spinal meningiomas in women in los angeles county ...spinal tumors is the preponderance of...

%“()l. 4. 333-339. Ju,:e /995 Cancer Epidemiology, Biomarkers & Prevention 333

3 The abbreviations used are: CSP, Cancer Surveillance Program: ERT. estrogen

replacement therapy; OR. odds ratio.

Spinal Meningiomas in Women in Los Angeles County:Investigation of an Etiological Hypothesis1

Susan Preston-Martin,2 Kristine Monroe, Pey-jiuan Lee,Leslie Bernstein, Jennifer Kelsey, Sean Henderson,Deborah Forrester, and Brian Henderson

Departments of Preventive Medicine [S. P-M., K. M., P-j. L., L. B., S. H.,

B. H.l and Radiology ID. Fl, University of Southern Califomia, Los Angeles,

California 9(8)33, and Stanford University. Stanford. California 94305 [J. K.l

Abstract

A series of 3 studies explored the hypothesis that thepreponderance of spinal meningiomas amongpostmenopausal women relates to their higher prevalenceof spinal osteoporosis: (a) medical records showed thatmeningiomas in women, unlike other spinal tumors,usually arise in the mid thoracic spine where osteoporoticvertebral fractures predominate; (b) radiographicevidence of osteoporosis was seen commonly withmeningiomas but not with other spinal tumors; and(c) age-adjusted multivariate analysis of data from aninterview study of 81 women with spinal meningioma and155 random digit dial controls showed 6 factors related torisk. Four factors were protective: (a) current use (atdiagnosis) of estrogen replacement therapy [odds ratio(OR) = 0.2; 95% confidence interval (CI) 0.1-0.61;(b) past use of oral contraceptives (P trend <0.01);(c) past participation in sports (OR 0.5; CI 0.2-0.9);and (d) premenopausal status (OR = 0.2; CI = 0.1-0.7).Risk increased among women who had ever smokedcigarettes (OR 1.7; CI 0.9-3.1) or had a history ofhigh dose radiography (>500 mrad exposure to activemarrow/examination; includes upper or lowergastrointestinal series and/or cardiac angiography; OR2.9, and CI 1.6-5.3), although no association was seen

with prior radiotherapy. Other results that did not

support the hypothesis include findings that cases andcontrols were similar in mean body weight and in theproportion who had postmenopausal fractures or heightloss. In conclusion, these studies lend some support to ourhypothesis, but other known meningioma risk factorssuch as ionizing radiation also appear important. Wepropose that osteoporotic collapse fractures of thevertebrae can traumatize the spinal meninges, causing

damage and subsequent repair of the meninges, and thatthe cell proliferation that occurs during the repairprocess increases the likelihood of tumor developmenL

Received 10/13/94: revised 12/21/94; accepted 12/21/94.

I Supported in part by American Cancer Society Grants SIG-2 and FRA-329 and

National Cancer Institute Grant CA17054.

2 To whom request for reprints should be addressed, at Department of Preventive

Medicine. University of Southern California School of Medicine, ParkviewMedical Building B301. 1420 San Pablo Street. Los Angeles. CA 90033-9987.

Introduction

Although spinal meningiomas are uncommon, they show cer-tam striking descriptive features, which suggests that an epide-miological study of these tumors may make a special contni-bution to defining the roles of both trauma and female

hormones in the neoplastic process in a nonreproductive organ.The most striking feature of the descriptive epidemiology of

spinal tumors is the preponderance of meningiomas in womenand the sharp postmenopausal rise in the incidence of this tumor(Ref. 1; Fig. 1). Both spinal meningiomas and spinal osteopo-rosis occur predominantly in the thoracic spinal region ofwomen over age 50 years (2, 3). We hypothesize that spinal

meningiomas may be related to trauma to the meninges fromsevere osteoporotic changes in the spine and may, thereby, alsobe associated with osteoporosis risk factors such as indicators

of low ovarian steroid levels.We conducted a series of case-control studies of spinal

meningiomas in women in Los Angeles County (Los Angeles,CA) designed to investigate this hypothesis: (a) a descriptivestudy reviewed pathology reports and compared the location ofspinal meningiomas to the location of other spinal tumors.

