Effectiveness and Costs of Osteoporosis

Screening and Hormone Replacement

Therapy, Vol. II: Evidence on Benefits,

Risks, and Costs

August 1995

OTA-BP-H-144

GPO stock #052-003-01424-6
M

enopause typically occurs in women around age 50. Accompanying this life event is a decline in estrogen levels and an increase in

the rate of decline in women’s bone density. This rapid bone loss

increases women’s subsequent risk of developing osteoporosis, a

disease characterized by low bone density and increased bone fragility.

Among the most serious consequences of osteoporosis is fracture of the hip,

which may result in substantial morbidity, prolonged hospitalization, and

death. Estrogen can prevent bone loss after menopause by replacing the

body’s own estrogen. Given the serious consequences of osteoporosis,

some osteoporosis experts have recommended that women have their bone

mineral density measured at the time of menopause and those with the lowest bone mineral density be offered hormone replacement therapy, comprising estrogen given alone or in combination with the hormone progestin.

This background paper, Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy, assesses the medical benefits and

costs of both screening and hormone replacement therapy. It is divided into

two volumes. The first volume, Cost-Effectiveness Analysis, presents the

results of a model that estimates the cost per year of life gained from osteoporosis screening and hormone replacement therapy in postmenopausal

women. The second volume, Evidence on Benefits, Risks, and Costs, provides the basis for the assumptions about the costs and effects of screening

and hormonal replacement therapy used in the cost-effectiveness model.

This background paper is one of three documents resulting from OTA’s

assessment of policy issues in the prevention and treatment of osteoporosis.

This assessment was requested by the Senate Special Committee on Aging,

Senator Charles Grassley and Senator John Glenn, and the House Select

Committee on Aging, Representative Olympia J. Snowe, Representative

Benjamin A. Gilman, and former Representatives Brian J. Donnelly,

Thomas J. Downey, and Patricia F. Saiki. Two background papers in this series have been issued, both in July 1994: Public Information about Osteoporosis: What’s’ Available, What’s Needed?, and Hip Fracture Outcomes in

People Age Fifty and Over.

ROGER C. HERDMAN

Director

Foreword

iii
Preface

T

his volume, “Evidence on Benefits, Risks, and Costs of Hormonal

Replacement Therapy,” is a companion to the volume “Cost-Effectiveness Analysis” of the OTA background paper “Effectiveness

and Costs of Osteoporosis Screening and Hormone Replacement

Therapy.” This volume reviews evidence on the impact of hormonal replacement therapy (HRT) on bone density, fractures, breast cancer, endometrial cancer, gallbladder disease, and heart disease that underlies the assumptions used in OTA’s cost-effectiveness analysis. This volume also

includes information about hormonal replacement therapy dosage regimens; reviews the relationship between bone mineral density and hip fracture; and summarizes the costs of bone mineral density screening, intervention, and diseases affected by HRT.

This volume is organized as a series of appendices. Several appendices

review HRT’s impacts on disease, including:

■ Appendix B: “Evidence on Hormonal Replacement Therapy and

Fractures,”

■ Appendix F: “Evidence on Hormonal Replacement Therapy and

Breast Cancer,”

■ Appendix G: “Evidence on HRT and Endometrial Cancer, ”

■ Appendix H: “Evidence on HRT and Gallbladder Disease,” and

■ Appendix I: “Evidence on HRT and Coronary Heart Disease.”

Appendix D, “Summary of Hip Fracture Prediction Methods,” details

the method for predicting the number of hip fractures used in OTA’s cost-effectiveness analysis. The appendix describes the specific parameter assumptions and sources of data regarding the longitudinal distribution of

bone mass in menopausal women from ages 50 to 90. The appendix also

describes the specific parameter assumptions and sources of data regarding

the short-term relationship of bone mass to fractures at each age.

Appendix E, “Hormonal Replacement Therapy Regimens,” describes

the types of estrogens and progestins used for hormonal replacement therapy, their doses, and their administration. The appendix also describes the

impact of hormonal replacement therapy on menopausal symptoms, and

adverse effects of HRT, such as bleeding and premenstrual-tension-like

symptoms. The appendix also describes the impact of these various dosage

regimens on compliance with HRT.

Appendix J, “Methods for Estimating Costs,” provides the basis for

OTA’s assumptions concerning the costs of bone mineral density measurement, hormone replacement therapy, heart disease, hip fractures, gallbladder disease, endometrial cancer, and breast cancer.

v
Advisory Panel

Robert P. Heaney

John A. Creighton Professor

Creighton University

Omaha, Nebraska

Steven R. Cummings

Research Director

College of Medicine

University of California

San Francisco, California

Barbara L. Drinkwater

Research Physiologist

Pacific Medical Center

Seattle, Washington

Deborah T. Gold

Assistant Professor

Duke University Medical Center

Durham, North Carolina

Susan L. Greenspan

Director

Osteoporosis Prevention and

Treatment Center

Beth Israel Hospital

Boston, Massachusetts

Caren Marie Gundberg

Assistant Professor

Department of Orthopedics

Yale University School of

Medicine

New Haven, Connecticut

Sylvia Hougland

Dallas, Texas

Conrad C. Johnston

Director

Division of Endocrinology &

Metabolism

Indiana University School of

Medicine

Indianapolis, Indiana

Shiriki K. Kumanyika

Associate Director for

Epidemiology

Center for Biostatistics &

Epidemiology

College of Medicine

Pennsylvania State University

Hershey, Pennsylvania

Edward O. Lanphier, II

Executive Vice President for

Commercial Development

Somatix Therapy Corporation

Alameda, California

Donald R. Lee

Vice President

Procter and Gamble

Pharmaceuticals

Norwich, New York

Robert Lindsay

Chief, Internal Medicine

Helen Hayes Hospital

West Haverstraw, New York

Betsy Love

Program Manager

Center for Metabolic Bone

Disorders

Providence Medical Center

Portland, Oregon

Robert Marcus

Director

Aging Study Unit

Virginia Medical Center

Palo Alto, California

Lee Joseph Melton, Ill

Head, Section of Clinical

Epidemiology

Department of Health Sciences

Research

Mayo Clinic

Rochester, Minnesota

Gregory D. Miller

Vice President

Nutrition Research/Technical

Services

National Dairy Council

Rosemont, Illinois

Note: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the panel members. The panel

members do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for the report and

the accuracy of its contents.

vi
Morris Notelovitz

President and Medical Director

Women’s Medical & Diagnostic

Center & the Climacteric Clinic,

Inc.

Gainesville, Florida

William Arno Peck

Dean

Washington University School of

Medicine

St. Louis, Missouri

Diana B. Petitti

Director, Research and Evaluation

Kaiser Permanence

Southern California Permanence

Medical Group

Pasadena, California

Neil M. Resnick

Chief, Geriatrics

Brigham and Women’s Hospital

Boston, Massachusetts

Gideon A. Rodan

Executive Director

Department of Bone Biology

Merck, Sharp & Dohme Research

West Point, Pennsylvania

Mehrsheed Sinaki

Professor, Physical Medicine and

Rehabilitation

Mayo Medical School

Rochester, Minnesota

Milton C. Weinstein

Henry J. Kaiser Professor

Health Policy and Management

Harvard School of Public Health

Boston, Massachusetts

vii
Project Staff

Clyde J. Behney

Assistant Director, OTA

Sean R. Tunis

Health Program Director

ADMINISTRATIVE STAFF

Louise Staley

Office Administrator

Carolyn Martin

Administrative Secretary

Monica Finch

Word Processing Specialist

PRINCIPAL CONTRACTORS

Dennis M. Black

Department of Clinical

Epidemiology

University of California, San

Francisco

Elliott Pickar

Consultant,

Rockville, MD

PROJECT STAFF

Robert McDonough

Study Director

Judith L. Wagner

Senior Associate

Katie Maslow

Senior Associ ate

Douglas Teich

Senior Analyst

Laura Stricker

Research Assistant

William Adams

Research Assistant

Julia Bidwell

Research Assistant

Angela Schreiber

Research Assistant

Viii
contents

Appendix A: Acknowledgments 1

Appendix B: Evidence on Hormone

Replacement Therapy and Fractures 5

References 17

Appendix C: Evidence on HRT and

Bone Loss 19

Conclusions 30

References 31

Appendix D: Summary of Hip Fracture

Prediction Methods 35

Requirements of the OTA Hip Fracture Prediction

Model 3 5

Measuring Bone Mass 35

Predicting Bone Mass Over Time 36

Relationship of Bone Mass to Hip Fracture Risk 44

References 47

Appendix E: Hormonal Replacement Therapy

Regimens 49

Estrogen Dosing Regimens 49

Therapy with PERT 53

Acute Indications for HRT 54

Evaluation and Followup of Women Taking HRT 55

Compliance with HRT 56

References 59

Appendix F: Evidence on Breast Cancer and

Hormonal Replacement Therapy 65

Biological Plausibility 65

Case-Control Studies 66

Cohort Studies 67

Clinical Trials 68

Combined Estrogen-Progestin Therapy and Breast

Cancer Risk 68

ix
Stage of Breast Cancer at Diagnosis in HRT Users

Versus Nonusers 70

Breast Cancer Mortality in HRT Users Versus

Nonusers 71

Conclusions 72

References 73

Appendix G: Evidence on HRT and

Endometrial Cancer 111

Duration and Dose of Estrogen 112

Recency of Use of Estrogen 112

Stage and Grade of Endometrial Cancer 112

Estrogen Use and Survival from Endometrial

Cancer 114

Estrogen/Progestin Replacement Therapy 115

Implications for OTA’s Cost Effectiveness Model 117

References 118

Appendix H: Evidence on HRT and

Gallbladder Disease 159

References 165

Appendix 1: Evidence on HRT and Coronary

Heart Disease 167

How Estrogen May Affect CHD 167

Evidence on ERT and CHD 168

Evidence on PERT and CHD 189

Conclusions 191

References 193

Appendix J: Methods for Estimating

costs 201

BMD Screening Cost 201

HRT Cost 201

Cost of Heart Disease 204

Cost of Hip Fracture 205

Cost of Cholecystectomy 205

Breast Cancer Costs 205

Endometrial Cancer Costs 207

References 210

Appendix K: Abbreviations and

Glossary 211

x
OTA wishes to express its appreciation to the following individuals and organizations that provided

assistance with this volume. These individuals do not necessarily approve, disapprove, or endorse this

report. OTA assumes fill responsibility for the volume and the accuracy of its contents.

Colette Z. Andrea Anne P. Clark

Metra Biosystems Inc. Division of Research Grants

Mountain View, CA National Institutes of Health

Bethesda, MD

Claude D. Arnaud

Department of Medicine Robert S. Epstein

School of Medicine Merck & Co., Inc.

University of California West Point, PA

San Francisco, CA

Martin Brown

National Cancer Institute

Bethesda, MD

Bruce Ettinger

Kaiser Foundation Research Institute

Oakland, CA

Warren Browner Ronald G. Evens

University of California Mallinckrodt Institute of Radiology

San Francisco, CA Washington University Medical Center

Saint Louis, MO

Natalie Cannon

Administration on Aging

U.S. Department of Health and Human Services

Seattle, WA

1
2 Cost Effectiveness of Screening for Osteoporosis

Susan C. Fox

Women’s Health/Preventive Medicine

Strang Cancer Prevention Center

New York, NY

Ted Ganiats

Division of Family Medicine

School of Medicine

University of California, San Diego

La Jolla, CA

Deborah Grady

Departments of Epidemiology and of Medicine

University of California

San Francisco, CA

Carolyn Green

B.C. Office of Health Technology Assessment

The University of British Columbia

Vancouver, British Columbia

Maria Greenwald

Society for Clinical Densitometry

Norwich, NY

Jay Hawkins

Metra Biosystems Inc.

Mountain View, CA

Elina Hemminki

STAKES

National Research and Development Centre for

Welfare and Health

Helsinki, Finland

Thomas Holohan

Office of Health Technology Assessment

Agency for Health Care Policy and Research

Rockville, MD

Dean K. Jenkins

Metra Biosystems Inc.

Mountain View, CA

Robert M. Kaplan

Department of Family and Preventive Medicine

University of California, San Diego

La Jolla, CA

John C. LaRosa

Office of the Chancellor

Tulane University Medical Center

New Orleans, LA

Barbara Lindheim

Therapeutics Strategic Marketing

Sterling Winthrop, Inc.

New York, NY

Nick Marmontello

Wyeth–Ayerst Laboratories

Philadelphia, PA

Deborah Marshall

SBU

The Swedish Council on Technology Assessment in

Health Care

Stockholm, Sweden

Brian McCue

Office of Technology Assessment

Congress of the United States

Washington, DC

Joan McGowan

Bone Biology Program

National Institute of Arthritis, Musculoskeletal, and

Skin Diseases

Bethesda, MD

Irma L. Mebane-Sims

National Heart, Lung, and Blood Institute

Bethesda, MD
Appendix A Acknowledgments 13

Alvaro Munoz

School of Hygiene and Public Health

The Johns Hopkins University

Baltimore, MD

Eleanor M. Perfetto

Wyeth–Ayerst Research

Philadelphia, PA

Mary Lake Polan

Department of Gynecology and Obstetrics

Stanford University Medical Center

Stanford, CA

Arnold Potosky

Applied Research Branch

National Cancer Institute

Rockville, MD

Jerilynn C. Prior

Department of Medicine

The University of British Columbia

Vancouver, British Columbia

William Randolph

Bethesda, MD

Lynn Rosenberg

Slone Epidemiology Unit

Boston University School of Medicine

Brookline, MA

Philip D. Ross

Hawaii Osteoporosis Center

Honolulu, HI

Carl A. Roth

National Heart, Lung, and Blood Institute

Bethesda, MD

Charles W. Slemenda

Department of Medicine

School of Medicine

Indiana University

Indianapolis, IN

Karen K. Steinberg

National Center for Environmental Health

Centers for Disease Control and Prevention

Atlanta, GA

David B. Thomas

Division of Public Health Services

Fred Hutchinson Cancer Research Center

Seattle, WA

Anna N.A. Tosteson

Department of Medicine

Dartmouth Medical School

Lebanon, NH

Wulf H. Utian

Department of Obstetrics and Gynecology

University MacDonald Womens Hospital

Cleveland, OH

Richard D. Wasnich

Hawaii Osteoporosis Center

Honolulu, HI

Joel B. Weinstein

Hologic, Inc.

Waltham, MA

Andrew R. Willan

Hamilton, Ontario

Larry Shulman

Bethesda, MD
Appendix B:

Evidence

on Hormone

Replacement

Therapy and Fractures B

A

small number of studies have examined

directly the relationship between use of

hormonal replacement therapy and risk of

hip fracture (table B-1). These studies, all

of which are of observational design, found a lower incidence of hip fracture in estrogen users versus nonusers, although the differences in incidence did not always reach statistical significance.

The largest and most complete study of hormonal replacement therapy and hip fracture incidence was of a cohort of approximately 23,000

users of hormonal replacement therapy from the

Uppsala Health Care Region of Sweden (14). The

Uppsala Health Care Region comprises six counties and one-sixth of the total population of Sweden. The authors included in the cohort all women

living in the region who were age 35 years and older (mean age 53.7 years at study entry) and who

filled at least one prescription for a noncontraceptive estrogen-containing preparation between

April 1977 and March 1980. HRT users were

identified through the region’s prescription record

database, which includes records of prescriptions

filled at all pharmacies within the region. The authors determined the incidence of first hip fracture

in this cohort through 1983 by using each

woman’s unique national registration number to

link each woman’s prescription record with theregion’s registry of hospital admissions. The mean

duration of observation of members of this cohort

was 5.7 years.

Hormone use before 1977 and after 1980 was

ascertained by mailing questionnaires to a random

sample of 735 women from the cohort in 1980 and

again in 1984 (14). Nine percent had not taken the

prescribed drug, half of the cohort had begun hormone replacement therapy before the beginning of

the study period, and the median duration of HRT

was approximately 3.5 years. Approximately one

third of the HRT users were prescribed a combined regimen of estrogen and progesterone; the

other two thirds used estrogen alone.

The incidence of hip fractures in the cohort was

compared with that of the background population

of women age 35 and older in the region (14). The

study demonstrated a statistically significant reduction in risk of hip fractures in users of hormonal replacement therapy (relative risk 0.79).

Women who received hormonal replacement

therapy with conjugated estrogens or estradiol

showed a significantly reduced risk of hip fracture

(relative risk 0.70), whereas virtually no protective effect was found in women prescribed estriols, which are much weaker than the conjugated

estrogens or estradiol typically prescribed for hormonal replacement therapy in the United States.

5
6 Cost Effectiveness of Screening for Osteoporosis

The data indicated that the protective effect of

the more potent estrogens was concentrated in

women who initiated therapy within a decade after

menopause (relative risk 0.55 for women less than

60 years of age at initiation of therapy); no significant protective effect of hormonal replacement

therapy was found for women 60 years or older at

the time of initiation of therapy (14). However,

the data may not be sufficient to indicate whether

hormonal replacement therapy has a protective effect for older women because of the relatively

small number of cohort members greater than 60

years of age, and the relatively few older members

of the cohort who were prescribed the more potent

estrogens.

The study also found a greater protective effect

of estradiol and conjugated estrogens for trochanteric hip fractures (relative risk 0.60 (95 percent

confidence interval 0.35 to 0.96)) than for cervical

hip fractures (0.73 (0.55 to 0.95)) (14). This finding supports earlier claims that trabecular bone,

which constitutes a larger part of the bone structure in the trochanteric than in the cervical part of

the femur, is more rapidly affected by hormonal

changes than is cortical bone.

HRT has also been found to be effective in reducing other types of osteoporosis-related fractures. Cauley and colleagues, reporting on the

Study of Osteoporotic Fractures cohort, found a

decrease in risk of fractures in elderly women who

currently used HRT, but not in elderly women

who previously used HRT (l). The Study of Osteoporotic Fractures cohort includes 9,704 nonblack women 65 years of age or older who were

recruited from population-based lists from four

regions of the United States between September

1986 and October 1988. Members of the cohort

were interviewed about HRT use and osteoporosis

risk factors upon entry into the study, and women

were contacted every four months for up to 6.5

years afterwards to determine whether they had a

fracture.

Compared to women who had never used HRT,

current users of HRT had a significantly decreased

risk for wrist fractures (relative risk 0.46 (95%

confidence interval 0.29 to 0.72)) and all nonspinal fractures (relative risk 0.69 (0.57 to

0.83)) 1 (l). The relative risk of hip fracture was

decreased but not statistically significant (relative

risk 0.80 (0.5 1 to 1.26)). By contrast, no association was found between previous use of HRT and

the risk for either hip fractures (relative risk 1.00

(0.72 to 1.07)) or for all nonspinal fractures (relative risk 0.97 (0.85 to 1.1 l)). Previous users had a

15-percent decrease in the risk for wrist fracture,

but the decrease was not statistically significant

(relative risk 0.85 (0.65 to 1.11)). Among current

users, the effect of PERT on fracture incidence

was similar to the effect of ERT.

The investigators also found that the association between current HRT use and risk for wrist

fractures and all nonspinal fractures was similar in

those younger and older than 75 years of age (1)

(table B-l). They also found an 80 percent decrease in the risk for hip fractures among women

older than 75 years of age (relative risk 0.18 (0.04

to 0.77)), but found no effect on hip fracture in

those 75 years of age or younger (relative risk 0.94

(0.52 to 1.69)).

Finally, the investigators found that HRT is

more effective if initiated within 5 years of menopause and if used longer than 10 years (l). The investigators found little effect of duration of use

among current HRT users on the occurrence of all

nonspinal fractures, but more than 10 years of use

was associated with a substantial reduction in the

risk for wrist and hip fractures (table B-l).

Women who began using HRT within five years of

menopause were found to have substantially

greater reductions in risk of wrist, hip, and all nonspinal fractures than women who began using

HRT more than 5 years after menopause (table

B-l).

] The investigators did not examine the incidence of spinal fractures in the cohort.
Number of

Study participants

Gordan 120 on estrogen,

(1973) 100 on

androgens or

anabolic

steroids

Study design Type of fracture Description of study and population Resultsa

Hammond 301 estrogen Retrospective Unspecified

(1979) users, 309 cohort with

controls Internal controls

Hutchinson 80 cases (107.

(1979) estrogen

users); 80

controls (25%

estrogen users)

Prospective cohort Fracture type Subjects were postmenopausal women, average

with internal unspecified age 62 at study entry, with osteoporosis as

controls determined by spinal x-ray evidence, who

were seen at a San Francisco, CA, clinic

between 1948 and 1973. All subjects

completed more than two years of hormone

therapy. A total of 1,664 patient-years was

studied including 1,507 patient-years of CEE

and 157 patient-years of androgens and

anabolics.

Subjects were patients at Duke Hospital or

clinics (Durham, NC) between 1940 and 1979

for diagnoses related to estrogen deficiency

and who had been followed at Duke for at

least 5 years.

Estrogen use was defined as use greater than 5

years. Average age at study entry for estrogen

users was 42.9 years, whereas average age

for nonusers at study entry was 49.6 years.

Average age of estrogen users at end of study

was 56 years. Only 16 of the estrogen-treated

group of 301 patients were black whereas 104

of the 309 patients not treated with estrogens

were black.

Hospital-based Hip and distal Cases were admitted to Yale-New Haven

case-control radius fractures Hospital (Connecticut) between 1974 and

1977. Controls were inpatients from the

orthopedic service during those same years,

matched for race, age, and discharge date to

cases. All cases and controls were between

40 and 80 years of age. Information was

gathered through review of medical records

and Interviews Estrogen use was defined as

use greater than 6 months

CEE 1.25mg. 3 fractures/1 ,000

patient-years,

CEE 0.60mg. 25 fractures/

1,000 patient-years,

Androgens and anabolics 40

fractures/1 ,000 patient-years

No tests of statistical

significance were provided.

Estrogen-treated patients had

an 8.6% fracture incidence

during study period.

Patients not treated with

estrogen had a 15.9%

fracture incidence during

study period (relative risk

0.54).

No tests of statistical

significance were provided.

Odds ratio “for protection” was

3.0 (p = 0.01) for estrogen

users versus nonusers, odds

ratio increases to 3.5 if

estrogens are begun within 5

years of menopause

(p = 0.01)
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Lindsay 58 mestranol-

(1 980) treated

patients; 42

controls

Weiss (1980) 327 cases (34%

estrogen

users), 576

controls (52%

estrogen users)

Johnson 168 cases (29.2%

(1981) estrogen

users); 336

controls (36%

estrogen users)

Prospective cohort Spine and radius Estrogen users and controls were post

with internal fractures oophorectomy patients followed at a clinic in

controls Britain for a mean duration of 9 years.

Estrogen users were treated with mestranol,

23.3mcg mean dose. All subjects were

followed with spinal x-rays. All subjects were

elderly patients with preexisting osteoporosis.

Population-based Hip and distal Cases were white women, aged 50 to 74 years,

case-control radius fractures followed in 59 outpatient orthopedic clinics in

King County (Seattle), WA, for hip fractures

and wrist fractures that occurred between

1978 and 1979. Controls were of the same

ages as cases and selected from the same

region. All subjects were interviewed about

estrogen use, fracture history, and

osteoporosis risk factors.

Hospital based Hip fractures Cases and controls were members of the

case-control Kaiser-Permanente Medical Program of

Portland, OR, who were identified through

medical records. Cases were women between

52 and 80 years old hospitalized for fracture of

the proximal end of the femur between 1965

and 1975. Two hospital controls were selected

for each case, matched for age and date of

discharge, Estrogen use was ascertained from

medical records.

Estrogen exposure was defined as written order

in the medical records of estrogens taken

during or after the year of menopause and

prior to hospitalization Authors noted that the

number of cases was sufficient only to detect

a reduction of risk of about 50 percent or

greater.

There was a significant

reduction in wedge

deformities of index

vertebrae (T4 and L2)

estrogen users. No tests of

statistical significance were

performed.

Current use. relative risk 0.42

(0.30-0.63) in hip fracture

patients versus controls.

Long-term use (> 10 yr.). relative

risk 0.46 (0.30-0,69) in hip

fracture patients versus

controls. Decreased risk of

hip fracture was seen only

with more than 5 years of

hormonal replacement

therapy.

Relative risk of hip fracture in

estrogen users versus

nonusers was 0.72

(0.48-1 .09) (p= 0.06).

Controls were more likely to

have long duration (at least 36

months) of exposure and

more likely to begin estrogen

within three years of

menopause than cases,

although differences did not

achieve statistical

significance.

I
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Paganini-Hill 91 Cases (49%

(1981) estrogen

users); 166

controIs (52% 

estrogen users)

Kreiger 98 cases; 884

(1982) controls (83

trauma

controls, 801

nontrauma

control)

Riggs (1982) Five groups,

including 45

receiving no

treatment and

32 receiving

estrogen with

calcium

Population-based Hip fractures Cases and controls were residents of Leisure

case-control World Retirement Community, Los Angeles,

CA. Cases were postmenopausal women who

had hip fractures between 1974 and 1978,

were less than 80 years of age, and were

identified from local hospital records. Controls

were selected from the retirement community,

matched for age, race, and date of entry into

the community. Estrogen use was recorded

from outpatient medical records and personal

interviews.

Hospital-based Hip fractures Cases and controls were admitted to inpatient

case-control surgical services at a Connecticut hospital

between 1977 and 1979. Controls were

admitted for nongynecologic diagnoses. Two

control groups were used for comparison:

trauma controls and nontrauma controls. Ever

use was defined as use greater than 6

months.

Prospective cohort Vertebral Study subjects were postmenopausal women

with internal fractures referred to the Mayo Metabolic Bone Disease

controls Clinic, Rochester, MN, between 1968 and

1980. Estrogen users received 0.625 to 2.5

mg/d of CEE with 1,000 to 3,000 mg/d of

calcium. Fifteen estrogen users had also

received vitamin D (50,000 units once or twice

weekly). Mean age of estrogen users was

63.8, and mean age of untreated group was

62.9. Subjects were followed up in clinic,

mean duration of followup for estrogen users

was 4,5 years, and for subjects assigned to

Relative risk with long-term use

(> 60 months) was 0,42

(0.18-0.98) in hip-fracture

cases versus community

controls.

Protective effect of greater than

60 months estrogen use was

limited to oophorectomized

women, relative risk was 0.14

(0.03-0.70), relative risk of

estrogen use in hip fracture

cases with natural

menopause was 0.86

(nonsignificant).

Relative risk in ever users

versus nonusers was 0.5

(0.3-1.1) for cases and

trauma controls, 0.5 (0.3-0.9)

for cases and nontrauma

controls.

The fracture rate was 834 per

thousand person-years in the

untreated patients and 181

per thousand person-years

in the estrogen group (p <

1X10-6

placebo, 2.0 years.
Number of

Study participants Study design Description of study and population Resultsa

Williams 344 cases (34% Population-based Hip and forearm Study subjects were white women ages 50 to 74

(1982) estrogen case-control fractures who had sustained hip or forearm fractures

users); 567 between 1976 and 1979. Cases were followed

controls (52% by orthopedic surgeons in King County,

estrogen users) Washington. Controls were a random sample

of white female residents of King County in the

same age range. Estrogen use was

ascertained by interviews with study subjects.

The beneficial effect of estrogen

use in preventing hip and

forearm fractures varied

according to a woman’s

weight and smoking status,

being greatest in thin women

who smoked cigarettes and

near zero in heavy

nonsmokers.

Reduction in risk of forearm

fracture in thin smokers by

use of estrogen. 4.7

Reduction in risk of hip fracture

in thin smokers by use of

estrogen: 7.1

Reduction in risk of forearm

fracture in average weight

smokers by use of estrogen:

0.8

Reduction in risk of hip fracture

in average weight smokers

by use of estrogen. 4,4

No tests of statistical

significance were done.

I
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Ettinger 245 estrogen Retrospective Wrist, spine, and Study subjects were white postmenopausal

(1985) users; 245 cohort with all fractures women, average age 73 years, identified from

controls internal controls review of pharmacy records dated between

1968 and 1971. Black women were excluded

from the study because of the low incidence

of fractures in this group. Subjects were

followed for an average of 17.6 years. Study

subjects were followed at the Kaiser

Permanence Medical Center, San Francisco,

CA. Controls were matched for age and length

of membership in the health plan, Estrogen

use was defined as use begun within three

years of menopause and at least 5 years of

estrogen use. Fracture incidence and

continued estrogen use was determined by

reviewing medical records.

Kiel (1987) 2,873 women Retrospective Proximal femur Study subjects were members of the

(667 estrogen cohort with fractures Framingham (Massachusetts) Heart Study

users) internal controls cohort between 1948 and 1985. Subjects

were ages 30 to 62 years old at the 1st

biennial examination held between 1948 to

1951. Only women who reached menopause

during the study interval were included in this

analysis. Information on fractures was

gathered from review of hospital records and

interviews of subjects at the cohort’s 18th

biennial examination (1983-1985). Subjects

had provided information about estrogen use

at most of the biennial examinations.

Relative risk for osteoporotic

fracture was 2.2 (1 ,5-3.8) (in

nonusers versus users);

relative risk for spine

fractures was 2.7 (1 .0-8.1).

There was no significant

difference in risk of hip

fractures or wrist fractures

between users and

nonusers,

Unadjusted relative risk in

women who have taken

estrogen within the previous

two years versus never users

was 0,34 (0.08-0,64),

Unadjusted relative risk in

women with any estrogen

use versus nonusers was

0.69 (0.46-1 .03).

Unadjusted relative risk for

recent users of less than one

year was 0.32 (0.09-1 .21);

relative risk in recent users

for more than one year was

0.14 (0.03-0.76).
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Naessn

(1 990)

Paganini-Hill

(1991)

23,246 women (all

HRT users)

8,600 women

(4,866 ever

estrogen users)

Prospective cohort

with external

controls

Prospective cohort

with internal

controls

Hip fractures Cohort included all women 35 years of age or

older from the Uppsala Health Care Region of

Sweden who received noncontraceptive

estrogens from April 1977 to March 1980.

Comparisons were made with expected rates

of incidence of hip fracture in women in the

background population. Women were followed

for an average of 5.7 years.

Hip fractures Cohort Includes postmenopausal women who

were residents of Leisure World Retirement

Community, Los Angeles, CA. Mean age of

residents was 73 years. Mailed questionnaires

were sent in 1981, 1982, 1983, and 1985.

Cohort was followed for area hospital

admissions and local health department death

certificates through 1988.

Relative risk was 0.79 (0.68 to

0.93) in estrogen users

compared with the

background population

Relative risk for ever use was

1.02 (0.81-1 .27)

Dose,

< 0.625mg CEE: 0.84

(0.58-1 .21)

> 1,25mg CEE: 0.91 (0.64-1.29)

Duration:

<3 years, 1,19 (0.89-1 .60)

4-14 years: 0,89 (0.63-1 .23)

>15 years 0,88 (0,63-1 .24)

Recency (years since last

estrogen use):

>15 years: 1,15 (0.88-1 .50)

2-14 years. 0.88 (0.63-1 .23)

O-1 years. 0.80 (0.53-1 .21)

Duration and Recency.

<3 years,

>15 yrs. 1,33 (0.97-1 ,82)

2-14 yrs. 0.79 (0.38-1 .60)

O-1 yrs. 0.87 (0.28-2.73)

4-14 years:

> 15 yrs. 0.95 (0.61 -1.49)

2-14 yrs. 0.86 (0.52-1 .42)

O-1 yrs. 0.72 (0.31-1 ,64)

> 15 years:

> 15 yrs. 0.57 (0.1 8-1 .79)

2-14 yrs. 0,97 (0.61-1 .53)

O-1 yrs. 0.85 (0.53-1 .38)

—

o
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Kanis (1992) 2,086 cases, Population-based Hip (femoral The Mediterranean Osteoporosis Study

3,532 controls case-control neck) fractures examined the incidence of hip fracture in men

and women aged 50 years or over from 14

centers from six countries in Southern Europe.

Cases were women over age 50 (mean age

78 years) who had a hip fracture over a

one-year period (1988 to 1989). Cases were

identified by surveillance of hospitals, private

clinics, and nursing homes in the catchment

area. Controls of the same age and who were

neighbors of cases or were sampled from

population registers were identified.

Information about use of drugs affecting bone

was obtained by interview. Investigators from

each center provided prospective information.

Only 1.9 percent of cases and 3.5 percent of

controls had ever used estrogen.

Lufkin (1992) 75 women Randomized

clinical trial

Vertebral

fractures

Study subjects were postmenopausal white

women, 47 to 75 years of age, with

established osteoporosis (defined as BMD

below the 1Oth percentile of normal

postmenopausal women and one or more

vertebral fractures) seen at Mayo Clinic,

Rochester, MN. Subjects were randomly

assigned to placebo or treatment with

transdermal estrogen (Estraderm patch) for 3

weeks out of a 4-week cycle, with 10 mg/d

oral medroxyprogesterone acetate. The study

duration was one year.

Relative risk 0.45 (0,30 to 0,67)

(P = 0.0001) in ever users

versus never users.

Adjusted relative risk 0,55 (0,36

to 0.85) (p = 0.01) (adjusted

for center, age, body mass

index, and previous fragility

fractures).

Fracture risk stratified by age,

<80 years,

Adjusted relative risk 0.51 (0.31

to 0.84) (p = 0.009)

>80 years,

Adjusted relative risk 0,70 (0.29

to 1.66) (NS)

Duration:

Less than median duration of

estrogen use:

relative risk 0.86 (0.51 to 1,46)

Greater than median duration:

relative risk 0.29 (0.1 3 to 0,61 )

Eight new fractures occurred to

seven women in the estrogen

group, whereas 20 new

fractures occurred in 12

women in the placebo group

(relative risk 0.39 (0.16 to

0.95).
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Spector 1,075 HRT users, Retrospective Osteoporotic HRT users were women, average age 52, who

(1992) 1,471 controls cohort with fractures attended a Dulwich, South London, UK,

external controls menopause clinic for hormone replacement

therapy between January 1976 and

December 1986. Controls were

postmenopausal women of the same age from

the registers of four general practices in

Greater London. Information was gathered by

questionnaire and review of medical records.

Most HRT users (65%) received subcutaneous

estrogen implants (50 to 100 mg estradiol)

every six months, usually in combination with

100 mg testosterone. Cyclical progestins were

given for 12 days each cycle to most estrogen

users who had not had a hysterectomy.

Average duration of HRT use was 51 months.

Grisso 144 cases (4%

(1994) HRT users),

218 community

controls (8%

HRT users),

181

hospitalized

controls

Case-control study Hip fracture Cases were black women admitted with first hip

with both fracture to 1 of 30 hospitals in New York and

hospital and Philadelphia, Community controls were black

community women living in the community who were

controls matched to cases by age and geographic

area, Hospital controls were black women

matched by age and hospital. Information was

obtained through personal interviews.

Relative risk of distal radius

fractures was 0.70 (0.32 to

1,55) compared with

pre-HRT fracture rates and

0.63 (0.31 - 1.31) compared

with nonusers.

Relative risk of osteoporotic

fractures was 0.96 (0.55 -

1.68) compared with

pre-HRT fracture rates and

0.71 (0.43 to 1.16) compared

with nonusers.

There was a trend toward

decreased incidence of

fractures with increased

duration of use for

osteoporotic fractures

(P = 0.06) and wrist fractures

(p= 0.03).

There were 6 reported fractures

of the hip in the nonusers

compared with none among

estrogen users (p = 0.15).

Fracture risk stratified by age*:

Less than 75 years old:

adjusted odds ratio 0.05

(0.01 -0.6) compared with

community controls

adjusted odds ratio 0.1

(<0.1 -0.5) compared with

hospital controls

o
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Grisso-cent.

(1994)

Lafferty

(1994)

157 women (52% Prospective cohort Vertebral Study subjects were all white postmenopausal

estrogen users) with internal compression women between 43 and 60 years of age seen

controls fractures and in a Cleveland, OH, private practice between

peripheral 1964 and 1983. Subjects were followed

fractures though 1989, All estrogen users received

0.625mg/day CEE for the first 25 days per

month After 1983, 5mg/day of

medroxyprogesterone acetate was given for

12 days each month, Estrogen use was

defined as use of at least 3 years duration

(68% of ERT users took estrogens for more

than 10 years).

Age 75 years or more:

adjusted odds ratio 0.3

(0.1 -1 .2) compared with

community controls

adjusted odds ratio 1.1

(0.2-6.3) compared with

hospital controls

Duration*:

1 to 6 years: adjusted odds

ratio 0.7 (0.2-3.1 )

more than 7 years: adjusted

odds ratio 0.2 (0.1-1 .0)

compared with community

controls

Recency (time since last use)*:

less than 5 years: adjusted

odds ratio 0.0 (0-0.95)

5 or more years: adjusted odds

ratio 0.6 (0,2-1 .7)

compared with community

controls

● All results are for HRT use for 1 year or

more

Relative risk of spinal

compression fracture 0.27

(0.12-0.60) in estrogen users

versus nonusers; relative risk

of peripheral fracture was

0.23 (0.06-0.97); relative risk

of all fractures was 0.28

(0.09-0.89).

o
Number of

Study participants Study design Type of fracture Description of study and population Resultsa

Cauley 9,704 women Prospective cohort Hip fractures, Subjects were nonblack women 65 years of age

(1995) (13.7% current with internal wrist fractures, or older who were members of the Study of

users) (27.4°A controls and all Osteoporotic Fractures cohort, a prospective

ever users) nonspinal study conducted at four clinical centers in the

fractures United States. The SOF cohort was recruited

from population-based lists of women (voter

registration, driver’s license, and health

maintenance organization membership lists).

Black women were excluded because of their

low incidence of fractures. Information on HRT

use and risk factors was gathered from

interviews at baseline and information about

incident fractures was gathered by postcard

or telephone every 4 months. Subjects were

recruited from September 1986 to October

1988, and followed through March 1993.

Duration of followup ranged from 0.02 to 6.5

years.

Current versus past HRT use:

Hip fractures:

current HRT use:

age adjusted relative risk 0.80

(0.51-1 .26)

risk-factor adjusted relative

risk’ 0.60 (0,36-1 .02

past HRT use:

age adjusted relative risk 1.00

(0.72-1 .07)

risk-factor adjusted relative

risk 1.03 (0.69-1 .55)

Wrist fractures:

current HRT use:

age adjusted relative risk 0.46

(0.29-0.72)

risk-factor adjusted relative

risk 0.39 (0.24-0.64)

past HRT use:

age adjusted relative risk 0.85

(0.65-1 .11)

risk-factor adjusted relative

risk 0.81 (0,62-1 .07)

All nonspinal fractures,

current HRT use:

age adjusted relative risk 0.69

(0.57-0.83)

risk-factor adjusted relative

risk 0.66 (0.54-0.80)

past HRT use.

age adjusted relative risk 0.97

(0.85-1 .11)

risk-factor adjusted relative

risk 0,94 (0,83-1 .08)

* Relative risk was adjusted for multiple

osteoporosis risk factors

a

95 percent confidence intervals are given in parentheses, unless otherwise specified

—

KEY: BMD = bone mineral density; CEE = conjugated equine estrogen, ERT = estrogen replacement therapy; HRT = hormonal replacement therapy;

SOURCE: Office of Technology Assessment, 1995
Appendix B Evidence on Hormone Replacement Therapy and Fractures 117

Providing further support for the proposition

that hormonal replacement therapy reduces fracture incidence are a number of clinical trials of

hormonal replacement therapy in postmenopausal

women which demonstrate statistically significant reductions in incidence of osteoporosis-related fractures other than hip fracture in users of

hormonal replacement therapy (13,17) (table

B-l).

One controlled clinical trial demonstrated the

effectiveness of hormonal replacement therapy in

reducing the incidence of vertebral fractures in a

group of women with established osteoporosis

(13). In this study, 75 postmenopausal women, 47

to 75 years of age, with one or more vertebral fractures due to osteoporosis, were randomly assigned

to treatment with an estradiol patch and oral medroxyprogesterone acetate or a placebo patch.

Bone mineral density and vertebral fractures were

assessed at the beginning of the study and after

one year. Bone mineral density was maintained or

increased in the treatment group at all sites measured. Eight new fractures occurred in 7 women in

the estrogen group, whereas 20 occurred in 12

women in the placebo group, yielding a significantly lower vertebral fracture rate in the estrogen

group (relative risk 0.39 (95 percent confidence

interval 0.16 to 0.95)).

Estrogen treatment would probably also decrease hip fracture rates, as it does vertebral fracture rates, because bone mineral density in the

estrogen group increased at the hip sites studied.

The reduction in hip fracture rates may not be proportional to the reduction in vertebral fracture

rates, however, in part because of differences in

the qualitative features of the bone at both sites,

and because such factors as neuromuscular weakness, postural instability, and the tendency to fall

play a greater role in fractures of the hip.

Controlled clinical trials of the relation between HRT use and vertebral fracture have been

possible because of the relatively large number of

vertebral fractures in postmenopausal women and

the relatively early age at which vertebral fractures

typically occur. Conducting a controlled clinical

trial of hormonal replacement therapy and hip

fracture presents much greater problems, however, due to the relatively low incidence of hip fractures relative to vertebral fractures, the long

duration between menopause and the age at which

most hip fractures occur (above 65 years), and difficulties in maintaining compliance with hormonal replacement therapy over that long a time

period.

REFERENCES

1. Cauley, J., Seeley, D., Ensrud, K., et al., “Estrogen Replacement Therapy and Fractures in

Older Women,” Annals of Internal Medicine

122:9-16, 1995.

2. Ettinger, B., Genant, H. K., and Cann, C. E.,

“Long-Term Estrogen Replacement Therapy

Prevents Bone Loss and Fractures,” Annals of

Internal Medicine 102(3):319-324, 1985.

3. Gordan, G., Picchi, J., and Roof, B., “Antifracture Efficacy of Long-Term Estrogens for

Osteoporosis,” Transactions of the Association of American Physicians 86:326-332,

1973.

4. Grisso, J., Kelsey, J., Strom, B., et al., “Risk

Factors for Hip Fracture in Black Women,”

New England Journal of Medicine 330(22):

1555-1559, 1994.

5. Hammond, C., Jelovsek, F., Lee, L., et al.,

“Effects of Long-Term Estrogen Replacement Therapy: I. Metabolic Effects,” American Journal of Obstetrics and Gynecology

133(5):525-536, 1979.

6. Hutchinson, T., Polansky, S., and Feinstein,

A., “Postmenopausal Oestrogens Protect

Against Fractures of Hip and Distal Radius: A

Case Control Study,” Lance? 705-709, 1979.

7. Johnson, R. E., and Specht, E. E., “The Risk of

Hip Fracture in Postmenopausal Females

with and Without Estrogen Drug Exposure,”

American Journal of Public Health 71(2);

138-144, 1981.

8. Kanis, J. A., Johnell, O., Gullberg, B., et al.,

“Evidence for Efficacy of Drugs Affecting

Bone Metabolism in Preventing Hip Fracture,” British Medical Journal 305(7):

1124-1128, 1992.
18

9

10

11.

12.

13.

14.

15.

Cost Effectiveness of Screening for Osteoporosis

Kiel, D.P., Felson, D.T., Anderson, J. J., et al.,

“Hip Fracture and the Use of Estrogens in

Postmenopausal Women: The Framingham

Study,” New England Journal of Medicine

317(19):1169-1174, 1987.

Kreiger, N., Kelsey, J.L., Holford, T.R., et al.,

“An Epidemiologic Study of Hip Fracture in

Postmenopausal Women,” American Journal

of Epidemiology 116(1): 141-148, 1982.

Lafferty, F.W., and Fiske, M. E., “Postmenopausal Estrogen Replacement: A Long-Term

Cohort Study,” American Journal of Medicine 97(1):66-77, 1994.

Lindsay, R., Hart, D. M., Forrest, C., et al.,

“Prevention of Spinal Osteoporosis in Oophorectomized Women,” Lancet 1151-1154,

1980.

Lufkin, E.G., Wahner, H. W., O ‘Fallen,

W.M., et al., “Treatment of Postmenopausal

Osteoporosis with Transdermal Estrogen,”

Annals of Internal Medicine 117(1):1-9,

1992.

Naessen, T., Persson, I., Adami, H. O., et al.,

“Hormone Replacement Therapy and the

Risk for First Hip Fracture,” Annals of Internal Medicine 113:95-103, 1990.

Paganini-Hill, A., Chao, A., Ross, R. K., et

al., “Exercise and Other Factors in the Preven16.

17.

18.

19.

20.

tion of Hip Fracture: The Leisure World

Study,” Epidemiology 2(l): 16-25, 1991.

Paganini-Hill, A., Ross, R. K., Gerkins, V.R.,

et al., “Menopausal Estrogen Therapy and

Hip Fractures,” Annals of Internal Medicine

95(1):28-31, 1981.

