991;2:116-22. research,

Am J Public

1982;72:1336-44. Langbein

in the Social

LI, Lichtman

Sciences,

no. 07-010.

AJ. Ecologic Beverly

Inference.

Hills,

CA:

Series on Quantitative Sage;

1978.

Applications