These distributions were then compared to published data onthe distribution of vertebral fractures by location; (b) a radio-graph review study compared X-ray evidence of spinal osteo-porosis in meningioma cases and in patients with other spinal

tumors; and (c) an interview study compared cases and controlsin regard to symptoms of spinal osteoporosis (e.g. , loss inheight), indicators of hormonal status (e.g. , menstrual and re-

productive history and use of exogenous estrogens), and pre-viously suggested risk factors for intracranial meningiomas

(e.g. , X-rays, trauma, neurofibromatosis, and N-nitroso com-pounds) or osteoporosis (e.g., prolonged immobility, thinness,and cigarette smoking).

Materials and Methods

Files of the Los Angeles County University of Southern Cali-fornia CSP3 were used as the source of patients with spinaltumors. The CSP has collected information on all tumors (be-nign and malignant) of the central nervous system among

county residents since 1972 (1).

Review of Medical Records for Location of Spinal Tumors.CSP abstracts and attached pathology reports were reviewedand tumor location within the spine (i.e., CI-7, TI-12, LI-S. and5) was recorded for all patients with diagnosis of spinal gliomaor spinal meningioma from 1972 to 1985. Information on thelocation of the tumor within the spine was available for 152women with meningiomas and for 129 men and women withgliomas; men were included in this comparison because of the

on July 7, 2020. © 1995 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

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25-341 5-24 35-44 55-64

Age at diagnosis (years)

334 Spinal Meningiomas in Los Angeles Women

1.4

0�

00

:1.00)ci0)

�O.80)

�0C.)

.� 0.6

C

0.2

0.0

Fig. 1. Annual age-specific incidence/1(X),tXX) of spinal tumors (benign and

malignant) by major histological type (gliomas, meningiomas and nerve sheath

tumors) and sex, Los Angeles County. 1972-1987, all ethnic groups combined.

extreme rarity of spinal gliomas in women and because the twogenders appeared similar in subsite distribution of these tumors.The distributions by location of groups of tumors were com-

pared with the use of a Mantel-Haenszel � test.

Radiograph Review for Evidence of Osteoporosis. During1986 we obtained radiographs of the spine for a sample offemale patients ages 40 years or over with spinal tumors diag-nosed from 1980 to 1985. We included patients with other typesof spinal tumors for comparison because we were unable to find

published data on radiographic changes in normal women ofsimilar ages (i.e. , women asymptomatic for osteoporosis).These were obtained by contacting hospitals and asking thatthey mail the radiographs to us. Radiographs for 2 of the 69women could not be located, and after 2 mailings hospitalsmailed us available radiographs on all but 1 of the remaining 67women. One of us (D.F., a radiologist who specializes in bone

diseases) reviewed radiographs on 48 women with meningio-mas and on 18 women with other spinal tumors for evidence of

osteoporosis, including various degrees (mild, moderate, andsevere) of loss of bone density and vertebral collapse. The

criteria used for each category were: mild, loss of secondarytrabeculae (accentuation of vertical stniations); moderate, lossof primary and secondary trabeculae (lucent appearance tovertebral bodies with accentuation of cortical frame); and Se-

vere, compression fractures of multiple vertebral bodies. Al-though these data are limited severely by small numbers (es-

pecially in the comparison group), the proportion of womenwith radiographic evidence of osteoporosis was compared for

the two groups of women taking age into account.

Case-Control Interview Study. Female residents of Los An-geles County ages 20-74 years with a spinal meningiomadiagnosed from 1978 to 1985 were eligible for inclusion as

cases in the interview study. Some of the women in the radio-graph review study were also included in the interview study.

Because of the type of information asked in the interview, a

subject had to be alive and able to be interviewed in English tobe included in the study. The CSP identified 95 eligible casesin addition to 7 who were deceased but otherwise eligible and4 who did not speak English well enough to be interviewed.