Riggs, B. L., Seeman, E., Hodgson, S.F., et

al., “Effect of the Fluoride/Calcium Regimen

on Vertebral Fracture Occurrence in Postmenopausal Osteoporosis,” New England Journal of Medicine 306(8):446-450, 1982.

Spector, T. D., Brennan, P., Harris, P. A., et al.,

“Do Current Regimes of Hormone Replacement Therapy Protect Against Subsequent

Fractures?” Osteoporosis International

2:219-224, 1992.

Weiss, N. S., Ure, C. L., Williams, J. H., et al.,

“Decreased Risk of Fractures of the Hip and

Lower Forearm with Postmenopausal Use of

Estrogen,” New England Journal of Medicine

303(21):1195-1198, 1980.

Williams, A.R., Weiss, N. S., Ure, C. L., et al.,

“Effect of Weight, Smoking, Estrogen Use on

the Risk of Hip and Forearm Fractures in

Postmenopausal Women,” Obstetrics & Gynecology 60(6):695-699, 1982.

I

I

I
Appendix C:

Evidence

on HRT

A

large number of controlled clinical trials

have demonstrated that hormone replacement therapy (HRT) is able to reduce the

rate of bone loss in postmenopausal

women. Most of the controlled clinical trials of

HRT on bone mass have been for a duration of

three or fewer years (table C- 1 ). The first pages of

table C-1 (“HRT and Bone Mineral Density: Clinical Trials of 3 or Fewer Years”) provide details of

the design and results of each of the studies. The

percentage change in bone mass from the baseline

measurement to the end of the study is provided

so that we may compare bone mass data that are

given in disparate units (e.g., bone mineral content (usually measured in grams per centimeter

(g/cm)) and bone mineral density (usually measured in grams per square centimeter (g/cm2

)).

Virtually all of these studies have shown that

HRT, begun soon after menopause, maintains or

increases bone mass within the first three years after menopause. Although HRT may reduce the

rate of bone loss after menopause, HRT is not able

to substantially restore bone mass that is lost. The

increases in bone mass seen with initiation of therapy soon after menopause are small, generally in

the range of 1 to 3 percent of the total bone mass.

A number of investigators have questioned

whether there is a significant subgroup of postmeand

Bone Loss c

nopausal women who fail to respond to HRT ( 16).

Recent analyses have found that the proportion of

women who fail to respond to hormone replacement therapy is relatively small (20).

Only a handful of studies of HRT and bone

mineral density have followed women more than

three years after initiation of therapy (table C-2),

and these studies have shown that HRT maintains

bone mass or reduces the rate of bone loss in postmenopausal women compared with placebo. In a

retrospective cohort study, Meema and colleagues

contacted postmenopausal women who had a

bone mass measurement at a university clinic four

to 10 years previously and asked them to volunteer for a second bone mass measurement (36).

Eighty two volunteers were identified, 29 of

whom had been treated continuously with estrogens. After an average followup period of six

years, the estrogen-treated women showed no significant changes in bone mass and cortical thickness, whereas untreated women had significant

decreases in bone mass and cortical thickness. In

a cross-sectional study, Moore examined the bone

mineral density of 65 postmenopausal women between 55 and 75 years of age who were at least 10

years from menopause (37). Long-term estrogen

users were defined as those women who had begun therapy within five years of menopause and

I 19
20 Cost Effectiveness of Screening for Osteoporosis
Duration of

monitoring

of bone

Study Number of participants density Type of treatment Results

Christiansen

(1981 b)

part I: 43 treated; 51

controls.

Part II: 35 treated, 42

controls

Finn Jensen (1 982) 31 treated; 43 controls

Lindsay (1984)

Christiansen (1984)

887 treated patients divided

among four groups; 21

controls

2 treatment groups and one

placebo group, E2 +E3

+P: 22 patients; E2 +P: 20

patients; placebo group:

23 patients

3 years, Part

I: first two

years of

study; Part

II: third

year of

study

18 mo. (6

mo. run-in

period)

2 years

1 year

Patients treated with Trisequens forte

(17-beta-estradiol (4mg) and estriol (2mg) days

1-12, 17-beta-estradiol (4mg) estriol (2mg) and

norethisterone acetate 1 mg days 13-22,

17-beta-estradiol (1 mg) and estriol (0.5mg) days

23-28), All patients received 500mg calcium per

day.

Patients divided into four groups,

1,25(OH)2 D3 (0.50 mg/d) + 500mg calcium, 19

patients; Trisequens + 500mg calcium, 11

patients; 1 ,25(OH)2 D3 (0.50mg/d) + Trisequens +

500mg calcium: 20 patients; 500mg calcium 24

patients

Patients assigned to either placebo group or to CEE

at one of four dosage levels: 0,15mg/day,

0.3mg/day, 0.625 mg/day, and 1.25mg/day

Two treatment groups, 17 beta-estradiol and

norethisterone acetate; 17 beta-estradiol, estriol,

and norethisterone acetate, placebo group

Daily doses used were, 17-beta-estradiol 2mg from

days 1-22, 1 mg from days 23-28, estriol: 1 mg

days 1-22, 0.5mg days 23-28, norethisterone

acetate, 1 mg days 13-22. All patients received

500mg/d calcium,

Part I:

HRT (g/cm)

Placebo

Part II:

HRT

Placebo

HRT

Placebo

Post six month run-in period,

1,25 + calcium

calcium + hormones

1,25 + hormones + calcium

calcium

Placebo

0.15mg/d

0.30mg/d

0.625mg/d

1.25mg/d

E2+P

E2+E3+P

Placebo

2.5% 

-3.8%

3.7% 

0.2%

-2.4%

-5.7%

-1.91 %

+3.62%

+3.06%

-0.39%

-8.23%

-8.51 %

-5.01 %

-0.24%

-0.00%

+0.52%

+1.53% 

-3.3%
—

Duration of

monitoring

of bone

Study Number of participants density Type of treatment Results

Caniggia (1984) 22 patients group 1: (n=5) 1 year Four groups: Placebo -8.O%

1,25(OH) 2 D3, group 2: l ,25 (OH)2 D3 (0.5mcg) 1 ,25(OH)2D3 +9.O%

(n=5) estradiol valerate, ■ ,25 (OH)2 D3 0.5mcg+ 1 ,25(OH)2D3+-E2 +6.0%

group 3: (n=7) 1,25(OH)2 estradiol valerate (2mg/d) E2 +9.0%

D & estradiol valerate ■ stradiol valerate (2mg/d)

group 4: (n=5) placebo n placebo

No statistical analysis of data.

Gotfredsen (1986) 52 treated, 52 controls 1 year Treated patients received either 17-beta-estradiol, Placebo:

either percutaneously (one daily dose of 5g, Head

corresponding to 3mg 17-beta-estradiol) or orally Chest

(sequentially administered oral 17-beta-estradiol Arms

2mg and for 10 days each cycle 1 mg cyproterone Pelvis

acetate). Legs

Spine

HRT:

Head

Chest

Arms

Pelvis

Legs

Spine

-5. O+-1.5%

-7.0+-2.0%

-3.0+-1.0%

-5.5+-1.5%

-4.3+-0.3%

-3.0+-2.5%

+ 1.7+-1.3 %

+2.3+-2.0%

+0.3+-0.5%

-1.0+-2.0%

-0.7+-0.25%

-2.1+-1.5%

DPA lumbar spine.

HRT + 1.0%

Placebo 0.0%

DPA total spine.

HRT 0.0%

Placebo -2.5%

SPA forearm

HRT o o%

Placebo -2.0%
Appendix C Evidence on HRT and Bone Loss 123
Duration of

monitoring

of bone

Study Number of participants density Type of treatment Results

Munk-Jensen 50 continuous estrogen and 18 months Group 1, continuous estradiol 2mg and

(1988) progestogen; 50 (including norethisterone acetate 1 mg; group 2, cyclic

sequential estrogen and 6 mo. estradiol 2mg and 10 days per month 1 mg

progestogen, 51 placebo run-in norethisterone acetate; group 3, placebo.

period) 6 month run-in period where all patients were

untreated

Riis (1988) 21 treated,

22 controls

2 years Patients assigned to either continuous

17- β -estradiol, 2mg, and norethisterone acetate, 1

mg, or placebo

Genant (1 990) 94 treated; 28

placebo-controls

1 year 30 patients treated with 0.3mg estrone sulfate; 32

patients treated with 0.65mg estrone sulfate, 32

patients treated with 1.25mg estrone sulfate.

Purpose of study was to determine minimum

effective dose of estrogens. All patients given

1,000mg elemental calcium supplementation

Lindsay (1990) 22 estrogen treated; 18 2 years All treated and controls given calcium to bring their

controls total intake to 1,500mg/d, treated patients

received CEE 0.625 mg/d, and those with an intact

uterus received medroxyprogesterone 5 to 10mg

for 12-14 days a month

Distal forearm,

Estrogen and progesterone

(continuous)

Estrogen and progesterone

(sequential)

Placebo

Lumbar spine:

Estrogen and progesterone

(continuous)

Estrogen and progesterone

(sequential)

Placebo

Forearm (prox,).

HRT

Placebo

Forearm (distal):

HRT

Placebo

Spine:

HRT

Placebo

0.3mg estrone sulfate

0.625mg estrone sulfate

1.250mg estrone sulfate

Placebo

Vertebrae.

Controls

Treated

Hip:

Controls

Treated

-0.8+-0.6%

-2.0+-O.5%

-5.6+-0.55%

+4,2+-0.8 %

+3.2+-0.55%

+ 1.0+-1 .9%

-4.5+-2.7%

+0.8+-3.8 %

-7.5+-3.8 %

+5.4+-7.7%

-3.7+-8.0%

-3.22%

+ 1.38%

+2.62%

-0.82%

-7.6%

+6.4%

-4.13%

+9.2%
Duration of

monitoring

of bone

Study Number of participants density Type of treatment Results

Resch (1990) 9 treated, 9 controls 1 year Nine patients treated with Trlsequens; nine patients HRT +8.84%

treated with placebo, all patients received 500mg Placebo 0.0%

calcium; Trisequens is estradiol (2mg) and

norethisterone acetate (1 mg)

Stevenson (1990) 66 treated, 18 mos. 33 patients treated with transdermal 17- β estradiol Transdermal:

30 controls 0.05mg daily with transdermal norethisterone Spine (L2-L4)

acetate 0.2mg to 0.3mg per day for 14 days a Femoral neck

cycle; 33 patients treated with oral CEE 0.625mg Wards triangle

daily with dl-norgestrel 0.15mg daily for 12 of the Trochanteric

28 days Oral HRT:

Spine

Femoral neck

Wards triangle

Trochariteric

Untreated:

Spine

Femoral neck

Wards triangle

Trochanteric

+3. 14%

+3. 14%

+ 1 .0%

0.0%

+ 1 .71%

+ 1.00%

+2.00%

+2.66%

-1.93%

-3.16% 

-4.32%

-2.15%
26 I Cost Effectiveness of Screening for Osteoporosis

I

I
Duration of

Number of Study monitoring

Study participants design bone mass Type of treatment Results

Meema, et al.

(1 975)

Lindsay, et al.

(1978b)

Nachtigall, et al.

(1979)

Lindsay, et al.

(1980)

29 control

53 treated

14 controls; 15

treated 8 years; 14

treated, then

treatment

withdrawn

67 treated

62 controls

42 control

58 treated

Retrospective 4 to 10 years Most frequently used hormone preparations

cohort followup (6 were conjugated equine estrogens

years (0.625mg or 1.25 mg) usually

average administered cyclically

followup)

Clinical trial 8 years Mean daily dose 27.6 mcg mestranol; 14

patients placebo; 14 patients 4 yrs.

mestranol treatment then placebo 4

years; 15 patients received 8 years of

mestranol treatment

Clinical trial 10 years Treated patients received CEE 2.5mg/day

and 7 days each month

medroxyprogesterone acetate 10mg.

Clinical trial Mean duration Treated with mestranol mean daily dose

9 years 23.3mcg

Castrates: +1.92%

Estrogen-treated -7.78%

Untreated +1.12%

Natural menopause: -6.30%

Estrogen-treated

Untreated

Placebo group -11.9%

Estrogen group -0.7%

Estrogen, then withdrawal -10.070

after 4 years

<3 years from LMP:

Estrogen-treated

Placebo control

>3 years from LMP:

estrogen-treated

placebo control

Placebo:

Metacarpal

Radius

Estrogen-treated:

Metacarpal

Radius

+8.67%

-9.00%

-0.5070

-11.29%

-10.4%

-9.45%

-1 .90%

-2.1 5%

KEY: LMP = last menstrual period.

SOURCE: Office of Technology Assessment, 1995

o
28 I Cost Effectiveness of Screening for Osteoporosis

who continued for a duration of at least 10 years.

The mean duration of estrogen use among longterm estrogen users was 19.8 years. Controls were

postmenopausal women who used estrogen for

less than one year. There was a significant difference in mean spinal bone mineral density between

long-term estrogen users (1.21 9 g/cm2) and controls (1.092 g/cm2

), and this significant difference

was retained after controlling for age and type of

menopause.

In the only long-term prospective clinical trial

of HRT and bone mineral density, 84 pairs of postmenopausal nursing home patients were randomly assigned to estrogen and progesterone or placebo (39). After 10 years, HRT-treated women had

no significant decrease in bone mass. Women who

began HRT within three years of menopause had a

small but significant increase in bone mass after

1() years. Women assigned to placebo had a significant decrease in bone mass.

A number of studies have demonstrated that

HRT is able to halt or possibly reverse bone loss

even if it is started long after menopause (9,31,

32,35,41,43,45). Gains in bone mass of 5 to 10

percent or more have been found after initiation of

HRT in the elderly. In a prospective study of 397

postmenopausal women between the ages of 51

and 80 years, Quigley found that estrogen replacement therapy reduced bone loss to about the same

rate for estrogen users regardless of age (43).

Ettinger and Grady predicted that beginning

therapy later in life may provide almost as much

protection against osteoporotic fractures as starting at menopause (12). Ettinger and Grady used

data on the effects of hormone replacement therapy on bone density, and the association of bone

density to fracture risk to estimate and compare

the expected benefits of three possible treatment

scenarios: 1 1) beginning therapy at menopause

and continuing for the remainder of life; 2) beginning therapy at menopause and stopping at age 65;

and 3) beginning therapy at 65 and continuing for

the remainder of life (12). Their model included a

number of key assumptions, based on their review

of studies of the impact of hormonal replacement

therapy in the elderly, including the assumption

that bone mass would increase by 5 percent to 10

percent in the first two years after initiating therapy in the elderly. The investigators concluded that

women who begin therapy at menopause and stop

at age 65 have only a small (8 percent) increase in

bone density at ages 75 to 85, the ages of highest

hip fracture incidence, compared to never users,

which translates into a 23-percent reduction in

fracture incidence. Women who begin therapy at

menopause and continue for the remainder of life

were predicted to have the highest mean bone density at ages 75 to 85, about 22 percent higher than

never users, and the greatest reduction in fracture

incidence, a 73-percent reduction. But women

who began HRT at age 65 had almost as great an

increase in bone density, from 14 to 19 percent,

and almost as great a reduction in fracture incidence, from 57 to 69 percent, as women who began HRT at menopause and continue for the rest of

their lives.

Ettinger and Grady argued that starting hormone therapy later in life would halve the period

of hormone exposure, reducing the potential risks

of very long-term estrogen therapy (12).

There are several other reasons for beginning

HRT in the elderly. Many of the early estimates of

the rate of bone loss with aging were derived from

cross-sectional studies, which may be biased if

there are cohort effects. Recent prospective studies of bone loss with aging demonstrate that bone

loss may accelerate with aging. Jones and colleagues reported on the rate of bone loss in 769

residents of Dubbo, Australia, aged 60 years and

older, followed between January 1989 and June

1993. They found that bone loss at the hip was almost 1 percent per year in women, and about 0.8

] OTA’s estimates of the impact of hormonal replacement therapy on fracture risk were calculated in a similar manner. See appendix D.
Appendix C Evidence on HRT and Bone Loss 29

percent in men, and that bone loss increased with

advancing age in both sexes (23).2

Recent data on the relation of bone mass to fracture risk in the elderly show that there continues to

be a strong relationship of bone mass to hip fracture risk, even after age 80, so that therapies that

slow bone loss will reduce fracture risk in this age

group(3).

In addition, there is evidence from prospective

studies that the rate of bone loss immediately after

menopause may not be as great as previously

thought, and the period of accelerated bone loss

may not last as long as was predicted from crosssectional studies (3). Finally, at age 65, densitometry can more precisely estimate the subsequent

risk of hip fractures and target treatment more effectively (3).

There are, however, a number of reasons to

question whether this type of model overestimates

the number of fractures avoided by preserving

bone mass in the elderly. Reports are inconclusive

regarding how HRT initiated after substantial

bone is lost affects fracture incidence (25). (See

appendix B for discussion.)

In addition, progressive bone loss is associated

with erosion and perforations in the trabecular

structure, or struts, in cancellous bone (24,33).

These perforations decrease the structural integrity of bone out of proportion to the amount of bone

lost. Interventions such as estrogen that reduce

bone resorption are at best capable of thickening

the trabecular elements that remain, but are unlikely to be able to repair perforated trabeculae.

Finally, such a strategy would not be as effective in preventing wrist and vertebral fractures,

which have a peak incidence earlier in menopause

than hip fractures.3

After cessation of therapy, bone loss accelerates to a rate equivalent to that of untreated women

at menopause (7,30,43). Thus, one would predict

that the benefits of HRT on bone mineral density

are maintained only so long as therapy is continued, and these benefits dissipate after cessation of

therapy. Studies of bone mass in elderly women

support this prediction. Felson and colleagues

measured bone mass in 670 elderly women (mean

age 76 years) in the Framingham study cohort to

determine whether their bone mass was affected

by earlier estrogen use (14). They found that,

among the 212 women who had received estrogen

therapy, only those who had taken estrogen for

seven or more years had significantly higher bone

mass than women who had not taken estrogen.

The differences in bone mass between long-term

users and nonusers was greatest among women

under 75 years old (11.2 percent). Among longterm estrogen users 75 years old or older, bone

density was only 3.2 percent higher than in

women who had never taken estrogen around the

time of menopause, and even those who had taken

estrogen for 10 years had ceased therapy by the

time they were 60 to 65 years old. Of the 24

women 75 years old or older who had taken estrogen therapy for at least seven years, only two had

begun therapy at 60 years of age or later, and only

three were still taking estrogen when their bone

density was measured.

HRT has been found to reduce postmenopausal

bone loss regardless of the route of administration

(45,49,50). Lufkin and colleagues compared bone

loss in 75 osteoporotic women randomly assigned

to transdermal estrogen patches and progesterone

tablets or to placebo patches and tablets (32). They

found that bone mass was significantly greater in

those who received the transdermal estrogen patch

compared with those who received placebo.

Those women receiving transdermal estrogen had

a median annual increase in bone mass of 5.3 percent in the lumbar spine, compared to an increase

of 0.2 percent for women receiving placebo. In a

two-year clinical trial, Ribot and colleagues randomly assigned 94 postmenopausal women to a

transdermal estrogen patch, a topically applied estrogen gel, or to a placebo (46). At the end of the

2 They reported no significant bone loss at the spine, which was perhaps due to the presence of spinal arthritis (23).

3 Wrist fractures and vertebral fractures, however, cause relatively little morbidity compared with that incurred by hip fracture.
30 Cost Effectiveness of Screening for Osteoporosis

study, bone mineral density had increased significantly for the transdermal estrogen patch group

and the percutaneous estrogen gel group, but not

for the placebo group. There was no significant

difference in the percent increase in bone density

between the transdermal estrogen patch group and

the percutaneous estrogen gel group.

The combination of estrogen and progestin, either given sequentially or as continuous combined

therapy has been found as effective as estrogen

alone in reducing postmenopausal bone loss

(5,6,7,10,13,19,29,31,34,38,40,41 ,42,45,47,50).

In fact, a number of studies have demonstrated

that progestins alone are effective in reducing

bone loss in postmenopausal women (1,16,26,

29). Lindsay and colleagues demonstrated the

ability of progestins to reduce bone loss in a clinical trial involving 30 postmenopausal women randomly assigned to the progestin gestranol, the estrogen mestranol, or placebo (29). Women treated

with gestranol showed no significant change in

bone mineral density after one year, and women

treated with mestranol showed a nonsignificant

increase in bone mineral density. Women assigned

to placebo, however, showed a significant decline

in bone mineral density after one year.

Abdalla and colleagues showed that progestin

was able to increase bone mineral density in postmenopausal women in a cohort study of the progestin norethisterone versus placebo (l). Women

assigned to norethisterone were referrals to a

Glasgow, Scotland menopause clinic, and controls were patients chosen from placebo groups of

other clinical trials matched to the treatment group

for age, years since menopause, and initial bone

mass. After two years, the bone mass of women

assigned to norethisterone increased by 3.3 percent, whereas the bone mass of the matched controls declined by 5 percent. The difference in bone

mass between the two groups after two years was

statistically significant (p < 0.002).

Although progestins have been demonstrated

to prevent bone loss in postmenopausal women,

they do not appear to be as effective as estrogens in

maintaining bone mass, especially mass of trabecular bone. Gallagher and colleagues randomly assigned 81 postmenopausal women to four groups:

treatment with the progestin Provera R (medroxy -

progesterone acetate), the estrogen Premarin

(conjugated equine estrogen), Premarin plus Provera, or placebo (16). The group receiving Premarin plus Provera received half the dose of estrogen

as the Premarin only group and half the dose of

progestin as the Provera only group. After two

years, bone mass of the spine (composed primarily of trabecular bone) was maintained in the Premarin group and the Premarin plus Provera group,

but was lost in the Provera group and the placebo

group. Bone density of the wrist (composed primarily of cortical bone) was lost in all four groups,

but was least in the Premarin only, Provera only,

and Premarin plus Provera groups, and was greatest in the placebo group. For both cortical bone

and trabecular bone, Premarin alone was better

able to maintain bone mass than Provera alone.

CONCLUSIONS

Controlled clinical trials have demonstrated that

HRT is able to halt bone loss and perhaps increase

bone mass in postmenopausal women. For this

analysis, OTA has assumed as a base case that

HRT maintains bone mass for as long as it is taken.

There is less information about whether HRT is

able to maintain bone mass over the long term.

OTA also assumed that initiation of HRT at age 65

was able to maintain bone mass. Two recent reviews of studies of bone density have concluded

that bone mass is lost in long-term HRT users, but

at a rate that is one-half to one-third that of nonusers (3, 12). OTA assumed as a worst case that bone

mass in HRT users is lost at half the rate of nonusers. Studies have demonstrated that bone loss is

halted or reduced only as long as HRT is used.

OTA assumed that, upon cessation of HRT use,

bone mass is lost at a rate similar to the rate of bone

loss at menopause.

Because there are relatively few data on the reduction of fracture in long-term estrogen users,

OTA used data on the effects of HRT on bone density and the association of bone density on fracture

risks to estimate the risks of hip fracture in HRT

users at each age. This assumption is discussed in

more detail in appendix D.
Appendix C Evidence on HRT and Bone Loss 31

REFERENCES

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2. Aitken, J., Hart, D., and Lindsay, R., “Oestrogen Replacement Therapy for Prevention of

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3. Black, D. M., “Why Elderly Women Should

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4. Caniggia, A., Delling, G., Nuti, R., et al.,

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5. Christiansen, C., Christensen, M. S., McNair,

P., et al., “Prevention of Early Postmenopausal Bone Loss: Controlled Two-Year Study in

315 Normal Females,” European Journal of

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6. Christiansen, C., Christensen, M. S., Rodbro,

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D3 on Itself or Combined with Hormone

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7. Christiansen, C., Christensen, M. S., and

Transbol, I., “Bone Mass in Postmenopausal

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1:459-461, 1981b.

8. Christiansen, C., Mazess, R., Transbol, I., et

al., “Factors in Response to Treatment of Early Postmenopausal Bone Loss,” Calcified

Tissue International 33:575-581, 1981c.

9. Christiansen, C., and Riis, B.J., “17-Estradiol and Continuous Norethisterone: A

Unique Treatment for Established Osteoporosis in Elderly Women,” Journal of Clinical

Endocrinology and Metabolism 71(4):

836-841, 1990.

10. Christiansen, C., and Rodbro, P., “Does Oestriol Add to the Beneficial Effect of Combined Hormonal Prophylaxis Against Early

Postmenopausal Osteoporosis?” British

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91(5):489-493, 1984.

11. Civitelli, R., Agnusdei, D., Nardi, P., et al.,

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12. Ettinger, B., and Grady, D., “Maximizing the

Benefit of Estrogen Therapy for Prevention of

Osteoporosis,” Menopause l(l): 19-24, 1994.

13. Farish, E., Hart, D. M., Gray, C. E., et al., “Effects of Treatment with Oestradiol/Levonorgestrel on Bone, Lipoproteins and Hormone

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14. Felson, D.T., Zhang, Y., Hannan, M.T., et al.,

“The Effect of Postmenopausal Estrogen

Therapy on Bone Density in Elderly

Women,” New England Journal of Medicine

329(16):1141-1146, 1993.

15. Finn Jensen, G., Christiansen, C., and

Transbol, I., “Treatment of Post-Menopausal

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16. Gallagher, J., Kable, W., and Goldgar, D.,

“Effect of Progestin Therapy on Cortical and

Trabecular Bone: Comparison with Estrogen,” American Journal of Medicine 90:

171-178, 1991.

17. Genant, H., Baylink, D., Gallagher, J., et al.,

“Effect of Estrone Sulfate on Postmenopausal

Bone Loss,” Obstetrics & Gynecology

76(4):579-584, 1990.

18. Gotfredsen, A., Nilas, L., and Riis, B. J.,

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32 Cost Effectiveness of Screening for Osteoporosis

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19. Grey, A. B., Cundy, T. F., and Reid, I. R.,

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20. Hassager, C., Jensen, S. B., and Christiansen,

C., “Non-Responders to Hormone Replacement Therapy for the Prevention of Postmenopausal Bone Loss: Do They Exist?” Osteoporosis International 4:36-41, 1994.

21. Horsman, A., Gallagher, J. C., Simpson, M.,

et al., “Prospective Trial of Oestrogen and

Calcium in Postmenopausal Women,” British

Medical Journal 2:789-792, 1977.

22. Horsman, A., Jones, M., Francis, R., et al.,

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Medicine 309(23):1405-1407, 1983.

23. Jones, G., Nguyen, T., Sambrook, P., et al.,

“Progressive Loss of Bone in the Femoral

Neck in Elderly People: Longitudinal Findings from the Dubbo Osteoporosis Epidemiology Study,” British Medical Journal

309:691-695, 1994.

24. Kanis, J. A., “Treatment of Osteoporosis in

Elderly Women,” American Journal of Medicine 98( Suppl. 2A):60S-66S, 1995.

25. Langer, R. D., and Barrett-Connor, E., “Extended Hormone Replacement: Who Should

Get It, and for How Long?” Geriatrics

49(12):20-24, 1994.

26. Lee, J. R., “Osteoporosis Reversal with

Transdermal Progesterone” (letter), Lancet

336:1327, 1990.

27. Lindsay, R., Hart, D. M., and Clark, D. M.,

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for Prevention of Postmenopausal Bone

Loss,” Obstetrics & Gynecology 63(6):

759-763, 1984.

28. Lindsay, R., Hart, D., Forrest, C., et al., "Prevention of Spinal Osteoporosis in Oophorectomised Women,” Lancet 2(8205):

1151-1154, 1980.

29. Lindsay, R., Hart, D. M., Purdie, D., et al.,

“Comparative Effects of Oestrogen and Progestogen on Bone Loss in Postmenopausal

Women,” Clinical Science and Molecular

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30. Lindsay, R., Hart, D. M., MacLean, A., et al.,

“Bone Response to Termination of Estrogen Treatment,” Lancet 1(8078):1325-1327,

1978b.

31. Lindsay, R., and Tohme, J. F., “Estrogen

Treatment of Patients with Established Postmenopausal Osteoporosis,” Obstetrics & Gynecology 76(2):290-295, 1990.

32. Lufkin, E. G., Wahner, H. W., O’Fallen,

W.M., et al., “Treatment of Postmenopausal

Osteoporosis with Transdermal Estrogen,”

Annals of Internal Medicine 117(1): 1-9,

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33. Manolagas, S. C., and Jilka, R. L., “Bone Marrow, Cytokines, and Bone Remodeling—

Emerging Insights into the Pathophysiology

of Osteoporosis,” New England Journal of

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34. Marslew, U., Overgaard, K., Riis, B.J., et al.,

“Two New Combinations of Estrogen and

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Calcium, and Lipid Metabolism, Climacteric

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35. Marx, C. W., Dailey, G. E., HI, Cheney, C., et

al., “Do Estrogens Improve Bone Mineral

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65?” Journal of Bone and Mineral Research

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36. Meema, S., Bunker, M. L., and Meema, H. E.,

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37. Moore, M., Bracker, M., Sartoris, D., et al.,

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38. Munk-Jensen, N., Pors Nielsen, S., Obel,

E. B., et al.. “Reversal of Postmenopausal Ver-
Appendix C Evidence on HRT and Bone Loss 33

tebral Bone Loss by Oestrogen and Progestogen: A Double Blind Placebo Controlled

Study,” British Medical Journal 296(6630):

1150-1152, 1988.

39. Nachtigall, L.E., Nachtigall, R. H., Nachtigall, R. D., et al., “Estrogen Replacement

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40. Nielsen Television Research Services, 1990

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41. Nordin, B. E. C., Horsman, A., Crilly, R., et

al., “Treatment of Spinal Osteoporosis in

Postmenopausal Women,” British Medical

Journal 280:451-455, 1980.

42. Prince, R.L., Smith, M., Dick, I. M., et al.,

“Prevention of Postmenopausal Osteoporosis: A Comparative Study of Exercise, Calcium Supplementation, and Hormone-Replacement Therapy,” New England Journal of

Medicine 325(17 ):1189-1 195, 1991.

43. Quigley, M.E.T., Martin, P. L., Burnier, A. M.,

et al., “Estrogen Therapy Arrests Bone Loss

in Elderly Women,” American Journal of Obstetrics and Gynecology 156(6): 1516-1523,

1987.

44. Reeker, R.R., Saville, P. D., and Heaney, R.P.,

“The Effects of Estrogens and Calcium Carbonate on Bone Loss in Postmenopausal

Women,” Annals of Internal Medicine 87:

649-655, 1977.

45. Resch, H., Pietschmann, P., Krexner, E., et

al., “Effects of One-Year Hormone Replacement Therapy on Peripheral Bone Mineral

Content in Patients with Osteoporotic Spine

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1990.

46. Ribot, C., Tremollieres, F., and Pouilles,

J. M., “Prevention of Postmenopausal Bone

Loss by Long-Term Parenteral Administration of 17 Estradiol: Comparison of Percutaneous and Transdermal Route,” Osteoporosis: Physiological Basis, Assessment, and

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(New York, NY: Elsevier Science Publishing

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47. Riis, B.J., and Christiansen, C.. “Continuous

Oestrogen-Progestogen Treatment and Bone

Metabolism in Post-Menopausal Women,”

Maturitas 10:51-58, 1988.

48. Riis, B., Thomsen, K., and Christiansen, C..

“Does Calcium Supplementation Prevent

Postmenopausal Bone Loss? A DoubleBlind, Controlled Clinical Study,” New England Journal of Medicine 316(4): 173-177.

1987a.

49. Riis, B., Thomsen, K., Strom, V., et al., “The

Effect of Percutaneous Estradiol and Natural

Progesterone on Postmenopausal Bone

Loss,” American Journal of Obstetrics and

Gynecology 156(1):61-65, 1987b.

50. Stevenson, J., Cust, M., Gangar, K.. et al.,

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Appendix D:

Summary of

Hip Fracture

Prediction

Methods D

T

his appendix describes the assumptions

used in OTA’s analysis of the impact of

hormone replacement therapy (HRT) on

hip fractures.l

OTA’s model assumes that HRT affects fracture

risk through its impact on bone mass as measured

by bone mineral density (BMD). The rationale for

this assumption is twofold. First, the causal relationship between HRT and bone loss is well-established and precisely estimated, at least in the

short-run. In contrast, the evidence of a direct relationship between HRT and fracture rests on studies with relatively weak designs that do not lend

themselves readily to precise estimates of effect

size. (See appendices B and C.) Second, the relationship between BMD measured at each age and

the risk of hip fracture has been quantified in some

recently reported studies.

REQUIREMENTS OF THE OTA HIP

FRACTURE PREDICTION MODEL

OTA’s model predicts the probability of hip fracture at every age between 50 and 90 as a function

of an individual’s BMD at age 50. The model is

based on earlier work by Black and colleagues on

the relationship between bone mass at menopause

and lifetime risk of hip fracture (3). In that model,

as in the present one, BMD at any age is predicted

from BMD at menopause. (OTA used age 50 as a

reasonable proxy for the age at menopause.) The

predicted BMD at each age is then used to estimate the risk of fracture at that age.

The parameters required for such a model fall

into two general categories: 1) those related to the

longitudinal distribution of BMD; and 2) those relating BMD to the short-term risk of fracture.

Most of the data available to estimate these relationships are based on studies of white women,

the group at highest risk of osteoporosis and the

only ethnic-sex group for whom data are available

for estimations of sufficient precision for modeling. Where data on racial or ethnic groups or sexes

other than white women are available, however,

their findings are described in this appendix.

MEASURING BONE MASS

Different technologies are available for measuring

bone mass at different sites in the body. How and

1 This appendix is based on a contract report prepared in 1992 for OTA by Dennis Black (1). The data in that report reflected information

available in 1992 .That report describes methods for predicting wrist, spine, and all fractures as well as hip fractures.

 35
36 Cost Effectiveness of Screening for Osteoporosis

where bone mass is measured can affect its predictive power for hip fracture.2 OTA’s model is based

on bone mineral density measured at the proximal

radius (the lower forearm above the wrist) using

single photon absorptiometry as the measurement

technology. The primary reason for this choice is

that the proximal radius is the only site for which

there are sufficient data from a number of sources

to make reasonable estimates of all parameters of

the model. In particular, the proximal radius is the

only site for which the longitudinal pattern of

bone mass measurement over time has been characterized. 3 Because OTA’s model requires consistent data on both changes in bone mass and the

relationship between bone mass and fracture, no

other site is feasible for modeling at present.

There has been some discussion in the literature

about whether bone mineral content (gm/cm)

(BMC) or density (actually areal density, gm/cm2)

is a better predictor of fracture risk. For predicting

hip fracture, an analysis of data from the Study of

Osteoporotic Fractures (SOF) showed that BMC

was approximately the same as bone mineral density in predicting fracture (5). For predicting all

fractures, other analyses performed on the SOF

data have shown similar results. Although most

studies have reported results in terms of BMD,

some have reported BMC. This appendix treats

these results as interchangeable, although the predictive model is measured in terms of BMD.

PREDICTING BONE MASS OVER TIME

The OTA model assumes that bone mass at any

age follows a normal distribution with an age-specific mean and standard deviation. The evidence

to support this assumption is summarized in the

next section. If BMD at any age is normally distributed over the cohort of individuals in the age

category, then the joint probability distribution of

BMD at any two ages can be assumed to be bivariate normal. This implies that a woman’s BMD at

a given age, t, is related to her BMD at the previous age, t -1, according to the following formulas:

CMBM Dt = t + t ( B M Dt - 1- t - 1

CSDVt = t

2 (1 - t 2

))

1/2

B M Dt = Z * CSDVt + CMBMDt

where:

BMD = a woman’s BMD at age t;

μ t

= the mean BMD in the population of women

at age t;

 σ t= the standard deviation of BMD in the population of women at age t;

ρ = the correlation between a woman’s BMD at

age t and her BMD at age t–1.

CBMDt = the conditional mean of the probability

distribution of BMD values at age t in women with

BMD value at age t–l of BMD t-l;

CSDVt = conditional standard deviation at age t;

2 Although a paper from the Hawaii Osteoporosis Center (29) has suggested that bone mass measurements taken at the calcaneus (heel)

predicted all fractures better than did measurements taken at the radius (a bone of the lower part of the arm) or in the spine, the Study of Osteoporotic Fractures (the only other study which has measured bone mass at the calcaneus) has shown a relationship of approximately equal magnitude

between bone mass and fracture risk at all sites (radius, calcaneus, spine and hip) for all fractures and for wrist fractures (3). For hip fractures, the

three appendicular sites (proximal radius, distal radius and calcaneus) have been shown to be approximately equal as predictors (5) although

recent data have suggested that bone mass at the proximal femur (thighbone) is abetter predictor of hip fracture risk than bone mass at the other

sites (2,6). Unfortunately, no data on the longitudinal distribution of bone mass at the hip or the long-run predictive accuracy of any densitometry

method are yet available.

3 After the proximal radius, the bone mass site studied most frequently is the spine. At present, however, the information available to estimate

the parameters of the model are insufficient for three reasons. First, most studies of bone mass at the spine are either small, have a very wide age

range, or have been performed on samples of women who are unrepresentative of the general population of women. Second, bone mass at the

spine is measured by several techniques, including quantitative computed tomography, dual photon absorptiometry, and dual x-ray absorptiometry, each of which might show a unique longitudinal pattern or relationship to fracture risk. Third, as women age and develop anatomical

abnormalities (e.g., vertebral deformities, osteophytes, etc.,) the spine presents special difficulties as a site for bone mass measurement.
Appendix D Summary of Hip Fracture Prediction Methods 37

1 0.415 0.412 0.372 0.396

5 0.484 0.484 0.438 0,441

10 0.521 0.522 0.473 0.476

25 0.582 0.584 0.532 0.529

50 0.651 0.650 0.598 0,596

75 0.719 0.719 0.663 0,659

90 0.781 0.780 0.722 0,722

Mean (gm/cm2) 0.6507 0.5978

Standard deviation 0.1015 0.09705

a Predicted values based on a normal distribution with the observed mean and standard deviation.

SOURCE: D. M. Black, “Cost Effectiveness of Screening for Osteoporosis’ Review of Bone Mineral Density and Fracture Parameters Required for

Model,” University of California, San Francisco, CA, unpublished OTA contract

Z = a random number drawn from the standard

normal distribution.

Thus, knowledge of the mean and standard deviation of the BMD distribution at each age, and the

coefficient of correlation between the two distributions, permits the generation of a BMD trajectory for an individual woman over her lifetime.

This section reviews the evidence on the following aspects of the BMD prediction formula

given above:

■ Age-specific distribution of BMDs

■ Correlation between BMD values at successive

ages

❚ Age-Specific Distribution of BMDs

The age-specific distribution of BMDs is defined

by the general shape of the distribution (i.e.,

whether it is a normal, or bell-shaped curve, or defined by some other general form) and, if it is a

normal distribution, its mean and standard deviation.

Shape of the BMD Distribution

Three large studies of bone mass are available to

assess the shape of the BMD distribution.

■ Study of Osteoporotic Fractures (SOF): The

unpublished analysis in table D-1 compares the

■

■

report, Nov. 17, 1992

observed percentiles for bone mass at the proximal radius to the predicted percentiles based on

a normal distribution. There is close agreement

between the observed and predicted values, indicating that the normal distribution provides

an excellent approximation to the observed,

empirical distribution (1).

University of Indiana: A study of bone mass in

583 women showed that the fit of bone mass

data to a normal distribution was excellent (19).

The investigators of this study have reported

that they have found no evidence of significant

skewing or other nonnormality in their crosssectional data (15).

University of Iowa: In a cross-sectional study of

bone mass in 217 Caucasian women, bone

mass variables were found to have a normal

distribution (24).

These findings and the lack of any report suggesting that bone mass departs from a normal distribution, strongly suggest that at any age the

distribution of bone mass across women is normal.

Age-Specific Means

Ideally, bone loss could be estimated directly from

longitudinal data on cohorts of women followed

for long periods of time. However, few such studies with sufficiently large numbers of subjects are
38 Cost Effectiveness of Screening for Osteoporosis

available. In the absence of such longitudinal data,

bone loss can be estimated from age-specific

means derived from cross-sectional data. OTA

used a combination of longitudinal and cross-sectional studies to estimate change in bone mass

with age.

It is possible to establish age-specific means

from cross-sectional studies of bone mass in population-based samples of individuals, but there are

a number of potential problems in using cross-sectional data to estimate longitudinal changes in

bone mass.4 First, the sample maybe biased. Second, the sample must be large enough in each age

category to allow for sufficient precision. Third,

cross-sectionally estimated changes in bone mass

may differ from those estimated from longitudinal

studies if there are cohort effects, such as nutritional factors or medication use patterns that vary

with age.

Although many cross-sectional studies address

the relationship of bone mass to age, most of these

data are not very informative because they are

from small studies without population-based

samples. Two studies described in this section are

exceptions.

Data from six separate studies of bone mass

formed the basis for estimates of age-specific

mean BMD. Each is described in detail below.

University of Indiana

A total of 268 women were studied longitudinally

and 583 were studied cross-sectionally. They were

recruited as two distinct samples. The cross-sectional sample was younger (under age 65) and

consisted primarily of gynecology clinic patients

and employees of the Indiana University Medical

Center. The longitudinal sample consisted of a

group of older subjects (over age 55, mostly over

age 65) who were residents of a retirement home.

The older women had repeated bone mass measurements (between three and 45, with a mean of

20 measurements) over followup periods ranging

from six weeks to seven years (mean = 4 years).

The samples have been used for a number of different analyses. The exact participants and measurements used have differed in the various

reports of the study depending on the research

question being addressed.

One analysis of these data compared longitudinal with cross-sectional estimates of mean BMC

in post-menopausal women (19). This analysis

showed that the cross-sectional results agreed

closely with longitudinal results. The results

showed a quadratic relationship between BMC

and age which was essentially linear in the age

range 50 to 70. The average rate of bone loss decreased after about age 70, and there is a suggestion of an increase in bone mass after age 70. The

actual rates of loss in the data are not useful for the

purposes of the OTA study, because they were adjusted for body weight without reporting enough

information to calculate overall population

means.

A more recent analysis of the same data looked

in detail at bone loss in the period zero to five years

after menopause and five to 10 years after menopause (18). The large number of repeat measurements over time gives very precise estimates of

bone loss. For the period zero to five years after

menopause, a total of 89 women were available

for analysis with an average of 11 measurements

during the five-year period. These women showed

an average loss of about 1.6 percent per year over

the five years. For the period five to 10 years after

menopause, a total of 47 women were used with

an average of eight measurements each during the

five years. These women showed an average loss

of about 1.2 percent per year over the five years.

University of Iowa

A sample of 217 Caucasian women from a rural

community in Iowa between the ages of 22 and 80

4 Several studies have compared cross-sectional to longitudinal data sets for estimating bone 10SS with age (7,19). Only Davis and colleagues

found the two approaches to lead to different results, although the methodology in their paper is difficult to interpret. Also, the data set which

Davis used (a cohort of Japanese American women) may have cohort effects not present in other data sets.
Appendix D

Age at first Number of Percent loss per

measurement women year

45-49 19 1.3%

50-54 36 2.O%

55-59 60 1.2%

60-64 55 1.2%

65-69 60 1.3%

70-74 43 1.2%

75-79 53 1.3%

SOURCE: M. Sowers, M. Clark, B. HoIIis, et al., “Prospective Study of

Radial Bone Mineral Density in a Geographically Defined Population

of Postmenopausal Caucasian Women, ” Calcified Tissue International 48:232-239, 1991.

had bone mass measured at the radius in 1984, and

181 of them had repeat measurements made five

years later in 1989 (24,25). The strength of thesedata is that they were collected longitudinally over

a long period of time (five years). However, the

precision of estimates based on the data is limited

due to the small numbers of participants. The average annual bone loss for women who were postmenopausal at the time of followup is given in

table D-2.

For ages 50 and over, the confidence intervals

around the mean percent loss are approximately

plus or minus 0.3 to 0.4 percent. The loss rates in

this study are approximately the same as other

studies. There is an approximate doubling of the

rate of loss during the five years after menopause.

University of Copenhagen

121 women who were six months to three years

post-menopausal and who were 45 to 54 in 1977

had BMD measured in the forearm. Their BMD

measurements were repeated 12 years later in

1989 (14). The mean loss averaged 1.7 percent per

year over the 12 years.