Physicians advised us not to contact 4 women, we were unableto locate 6, and 4 refused to participate. We interviewed 81women; this represents 95% ofthe 85 women contacted about the

study or 76% of the 106 women identified originally by the CSP.Female controls, frequency matched by decade of birth,

were identified by random digit dialing with the use of amethod described in detail previously (4). Every effort wasmade to interview controls in each decade of birth stratum inthe order identified until the number of controls sought in thatstratum was reached. Over 90% of Los Angeles residences areestimated to have telephones (5), and all case subjects includedin the study had telephones. The response rate at the householdscreening stage was 79%. Of the 206 telephone numbersthought to be residences of eligible controls, 20 turned out to beineligible because of gender, age, or inability to speak English;

31 refused to be interviewed. We completed an interview with155 (83%) ofthe 186 eligible controls contacted. Therefore, the

75+ overall response rate was 0.83 X 0.79 (66%).

Because controls were not individually matched to cases itwas necessary to calculate a reference age for each. Age stratawere created using birth year, i.e. , cases and controls werematched on birth year and divided into strata. Each stratum

consisted of 1-3 birth years. With the use of the diagnosis datesof the cases, the variable “mean age of diagnosis” was createdwithin each stratum. Mean age at diagnosis was then used to

determine the reference age for the controls within each stra-tum; a corresponding reference date was also determined. In the

analysis each variable was adjusted to assure that only eventsthat had occurred before the calculated reference age wereincluded. For X-ray variables only events more than 5 yearsbefore reference age were included. We verified that the mean

age at interview was similar for cases and controls.A standardized questionnaire was administered by tele-

phone by one trained interviewer. Only study subjects them-selves were accepted as respondents because it was felt thatinformation from proxy respondents would be unreliable forseveral of the exposures of major interest, in particular, mdi-cators of hormonal status, or osteoporosis, and suggested os-teoporosis risk factors. The questionnaire covered demographicvariables, menstrual and reproductive history, use of exogenous

estrogens, indicators of osteoporosis (such as height loss, his-tory of bone fractures, previous spinal trauma, and other back

and neck problems), exposure to X-rays, central nervous systeminfections, history of spinal taps and spinal anesthesia, cigarettesmoking history, alcohol use, dietary and other sources of

exposure to N-nitroso compounds, use of vitamins, job history,physical activity on the job, and strenuous exercise and serious

involvement in sports during various decades of life. Interviewswith the 81 cases and the 155 controls averaged 30 mm and

were conducted from March 1985 to April 1987.

Because age is related so strongly both to meningiomaincidence, as well as to most factors of primary interest (e.g.,menopausal status and use of hormone replacement therapy),

all analyses were adjusted by age (usually birth year strata of�2 years). Other potential confounders (e.g. , socioeconomicstatus) were considered, but none was found to be important.The OR was used as the measure of association between risk ofspinal meningioma and variables of interest. Logistic regressionanalyses were used to calculate point estimates and 95% con-

fidence intervals of summary OR for dose-response analysis ofa single variable considered at more than two levels, for tests of



Cancer Epidemiology, Biomarkers & Prevention 335

Table 1 Distributions of spinal meningioma cases and random digit dial

controls by age and socioeconomic status, Los Angeles County, 1978-1985

Cases Controls

No. % No.

Age (yr)

<35 3 3.7 14 9.0

35-39 2 2.5 4 2.6

4(1-44 6 7.4 7 4.5

45-49 5 6.2 21 13.6

50-54 11 13.6 9 5.8

55-59 10 12.4 19 12.3

60-64 10 12.4 20 12.9

65-69 20 24.7 39 25.2

�70 14 17.3 22 14.2

Total 81 155

SES”

1 (high) 1 1.2 2 1.3

2 11 13.6 25 16.1

3 21 25.9 46 29.7

4 36 44.4 54 34.8

5 (low) 12 14.8 28 18.1

Total 81 155

(‘ SES, socioeconomic status: Hollingshead scale used for SES classification (27).

trend, and for multivariate analyses (6). P values are based on

a likelihood ratio test and are two-sided. Tests for trend arecontinuous whenever possible. A multivariate analysis, con-trolled for age, considered primary variables (related to osteopo-rosis) and one secondary variable (X-rays that are known to causeintracranial meningiomas).

Results

Location of Spinal Tumors. Results of the CSP record reviewstudy indicate that the majority of meningiomas (59%) occur inthe thoracic spine between T3 and T9. Only 22% of gliomas inboth sexes combined (29% in women) occur between T3 andT9. The difference in these distributions is highly significant (p

< 0.0001).

Radiograph Review. Radiographs were reviewed from 48meningioma and 18 other Los Angeles County women ages 40

years and over with a spinal tumor first diagnosed from 1980 to1985. One-half (9) of the other tumor patients and two-thirds(32) of the meningioma patients had some radiographic cvi-

dence of osteoporosis. For 15 meningioma patients (47%) com-pared to only 2 other tumor patients (22%) the osteoporotic

changes were classified as moderate or severe. Because thesemeningioma patients were on average older than the othertumor patients and because osteoporotic change is so closelyassociated with age, we also limited the comparison to thosepatients who were ages 45-54 years at tumor diagnosis. In eachtumor group there were 7 patients in this age range, and theaverage age at diagnosis was 50.0 years for those with menin-gioma and 51.6 years for the other spinal tumor patients. Five(71%) ofthe meningioma patients and only 1 (14%) ofthe othertumor patients in this age group had spinal osteoporosis (P

0.10 using the Fisher exact test), and only meningioma patients(3 patients) showed severe osteoporotic changes.

Interview Study. Cases and controls were similar in theirdistributions on a number of demographic factors including ageand socioeconomic status (Table 1). Most were white, and only10% of both cases and controls were black. At reference date,

Table 2 Age-adjusted comparison of women with spinal meningiomas to

controls on various reproductive factors, Los Angeles County, 1978-1985

No.OR 95% CI P trend”

Cases Controls

Age at menarche (yrs)

�11 14 26 1.0 0.33

12-13 32 81 0.7 0.3-1.6

14+ 34 48 1.3 0.6-2.9

Pregnancy status

Never pregnant 17 25 1.0

Ever 64 130 0.7 0.4-1.5

Age at 1st pregnancy (yrs)

14-19 16 28 1.0 0.36

20-24 29 56 0.9 0.4-2.0

25-29 13 29 0.8 0.3-2.0

30+ 6 17 0.6 0.2-1.9

Still menstruating

No 70 114 1.0

Yes 11 41 0.3 0.1-4).8

Age at last menstrual period

�44 12 18 1.0 0.55

45-54 30 59 0.8 0.3-1.8

55+ 6 13 0.7 0.2-2.4

Use of oral contraceptives

Never 66 108 1.0 0.04

�36 months 10 24 0.6 0.2-1.5

�37 months 5 23 0.3 0.1-1.0

Use of ERT�’

Never 42 62 1.0 0.13

Past user 24 31 1.2 0.6-2.4

Current user 4 21 0.3 0.1-1.8

Duration of ERT (yrs)

Never 42 62 1.0 0.31

�5 18 28 1.0 0.5-2.0

>5 10 24 0.6 0.3-1.4

“ Trend tests used continuous data whenever available.S Analysis restricted to women with natural menopause.

52% of cases and 50% of controls were married. The distribu-tions by religion were also similar except that a higher propor-tion of cases was Jewish (23.5, compare 8.4%; P = 0.001). No

striking differences were apparent in the distributions by theirlongestjob, and the only specific jobs held by a notably higherproportion of cases than controls were hairdresser (4, compare

1), sewer/stitcher (3, compare 1), and cashier (3, compare 0).

The circumstances leading to the diagnosis of a spinalmeningioma were evaluated. The majority (94%) of cases con-suited a physician because they had tumor-related pain ordysfunction. The remaining 5 cases were diagnosed inciden-tally when consulting a physician because of a fall (2 cases),another accident (2 cases), or after having a scan for anotherreason that happened to show the tumor (1 case).