Hawaii Osteoporosis Center

A cohort of 1,098 Japanese-American women, all

post-menopausal, was established in 1981. This

cohort has been extensively followed with repeat

Summary of Hip Fracture Prediction Methods 39

BMC at the proximal radius

Mean Percent loss

Age N (gm/cm) per year

43-49 11 .849

50-54 38 ,797

55-59 196 ,790

60-64 411 ,745

65-69 306 .687

70-74 108 .669

75-79 24 .577

KEY BMC = bone mineral content

—

1.2%

1.2%

1.1%

1.2%

0.5%

2.7%

SOURCE K Yano, R.D. Wasnich, J.M. Bogel, et al , “Bone Mineral

Measurements Among Middle-Aged and Elderly Japanese Residents in Hawaii,” American Journal of Epidemiology 119751-764,

1984.

bone mass measurements. One analysis examined

change in bone mass with age among post-menopausal women who did not use estrogen (7). These

loss rates were adjusted for height, weight, and

bone width. Longitudinal analyses (n = 636

women, mean length of followup = 3.2 years) in

the same paper showed that the rate of loss was

about 1.5 percent per year at age 55 and declined

to about 0.8 percent at age 75. Cross-sectional

analyses of bone density in 677 women showed a

decrease in mean bone mass of approximately 1

percent for each year of age for women around the

age of 55. The mean decrease by age increased to

about 1.25 percent for each year of age for women

around 75 years old.

The results of another cross-sectional analysis

on the same sample, which did not exclude estrogen users, are shown in table D-3 (30). Through

the early post-menopausal years, the results are

essentially constant at about 1.2 percent per year.

The results for age 70 to 74 are at odds with the remainder of the data and suggest either a typographic error (e.g., .699 should be .629) or

imprecision due to small sample size.

An important caveat in interpreting analyses of

these data is that the sample is drawn from a very

special population (Japanese-American women
40 Cost Effectiveness of Screening for Osteoporosis

living in Hawaii) which may not reflect loss rates

in a larger population. However, the general pattern of change in bone density with age is helpful

in confirming the pattern found in other data sets.

Study of Osteoporotic Fractures

The largest cross-sectional study (9,704 women

over age 65) of bone mass, the SOF should be reasonably representative of healthy white women

over age 65 years in the U.S. (5). Data are available for bone mass measured by SPA in the proximal radius, distal radius and calcaneus, but only

in women over the age of 65.

Steiger and colleagues recently reported an

analysis of cross-sectional bone loss in SOF (26).

However, that paper does not exclude current estrogen users. The data shown in table D-4 are the

same as those in the Steiger paper but exclude estrogen users.

Framingham Osteoporosis Study

The investigators in the Framingham study performed cross-sectional analysis of bone mass at

various sites, including the proximal radius in 708

women over age 68 years. At the time of preparation of this report, no data had yet been published.

However, preliminary results have suggested a

constant loss rate of about 0.9 percent per year

from ages 68 to 90 (1 ,13).

OTA’s Estimate

Qualitatively, most studies have shown a slightly

higher rate of bone loss at the appendicular sites

just after menopause, which slows after about age

55 or 60. One interesting consistency among the

data presented above is that the acceleration in

bone loss just after menopause at these sites is

only slight.

For the age range of 50 to 65, the various studies provide consistent results. The longitudinal

data from Copenhagen suggest an average rate of

loss of 1.7 percent per year for the 12 years after

menopause. The Iowa data show a 1.6 percent loss

for the five years after menopause with a 1.2 percent loss for the next five years. The estimated

rates of loss from these three studies are quite conBone mass at the proximal

radius

Mean Percent loss

Age N (gm/cm2

) per year

65-69 1,864 .650 —

70-74 1,507 .620 0.9%

75-79 907 .598 0.7%

80-85 537 .566 1.O%

85-89 140 .541 0.9%

SOURCE:S.R. Cummings, D.M. Black, M C. Nevitt, et al , “Appendicular Bone Density and Age Predict Hip Fracture in Women, ” Journa/

of the American Medical Association 263:665-668, 1990

sistent given the inherent imprecision due to limited sample size. Some of the discrepancies

among the studies may also be due to differences

in the study population, methods of analysis, or

differences in measurement technique.

The only longitudinal study in the age range of

65 and over is the study from Iowa which showed

a mean loss of about 1.2 percent per year. Two

large cross-sectional studies are available of

women over age 65 years. SOF is much larger than

any other study and shows a constant rate of loss

after 65 of 0.8 percent per year. The results from

the Framingham study are consistent with those

from SOF showing an average loss of about 0.9

percent per year after age 65.

Based on the results of these studies, OTA developed a base-case set of assumptions about the

rate of change in mean bone mass of a population

of women as they age. These assumptions are

shown in table D-5. Alternative assumptions reflecting reasonable upper and lower bounds on the

bone loss rate are also shown in the table.

In addition to the percentage of bone loss in

each year, the OTA model requires an estimate of

mean BMD at each age. Although all the studies

described above are consistent in their estimates

of loss rates, recorded bone density levels vary

with each densitometer. Consequently, it is not

possible to pool mean values from various
Appendix D Summary of Hip Fracture Prediction Methods 41

Annual rate of loss

Age interval Base case Slow loss Fast loss

50-54 1.8% 1.6% 2.0%

55-59 1.3% 1.2% 1.5%

60-64 1.0% 0.9% 1.2%

> 6 5 0.9% 0.8% 1.2%

SOURCE: Office of Technology Assessment, 1995.

sources. OTA used the estimated mean BMD value from SOF for ages 65 to 69 (0.650 gm/cm2

) as

an anchor value for the age-specific BMD levels.

The means at the other ages were calculated from

this value at age 67 using the loss rates given in

table D-5. The derived age-specific means are

shown in table D-6 for the base assumptions and

two alternative assumptions. Under the base assumption, there is an overall loss of 35 percent between ages 50 and 90. For the slow loss

assumption set, there is an overall loss of 32 percent and under the fast loss assumption set, the

overall loss is 42 percent.

Age Specific Standard Deviations

The requirements for estimating the standard

deviations of the distribution of BMDs are similar

to estimating their means: a large, randomly chosen sample in which estrogen users have been excluded. Longitudinal data are not required,

however. Again, the problem of scaling of bone

density values taken from different densitometers

makes comparisons across studies difficult, and

the values of a given study must be used as an anchor. An important question in analyzing the data

available on standard deviation is whether it varies with age.

Because of its size and relatively representative

sample, the SOF study provides the best estimates

of standard deviation for women overage 65. Unpublished data from that study for women who

have never used estrogen are shown in table D-7.

Although these data suggest that, at least for

women over 65 years of age, the standard deviation is fairly constant, other studies suggest some

Assumption set

Age Base slow loss

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

0.814

0.799

0.785

0.771

0.757

0.743

0.733

0.724

0.714

0.705

0.696

0.689

0.682

0.675

0.669

0.662

0.656

0.650

0.644

0.638

0.633

0.627

0.621

0.616

0.610

0.605

0.599

0.594

0.588

0.583

0.578

0.573

0.568

0.562

0.557

0.552

0.547

0.542

0.538

0.533

0.528

0.796

0.783

0.770

0.758

0.746

0.734

0.725

0.717

0.708

0.699

0.691

0.685

0.679

0.673

0.667

0.661

0.655

0.650

0.645

0.640

0.635

0.629

0.624

0.619

0.614

0.610

0.605

0.600

0.595

0.590

0.586

0.581

0.576

0.572

0.567

0.563

0.558

0.554

0.549

0.545

0.540

Fast loss

0.844

0.827

0.811

0.794

0.778

0.763

0.751

0.740

0.729

0.718

0.707

0.699

0.690

0.682

0.674

0.666

0.658

0.650

0.642

0.634

0.627

0.619

0.612

0.605

0.597

0.590

0.583

0.576

0.569

0.562

0.556

0.549

0.542

0.536

0.529

0.523

0.517

0.511

0.504

0.498

0.492

SOURCE: Office of Technology Assessment, 1995; D.M. Black, “Cost

Effectiveness of Screening for Osteoporosis: Review of Bone Mineral

Density and Fracture Parameters Required for Model, ” University of

California, San Francisco, CA, unpublished OTA contract report,

NOV. 17, 1992.

variation with age. Data from the Indiana University sample of 268 post-menopausal women sug-
42 Cost Effectiveness of Screening for Osteoporosis

65-69 1,864 .102

70-74 1,507 .100

75-79 907 .097

80-84 537 .096

85+ 140 .095

KEY: BMD = bone mineral density; SOF = Study of Osteoporotic

Fractures,

SOURCE: D. M. Black, “Cost Effectiveness of Screening for Osteoporosis: Review of Bone Mineral Sensity and Fracture Parameters Required for Model, ” University of California, San Francisco, CA, unpublished OTA contract report, Nov. 17, 1992

gested that there is an increase in standard deviation with age, but no estimates of standard deviation were reported (19). Data from the University

of Copenhagen study, on the other hand, showed

a decrease in the standard deviation between the

first measurement (age 45 to 54) and the second

(age 57 to 66), by about 0.5 percent per year. The

Framingham cross-sectional data also showed a

decrease—about 0.6 percent per year-in women

over age 68. The University of Iowa 1983 crosssectional sample showed age-specific standard

deviations of BMD that varied from a high of

0.119 gm/cm2 (age 70 to 74) to a low of 0.081 gm/

cm

2 (age 65 to 69). There was no clear trend with

age, although the precision of the estimates is limited by the small numbers within each age group.

Estimates of standard deviations are less precise than estimates of means; it is therefore difficult to conclude from these data whether there is a

real decrease in the variation of bone mass with

age. In addition, the value of the standard deviation of bone mass depends on the technique used

to measure bone mass as well as the population

from which the sample was drawn. The data are

most consistent with a slight decrease of standard

deviation with age. However, the small decrease

suggested would have a negligible effect on any

results of the model. Therefore, OTA assumed that

the standard deviation of bone mass at the proximal radius is 0.10 gm/cm2 and does not change

with age in the age range 50 to 90 years.

❚ Correlation Between Values of Bone

Mass at Two Ages

The model requires an estimate of the correlation

between bone mass at the age at which BMD

screening takes place and at later ages. For example, if screening for bone mass occurs at age 50,

the model requires the correlation between bone

mass at age 50 and bone mass at ages 51, 52, etc.

The correlation required is the correlation between the true values of bone mass in successive

years, not the measured values, because it is the

true values that predict fracture. For long-term

studies (e.g., at least five to 10 years), the correlation between the true values will be about the same

as that between the measured values. However, in

studies of shorter duration, measurement error

plays a larger role artificially deflating the correlation.

The accuracy of the estimate of this model parameter is important, because changes in the estimates would have large effects on the resulting

fracture rates. Fortunately, sufficient data exist

(see below) to restrict its possible values, and

within this range its effect on outcomes is only

moderate.

To estimate the long-term correlation, longitudinal data must be collected over as long a period

of time as possible. For example, to estimate the

correlation between bone mass at age 50 and age

65, 15 years of followup data are needed on a cohort who were age 50 at the initial measurements.

For the correlation between BMD at age 50 and

BMD at age 80, a 30-year followup period is necessary. The ideal data set would have bone mass

measured on a large random sample of women

from the age of 50 to 90. Clearly, such data do not

(yet) exist.

Three studies have reported the correlation between bone mass measurement at widely separated intervals. The University of Indiana analysis

of post-menopausal women estimated the correlation between bone mass measured within two
Appendix D Summary of Hip Fracture Prediction Methods 43

years of age 50 with bone mass measured about 10

years later based on the experience of 34 women

(18). The data showed a correlation of about 0.81

between measurements taken at ages 50 and 60

and a correlation of about 0.7 between measurements made at ages 50 and 70.

For women over age 55, the University of Iowa

study found that the correlation between the two

measurements taken five years apart was greater

than 0.9 (24). However, the exact 5-year correlation was not given.

Finally, in the University of Copenhagen study

of 121 post-menopausal women aged 45 to 54 at

entry, the correlation between the first measurement and the second taken 12 years later was 0.8

(95 percent CI: 0.7 to 0.9) (14).

The two long-term data sets on early postmenopausal women agree closely in showing a

10-year correlation of about 0.8. OTA used this

value as the base assumption about the longitudinal correlation from age 50 to age 60. For ages 50

to 70, we used the estimate of 0.7 from the University of Indiana. Beyond age 70, for the base assumption, a quadratic function was fit under the

assumption that the degradation in correlation

continues after age 70 in the same pattern as before

age 70.

Alternative assumptions are possible. Figure

D-1 shows three alternative correlation trajectories. Under the base-case assumptions, the extrapolation of correlation beyond age 70 (pattern B in

figure D-1) continues to decrease along the same

quadratic pattern as before age 70. As a woman

ages and becomes less active and more ill, however, a second acceleration in bone loss may occur.

Since this increased bone loss would be associated

with factors that could not be predicted from bone

mass at age 50, a decreased correlation between

bone mass at age 50 and bone mass beyond age 65

would result. Pattern C represents the decreased

correlation that might be associated with increased bone loss associated with severe immobility and/or illness or extreme old age.

Another correlation trajectory (pattern A in figure D-1) maps a correlation of bone mass at each

age with bone mass at age 50 that is higher than the

Improved tracking

0.8

 (A)

I

 (B)

 (C)

I

50 55 60 65 70 75 80 85

Age

SOURCE D.M. Black, “Cost Effectiveness of Screening forOsteoporoSIS: Review of Bone Mineral Density and Fracture Parameters Required

for Model,” University of California, San Francisco, CA, unpublished

OTA contract report, Nov 17, 1992

base-case pattern. This might occur if a more precise measurement of bone mass was made.

There is little published data specifically addressing the correlation between bone mass at age

65 and later ages. However, the correlation of

bone mass between age 65 and subsequent ages

will almost certainly be better than correlations

with age 50, because a relatively high rate of perimenopausal bone loss after age 50 adds greater

variability to predicting later values. Thus, the

correlation between bone mass at age 65 and ages

above 65 will almost certainly be higher than the

correlation between bone mass at age 50 and later

ages.

Because the OTA model uses year-to-year correlation estimates, the estimates projected in figure D-1 probably represent too steep a loss of

correlation in later years. Consequently, we revised the correlation pattern after age 65 to account for the higher correlation pattern at older

ages. Figure D-2 contains the results. Pattern D

represents a correlation after age 65 that is slightly
44 Cost Effectiveness of Screening for Osteoporosis

Reduced tracking

I .7

0.2 ! I I I I 1 [

65 70 75 80 85

Age

SOURCE: D. M. Black, “Cost Effectiveness of Screening for OsteoporoSiS: Review of Bone Mineral Density and Fracture Parameters Required

for Model,” University of California, San Francisco, CA, unpublished

OTA contract report, Nov. 17, 1992,

higher than that assumed after age 50 (pattern B in

figure D-l). This pattern was used as the base-case

assumption. Pattern E is analogous to the data

from Hui for peri-menopausal women showing a

correlation of 0.90 after five years (at age 70), a

correlation of 0.80 after 10 years, etc. This pattern

probably represents a lower limit on the correlation of bone mass after age 65 (18).

The OTA model requires correlations between

bone mass at each age and bone mass at the next

highest age. The patterns above include only the

correlation between age 50, or age 65, and subsequent ages. However, the cost-effectiveness model requires the correlation between, for example,

bone mass at ages 60 and 65 and between ages 80

and 85. We required a pattern of short-term correlations that approximates the long-term correlations shown in the figures above.

To approximate the long-term pattern in the

base-case (pattern C in figure D-1) we assumed

that the correlation between bone mass at any age

and subsequent bone mass five years in the future

is 0.90 forages 50 to 60 and 0.95 for ages over 60.

If the correlations follow an autoregressive model,

then the correlations between any two points can

be found simply by multiplying the correlations in

between. For example, the correlation between

age 50 and 60 is 0.9 x 0.9 or 0.81. Under the autoregressive model, the long-term pattern closely

approximates pattern C. Similar sets of short-term

correlations could be developed for the other longterm correlation patterns above.

RELATIONSHIP OF BONE MASS TO

HIP FRACTURE RISK

At any age, the OTA model must predict the probability of hip fracture as a function of the woman

current BMD. Following work of Black and colleagues, OTA assumed a logistic relationship between BMD and hip fracture risk (4). A logistic is

given by the following formula:

1

P =

1 + e t+ t x

where:

P is the probability of hip fracture at a given age;

α is a constant term that varies with age;

β is a term that varies with BMD, but not with age;

and

x is the individual’s BMD at the age in question.

When the risk of fracture is less than about 10

percent (as is the case for all hip fracture risks considered in this appendix), the logistic relationship

between bone mass and risk is essentially linear.

Therefore, data fitted to any other functional form

that is similarly linear would yield essentially the

same results as those obtained from fitting data to

estimate the parameters (α,β ) of the logistic model. However, if a nonlinear relationship (e.g.,

threshold model) were the true relational form between BMD and hip fracture, the logistic assumption would yield substantially erroneous results. It

is therefore important to establish the validity of

the logistic (or linear) relationship.

There is only one source of data (SOF) that has

published data relating bone mass to risk of hip

fracture (5). The results of that analysis suggest

that the relationship of bone mass to hip fracture
Appendix D Summary of Hip Fracture Prediction Methods 45

Age group N Fractures SD RRa

95% CI

65-74 6,896 934 0.10 1.36 (1 .27,1 .45)

75+ 2,441 470 0.10 1.33 (1 .21,1 .47)

aRelative hazard per standard deviation decrease in bone mass.

SOURCE: D. M. Black, “Cost Effectiveness of Screening for Osteoporosis’ Review of Bone Mineral Sensity and Fracture Parameters Required

for Model,” University of California, San Francisco, CA, unpublished OTA contract report, Nov. 17, 1992

risk follows a linear pattern and that the logistic

model is therefore a consistent description of the

true relationship. A statistical test for the goodness of fit of the data to a logistic model did not

reject the null hypothesis that the relationship is

logistic.

The relationship between bone mass and fracture probability is usually estimated in terms of a

standardized relative risk: the ratio of risk of a person whose bone mass is one standard deviation

below the mean to the risk of a person whose bone

mass is at the mean.

A critical assumption of the OTA model is that

the relative risk of fracture is constant across age

groups (or, alternatively, that β is constant across

all age groups). For example, if the relative risk of

fracture of a 70-year-old woman whose BMD lies

1 standard deviation below the mean BMD of

70-year-old women is 3, then the relative risk of a

50-year-old woman with BMD at 1 standard deviation below mean BMD of 50-year-old women is

also 3. This assumption is equivalent to stating

that there is no interaction between bone mass and

age in predicting hip fractures. Virtually all published analyses in this field have included this assumption (e.g., 3,5,1 1,12,17,22,28).

Fortunately, data available to test the interaction between bone mass and age suggest that the

assumption is valid. Table D-8 shows data provided by the SOF on the relationship of BMD

(measured in the proximal radius) to hip fracture

risk in ages 65 to 75 compared with ages 75 and

over. There is a very slight suggestion of decreasing strength in the relationship of bone mass to hip

fracture risk with increasing age. However, the

large overlap in the two confidence intervals

shows that the differences do not approach statistical significance. A recent analysis of SOF data of

radical BMD prediction of hip fracture found no

difference between women over 80 years of age

and those under 80 years of age (23). Therefore,

OTA assumed that the relative risk relating to

bone mass and hip fracture risk is constant across

all ages in the model.

❚ Relative Risk of Bone Mass

and Hip Fracture

Several sources of data are available on the shortrun risk of hip fracture as a function of bone mass.

SOF published data using bone mass at three

sites to predict hip fracture in the sample of 9,704

women (5). The average followup was 1.7 years.

The standardized age-adjusted relative risk for

BMD (gm/cm2

) at the proximal radius was 1.4

(1.1 to 1.9). Analysis using BMC as the measure

found slightly lower relative risks.

The University of Indiana reported on a total of

23 first hip fractures in 135 residents of a retirement home (17). Bone mass (gm/cm2

) at the proximal radius was used as the predictor of hip

fracture. The relative risk (95 percent CI) was 1.9

(1.3, 2.8) per 0.1 gin/cm of BMC (approximately

1 SD). Age was not a significant predictor of hip

fracture after adjustment for BMC.

An analysis of the data on 1,076 women in Malmo, Sweden, found that after adjusting forage, the

relative risk was 1.8 (95 percent CI: 1.3 to 2.4) for

BMC of the mid-radius. However, since these

findings were not age-adjusted, they overestimate

the age-specific relationship of bone mass to risk

and therefore may not be of direct relevance to this

study. (20,2 1). A recent analysis of a cohort of 304

women in Rochester, Minnesota, who were fol-
46 Cost Effectiveness of Screening for Osteoporosis

Annual incidence of hip fracture

Age (per 100.O00)

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

69.5

135.4

169.6

314.3

493.5

1,033.2

1,669.3

2,552.5

SOURCE M.E. Farmer, L R., White, J, A., Brody, et al., “Race and Sex

Differences in Hip Fracture Incidence, ” American Journal of Public

Health 74:1374-1380, 1984.

lowed for an average of eight years, found a standardized relative risk of hip fracture of 2.7

(95-percent CI: 1.5 to 5.0) (21).

Black and colleagues performed a meta-analysis to calculate a pooled estimate and confidence

interval for the relative risk of hip fracture forageadjusted levels of bone mass in the radius, the only

measurement site that was common to all three

studies (4). Standard meta-analytic methods permit estimation of a pooled treatment effect and

confidence intervals for data from numerous clinical trials (10). This pooled relative risk is calculated as the weighted mean of the individual

standardized relative risks from each study, using

the squares of the inverse of the standard error of

the relative risk as the weights. The resulting combined relative risk was 1.65, with a 95 percent confidence interval of between 1.4 and 2.0. On the

basis of this meta-analysis, OTA used a value of

1.65 as the base assumption for relative risk of hip

fracture.

Relative risk per standard

deviation 1.65

Corresponding value of

beta (6) -5.0078

Values of alpha (a)

Bone loss = base case

assumption

Age

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

Bone loss = slow

Age

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

Bone loss = fast

Age

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

Value of a

-3.465

-3.10272

-3.0874

-2.62888

-2.32062

-1,70997

-1.35219

-1.04624

-0.2460

-0.2283

-0.2870

-0.2533

-0.3520

-0.3655

-0.1783

-0.3261

-3.3348

-3.0226

-3.0473

-2.6289

-2.3657

-1.8001

-1.4824

-1.2015

❚ Calculation of the Constant Term

for the Logistic Model

We have assumed that the relative risk relating

bone mass to fracture is the same for all age

groups. The absolute risk of fracture does increase

with age, however. The constant term in the logistic model, a, must be estimated for each age to adjust the absolute risk for differences in age.

SOURCE: Off Ice of Technology Assessment, 1995, D M Black,

“Cost Effectiveness of Screening for Osteoporosis Review of Bone

Mineral Density and Fracture Parameters Required for Model, ” University of California, San Francisco, CA, unpublished OTA contract

report, Nov. 17, 1992.

Under the assumption of an age-invariant relative risk, the constant term can be estimated using

age-specific hip fracture incidence data (i.e., no

age-specific data on the relationship of bone mass
Appendix D Summary of Hip Fracture Prediction Methods 47

to fracture is required). This method has been described elsewhere (4).

Briefly, the overall age-specific incidence of

fracture (P(Ft)) is the mean of the bone-mass-specific incidence (P(Ft

|BMt)) weighted by the agespecific distribution of bone mass f(BMt

)) or:

If we have data on the age-specific incidence of

fracture and on the age-specific distribution of

bone mass (both of which are readily available

from cross-sectional studies) and we know the relative risk parameter (β) for the logistic model, the

only unknown in the logistic function equation is

the parameter α t.

OTA used data from the National Hospital Discharge Survey to estimate the age-specific incidence of hip fracture (8). Table D-9 shows those

incidence estimates. Other population-based

studies have yielded similar annual incidence

rates of hip fracture among white women (9,27).

Based on these data, the values of the parameters a

and β in the logistic function are as given in table

D-10.

REFERENCES

1. Black, D. M., “Cost Effectiveness of Screening for Osteoporosis: Review of Bone Mineral Density and Fracture Parameters Required

for Model,” University of California, San

Francisco, CA, unpublished OTA contract report, Nov. 17, 1992.

2. Black, D. M., “Why Elderly Women Should

be Screened and Treated to Prevent Osteoporosis,” American Journal of Medicine 98

(Suppl. 2A):67S-75S, 1995.

3. Black, D., Cummings, S., Genant, H., et al.,

“Axial and Appendicular Bone Density Predict Fractures in Older Women,” Journal of

Bone Mineral Research 7(6):633-638, 1992.

4. Black, D., Cummings, S., and Melton, L.,

III., “Appendicular Bone Mineral and a

Woman’s Lifetime Risk of Hip Fracture,”

Journal of Bone Mineral Research

7(6):639-646, 1992.

5. Cummings, S.R., Black, D. M., Nevitt, M. C.,

et al., “Appendicular Bone Density and Age

Predict Hip Fracture in Women,” Journal of

the American Medical Association 263:

665-668, 1990.

6. Cummings, S.R., Black, D. M., Nevitt, M. C.,

et al., “Bone Density at Various Sites for Prediction of Hip Fractures,” Lance?, 341:72-75,

January 1993.

7. Davis, J.W., Ross, P. D., Wasnich, R. D., et al.,

“Comparison of Cross-Sectional and Longitudinal Measurements of Age-Related

Changes in Bone Mineral Content,” Journal

of Bone Mineral Research 4:351-357, 1989.

8. Farmer, M.E., White, L.R., Brody, J. A., et al.,

“Race and Sex Differences in Hip Fracture Incidence,” American Journal of Public Health

74:1374-1380, 1984.

9. Fisher, E., Baron, J., Malenka, D., et al., “Hip

Fracture Incidence and Mortality in New

England,” Epidemiology 2(2): 116-122,1991.

10. Fleiss, J., and Gross, A., “Meta-Analysis in

Epidemiology, with Special Reference to

Studies of the Association Between Exposure

to Environmental Tobacco Smoke and Lung

Cancer: A Critique,” Journal of Clinical Epidemiology 44(2):127-139, 1991.

11. Gardsell, P., Johnell, O., and Nilsson, B.E.,

“Predicting Fractures in Women by Using

Forearm Bone Densitometry,” Calcified Tissue International 44:235-242, 1989a.

12. Gardsell, P., Johnell, O., and Nilsson, B. E.,

“Predicting Various Fragility Fractures in

Women by Forearm Bone Densitometry. A

Follow-Up Study,” Calcified Tissue International 44(4):235-242, 1989b.

13. Hannan, M.T., Felson, D.T., and Anderson,

J.J., “Bone Mineral Density in Elderly Men

and Women: Results from the Framingham

Osteoporosis Study,” Journal of Bone and

Mineral Research, 7(5):547-553, May 1992.

14. Hansen, M. A., Overgaard, K., Riis, B.J., et

al., “Potential Risk Factors for Development of Postmenopausal Osteoporosis—Examined Over a 12-Year Period,” Osteoporosis

International 1:95-102, 1991.
T

he proportion of post-menopausal women

who use hormone replacement therapy

(HRT) has increased in the United States

during the last two decades (13). While

use of HRT has increased, the average dose and

duration of use of postmenopausal estrogens has

decreased until recently (64). This is due in part to

the discovery that the cancer-causing effects of

postmenopausal estrogen are related to its dose

and duration.

This appendix describes the range of choice regarding the dose, routes of administration, and

combinations of hormones currently in use or under study as treatment for postmenopausal HRT.

This appendix also describes the appropriate follow-up of women on HRT. Finally, this appendix

describes how dosing regimens may affect compliance with HRT and describes other factors that

affect HRT compliance.

HRT involves the administration of estrogen

alone or in combination with progestins. In the

past, estrogen was typically administered without

progestin (unopposed estrogen) in estrogen replacement therapy (ERT). Currently, the most

commonly used regimens for a woman with a

uterus include a progestin either in sequence with

estrogen (e.g., 25 days of estrogens with a concurrent progestin administered during the last 12 to

Appendix E:

Hormonal

Replacement

Therapy

Regimens E

14 days and a three-day drug-free period) or in

continuous combination with estrogen. These

progestin/estrogen therapies (PERTs) alter the

benefit-risk profile of HRT.

In the United States, conjugated equine estrogen (CEE) (Premarin, Wyeth-Ayerst) is the most

commonly used form of estrogen for HRT.1,2

There are a number of other estrogens used for

HRT.3 Table E-1 lists the estrogens either approved for osteoporosis by the Food and Drug Administration or accepted for this use by a

committee of the United States Pharmacopoeia. In

addition to the estrogens listed in the table, the estrogens quinestrol (Estrovis tablets, Parke-Davis)

and chlorotrianisene (TACE capsules, Marion

Merrel Dow) are approved by the FDA for treatment of menopausal symptoms (61).

ESTROGEN DOSING REGIMENS

A central question for clinical management of

postmenopausal HRT patients is how small a dose

of estrogen may be administered without losing

the beneficial effects of the therapy. The reduction

in bone loss or menopausal symptoms must be

weighed against the adverse effects of estrogens.

The higher the dose of estrogen, the more likely

are side effects, such as breast tenderness or fluid

I 49
50 Cost Effectiveness of Screening for Osteoporosis

retention (15, 27, 28).4 In addition, higher doses

may increase the risk of estrogen-related illness

such as endometrial cancer or gallbladder disease.

Several studies have demonstrated that doses

of at least 0.625 mg per day of CEE or its equivalent are necessary to prevent or greatly reduce

bone loss in the spine in peri- or postmenopausal

women (36,46,72). Lower doses offer only partial

protection against bone loss (46,47). The minimal

dosage of estrogen adequate to prevent bone loss

in postmenopausal women is discussed in greater

detail in appendix C.

The American College of Obstetricians and

Gynecologists recommends the following estrogen dosages for osteoporosis (l):

Estrogen Dose

conjugated estrogen 0.625 mg/day

transdermal estradiol 0.05 mg twice a week

micronized estradiol 1.0 mg/day

estrone sulfate 1.25 mg/day

For women who have not had hysterectomies,

ACOG recommends the addition of a progestin to

the estrogen. They recommend a dose of 10 mg/

day for 12 days a month to reduce the incidence of

hyperplasia and endometrial cancer. ACOG and

the American College of Physicians see no reason

to add progestin to estrogen for a woman without

a uterus.

❚ Routes of Administration

There are a number of routes for delivery of estrogens other than by mouth. Intramuscular injections have been tested, but they are no longer used,

not only because they are uncomfortable but also

because estrogen plasma concentrations are unstable with this method of administration (68).

Vaginal rings and vaginal creams have also been

investigated (53,63), but plasma estrogen levels

are unstable, probably because of irregular ab1 There are currently no generic forms of conjugated estrogens on the market, but there are generic forms of some of the other estrogens used

for postmenopausal replacement therapy. In 1989, the Center for Drug Evaluation and Research of the FDA rejected applications for new drug

approval submitted by Barr Laboratories for five dosage strengths of generic conjugated estrogen (7). Although the extent of absorption of the

estrogen was the same as that of Premarin, the brand-name drug manufactured by Wyeth-Ayerst, the FDA ruled that the generic manufacturer

must demonstrate that the rate of absorption must be the same in order for the generic products to be considered bioequivalent to the innovator

drug. Barr Labs claimed that this was inconsistent with a January 1989 determination by the FDA’s Fertility and Maternal Health Drugs Advisory

Committee that the rate of absorption was not relevant to bioequivalence (7).

Although a few members acknowledged that there was no conclusive evidence that the rate of estrogen absorption is important in determining the safety and efficacy of conjugated estrogens, the FDA’s Generic Drugs Advisory Committee concluded in February 1991 that the rates of

absorption must be the same to establish bioequivalence (16). The FDA contended that different absorption rates could make conjugated estrogens ineffective in treating osteoporosis. In addition, more rapid absorption of estrogen into the blood stream could lead to higher peak drug

plasma concentrations which could increase the risk of endometrial cancer (30).

At present, sponsors of generic conjugated estrogen products are required to perform studies of the blood concentration-time profiles of five

of the predominant estrogens in Premarin brand of conjugated equine estrogen (4). As of 1995, there were no generic conjugated estrogens on the

market, although the generic manufacturer Duramed had an ANDA pending for a 0.625 mg formulation (4). Wyeth-Ayerst, manufacturer of

Premarin brand of conjugated estrogen, has argued that a conjugated estrogen product that does not also contain a sixth form of estrogen, delta(8,9)-dehydroestrone, is not substantially equivalent to Premarin.

2 Data from Wyeth-Ayerst, manufacturers of the most widely prescribed postmenopausal estrogen, show that three types of physician specialists — obstetrician-gynecologists, internists, and family-practitioners — wrote 90 percent of estrogen prescriptions. Obstetrician-gynecologists prescribe the most, with 2,897,000 prescriptions, or 43 percent of prescriptions for postmenopausal estrogens.

3 The estrogens used in hormone replacement therapy are much less potent than the synthetic estrogens used in oral contraceptives. Because

of this difference in potency, the side effect profile of estrogens used in hormonal replacement therapy differs from that of estrogens used for

contraception.

4 Fibroid tumors and endometriosis may alSO be exacerbated by HRT. Fibroids and endometriosis are both estrogen-dependent conditions

that regress at menopause. HRT in postmenopausal women who had significant problems from either of these diseases premenopausally requires careful surveillance: fibroids may enlarge, and endometriosis maybe reactivated. If HRT is subsequently discontinued, the fibroids will

again shrink. However, the sequelae of endometriosis, such as chocolate cysts or adhesions, may persist even after estrogen has been withdrawn,

and continue to cause symptoms (20).
Recommended dosages for osteoporosis

Generic name Brand name (t.m.) Manufacturer FDA-approved indications and/or menopausal symptomsa,b

Conjugated equine Premarin tablets

estrogen

Diethylstilbestrol

Estradiol

Wyeth-Ayerst 1 )

2)

3)

4)

5)

6)

(DES)’ Diethylstilbestrol Lilly 1)

enteric-coated 2)

tablets d

Diethylstilbestrol

tablets d

Esterified estrogens Estratab tablets Solvay 1)

Menest tablet SmithKline

Beecham 2)

3)

4)

5)

Estrace tablets Bristol-Myers 1 )

Moderate to severe vasomotor Menopausal symptoms: 0,625 mg to 1.25

symptoms of menopause mg a day cyclically or continuously

Vaginal or urethral atrophy Osteoporosis: 0.3 mg to 1.25 mg a day,

Osteoporosis

Hypoestrogenism due to castration,

cyclically or continuously

hypogonadism, or primary ovarian

failure

Breast cancer

Prostatic carcinoma

Breast cancer

Prostatic carcinoma

Neither the USP DI nor the product labeling

includes dosage information for

osteoporosis or menopausal symptoms.

Menopausal symptoms: 0,625 mg to 1.25

mg, cyclically or continuously

Moderate to severe vasomotor

symptoms of menopause

Vulvar or vaginal atrophy

Hypoestrogenism due to hypogonadism,

castration, or primary ovarian failure

Breast cancer

Prostatic carcinoma

Osteoporosis Menopausal symptoms: 0.5 mg to 2 mg a

Emcyt capsules Squibb 2) Moderate to severe vasomotor day, cyclically or continuously

Pharmacia Adria symptoms of menopause Osteoporosis: 0.5 mg a day, cyclically or

3) Vulvar or vaginal atrophy continuously

4) Hypoestrogenism due to hypogonadism,

castration, or primary ovarian failure

5) Breast cancer

6) Prostatic carcinoma

m
—

Generic name Brand name (t.m.) Manufacturer FDA-approved indications

Estropipate

Ethinyl estradiolc

Ogen tablets Upjohn

Ortho-est tablets Ortho

Estradiol transdermal Estraderm Ciba 1 ) Osteoporosis

system 2) Moderate to severe vasomotor

symptoms of menopause

3) Vulvar or vaginal atrophy

4) Hypoestrogenism due to hypogonadism,

castration, or primary ovarian failure

1) Osteoporosise

2) Moderate to severe vasomotor

symptoms of menopause

3) Vaginal or vulvar atrophy

4) Hypoestrogenism due to hypogonadism,

castration, or primary ovarian failure

Estinyl tablets Schering 1) Moderate to severe vasomotor

symptoms of menopause

2) Hypogonadism

3) Prostatic carcinoma

4) Breast cancer

Recommended dosages for osteoporosis

and/or menopausal symptomsa

’

b

Osteoporosis or menopausal symptoms:

One transdermal dosage system delivering

0.05 mg or 0.10 mg, per day worn

continuously and replaced twice a week

Menopausal symptoms: 0.75 mg to 5 mg

estropipate per day, cyclically or

continuously

Osteoporosis: 0.75 mg per day for 25 days

of a 31-day cycle

Menopausal symptoms: 0.02 mg of 0.05

mg per day, cyclically or continuously

,

a Dosages are for vasomotor symptoms of menopause.

b Dosages were those recommended in the USP DI, See the United States Pharmacopeial Convention, USP Dispensing Information (USP Dl): Volume 1—Drug Information for the Health Care

Professionl (Taunton, MA Randy McNally, 1995).

c A U.S. Pharmacopeia Advisory Committee has accepted osteoporosis as an unlabeled indication for this product. An indication for postmenopausal osteoporosis, however, is not included in the

FDA-approved labeling for this product See The United States Pharmacopeial Convention, USP Dispensing Information (USP DI): Volume 1—Drug Information for the Health Care Profession/

(Taunton, MA Rand McNally, 1995).

d Diethylstilbestrol is available only as a generic In the United States.

e The FDA-approved labeling of Ortho-est (Ortho) brand of estropipate does not include an indication for osteoporosis

Key: CEE = conjugated equine estrogen, HRT = hormone replacement therapy, t m = trademark

SOURCE: Office of Technology Assessment, 1995
Appendix E Hormonal Replacement Therapy Regimens 53

sorption due to day-to-day changes in vaginal

blood flow and secretion.

Implantation of continuously released estrogen

under the skin (subcutaneous implantation) appears to result in stable estrogen levels (68). But

once inserted, the implants are difficult to remove

in case of overdose or intolerance (76).

Administration of estrogen through a patch or

cream applied to the skin (percutaneous transdermal administration) has proved effective in treating postmenopausal symptoms (14,22) and in

reducing vertebral bone loss after menopause

(72).

Transdermal medication may increase compliance because it eliminates the need for multiple

dose scheduling, is easily administered, requires

only twice weekly application, and is reversible

(78). However, the gel is difficult to administer accurately (68). Absorption is proportional to the

surface of application, and this surface cannot be

determined accurately. In addition, between 5 and

20 percent of women may develop skin irritation

(79).

THERAPY WITH PERT

The primary indication for adding progestins to

estrogen replacement therapy is to reduce the risk

of estrogen-induced irregular bleeding, endometrial hyperplasia (abnormal overgrowth of the inner lining of the uterus, or endometrium), and

endometrial cancer (26,87). (See appendix G). In

the Postmenopausal Estrogen/Progestin Interventions (PEPI) study, almost half of the women

assigned to unopposed estrogen therapy experienced endometrial hyperplasia over the two year

clinical trial (91); the PEPI trial protocol required

that these women be taken off of estrogen. Because of the unexpectedly large proportion of

women on ERT who developed hyperplasia in

PEPI, the directors of the Women’s Health Initiative long-term clinical trial of hormonal replacement therapy decided to place all women assigned

to unopposed estrogen on PERT.

A number of progestins can be used for PERT.5

The most commonly used progestin in the United

States is medroxyprogesterone (Provera, Upjohn). In addition, the FDA has recently approved

a combination of medroxyprogesterone acetate

and conjugated equine estrogen for the prevention

of osteoporosis. (See table E-2.)

Progestins produce progressive endometrial

atrophy, converting adenomatous hyperplasia to

normal endometrium (85). Numerous studies

show that combined estrogen/progestin therapies

can return 98 to 99 percent of preexisting hyperplasia back to normal endometrium (32,73). (See

appendix G.) Observational studies also show that

PERT users have a lower risk of endometrial cancer than ERT users (42).

An important unresolved issue regarding PERT

is whether the benefits of progestins in protecting

the endometrium are outweighed by the effect of

progestins on the risk of coronary heart disease

(CHD). Epidemiologic studies of the relationship

of HRT to CHD have been largely limited to unopposed estrogens; the effect of progestin supplementation on heart disease risk has not been as

extensively evaluated, but recent evidence suggests that adding progestins to HRT may attenuate

the beneficial effects of ERT on heart disease. (See

appendix I.)

Progestins are more often responsible than estrogen for making hormonal replacement therapy

unacceptable for some women, because adverse

effects are common with progestins (71). Progestins can produce breast tenderness, bloatedness,

edema, abdominal cramps, and an iatrogenic premenstrual-like syndrome (71,87). Patients also

commonly experience side effects such as anxiety,

irritability, depressed mood, and drowsiness.

One of the primary reasons for stopping HRT is

discomfort with periodic bleeding (18). With sequential therapies, regular bleeding occurs with

85 percent of patients (31,87). This proportion decreases with time, and by age 65, 60 percent continue to experience light bleeding (33). Patients

5 Synthetic Progesterone are often used in hormonal replacement therapy since natural progesterones cannot be absorbed orally.
54 Cost Effectiveness of Screening for Osteoporosis

Brand

name Recommended dosage for

Generic name (tin.) Manufacturer FDA-approved indications secondary amenorrheab

Medroxyprogesterone Amen Carnick 1 ) Secondary amenorrhea Secondary amenorrhea. May

acetate Curretab Solvay 2) Abnormal uterine bleeding be given in dosages of 5 to

Cycrin

10 mg daily for from 5 to 10

Esi Pharma days.

Provera Upjohn

Norethindrone acetate Aygestin Esi Pharma 1) Secondary amenorrhea Secondary amenorrhea: May

Norlutate Parke-Davis 2) Endometriosis be given in dosages of 2.5 to

3) Abnormal uterine bleeding 10 mg daily for 5 to 10 days

during the second-half of the

theoretical menstrual cycle.

a A U.S. Pharmacopeia Advisory Committee has determined that osteoporosis IS an accepted indication for these products. An indication for osteoporosis, however, IS not included on the FDA-approved labeling for these products See The United States Pharmacopeial Convention, USP

Dispensing Information (USP DI): Volume 1—Drug Information for the Health Care Professional (Tauton, MA: Rand McNally, 1995)

b The FDA-approved product Iabeling does not have dosage recommendations for use Of these products with estrogen in Osteoporosis

KEY: t.m. = trademark

SOURCE Off Ice of Technology Assessment, 1995

may be willing to tolerate bleeding for relief of

menopausal symptoms, but to an asymptomatic

woman in her 60s and 70s who is taking estrogens

for the prevention of osteoporosis and cardiovascular disease, the persistent bleeding and other

side effects may be intolerable (26).

Compliance may be improved with new continuous combined regimens of PERT that reduce

the frequency of menstrual bleeding. Continuous

PERT involves daily administration of estrogen

and a low dose of progestin (70). Several studies

show that continuous PERT can relieve menopausal symptoms, eliminate periodic bleeding

within several months of initiation, and avoid endometrial hyperplasia (5,28,37,40,48,70,84,91).

Most studies to date have found between onethird and one-half of patients were bleeding after

three months of continuous PERT, but most patients were amenorrheic after 12 months. And

most studies reported 90 percent or greater atrophic endometrium at 12 months.

Another approach to reduce the frequency of

bleeding and improve compliance is to give sequential PERT with less than monthly progestin

therapy. For example, Williams and colleagues

found that that there was less vaginal bleeding

when progestins were administered for 14 days

every three months than when given for 14 days

every month (90). Menopausal women find less

than monthly bleeding more acceptable than

monthly bleeding (6).

ACUTE INDICATIONS FOR HRT

The most common indication for HRT is relief of

menopausal symptoms (41).6 Hot flashes, or vasomotor symptoms, are the most common symptom of menopause that causes women to seek

medical attention (81). Hot flashes occur in 60 to

75 percent of women at the time of menopause

(52,82). They are typically more severe in women

with surgical menopause, because the severity of

6 The American College of Physicians distinguishes between diagnoses for short-term and long-term HRT (3). Short-term HRT is prescribed

for women who suffer from postmenopausal symptoms, such as hot flashes and atrophic vaginitis. The American College of Physicians suggests

therapy of one to five years for the treatment of symptoms associated with menopause. The goals of long-term HRT are the prevention of osteoporosis and decrease in the risk of heart disease. The American College of Obstetricians and Gynecologists recommends that for treatment of

menopausal symptoms, the lowest dosage of estrogen that provides effective relief should be used (1).
Appendix E Hormonal Replacement Therapy Regimens 55

vasomotor symptoms is thought to be related to

the rapidity in decline of estrogen (51). At first,

flashes usually occur several times a day, and

often interrupt sleep (25). Irritability, fatigue, and

anxiety can result from sleep deprivation. For

most patients, vasomotor symptoms are self-limiting, but for 25 to 50 percent of women, these

flashes persist more than five years (77,82). Clinical trials have demonstrated that estrogen is effective in relieving these symptoms in about 95

percent of patients (19,75).