Table 2 compares women with spinal meningiomas tocontrol women on various reproductive factors. Cases and

controls are similar in age at menarche (means of 13.2 and 12.9years, respectively). A higher proportion of controls had everbeen pregnant, and they tended to have had a first pregnancy ata younger age, but none of these differences reaches statistical

significance. The distribution of cases and controls by numberof pregnancies was not different (P = 0.38). In these age-adjusted comparisons a significantly lower proportion of caseswas still menstruating at reference date (OR 0.3; P 0.02),




Table 3 Age-adjusted comparison of women with spinal meningioma andcontrol women on smoking and sport participation. Los Angeles County,

1978-1985

Cases

No.

ControlsOR 95% Cl P trend

Pack.ycars of smoking

Never 35 81 1.0 0.33

1st half �24.5 24 37 1.5 0.8-3.0

2nd half >24.5 22 37 1.3 0.8-3.0

Sports participation

No sports

Sports

59

22

92

63

1.0

0.6 0.3-1.0


No sports

�l08 months

59

11)

92

34

1 .0

0.5 0.2-1.1

0.13

>lt)8 months 12 29 0.7 0.3-1.4

and risk was reduced significantly among current users ofERT. Cases tended to have menopause at a younger age andshorter use of ERT, but these differences were not statisticallysignificant.

Although a higher proportion of cases smoked, no trendrelated the number of pack-years smoked and meningioma risk

(Table 3). A smaller proportion of cases than controls everdrank various alcoholic beverages regularly (at least once aweek for 6 months or longer), and the level of alcohol con-

sumption among controls was also somewhat higher. Only 1

case might be considered a heavy or moderate drinker (versus

7 controls).Cases and controls were similar in their distributions by

job activity level; about 20% rated their longest held job assedentary (1 on a 5-point activity scale), and about 15% ratedtheir most active job as moderately or very active (4 or 5 on thescale). There also were no apparent differences in the amountof lifting of objects over 10 pounds (or over 25 pounds) re-quired in jobs held by cases versus controls. A lower proportionof cases, at some time in their lives, had done regular strenuousexercise (e.g., jogging, lap swimming, and cycling), partici-pated in competitive sports (e.g., track and field and running),or had some other serious involvement in sports (OR 0.6;P = 0.06; Table 3).

A higher proportion of cases had various specific radio-graphic examinations of the trunk 5 or more years prior to

diagnosis including thyroid scans, upper or lower gastrointes-tinal series, cardiac angiograms, and certain spinal X-rays

(Table 4). For some of these examinations risk increased withthe number of times each was performed as indicated by the Pvalue for trend. No increase in risk was seen relating to a

number of other radiographic examinations including i.v. py-elograms, gallbladder series, mammograms, chest fluoroscopy,

other chest X-rays, and X-ray examinations of the shoulders,abdomen, pelvis, hips, or teeth. Six versus 7% of cases and

controls had a history of radiation treatment that would haveincluded at least one portion of the spine in the radiation field.

Other factors investigated included body size; variousindicators of osteoporosis; other medical conditions (including

back problems and activities that might relate to the develop-ment of back problems); medical procedures involving thespine; exposures to substances that contain N-nitroso com-pounds; and consumption of cured meats, citrus fruits, andvitamin supplements. Mean body weight was slightly greatenfor cases compared to controls both at age 40 years (135.3,

Table 4 Age-adjusted comparison of women with spinal meningioma and

control women on whether they had various radiographic examinations more

than 5 years before diagnosis age, and on total number of each type of

examination, Los Angeles County, 1978-1985

No. of No. of 95% CI” MeanType of exam OR dose

Cases Controls (P trend)(mrad)

Thyroid scan

Never 69 145 1.0 (<0.01) 44

Ever 12 10 2.6 1.1-6.2

Upper GI

Never 44 1 12 1.0 (0.10) 535

Ever 37 43 2.2 1.4-3.8

Lower GI

Never 47 125 1.0 (0.04) 875

Ever 34 30 3.0 1.6-5.4

IVP

Never 75 135 1.0 (0.53) 420

Ever 6 19 0.6 0.2-1.5

Cardiac angiography

Never 76 151 1.0 (0.14) 1133

Ever 5 3 3.3 0.8-14.3

Gallbladder series

Never 75 133 1.0 (0.22) 168

Ever 6 22 0.5 0.2-1.2

Cervical spine

Never 70 141 1.0 0.07 52

Ever 11 14 1.6 0.7-3.8

Thoracic spine

Never 77 147 1.0 0.87 247

Ever 4 8 1.0 0.3-3.3

Lumbar spine

Never 61 128 1.0 0.65 347

Ever 20 27 1.6 0.8-3.0

“ Upper GI, upper gastrointestinal series with barium swallow; lower GI, lowergastrointestinal series with barium enema; IVP, iv. pyelogram.S Continuous.