Estrogen has been found to relieve symptoms

of menopause that affect the vagina, uterus, urethra, and bladder.7 Estrogen replacement therapy

can prevent the vaginal atrophy associated with

menopause and maintain the normal tone of supporting ligaments and elastic tissues of the uterus

and vagina (9,80,89). Vaginal atrophy may result

in vaginal dryness, itching, burning, and infection. Vaginal atrophy can also result in pain with

vaginal intercourse and resultant sexual dysfunction (10). Estrogen can also prevent atrophy of the

bladder and urethra and the resultant painful

urination, urgency, stress incontinence, frequency

of urination, urination at night, and dripping after

voiding (24,29,66,80).

The absence of estrogen may cause skin to become thinner, as the amount of collagen in the skin

decreases (10,80). Estrogen stimulates the synthesis of collagen, and in postmenopausal women receiving estrogen, the collagen of the skin is

maintained at premenopausal levels (11).

Some investigators have shown reductions in

anxiety and depressed mood, and improvements

in feelings of well being in women on HRT

(21,56,88,89). This effect may be independent

from its impact on menopausal symptoms (45).8

EVALUATION AND FOLLOWUP

OF WOMEN TAKING HRT

Before hormonal replacement therapy is begun by

a postmenopausal woman, the American College

of Physicians (ACP) recommends that her physical condition should be assessed by a physician

(3). The doctor should be aware of her medical

history and her current health in light of contraindications to HRT. These contraindications include

unexplained vaginal bleeding, acute liver disease,

chronic impaired liver function, recent vascular

thrombosis, breast cancer, and endometrial

cancer.

The American College of Obstetricians and

Gynecologists (ACOG) recommends that women

taking hormonal replacement therapy be monitored every year (1). At that time breast and pelvic

examinations should be performed, a Pap smear

should be taken, and cholesterol level and blood

pressure should be monitored. If the woman is on

a regime that includes a progestin and there is no

excess or prolonged bleeding, there is no need for

an annual endometrial biopsy. Mammograms

should be performed annually on women over the

age of 50.

Endometrial biopsy is not deemed to be necessary in patients on sequential PERT because the

onset of bleeding can be a useful predictor of endometrial status. Patients with proliferation and

7 Alternatives to estrogen, such as progestogens, clonidine, or ergot alkaloids, have been used for symptomatic relief of vasomotor symptoms in women who are not candidates for estrogen replacement therapy (75,81). But none of these alternatives will prevent atrophy of the vagina (81).

8 A major difference of opinion persists as to whether estrogen therapy has any direct positive effect on mood, or whether the improved

well-being reported by some women is simply due to their relief from vasomotor symptoms, and possibly due to a placebo effect (60). Some

studies purport to show that a large portion of the influence of hormone replacement on affect is due to alleviation of hot flashes by hormone

replacement (23). Yet other studies have demonstrated that estrogen therapy directly affects mood (12). Campbell and Whitehead, in a doubleblind study of 64 women over four months, demonstrated significant improvements in certain psychological problems such as anxiety, irritability, worry about age, and optimism. They found that estrogen significantly improves anxiety and other psychological symptoms even in menopausal women who had had no vasomotor symptoms. However, a direct biological effect of loss of estrogen with menopause on depressed mood

has not been demonstrated (35). Although estrogen may help alleviate depressed mood that accompanies menopause (44), major depression

requires psychiatric treatment (35).
56 Cost Effectiveness of Screening for Osteoporosis

hyperplasia of the endometrium bleed earlier in

the cycle than is normal with sequential PERT

(59,87).

COMPLIANCE WITH HRT

A number of studies that have examined rates of

compliance with HRT have in general found longterm compliance rates to be low. One study of

1,586 women enrolled in the Harvard Community

Health Plan who received new prescriptions for

HRT found that 27 percent stopped taking HRT

within 100 days of receiving the prescription and

40 percent had stopped after one year (50).

Some studies distinguish between commencement compliance (the proportion of women

prescribed HRT who initiate therapy) and maintenance compliance (proportion of women on HRT

who continue to take it over a specified period of

time). Speroff et al. (1991) estimated that the commencement compliance rate for women with natural menopause is between 21 and 60 percent (69).

The five-year maintenance compliance rate is between 5 and 34 percent. For women with bilateral

oophorectomies, the commencement compliance

rate is between 31 and 89 percent. Their five-year

maintenance rate is 13 to 71 percent (69).

Compliance with HRT tends to decrease over

time. One study conducted for Wyeth Ayerst examined compliance with HRT in postmenopausal

women who were members of a prepaid group

health benefit plan and who filled prescriptions

for conjugated equine estrogens (Premarin,

Wyeth Ayerst) (83). Data on rates of compliance

were gathered from pharmacy and medical records. Compliance rates were determined by

comparing the number of days Premarin was prescribed to the number of days for which Premarin

was dispensed. They found that compliance declined from 62.7 percent over one year, to 56.1

percent over three years and to 46.8 percent over

seven years.

Compliance with HRT is affected by various

factors, and knowledge of these factors suggests

ways of improving compliance. In addition,

knowledge of these factors is important in understanding how bias may affect our interpretation of

observational studies of HRT’s risks and benefits.

(See appendices F and I for a discussion of bias.)

In general, compliance rates with drugs will be

lower if the patient suffers no physical symptoms

or if the symptoms disappear before the end of the

treatment (62). Women who suffer from more severe menopausal symptoms, such as hot flashes,

are more likely to use hormone replacement therapy. It has been found that women with surgical

menopause are more likely to use and comply

with long-term hormone replacement therapy, in

part because their menopausal symptoms tend to

be more severe (13,43). Leaner women are more

likely to use hormonal replacement therapy; because body fat is an important nonovarian source

of estrogen production, thin women tend to have

more severe menopausal symptoms than women

who are heavier (34). Women who smoke cigarettes are more likely to take HRT, possibly because of an antiestrogenic effect of smoking,

which intensifies menopausal symptoms (38).

But the proportion of women who use HRT for relief of acute menopausal symptoms declines in the

years following menopause as these symptoms diminish in frequency and severity.

Women typically do not suffer symptoms of osteoporosis, such as hip fractures or kyphosis, until

many years after menopause. Because low bone

mineral density (BMD) does not have obvious

symptoms unless fracture occurs, bone density

measurement may increase commencement and

maintenance compliance with HRT. Some experts

have suggested physicians could use densitometry to help patients who are undecided about initiating HRT to “visualize” their low bone mass

(57).9 In addition, maintenance compliance might

9 Measurements of biochemical markers of bone resorption may also be used to improve compliance with HRT. These markers may allow the

clinician to identify patients who are failing to respond to HRT, which may be because the patient is not complying with the prescribed regimen

(41a). The use of biochemical markers of bone resorption as a tool to improve compliance with HRT has not been evaluated (Id.).
Appendix E Hormonal Replacement Therapy Regimens 157

be improved by using densitometry to follow a patient’s bone density over time, although there is no

evidence available to test this possibility.

Women with below-normal BMD as determined by densitometry are more likely to take estrogen as a preventive measure for osteoporosis

(65). One study surveyed 261 women in California who had had their BMD measured. Postmenopausal women who had below-average

BMD for their age, sex, and race combination

were five times as likely to begin taking estrogen

as women with normal densitometry results (odds

ratio 8.4, 95 percent confidence interval 3.4 to

20.9). While the study showed that more women

with low BMD at densitometry initiated estrogen

replacement therapy than women with normal

BMD, it did not report on the effect of densitometry on long-term compliance with HRT. Another

study of compliance with HRT among 352 postmenopausal women who had BMD measurements, however, found that 40 percent of the

women who were recommended HRT for low

bone density were not taking HRT eight months

after referral (67)

Women’s attitudes and beliefs about HRT affect compliance with hormonal replacement therapy. In general, compliance with drugs will be

lower if the patient is not convinced the medication will help or if the patient is afraid of the development of side effects (62). Many women are

resistant to taking HRT because it is “not natural”

(54). Women may discontinue HRT because of

unacceptable side effects, such as resumed menstruation, breast tenderness, weight gain, headaches, and abdominal bloating (55). In addition,

women may decide not to use HRT because it may

increase their risk of endometrial cancer and

breast cancer.

Greater patient education about the magnitude

and direction of effects and risks may improve

compliance with HRT. In general, compliance is

better with more patient education about the disease and the regimen (55).

The uptake and compliance with HRT may also

be affected by physicians’ beliefs and recommendations. A number of factors appear to influence

physicians in their prescribing of HRT, including

estimates of benefits and risks that may not be

supported by scientific data (74). In addition,

some physicians appear to use patterns of administration of HRT that may diminish the chance of

appropriate patient compliance and fail to adjust

therapy when problems occur (74).

The clinical setting may also have an impact on

compliance. Experimental clinical trials of HRT

have generally shown better rates of compliance

than studies of HRT compliance outside of the

trial setting. For example, one clinical trial of HRT

in women with hysterectomies showed perfect

compliance during the 18 months of the study

(39). A clinical trial of estrogen patches showed

perfect compliance over four months (58). Both of

these clinical trials involved small samples of

women (22 and 12, respectively.) In addition,

compliance may be better in clinical trials because

there are more intensive efforts at follow-up than

generally occur in the normal clinical settings.

Compliance is also affected by the age at which

hormonal replacement therapy is initiated. Elderly postmenopausal women more frequently object

to the resumption of menstrual bleeding induced

by PERT than perimenopausal and early postmenopausal women (6). Other factors also affect the

compliance of elderly patients with medication

regimens. A patient is less likely to comply if she

has a poor understanding of the prescription

instructions, if the therapy is long term, or if the

prescription has complex instructions (62). An elderly woman may suffer from impaired vision or

hearing that could impede her ability to read a

drug label or hear instructions for its use. In addition, many elderly people live alone, and it has

been shown that people who live alone are less

likely to comply with a medication regimen than

those who do not (62). In addition, the expense of

certain medications may have an impact on compliance by the elderly with limited fixed incomes.

Behavioral patterns of women who take estrogen, such as regular physician visits (to refill prescriptions, for example), differentiate them from

women who do not take estrogen. In order to examine the effect of health behaviors on HRT use,
58 Cost Effectiveness of Screening for Osteoporosis

Recommended dosages for

Brand osteoporosis and

Generic name name (t.m.) Manufacturer FDA-approved indications menopausal symptoms

Conjugated estrogens Prempro Wyeth-Ayerst 1) Moderate to severe

and medroxyprogesterone vasomotor symptoms

acetate for continuous of menopause

HRT 2) Vulvar and vaginal

atrophy

3) Osteoporosis (in

women with an intact

uterus)

Conjugated estrogens Premphase Wyeth-Ayerst 1) Moderate to severe

and medroxyprogesterone vasomotor symptoms

acetate for sequential HRT of menopause

2) Vulvar or vaginal

atrophy

3) Osteoporosis (in

women with an intact

uterus)

Menopausal symptoms.

0.625 mg CEE and 2.5 mg

medroxyprogesterone

acetate daily

Osteoporosis: 0.625 mg CEE

and 2.5 mg

medroxyprogesterone

acetate daily

Menopausal symptoms.

0.625 mg CEE (cyclic

administration) and 5 mg

medroxyprogesterone

acetate for last two weeks of

cycle

Osteoporosis: 0.625 mg CEE

(cyclic administration) and 5

mg medroxyprogesterone

acetate for last two weeks of

cycle

KEY: CEE = conjugated equine estrogen, HRT = hormone replacement therapy, t m = trademark

SOURCE: Office of Technology Assessment, 1995

Barrett-Connor et al. studied 1,057 postmenopausal women from the same socioeconomically upper-middle-class community in California who

participated in a clinic evaluation of their estrogen

use patterns (8). After an average of 4.4 years later,

95 percent of these women completed a mailed

health survey questionnaire. This questionnaire

asked them about recent changes in lifestyle behaviors that affect their health, such as consumption of dietary fat, salt use, and exercise habits, as

well as frequency of blood pressure checkups,

mammograms, and Pap smears.

The study found that women who were currently using HRT were significantly more likely to

have recently implemented new healthy lifestyle

behaviors than women who had never used HRT

(8). For example, 70 percent of the women who

were currently using HRT had had a mammogram

in the last year, whereas only 45 percent of the

women who had never used HRT had had one.

Thirty-eight percent of current users had increased

their daily exercise over the past year, whereas

only 29 percent of never users had increased their

exercise. Women who never used HRT were less

likely to have implemented healthy behavior

changes, and were least likely to have had screening evaluations than women who had used HRT.

Compliance may be affected by the type of

packaging. One study of 177 patients compared a

calendar-oriented system of HRT packaging to

conventional packaging of HRT (50). Compliance

rose from 23 percent when the pills were provided

in conventional packaging to 82 percent when the

pills were provided in a prepackaged blister card

system. Wyeth-Ayerst introduced a prepackaged

blister card system of packaging in 1995. (See

table E-3.)

Thus, a variety of factors affect compliance

with HRT. Increased awareness of the factors affecting compliance with HRT suggests ways of

improving long-term compliance.
Appendix E Hormonal Replacement Therapy Regimens 59

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of Obstetrics and Gynecology 99:325-328,

1992.

68. Sitruk-Ware, R., “Estrogen Therapy During

Menopause: Practical Treatment Recommendations,” Drugs 39(2):203-217, 1990.

69. Speroff, T., Dawson, N., Speroff, L., et al., ”A

Risk-Benefit Analysis of Elective Bilateral

Oophorectomy: Effect on Changes in Compliance with Estrogen Therapy on Outcome,”

American Journal of Obstetrics and Gynecology 164(1 Pt 1): 165-174, 1991.

70. Sporrong, T., Hellgren, M., Samsioe, G., et

al., “Comparison of Four Continuously Administered Progestogen Plus Estradiol Combinations for Climacteric Complaints,”

British Journal of Obstetrics and Gynecology 95:1042-1048, 1988.

71. Stevenson, J. C., “Strategies to Increase Estrogen Acceptance and Utilization and to Decrease Side Effects,” Postgraduate Medicine

Spec. No.:15-17; discussion 33-43, April

1989.

72. Stevenson, J., Cust, M., and Gangar, K., “Effects of Transdermal Versus Oral Hormone

Replacement Therapy on Bone Density in

Spine and Proximal Femur in Postmenopausal Women,” Lancet 336:265-269, 1990.

73. Studd, J., Thorn, M., Paterson. M., et al.,

“The Prevention and Treatment of Endometrial Pathology in Postmenopausal Women

Receiving Estrogen,” The Menopause and

Postmenopause, N. Pasetto, R. Paoletti, and

J.L. Ambrus (eds.) (Lancaster, England: MTP

Press, 1980.)

74. Stumpf, P. G., and Trolice, M. P., “Compliance Problems with Hormone Replacement Therapy,” Obstetrics and Gynecologic

Clinics of North America 21(2):219-229,

1994.

75. Tataryn, I. V., Lomax, P., Meldrum, D. R.. et

al., “Objective Techniques for the Assessment of Hot Flashes,” Obstetrics & Gynecology 57:340, 1981.

76. Thorn, M., Collins, W., and Studd, J., “Hormonal Profiles in Post-Menopausal Women

After Therapy with Subcutaneous Implants,”

British Journal of Obstetrics and Gynecology 88:426-433, 1981.

77. Thompson, B., Hunt, S. A., Pumo, D.,

“Menopausal Age and Symptomalogy in

General Practice,” Journal of Biological Science 5:71-82, 1973.

78. Transdermal HRT Investigators Group, “A

Randomized Study to Compare the Effective-
Appendix E Hormonal Replacement Therapy Regimens 63

ness, Tolerability, and Acceptability of Two

Different Transdermal Estradiol Replacement Therapies,” International Journal of

Fertility and Menopausal Studies 38(1):5-11,

1993.

79. Utian, W., “Transdermal Estradiol Overall

Safety Pro file,” American Journal of Obstetrics and Gynecology 156: 1335-1338, 1987.

80. Utian, W. H., “Biosynthesis and Physiologic

Effects of Estrogen and Pathophysiologic Effects on Estrogen Deficiency: A Review,”

American Journal of Obstetrics and Gynecology 161: 1828-1831, 1989.

81. Varner, R. E., “Acute Indication for Hormonal

Therapy in the Menopause,” Emergency

Medicine :93-100, Oct. 30, 1990.

82. Walsh, B., and Shiff, I., “Vasomotor

Flushes, ’’Annals of the New York Academy of

Science 592:346-356, 1990.

83. Walsh America/PDS, PDS Beta Premarin

Patient Study, Wyeth-Ayerst, 0690-9001-

4060 (Phoenix, AZ: January 1991).

84. Weinstein, L., Bewtra, C., and Gallagher, J.,

“Evaluation of a Continuous Combined LowDose Regimen of Estrogen-Progestin for

Treatment of the Menopausal Patient, ’’American Journal of Obstetrics and Gynecology

162:1534-1539, 1990.

85. Wentz, W., “Progestin Therapy in Endometrial Hyperplasia,” Gynecologic Oncology

2:362-367, 1974.

86. “WHI Trial Discontinues Use of Unopposed

Estrogen for Study Participants Due to

NHLBI PEPI Findings,” The Blue Sheet Jan.

18, 1995, pp. 5-6.

87. Whitehead, M., Hillard, B., and Crook, D.,

“The Role and Use of Progestins,” Obstetrics

& Gynecology 75(4) :59S-75S, 1990.

88. Wiklund, I., Berg, G., Hammar, M., et al.,

“Long-Term Effect of Transdermal Hormonal Therapy on Aspects of Quality of Life in

Postmenopausal Women,” Maturitas

14(3):225-236, 1992.

89. Wiklund, I., Karlberg, J., and Mattson, L. A.,

“Quality of Life of Postmenopausal Women

on a Regimen of Transdermal Estradiol Therapy: A Double-Blind Placebo-Controlled

Study,” American Journal of Obstetrics and

Gynecology 168(3 Pt 1):824-830, 1993.

90. Williams, D. B., Voigt, B.J., Fu, Y. S., et al.,

“Assessment of Less than Monthly Progestin

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91. Writing Group for the PEPI Trial, “Effects of

Estrogen or Estrogen/Progestin Regimens on

Heart Disease Risk Factor in Postmenopausal

Women,” Journal of the American Medical

Association 273(3):199-208, 1995.
Appendix F:

Evidence on

Breast Cancer

and Hormonal

Replacement Therapy F

B

reast cancer, after lung cancer, is the second leading cause of death from cancer.

The American Cancer Society estimates

that one in nine American women will develop breast cancer during her lifetime (65). The

impact of hormone replacement therapy (HRT) on

the risk of breast cancer, even if small, would be

substantial given the high baseline risk, as well as

the societal cost, of this illness. For this reason,

this question has been one of the most widely studied with modern epidemiologic techniques. Unfortunately, given the complexity of the issues

involved, no clear-cut answer is available at this

time.

This appendix reviews the evidence linking

HRT to an increase in the risk of breast cancer.

First, the biological plausibility of a link between

HRT and breast cancer risk will be reviewed. Second, the epidemiological evidence of HRT and

breast cancer risk will be reviewed. Virtually all of

the epidemiological evidence is observational,

consisting of case-control studies and cohort studies. The findings, and discussion of the strengths

and weaknesses of the studies on which they are

based, follow.

BIOLOGICAL PLAUSIBILITY

The relationship of HRT and breast cancer is consistent with a number of observations. Bittner first

suggested that estrogen could increase the incidence of breast cancer, by examining the role of

estrogens in the development of mammary tumors

in mice (3). Subsequently, Moolgivkar and Knudson proposed that estrogen could increase the risk

of breast cancer by increasing the rates of division

and numbers of breast cells, which increases the

likelihood that an initiating factor (such as ionizing radiation, chemicals, or viruses) will damage

cellular DNA (51). Such DNA damage, in turn,

leads to a series of errors in cell division, producing so-called “intermediate” cells, which finally

results in transformed, or malignant cells.

The hypothesis that HRT increases breast cancer risk is further supported by observations that

factors that increase a woman’s exposure to estrogen and progestin increase her risk of breast cancer. Thus, early menarche (age of onset of

menstruation) and late menopause are associated

with an increased breast cancer risk (75). Also,

women who have had surgical removal of the ovaries have a lower breast cancer risk (77). There is

also strong evidence that obese postmenopausal

women are at an increased risk of breast cancer

(19). This may be because the chief source of estrogen after menopause is the conversion in fat tissue of the hormone androstenedione, made in the

adrenal gland, to the estrogen estrone (46).

165
66 Cost Effectiveness of Screening for Osteoporosis

It is uncertain whether the addition of progestins would increase the risk of breast cancer above

estrogen alone. Key and Pike have reviewed the

experimental evidence bearing on the hormonal

control of breast cell division (42). They noted

that breast cell division peaks during the later

phase of the menstrual cycle, corresponding to a

progesterone peak. They concluded that, although

knowledge of the hormonal control of division

rates was incomplete, the available data could

support two possible interpretations.

The first model suggests that women receiving

a combination of estrogen and progestin will have

an increased risk of developing breast cancer over

those receiving estrogen alone. This “estrogen

plus progesterone” model posits that estradiol, the

major ovarian estrogen, itself may induce breast

cell division in the early phase of the menstrual

cycle. However, the addition of progesterone, produced in the later phase of the menstrual cycle, induces much more cell division, perhaps because

estrogen produced in the early phase of the

menstrual cycle has stimulated the formation of

progesterone receptors on breast cells (42). This

increased cellular proliferation then places the

breast tissue at risk for malignant change.

The alternative model suggests that the addition of a progestin will have little effect on the risk

of breast cancer associated with estrogen. This

“estrogen alone” hypothesis is supported by experimental data demonstrating that progesterone

shows little significant cell division-stimulating

effect. These results suggest that cell division is

induced by estradiol alone, with little contribution

by progesterone (42). Such an explanation, the authors note, requires a dose-response relationship

between the plasma concentration of estradiol,

which peaks at the end of the early phase of the

menstrual cycle, and the amount of breast cell division. Furthermore, such a model must account

for the 4-to 5-day lag between these changes in estradiol concentration and the subsequent changes

in rates of cell division observed in breast tissue.

CASE-CONTROL STUDIES

Tables F-1 and F-2 at the end of this appendix

present the results of 30 case-control studies of the

risk of breast cancer in users of hormonal replacement therapy. The fourth column of the table

compares the risk of breast cancer among never

users of hormonal replacement therapy with those

who have ever used hormonal replacement therapy. Of these 30 case-control studies, five showed

an increased risk of breast cancer among ever users (30,33,37,44,83). Nineteen studies demonstrated no increased risk of breast cancer in ever

users of hormonal replacement therapy. However,

most of these latter studies found increased risks

among certain subgroups of users. The other 6

studies either did not compare ever users to never

users (2,23,35) or did not provide statistical analysis of results (19,48,60).

❚ Duration

The fifth column of tables F-1 and F-2 describe the

relationship of breast cancer risk to duration of estrogen use. Most of the studies finding no increase

in the risk of breast cancer among ever users also

found no correlation of breast cancer risk with

duration of use. However, several studies, including most studies which have found the risk of

breast cancer to increase among ever users have

found that the risk of breast cancer increases with

longer durations of use (2,6,18,23,27,28,44,63,

84). In addition, two studies found increased risks

among users with the greatest cumulative dose,

which is based on average daily dose multiplied

by the duration of use (63,82). However, Jick

found an increased risk among ever users, but did

not find a correlation with duration of use (80).

Three studies found increased risk only among

women with shorter durations of use (33,35,53).

In these studies, increased risk of breast cancer

among the groups of users of the longest duration

may have been difficult to detect because of the

relatively smaller number of women in these

groups.
Appendix F Evidence on Breast Cancer and Hormonal Replacement Therapy 67

❚ Dose

The sixth column of tables F-1 and F-2 describe

the relationship of breast cancer to the dose of estrogen. Bergkvist found a significantly increased

risk of breast cancer among users of the potent estrogen diethylstilbesterol and among users of

“other” estrogens, which included users of relatively high dose injectable forms of estrogen (2).

However, the study found no correlation of risk

with the doses of oral conjugated estrogens (CE)

that are commonly used in hormonal replacement

therapy (2). Hoover found a trend toward increased risk among users of high doses of estrogens (greater than 1.25 mg CE per day or the

equivalent) (28). Hulka found an increased risk of

breast cancer among users of injectable estrogens,

but no significant increased risk among users of

the highest doses of oral estrogens (greater than

1.25 mg CE per day or the equivalent) (33). Four

studies found no correlation between risk of breast

cancer and dose of estrogen (37,39,40,49).

❚ Recency

The sixth column of tables F-1 and F-2 describe

the relationship of the recency of estrogen use, or

the time since last use of estrogen, to the risk of

breast cancer. Thirteen case-control studies have

examined this issue. Of those, seven found no

relationship between recency of estrogen use and

breast cancer risk. Hulka found an increased risk

of breast cancer among users whose last dose was

two to five years past, but no increase in risk

among users whose last dose was within the past

year or among those whose last dose was six or

more years ago (33). Kaufman found a reduced

risk of breast cancer among women with a surgical

menopause whose last dose was 10 or more years

ago (39). The author explains that this low relative

risk may be due either to chance or the fact that

women who have had their ovaries removed and

are more likely to be prescribed estrogen generally

for a short period of time also have a lower risk of

breast cancer (39). La Vecchia found a significantly increased risk of breast cancer among users of

estrogens whose last dose was 10 or more years

ago, but this risk was only marginally significant

when adjusted for a number of confounding factors (44). Nomura found a significantly increased

risk of breast cancer among women of Japanese

ancestry whose last dose was eight or more years

ago when compared with community controls but

not when compared with hospital controls (53).

No correlation of risk with recency of use was

found among white women (53).

❚ Time Since First Use

The sixth column of tables F-1 and F-2 present

data on the relationship of breast cancer to the time

since first use of HRT, or latency. Eleven of the

case control studies address this issue. Eight of the

case control studies show no correlation of risk

with time of first HRT use. Ewertz found an increased risk among women with natural menopause more than five years prior to breast cancer

diagnosis, and whose first dose of hormonal replacement therapy was more that 12 years ago. No

similar increase in risk was found in women with

natural menopause within five years of breast cancer diagnosis or women with surgical menopause

(18). Hulka found an increased risk among

women whose first dose of hormonal replacement

therapy was five to nine years ago, but no significant increase in risk was detected in users whose

first dose was 10 or more years ago (33). Weinstein found on increased risk of breast cancer only

in women 10 to 19 years since first use (80).

COHORT STUDIES

Cohort studies of the relationship of breast cancer

to use of hormonal replacement therapy are presented in tables F-3 and F-4 at the end of this appendix. Of the 18 studies identified by OTA,

seven demonstrated a statistically significant increased risk of breast cancer among users of hormonal replacement therapy. Six studies did not

show an increased risk of breast cancer that was

statistically significant. One study found a decreased risk of breast cancer among users of hormonal replacement therapy (78). Three studies

provided no statistical analysis of results. One

study demonstrated a decreased risk of breast cancer among users of estrogen with progesterone,
68 Cost Effectiveness of Screening for Osteoporosis

but this study did not control for confounding

variables (20). A decreased risk of breast cancer

among users of estrogen and progesterone was

also found in the only clinical trial to examine this

issue (52) (described below); however, a lower

risk of breast cancer in users of estrogen and progesterone has not been confirmed by other studies

(2,67).

❚ Duration

Tables F-3 and F-4 also show the effect of the

duration of use of hormonal replacement therapy

on breast cancer risk. Some studies were able to

demonstrate an increase in risk of breast cancer

with increasing duration of use (2,29,61). However, five studies were not able to detect an increase

in risk with increased duration of use. Colditz

found an increased risk among current users of

five to 10 years, but not among users of shorter or

longer durations (13). Schairer found an increased

risk only of preinvasive (in situ) cancers with

duration of ERT use (67).

❚ Dose

The few cohort studies that have looked at the

relationship of dose to risk of breast cancer have

not consistently demonstrated an increased risk

with increasing dose of estrogen (13,29,61).

❚ Recency and Time Since First Use

Some studies have demonstrated an increased risk

with current users of estrogen, but not with past

users (13, 14,89). Other studies have found that the

risk of breast cancer increases with time since first

use (34,35).

CLINICAL TRIALS

Only one clinical trial has examined the relationship of hormonal replacement therapy to breast

cancer risk (52). Subjects were continuously hospitalized postmenopausal women. Treated

women and control group members were matched

for age, smoking history, and medical diagnosis.

The treatment group received estrogen-progestin

hormone replacement therapy. The control group

received placebo. Double-blinded randomization

was discontinued after 10 years. In the subsequent

12 years, women were offered the choice of starting, stopping, or continuing hormone replacement therapy. During the 10-year clinical trial,

there were no significant differences in breast cancer incidence between the treated and the placebo

group. After 22 years of follow-up, there was a

statistically significant increase in breast cancer

risk in never users of hormonal replacement therapy versus ever users. However, the size of this

study was quite small, involving 89 pairs of

women, and the results are unstable.

COMBINED ESTROGEN-PROGESTIN

THERAPY AND BREAST CANCER RISK

It is uncertain whether the addition of progestins

to estrogen replacement therapy would alter HRT

users risk of breast cancer, as few studies have examined this issue. Bergkvist and colleagues examined this issue in a study of breast cancer in a

cohort of 23,000 women from the Uppsala Health

Care Region of Sweden. They found a significant

increase of breast cancer in users of estrogen

alone; they also found a similar increase in risk of

breast cancer among users of combined estrogen

and progestin. The increase in risk among combined estrogen-progestin users, however, did not

reach statistical significance, in part due to the relatively small number of users of combined estrogen-progestin in the cohort. The investigators

concluded that progestins offered no protection

against the development of breast cancer (2).

A recent cohort study by Schairer and colleagues found- that users of estrogen-progestin

combinations may have a higher risk of breast

cancer than users of estrogen alone (67). The study

examined the incidence of breast cancer among

49,017 postmenopausal women who had participated in the Breast Cancer Detection Demonstration Project (BCDDP). For ever users of estrogen

alone, there was no increased risk of breast cancer.

For users of estrogen and progestin combinations,

however, there was an increased risk of breast cancer that was of marginal statistical significance
Appendix F Evidence on Breast Cancer and Hormonal Replacement Therapy 69

(relative risk 1.2 (95 percent confidence interval

1.0 to 1.6)).

All of the studies of hormone replacement and

breast cancer risk, except one, are observational,

so the possible impact of selection bias cannot be

entirely ruled out. Barrett-Connor explained that

it is uncertain how selection bias may affect theresults of studies of HRT use and breast cancer ( 1 a).

Some biases may result in an exaggerated estimate of breast cancer risk in HRT users. For example, women who take hormonal replacement

therapy tend to be more educated and of higher

socioeconomic status than other women (la).

Studies have shown that women of higher socioeconomic class are at higher risk of breast cancer.

Therefore, epidemiological studies that fail to account for differences in socioeconomic status between HRT users and nonusers may overestimate

the risk of breast cancer in HRT users.

Women on HRT have been found to be more

likely to have mammograms (2a). Breast tumors

in HRT users are therefore more likely to be detected. This bias may explain for the lower stage

and grade of tumors detected in HRT users, and

the improved prognosis of breast cancers in HRT

users (la,9). (See discussion below.)

Other biases may result in an underestimate of

breast cancer risk in HRT users (la). Women who

have an early menopause or surgical removal of

the ovaries (oophorectomy) are more likely to be

treated by their physicians with HRT. Breast cancer risk in these women may be underestimated

because both early menopause and oophorectomy

are associated with decreased risks of breast cancer. Women are more likely to be prescribed estrogen if they have menopausal symptoms, and thin

women tend to have more severe menopausal

symptoms. Thin women are also at decreased risk

of breast cancer, so this is another source of bias.

Physicians may be reluctant to prescribe HRT

to women with benign breast disease or a family

history of breast cancer, another source of decreased estimate of risk (la). And some physicians will not prescribe HRT until their patient has

had a mammogram, and if the mammogram is abnormal, will not prescribe HRT.

Women who take hormonal replacement therapy are more likely to engage in other healthy behaviors. And women who are willing to take

hormonal replacement therapy long-term are, by

definition, more compliant. As has been discussed

in detail in Appendix I, compliant women are less

likely to get heart disease, cancers, and other diseases. Although epidemiological studies have attempted to statistically control for many of these

sources of bias, it has not been possible to completely control for so-called compliance bias because of its ill-defined nature.

The uncertainty about the relation between

breast cancer risk and hormone replacement therapy will not be resolved until we have the results of

a randomized clinical trial of HRT in postmenopausal women (32). Because the increase in risk of

breast cancer in HRT users appears to be small, a

large study would be required to have sufficient

statistical power to detect this small increase in

risk. Given that the risk of breast cancer increases

with duration of use, the controlled clinical trial

would take 10 or more years to complete.

The Women’s Health Initiative, sponsored by

the National Institutes of Health, is a large longterm randomized clinical trial examining the effect of hormone replacement therapy on heart

disease and osteoporosis in postmenopausal

women. (See description in Appendix I.) This trial

will also help to resolve many of the questions

about the relationship between hormone replacement therapy and breast cancer risk and other diseases affected by hormone replacement therapy.

Problems with conducting such a study arc the

expense of the trial and the practical problems in

conducting a clinical trial long-term. Also, because sequential and continuous hormonal replacement therapy causes bleeding and other

symptoms, both the investigator and the subject

will become aware of their assignment, introducing a source of bias. Finally, by the time the trial is

completed, new HRT regimens may be available,

raising the question of whether the results of the

Women’s Health Initiative apply to these new regimens.
70 Cost Effectiveness of Screening for Osteoporosis

STAGE OF BREAST CANCER

AT DIAGNOSIS IN HRT USERS

VERSUS NONUSERS

There is some evidence that estrogen users develop breast cancer of lower stage and grade than

breast cancers in nonusers. This maybe an artifact

of surveillance bias or may be because estrogen

induces a less malignant form of breast cancer. In

a population-based case control study of breast

cancer in postmenopausal women, Brinton and

colleagues found that there was a significant trend

of greater risk of breast cancer with increased

duration of HRT use, and that this increase in risk

was greatest for the lowest stage tumors (6). After

10 or more years of estrogen use, the increase in

risk of large (greater than 1 cm) invasive breast

cancers was 1.29 (p less than 0.05), but the increase in risk of small (1 cm or less) tumors and

carcinoma in situ was 1.51 (p less than 0.05) and

1.90 (p less than 0.05), respectively.

Hunt and colleagues, in a study of a cohort of

4544 British women receiving HRT at menopause

clinics, found that, of the 40 breast cancers that developed among the cohort that were identified by

stage, 27 (68 percent) were classified as Stage I

(nonmetastatic tumors 2 cm or less) at diagnosis,

which is a higher proportion of early stage tumors

at diagnosis than expected based on comparison

with stage at breast cancer diagnosis in the general

population (34). The lower than expected stage of

breast cancer at diagnosis in cohort members,

however, could be explained by the fact that 1) the

average member of the cohort had been followed

for less than 5 years, and 2) cohort members, all of

whom were on HRT at recruitment, presumably

did not have any previous diagnosis of breast cancer at that time (57).10

Squiteri and colleagues found that hormone users present with slower growing breast tumors of

earlier stage than nonusers, possibly resulting in

improved prognosis (70). Breast cancers from 35

women who had taken HRT (mostly estrogen and

progestin combinations) were compared to breast

cancers from postmenopausal women who had

never taken hormones, matched for age and type

of breast cancer to HRT users. They found that

HRT users had smaller tumors, significantly less

spread to lymph nodes, and had significantly lower S-phase fractions (a measure of the rate of cancer cell division). The investigators concluded

that the small tumor size, low S-phases, and limited nodal involvement of HRT users suggests

that, despite a possibly increased risk of breast

cancer, the mortality rate for breast cancer in HRT

users will not be increased in comparison with

nonusers. The investigators could not rule out the

possibility, however, that the results may have

been due to better surveillance and earlier diagnosis of breast cancer in HRT users.

Bonnier and colleagues concluded that the lower stage of breast cancers in HRT users was not due

to surveillance bias (4). The investigators compared 68 postmenopausal women who were receiving HRT at the time of diagnosis of breast

cancer with 282 breast cancer patients who had

not received prior HRT, and whose date and age of

onset of breast cancer were similar to that of the

breast cancer patients that had received HRT. Patients who developed breast cancer during HRT

had fewer locally advanced cancers (tumors that

had extended into lymph nodes) and more welldifferentiated cancers. In addition, the probability

of metastasis-free survival tended to be better in

HRT users. The investigators found that the favorable prognosis in HRT users was not likely to be

due to better cancer surveillance among HRT

users, because x-ray detection was not more frequent among patients undergoing HRT. In addition, the delay between first symptoms and

1 Hunt and colleagues also found that short term users of HRT had a significantly lower death rate from breast cancer than would be expected

by comparison with population age-specific breast cancer death rates (observed to expected ratio = 0.55 (0.28-0.96)) (34). As Pike and colleagues explained, however, for a member of the cohort to die during the five year follow up, she had to first be diagnosed with breast cancer and

then die of that disease (57). The expected number of such deaths cannot be derived straightforwardly from population age-specific death rates.
Appendix F Evidence on Breast Cancer and Hormonal Replacement Therapy 71

diagnosis was slightly but not significantly shorter in HRT users.

Additional information is needed on whether

the addition of progestin has an impact on the

stage and grade of breast cancer related to estrogen. Schairer and colleagues, reporting on the results from the BCDDP cohort (described above)

found that estrogen-progestin combinations were

related to a larger risk of preinvasive (in situ) cancers (relative risk 2.3 (95 percent confidence interval 1.3 to 3.9)) than estrogen alone (relative risk

2.3 (95 percent confidence interval 1.3 to 3.9)),

but neither estrogen or estrogen-progestin combinations were related to an increased risk of invasive cancers (67).

Jones and colleagues found evidence that tumors induced by estrogen-progestin combinations may have a better prognosis than tumors

induced by estrogen alone (38). The investigators

identified 460 perimenopausal and postmenopausal breast cancer patients hospitalized in Perth,

Western Australia, between January 1990 and December 1991. They questioned each of the patients about HRT use, and reviewed medical

records and pathology reports for data related to

breast cancer prognosis. They found that the mean

level of estrogen and progestin receptors was lowest in users of estrogen alone highest in users of estrogen-progestin combinations, consistent with a

better prognosis for estrogen-progestin users.

Levels of Cathepsin D, which is inversely related

to breast cancer risk, were highest in users of estrogen alone, and lowest in nonusers. The tumors

were smallest in estrogen-progestin users, and

largest in users of estrogen alone, although the difference was not statistically significant. There was

no significant difference in lymph node involvement of cancer between estrogen-progestin users

and users of estrogen alone. The percentage of all

HRT users with involved lymph nodes (23 percent), however, was significantly lower than the

percentage of nonusers (44 percent). The authors

stated that they could not rule out that this last

finding could have been due to differences in surveillance.

BREAST CANCER MORTALITY IN HRT

USERS VERSUS NONUSERS

There is conflicting evidence about whether an increased incidence of breast cancer among HRT users results in an increased rate of breast cancer

deaths. A number of studies have found that estrogen users do not have an increase in deaths from

breast cancer. Petitti and colleagues analyzed the

26 breast cancer deaths that occurred during 13

years followup of the 6,093 women in the Walnut

Creek cohort (56). The relative risk of death from

breast cancer for women who used HRT but not

oral contraceptives was 0.8 (0.4 to 1.8) compared

to women who used neither HRT nor oral contraceptives.

Vakil and colleagues also found reduced breast

cancer mortality among postmenopausal estrogen

users in a cohort of 1,483 postmenopausal women

from Ontario and Saskatchewan (78). The ratio of

observed to expected mortality from breast cancer

among HRT users was 0.48 (p less than 0.01) for

the Ontario women and 0.45 (p less than 0.01) for

the Saskatchewan women.

In a cohort study of 8,881 postmenopausal residents of Leisure World Retirement Community in

Los Angeles, Henderson and colleagues found a

reduction in breast cancer mortality among estrogen users of 0.81 (no confidence interval provided) (26). Although the investigators did not

have information about breast cancer stage at

diagnosis, they suggested that estrogen users may

have less extensive cancers at diagnosis than nonusers because of increased breast cancer surveillance among estrogen users and better health

awareness of women who use estrogens.

Bergkvist and colleagues, in an analysis of survival rates in women with breast cancer in the

Uppsala Health Care Region of Sweden, found

that ever users of HRT had significantly greater

survival rates than never users (2). The investigators compared survival rates in 261 breast cancer

patients who used HRT prior to diagnosis with

6,617 breast cancer patients from the same geo-
72 Cost Effectiveness of Screening for Osteoporosis

graphic region who did not have any recorded use

of HRT.

Information on estrogen use was obtained from

a regional prescription database and from a mailed

questionnaire, and information on breast cancer

survival was obtained from the Swedish National

Cancer Registry (2). (The registry did not, however, have information about tumor stage and grade.)

The investigators found that the relative 8 year

survival rate of women diagnosed with breast cancer who used hormonal replacement therapy was

10 percent higher than those who had not taken

hormonal replacement therapy, which corresponded to a 40 percent reduction in excess

mortality (2). Separate analysis of relative survival by age at diagnosis showed a significant survival advantage for estrogen-treated women at each

age over 50, and was greatest for estrogen-treated

women 60 years old and older at diagnosis, with

an approximately 40 percent lower mortality rate

than never users with breast cancer.

The relative survival rates were highest for

women who were current users of HRT at diagnosis, and the survival advantage of estrogen users

was decreased with longer time between cessation

of estrogen and diagnosis, so that the survival

rates of estrogen users who had stopped taking estrogens more than 12 months before diagnosis

was close to that of never users of estrogens (l).

Also, the relative survival rates were best among

women treated with progestins combined withestrogen during part or all of the course of HRT.

There were several possible alternative explanations of these results. First, a favorable impact of estrogens on forces of mortality other than

breast cancer, most notably heart disease, may

have accounted for the favorable survival rates of

HRT users. Second, women who are prescribed

HRT represent a healthy selection of the general

population. Third, the favorable survival rates of

HRT users maybe due to surveillance bias (2).

A subsequent study of breast cancer mortality

by the same group attempted to correct for the

“healthy user” effect (85). Despite these corrections, the investigators found no increase in breast

cancer mortality, either overall or in subgroups,

despite increased incidence.

Results of a study by Strickland and colleagues

suggest that the favorable survival of breast cancer

patients who used HRT is due to surveillance bias

(73). The investigators compared the survival

time between diagnosis and death of 256 postmenopausal women with breast cancer, 174 of whom

were never users of estrogens, 21 of whom were

past users of estrogens, and 61 of whom were currently using estrogens at the time of diagnosis. Information on survival time, as well as stage of

breast cancer at diagnosis, was obtained from the

Southwestern Oncology Group Tumor registry.

They found that the median time between breast

cancer diagnosis and death was less than 84

months for never users and past users of estrogens,

and was 143 months for current users of estrogens.

After controlling for stage of breast cancer at diagnosis, however, the survival time for never users

and past users of HRT was not significantly different from current users.

CONCLUSIONS

Although the evidence on the link between estrogen therapy and the risk of breast cancer is based

almost entirely on case-control and cohort studies,

which cannot entirely control for biases and confounding factors (64), the inconsistency in results

among both kinds of studies suggests that the effect of estrogens on breast cancer is likely to be

small. Indeed, when they were found, such

associations were generally weak. Discrepancies

in the results among studies are not readily explained by study design or implementation and

may likely be due to chance.

For purposes of this model, we assumed in the

base case that the relative risk of breast cancer

with HRT would be a modest 1.35 times the baseline rate in the population of women of a certain

age, but the higher risk would not occur until the

duration of use had exceeded 9 years. This increase in risk is consistent with the range of estimates of breast cancer risk with long-term use
Appendix F Evidence on Breast Cancer and Hormonal Replacement Therapy 73

from several recent metaanalyses and epidemiological reviews (Grady (relative risk 1.25 (95 percent confidence interval 1.04 to 1.51) for eight or

more years of ERT use) (21); Steinberg (relative

risk 1.3 (1.2 to 1.6 after 15 years of use) (72); Colditz (relative risk 1.23 (95 percent confidence interval 1.08 to 1.40) for 10 or more years of

estrogen use) (12); Sillero-Arenas (relative risk

1.23 (1.07 to 1.42) after more than 12 years use)

(69); Hulka (relative risk approximately 1.3 to 1.5

with long-term use) (31); Steinberg (relative risk

1.15 to 1.29 after 10 years of CEE use) (71); Mack

(relative risk 1.2 at 5 years of use, increasing to 1.4

at 10 years of use) (47); Prentice (relative risk 1.3

for ever use, and possibly larger risks with longterm use) (59).

Once duration exceeds nine years, the relative

risk of breast cancer is assumed to remain elevated

for the rest of the woman’s lifetime. This assumption is consistent with the observation that breast

cancer risk remains elevated in women with late

menopause and the hypothesis by Pike that HRT

induces a hormonal milieu similar to late menopause (57,58).