� Mean dose to active bone marrow. All based on 1970 estimates of Shleien (21)

except thyroid scan (22).

compare 134.5 pounds) and at interview (145.2, compare 142.6

pounds). Few women had been told by a physician that they hadosteoporosis (3% of cases, compare 2% of controls). Amongsubjects who were over age 45 years at reference date, 1 1 and10% of cases and controls, respectively, reported that they were

shorter now than at age 40; 2 cases and 3 controls were 2 ormore inches shorter. One-third of both cases and controls had

ever broken a bone, but few of these fractures had occurredafter age 40. No case (compare 4 controls) had broken her hip.Over 90% of cases and controls who had fractures had brokena bone in one of their extremities, and overall, a higher pro-portion of cases reported having had only 1 fracture. Threecases and only 1 control had been bedridden or in a wheelchairfor longer than 1 year.

No subjects had a history of toxoplasmosis, encephalitis,

or other spinal cord infection or a personal or family history ofdiseases such as neurofibromatosis known to predispose tospinal tumors. Few cases and controls had a history of certainrare medical conditions that were of interest because they might

have required multiple radiographic examinations of the back(scoliosis). Similar proportions of cases and controls ever hadproblems with the low back (38.5 and 37.2% respectively), buta larger proportion of cases had problems with the midback



Cancer Epidemiology, Blomarkers & Prevention 337

Table 5 Multivariate model including menstrual status, estrogen replacement

therapy, oral contraceptive use, sports participation, smoking history, and

history of selected high dose radiographic examinations, case-control study of

spinal meningiomas, Los Angeles County, 1978-1985

OR” 95% CI”

Still menstruating

No 1.0

Yes 0.2 0.1-0.7

ERT use

Never 1.0

Past 0.9 0.4-1.8

Current 0.2 0.1-0.6

Oral contraceptive use

Never 1.0 (P for trend 0.01)

LE 3 years 0.4 0.2-1.3

GT 3 years 0.2 0.1-0.7


Never 1.0

Ever sports 0.5 0.2-0.9

Smoking history

Never 1.0

Ever smoked 1.7 0.9-3.1

High dose radiography”

Never 1.0

Ever 2.9 1.6-5.3

“ Each adjusted for reference age as well as for other variables in the table.

b Ever had a radiographic exam involving >500 mrad exposure to active marrow

(i.e., upper gastrointestinal series with barium swallow or lower gastrointestinal

series with barium enema, and/or angiogram).

(20.0 and 13.2%, respectively) and neck (29.2 and 19.4%

respectively).Similar proportions of cases and controls had a history of

selected medical conditions, including a previous cancer, dia-betes, polio, rheumatoid arthritis, arthritis in the back, slippeddisc, and meningitis; the frequency of each of these conditionswas < 10%. About 40% of both cases and controls had ever had

a spinal tap or spinal anesthesia such as a saddle block. Casesand controls were similar on N-nitroso related variables, such asdaily use of face makeup and consumption of cured meats in theyear before the interview and 20 years earlier, except that 4cases versus 0 controls had burned incense daily. The distnibu-tions by frequency of consumption of citrus fruit 20 years agowere also similar.

Subjects were also asked about their use of 5 types ofvitamin or mineral supplements, multivitamins; vitamins C, E,

and D; and calcium. Proportionately fewer cases than controlsever took muitivitamins regularly (at least once a week for 6months or longer; 43.2, compare 52.9%) and fewer took themat least daily (40.7, compare 47.7%). The OR for daily use ofmultivitamins for 20 years or longer was 0.4 (95% CI = 0.2,1.1; P trend for years of use 0.26). Similar proportions ofcases and controls even took vitamins C (about 33%) or E(about 20%), and the number of years of daily use was also

similar. Only 1 case and 1 1 controls ever took vitamin D daily.A smaller proportion of cases ever took calcium regularly (27.2,

compare 35.5%) on daily (23.5, compare 31.6%), but there wasno trend relating risk to years of daily calcium supplementation.

Over two-thirds of subjects who took calcium began taking it atage 50 years or older.

The multivaniate analysis included factors shown in pre-vious studies to relate to osteoporosis (including menopausalstatus, exogenous estrogen use, physical activity, and smoking)

and X-rays (because ionizing radiation is the only factor knownto cause intracranial meningiomas). This analysis was alsodone, excluding the four cases for whom a traumatic event (fall

on other accident) immediately preceded tumor diagnosis, andthe results were essentially unchanged.

Six factors appear to be independently related to risk inTable 5. Premenopausal status, use of oral contraceptives, ERTuse, and exercise are all protective. Smoking and high doseradiography to the trunk increase risk.

Discussion

We undertook this series of studies of spinal meningiomas inwomen to test our hypothesis that this disease may be associ-ated with osteoporosis-related trauma, in particular with traumato the spinal meninges either by direct contact with bone

fragments from a collapse fracture of the vertebrae or by thestretching or tearing of the meninges that occurs when a dow-

ager’s hump develops. This hypothesis arose in the context ofwhat we knew about the association seen between intracranialmeningiomas and head trauma (7-9) and the observation of the

sharp increase in incidence of spinal meningiomas amongwomen after the menopause.

Study Limitations. Small numbers were a problem in allphases of this investigation, particularly as noted previously, inthe radiograph review because of the extreme rarity of spinal

tumors other than meningioma among women over age 45years. After consultation with radiologists we were unable to

think of any other suitable comparison group for whom radio-graphs would be available. Also, in the review of some radio-

graphs the presence of the tumor may have obscured evidenceof osteoporosis. However, this is more likely to have been aproblem for meningioma patients because, compared to patientswith other types oftumors, they are more likely to have both the

osteoporotic changes and the tumor in the thoracic spine. Sucha situation would tend to bias results toward the null.

Because interview study participants needed to be toldhow we got their names, the interviewer was not blinded as to

case or control status. However, interview technique was stan-dard for all subjects and included use of a questionnaire with averbatim script. Neither the interviewer nor the participantsknew the primary study hypothesis to which only a smallproportion of the many interview questions related. Poor recall

is a problem for a number of the variables queried. Although wedid not attempt to validate interview information in this study,other studies have compared similarly collected interview dataon X-rays and ERT to data recorded in medical charts and have

determined that recall is not biased and is good enough to useas the basis of comparison in case control studies (10, 1 1).

Selection bias was minimized by including all eligible cases ina defined geographic area and the first eligible controls in eachstrata.

Possible alternate explanations for our findings shouldalso be considered. It is possible, for example, that osteoporosismight be associated with the diagnosis of meningioma rather

than its etiology. This possibility cannot be ruled out entirelybut seems unlikely. The pain and dysfunction that brought thesewomen to the doctor and led to their tumor diagnosis were

described on the tumor registry abstract and by the womanduring the interview as tumor-related symptoms. Also, verte-

bral collapse fractures most often go undiagnosed because theyusually don’t cause pain (3). Indeed, only 3% of patients hadever been told by their physicians that they had osteoporosis.Also, the possibility that the tumors themselves may causevertebral fractures cannot be ruled out.




Factors Related to Osteoporosis. Two recent clinical papers

discussing the pathogenesis and prevention of osteoporosis

provide a cursory summary of associated risk factors and pro-

tective factors (12, 13). The epidemiological literature indicatesthat the association with various factors has varied considerablyin its consistency. Consistently protective effects among post-

menopausal women under age 75 years have been seen for ERT

(14) and physical activity (15). Good evidence for the effect ofcigarette smoking on bone density is available from a recenttwin study (16). The effects of obesity (17), oral contraceptiveuse (18), and micronutrients (19) are far less well defined.