Because of the great uncertainty about the magnitude and exposure pattern of risk elevation, the

best case assumption was that there would be no

increased risk of breast cancer among users of

HRT. This estimate is consistent with the metaanalysis by Dupont and Page (16), who limited their

analyses to studies of conjugated estrogens, and

excluded European studies where use of stronger

synthetic estrogens is common. This estimate is

also consistent with the metaanalyses of Khoo and

Chick (43) (no increase in breast cancer risk),

Henrich, (24) (no increased risk of breast cancer

among ever-users of estrogens) and Armstrong

(summary relative risk 0.96 (0.89 to 1.05) after adjustment for menopausal status; no effect of duration of use) (l).

Under the worst case, we assumed a relative

risk of 2.0 after 9 years of therapy. This worst-case

estimate is consistent with the largest relative

risks of breast cancer found in cohort studies of

HRT users (2,35,50,76); these large increases in

risk were generally associated with long-term use.

This estimate is also within the range of estimates

from epidemiological reviews by Persson and colleagues (relative risk 1.5 to 3.0 with 10 to 15 years

of use) (55), Pike (relative risk 1.75 after 20 years

of ERT use) (57) and Henderson and colleagues

(relative risk 1.5 to 2.0 if moderate doses of CEE

are used for 10 to 20 years) (26). We have also assumed that there was no difference in stage distribution or mortality from breast cancer in

estrogen users. Observational studies that have

found better stage and grade breast cancers in HRT

users have inherent risks of surveillance bias.

Finally, we have assumed that, once diagnosed

with breast cancer, women would be taken off

HRT. There is, however, a debate in the literature

over whether women previously treated for breast

cancer may start or resume HRT ( 11, 15,36,45,74).

Proponents argue that there is little direct evidence

that HRT has an adverse effect on women previously treated for breast cancer who subsequently received HRT (81). The National Cancer

Institute recently announced the initiation of a

randomized clinical trial to determine the influence, if any, of HRT on the clinical course of breast

cancer (79).

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Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of oases breast canoer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen USe a,b estrogen USe a,b of estrogen USe a,b

Boston

Collaborative

Drug

Surveillance

Program

(1974)

Sartwell

(1977)

Wynder (1 978)

Cases and controls were consecutive

postmenopausal patients, ages 45 to

64 years, admitted to the general

medicine and surgical wards of 24

hospitals in the Greater Boston area in

1972. Cases had surgically confirmed

breast cancer. Controls were

postmenopausal women who were

admitted to these hospitals with acute

illnesses, elective surgery, or

orthopedic treatment. Patients were

interviewed during admission.

Cases were women 20 to 74 years of

age with carcinoma of the breast

admitted to Johns Hopkins Hospital

between 1969 and 1972. Controls

were chosen from among other

patients except those from the

obstetric or gynecology services. All

subjects were given a questionnaire by

an interviewer.

Cases were pre- and postmenopausal

white women selected from seven

hospitals in New York City, with

diagnosis of breast cancer between

1969 and 1975. Controls were white

women admitted to the surgical

services of these same hospitals

during the same period. All subjects

were interviewed.

51 breast cancer 9% of cases were estrogen “Duration of use in the cases

cases; 774 controls users; 8% of controls were of breast cancer . . was

estrogen users; the similar to that of control

difference was not users. ”

statistically significant

284 cases (65,8% Adjusted RR: 0.82 (0.6-1 .2)* <6 mo.: 0.87

post menopausal) 6-11 mo.: 0.61

(1 9.7% 1-1.9 yrs.: 1.40

noncontraceptive ● adjusted for age, race, marital

status, menopausal history, and 2-4.9 yrs.: 0.70

estrogen users); 367 pregnancy history. >5 yrs.: 0.62

controls (76.8% None of the adjusted relative

postmenopausal)

(26.7%

risks were significantly

different from unity.

noncontraceptive

estrogen users)

785 cases (267 34.1 % of postmenopausal

postmenopausal); cases and 36.8% of

2,231 controls (630 postmenopausal controls

postmenopausal) used estrogen

(nonsignificant difference).

o
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen us&b estrogen use a,b of estrogen use a,b

—.— — —

Ravnihar Cases and controls were women ages

(1979) 15 to 64 years selected from patients

admitted to a Slovenian hospital.

Cases were women admitted for

aspiration or biopsy of malignant or

benign breast diseases. Two controls

from other hospital services were

selected for each case and matched

for age and date of admission.

Interviews were conducted between

1972 and 1974.

Jick (1980) Cases were postmenopausal women,

ages 45 to 64, identified from a

prepaid health care organization’s

(Group Health Cooperative of Puget

Sound) records as having the

diagnosis of breast cancer between

1975 and 1978. Controls were

postmenopausal women ages 45 to 64

years matched for age with cases and

hospitalized about the same time.

Information on cases and controls was

obtained from interviews and medical

374 breast cancer

cases (184 were

ages 50 to 64), 748

breast cancer

controls (368 were

ages 50 to 64)

97cases (39%

current estrogen

users); 139 controls

(37% current users)

Ages 50-64. cases 11.4%

controls 11.7%

No tests of statistical

significance were

performed.

Natural menopause: 3.4

(90% 2.1 -5.6) for current

users (last use within 12

months of date of diagnosis)

versus nonusers,

Hysterectomized women.

1,1 (90% 0.7-1 .9)

Ages 50 to 64:

<24 mo.:

11/1 84 breast cancer cases

30/368 controls

>24 mo.:

3/1 84 breast cancer cases

8/368 controls

unknown duration 7 cases,

5 controls

Duration had no effect on

risk of breast cancer.

Current users (ages 50 to

64). 1/1 84 breast cancer

cases

5/368 controls

Past use:

20/1 84 breast cancer cases

38/368 controls

Dose had no effect on risk of

breast cancer.

and pharmacy records.
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Kelsey (1 981 ) Cases were women ages 45 to 74

years admitted to Connecticut

hospitals between 1977 and 1979 with

newly diagnosed breast cancer.

Controls were women of the same age

span admitted to other surgical

services (excluding gynecology)

between 1977 and 1979. All cases and

controls were interviewed.

330 cases (9% One or both ovaries intact At least one ovary intact

users); 1,348 controls (pre- and postmenopausal). (pre- and postmenopausal).

(10% users) O.R. 0.9 (0.6-1 .2) 1-49 mg - months. O.R. 0.9

Both ovaries removed: O.R. (no c.i.)

0.9 (0.5-1 .5) >50 mg - months: O.R. 0.6

(test for trend: p= 0.08)

Both ovaries removed:

1-49 mg - months: O.R. 0.7

(no c.i.)

>50 mg - months: O.R. 1.0

(test for trend: P= O.88)

“For estrogen-replacement

therapy, there is a

nonsignificant decrease of

less than 5 percent in risk for

breast cancer with each

year of use. ”
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen USe a,b estrogen USe a,b of estrogen use a,b

Hulka (1 982) Cases were postmenopausal women

admitted to two North Carolina

hospitals between 1977 and 1978 with

a diagnosis of breast cancer. Hospital

controls were postmenopausal women

admitted to these same hospitals with

problems that were not gynecologic or

referable to the breasts. Controls were

matched to cases by age, race, date

of admission, and hospital.

Postmenopausal community controls

were obtained from hospital referral

regions. All study subjects were

interviewed.

163 cases (52 users), Estrogen use was defined

372 hospital controls as use greater than 6

(90 users), 737 months.

community controls Ever use:

(171 users) natural menopause 1.8 (p <

0.05) (comm. controls); 1.7

(p < 0.05) (hosp. controls)

Ever use (oral estrogens

only, excluding users of

injectable estrogens): 1.3

(NS) (comm. controls); 1.2

(NS) (hosp. controls)

Surgical menopause. 1.3

(NS) (comm. controls); 1.2

(NS) (hosp. controls)

Natural menopause.

0,5-3 yrs.: 2.1 (p < 0.05)

(comm. controls); 2.6 (p <

0.05) (hosp. controls)

4-9 yrs. :1.5 (NS) (comm.

controls); 1.6 (NS) (hosp.

controls)

10+ yrs.: 1.7 (NS) (comm.

controls); 0.7 (NS) (hosp.

controls)

Natural menopause.

<0,625 mg conjugated

estrogen (or equivalent). 1.9

(NS) (comm. controls), 1.8

(NS) (hosp. controls)

>0,625 mg: 1,0 (NS)

(comm. controls), 0.8 (NS)

(hosp. controls)

Injectable, 4,4 (p < 0.05)

(comm. controls) 4.0 (p <

0.05) (hosp. controls)

Recency (time since last

use): Natural menopause.

O-1 yr.: 1.6 (NS) (comm.);

1,3 (NS) (hosp.)

2-5 yrs., 2,2 (NS) (comm.),

3.2 (p < 0.05) (hosp.)

6+ yrs.: 1.8 (NS) (comm.);

1.8 (NS) (hosp.)

Latency (time since first

use): Natural menopause:

0.5-4 yrs.: 1.2 (NS) (comm.);

1,7 (NS) (hosp.)

5-9 yrs.: 2.4 (p < 0.05)

(comm.), 3.1 (p< 0.05)

(hosp.)

0

10-14 yrs.: 2.1 (NS)

(comm.): 1.3 (NS) (hosp.)

15+ yrs.: 1,5 (NS) (comm.);

1.4 (NS) (hosp.)

I
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Sherman Cases were white patients seen for 113 cases (32% Estrogen use was defined

(1983) breast cancer surgery at the University users), 113 controls as use for more than one

of lowa Hospitals between 1974 and (45% users) month,

1978. Controls were patients without Unadjusted RR 0.71

history of cancer from the general (0.34-0.1 1)

medicine and surgery wards, matched

for age and hospital payment category.

Adjusted RR* 0.55

A trained interviewer administered a

(p= 0.029)

questionnaire to all subjects. *adjusted for weight and height
Number of cases

Author Description of cases and controls and controls

Horowitz Cases and controls were

(1984) postmenopausal women, age 45 or

older, evaluated at Yale New Haven

Hospital, Connecticut, between 1976

and 1979. Patients with clinical

conditions making them unlikely to

have received postmenopausal

estrogens were excluded from control

groups chosen to reduce the likelihood

of ascertainment bias and detection

bias. Four case control groups were

compared.

Group 1.150 breast cancer patients

initially diagnosed by mammography

were compared to 150 women with

mammographically normal breasts.

Group 2: same 150 breast cancer

patients were matched with 150

women with benign breast disease by

mammography.

Group 3:107 breast cancer patients

with initial diagnosis by breast biopsy

were matched with 107 control patients

with histologically benign disease.

Group 4:257 breast cancer patients

were matched to 257 control patients

chosen from the medical or surgical

wards of the hospital (conventional

control group).

Data were obtained from hospital and

physician office records.

257 breast cancer

cases, including 150

breast cancer cases

diagnosed by

mammography, and

107 breast cancer

cases diagnosed by

biopsy.

Control group 1: 150

(normal by

mammography)

Control group 2: 150

(benign breast

disease by

mammography)

Control group 3: 107

(histologically normal

biopsy)

Control group 4: 257

(hospitalized patients

with other diagnoses)

(conventional control

group)

Relationship of breast

Relationship of Relationship of breast cancer to dose,

breast cancer to cancer to duration of recency, and latency

estrogen use a,b estrogen USe a,b of estrogen use a,b

Estrogen use was defined

as at least 0.3 mg/day of

estrogen for at least three

months.

Group 1: O.R. 0.4 (0.3-0.7)

Group 2: O.R. 0.5 (0.3-0.8)

Group 3: O.R. 0.8 (0.5-1.4)

Group 4: O.R. = 0.9 (0.5-1 .7)

when only those medical

records which had

specific notations about

use or nonuse of

estrogens were used; O.R.

= 3.3 (2.2-5.0) when those

medical records with no

specific notations about

estrogen use were

classified as nonusers.

I
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Kaufman Cases and controls were from several

(1984) hospitals in the United States and

Canada. Cases were pre- and postmenopausal women younger than 70

years of age (median age 51 )

admitted to these hospitals between

1976 and 1981 with the diagnosis of

breast cancer made no more than six

months prior to admission. Controls

were women less than 70 years of age

(median age 51) who were admitted to

these hospitals for malignant

conditions judged to be unrelated to

noncontraceptive estrogen, and with

age within one decade of control

subjects.

1,610 cases Estrogen use was defined

(925 as use at least 18 months

postmenopausal), prior to admission,

1,606 controls Pre- and postmenopausal

(1 ,127 ever use of

postmenopausal) noncontraceptive estrogens:

conjugated estrogens: 0.9

(0.7-1.1)

nonconjugated estrogens:

0.8 (0.6-1 .1)

all estrogens: 0.8 (0.5-1 .2)

Premenopausal use of

conjugated estrogen: 1.3

(0.6-2.9)

Postmenopausal use of

conjugated estrogen: 0.8

(0.7-1 .1)

Duration of conjugated

estrogen use:

Natural menopause:

<1 year: 0.9 (0.5-1 .5)

1-4 years: 0.9 (0.5-1 .5)

5-9 years: 0.7 (0.4-1 .5)

>10 years: 1.3 (0.6-2.8)

Hysterectomy only:

<1 year: 1.3 (0.5-3.3)

1-4 years: 1.2 (0.5-2.8)

5-9 years: 0.7 (0.2-1 .7)

>10 years: 0.3 (0.1-1 .0)

Hysterectomy and

oophorectomy:

<1 year: 0.4 (0,1 -1 .0)

1-4 years: 0.8 (0.4-1 .6)

5-9 years: 1.1 (0.5-2.3)

>10 years: 0.5 (0.2-1 .0)

Natural menopause:

<1.25 mg: 1.2 (0.5-2.5)

>1.25 mg: 0.7 (0.3-1.5)

Hysterectomy:

<1.25 mg: 0.7 (0.2-3.3)

>1.25 mg: 0.4 (0.2-1 .0)

Hysterectomy and

oophorectomy:

<1.25 mg: 2.0 (0.6-6.4)

>1.25 mg: 0.5 (0.3-1 .0)

Natural menopause:

—all use within 10 yrs.

before admission: 1.0

(0.6-1 .5)

—all use ending >=10 yrs.

before admission: 0.5

(0.3-1.1)

—use spanning 10 yrs.

before admission: 1.4

(0.8-2.4)

—last use within 10 yrs. plus

current use (use within

past year): 0.6 (0.3-1 .2)

Hysterectomy and

oophorectomy:

—use within 10 yrs. before

admission: 1.0 (0.5-1 .8)

—use ending >= 10 yrs.

before admission: 0.3

(0.1 -0.8)C

—use spanning 10 yrs. bef

ore admission: 0.5

(0.3-1 .0)

—use within 10 yrs. plus

current use (use within

0

past year): 1.2 (0.5-2.6)
Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen USe a,b of estrogen USe a,b

Nomura Cases were white women or women of

(1986) Japanese ancestry, ages 45 to 74

(average age 57 for Japanese, 61 for

white), diagnosed with breast cancer

between 1975 and 1980 in one of

seven hospitals in Oahu, Hawaii. One

hospital control was selected for each

case, matched for sex, race, age,

Oahu residency, time of

hospitalization, and hospital. Controls

with a diagnosis of cancer were

excluded. One neighborhood control

was selected for each case, matched

for sex, race, age and Oahu residency.

Patients were interviewed.

Kaufman Followup on cohort described in

(1991) Kaufman (1987). Cases were

postmenopausal women ages 40 to 69

years (median age 59 years)

diagnosed with breast cancer between

1980 and 1986 and hospitalized in one

of several hospitals in seven U.S. and

Canadian cities. Controls were

postmenopausal women ages 40 to 69

years (median age 59 years)

hospitalized with malignant and

nonmalignant nongynecological

conditions judged to be unrelated to

estrogen use. Data were obtained form

interviews and hospital records.

161 white cases; 161

hospital controls, 159

neighborhood

controls

181 Japanese cases;

183 hospital controls,

181 neighborhood

controls

Japanese:

1.1 (0.7-1.6) compared with

neighborhood controls,

1.0 (0.6-1 .4) compared with

hospital controls

Whites:

0.9 (0.5-1.3) compared with

neighborhood controls;

0.7 (0.4-1 .1) compared with

hospital controls

1,686 cases (18Y0 RR 1.2 (1 .0-1.4)

users); 2,077 controls Type of estrogen:

(17% users) unopposed: 1.2 (1 .0-1.4)

conjugated: 1.3 (1 .0-1.6)

other estrogen. 1.3 (0.6-2.8)

opposed by progestin: 1.7

(0.9-3.3)

Whites:

1-12 me.: 0.9 (0.4-2.0)

community controls; 0.5

(0.2-1.0) hospital controls

13-72 me.: 0.7 (0.4-1.5)

community controls; 1.4

(0.6-2.9) hospital controls

73+ mo.: 1.3 (0.7-2.6)

community controls; 0.8

(0.4-1 .6) hospital controls

Japanese.

1-12 me.: 2.4 (1 .3-4.7)

community controls; 1.0

(0.6-1.8) hospital controls

13-72 mo.: 0.7 (0.3-1.5)

community controls; 0.6

(0.3-1 .2) hospital controls

73+ mo.: 1.9 (0.8-4.4)

community controls; 1.2

(0.6-2.4) hospital controls

< 1 year: 1,3 (1 ,0-1.8)

1-4 years: 1.2 (0.9-1.6)

5-9 years: 1.4 (0.9-2.2)

10-14 years: 1.0 (0.6-1.6)

>15 years. 0.9 (0.4-1 .9)

Recency (time since last

use), Whites:

<8 yrs.: 1.3 (0,6-2.8)

community; 1.2 (0.6-2.6)

hospital

8-16 yrs.: 0.7 (0.3-1.4)

community, 0.5 (0.2-1 .0)

hospital

16 + yrs.: 1.1 (0.6-2.2)

community; 0.8 (0.4-1.5)

hospital

Japanese:

<8 yrs.: 1,0 (0.5-1 .9)

community; 0.8 (0.4-1.7)

hospital

8-16 yrs.: 2.3 (1 .1-4.7)

community; 1.1 (0.6-1 .9)

hospital

16 + yrs.: 2.6 (1 .1-6.1)

community, 1.0 (0.5-2.0)

hospital

<1.25 mg: 0.8 (0.4-1 .5)

> 1.25 mg: 1,2 (0.7-2.0)

mixed mg: 1.6 (0.6-4.0)

Recency (time since last

use):

<12 mo.: 1.1 (0,7-1.6)

12-35 mo.: 1.3 (0.8-2.4)

36-59 mo.: 0.8 (0.4-1 .4)

60-119 mo.: 1.5 (1 ,0-2.2)

>120 mo.: 1.2 (0,9-1 .6)

Number of years since 5

years of use.

<5 yrs.: 2.0 (0.9-4.2)

5-9 yrs.: 1.3 (0.9-2.1)

10-14 yrs.: 0.5 (0.2-1 .0)

>15 yrs.: 1.3 (0.7-2.4)

II
Appendix F Evidence on Breast Cancer and Hormonal Replacement Therapy 187
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen usea,b estrogen use a,b of estrogen use a,b

La Vecchia European multicenter study (1986

(1992) study updated to Dec. 1990); cases

were ages 26 to 74 years (median age

56 years) with histologically confirmed

breast cancer admitted to one of

several hospitals in Northern Italy.

Controls were 25 to 74 years (median

age 56 years) admitted to hospitals in

Northern Italy for acute conditions that

were not hormonal, gynecological, or

malignant.

Cases and controls were questioned

by trained interviewers. Results

include both pre- and postmenopausal

women, Subjects were followed from

1983 to 1990

3,037 cases (4.9% RR 1.4 (1.1-1.8) adjusted for

users); 2,569 controls age

(3.5% users) Adjusted RR * 1.3 (1 .0-1 .8)

(This represents a lower risk

estimate than the 1986

study, with regression

towards the mean overall

results from other studies.)

Updated results may be

overestimated by using

orthopedic controls, which

may be inversely related to

estrogen use (but separate

analyses by diagnostic

subcategories did not lead

to any appreciable

difference in risk).

<3 years, RR 1,2 (0.9-1 ,7) Recency (time since last

adjusted for age use).

Adjusted RR 1.2 (0.9-1 .7) <10 yrs.: RR 1,3 (0.9-1 .5)

>3 years, RR 1,5 (0,9-2.5) adjusted for age

adjusted for age Adjusted RR: 1.2 (0.8-1 .8)

Adjusted RR 1.5 (0,9-2.6) >10 yrs.: RR 1.5 (1.1 -2,3)

(test for trend, p < 0.05) adjusted for age

Adjusted RR: 1.5 (1 .0-2.3)

Latency (time since first

use).

<10 yrs.: RR 1,5 (1 ,0-2.3)

adjusted for age

Adjusted RR 1.3 (O 8-2.0)

>10 yrs.: RR 1.4 (1 ,0-2.0)

adjusted for age

Adjusted RR 1.4 (1 .0-2.0)

Risk estimates may be

affected by higher

socioeconomic status of

users but risk estimates

were not modified by

alliance of indicators of

socioeconomic status.

*Adjusted for age, geographic area,

marital status, education, benign

breast disease, family history of

breast cancer, nulliparity, age at first

birth, age at menarche, type of

menopause, age at menopause,

body mass index, and oral

contraceptive use

a Unless otherwise specified, measured relationship i S relative risk of breast cancer in HRT

b 95% confidence interval is given in parentheses

C This low relative risk may be due to chance or due to the fact that women who have ovaries removed at a young age’

generally for a short period of time

KEY: C.l. = confidence interval; NS = not statistically significant; O R = odds ratio; RR = relative risk

SOURCE: Office of Technology Assessment, 1995

1 ) have lower risk of breast cancer, (2) are more likely to be prescribed estrogen,
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Mack (1 975) Cases and controls were white female

residents of a retirement community in

Southern Los Angeles, median age 71.

Cases were diagnosed with breast

cancer between 1971 and 1975.

Controls were selected from a roster of

all women in the community, matched

with cases for age and date of entry

into the community. Information was

gathered from questionnaires and

medical records.

Casangrande Two groups of subjects were selected.

(1976) Group I was composed of case-control

pairs who were white residents of Los

Angeles County Cases were between

50 and 64 years of age at diagnosis of

breast cancer, diagnosed between

1969 and 1972. A control, matched for

age and socioeconomic status, was

selected from the outpatient rosters of

each index cases’ referring physician.

Group II cases were white patients

whose breast cancers were diagnosed

between 1972 and 73, and who were

between the ages of 50 and 59 at

disease diagnosis, lived in SIX middle

class white health districts of eastern

Los Angeles Cases were matched

with healthy control neighbors ages 50

to 59 years

99 cases breast Ever use 1.6 (no c.i.)

cancer, 396 controls Use at least 5 years before

(26% ever users of diagnosis. 1.7 (no c.i.)

estrogen among

controls)

Group 1: For women with natural

60 cases; 53 controls menopause.

Group II Group 1: unadjusted RR 0.47

33 cases, 27 controls (no c.i.);

adjusted RR* 0.75

Group 11: unadjusted RR

2,15 (no c.i.); adjusted RR*

3.1

Pooled estimate, 1.2 (p -

0.40)

*adjusted for age at menopause
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen USe a,b

ROSS (1980) Cases were white women diagnosed

with breast cancer between 1971 and

1977, between 50 and 74 years of

age, from two Los Angeles retirement

communities. Two postmenopausal

controls were selected for each case

from the same community, matched for

age, race, move-in date, and marital

status. Estrogen use was ascertained

from interviews, medical records, and

pharmacy records.

Hoover (1981 ) Cases were all women with breast

cancer identified from the tumor

registry of Kaiser Foundation Health

Plan of Portland, Oregon occurring

from January 1969 to December 1975.

Controls were drawn from 5% of a

random sample of all members of the

Kaiser Foundation Health Plan.

Information was gathered from

medical records. Average age of

cases and controls was 57.

138 cases of breast Estrogen use was defined

cancer, 281 controls as use beginning more than

4 months preceding

diagnosis.

All: 1.1 (0.8-1.9)

Ovaries intact: 1.4 (0.7-2.4)

Ovaries removed. 0.8

(0.5-3.5)

345 cases; Ever use: 1.4 (1 .0-2.0)

611 controls Natural menopause: 1.3

(69% estrogen users) (0.8-2.1)

Oophorectomized women.

1.5 (0.3-6.6)

> 7 yrs.: 1.8

(test for trend. p = 0.02)

Number of prescriptions

noted,

0.1.00

1 : 1.1

2-4: 1.3

5-9. 1.8

> 10: 1.8

(test for trend: p = 0.013)

Years between first and last

prescription.

none 1.00

<4, 1,4

>5, 1.7

(test for trend. D = 0.022)

Total mg dose (TMD) (=

daily dose x duration)

No exposure (O TMD).

ovaries intact. 1.0

ovaries removed: 1.0

all. 1.0

Low exposure (< 1.500

TMD):

ovaries intact: 0.9 (0.4-1.7)

ovaries removed: 0.9

(0.2-3.2)

all: 0.8 (0.5-1 .5)

High exposure (>= 1,500

TMD) (3 yrs. x 1.25 mg/d):

ovaries intact: 2.5 (1 .2-5.6)

ovaries removed: 0.7

(0.2-2.4)

all: 1.9 (1 .0-3.3)

Usual daily dose:

nonuser: 1.00

< 1 .25mg, 1.4

> 1.25mg, 1.8

(test for trend.

p = 0.005)

I
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen usea,b estrogen use a,b of estrogen USe a,b

Hiatt (1 984) Study subjects were identified from list 119 cases, 119 RR 0.7 (0.3-1 .6) Chart of notations of Three or more years since

of operations performed in all Northern controls (90% estrogen use >=5 yrs.: 2.1 first use, 0.8 (0.4-1.9)

California Kaiser Foundation Health estrogen users) (1 .2-3,6)

Plan hospitals between 1953 and Duration >= 3 yrs.: 1.8

1979. Cases were identified by (0.9-3.6)

hospital discharge records. Controls

were chosen from women with same

age, year of oophorectomy, and date

of entry into health plan membership.

Information was gathered from

medical records.

Brinton (1986) Subjects for the study were from a 1,960 cases; 2,258 1.03 (0.9-1.2)

multicenter breast cancer screening controls

program. Cases were white women

who underwent natural or surgical

menopause at least three months prior

to the diagnosis of breast cancer;

cases were diagnosed between 1973

and 1980. Controls were chosen from

women who did not have biopsy

during course of screening and were

matched to the cases for race, age,

time of entry, medical center and

length of continuation in the program.

Information was gathered through

home interviews.

<5 yrs.: 0.89 (0,8-1.0) Premarin 0.3 mg:

5-9 yrs.: 1.09 (0.9-1.3) <10 yrs. use: 1.04(NS)

10-14 yrs.: 1.28 (0.9-1 .6) 10+ yrs. use: 0.76(NS)

15-19 yrs.: 1.24 (0.9-1 .8) total: 0.99 (0.7-1 .4)

20+ yrs.: 1.47 (0.9-2.3) Premarin 0.625 mg:

(test for trend: p < 0.01) <10 yrs. use: 0.90(NS)

10+ yrs. use: 1.94 (p < 0.05)

total: 1.05 (0.8-1 .3)

Premarin 1.25 mg:

<10 yrs. use: 0.94(NS)

10+ yrs. use: 1.13(NS)

total. 1.02 (0.9-1.2)

Premarin 2.5 mg:

<10 yrs. use: 0.77(NS)

10+ yrs. use: 1.00(NS)

total: 0.84 (0.5-1.4)

Years since initial use:

<1 o: 1.03 (0.9-1 .2)

10-14: 1,15 (0.9-1.4)

15-19: 0.95 (0.7-1.2)

20+: 0,97 (0.7-1 .2)

(test for trend. p = 0.45)
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen USe a,b

McDonald Cases were white female residents of

(1986) King County, Washington, ages 50 to

74, in whom breast cancer was

diagnosed from July 1977 through

August 1978, cases were identified

from a cancer reporting system.

Controls were white female residents of

King County, 50 to 74 years old,

without breast cancer. All cases and

controls were interviewed.

Hunt (1987) Subjects were women, ages 45 to 54

receiving hormonal replacement

therapy, recruited from 21 menopause

clinics around Britain. Recruitment was

both retrospective and prospective.

Subjects were followed from 1978 to

1982. Two controls were selected for

183 cases, 531 Estrogen use was defined

controls as at least 1 yr. of estrogen

use

Overall. 0.74 (0.51 -1 .08)

Natural menopause O 76

(0.46-1 .26)

Hysterectomy with

oophorectomy: 1.28

(0.43-3.80)

“[S]ome variation In

proportions was present

between different

hysterectomy-oophorectomy

subgroups. However, each

of these differences could

easily have been due to

chance “

53 breast cancer

cases, 106 controls

1-5 yrs.: O 83

>6 yrs.: 0,68

(test for trend p = 0.06)

Never: 1.00

0.2-1.0 mg: 0.55

> 1.0 mg: 0,81

(test for trend. p = 0.22)

Recency (time since last

use): Never 1,00

current user or <= 5 yrs.: 0.75

>6 yrs.: 0.76

(test for trend. p = 0.14)

Latency (time since first

use). Never. 1.00

<10 yrs.: 0,73

> 10 yrs.: 0.74

(test for trend: p=O.11)

Adjusted’ RR 12-30

months 1.0 (no c.i.)

31-48 months 48 (1 .5-156)

49-72 months 5.3 (1 .4-202)

>73 months, 36 (0,9-1 5,0)

*adjusted for uterine and ovarian

each case from cohort. status

I
Number of cases

Author Description of cases and controls and controls

Wingo (1 987) CASH study, all subjects were 1,369 cases, 1,645

postmenopausal women enrolled from controls

eight different geographic areas in the

United States. Cases were women 25

to 54 years old with cancer diagnosed

between 1981 and 1982 and Identified

through the SEER cancer registry.

Controls were selected from the same

geographical area by random digit

dialing of residential telephone

numbers. Information was gathered

through interviews.

Relationship of

breast cancer to

estrogen usea,b

Adjusted RR for users of

more than 3 months versus

nonusers. 1,0 (0,9-1.2)

All women. 1.0 (0.9-1.2) ever

users versus nonusers

Hysterectomy and bilateral

oophorectomy: ever users

versus nonusers: 1.3

(0.9-1.9)

Hysterectomy only ever

users versus nonusers: 1.1

(0.8-1 .5)

Natural menopause: ever

users versus nonusers: 0.8

(0.6-1 .1)

Relationship of breast

Relationship of breast cancer to dose,

cancer to duration of recency, and latency

estrogen use a,b of estrogen use a,b

All women

< 1 year 1,0 (0,7-1 .3)

1-4 yrs.: 1.1 (0.8-1.3)

5-9 yrs.: 1.1 (0.8- 1.5)

10-14 yrs.: 0.8 (0.5-1.3)

15-19 yrs.: 1.3 (0.6-2.6)

>20 yrs.: 1.8 (0.6-5.8)

(test for trend. p = 0.7)

Hysterectomy with bilateral

oophorectomy.

<1 year: 1,6 (0.9-2,8)

1-4 yrs.: 1.3 (0.9-2.0)

5-9 yrs.: 1.1 (0.7-1 .8)

10-14 yrs.: 1.5 (0.8-2.9)

>15 yrs.: 1.7 (0,7-4,4)

(test for trend: p = 0.9)

Hysterectomy only.

<1 year: 0.9 (0.6-1 .5)

1-4 yrs.: 1.1 (0.8-1 .6)

5-9 yrs.: 1.6 (1 .0-2.8)

10-14 yrs.: 0.6 (0.3-1 .2)

>15 yrs.: 2.0 (O. 7-5.5)

(test for trend: p = 0.7)

Natural menopause.

< 1 year: 0.8 (0.4-1 .4)

1-4 yrs.: 0.9 (0.6-1 .3)

>5 yrs.: 0.7 (0.3-1.4)

(test for trend. p = 0.6)

Dose (ever users compared

with never users)

(milligram-months):

<25 1 1 (0,8-1 .5)

25-499. 1.3 (0.9-1.9)

50-749. 1.1 (0.7-1.8)

75-99 .9.1.9 (1.1 -3.3)

> 100: 0.8 (0.6-1 .2)

(test for trend p = 0.03)

Recency (time since last

use):

<1 yr.: 1.0 (0.8-1.2)

1-4 yrs.: 1.2 (0.9-1 .6)

5-9 yrs.: 1.1 (0.8-1 .6)

>10 yrs.: 1.0 (0.5-1 .8)

(test for trend: p = 0.06)

Latency (time since first

use): All women:

< 1 year: 0.9 (0.5-1.5)

1-4 yrs.: 1.1 (0.8-1.4)

5-9 yrs.: 1.1 (0.8-1.4)

10-14 yrs.: 0.9 (0.7-1 .3)

15-19 yrs.: 1.1 (0.6-2.1)

>20 yrs.: 1.7 (0,8-3,7)

(test for trend: p = 0.8)
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen USe a,b estrogen use a,b of estrogen USe a,b

Ewertz (1 988) Cases were pre- and postmenopausal

women below 70 years of age

diagnosed with breast cancer between

1983 and 1984, Identified from the files

of a Danish clinical trial of breast

cancer therapy and from a Danish

cancer registry. Controls were a

random sample of women from the

general population, stratified for age,

identified from a Danish population

registry. Data were collected by mailed

questionnaire.

1,484 cases (56.2% Menopausal.’

postmenopausal), 1,16 (0.64-2.1 1)

1,334 controls (58.9% Post-menopausal”

postmenopausal) 1,28 (0.96-1 .71)

Artificial menopause.

1.04 (0.69-1 .57)

● “menopausal” defined as natural

menopause within 5 years of

diagnosis

**’’postmenopausal” defined as

natural menopause more than 5

years before diagnosis

“Exposure to estrogen or

progestagen, alone or in

combination-type therapy,

did not affect the breast

cancer risk. Sequential

therapy with oestrogen and

progestagen ., was

associated with an

increased risk of

borderline statistical

significance (RR=1.36

(0.98-1 .87)).”

Menopausal:

<3 years, 1.08 (0,51 -2.27)

3-5 yrs.: 1.10 (0.38-3.21)

6+ yrs.: 1.57 (0.55-4.44)

(test for trend: p = 0.44)

Postmenopausal.

<3 yrs.: 0,89 (0,56-1 .41)

3-5 yrs.: 0.93 (0.52-1 .68)

6-8 yrs.: 1.82 (0.98-3.37)

9-11 yrs.: 1.34 (0.70-2.54)

124 yrs.: 2.32 (1 .31 -4.12)

(test for trend: p = 0.002)

Artificial menopause:

<3 yrs.: 1,01 (0.55-1 .85)

3-5 yrs.: 0.81 (0.39-1 .70)

6-8 yrs.: 1.52 (0.65-3.53)

9-11 yrs.: 1.44 (0.70-2.96)

12+ yrs.: 0.88 (0.48-1 ,64)

(test for trend p > 0.5)

Recency (time since last

use). Menopausal:

<3 yrs.: 1,59 (0,80-3,16)

3+ yrs.: 0.53 (0.19-1 .45)

Postmenopausal:

<3 yrs.: 1.48 (1 .01 -2.15)

3-5 yrs.: 1.13 (0.56-2.30)

6-8 yrs.: 0.99 (0.52-1 .88)

9+ yrs.: 1.18 (0.68-2.02)

Artificial menopause:

<3 yrs.: 1.09 (0.70-1 .71)

3-5 yrs.: 0.57 (0.21-1 .51)

6-8 yrs.: 2.76 (0.73-10.5)

9+ yrs.: 0.91 (0.39-2.11)

Latency (time since first

uses):

Menopausal:

<6 yrs.: 1,84 (0,84-4,04)

6+ yrs.: 0.57 (0.25-1 .30)

Postmenopausal:

<6 yrs.: 0,95 (0.45-2,02)

6-8 yrs.: 1.10 (0.60-2.04)

9-11 yrs.: 103 (0.62-1 .73)

12+ yrs.: 174 (1.19-2 55)

Artificial menopause.

<6 yrs.: 1,07 (0,53-2.16)

6-8 yrs.: 1,48 (0.71-3.09)

9-11 yrs.: 127 (0.64-2 49)

o

12+ yrs.: 0.89 (0.52-1 .50)
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen usea,b estrogen USe a,b of estrogen use a,b

Rohan (1988) Cases were women from Adelaide,

South Australia, with breast cancer

reported to a cancer registry between

1982 and 1984, and who were 20 to 74

years old at the time of diagnosis.

Controls were women from Adelaide

with no history of breast cancer,

identified from electoral rolls.

Information was obtained through

questionnaires. Reported here is

information only on those women who

were postmenopausal (no menses

within 12 months or surgical

menopause).

281 cases; 288 Unadjusted RR 0.88

controls (0.57-1 .37)

Adjusted RR ● 1.03

(0.62-1 .69)

Women with bilateral

oophorectomy: 0.30

(0.09-0.94) adjusted for age

Natural menopause: 1.01

(0.69-1 ,47) adjusted for age

* adjusted for years of educalion,

practice of breast self-examination,

history of breast cancer in first

degree relative, age at last

menstrual period, and history of

bilateral oophorectomy

<24 me,, unadjusted, 1.02

(0,61-1 .72)

adjusted: 0.99 (0.56-1 .76)

>24 me,, unadjusted: 0.61

(0.29-1 .31)

adjusted: 0.94 (0.40-2.21 )

A relatively small number of

women used exogenous

estrogens and only a

minority reported relatively

long durations of use

Recency (time since last

use): <= 2 yrs.: unadjusted.

0.85 (0.32-2.25)

adjusted. 1.25 (0.44-3.58)

>2 yrs.: unadjusted, 0.90

(0.54-1 .48)

adjusted: 0.88 (0.51 -1 .54)

Latency (time since first

use):<= 15 years since first

use: unadjusted: 0.80

(0.44-1 .45)

adjusted: 0.79 (0.41-1 ,55)

>15 years, unadjusted: 1.10

(0.58-2.08)

adjusted: 1.27 (0.63-2.54)

> 15 years since first and

estrogen therapy >=24 me.:

1.54 (0.43-5.45)

Age at first use:

<45 y.o.: unadjusted: 0.64

(0.31-1 .33)

adjusted. 0.79 (0.35-1 .80)

>45 y.o.: unadjusted: 1.12

(0.66-1 .92)

adjusted. 1 12 (0.61-2.04)
96 Cost Effectiveness of Screening for Osteoporosis
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of oases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Palmer (1991 ) Cases were women under age 70 who

had breast cancer diagnosed more

than six months before interview,

identified at a major cancer treatment

hospital in metropolitan Toronto

between 1982 and 1986. Controls

were identified from tax assessment

rolls of all residents of Ontario. Two

controls were matched to each case

for age and neighborhood; 41 percent

of cases and 42 percent of controls

were pre- or postmenopausal. Cases

and controls were interviewed in their

homes.

Yang (1992) Cases were all British Columbia

women under 75 years of age who

were diagnosed with breast cancer

during 1988 and 1989. Controls were

drawn from voter registration lists from

the same province, and were matched

with cases on the basis of age.

Analysis included only

postmenopausal women. Information

was gathered by mailed questionnaire.

607 breast cancer Estrogens alone: 1.0 Conjugated estrogens.

cases; 1,214 controls (0.7-1.3) <1 yr.: 0.9 (0,5-1 .7)

Estrogen plus progesterone: 1-4 yrs.: 0.7 (0.4-1 .3)

0.6 (0.2-2.0) 5-9 yrs.: 0.8 (0.4-1 .6)

10-14 yrs.: 0.6 (0.2-1 .8)

>15 yrs.: 1.4 (0,6-3,3)

669 cases; O.R. 1.0 (0.8-1 .3) Long-term use (>= 10 years):

685 controls for ever use of unopposed O.R. 1.6 (1 .1-2.5)

estrogen

O.R. 1.2 (0.6-2.2)

for ever use of estrogen and

progesterone

Recency (time since last

use). Never: 1.0

<1 yr.: 0.4 (0.2-0,9)

1-2 yrs.: 5.2 (2.0-13)

3-4 yrs.: 1.0 (0.3-3.1)

5-9 yrs.: 0.4 (0.2-1 .1)

>10 yrs.: 0.8 (0.4-1.4)

Latency (time since first

use): Never: 1.0

Less than 5 yrs. total use

and < 10 yrs. since first use.

0.8 (0.4-1 .5)

10-19 yrs.: 0.9 (0.5-1 .8)

>20 yrs.: 0.5 (0.2-1 .6)

Five or more years total use

and < 10 yrs. since first use:

0.9 (0.3-2.5)

10-19 yrs.: 0.5 (0.2-1 .0)

>20 yrs.: 2.1 (0,9-5.0)

Current use:

O.R. 1.4 (1 .0-2.0)

o

I
Relationship of breast

Relationship of Relationship of breast cancer to dose,

Number of cases breast cancer to cancer to duration of recency, and latency

Author Description of cases and controls and controls estrogen use a,b estrogen use a,b of estrogen use a,b

Weinstein Cases were female residents of Long 1,436 cases; There was no significant There was no significant There was no significant

(1993) Island, NY, aged 20 to 79, who were 1,419 controls association between association of risk with association of HRT with

diagnosed with breast cancer from ever-use of HRT and breast duration of use. recency of estrogen use.

January 1984 to December 1986. Age- cancer risk. There was a significant

and county-matched controls were increased risk of breast

selected from driver’s license files. cancer in women with 10 to

19 years since first

exposure.

a Unless otherwise specified, measured relationship is relative risk of breast cancer in HRT.

b 95% confidence interval is given in parentheses.

KEY: Cl, = confidence interval; NS = not statistically significant; O R = odds ratio; RR = relative risk.

SOURCE: Office of Technology Assessment, 1995.
Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska,b

Thomas White women who were initially treated

(1982) for biopsy-proven benign breast

diseases from 1942 to 1975 in a single

private surgery practice were followed

through 1976 for development of

breast cancer. Patients were followed

up through letters, phone calls, clinic

records, and death certificates.

Average follow-up was 12,9 years.

Bush (1983) Participants were white women, aged

40 to 69 years at baseline, and

followed for an average of 5.5 years.

All women in the cohort were

participants in the Lipid Research

Clinics Program Follow-up Study,

conducted in 10 North American

Clinics between 1972 and 1976. All

subjects were examined at initiation,

and were followed with clinic visits and

by review of death certificates.

Information on decedents was

gathered from medical records and

family members.

Petitti (1987) Walnut Creek Contraceptive Drug

Study; subjects were women aged 18

to 54 recruited from December 1968 to

February 1972. All subjects received a

history and physical exam at initiation

and were followed by subsequent

exam or questionnaire through 1977

Until the end of 1983, deaths were

Identified through the California Death

Index Users of oral contraceptives

were excluded from this analysis.

1,439 women (66 cases

breast cancer) (504

estrogen users)

2,270 white women (593

users, 1,677 nonusers)

3,437 women who never

used oral contraceptives

or estrogen; 2,656

women who had used

estrogens, but not oral

contraceptives

Unadjusted RR 1.80 No evidence was seen of an

(1 ,04-3.10) increased relative risk of

adjusted RR 1.84 breast cancer with

(1 ,05-3,23) increased duration of

There was no variance estrogen use.

for age or year of first

use.

Breast cancer deaths:

users: O

nonusers. 12

No statistical analysis of

breast cancer deaths

was provided.

Risk of breast cancer

death in users 0.8

(O 4-1.8) adjusted for

age
. . .. .. . . .

Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska,b

Bergkvist Women who had been prescribed

(1989) estrogens for conditions related to the

menopause were identified through

records of the pharmacies in the

health care region around Uppsala,

Sweden. Recruitment began in April

1977 and ended in March 1980 and

subjects were followed for an average

of 6 years. Expected numbers of

breast cancer cases were estimated

according to incidence rates of breast

cancer in the region. Median age of

women in the cohort was 53.7 at time

of inclusion into study. Information was

gathered by mailed questionnaire from

a subcohort of 1 in 30 women

randomly chosen from the cohort.

23,224 women age 35 RR 11 (1 .0-1 .3) All HRT users.

and older who had filled Study suggested there <6 mos.: 0,7 (0,4-1 .0)

at least one prescription was no protection from 7-36 mos.: 1.1 (0.9-1 .4)

for estrogen; 253 breast the addition of 37-72 mos.: 1.0 (0,8-1 .4)

cancer cases progesterone. 73-108 mos: 1.3 (0.9-1 .9)

> 109 mos,: 1.7 (1,1 -2,7)

estrogen only.

<6 mos,: 0.8 (0,5-1 ,4)

7-36 mos.: 1.1 (0.8-1 .5)

37-72 mos.: 0.9 (0.6-1 .3)

73-108 mos.: 0.9 (0.5-1 .6)

>109 mos,. 1,8 (1 ,0-3.1)

estrogen plus

progesterone.’

<6 mos.. 0.5 (0,2-1 .8)

7-36 mos.: 0.7 (0.3-1 .3)

37-72 mos.: 0.9 (0.3-2.6)

73-108 mos,: 4.4 (0,9-22.4)

>109 mos,: (no estimate)

*Only a small number of women

received combination therapy, so

confidence Intervals are wide

o
Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska,b

Mills (1989) Subjects were white Seventh-Day

Adventist women, residing in

California, who completed a

questionnaire and who were followed

for 6 years, from 1976 and 1982. Mean

age of cohort in 1976 was 55,4 years.

Information was gathered from annual

questionnaires, tumor registries and

for cases, from medical records.

20,341 women in cohort Unadjusted RR 1.67

(80% postmenopausal at (1.1 7-2.39)

study initiation) (66% adjusted RR’ 1.39

ever users of HRT); 215 (1 ,00-1 .94)

cases of breast cancer

*adjusted for age, ages at

menarche, first birth, and

menopause, Quetelet’s Index,

maternal breast cancer, and a

history of previous benign

breast disease

natural menopause: 1.74

(1 .10-2,74)

hysterectomy, 1.30

(0.78-2.18)

<1 yr.: 2,28 (1 .38-3.79)

1-5 yrs.: 1.56 (0.95-2.56)

6-10 yrs.: 2.75 (1.64-4.64)

10+ yrs.: 1.53 (0.92-2.54)

There was no strong

increase in risk with duration

of HRT.

<1 yr,: 2.28 (1 .38-3.79)

1-5 yrs.. 1.56 (0.95-2.56)

6-10 yrs.. 2.75

(1 .64-4.64)

10+ yrs.. 1.53

(0.92-2.54)

There was no strong

increase in risk with

duration of HRT.
.

Author Description of study

Colditz (1 990) Female registered nurses 30 to 55

years of age completed a mailed

questionnaire. Follow-up

questionnaires were mailed every 2

years. Data were gathered between

1976 and 1986. Only those RNs that

were postmenopausal are included in

these results.

Relationship of

Number of study estrogen use to

subjects breast cancer risk

23,607 postmenopausal Current use: 1.40

female registered (1 ,16-1 .67)

nurses; 722 cases of

breast cancer

Relationship of duration

of estrogen use to breast

cancer riska,b

Relationship of dose,

recency, and latency of

estrogen to breast

cancer riska,b

Current users:

1-11 mos.: 1,28 (0.8-2.1)

12-23 mos.: 1,32 (0.8-2.2)

24-35 mos.: 1.44 (0.9-2.2)

36-59 mos.. 1.26 (0.9-1 .9)

60-119 mos.. 1.62 (1 .2-2,1)

120-179 mos.: 1.28 (0.8-2.0)

>180 mos,: 1,19 (0,6-2.2)

Current users

0.3 mg/d:1 .55 (1 .0-2.5)

0.625 mg/d: 1.42

(1 .0-1 .9)

1,25 mg/d:1.48 (1 .0-2.2)

<1,25 mg/d: 2.27

(1 .0-5,3)

Trend with increasing

past users: dosage was not

1-11 mos.: 1.00 (0.7-1 .4) significant (test for trend:

12-23 mos.: 1.05 (0.7-1 .5) p = 0.56).

24-35 mos.: 0.65 (0.4-1 .1)

36-59 mos.. 1.02 (0.7-1 .5)

current use. 1.40

(1 .16-1 .67)

60-119 mos.: 1.05 (0.7-1 .5) past use. 0.99

120-179 mos.: 0.92 (0.5-1.7) (0.82-1.19)

>180 mos.: 0,79 (0,3-2.5)

time since last use:

current 1.36 (1.1 1-1 ,67)

1-11 mos.. 1.62

(0.98-2.67)

12-35 mos.. 1.09

(0.79-1 .50)

36-59 mos.: 0.89

(0.60-1 .31)

60-119 mos.. 0.93

(079-1 .47)

> 120 mos. 0,70

(0.45-1 .10)
.

Author Description of study —.

Henderson Prospective study of postmenopausal

(1991) female residents of Leisure World

Retirement Community in Southern

California. Residents are

predominantly white, moderately

affluent, and well-educated. Median

age of cohort was 73 at study

initiation. Study was initiated in 1981,

average follow-up is 7.5 years.

Information was gathered through

mailed questionnaires and death

Number of study

subjects —

8,881 postmenopausal

women (the number of

deaths from breast

cancer was not specified

in report) (57% ever

estrogen users)

Relationship of

estrogen use to

breast cancer risk

RR 0,81 (c. I. not

reported) for breast

cancer deaths in ever

users versus never users

of estrogen

Relationship of duration

of estrogen use to breast

cancer riska,b

recency, and latency of

estrogen to breast

cancer riska,b

After adjusting for age, there

was no evidence of

increased risk with

increasing duration of use

among current users (test

for trend: p =0.41) or past

users (test for trend p =

0.46).

Breast cancer incidence

current use. RR 1.33

(1,1 2-1 ,57) adjusted

for age

past use: RR 0.90

(0.77-1 .04) adjusted

for age

registries.

Colditz (1 992) Subjects were female registered O 480,665 person-years of Ever use 1.08

nurses 30 to 55 years of age 1976. follow-up, 1,050 incident (0.96-1 .22) adjusted for

Reported here are results of 12 years cases of breast cancer age

of follow-up. Data was obtained by current use of hormones:

questionnaires mailed every two years, 1.33 (1 .12-1 .57)

cases of breast cancer were adjusted for age

confirmed by review of pathology

reports and hospital records. current use of

unopposed estrogen:

1,42 (1.1 9-1 .70)

current use of estrogen

and progesterone: 1.54

(0.99-2.39)

current use of

progesterone alone: 2.52

(0.66-9.63)

current use of

conjugated estrogens

1,42 (1 .19-1 .20)

current use of estrogen/

progestin 1.54

(0.99-2.39)

current use of estrogen/

testosterone 2.45

(0.95-6.35) —
Author Description of study

Schairer Subjects were participants in the

(1994) Breast Cancer Detection

Demonstration Project, a breast

cancer screening program conducted

between 1973 and 1980. (The analysis

reported here included all women who

did not have a menses for at least 3

months prior to an interview. Reported

here is followup through 1989).

Information was collected by

telephone interviews mailed

questionnaires, and pathology reports.

Average age at start of followup was

57.4 years. Mean duration of followup

was 6,2 years.

Relationship of

Number of study estrogen use to

subjects breast cancer risk

49,017

(1,185 breast cancer

cases) (46.2 of

person-years in study

involved ERT, 6% with

combined PERT)

Relationship of dose,

Relationship of duration recency, and latency of

of estrogen use to breast estrogen to breast

cancer riska,b cancer riska,b

Current ERT users: 1.3

(1 .1-1 .5)

past users: 0.9 (0,8-1 .1)

Current PERT users: 1.2

(0.9-1 .6)

past users: 1.4 (1 .0-2.0)

estrogen alone:

1.0 (0.9-1 .2)

estrogen and progestin. 1.2

(1 ,0-1 .6)

in situ tumors only: estrogen

alone:

1.4 (1 ,0-2.0)

estrogen and progestin. 2.3

(1.3-3.9)

no significant association of

ERT or PERT with invasive

tumors

duration of use: There was

no significant association of

use of ERT with duration of

use. However, risk of in situ

breast cancer rose with

increasing duration of use,

with users of 10 years or

more having about twice the

risk as non users (test for

trend, p= 0.02).

There was no clear pattern

of risk associated with

duration of use for PERT

users, either for all cancers,

in situ cancers or invasive

tumors.

0

a Unless otherwise specified, measured relationship IS relative risk of breast cancer in HRT

b 95 % confidence Interval is given in parentheses.

KEY: c.i. = confidence interval; O.E. ratio = observed to expected ratio: OR = odds ratio; NS = not statistically significant; RR = relative risk

SOURCE: Office of Technology Assessment, 1995

I
Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska,b

Burch (1 974) Subjects were hysterectomized women

on estrogen replacement therapy,

followed for an average of 14.32 years.

Expected number of deaths from U.S.

Public Health Service cancer morbidity

statistics.

Hoover (1976) The medical records of all white

women seen in one private practice in

Louisville, KY, from 1939 to 1972, were

reviewed. Expected rates for the

general population were obtained from

Second and Third National Cancer

Surveys. Average age of women in the

cohort was 49 years. Mean follow-up

was 12 years.

1,000 hysterectomized Observed breast cancer

women cases. 33, expected.

23.7

observed breast cancer

deaths: 6: expected:

7,85

No statistical analysis of

the data was

presented.

1,891 women in cohort; RR 1.3 (1 .0-1 .7)

49 cases of breast

cancer developed

<5 yrs.: 0.9 (0,5-1 .5)

5-9 yrs.: 1.2 (0.6-2.0)

10-14 yrs.: 1.3 (0.6-2.4)

15+ yrs,: 2.0 (1,1 -3.4)

Trend of greater risk with

increased duration is

statistically significant

(p= 0.02).

A finer breakdown of the

follow-up duration after 10

years indicated that the

excess becomes manifest

after about 12 years of

estrogen use.

10-12 yrs.: 1.2 (no c.i.)

13-16 yrs.: 1.9

17-24 yrs.: 2.0

“The increased risk

associated with stronger

medication and

non-daily regimens are

based on small numbers

but are statistically

significant. ”

10+ years follow-up.

0.3 mg: 1.6 (0.9-2.7)

0.625 mg. 1.1 (0.5-2.0)

>0,625 mg: 2.7(1 ,2-5.3)

There was no statistically

significant increase in

breast cancer risk with

less than 10 years

followup.
. .. ...

—

Number of study

Author Description of study subjects

Relationship of dose,

Relationship of Relationship of duration recency, and latency of

estrogen use to of estrogen use to breast estrogen to breast

breast cancer risk cancer risk a,b cancer riska,b

Hammond Subject had been followed at least 5

(1979) years at Duke University Medical

Center, Durham, NC, with diagnoses

associated with a hypo-estrogenic

state (e.g., premature ovarian failure or

pituitary tumor). Information was

gathered retrospectively from medical

records, and in some cases from

referring physicians, patients, or death

certificates. Subjects were divided into

two groups. those who never received

estrogen and those who received

estrogen for longer than 5 years.

(Those estrogen users for 5 years or

less were excluded.) The observed

incidence of breast cancer was

compared to age and race-specific

incidence rates from the Third National

Cancer Survey (southeast United

States).

Subjects were women from Wilford Hall

USAF Medical Center in San Antonio,

Texas who received various forms of

hormonal therapy. Patients with a

diagnosis of breast cancer between

1975 through 1981 were identified

from a tumor registry. Expected values

were obtained from the Third National

Cancer Survey (1975) and the National

Cancer Institute Surveillance,

Epidemiology, End Result (SEER) data

(1980). Information was gathered from

mailed questionnaires, clinic and

hospital records, and registries.

Gambrell

(1983)

301 patients treated with

estrogen and 309

untreated patients

5,563 women; 53 cases

of breast cancer

Estrogen users. O.E.

ratio 1.06 (O 3-2.7) for

whites

No breast cancers

occurred in nonwhite

estrogen users.

nonusers of estrogen

O.E. ratio 0.5 (O.1-1.5)

for whites

O.E. ratio 0.5 (0.0-2.9)

for nonwhites

Estrogen plus

progesterone O 3

(0.1-0.8)

estrogen only. 0.7

(0.5-1.1)

estrogen vaginal cream:

0.4 (0.2-1 .6)

progesterone or

androgen users.

(0.3-1.5)

untreated women

(1 .1-1 9)

0.7

1,4

o

This study was criticized

for falling to control for

confounding functions,

including age,

I
Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska

’

b

Vakil (1983) Incidence of breast cancer in a cohort

of women, 32 to 62 years of age,

receiving estrogen treatment for

menopausal symptoms among the

patients of 20 gynecologists in the

metropolitan Toronto area was

compared to two control groups: the

age-specific breast cancer incidence

rates of the female populations of

Ontario and of Saskatchewan.

Estrogen therapy was begun between

1960 and 1970 and subjects were

followed up to 17 years. Information

was gathered from gynecologists and

cancer and death registries.

Hunt (1987) Subjects were women receiving

hormonal replacement therapy,

recruited from 21 menopause clinics

around Britain. Subjects were followed

from 1978 to 1982. Most women were

45 to 54 years of age at time of

recruitment. Subjects were recruited

both retrospectively and prospectively.

Expected numbers were obtained from

cancer registry roles. All patients were

interviewed at study initiation. Deaths

1,483 menopausal Standard mortality ratio

women for breast cancer. 0.48

(p < 0,01) compared

with Ontario controls,

0.45 (p< 0.01)

compared with

Saskatchewan controls

standard incidence ratio

of breast cancer. 0.62

(p < 0,01) compared

with Ontario controls;

0.70 (p < 0.01)

compared with

Saskatchewan controls

4,544 women; 503 cases O.E. ratio breast cancer

of breast cancer incidence 1.59

(1 18-2,10)

hysterectomy only O.E.

ratio 3.08

hysterectomy and

oophorectomy

O.E. ratio 166

natural menopause.

O.E ratio 1.19

There was no significant Interval since first use of

increase in incidence with HRT:

increasing duration of O-4 years. O.E. ratio 1.40

estrogen use (0.85-2.46)

5-9 years. O.E. ratio 1.45

(0.88-2.24)

10+ years O.E. ratio

3.07 (1 .47-5.64)

There was evidence of a

trend in ratio with interval

since first use (test for

were reported from central registries. trend. p = 0.08).
108 Cost Effectiveness of Screening for Osteoporosis
Relationship of dose,

Relationship of Relationship of duration recency, and latency of

Number of study estrogen use to of estrogen use to breast estrogen to breast

Author Description of study subjects breast cancer risk cancer riska,b cancer riska,b

Risch (1 994) Subjects were women ages 43 to 49

years of age in 1976, resident in

Saskatchewan, Canada, who were

identified for the master file of the

government health Insurance plan that

covers virtually all residents of the

province. These women’s health plan

registration number was used to obtain

their prescription records form the

plan’s pharmacy database for the

period from January 1976 to June

1987, The women’s health plan

registration number allowed the

investigators to Iink the women’s

pharmacy records to the

Saskatchewan Provincial Cancer

Registry. Thirty-one percent of the

cohort used in opposed estrogens

(mostly conjugated estrogens), 2,07

percent used opposed estrogens,

Estrogen use was defined as use of

3.5 years or more. .—

32,790 women (742 Unopposed estrogen

breast cancer cases) 1,33 (1.1 1-1 ,59)

both opposed and

unopposed estrogen

1.10 (O 35-O 42)

No breast cancer cases

occurred among the 171

subjects who used

opposed estrogens

progestins (both alone or

combined with estrogen)

0,93 (0.51 -1 68)

For unopposed estrogen,

risk increased by 7 percent

for each 252 tablets

prescribed (approximately

year of use) (RR 1072

(1 02-1.13)

For opposed estrogens,

there was no significant

I

increase in risk for each 252

tablets prescribed (RR 1,211

(0.72-2.05).

For unopposed progestins,

there was no significant

increase in risk for each 84

tablets prescribed (equal to

seven tablets per month for

12 months) (RR 1,0003

(O 80-1 25)).

a Unless otherwise specified, measured relationship IS relative risk of breast cancer in HRT

b 95% confidence Interval is given in parentheses

KEY: c.i. = confidence internal; NS = not statistically significant; O.E. ratio = observed to expected ratio; O.R. = odd ratio; RR = relative risk

SOURCE: Office of Technology Assessment, 1995

Unopposed estrogens,

1 to 126 tablets/yr. 1,039

(O 78-1 38)

127-378 tablets/yr

1,161 (0,83-1 63)

379-756 tablets/yr

1,041 (0,66-1 63)

>757 tablets/yr 1.498

(1 ,05-2,13)
E

ndometrial cancer, the most common gy -

necologic cancer, occurs in about one

woman out of 1,000 in the population each

year (15). An average 50-year-old white

woman has a 2.6 percent lifetime risk of endometrial cancer (l). And about eight out of every 100

women diagnosed with endometrial cancer die of

this disease (l). Evidence that estrogen replacement therapy increases the risk of endometrial

cancer is well established and is consistent with a

variety of observations.

The relationship of endometrial cancer with use

of estrogen replacement therapy is consistent with

trends in the incidence of endometrial cancer. In

the United States, there was a dramatic increase in

prescriptions for estrogen replacement therapy

between the mid- 1960s and the early 1970s (47).

Estrogen was usually prescribed alone, without a

progestin, and was given for three weeks out of a

four-week cycle. A rise in incidence of endometrial cancer coincided with this increase in prescriptions for estrogen. By 1976, the first casecontrol studies were published that revealed

significant increases in risk of endometrial cancer

in estrogen users compared with nonusers (57,73,

92). After these reports, sales of estrogen replacement therapy began to drop, as did endometrial

cancer rates (47). Since 1980, prescriptions foresAppendix G:

Evidence

on HRT and

Endometrial

Cancer G

trogen replacement therapy have been on the rebound as physicians have been prescribing progestins in sequence with estrogens to prevent

estrogen from inducing endometrial hyperplasia

(19,47).

Obesity and other conditions associated with a

high level of endogenous estrogens are associated

with an increased risk of endometrial cancer, so it

is not surprising that estrogen replacement therapy also increases the risk of endometrial cancer

(7).

The increase in endometrial cancer with estrogen replacement therapy is also physiologically

plausible, and is consistent with observations

about the relationship of estrogen to the endometrium. Estrogen is a growth hormone for the endometrial tissue lining the inside of the uterus. In

premenopausal women, estrogen levels begin to

rise at the beginning of the monthly menstrual

cycle, and progesterone levels increase near the

end of the cycle, causing the endometrial tissue to

mature. In the absence of implantation of a fertilized egg into the endometrium, estrogen and progesterone levels fall and the endometrial tissue is

sloughed off, resulting in menstruation.

If estrogen stimulation continues unopposed

by progesterone, the endometrium continues to

grow, producing hyperplasia, or overgrowth of the

I 111
112 Cost Effectiveness of Screening for Osteoporosis

endometrium (19). Hyperplasia has been shown

to advance to carcinoma in situ, and eventually to

endometrial cancer (31,52,63). This progression

has been observed in patients with diseases characterized by excessive unopposed estrogen secretion, such as Stein-Leventhal Syndrome (74), estrogen-producing tumors (32), and certain types

of infertility (69). Progestins have been shown to

produce maturation of estrogen-primed endometrium and regression of hyperplastic tissue to normal endometrium (79). It has even led to regression of some well-differentiated carcinomas in

some patients (24,67).

Numerous case-control and cohort studies have

documented an increase in endometrial cancer

with use of estrogens. These are presented in

tables G-1 to G-4 at the end of this appendix.

Up to 20-fold increases in risk of endometrial

cancer have been detected in case-control studies

of estrogen replacement therapy. (See tables G-1

and G-2.) Among case-control studies, relative

risks are generally lower in hospital-based casecontrol studies that use as controls women with

gynecologic problems, probably because uterine

bleeding is one of the most common gynecologic

problems and estrogen commonly causes this

symptom (28). Relative risks are generally higher

in population-based case-control studies and hospital-based case-control studies that use as controls women without gynecologic problems, in

part because surveillance for endometrial cancer

is increased among women taking estrogen (28).

DURATION AND DOSE OF ESTROGEN

Studies of the relationship of endometrial cancer

to duration of estrogen replacement therapy indicate that significant increases in risk of endometrial cancer can be detected in as little as six

months to one year after initiation of estrogen replacement therapy (4,58,72,75,92). Epidemiologic studies have shown that the risk of endometrial

cancer increases with increased duration of use.

(See tables G-1 to G-4.) For 10 or fewer years of

use, the risk ranges from no significant increase to

a 36-fold increase in risk. For more than 10 years

of use, the increase in risk has been estimated to be

as little as 2.6 to as great as 63.

The risk of endometrial cancer has been shown

to be related to dose of estrogen. (See tables G-1 to

G-4.) Hence, the minimum effective dose to maintain bone mineral density and to relieve postmenopausal symptoms is commonly prescribed.

(See appendix E.)

RECENCY OF USE OF ESTROGEN

The risk of endometrial cancer decreases after

cessation of therapy. Some studies have reported

that risks of endometrial cancer returned to levels

of nonusers after only six months to two years (40,

57), while others have found the increase in risk to

persist for up to 15 years after estrogen replacement therapy is stopped (8,62,70,72). The data

comparing the trends of estrogen prescription volume with endometrial cancer incidence are more

consistent with a short time interval between

cessation of estrogen replacement therapy and decline in endometrial cancer risk (5).

STAGE AND GRADE OF

ENDOMETRIAL CANCER

Endometrial cancer arising in estrogen users is of

lower stage and grade and much less likely to result in death than endometrial cancer arising in

nonusers of estrogen. A number of case-control

studies have consistently found a lower stage and

grade of endometrial cancer in estrogen users.

(See table G-3.) Virtually all endometrial cancers

in estrogen users are diagnosed before they have

spread beyond the uterus. In cases where endometrial cancer has not spread beyond the uterus, hysterectomy is usually curative. The survival among

estrogen users diagnosed with endometrial cancer

is favorable (12). Barrett-Connor reported that

women not on estrogen survive less well than

women with endometrial cancer taking estrogen

(6). Furthermore, there was little evidence that

mortality from endometrial cancer increased during the period of rising incidence of the disease

from estrogen use in the population (47).
Appendix G Evidence on HRT and Endometrial Cancer 113

However, some users of estrogen replacement

therapy do develop cancers that have spread beyond the uterus (Stage III and Stage IV) (23, 70,

72), and some estrogen users die of this complication (18,57,62).

There are several factors that may account for

this relatively favorable prognosis. First, the lower stage and grade of endometrial cancer in estrogen users may be due to detection bias. Estrogen

users are closely monitored with endometrial

biopsies annually and at times of irregular bleeding. Vaginal bleeding is an early symptom of endometrial cancer, and women taking estrogen replacement therapy may bleed earlier and be

biopsied earlier than women receiving less regular

medical care (7,56). The favorable stage and grade

may also be due in part to case ascertainment —

the detection of occult cancers in the endometrium

of users who bleed because they are taking estrogen (38). The apparently favorable survival experience of user cases is also likely due in part to patients with estrogen-induced benign hyperplasia

mislabeled as cases (56). Bias may also be

introduced by a greater likelihood of estrogen

treatment in women who have menopausal problems associated with unsuspected cancer or a

greater likelihood of cancer (56).

The lower stage and grade of estrogen-induced

tumors may be because these tumors are more benign than tumors that arise in the absence of estrogen. Estrogen-induced endometrial cancers may

be better differentiated and slower growing than

endometrial cancers that arise in the absence of inducement by exogenous estrogen.

Estrogen-induced irregular bleeding, hyperplasia, and localized cancers of the endometrium result in an increased prevalence of hysterectomy

among estrogen users (20). Thus, even though the

endometrial bleeding, hyperplasia, and cancers

associated with estrogen use do not substantially

increase mortality, they do contribute to medical

costs associated with estrogen replacement therapy (15).

Weiss and colleagues were among the first to

suggest that endometrial cancers that arise in

women taking estrogen replacement are on average less aggressive than those that arise in women

who have not taken estrogen replacement (82).

The author reviewed five case-control studies examining the association between prior postmenopausal estrogen use and endometrial cancer prognosis. They found that, although estrogen use is

associated with an increased risk of endometrial

cancer, that association tended to weaken when

only invasive and high-grade tumors are considered. The authors explained that one possible reason for this finding was that tumors that arise in

the presence of exogenous estrogens are on average less aggressive than those that arise in their absence. Another possible explanation, they noted,

was detection bias, that endometrial cancer in estrogen users may be detected earlier than in nonusers of estrogen. This may be because estrogen users may tend to seek care more promptly than

nonusers, their access to medical care may be

greater, or the physicians of estrogens may detect

endometrial cancers early because they are particularly wary of the development of these cancers in

their patients on estrogen.

A third possible explanation, according to the

authors, is overdiagnosis of endometrial cancer in

estrogen users. Because the histological criteria

for separating the more advanced cases of endometrial hyperplasia are ambiguous, some cases of

estrogen-related advanced hyperplasia are being

incorrectly labeled as early endometrial cancer,

giving rise to a false association of estrogen use

with low-grade, low-stage cancers.

Deligdisch and Holinka have provided additional evidence that patients known to be at increased risk of endometrial cancer due to exposure

to estrogen are likely to develop better differentiated and less aggressive forms of cancer (16).

The researchers examined the cellular characteristics of the tumors of 95 patients with Stage I endometrial cancer. Noting that endometrial hyperplasia is excessive growth of endometrial tissue

caused by estrogen stimulation, they found that

endometrial cancers with hyperplasia were better

differentiated and less invasive than endometrial

cancers without hyperplasia.
114 Cost Effectiveness of Screening for Osteoporosis

ESTROGEN USE AND SURVIVAL FROM

ENDOMETRIAL CANCER

Epidemiologic studies have consistently found

that, among postmenopausal women diagnosed

with endometrial cancer, estrogen users have

markedly better survival than never users of estrogen.

Robboy et al. concluded that survival differences between estrogen users and nonusers was

due to differences in grade of tumor at diagnosis

(68). The authors identified 274 women treated

for endometrial cancer at the Massachusetts General Hospital between 1940 and 1971. Pathological specimens for each woman were examined to

confirm the diagnosis of endometrial cancer. Hospital and clinic records were available for 190 of

these women, and were reviewed for a history of

postmenopausal estrogen use. They found that 85

percent of the 274 patients with endometrial cancer were stage I at diagnosis, and 7 percent were

stage II, with no significant difference in stage at

diagnosis between estrogen users and nonusers.

However, the tumors that developed in estrogen

users were significantly more differentiated than

those that developed in nonusers (p less than

0.05). Five- and 10-year survival was also significantly better in users than in nonusers, but survival in users and nonusers was not significantly different once adjusted for differences in grade of

tumor.

The authors did not rule out that their findings

could be explained by earlier detection in estrogen

users because of better endometrial cancer surveillance. This explanation was supported by the

fact that the average age of estrogen users at diagnosis was four years less than nonusers (56 versus

60 years of age, p less than 0.02).

Elwood et al. concluded that survival differences between estrogen users and nonusers is almost entirely due to differences in the stage and

grade of endometrial cancers at diagnosis (1 8). Elwood et al. studied 494 women seen at a Vancouver clinic between 1968 and 1972 for treatment of

newly diagnosed endometrial cancer. All patients

were followed until death or to 1975. Information

on estrogen use was based on both the patient’s

history and the response of the family physician to

a letter requesting more detailed information. The

investigators compared the stage and grade of endometrial cancer in ever users of CEE to never users of postmenopausal estrogens. Only 8 percent

of CEE users had Stage H or III cancers at diagnosis, compared with 16 percent of nonusers. And 43

percent of tumors in CEE users were well differentiated, compared with 29 percent of nonusers.

The 5-year survival rate, after adjustment for

age, was 94.2 percent in ever users of CEE and

was 81.3 percent in nonusers, a difference that was

highly significant (p = 0.001). When differences

in stage were taken into account, survival was not

significantly different between the two groups.

Collins et al. studied endometrial cancer stage,

grade, and survival in 860 women referred to a

London, Ontario cancer clinic between 1967 and

1976 (13). Information on prior estrogen use was

obtained through a questionnaire. About one third

of the patients had a history of estrogen use, defined as use of estrogen for 6 months or more before diagnosis.

At all stages of endometrial cancer, estrogen

users had a significantly greater 5-year survival

than nonusers. The researchers found that, after

adjusting for a number of risk factors for mortality, endometrial cancer patients with no history of

prior estrogen use had a 5.4 times greater risk of

death from cancer than endometrial cancer patients with a history of prior estrogen use.

The authors posited that endometrial cancer patients with a history of estrogen use had higher

survival rates because cancers associated with

prior estrogen use are less aggressive tumors. The

authors, however, did not rule out the possibility

that selection or surveillance bias may have confounded their findings.

In a study of 379 white women ages 50 to 74

from King County, Washington, with newly diagnosed endometrial cancer, Chu and colleagues

concluded that although the use of postmenopausal estrogen leads to an increased risk of endometrial cancer, there is no increased risk of endometrial cancer death in postmenopausal estrogen

users (12). The authors obtained information on
Appendix G Evidence on HRT and Endometrial Cancer 115

cases of endometrial cancer diagnosed between

January 1975 and April 1976 from the Cancer Surveillance Center, a population-based registry

serving western Washington State. Additional information was obtained from interviews of the patient’s physician. Information on estrogen use,

medical and reproductive history, and risk factors

for endometrial cancer was obtained by interviewing the patient; for the 12 percent of study participants who could not be interviewed, this information was obtained by reviewing the medical

records of primary care physicians. Fully 98 percent of estrogen users (defined as use of estrogen

for one or more years after menopause) had tumors stage O or I at diagnosis, compared with 88

percent of nonusers. Only 2 percent of estrogen

users had stage II or III cancers at diagnosis,

compared to 12 percent in nonusers, a difference

that was statistically significant.

Estrogen users with endometrial cancer had a

small but significantly better four-year survival

rate than women of the same age in the general

population, as calculated from Washington state

life tables for white women (relative survival ratio

1.05 (1.04-1.06)). Estrogen users with endometrial cancer also had a significantly better fouryear survival than nonusers with endometrial cancer, the latter group having a relative survival ratio

of 0.89 (0.80-0.99) compared with women of the

same age.

The authors stated that the possibility that these

results were due to self selection or detection bias

could not be ruled out. They also mentioned that

other factors that may confound the interpretation

of their results include differences in follow-up

between estrogen users and nonusers, differences

in cancer therapy between estrogen users and nonusers. They also noted that the interpretation of results may be limited by the relatively short (fouryear) follow-up period.

ESTROGEN/PROGESTIN

REPLACEMENT THERAPY

Because even a relatively benign cancer is an unacceptable complication, most physicians add a

progestin to suppress endometrial hyperplasia

(16). There is substantial evidence that women

who take progestins with estrogen are at no increased risk of developing endometrial cancer

compared with postmenopausal women who do

not take estrogen.

Until recently, only large-scale cross-sectional

studies were available on the effect of combined

estrogen and progestin therapy on endometrial

cancer risk, and these studies showed that the

combination reduced the incidence of endometrial

cancer to below that of an untreated population

(25). A number of prospective studies have shown

that the incidence of endometrial cancer is increased with unopposed estrogen replacement

therapy, but not with combined estrogen and progestin therapy (25, 64).

Persson et al. examined the incidence of endometrial cancer in hormone replacement therapy

(HRT) in the Uppsala health care region, which

serves one-sixth of the population of Sweden (64).

Using the region’s prescription database, he was

able to identify 23,244 women over age 35 who

filled one or more prescriptions for HRT between

April 1977 and March 1980. Women from the cohort who developed endometrial cancer were

identified from the region’s cancer registry. Information on lifetime exposures to estrogen and

progestin, compliance, and sociodemographic

data were obtained on 735 randomly selected

members of the cohort. Comparison was made to

women in the general background population.

A relatively high proportion of the HRT users

in this cohort were receiving progestin and estrogen replacement therapy (PERT), allowing comparison to be made with estrogen replacement

therapy (ERT) (64). The investigators found that,

while users of ERT has a significantly increased

risk of endometrial cancer (relative risk 1.8 (95

percent confidence interval 1.1 to 3.2) after exposure to any estrogen for 6 years), users of PERT

were at no increased risk (relative risk 0.9 (95 percent confidence interval 0.4 to 2.0)).

However, for some of the less androgenic progestins (such as medroxyprogesterone acetate

(Provera), the most commonly used progestin in

the United States), and in the regimens and lower
116 Cost Effectiveness of Screening for Osteoporosis

doses commonly used today, there are insufficient

studies with endometrial cancer as an endpoint;

most studies of efficacy look at an intermediate

endpoint, such as reversal of endometrial hyperplasia. Medroxyprogesterone acetate, in a dose of

10 mg for 12 days, is the least androgenic regimen

that has been best documented to prevent hyperplasia (63,85).

Although courses of medroxyprogesterone

acetate of fewer than 12 days have been shown to

reduce the incidence of estrogen-induced endometrial hyperplasia (86), the minimum duration to

reduce the incidence to zero is 12 days per month

(64,78,87).

Some clinicians prefer a lower dose, 2.5 or 5

mg, of medroxyprogesterone acetate. These

smaller doses are often given concurrently with

estrogen throughout the month (7,84). A continuous low-dose regimen avoids the withdrawal

bleeding of cyclic progestin, which may lead to

poor compliance. In addition, these lower doses

are less likely to induce premenstrual-type symptoms associated with progestins Long-term data

on the ability of continuous low-dose progestin to

protect the endometrium overtime is limited (85).

Additional data is also needed on the effects of

these treatments on lipids, lipoproteins, and other

metabolic parameters (11).

One recent case-control study provides evidence that menopausal women taking estrogen replacement therapy can significantly reduce their

risk of endometrial cancer if they also take medroxyprogesterone (45). The study examined

women between the ages of 50 and 64 who were

treated from 1979 to 1989 at Group Health, a

Seattle, Washington health maintenance organization. Researchers identified 172 cases of endometrial cancer and compared use of hormones in

these women with that of 1,720 women who did

not have cancer. Users of combined therapy used

medroxyprogesterone acetate, 10 mg per day,

most for 10 days each month.

Current users of estrogen alone had a relative

risk of endometrial cancer of 6.5 (95 percent confidence interval 3.1 to 13.3), whereas current users

of estrogen and progesterone had a relative risk of

1.9 (95 percent confidence interval 0.4 to 8.7).

Past users of estrogen alone or estrogen and progestin had no increased risk of endometrial cancer.

The study found that users of estrogens for three to

four years had a relative risk of 1.9 (95 percent

confidence interval 0.4 to 8.7), and that users of

five years or more had a relative risk of 22 (95 percent confidence interval 1.5 to 24.1). Users of estrogen and progestin for more than three years had

a relative risk of 1.3 (95 percent confidence interval 0.5 to 3.4). The researchers concluded that

there does not appear to be any substantial increase in risk associated with combined use with

increasing duration of therapy. The researchers

cautioned, however, that there were relatively few

women who used combined therapy for more than

five years.

A number of clinical trials have demonstrated

that the sequential or continuous addition of a progestin reduces the incidence of or eliminates endometrial hyperplasia, thought to be a precursor to

endometrial cancer. Woodruff and Pikar examined

the incidence of hyperplasia in a one-year, randomized clinical trial of conjugated estrogens

(Premarin) and medroxyprogesterone acetate

(Provera) in 1,724 postmenopausal women (91).

The subjects were divided into five groups: two

groups received continuous estrogen/progestin

regimens, two groups received sequential estrogen/progestin regimens, and one group received

unopposed estrogen regimen. 1 They found that,

while endometrial hyperplasia developed in 20

percent of women on Premarin alone, hyperplasia

1 The regimens examined were as follows: (1)0.625 mg Premarin plus 2.5 mg Provera daily; (2) 0.625 mg Premarin plus 5 mg Provera daily;

(3) 0.625 mg Premarin daily plus 5 mg Provera for 14 days per month; (4) 0.625 mg Premarin plus 10 mg Provera for 14 days per month; and (5)

0.625 mg Premarin daily unopposed by progestin (Woodruff, 1994).
Appendix G

developed in one percent or less of women in the

four Premarin/Provera groups (91).2

Other trials of sequential or continuous regimens using other estrogens and progestins have

demonstrated less hyperplasia in PERT users than

in users of estrogen alone (21,90).

Although the incidence of endometrial cancer

is reduced in estrogen-progestin users, the risk of

endometrial cancer is not eliminated completely.

One group of investigators reported on 25 postmenopausal women who developed endometrial cancers while taking PERT for one or more years (59).

Twenty-three (98 percent) of the women had cancers limited to the uterus, but two had disease extending beyond the uterus. All of the women were

alive and disease free after a median follow-up of

26 months. The endometrial cancers that did occur

among PERT users were usually associated with

regimens that had inadequate doses of progestins.

IMPLICATIONS FOR OTA’S COST

EFFECTIVENESS MODEL

The evidence is strong that endometrial cancer

risks begin to rise soon after the initiation of ERT.

Following the weight of the evidence presented in

tables G-1 and G-2, OTA assumed that the relative

risk of endometrial cancer during the first nine

years of ERT would be 2.5 and in subsequent

years would rise to 7.0. The sensitivity of results

to changes in these assumptions was also tested.

For the case most favorable to ERT, OTA assumed

that relative risk of endometrial cancer is 1 for the

first nine years of therapy and rises to 2.0 during

the 10th and subsequent years of ERT. This best

case is based on the assumption that the apparent

increased risk of endometrial cancer in ERT users

is largely due to surveillance bias. In the worst

case, the relative risk would be 7.5 in the first nine

years of ERT and 15.0 thereafter. This estimate is

based on epidemiological studies that detected the

highest risks of endometrial cancer in HRT users.

Evidence on HRT and Endometrial Cancer 117

In a recent metaanalysis, Grady et al. estimated

a risk of endometrial cancer in ERT users that was

intermediate between OTA’s base case and worst

case estimates (28). They concluded that the risk

of endometrial cancer increased with prolonged

duration of ERT use, from a relative risk of 1.4(95

percent confidence interval 1.0 to 1.8) for less than

one year of use, 2.8 (95 percent confidence interval 2.3 to 3.5) for two to five years of use, 5.9 (95

percent confidence interval 4.7 to 7.5) for six to 10

years of use, and 9.5 (95 percent confidence interval 7.4 to 12.3) for more than 10 years of use (28).3

For PERT users, OTA assumed that there

would be no increase in endometrial cancer risk

over that of the baseline population. This is consistent with the estimates of endometrial cancer

risk from the metaanalysis by Grady and colleagues, who found that case-control studies estimated a slightly increased risk of endometrial cancer in PERT users (relative risk 1.8), whereas the

few cohort studies of PERT users have estimated a

slightly decreased risk of endometrial cancer (relative risk 0.4) (28).

In modeling the impact of HRT on endometrial

cancer, OTA made a number of simplifying assumptions. In the case of ERT, OTA assumed that

the relative risk of endometrial cancer would subside to that of the baseline population in the year

following cessation of HRT. This assumption is

consistent with observations that the risk of endometrial cancer drops rapidly after discontinuing

estrogen use. There are, however, a number of

studies that have been able to detect relatively

small elevations in risk of endometrial cancer that

persist several years after cessation of therapy.

Grady et al. estimated a relative risk of endometrial cancer of 2.3 (95 percent confidence intervals

1.8 to 3.1 ) five or more years after discontinuation

of long-term ERT use (28).

OTA assumed that endometrial cancers in HRT

users would be early stage and grade, and would

2 Although the incidence in endometrial hyperplasia did not differ significantly among the Premarin/Provera groups, none of the women

who received the sequential or continuous regimens with the highest dosages of progestins developed endometrial hyperplasia (91).

3 An earlier metaanalysis by Grady and colleagues estimated a relative risk of 8 in long-term estrogen users (28).
118 Cost Effectiveness of Screening for Osteoporosis

be cured by hysterectomy. OTA also assumed, for

simplicity, that there would be no endometrial

cancer deaths in HRT users. The metaanalysis by

Grady et al. estimated that ERT is related to a large

increase in risk of early stage cancers (relative risk

4.2 (95 percent confidence interval 3.1 to 5.7) for

Stage O and 1 cancers) (28). They found a trend toward later stage endometrial cancers in ERT users

that did not reach statistical significance (relative

risk 1.4 (95 percent confidence interval 0.8 to 2.4)

for Stage 2 to 4 cancers).

Observational studies have been unable to detect a significantly increased risk of endometrial

cancer death in ERT users (20,49,62,65). This

may be due in part to the small number of endometrial cancer deaths in these studies. In a metaanaly -

sis, Grady and colleagues were able to use pooled

data from these studies to detect a trend toward increased endometrial cancer deaths in ERT users

that failed to reach statistical significance (relative

risk 2.7 (95 percent confidence interval 0.9 to

8.0)) (28). Because endometrial cancer is less

common than breast cancer, hip fracture, or heart

disease, and because there are relatively small

numbers of invasive endometrial cancers and

deaths due to HRT-induced endometrial cancer,

OTA’s simplifying assumptions about endometrial cancer stage and endometrial cancer deaths in

ERT users should not have a substantial impact on

the results of OTA’s analysis.

OTA also assumed that women diagnosed with

endometrial cancer would remain off hormonal

replacement therapy. It was previously thought

that HRT could induce the growth of any residual

endometrial cancer cells, and thereby increase the

risk of recurrence. There is a growing consensus,

however, that a history of endometrial cancer is

not a contraindication to continuing HRT, at least

with respect to women who have had hysterectomies for tumors that have not spread beyond the

uterus (3,14,60). It is doubtful, however, that most

women would be willing to resume HRT after

having had endometrial cancer.

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122 Cost Effectiveness of Screening for Osteoporosis

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124 Cost Effectiveness of Screening for Osteoporosis
Appendix G Evidence on HRT and Endometrial Cancer 125

G00 
126 I Cost Effectiveness of Screening for Osteoporosis

I

v o

I

13333333333
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen usea,b estrogen usea,b estrogena,b estrogen use a,b

Wigle (1 978) Cases were women aged 55 to 74

years with histologically confirmed

endometrial cancer who first

attended an Alberta, Canada cancer

clinic during the period 1971 to

1973. Controls were women aged 55

to 74 years who attended the cancer

clinic for any primary cancer other

than breast, cervix, uterus, ovary, or

other female genital organs.

Information on HRT use and risk

factors was gathered by

questionnaire.

Jick (1979) Cases were women 50 to 64 years of

age who were members of Group

Health Cooperative of Puget Sound,

Seattle, Washington, who were

diagnosed with endometrial cancer

from January 1972 to June 1977.

Controls were members of the same

age that were hospitalized for other

conditions at the same age as cases.

Information was obtained from

telephone interviews and clinic

records,

—

202 cases (47.2%

estrogen users),

1,243 controls

(26.3% estrogen

users)

67 cases (89.6%

estrogen users); 74

controls (43.2%

estrogen users)

Any use, 2,2

(p< 0.01)

Estrogen users was

defined as users of

hormonal

replacement

therapy or oral

contraceptives.

Ever use:

relative risk 11.2 (4,2

-21 .1)

1-4 years 1.8

(p< o 05)

> 5 years 5,2

(p< 0,05)

Duration of use:

O-4 years: 3.0

(0.5-14.9)

5-8 years: 36.0

(5.6-300.9)

9-12 years 63.0

(10,4-502.9)

13 years. 21.0

(4.6-107.9)

Relative risk

estimates were

calculated by

Grady (1995) from

published crude

data.

Current use. 2.7 (

p < 0,01)

Past use. 2.0

(p< 0,01)

Dose:

0.3 mg CEE: 4.3

(1 .2-15 .6)

0.625 mg CEE: 7.1

(2,8-1 7.6)

1.25 mg CEE: (8.4

(2,0-36.5)
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen us&b

estrogen USe a,b estrogena,b estrogen use a,b

Antunes Cases were all patients with

(1979) endometrial cancer admitted to six of

the 24 hospitals in the Greater

Baltimore area from 1973 to February

1977. Cases were ascertained from

hospital tumor registries, admissions

records, and pathology records.

Controls were female patients who

were matched with cases for

hospital, race, age, and date of

admission, One set of controls were

taken from hospital services other

than gynecology, obstetrics, and

psychiatry services. A second set of

controls was taken from the

gynecology service, Information was

gathered through personal

interviews, medical records, and

pathologenic specimens.

451 cases (20% Unadjusted relative None: 1.0 <1 mg: 3,5 (1 ,6-7,6)

estrogen users); risk <1 yr.: 2.2 (0,9-5,5) 1-2 mg: 7,1 (2,8-18)

446 controls from 6.0 (3.7-9.7) 1-5 yrs.: 2.9 (1 ,3-6.7) >2 mg.: 3.7 (0,8-16)

other services; 442 compared with >5 yrs.: 15 (4,9-45)

gynecology hospital controls

controls Unadjusted relative

risk

2.1 (1.5-NA)

compared with

controls from

gynecology service

Adjusted relative risk

5.5 (2.3-12.9)

compared with “

hospital controls

Adjusted relative risk

2.4 (1 ,5-3.7)

compared with

gynecology

controls

o
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b estrogena,b estrogen use a,b

Hulka (1980a) Cases were all women who had

received their initial therapy for

endometrial cancer at North Carolina

Memorial Hospital (NCMH) from

1970 through 1976; patients with

carcinoma “in situ” were excluded.

Cases were 60 years old, on

average, at admission. Gynecology

controls were women, average age

60 years, with intact uteri selected

from the pool of all gynecologic

admissions and consultations on

surgical or medical services of the

NCMH from 1970 through 1976

matched for age, race, and year of

admission, and with intact uterus;

excluded were women admitted to

the gynecologic oncology service

and women admitted primarily for

curettage or endometrial biopsy.