The series of studies reported here does provide some

evidence in support of our primary hypothesis. The comparisonof meningiomas and gliomas by location within the spine

showed that, unlike gliomas, meningiomas occur predomi-

nantly in the thonacic spine where most osteoporotic collapsefractures also occur; this observation provided only cincumstan-

tial support for our hypothesis but did provide the encourage-ment needed to pursue additional work. The radiograph reviewstudy was hampered by small numbers, in particular the small

number of nadiographs available for postmenopausal womenwith other histological types of spinal tumors, and by the

extreme rarity of these tumors. Nonetheless, our comparison ofradiognaphs of women ages 45-54 years at tumor diagnosis

showed a strikingly higher frequency of osteoponotic changes

(particularly severe changes) in the spines of meningioma com-pared to other spinal tumor patients.

The interview study asked about a number of risk factors

commonly (on occasionally) associated with osteoporosis. Allof the analyses controlled closely for age. Risk was found to be

associated with menopausal status and ERT use but not with

obesity. No association was found with indicators of osteopo-nosis such as height loss and hip fracture. Smoking was not

found to be associated with spinal meningioma risk. However,there was a suggestion that regular participation in sports,use of oral contraceptives, and vitamin supplementation mightbe protective because they appear to be in some studies ofosteoporosis.

Factors Related to Intracranial Meningiomas: IonizingRadiation. The interview study also asked about a number of

factors that had been shown previously to be related to the

development of intracranial meningiomas, in particular, ioniz-ing radiation (7, 20). Risk was increased among women with a

history 5 or more years before diagnosis of some radiographicprocedures that would expose the spine to high radiation doses(>500 mnad exposure to active bone marrow), including upperand lower gastrointestinal series and angiognaphy to the trunk

(21, 22). However, no association was seen with radiationtreatment to the neck on trunk that might have exposed the spineto relatively high doses of radiation. No association was seenwith radiographic procedures, such as dental and chest X-nays

and mammography, which expose the spine to no or very lowdoses of radiation.

Other Suggested Risk Factors. Exposures to N-nitnoso com-pounds on their precursors, such as from frequent use of face

makeup on from eating cured meats, have been associated withintracranial tumors (7, 23) but were not found in this study to

be related to spinal meningiomas. Consumption of citrus fruitand juice and daily supplementation of vitamins C and E were

also found not to be related; these vitamins (and citrus which ishigh in vitamin C) inhibit the endogenous formation of N-nitroso compounds, and citrus consumption has been associatedwith reduced risk of intracranial meningiomas (24, 25). How-

ever, long-term (�20 years) daily use of multivitamins did

reduce spinal meningioma risk; the explanation for such an

apparently protective effect of multivitamins remains obscure.We found no association with a number of other factors in-

cluding spinal infections, medical procedures involving thespine, lifting heavy objects at work, sleep position, and chronic

coughing.In summary, this series of studies provide some support

for the hypothesis that spinal meningioma occurrence amongpostmenopausal women relates to the development of vertebralosteoporosis. Our supposition is that the mechanism for thisrelationship is physical trauma to the spinal meninges followingosteoporotic collapse fractures of the vertebrae from eitherdirect contact with bone fragments or chronic stretching of themeninges. This mechanism postulates that physical trauma

damages the spinal meninges and leads to an increase in

cell proliferation in an attempt to repair this damage. When cellproliferation increases, the likelihood of tumor development

increases as well (26). Epidemiological and experimental cvi-dence suggest that this mechanism may be relevant to thegenesis of specific types of intracranial tumors, including men-ingiomas and acoustic neuromas (26).

Acknowledgments

We thank Dr. Leo Kinlen for first calling to our attention the striking increase in

spinal meningiomas among women over age 50 years, and Ann Hadley for

interviewing subjects.

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1995;4:333-339. Cancer Epidemiol Biomarkers Prev S Preston-Martin, K Monroe, P J Lee, et al. investigation of an etiological hypothesis.Spinal meningiomas in women in Los Angeles County:

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