Community controls were a sample

of women, average age 55 years,

with intact uteri residing in a major

referral area of NCMH, and matched

for age and racial group. Sources of

information included interviews and

review of medical records.

256 cases (32.8%

estrogen users);

224 gynecology

controls (22.9%

users); 321

community controls

(27.1% users)

White women.

1.8 (0,9-2.5)

compared with

gynecologic

controls; 1.4

(0.9-2.1) compared

with community

controls

Black women:

0.7 (0.3-2.1)

compared with

gynecologic

controls; 1.5

(0.4-5.1) compared

with community

controls

<3.5 yrs.:

0.8 (0.4-1.7

compared with

gynecology

controls;

0.7 (0.4-1 .3)

compared with

community controls

>3.5 yrs.:

4.1 (1 ,8-9.6)

compared with

gynecology

controls;

3.6 (1 .9-6.8)

compared with

community controls

<0,625 mg: 1.6 (NS)

compared with

gynecology

controls; 2.3 (NS)

compared with

community controls

>0,625 mg: 1.8 (NS)

compared with

gynecology

controls, 1.4 (NS)

compared with

community controls

In comparison of

cases to

community

controls, risk drops

to that of non-users

of estrogen after a

20-month

estrogen-free

interval; in

comparison to the

gynecology control

group, excess risk

disappeared 28

months after

cessation of

estrogen.
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b estrogena,b estrogen use a,b

Hulka (1980b) Cases were women, mean age 61

years, with endometrial cancer

receiving their initial therapy at North

Carolina Memorial Hospital (NCMH)

between 1970 and 1976.

Gynecologic controls were selected

from patients admitted to the

gynecology service and from

patients receiving gynecologic

consultations while inpatients on

surgical or medical services of the

NCMH during 1970 through 1976.

Admissions to the gynecologic

oncology service, women admitted

for dilation and curettage, and

women with a previous hysterectomy

were excluded. Controls were

matched for age, year of admission,

and race with cases. Community

controls were from a sample of

women over 30 years old (mean age

56 years) residing in the major

referral areas of NCMH, stratified by

age and within racial group. All had

intact uteri. Information was gathered

from interviews and medical records.

256 cases (32.8%

estrogen users),

224 gynecology

controls (22.9%

users), 321

community controls

(27.1 % users)

Duration of estrogen

use

< 3,5 years:

Stage 1A: 1.2 (NS)

Stage 1B: 0.9 (NS)

Stage 11: 0.7 (NS)

Stage III-IV: 0.6 (NS)

Grade 1. 1.0 (NS)

Grade 2: 0.7 (NS)

Grade 3: 0.6 (NS)

invasion:

myometrium and

beyond. 0.5 (NS)

Duration of estrogen

use

>3.5 yrs.:

Stage 1A: 7.6

(p< 0,05)

Stage IB: 1.6 (NS)

Stage Il: 3.3

(p< 0,05)

Stage III-IV 1.5

(NS)

Grade 1 55

(p< 0,05)

Grade 2: 19 (NS)

Grade 3 2.9

(p< 0.05)

Estrogen

strength=<O.625

mg.

Stage 1A: 5.8

(p < 0,05)

Stage IB-IV: 2.3

(NS)

Grade 1: 4.0

(p< 0.05)

Grades 2-3.2.5 (NS)

invasion:

endometrium: 5.2

(p< 0,05)

myometrium and

beyond: 2.1 (NS)

Estrogen strength >

0.625 mg:

Stage 1A: 8.5

(p< 0,05)

Stages IB-IV: 1.5

(NS)

Grade 1. 5.4

(p< 0,05)

Grades 2-3. 2.0 (NS)

Estrogen-free interval

> 6 me,,

Stage 1A: 2.5

(NS)

Stages IB-IV: 1.3

(NS)

Grade 1. 2.2 (NS)

Grades 2-3: 1.3 (NS)

invasion:

endometrium. 2.1

(NS)

myometrium: 2.0 (NS)

Estrogen-free interval

< 6 months:

Stage 1A. 8.8 (p

< 0.05) Stages

IB-IV: 2.1 (NS)

Grade 1. 6.2

(p < 0,05)

Grades 2-3. 2.3 (NS)

—
Appendix G Evidence on HRT and Endometrial Cancer 1131

I
.

Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b estrogena,b estrogen use a

’

b

Salmi (1980) Cases were all patients with

endometrial cancer diagnosed and

treated in the Department of

Obstetrics and Gynecology at the

University Central Hospital of Turku,

Finland, from 1970 to 1976. Controls

were women between the ages of 35

and 60 identified from Turku’s

continuing mass screening program

for cervical and breast cancer.

Women over 60 were identified from

the National Population Registry.

There were 585 controls, 282 of

which were matched for age, height,

weight, and social class. Information

on HRT use was gathered by

interviews.

318 cases (33% Matched pairs

hormone users); analysis

282 matched Any use of hormones.

controls; 585 total 0.6 (0.4-0.9)

controls (43.6% Use of hormones for

users) gynecological

conditions: 0.6

(0.4-0.9)

Use of estrogen:

0.4 (0.2-0.7)

Estrogen use was

defined as use of 6

months or more.

Estradiol only or

combined with

androgen.

0.3 (0.2-0.7)

Estriol only.

0.4 (0.1-1 .0)

Conjugated

estrogens:

5.0 (p < 0.05)

Other estrogens:

0.6 (0.2-1.4)
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen USe a,b estrogen usea,b estrogena,b estrogen use a,b

Stavraky Cases were all new patients between

(1981) 40 and 80 years of age with a

diagnosis of endometrial carcinoma

admitted to Victoria Hospital,

London, Ontario between September

1976 and October 1978 for

preoperative radiation. Two controls

for each patient were selected from

the hospital’s daily patient register,

one control was a woman with a

gynecologic disorder, matched for

age within.5 years; another control

was a woman with a nongynecologic

disease within the same age range;

hysterectomized women were not

included in control group.

Information was gathered by

questionnaire.

206 cases (58% unadjusted relative All durations: Gynecologic controls. Use <5 years

estrogen users), risk 2.4 (1 ,6-3.7) unadjusted relative <0,625 mg 1.9 duration

191 gynecologic compared with risk (0.9-3.6) Current users (use

controls (38% gynecologic 2.9 (1 .6-5.1) >0,625 mg 3.1 within past year).

users); 199 controls adjusted relative risk (1 ,5-6.3) adjusted relative risk

nongynecologic unadjusted relative 1.3 (0,5-3.7) Nongynecologic 1.3 (0,6-3,1)

controls (28% risk 4,3 (2.7-6,7) Risk by duration of controls. compared with

users) compared with

nongynecologic

controls

unadjusted relative

risk for

postmenopausal

women only

2,3 (1 ,5-3,7) <

compared with -

use among patients

and gynecologic

controls who

presented with

bleeding:

unadjusted relative

risk

2 years: 2.3

(0.5-7,9)

.

gynecologic

controls

unadjusted relative

risk for

postmenopausal

women only

4.8 (2.9-7.7)

compared with

nongynecologic

controls

2-4 years: 1,1

(0.5-2.5)

5-9 years: 4.1

(1 .4-10 .5)

1 O+ years, 11,0

(2.1-39.0)

adjusted relative risk.

O-4 yrs.: 0.7 (O 2-2,5)

5-10+ years: 2.3

(1 .8-8,4)

<0.625 mg 2.9 gynecologic

(1 .4-57) controls;

>0.625 mg 6.4 7,2 (2.6-20.3)

(2.5-14,5) compared with

nongynecologic

controls

Past users (cessation

of use

> 1 year ago):

adjusted relative risk

0.5 (0.2-1 .3)

compared with

gynecologic

controls,

1,0 ( 0,4-2.5)

compared with

nongynecologlc

controls

adjusted relative riskc Risk of endometrial

1.5 (0.9-2.7) cancer among

compared with patients and two

gynecologic control groups by

controls duration of

estrogen use

14,4 (5,0-41 .8)

compared with

nongynecologic

controls
Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b estrogena,b

adjusted relative riskc < 2 years,

4.8 (2.7-8.4) adjusted relative risk

compared with 0.7 (0.3-1.9)

non-gynecologic compared with

controls gynecologic

adjusted relative riskc controls,

for 1.6 (0,6-4.3)

postmenopausal compared with

women only nongynecologic

1.5 (0.8-2.8) controls

compared with 2-4 years.

gynecologic adjusted relative risk

controls 1.0 (0.4-2.2)

adjusted relative riskc compared with

for gynecology

postmenopausal controls;

women only 4.0 (1 .6-10 .1)

4.2 (2,2-8,0) compared with

nongynecologic

compared with controls

nongynecologic

controls 5-9 years:

Estrogen use was

adjusted relative risk

defined as use six

1.7 (0.7-4 1)

compared with

months or more. gynecologic

Relationship of

endometrial cancer

to recency of

estrogen use a,b

Use >= 5 years

duration:

Current users.

adjusted relative risk

4,3 (1 .9-9,7)

compared with

gynecologic

controls,

11.3 (4.9-25.5)

compared with

nongynecologic

controls

Past use.

adjusted relative risk

0.7 (0.2-2.7)

compared with

gynecologic

controls,

2.3 (0.6-8.5)

compared with

nongynecologic

controls

controls;

5.3 (2.2-1 2.4)

compared with

nongynecologic

controls

1 O+ years.

adjusted relative risk

6.4 (2.1-19.3)

compared with

gynecologic

controls,

o
Relationship of Relationship of Relationship of

Author Description of cases and controls

Kelsey (1 982) Cases were women ages 45-74

years old who were admitted from

1977 to 1979 to seven Connecticut

hospitals with newly diagnosed

endometrial cancer. Controls were

other women in the same age group

admitted to surgical services (except

gynecology) of those hospitals at the

same time as the cases. Information

on HRT use was obtained by

questionnaire.

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

and controls to estrogen use a,b estrogen use a,b estrogena,b estrogen use a,b

167 cases (47% Use >5 years: Use <1 yr.: odds

estrogen users), odds ratio 1.6 ratio 1.1 (no

903 controls (38% (1 .3-2,0) confidence

estrogen users) intervals provided)

1-2.5 yrs.: odds ratio

1,0

2.6-5.0 yrs.: odds

ratio 2.9

5.1-7.5 yrs.: odds

ratio 4.3

7.6-10,0 yrs.: odds

ratio 8.2

> 10 yrs,: odds ratio

2.7

(test for trend:

p < 0,001)
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen us&b

estrogen use a,b estrogena,b estrogen use a,b

La Vecchia Subjects were women admitted to

(1984) university and general hospitals in

the Greater Milan area between 1979

and 1983. Cases were diagnosed

with endometrial cancer within the

year prior to interview. Cases were

between 33 and 74 years old

(median age 60); 30 cases were

below 50 years of age. Controls were

women less than 75 years admitted

for acute conditions unrelated to risk

factors for endometrial cancer.

Women with gynecological,

hormonal, or neoplastic diseases or

who had undergone hysterectomy

were excluded from controls.

Information was gathered by

personal interview.

283 cases (25% Relative risk There was a

estrogen users); 2.3 (1 .6-3.2) adjusted significant trend of

566 controls (17% for body mass increasing risk with

users) index and age increasing duration

of use (test for

trend: p = 0.001).

Age <55 years:

<2 years use: 1,8

(0.9-3.6)

>2 years: 5.1

(1 .5-17.1)

(test for trend:

p = 0.002)

Age 55-64 years:

<2 yrs,: 1.5 (0.8-2-6)

>2 yrs,: 1,8 (0,7-4.5)

(test for trend:

p = 0.12)

Age >= 65 years:

<2 yrs.: 1,6 (0.7-3.5)

>2 yrs.: 1,4 (0.4-5.4)

(test for trend:

p = 0.29)
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of oases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen USe a,b estrogen USe a,b estrogena,b estrogen use a,b

Shapiro (1985) Cases were women with endometrial

carcinoma admitted to hospitals in

Boston, MA; Philadelphia, PA;

Baltimore, MD; Tucson, AZ; New

York, NY; Kansas City, MO; San

Francisco, CA; and London, Ontario;

ages 50-69 years, with no history of

other cancers. Controls were other

female patients on medical, surgical,

and orthopedic wards, ages 50-69

years, with no history of cancer,

admitted for conditions judged not to

be related to estrogen use. Patients

were interviewed between

September 1976 and December

1982.

425 cases (31 % Relative risk

estrogen users); 3.5 (2,6-4.7)

792 controls adjusted for age,

body-mass index,

and geographic

area.

Estrogen use was

defined as use of

conjugated

estrogen,

beginning at least

two years prior to

the date of

interview.

<1 year: 0.9 (0,4-1 ,8) < 1 year since last

1-4 years: 2.9 use.

(1 .8-4.7) < 1 yr. duration. —

5-9 years: 5.6 1-4 yrs.: 2.1 (0.9-4.7)

(3,4-9.3) 5-9 yrs.: 6.3 (3.0-13)

> 10 years: 10 >10 yrs.: 12 (5,9-24)

(5.9-18) 1-4 years since last

use:

< 1 yr. duration: 0,6

(0.2-2,0)

1-4 years: 3.1

(1 .3-7,4)

5-9 years: 5.2

(2.1-13)

> 10 years: 12

(4.8-32)

5-9 years since last

use:

< 1 yr. duration: 1,0

(0.3-3.5)

1-4 years: 4.0

(1 .4-12)

5-9 years: 6.3

(2,0-20)

> 10 years, 3,7

(0.8-18)
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of oases and controls and controls to estrogen use a,b estrogen USe a,b estrogena,b estrogen use a,b

Buring (1986) Cases were white women, aged

40-80 years, who were admitted to

the Boston Hospital for Women’s

Parkway Division with first diagnosis

of endometrial cancer made

between January 1970 and June

1975. Controls consisted of all white

women, aged 40-80 years, admitted

to the same hospital during the same

period for nonmalignant conditions

requiring surgery. Information was

gathered from hospital and clinic

records,

188 cases (39% Ever use: 2.4

estrogen users); (1 ,7-3,6)

428 controIs (17%. current use. 2.8

estrogen users) (1 ,8-4.2)

(current use defined

as use within the

year before index

admission)

< 1 yr.: 1,4 (no

confidence interval

provided)

I-4 yrs.: 2.0

5-9 yrs.: 6.4

10+ yrs.: 7.6

> 10 years since last

use:

< 1 yr. duration: 1,2

(0.4-3.6)

1-4 years: 3.5

(1 ,4-8.3)

5-9 years: 4.1

(1 .1-15)

> 10 years: —

0.3 mg, 0.625 mg: < 1 yr.: 2,4 (no

2.7 (1 ,6-4.9) confidence interval

1.25 mg, 2.5 mg: provided)

3.8 (2.2-6.6) 1 + yrs.: 4.6

1-2 yrs.: 4.2

3-4 yrs.: 5.9

5+ yrs.: 4.5

An excess risk of

endometrial cancer

was noted to

continue among

estrogen users who

had discontinued 5

or more years ago,

although there were

small numbers of

former users.

o
.. . ..

Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen USe a,b estrogen use a,b estrogena,b estrogen use a

’

b

Ewertz (1 988) Cases and controls were women

referred for radiotherapy at the

Oncology Department II of the

Finsen Institute, Copenhagen,

Denmark. Cases were ages 44 to 89

years (mean age 66 years) and were

identified between October 1977 and

December 1978. Controls were

patients with cervical cancer, from

same hospital, matched for age at

diagnosis. Data were derived from

hospital records.

Brinton (1993) Cases were menopausal women,

ages 20 to 74 years, newly

diagnosed with endometrial cancer

between June 1, 1987 and May 15,

1990 from seven hospitals in five

areas of the United States.

Population controls were matched to

the cases for age, race, and

residential area, identified by random

digit dialing and HCFA data tapes.

Information was gathered from home

interviews.

149 cases (56% 4.7 (2.9-7.7) ever

estrogen users); users vs. never

154 controls (21% users

estrogen users)

300 cases (24% Adjusted relative risk.

estrogen users); 3.0 (1.7-5.1)

207 controls (14% Progestin alone:

estrogen users) 1.8 (no confidence

interval)

Estrogens alone

3.4 (no confidence

interval)

Both short- and

long-term use

elevated the risk of

early stage tumors,

but an effect on

late-stage tumors

was seen only for

long-term use

(relative risk 2.1

Associations with

dose were

inconsistent

although women

who used low-dose

preparations

exclusively had the

lowest risk. There

were no striking

(0.7-6.4)). relationships

according to the

type of estrogen or

regimen used.

Although the highest

risks were for

recent estrogen

users, persistent

excess risks were

seen even for those

who had

discontinued use 5

or more years ago.
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b estrogena,b estrogen use a,b

Jick (1993) Cases were female members of

Group Health Cooperative of Puget

Sound, Washington, ages 50 to 64

with newly diagnosed endometrial

cancer between 1979 and 1989.

Controls were GHC members

matched for age and length of

membership in health maintenance

organization to cases. Cases were

identified from GHC’s file of

discharge diagnoses tumor registry.

Information was gathered from

pharmacy records and medical

records.

Levi (1993) Cases were women below 72 years

old who were diagnosed with

endometrial cancer in the Swiss

Canton of Vaud between 1988 and

1992, Controls were women of the

same age hospitalized for acute

conditions not related to cancer or

HRT.

172 cases (44% HRT Adjusted rate ratio:

users); Current ERT users:

1,720 COntrols (40% 6.5 (3.1 -13.3)

HRT users) Current PERT users:

1.9 (0.9-3.8)

Past ERT users:

1.0 (0.5-2.0)

Past PERT users:

0.9 (0.3-3.4)

158 cases (38% HRT Risk-factor adjusted

users); 468 controls relative risk 2,7

(20% HRT users) (1 .7-4.1)

Estrogen alone:

3-4 years: adjusted

rate ratio 1.9

(0.4-8.7)

>5 years: adjusted

rate ratio 22.0

(6.5-74.1)

Estrogen and

progesterone:

>3 years: adjusted

rate ratio 1,3

(0.5-3.4)

There was insufficient

data for women

who had used

estrogen and

progesterone for

more than 5 years.

Duration of use:

>5 years, 5,1

(2.7-9.8)

Estrogen:

0.3 mg: 4.3 (1 .2-15 .6)

0.625 mg: 7.1

(2.8-17.6)

1.25 mg: 8.4

(2.0-36.5)

Estrogen and

progesterone:

0.3 mg: 1.8 (0.4-8.0)

0.625 mg: 1.6

(0.7-3.6)

1.25 mg: 5.4

(1 .0-30 .7)

Recency of use:

> 10 years since last

use: 2.3 (1 ,2-4.5)

a 95 percent confidence intervals are shown in parentheses.

b Relationship is relative risk, unless stated otherwise.

c Adjusted for age, residence, number of pregnancies, education level, and menopausal status

KEY: HRT= hormonal replacement therapy; NS = not statistically significant

SOURCE: Off Ice of Technology Assessment, 1995
Appendix G Evidence on HRT and Endometrial Cancer 1141
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of oases and controls and controls to estrogen USe a,b estrogen use a,b estrogena,b estrogen use a,b

McDonald Subjects were all cases of

(1977) endometrial cancer among residents

in Olmstead County, Minnesota over

a 30 year period (1945 to 1974).

Cases were 25 years of age and

older. Four controls, age-matched

and residents of Olmstead County,

were selected for each case.

Information was gathered from

medical records.

Weiss (1979) Cases were all female residents of

King County, Washington, aged 50 to

74 years with newly diagnosed

endometrial cancer between January

1975 and April 1976. Cases were

identified from the Cancer

Surveillance System, a

population-based tumor registry

serving western Washington.

Controls were white women aged 51

to 74 years from King County

Identified from household surveys.

Information on HRT use and risk

factors was gathered through

interviews,

145 cases (27% All estrogens:

estrogen users); 0.9 (0.6-1.4)

580 controls (28% Conjugated

estrogen users) estrogens:

2.0 (1 .2-3.5)

322 cases (81 % ever

users);

289 controls (34%.

ever users)

All estrogens:

all durations: 0.9

(0.6-1 .4)

>6 mo. 2.3 (1 .4-3.6)

Conjugated

estrogens:

all durations: 2.0

(1 .2-3.5)

>6 me.: 4.9

(2.3-1 1.5)

> 1 year: 5.3

(2.1-14.4)

>2 years: 8.3

(2.9-29.9)

>3 years: 7.9

(2.9-21 .2)

Age-adjusted relative

risk:

1-2 years 1.2

(0.4-3.7)

3-4 years: 5.4

(2.5-1 1,5)

5-7 years: 4.7

(2.6-8.4)

8-10 years. 11,7

(6.2-21 .8)

11-14 years. 24.2

(1 1,8-49,4)

15-19 years 102

(5.3-20,0)

> 20 years, 83

Dosage of

conjugated equine

estrogens:

0.625 mg/day:

1.4 (0.3-5.9)

1.25-2.5 mg/day:

7.2 (3.0-14.9)

Age-adjusted relative Time since last use:

risk. >8 years: 3.0

<0.5 mg per day: (0.9-10.6)

2.5 (1 .1-5,3) 3-7 years: 3.8

0.6-1.2 mg per day:

(1 .5-9.5)

8.8 (5.0-12.7)

1-2 years: 5.3

(2.6-10.8)

> 1.25 mg per day: current use: 8.7

7.6 (5.0-1 1.6) (6.4-1 1.8)

(2.8-24.5)

II
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen usea,b estrogen use a,b estrogena,b estrogen use a,b

Obrink (1981) Swedish study comparing use of

estrogens among 622 cases of

endometrial cancer treated at

Radiumhemmet (Stockholm)

between 1974 and 1977 with

estrogen use of the average female

population, represented by a

randomly selected sample of 1,866

age-matched controls. Progestin

treatment was rare among cases and

controls.

Spengler Cases were newly diagnosed with

(1981) endometrial cancer between April 1,

1977 and December 31, 1977, and

were residents of metropolitan

Toronto between 40 and 74 years of

age. Cases were identified from the

records of the pathology

departments of 21 Toronto hospitals.

Two age-matched controls were

selected from the same

neighborhood and type of dwelling

as their respective case.

Neighborhood controls were

obtained by door-to-door canvassing

which started at the fourth dwelling

to the right of the case’s residence

and proceeded sequentially around

the block or through the apartment

building. No control had history of

hysterectomy or cancer. Information

was gathered by questionnaire and

by review of hospital and clinic

records.

622 cases (19.27.

estrogen users);

1,866 controls

88 cases (45% Odds ratio 2.9

estrogen users), (1 .7-5,1)

177 controls (22% Odds ratio matched

estrogen users) 3.2 (p= 0.0001)

Relative risk

(adjusted for age,

obesity, age at

menopause,

nulliparity, and

educational level) 3.7

(1 .8-7.6)

Estrogen use was

defined as use 1 or

more months during

or after menopause.

6-36 months:

7.5% cases, 8.O%

controls (NS)

37-72 months:

1 0.3% cases, 2.2%

controls (p < 0.001)

More than 6 years of

treatment was

uncommon.

1-6 months: 1.4 Conjugated equine

(0.5-4.4) estrogens:

7-24 months: 2.6 <1 mg: 2.0 (0,9-4.6)

(1 .0-6,5) >1 mg: 4.0 (1 .9-8.4)

25-60 months: 2.2 total: 3.0 (1 .7-5.3)

(0.7-6.5)

>60 months: 8,6

(3.2-23.0)
144 I Cost Effectiveness of Screening for Osteoporosis
Relationship of

Relationship of endometrial cancer

Number of cases endometrial cancer to recency of

Author Description of cases and controls and controls to estrogen use a,b estrogen use a,b

Lawrence Cases were women ages 40 to 69

(1989) years from hospitals in upstate New

York who had been diagnosed as

having advanced-stage (stages 2-4)

endometrial cancer in 1979-1981.

Controls were selected from the files

of licensed drivers maintained by the

New York State Department of Motor

Vehicles. Two controls were selected

for each case, matched by county of

residence and age. Information on

HRT use was gathered through

structured interviews.

84 cases (27% < 1 year: The risk of advanced No significant No significant

estrogen users); odds ratio 0.84 (no endometrial cancer association was association was

168 controls (24% confidence interval) increased found between dose found with recency

estrogen users) 1-5 years: significantly (p < and risk of interval and risk of

odds ratio 1.47 0.05) with duration of endometrial cancer. endometrial cancer.

use of estrogen pills.

> 5 years: No significant

odds ratio 2.21 association was

found for any other

variables or for

interaction between

longer estrogen use

and dosage greater

than 0.625 mg,

continuous mode of

administration, or

recency interval (the

time interval from the

last use of estrogen

to diagnosis).

Despite a statistically

significant correlation

between duration of

estrogen use and

advanced-stage

endometrial cancer,

estrogen use actually

contributed little to

the risk of

advanced-stage

disease.

Odds ratio=1.01

(1.00-1.03).
Author Description of cases and controls

Rubin (1990) Results from Cancer and Steroid

Hormone (CASH) Study, a

multicenter study conducted in 8

areas of the United States (Atlanta,

GA; Detroit, Ml; San Francisco, CA;

SeattIe, WA; Connecticut, Iowa, New

Mexico, and Utah). Cases were

postmenopausal women 40 to 54

years of age who resided in one of

the eight areas and who had an

endometrial cancer diagnosed

between December 1, 1980 and

December 31, 1982. Controls were

women with an intact uterus,

matched for age and geographic

area to cases. Information on HRT

use was obtained through interview.

Relationship of

Number of cases endometrial cancer

and controls to estrogen use a,b

196 cases (24% 1.9 (1 .3-2.8) ever

estrogen users); user vs. never user

986 controls (14’%. Estrogen use was

estrogen users) defined as 3 months

consecutive use of

estrogen

replacement therapy.

Relationship of Relationship of

endometrial cancer endometrial cancer

to duration of to dose of

estrogen USe a,b estrogena’

b

<2 yrs.: 1,3 (0.7-2,4) <0.625 mg per day,

2-5 years. 2.1 1.2 (0,5-2.7)

>6 years, 3.5 > 1.25 mg per day,

3.8 (1 .7-8.5)

Relationship of

endometrial cancer

to recency of

estrogen use a,b

Time since last use <

2 years

all use. 1.9 (1 .2-3.2);

duration <2 yrs.. 1.4

(07-3.0);

duration >= 2 yrs., 2.4

(1 ,3-4.4)

Time since last use

2-5 years:

all use. 1.5 (0.8-3.1),

duration <2 yrs.: 1.1

(o 4-3.3);

duration >= 2 yrs.: 2.0

(0.8-4.9)

Time since last use >=

6 years.

all use. 2.7 (1.1 -6.4);

duration <2 yrs.: 1.4

(0.4-5.2);

duration >= 2 yrs., 5.4

0
Relationship of Relationship of Relationship of

Relationship of endometrial cancer endometrial cancer endometrial cancer

Number of cases endometrial cancer to duration of to dose of to recency of

Author Description of cases and controls and controls to estrogen usea,b estrogen use a,b estrogena,b estrogen use a,b

Voight (1 991 ) Cases were all women diagnosed

with endometrial cancer between

Jan. 1, 1985 and Dec. 31, 1987 who

were residents of King County,

Washington, and who were 40 to 64

years of age at diagnosis ; cancer

cases were identified through the

cancer surveillance system at the

Fred Hutchinson Cancer Research

Center. Controls were recruited by

random telephone digit dialing;

controls were nonhysterectomized

women who were residents of King

County. Information on HRT use was

gathered through interviews.

158 cases (38% HRT Estrogen alone:

users); O.R. 3.1 (1 ,6-5.8)

182 controls (27% Estrogen plus

HRT users) progesterone:

O.R. 1.3 (0.6-2.8)

Progestin use <10

days per month plus

estrogen: O.R. 2,0

(0.7-5.3)

Progestin use >= 10

days per month plus

estrogen: O.R. 0.9

(0.3-2.4)

a 95 percent confidence intervals are shown in parentheses

b Relationship is relative risk, unless stated otherwise.

KEY: NS = not statistically significant,

SOURCE: Office of Technology Assessment, 1995.

Estrogen only use 23

years:

5.7 (2.5-1 2.8)

Estrogen use >3

years plus any use

of progestin: 1.6

(0.6-3.9)

Estrogen 23 years

plus progestin <10

days per me,: 2.4

(0.6-9.3)

Estrogen 23 years

plus progestin >= 10

days per month:

1.1 (0.4-3.6)
Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Author Description of cohorts Size of cohort use and dose of HRTa,b and latency of HRT usea,b

Gambrell (1979) Participants were postmenopausal 8,170 patient-years (81% HRT

outpatients at Obstetrics and Gynecology use);

Clinic, Wilford Hall USAF Medical Center, 14 endometrial cancer cases

Texas. Duration of estrogen therapy

ranged from 2.5 to 12 years. Recruitment

between 1976-1977 was prospective,

1975 recruitment was retrospective.

Bush (1983) Participants were white women, aged 40 2,270 white women (593 users,

to 69 years at baseline, and followed for 1,677 nonusers)

an average of 5.5 years. All women in the

cohort were participants in the Lipid

Research Clinics Program Follow-up

Study, conducted in 10 North American

clinics, between 1972 and 1976. All

subjects were examined at initiation, and

were followed with clinic visits and review

of death certificates. Information on

descendants was gathered from medical

Endometrial cancer incidence (cases per

1,000 pt.-years).

Estrogen alone: 6.8/1 ,000

PERT, 0.5/1 ,000 (p <0.01 compared to

estrogen)

progestin alone: 0/1 ,000

no therapy: 2/1 ,000 (NS compared to

estrogen)

Endometrial cancer deaths.

Nonusers: 1 death from an unspecified

genitourinary cancer.

Users: 1 death from uterine cancer,

o

records and family members.
 

.. ._ . .

Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Author Description of cohorts Size of cohort use and dose of HRTa,b and Iatency of HRT usea,b

Lafferty (1985) Cohort members were postmenopausal

women 45 to 60 years old followed at a

single private practice in Cleveland, OH.

All treated patients received conjugated

equine estrogen 0.6 mg daily for three out

of four weeks. Study was carried out

between 1966 and 1981, and patients

were followed for an average of 8.6 years.

Patients were followed with physical

exams twice annually.

Gambrell (1986) Participants were post-menopausal

women seen at Wilford Hall USAF Medical

Center (Texas) using various hormone

regimens were compared to untreated

women. Three years of retrospective data

were gathered for 1972-74 from medical

and pharmacy records and tumor registry.

Women were recruited between 1975 and

1979, and followed until 1983. Information

on HRT use and risk factors gathered at

clinic visits.

61 estrogen-treated women, 63 One case of endometrial cancer occurred

untreated controls in untreated controls, and two in

estrogen-treated women. No endometrial

cancer deaths occurred in untreated

controls and two deaths in

estrogen-treated women. The difference in

rates of endometrial cancer deaths were

not statistically significant, but the

population was very small.

2,905 postmenopausal women NO use: 245.5 endometrial cancer cases

with 27,243 patient-years of per 100,000 patient-years.

observation between 1975 and Unopposed estrogen: 390.6 per 100,000

1983 (31 endometrial cancer (NS vs. no use)

cases).

Estrogen and progesterone:

49.0 per 100,000 (p <0,0001 vs.

unopposed estrogen users) (p =< 0.005

vs. no use)

Estrogen vaginal cream: 73.6 per 100,000

users (p <0,005 vs. unopposed

estrogen users),

None of the differences between the other

groups were statistically significant,

I
Relationship of

endometrial cancer to

Relationship of endometrial cancer to duration, recency, and

Author Description of cohorts Size of cohort use and dose of HRT a,b latency of HRT usea

’

b

Stampfer (1986) Subjects were members of the nationwide

Nurses Health Study cohort. Cohort

members were registered nurses ages 30

to 55 years old in 1976. Subjects of this

study were cohort members who were

free of cancer and had intact uteri.

Information on HRT use and risk factors

was gathered by questionnaire every two

years, and deaths were identified through

state vital statistics records. There was

114,896 person-years of follow-up among

postmenopausal women in cohort.

Petitti (1987) Subjects were participants in the Walnut

Creek (California) Contraceptive Drug

Study. Subjects were 18 to 54 at study

initiation, and were recruited between

December 1968 and 1972. All subjects

received a complete history and physical

at study entry. Through 1977, reformation

was gathered from clinic visits and mailed

questionnaires. From 1978 to 1983,

information was gathered from the

California Death Index and death

certificates. Oral contraceptive users were

96,356 women in cohort with

intact uterus who were free of

cancer at baseline (no

information on number of

postmenopausal), among

postmenopausal women in

cohort, there were 70 cases of

endometrial cancer in 114,896

years)

3,437 never users of estrogen,

2,656 ever users of estrogen

Current use of postmenopausal HRT: 4.4 Current use and duration of

(2,2-7.1); Among past HRT users, there use >5 years: 6.9 (3.6-13.2)

was an increased risk with increasing Current use and duration of

duration. use <1 year. 3.5 (1 .2-10 .8)

Endometrial cancer deaths.

nonusers: 1

users. 5

RR endometrial cancer death

2.6 (0.4-1 5.5)

excluded from this analysis. . .

II
Author Description of cohorts

Pagnini-Hill Subjects were non-hysterectomized

(1989) women, aged 44-100 years (73 median)

at baseline from the Leisure World

(California) Retirement Community,

Subjects were recruited from June 1981 to

January 1987. Of estrogen users, 99%

had used unopposed estrogen. Average

duration of follow-up was 4.6 years.

Information was gathered by periodic

questionnaires.

Relationship of endometrial cancer to

Size of cohort use and dose of HRTa,b

5,160 non-hysterectomized Risk ratio for endometrial cancer in users

women is 10 (p < 0,0001) compared with

nonusers, No effect of dose on risk was

found. The relationship between HRT use

and incidence of endometrial cancer is

reported in Henderson (1991)

(Henderson, 1991),

Relationship of

endometrial cancer to

duration, recency, and

latency of HRT usea,b

Recency (years since

cessation of estrogen),

O-1 years. 25 (9,2-69)

2-7 years: 12 (no confidence

interval)

8-14 years: 8.1 (non

confidence interval)

15+ years: 5,8 (2.0-1 7)

Duration of estrogen use,*

< 2 years: 5.2 (no confidence

interval)

3-7 years: 7.0 (no confidence

interval)

8-14 years: 4 (no confidence

interval)

15+ years: 20 (7,2-54)

*Paper also has table showing

interaction of duration and years since

cessation of therapy
Relationship of

endometrial cancer to

Relationship of endometrial cancer to duration, recency, and

Author Description of cohorts Size of cohort use and dose of HRPa,b latency of HRT usea,b

Henderson (1991) Participants were residents of a Southern 8,881 postmenopausal women Relative risk endometrial cancer death:

California retirement community (Leisure 3.0 (no confidence interval provided) in

World), were almost entirely white, ever users vs. never users of estrogen.

moderately affluent, and well educated. The relationship between use of HRT and

Subjects were recruited between June endometrial cancer incidence in this

1981 and January 1987. The resident’s cohort is described in Pagnini-Hill (1989)

median age at study initiation in 1981 was (Pagnini-Hill, 1989),

73 years. Information was gathered by

periodic questionnaires and review of

local county death certificates. Virtually all

HRT users took unopposed estrogen.

Reported here are the results of 7.5 years

a 95 percent confidence intervals are shown in parentheses

b Relationship is relative risk, unless stated otherwise.

KEY: NS = not statistically significant; O.E. ratio = observed to expected ratio; PERT = estrogen/progestin combination therapy

SOURCE: Office of Technology Assessment, 1995
Author Description of cohorts Size of cohort

Hammond (1979) Participants were diagnosed between

1940 and 1969 with diseases related to

estrogen deficiency and followed for at

least 5 years by the Duke University

Obstetrics and Gynecology Service

(Durham, NC). Expected rates of

endometrial cancer were obtained from

the Third National Center Survey for the

Atlanta (Southeastern United States) area;

95.5% Of estrogen users received

conjugated estrogens. Data on ERT use

was obtained from hospital and clinic

records.

Vakil (1983) Study examined the incidence of

endometrial cancer in a cohort of women,

32-62 years of age, receiving estrogen

treatment for menopausal symptoms

among the patients of 20 gynecologists in

the metropolitan Toronto area. Incidence

rates in the cohort were compared to two

control groups: the age-specific

endometrial cancer incidence rates of the

female populations of Ontario and of

Saskatchewan. Estrogen therapy was

begun between 1960 and 1970, and

subjects were followed for up to 17 years

301 “hypoestrogenic” patients

who received ERT;

309 hypoestrogenic patients

never receiving estrogen,

14 patients developed

endometrial cancer

1,483 postmenopausal women

Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

use and dose of HRPa,b and latency of HRT usea,b

O.E. ratio 9.3 (4.7-16.7) in white women

receiving estrogen: 1.1 (0.3-3.9) in white

women not receiving estrogen

All patients who developed

adenocarcinoma of the endometrium

during estrogen therapy had received this

compound for at least five years.

Relative risk of endometrial cancer in ever

users

1.3 (no confidence interval provided
Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Author Description of cohorts Size of cohort use and dose of HRFa,b and latency of HRT USe a,b

Hunt (1987) This is the same cohort as described in

Hunt (1990) (Hunt, 1990). Cohort

members were British women receiving

hormone replacement therapy recruited at

21 menopause clinics. Subjects were

recruited prospectively between 1978 and

1982, and retrospectively before 1978;

nearly equal proportions were recruited

retrospectively and prospectively. Most

cohort members were aged 45-54 years

at recruitment. Thirty-six percent of cohort

had undergone hysterectomy, 2-2.5 times

the proportion in the British population.

Mean duration of follow-up was 67

months. Cancer registry rates for England

and Wales were used for determining

4,544 British women receiving O.E. ratio of endometrial cancer is 2.84

HRT (43% PERT users) (1 ,46-4.96) for current users of at least 1

year duration compared with expected

incidence. No deaths from endometrial

cancer occurred in the cohort. The

relationship of HRT use to endometrial

cancer death are reported in Hunt (1990),

below.

Latency (time since first use):

O-4 years. O.E. ratio 2.11

(0.57-5.39)

5-9 years. 3.03 (1.1 1-6.60)

10+ years, 5,71 (0.64-20.63)

There was evidence of a

rising trend in O.E. ratio with

interval since first use,

although the trend does not

reach statistical significance.

expected incidence.

II
Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Author Description of cohorts Size of cohort use and dose of HRTa,b and latency of HRT usea,b

Ettinger (1 988) Subjects were female members of Kaiser 181 estrogen users, 220 Risk ratio for endometrial cancer is 7.7

Foundation Health Plan, San Francisco, nonusers controls (2.4-24.5) for users compared with

CA, all who had filled at least 2 nonusers.

prescriptions for an oral estrogen Endocarconima developed in 9.9% of

preparation and were aged at least 53 users compared with 1.4% of nonusers.

years in 1986. Estrogen users were

menopausal women whose estrogen

therapy was begun within three years of

menopause and was used regularly for at

least 5 years. Nonuser controls were

women who had undergone spontaneous

(nonsurgical) menopause, were identified

from pharmacy records of health plan and

were matched for age and length of

membership in health plan. Mean age for

estrogen users was 67 years, mean age

of nonusers was 68.8 years. Clinical

material was obtained from 1965 to 1980.
Author Description of cohorts

Persson (1989) Cohort members were women age 35

years or older who had been prescribed

estrogens for the treatment of menopausal

problems in the Uppsala health care

region of Sweden during April 1977 to

March 1980, identified through

prescription records. Compliance,

sociodemographic data, and lifetime

exposures to estrogen and progesterone

were assessed by a mailed questionnaire

to 735 randomly selected members of the

cohort. In addition, characteristics of all

women with endometrial cancer were

assessed by questionnaires. Cases of

endometrial cancer were identified from a

cancer registry and medical records.

Expected outcome in the cohort was

determined from age-specific incidence

rates of endometrial cancer in the region

in the same years. Pathologic specimens

from all endometrial cancers and

pre-malignant lesions in the cohort and

the background population were

reviewed. Average observation period

Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Size of cohort use and dose of HRT a,b and latency of HRT use a,b

23,233 women on estrogens All HRT users: Duration of estrogen use:

(133,373 person-years); 74 1.4 (0.4-2.1) estrogen alone.

cases of endometrial cancer estrogen alone. 1.4 (1.1 -1 .9) <6 mos.: 1.1 (0.5-2,5)

and 33 pre-malignant lesions estrogen and progestin: 0.9 (0.4-2.0) 7-36 mos.: 1.4 (0,8-2.4)

37-72 mos.: 1.2 (0.6-2.2)

>73 mos., 1,8 (1,1 -3.2)

estrogen and progestin:

<6 mos.: O (0,0-1 2.7)

7-36 mos.: 1.4 (0.5-3.6)

37-72 mos.: 1.2 (0.3-5.5)

>73 mos.: O (0,0-456.1)

Endometrial cancer and

pre-malignant lesions

estrogen alone.

<6 mos.: 0,9 (0,4-2,1)

7-36 mos.: 1.6 (1 .0-2.5)

37-72 mos.: 1.6 (1 .0-2.6)

>73 mos.: 2,7 (1 ,8-4,2)

estrogen and progestin:

<6 mos.: 0,9 (0.2-4.3)

7-36 mos.: 1.6 (0.7-3.5)

37-72 mos.: 0.9 (0.2-4.1)

>73 mos.: O (0.0-211 8)

o
Relationship of endometrial

Relationship of endometrial cancer to cancer to duration, recency,

Author Description of cohorts Size of cohort use and dose of HRTa,b and Iatency of HRT usea,b

Hunt (1990) This is the same cohort as described in 4,544 long term users of HRT Observed endometrial cancer deaths. O

Hunt (1987) (Hunt, 1987). Subjects were (43% PERT users) expected endometrial cancer deaths:

women recruited from 21 menopause 2,70 (taking into account uterine status)

clinics around Britain; all had received at

least 1 year continuous treatment with O/E ratio: 0.00 (0.00-0.97)

hormonal replacement therapy before The previous report, Hunt (1987),

recruitment, All subjects were interviewed however, noted an elevated risk of

at recruitment. Most subjects were age 45 incident endometrial cancer (see above)

to 54 at first use of HRT. Mean duration of

HRT use was 66.9 months; 59& were

current estrogen users. The observed

mortality was compared to the expected

rates in the female population of England

and Wales.

a 95 percent confidence intervals are shown in parentheses.

b Relationship is relative risk, unless stated otherwise

KEY: NS = not statistically significant; O.E. ratio = observed to expected ratio; PERT =

SOURCE” Office of Technology Assessment, 1995

estrogen/progestin combination therapy,
T

here are several theoretical reasons to expect a causal link between estrogens and

gallbladder disease. In particular, estrogens increase the risk of gallstone formation. Gallstones form in the gallbladder, a

muscular sac in the abdomen that stores and releases bile, a substance that aids in fat digestion.

Gallstones are solidified bile. Bile is highly saturated with cholesterol, and it is thought that estrogen raises the concentration of cholesterol in bile,

increasing the risk of stone formation (2). Thus,

one would expect an increased prevalence of gallstones and symptomatic gallbladder disease in estrogen users (1 1).l

Tables H-1 to H-4 summarize the clinical studies evaluating the relationship between gallbladAppendix H:

Evidence on

HRT and

Gallbladder

Disease H

der disease and HRT. A small number of studies

have shown that the incidence of symptomatic

gallbladder disease increases approximately twofold in current users of oral estrogen replacement

therapy. The first report of an association came

from a case-control study conducted in the

mid- 1970s by the Boston Collaborative Drug Surveillance Program, which showed an increased incidence of surgically confirmed gallbladder

disease in current users of either oral contraceptive or oral estrogen replacement therapy (3).2

One of the two prospective cohort studies of estrogen replacement therapy and gallbladder disease found that women who were current or past

users of noncontraceptive estrogen had an age-adjusted relative risk of symptomatic gallstone dis-

] It is not known whether estrogens not taken by mouth would also increase the risk of gallstones. Some argue that estrogen taken by skin

patch or injection would not increase the risk of gallstone formation because estrogen taken by nonoral routes does not pass directly from the

intestine to the liver. By avoiding the first-pass effect on liver metabolism, nonoral routes of estrogen administration may reduce this increased

risk. A study by D’Amato and colleagues compared the effect of 17-beta estradiol given by skin patch and estradiol valerate given by mouth on

bile lipid levels in a postmenopausal woman (4). While both therapies increased the cholesterol level in the bile, only oral estrogen induced the

formation of cholesterol crystals.

2 The Boston Collaborative Drug Surveillance Program study was criticized for using hospitalized controls, one half of whom were being

treated for fracture or some other orthopedic problem. One commentator has argued that, since women with osteoporosis are less likely to be

taking estrogen replacement therapy, this design could have led to a spuriously low rate of estrogen use in the comparison group, compared with

usual use in the cases, and thereby a falsely elevated relative risk (1).

 159
Number of cases

Author Description of cases and controls and controls Resultsa

152 cases, Relative risk 2,5 (1 .5-4,2), there was “no

774 controls evidence of a relation with duration of use in

postmenopausal estrogen users. ”

Boston Collaborative Drug Cases were postmenopausal women 45 to 69 years old —

Surveillance Program with a diagnosis of “cholelithiasis” or “cholecystitis”

(1974) and subsequent cholecystectomy, who were

admitted to general medical and surgical wards of 24

hospitals in the Greater Boston area between

January and November 1972. Patients with diseases

that might either contraindicate estrogen therapy or

be related to their use were excluded. Controls were

hospital patients without a diagnosis of gallbladder

disease, venous thromboembolism, or breast tumors,

Honore (1980)

Scragg (1984)

Kakar (1988)

Cases were 262 perimenopausal women (ages 41 to 60

years) with symptomatic gallbladder disease treated

by cholecystectomy from 1975 to 1978 at a hospital

in Newfoundland, Canada, and diagnosed

pathologically as having cholesterol gallstones. A

control group, matched for age, consisted of women

treated surgically for diseases that have no known

association with estrogen replacement therapy.

Information on HRT use was obtained from a review

of medical records.

Cases were patients in 2 public hospitals in Adelaide,

Australia with gallstone disease diagnosed by

ultrasound or cholecystectomy between December

1978 and September 1980, Two control groups were

used for comparison. Hospital controls were women

who were hospitalized and had negative

cholecystograms. Community controls were women

from the community, matched to cases for age and

area of residence.

Subjects were women ages 41 to 74 enrolled in a

prepaid health plan in western Washington’s Group

Health Cooperative of Puget Sound Cases were

women who underwent gallstone surgery between

January 1979 and September 1988. Controls were

matched for sex, age, and residence with cases.

262 cases;

290 controls

Relative risk 3.72 (p < 0.005). There was a

significantly greater incidence of gallbladder

disease in obese HRT users than in nonobese

HRT users (p < 0.05),

200 cases, Mean duration of estrogen use was not

234 hospital controls, substantially different between cases and both

82 community control groups

controls

102 cases,

98 controls

Relative risk 1 18 (0,65-2,13) for users of 1 year

or more vs nonusers, Standardization for the

effects of age, race, obesity, parity, thiazide

use, and diagnosis of high blood pressure did

not alter appreciably the estimate of relative

risk.

o

II
Number of cases

Author Description of cases and controls and controls Resultsa

LaVecchia(1992) Subjects were women admitted to one of four hospitals

in Milan, Italy between 1987 and 1990. Cases were

women, ages 23 to 74 (median age 54), who

underwent cholecystectomy, and were discharged

with the diagnosis of cholelithiasis or cholecystitis.

Controls were women, ages 21 to 74 (median age

54), admitted for acute diseases other than digestive

or hormonal diseases or those potentially influencing

the use of female hormone preparations.

235 cases; Users of any duration:

583 controls unadjusted relative risk: 1.7 (0.9-3,1)

adjusted relative riskb

: 1.9 (1 ,0-3.6)

Use less than 2 years:

unadjusted relative risk: 1.7 (0.8-3.6)

adjusted relative riskb

: 1.8 (0.9-4,2)

Use 2 or more years:

unadjusted relative risk: 1.3 (0.5-3.8)

adjusted relative riskb

: 1.5 (0,5-4.5)

Less than 10 years since last use:

unadjusted relative risk: 1.1 (0.5-2.7)

adjusted relative riskb

: 1.3 (0.5-3,3)

Last use 10 or more years ago:

unadjusted relative risk: 2.3 (1 ,0-5.3)

adjusted relative riskb

: 2.4 (1 ,0-5.1)

a The results are followed by 95% confidence intervals in parenthesis.

b Relative risk was adjusted for age, education, area of residence, body mass index, parity, and age at menopause.

SOURCE: Office of Technology Assessment, 1995.

x
Number of

Author Description of study participants participants Resultsa

Diehl (1980) Subjects were obtained from a review of a sample of

medical records from patients enrolled in the Family

Health Center of the University of Texas Health

Sciences Center at San Antonio. Gallbladder disease

was defined as history of cholecystectomy,

gallbladder surgery, or abnormal cholecystogram.

Petitti (1981)

Pixley (1 985)

Subjects were adult female twins who volunteered to

undergo a health examination for a study. Subjects

were considered to have gallbladder disease if they

answered “yes” to the question, “Has a doctor ever

told you that you have had gallstones or gallbladder

trouble?”

Subjects were women aged 40 to 69 registered at two

Oxford, England general practices. All subjects were

screened with ultrasound for gallstones. Gallbladder

disease was defined as cholelithiasis on ultrasound

cholecystectomy.

Jorgensen (1988) Subjects were a random sample of women from

Copenhagen county, Denmark, ages 30, 40, 50, and

60 years, drawn in 1982 from the National Person

Register. Subjects were examined and/or interviewed

by telephone or mailed questionnaire. Examined

patients received ultrasonography to identify current

gallstone disease.

1,018 records

868 female twins

632 women recruited from

general practice registers

and 130 vegetarians.

2,301 women

“No trends in the prevalence of gallbladder

disease were seen in relationship to use of

conjugated estrogens. Our failure to

find associations with estrogen-containing

drugs may be related to our inability to

quantitate their cumulative use in our study

population. ”

Relative risk 2.0 (1 .1-3.6) for history of

physician-diagnosed gallbladder disease in

estrogen users versus nonusers.

Study concludes “no association [of gallstones]

was found with parity or use of exogenous

estrogens. ” No further information or statistical

analyses was provided on this issue.

Odds ratio 1.02 (0.25-4.26) for current or past

gallbladder disease in estrogen users versus

nonusers. Odds ratio 1.86 (0.89-3.86) for

estrogen users of 8 or fewer years versus

users of more than 8 years.

o

a The results are followed by 95% confidence Intervals in Parentheses unless otherwise specified

SOURCE: Office of Technology Assessment, 1995

II
Author Description of study participants

Petitti (1 988) Subjects were women 18 to 54 years old at time of entry into the

Walnut Creek (California) Contraceptive Drug Study cohort between

December 1968 and February 1972. Women who ever used oral

contraceptives were excluded from this analysis. Women with a

previous cholecystectomy were also excluded from this analysis.

Results of 10 to 13 year followup are presented. Patients were

examined at initiation of study and followed by examination,

questionnaire and/or reexamination. Cases were women who

underwent cholecystectomy for cholelithiasis or cholecystitis.

Grodstein (1 993) Subjects were postmenopausal U.S. registered nurses who were

enrolled in the Nurses Health Study. Information on postmenopausal

estrogen use and cholecystectomy was gathered by mailed

questionnaires every two years. Duration of follow-up was 8 years.

a The results are followed by 950/o confidence Intervals in parenthesis

Size of cohort Resultsa

16,638 women All ever users:

unadjusted relative risk 2.4 (1 .7-3.2) age-adjusted

relative risk 2.1 (1 .5-3.0)

past usersb:

unadjusted relative risk 1.8 (1.1 -2.9)

age-adjusted relative risk 1.6 (1.1 -2.5)

current users:

unadjusted relative risk 3.1 (2.2-4.9)

age-adjusted relative risk 2.7 (1 .8-4.0)

There was no evidence of a relationship of incidence

of cholecystectomy with duration of estrogen use.

54,845 postmenopausal Current users:

women risk-factor adjusted relative risk 2.1 (1.9-2.4)

Current users of 10 years or more.

risk-factor adjusted relative risk 2.6 (2.2-3.1 )

Current users of 1.25 mg CEE per day or more:

risk-factor adjusted relative risk 2.4 (2.0-2.9)

Past users of less than 2 years duration.

relative risk 1.4 adjusted for recency of use

Past users of 10 or more years:

relative risk 1,7 adjusted for recency of use

Most recent use 1 to 2.9 years ago.

risk-factor adjusted relative risk 1.6 (1.2 to 2.0)

Most recent use 5 or more years ago.

risk-factor adjusted relative risk 1.3 (1.1 to 1.6)

b Author notes that "We reviewed the medical records at the 39 past estrogen users who had cholecystectomies after 1977 and discovered that 12 Of them had reinitiated estrogen use after 1977 and

before their hospitalization for gallbladder disease When those 12 women were removed from the cases that had been considered past users, the age-adjusted relative risk of gallbladder disease in

past users decreased to 1.1 (95% confidence interval 0.7-1.8) When these 12 women were added to the current users, this relative risk estimate for current use increased to3 9 (95% confidence interval

2,6-5 .9. As study subjects who never experienced cholecystectomy and who initiated estrogen use after followup could not be relocated, these risk estimates where biased downward for past estrogen

use and upward for current estrogen use “

KEY: CEE = conjugated equine estrogen

SOURCE Office of Technology Assessment, 1995
164 Cost Effectiveness of Screening for Osteoporosis

Duration of

Author Description of study participants study Results —

Nachtigall Subjects were 84 pairs of postmenopausal 10 years Incidence of cholelithiasisa in treatment

(1979) inpatients at Goldwater Memorial Hospital in group: 4/84 (0.48%)

New York City, a hospital for chronic Incidence of cholelithiasis control group

diseases, matched for age and diagnosis. 2/84 (0.24%)

Treatment group received 2.5 mg CEE daily

with 10 mg medroxyprogesterone acetate for P>=0.05 (nonsignificant)b

7 days each month. Control group received

placebos.

a Author did not define “cholelithiasis. ”

b Author notes "These findings, however, should be interpreted with Caution Since the power of the test differences was generally low due tO the

small sample size. ”

SOURCE: Off Ice of Technology Assessment, 1995

ease of approximately 2.1, while current users had

a relative risk of 2.7 (16) (table H-3). The other cohort study found, after adjusting for confounding

factors, a relative risk of cholecystectomy of 2.6

in long-term current estrogen users. The only controlled clinical trial of estrogen use and gallbladder disease found doubled the incidence of

gallbladder disease in HRT users (12) (table H-4).

This difference did not reach statistical significance, which may be due to the small number of

women who participated in this study.

Some studies of symptomatic gallstone disease, however, have found no effect of estrogen

use on gallbladder disease (9). The differences

among studies may be due to differences in the

doses of estrogens used by participants, the average duration of use of estrogen, or the small numbers of persons involved in these studies (14).

These studies also were either case-control studies

or cross-sectional studies, which may have biased

their outcomes.

Although the strongest evidence, including the

prospective cohort studies of the issue, points to

an elevated risk of symptomatic gallstone disease

among current users, it is less certain whether the

risk of symptomatic gallstone disease remains elevated in those who have ceased estrogen therapy.

The studies to date have not found a statistically

significant relationship between past use and gallstone disease.

Although empirical studies have found an

increase in symptomatic episodes, hospitalization, and gallbladder removal (cholecystectomy)

among current estrogen users, they have failed to

detect an increased prevalence of gallstones

among estrogen users using imaging techniques

capable of detecting silent gallstones (6,11,17).

The failure to find increased incidence of asymptomatic gallstones raises the possibility that the

studies examining symptomatic disease may be

subject to surveillance biases (i.e., estrogentreated women are seen more frequently by their

doctors and are therefore more likely to be diagnosed and undergo surgery) (l).

Studies have not been able to consistently demonstrate an increased risk of gallbladder disease

with increased duration of use of estrogen replacement therapy (3, 16, 16a). Results from the Nurses

Health Study cohort demonstrated an increased

risk with duration of use in current users, but little

or no effect of duration in past users (16a) (table

H-3).

The results from the Nurses Health Study also

showed an increased risk with larger doses of estrogen (16a). This result is consistent with an earlier cohort study of oral contraceptive users that

found an increase in risk with increasing dose

(19).

The addition of progestins is unlikely to mitigate estrogen-induced increases in gallbladder
Appendix H Evidence on HRT and Gallbladder Disease 165

disease, since progestins also promote gallstone

formation (11).

On the basis of the studies outlined in tables

H-l to H-4, including the cohort studies of this issue(16), 0TA adopted a base case assumption that

the risk of symptomatic gallbladder disease would

be elevated by a factor of 2.5 while a woman is on

HRT. The risk would subside to that of the general

population of women at the time that HRT ceases.

We believe that the possible values of the relative

risk of symptomatic gallbladder disease due to

current HRT range from 1.0 (best case) to 3.0

(worst case).

The definitive treatment for gallbladder disease

is cholecystectomy, a standard surgical procedure

that is rarely fatal (13). For this analysis, we have

assumed that gallbladder disease results in health

care costs for surgical removal of the gallbladder

and hospitalization. We have assumed, however,

that gallbladder disease does not affect the years

of life lived.

OTA’s sensitivity analysis shows that our assumptions about the risk of gallbladder disease in

HRT users does not affect the outcome of the analysis greatly, since gallbladder disease affects

health care costs but not years of life lived.

REFERENCES

1. Barrett-Connor, E., “Putative Complications

of Estrogen Replacement Therapy: Hypertension, Diabetes, Thrombophlebitis, and Gallstones,” The Menopause. Biological and

Clinical Consequences of Ovarian Failure:

Evolution and Management, S. Korenman

(cd.) (Norwell, MA: Serono Symposia, USA,

1990).

2. Bennion, L., Ginsberg, R., Garnick, M., et al.,

“Effects of Oral Contraceptives on the Gallbladder of Normal Women,” New England

Journal of Medicine 294(4): 189-192, 1976.

3. Boston Collaborative Drug Surveillance Program, “Surgically Confirmed Gallbladder

Disease, Venous Thromboembolism, and

Breast Tumors in Relation to Postmenopausal

Estrogen Therapy,” New England Journal of

Medicine 290(1):15-19, 1974.

4. D’Amato, G., Cavallini, A., Mesa, C., et al.,

“Serum and Bile Lipid Levels in a Postmenopausal Woman After Percutaneous and Oral

Natural Estrogens,” American Journal of Obstetrics and Gynecology 160:600-601, 1989.

5. Diehl, A.K., Stern, M. P., Ostrower, V. S., et

al., “Prevalence of Clinical Gallbladder Disease in Mexican-American, Anglo, and Black

Women,” Southern Medical Journal

73(4):438-443, 1980.

6. Everson, R., Byar, D., and Bischoff, A., “Estrogen Predisposes to Cholecystectomy but

not to Stones,” Gastroenterology 82(1):4-8,

1982.

6a. Grodstein, F., Colditz, G. A., Stampfer, M. J.,

“Prospective Hormone Use and Cholecystectomy in a Large Prospective Study,” Obstetrics and Gynecology 83(1):5-11, 1993.

7. Honore, L. H., ’’Increased Incidence of Symptomatic Cholesterol Cholelithiasis in Perimenopausal Women Receiving Estrogen

Replacement Therapy: A Retrospective

Study,” Journal of Reproductive Medicine

25(4):187-190, 1980.

8. Jorgenson, T., “Gall Stones in a Danish Population: Fertility Period, Pregnancies, and Exogenous Female Sex Hormones,” G u t

29:433-439, 1988.

9. Kakar, F., Weiss, N., and Strite, S., “NonContraceptive Estrogen Use and the Risk of

Gallstone Disease in Women,” American

Journal of Public Health 78(5):564-566,

1988.

10. La Vecchia, C., Negri, E., D’Avanzo, B., et

al., “Oral Contraceptives and Non-Contraceptive Oestrogens in the Risk of Gallstone

Disease Requiring Surgery,” Journal of Epidemiology and Community Health

46(3):234-236, 1992.

11. Mack, T., and Ross, R., “A Current Perception of HRT Risks and Benefits,” Osteoporosis: Physiological Basis, Assessment, and

Treatment, H.F. DeLuca and R. Mazess (eds.)

(New York, NY: Elsevier Science Publishing

Co., Inc., 1990).
166 Cost Effectiveness of Screening for Osteoporosis

12. Nachtigall, L.E., Nachtigall, R. H., Nachtigall, R. D., et al., “Estrogen Replacement

Therapy II: A Prospective Study in the Relationship to Carcinoma and Cardiovascular

and Metabolic Problems,” Obstetrics & Gynecology 54(1):74-79, 1979.

13. Nahrwold, D.L., “Acute Cholecystitis,” Textbook of Surgery: The Biological Basis of

Modern Surgical Practice, 14th Ed., D.C. Sabiston, Jr., (cd.) (Philadelphia, PA: W.B.

Saunders Co., 1991).

14. Petitti, D., “Gallbladder Disease and Use of

Noncontraceptive Estrogens,” Geriatric

Medicine Today 9(3):56-63, 1990.

15. Petitti, D. B., Friedman, G.D., and Klatsky,

A. L., “Association of a History of Gallbladder Disease with a Reduced Concentration of

High-Density-Lipoprotein Cholesterol,” New

England Journal of Medicine 304(23):

1396-1398, 1981.

16. Petitti, D., Sidney, S., and Perlman, J., “Increased Risk of Cholecystectomy in Users of

Supplemental Estrogen,” Gastroenterology

94:91-95, 1988.

17. Pixley, F., Wilson, D., McPherson, K., et al.,

“Effect of Vegetarianism on Development of

Gall Stones in Women,” British Medical

Journal 291:11-12, 1985.

18. Scragg, R. K., McMichael, A.J., and Seamark, R. F., “Oral Contraceptives, Pregnancy,

and Endogenous Oestrogen in Gall Stone Disease - A Case-Control Study,” British Medical Journal 288: 1795-1799, 1984.

19. Strom, B., Tamragouri, R., Morse, M., et al.,

“Oral Contraceptives and Other Risk Factors

for Gallbladder Disease,” Clinical Pharmacology and Therapy 39:335-341, 1986.
Appendix I:

Evidence on

HRT and

c

oronary heart disease (CHD) is the leading

cause of death among U.S. women, surpassing the rates from cancer and other

diseases (13). Any change in the risk of

CHD due to hormone replacement therapy (HRT)

would profoundly alter the risk-benefit equation

of HRT.

Prior to menopause, women have a lower incidence of CHD than men. The Framingham study

showed that men had three times the incidence of

heart disease of age-matched premenopausal

women (50). Women within the first few years after natural menopause have no substantial increased risk of heart disease over premenopausal

women (21). However, by age 70, the incidence

of CHD is approximately the same in women and

men. Moreover, after surgical or premature menopause women develop a substantially increased

risk of CHD at an earlier age than women who undergo natural menopause at a later age (89).

HOW ESTROGEN MAY AFFECT CHD

One mechanism for a possible beneficial effect of

estrogen against CHD is the ability of estrogen to

favorably alter lipoprotein levels. Estrogen use

has been shown to increase the level of high density lipoprotein cholesterol (HDL) (8,16,23,53,57,

75,101). Studies have demonstrated that serum

concentrations of HDL are inversely related to the

Coronary

Heart Disease I

development of CHD (57,75). Estrogens also

lower the serum concentration of low density lipoprotein cholesterol (LDL), and LDL levels are directly related to the development of coronary heart

disease (8,15,16,23,46,53,57,86,).

The Lipid Research Clinics Follow-up study

showed that women using conjugated equine estrogens at the usual doses indicated for postmenopausal women had HDL levels 16.8 percent

higher than women not taking estrogens (15). Estrogen users also had LDL levels approximately 7

percent lower than those of nonusers. Coronary

heart disease deaths were reduced by 65 percent in

estrogen users compared with nonusers. The investigators concluded that this benefit was substantially mediated by the increase in HDL levels.

Recent research has demonstrated that elevations of HDL and decreases in LDL may also occur with percutaneous and subdermal estrogen

administration (46,105). However, there is evidence that transdermal estrogens do not produce

the same degree of favorable alterations of lipoprotein cholesterol levels as oral estrogens (10,

20,1 15). Oral estrogen has a much greater lipid effect (increasing HDL, decreasing LDL) than a

comparable transdermal dosage, perhaps because

of higher concentrations of estrogen in the portal

circulation of the liver with oral therapy.

1167
168 Cost Effectiveness of Screening for Osteoporosis

The cardioprotective effect of hormone replacement therapy may also be mediated through

lowering lipoprotein(a), an independent risk factor for heart disease in postmenopausal women

(69,95,100).

There is evidence that estrogen protects the

heart by reversing other changes in metabolism

that occur at menopause ( 106). Estrogen has been

found to reverse the unfavorable effects of menopause on glucose and insulin metabolism (69,74).

Central obesity is linked to heart disease risk, and

estrogen may reverse the changes in body fat distribution that results from loss of estrogen production at menopause (106).

Estrogen may also exert its heart protective effects by favorably altering the balance between

coagulation and fibrinolysis (18,82,97), by inhibiting platelet function (5), or by relaxing arterial

walls (58,124).1 Estrogen increases production of

prostacyclin, a prostoglandin in the arterial wall

(82) that reduces platelet aggregation (70) and

causes dilatation of the blood vessels (124). In

coronary artery occlusion, the release of thromboxane may induce the aggregation of platelets

and reduce blood flow. Prostacyclin counteracts

the effect of thromboxane by reducing platelet aggregation and increasing blood flow, and in this

way may reduce the risk of coronary artery occlusion.

Estrogen may also protect the heart by favorably altering cardiovascular hemodynamics. Receptors for estrogen have been found on arterial

walls (52,68), and estrogen may directly relax the

arteries throughout the body (22,25,58). By reducing the resistance to blood flow through the arteries, the work load on the heart is reduced (22).

By reducing the workload of the heart, its oxygen

needs are reduced. Thus, there is less likelihood

that the oxygen requirements of the heart will exceed the oxygen that is available from blood flowing through partially occluded coronary arteries

(87).

Rosano demonstrated in a clinical trial the immediate effect that estrogens have on heart disease

(87). The investigators studied the acute effect of

sublingual estradiol on exercise tolerance and

angina in 11 women with coronary artery disease.

The women did two exercise treadmill tests

(EKG) on two separate days. Forty minutes before

each test, they took sublingual estradiol or placebo, in random order. Six patients developed exertional angina and EKG changes after administration of sublingual estradiol, whereas all 11

developed angina and EKG changes on placebo.

The authors posited that this immediate beneficial

effect of estrogens maybe due to a direct coronary

artery relaxant effect of estrogen, dilation of peripheral arteries and arterioles, or to a combination

of these mechanisms.

EVIDENCE ON ERT AND CHD

All but four of the more than 30 studies that have

evaluated the effect of estrogen replacement therapy (ERT) on coronary heart disease (CHD) have

shown a reduced risk in estrogen users. The following is a discussion of the evidence on the relationship between ERT and cardiovascular disease

risk. Coronary evidence falls into five categories

based on methods and data sources:

■ hospital-based case-control studies,

■ population-based case-control studies,

■ prospective cohort studies,

■ cross-sectional studies, and

■ randomized clinical trials.

Each is discussed in turn.

❚ Hospital-Based Case-Control Studies

The earliest studies examining the risk of coronary heart disease in noncontraceptive estrogen

users used as “cases” individuals hospitalized for

myocardial infarction (heart attack) over a specified time period. “Controls” were a comparison

group of patients with other diagnoses from the

1 For recent reviews of the potentially important nonlipoprotein-mediated mechanisms of reduction in coronary heart disease risk, see K.F.

Ganger, B.A. Reid, D. Crook, et al., 1993; M. Riedel, W. Raffenbeul, and P. Lichtlen, 1993; J.C. Stevenson, D. Crook, I.F. Godsland, et al., 1994;

M.J. Tikkanen, 1993.
Appendix I Evidence on HRT and Coronary Heart Disease 169

same hospitals as the cases. The researchers then

determined which women in each group had or

had not had ERT in the past through interviews

with the women, medical records, and other

sources.

Five hospital-based case-control studies have

examined ERT among patients hospitalized for

myocardial infarction. (See table I-1.) Of these,

one showed an increased risk of coronary heart

disease among estrogen users (48), two showed

virtually no change in risk (88,91), and two

showed a decreased risk of CHD that was not statistically significant.2

A well recognized problem with case-control

studies is that the ascertainment of exposure to the

agent in question (e.g., estrogen) often depends on

the recall of the study participants. Because cases

may differ from controls in the accuracy of recall

of exposure, a biased estimate of risk can occur.

A second problem particular to hospital-based

case-control studies is that a control group composed of hospitalized patients is not likely to be

representative of the general population from

which the cases were drawn with regard to exposure to estrogen. In the context of ERT, the results

of hospital-based case-control studies are difficult

to interpret because many diseases are related in

some way to estrogen use. For example, some

members of the control group may have been hospitalized because of fracture, and women with

fracture are less likely to have used estrogen.

Even selecting controls from patients with diseases unrelated to estrogen use is problematical,

because some physicians may be less willing to

prescribe ERT to patients who are already burdened with other medications (103). The net effect

of this last bias would be to underestimate the impact of estrogen on heart disease risks.

The first case-control study that did not detect a

lower risk of CHD in estrogen users was of hospitalized patients aged 40 to 75 enrolled in the

Boston Collaborative Drug Surveillance Program. The relative risk of nonfatal myocardial infarction (MI) in estrogen users was 0.47, but the

relative risk was not significantly different from

one after statistical adjustment for differences in

heart disease risk factors between the two groups

(88). Also, heart disease risk is thought to be more

markedly reduced among those who are currently

using estrogen (“current users”) compared with

those that have used estrogens in the past (14), and

only eight of the 336 cases in the study (2 percent)

were “current users” of estrogens.

The second study finding no decreased risk was

of women aged 30 to 49 years old admitted to hospital coronary care units (91). The adjusted relative risk was near one both in patients who had

ever used estrogen (“ever users”) and in “current

users.” The results of this study may not be generalizable to all postmenopausal women because

it was conducted among women under 50 years of

age. Because of their young age, these women had

infrequent use of ERT and were at minimal risk of

coronary heart disease. Moreover, a substantial

proportion of controls in this study were fracture

patients (13,103).

Jick and colleagues reported the highest relative risk of coronary heart disease in estrogen users among all studies (48). They reported a

relative risk of first nonfatal MI of 7.5 (95 percent

confidence intervals 2.4 to 24) among estrogen users under 46 years of age and a relative risk of 4.2

(95 percent confidence intervals 1.0-18.8) among

postmenopausal estrogen users. This study had a

small number of cases and a large loss of study

participants over time. Sixteen of the 17 cases (94

2 The change in risk of disease in these studies is expressed either as a relative risk or as an odds ratio (42,94). The odds ratio is obtained from

the exposure ratio in the cases divided by the exposure ratio in the controls. To determine the odds ratio in a hospital-based case-control study of

myocardial infarction and estrogen use, one would calculate the ratio of estrogen users to nonusers among myocardial infarction patients (cases)

and divide that by the ratio of estrogen users to nonusers in the comparison patients hospitalized with other diagnoses (controls). Results of a

case-control study can also be expressed as a relative risk, which is the rate with which the disease occurs in exposed people divided by the rate of

the disease’s occurrence in unexposed people. If these two rates of occurrence are very small and if no distortions have occurred in the four

groups that make up the case-control study, the odds ratio will be approximately equal to the risk ratio.
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa,b

Rosenberg (1976) Cases were two sets of patients hospitalized Cases (set 1: 163; set 2: 173)

for myocardial infarction in the Boston (2.4% conjugated estrogen

Collaborative Drug Study. First set of cases users); controls (set 1: 2,536;

was from 21 hospitals in the United States, set 2: 4,194)

Great Britain, Canada, Germany, New

Zealand, Italy, and Israel, admitted since

1969, Second set was from general medical

and surgical wards of 24 Boston hospitals in

1972. Study subjects were ages 40 to 75

years; average age 54 years. Controls were

patients from same hospital admitted for

neoplasm, gallbladder disease, and breast or

reproductive organ disease. Data were

obtained from interviews and hospital

records. Current use was defined as use

during the month prior to hospitalization.

Jick (1 978a) Cases were women ages 39 to 45 years of 17 cases (53% estrogen users);

age discharged within the first 6 months of 34 controls (12% estrogen

1975 with a diagnosis of AMI. Cases were users)

identified from a national hospital discharge

database. Controls were drawn from the

national hospital discharge database, were

about the same age as cases, were

hospitalized for acute illnesses (other than

Ml) or elective surgery, and were discharged

about the same time as cases. Both cases

and controls had no other illnesses that

predisposed to Ml or contraindications to

estrogen use. Cases and controls had a

natural menopause, hysterectomies, or tubal

ligation, or their husband had a vasectomy.

Current estrogen use was defined as use of

noncontraceptive estrogens within 3 months

of admission.

Nonfatal Ml Current users:

age-adjusted relative risk

0.71 (0.34-1 .46)

risk-factor adjusted* relative risk

0.97 (0.49-1 .95)

*adjusted for age, history of Ml, angina, diabetes,

hypertension, and smoking

o

First nonfatal Ml Current estrogen use:

7.5 (90% confidence interval 2.4

to 24)

adjusted for type of sterilization

Ninety-four percent of cases, but only

47% of the controls, were cigarette

smokers.

I
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa,b

Jick (1 978) Cases were women ages 35 to 45 discharged

during the first 6 months of 1975 with a

diagnosis of AMI. Cases and controls were

identified from a national hospital discharge

database. Controls were women about the

same age as cases, who were hospitalized

for acute illnesses (other than Ml) or surgery,

and discharged about the same time as

cases. Results are reported for cases and

controls who had no serious chronic illnesses

(other than Ml in cases) or contraindications

to estrogen use. Current use was defined as

use of noncontraceptive estrogens within

three months of admission.

Rosenberg (1980) Cases were women ages 30 to 49 years of

age selected from interviews between July

1976 and April 1979 with a discharge

diagnosis of first Ml. Hospitals were located in

Greater Boston, Long Island, New York, and

the coastal area of northern New York City

and the Delaware Valley. Controls were

selected from the same hospitals as cases

but did not have a discharge diagnosis of Ml.

Information was gathered by nurse

interviewers. Current use was defined as use

within the month preceding admission,

Cases were white female patients 35 to 64

years of age admitted to 5 general hospitals

in Maryland with a first Ml between

1971-1972. Two controls were matched to

each case. Controls were females from the

same hospitals as cases, with no history of Ml

or abnormal Q waves on EKG, and matched

by age and date of admission. Data were

obtained from interviews and review of

medical records,

Szklo (1 984)

19 cases (53% estrogen users), First nonfatal Ml Current estrogen use

39 controls (10% estrogen 9.3 (lower 95% confidence interval 3.1)

users) adjusted for menopausal status

99 cases post menopausal First Ml

(18% current users) (24%

past users); 463 controls

Current users:

age-adjusted relative risk

1.39 (0.71 -2,74)

39 cases (28% ever users), 81 First Ml Ever users

controls age-adjusted OR 0,8 (NS)

risk-factor adjusted* OR 0,61

(0.20-1 .88)

risk-factor adjusted* OR for surgical

menopause only 0.37 (0.04-3,23)

*adjusted for history of cardiovascular disease,

smoking, educational level, and type of

menopause
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsab

La Vecchia (1987) Cases were women less than 55 years of age

admitted between January 1983 and

December 1984 to the coronary care units of

30 hospitals in Northern Italy. Controls were

matched to cases for index hospital and

5-year age group. Controls were admitted for

acute conditions except cardiovascular,

cancer, endocrine, gynecological, or primary

diagnosis potentially related to cigarette

smoking or hormone use. Data were gathered

by trained interviewers.

168 cases, 100 First Ml Current users:

pre-menopausal (5% current age-adjusted relative risk

users) (3% past users); 251 1.85 (0.68-5.01)

controls risk-factor adjusted* relative risk

2.95 (0.80-10.80)

Past users:

age-adjusted relative risk

1,01 (0.31-3.27)

risk-factor adjusted* relative risk

0.77 (0.1 6-3.60)

‘adjusted for multiple heart disease risk factors

“No relation was evident with duration of

use. ”

a Numbers in parentheses are 95 percent confidence intervals.

b Risk estimates are in terms of relative risk, unless otherwise specified,

KEY: AM I = acute myocardial infarction; EKG = electrocardiogram; ERT = estrogen replacement therapy; Ml = myocardial infarction; NS = not statistically significant; OR = odds ratio.

SOURCE: Office of Technology Assessment, 1995.

II
Appendix I Evidence on HRT and Coronary Heart Disease 173

percent) were smokers, which confounds interpretation of results. Also, the subjects were under

50 years of age, so the findings may not be generalizable to the overall population of postmenopausal women (14).

❚ Population-Based Case-Control Studies

Among the seven population-based case-control studies of myocardial infarction and ERT, all

but one demonstrated a trend toward decreased

relative risk of myocardial infarction in estrogen

users, although the results were statistically significant in only one of the studies that showed a

trend toward decreased relative risk (92). (See

table I-2.)

Population-based case-control studies differ

from hospital-based case-control studies in that

the cases and controls come from the community

or a sample of the general population. Controls selected from the community rather than a hospital

are likely to be more representative of the general

population from which the cases were drawn than

hospital-based case-control studies.

In one of the largest population-based casecontrol studies of myocardial infarction and estrogen use, Pfeffer and colleagues found among

current users of estrogens an adjusted relative risk

of 0.7 (0.3-1.4) for fatal and nonfatalMI(81 ). Estrogen use in this study was ascertained by review

of pharmacy records. In a reanalysis of Pfeffer’s

data, Ross found that estrogen use among cases

was underestimated, because one-third of the

women who had estrogen usage noted on their

medical records did not have records of estrogen

prescriptions in the pharmacy records (92). The

mean duration of use was less than three months,

which would also bias the findings toward an underestimate because such a short duration is unlikely to be sufficient for a plausible biological

effect (103).

Unlike the other case control studies in this

group which used myocardial infarction as an endpoint, Thompson and colleagues used a combined

endpoint of stroke and myocardial infarction

(111). In that study, each of 603 women with

stroke or myocardial infarction identified in 83

physicians’ practices were matched with two controls from the same physician’s practice and of the

same age. Estrogen use was ascertained from

medical records and patient interviews. Thompson showed a “weak” association between estrogen use and stroke and myocardial infarction, with

a relative risk of 1.36 in estrogen users (95 percent

confidence intervals 1.01 to 1.81). An association

between estrogen use and decreased risk of coronary heart disease may have been obscured by

combining the myocardial infarction endpoint

with the endpoint of stroke.

❚ Cohort Studies

The published results of 15 cohort studies all

showed a reduced risk of coronary heart disease in

estrogen users, although the results of one cohort

study, the Framingham study, are equivocal.

Most cohort studies followed women with and

without estrogen exposure, and thus had a control

group internal to the study. In three studies, however, mortality in a cohort of estrogen users was

compared with national mortality rates. These cohort studies without internal controls showed the

lowest apparent relative risk of cardiovascular disease with estrogen use. (See table I-3.) But women

who take estrogens are on average of higher socioeconomic status and more educated and therefore

are probably healthier than the general population

(19,103). Consequently, cohort studies without

internal controls may overestimate the effect of

estrogen exposure on cardiovascular disease.

The findings of cohort studies with internal

controls, including the Framingham study, are

summarized in table I-4. One of the largest cohort

studies of cardiovascular disease risk among postmenopausal estrogen users is the Lipid Research

Clinics Follow-up study, initiated by the National

Heart, Lung, and Blood Institute in 1971 (12,15).

Almost 2,300 women have been followed in this

study. A 1987 report noted a statistically significant reduction in incidence of CHD or stroke

death among current estrogen users (average

length of use 8.5 years) compared with nonusers.

The relative risk of cardiovascular death in estrogen users was 0.34. Adjustment for other potential
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Talbott (1 977) Cases were white female residents of

Allegheny County, Pennsylvania who had no

prior recorded history of heart disease and

who were ages 25 to 64 years old (mean age

55.6) when they died suddenly of

atherosclerotic heart disease outside of the

hospital between September 1973 and April

1975. Cases were identified from county

coroner records and death certificates. Cases

were matched to controls who were females

living on the same block and who were within

10 years of patient’s age. Information about

cases was gathered from interviews of

subjects’ family and physicians. Information

about controls was gathered from interviews

of subjects.

Pfeffer (1 978) Cases and controls were women ages 50 to

98 years who were residents of a Southern

California retirement community between

1964 and 1974. Cases had their first Ml while

in residence. Controls were drawn from a file

containing all women in residence during the

study interval. There were no black members

of the population. Data was obtained from

review of medical clinic and pharmacy

records,

ROSS (1981) Cases were women less than 80 years old

living in a retirement community near Los

Angeles who died of coronary heart disease

between 1971 and 1975 inclusive. For each

case a living and deceased female control

were selected, matched for race, age, date of

entry into the community, and, for deceased

control, date of death. The deceased control

was used to remove bias for extra medical

attention the cases may have had toward the

end of their Iives Data was gathered from

medical clinic records

64 cases (unknown number

postmenopausal)

(5% current users);

64 controls

171 cases

(30% ever users)

(8.7% current users); 171

controls

133 cases (percent ever users

not provided), 133 living

controls; 133 deceased

controls

Sudden death Current users:b

age-adjusted relative risk

0.34 (0.09-1 .30)

First Ml Ever users:

risk-factor adjusted* relative risk

0.86 (0.54-1 .37)

current users:

risk-factor adjusted* relative risk

0.68 (0.32-1 .42)

*adjusted for age, hypertension, and diabetes

Fatal coronary Ever users.

heart age-adjusted relative risk

disease living controls: 0.43 (0.24-0.75)

dead controls 0.57 (0.33-0.99)

risk- factor adjusted* relative risk

living controls. unchanged

dead controls. unchanged

*adjusted for multiple heart disease risk factors

II
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Bain (1981) Cases were postmenopausal female nurses 120 cases (53% ever users) First Ml Ever users.

ages 30 to 55 in 1976 who reported (27% current users), age-adjusted relative risk 0.9 (0.6-1.2)

hospitalization for Ml. Twenty female nurses 2,400 controls risk-factor adjusted* relative risk 0.8

hospitalized in the same year with no history (0.6-1 .3)

of Ml were matched as controls to each case current users.

on the basis of year of birth and menopausal age-adjusted relative risk 0.7 (0,5- 1,1 )

status at hospitalization. Information was risk-factor adjusted* relative risk 0.7

gathered by questionnaire. (0.4-1.1)

age-adjusted relative risk in women with

natural menopause 1,3 (0.5-3.4)

age-adjusted relative risk in women with

hysterectomy 1.0 (0,5-2,2)

age-adjusted relative risk in women with

hysterectomy and bilateral

oophorectomy 0.4 (0.2-0.8)

 *adjusted for multiple heart disease risk factors

Adam (1981 ) Cases were women ages 50 to 59 who died

of Ml in England and Wales during November

1978 identified from death certificates. Two

controls matched by age to cases were

randomly selected from the practice list of the

general practitioner responsible for the care

of the patient during life. Information was

gathered from hospital records, postmortem

reports, and questionnaires completed by the

subject’s general practitioner.

Croft (1989) A nested case-control was carried out on

cohort data collected during the Royal

College of General Practitioners’ oral

contraceptive study. Subjects were recruited

by U.K. general practitioners, and were

followed between May 1968 and July 1969.

The cases were all women who had had their

first AMI while under observation in the study.

Controls were chosen from randomly selected

general practice registers, matched for age

to cases. Medical records were examined.

76 cases

(12% ever users)

(3% current users);

152 controls

Fatal Ml Ever users:

unadjusted relative

0.65 (0.29-1 .45)

current users:

unadjusted relative

0.97 (0.41 -2.28)

risk b

risk b

158 cases (9 estrogen users), First Ml Ever users.

474 controls (32 estrogen unadjusted relative risk 0.8 (no c.i.

users) provided)

adjusted relative risk* 0.8 (0.3 to 1.8)

*adjusted for social class, smoking, use of oral

contraceptives, history of pre-eclampsia,

hypertension, and hysterectomy
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa

Beard (1989) Cases were female residents of Rochester,

Minnesota between 1960 and 1982 whose

first manifestations of heart disease were

sudden death or Ml occurring between the

ages of 40 and 59. Two controls matched by

age to each case were selected from women

seen at the Mayo Clinic. Information was

obtained from review of medical records.

Thompson (1989) Cases were white women ages 45 to 69 who

developed Ml or stroke between 1981 to

1986 and whose general practitioners

reported to Northwick Park Hospital, England.

Controls were white female clinic patients

matched for age and general practitioner.

Information gathered from review of medical

records and interviews.

86 cases Ml or sudden Ever users:

(27% ever users); 150 controls death risk-factor adjusted* odds ratio

0.55 (0.24-1 .30)

*adjusted for age, year, menopausal status,

smoking, hypertension, and diabetes

603 cases Ml and stroke Ever users of estrogen alone,

(94% past users); age-adjusted relative risk

1,206 controls 1.12 (0.79-1 ,57)

risk-factor adjusted* relative risk

1,09 (0,65-1 ,82)

past users of estrogen alone:

age-adjusted relative risk

0,86 (0.43-1 ,74)

risk-factor adjusted* relative risk

1,16 (0.43-3.12)

ever users of progestin alone.

age-adjusted relative risk

1.90 (1,1 1 -3,25)

risk-factor adjusted* relative risk

1.02 (0.45-2.32)

ever users of combined

estrogen -progestin:

age-adjusted relative risk 0,86

(0,43-1 .74)

risk-factor adjusted* relative risk 1.16

(0.43-3,12)

*adjusted for marital status, smoking, history of

hypertension venous thrombosis, stroke, Ml,

diabetes, and family history of Ml

0
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Rosenberg (1993) Cases were women, ages 45 to 69 (median 858 cases First Ml Ever users.

age 60 years), who were residents of (21% used unopposed risk-factor adjusted* relative risk 0.9

Massachusetts from 1986 until 1990. Controls estrogens, 3% used (0.7-1 .2)

were women, matched by metropolitan estrogen and progestins); recent users:

precinct and 5-year age group, with no prior 858 controls (21 % used risk-factor adjusted* relative risk

history of Ml, Ninety-eight percent of cases unopposed estrogens, 3.5% 0.8 (0.4-1 .3)

and 97 percent of controls were white. Data used estrogens and past users:

were gathered from interviews of physicians progestins) risk-factor adjusted* relative risk

and patients, 0.9 (0.7-1 .3)

unopposed estrogen users:

risk-factor adjusted relative risk 1.3

(0.4-4.9)

estrogen and progestin users:

risk-factor adjusted relative risk 1.2

(0.6-2.4)

progestin only users:

risk-factor adjusted relative risk 1.3

(0.4-4.9)

*adjusted for multiple heart disease risk factors

The estimated relative risk decreased with

increased duration of unopposed estrogen use to

06 (O 4-1 1) (test for trend p= 0.08), The

association of decreased risk with duration of use

was stronger with recent use (test for trend p<

O 05) than for past use (test for trend P=O. 86)
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Mann (1994) Cases and controls were women ages 45 to

64 years who were included in the generaI

practice files of the VAMP database of the

British National Health Service beginning in

June 1987 to May 1993. Cases comprised all

incidents of both fatal and non-fatal cases of

Ml where there were records of HRT

prescriptions within 6 months of the date of

the Ml. Controls were females in the same

age group with no prior history of Ml. Four

controls were matched to each case. Data

was gathered from computerized medical

1,521 cases Ml Ever users.

(7.7% ever users); age-adjusted odds ratio

6,084 controls (9.2% ever 0.82 (0.67-1 .01 )

users) risk-factor adjusted* odds ratio

0.83 (0.66-1 .03)

age-adjusted odds ratio for

estrogen-progestin 0.68 (0.47-0.97)

age-adjusted odds ratio for unopposed

estrogen 0.93 (0.47-1 .86)

*adjusted for history of smoking, diabetes,

hypertension, hysterectomy, and hyperlipidemia

records.

a 95 percent confidence intervals are reported after risk estimates.

b Figure obtained from reanalysis of data in original paper, included in meta-analysis by M.J. Stampfer, and G. A. Colditz,“Estrogen Replacement Therapy and Coronary Heart Disease A

Quantitative Assessment of the Epidemiological Evidence,” Preventive Medicine 20:47-63, 1991

KEY’ AM I = acute myocardial infarction; c.i. = confidence interval; HRT = hormonal replacement therapy; Ml = myocardial Infarction.

o

SOURCE: Office of Technology Assessment, 1995
. . . . . .. . . .

Author

Byrd (1977)

MacMahon

(1978)

Hunt (1990)

Relationship of hormonal

Measured replacement therapy to heart

Description of study Number of study subjects endpoint disease endpointsa,b

Cohort included women mean age 44 years,

who received hysterectomies from one

Nashville, TN, gynecologist from the late

1940s to 1977. All cohort members received

postmenopausal ERT (typically 1.5 mg CEE

per day), and were followed for at least 5

years (average duration of followup was 14,3

years). The women were followed up by

personal contacts, office visits, and

questionnaires. Expected rates of fatal heart

disease were obtained from the report of the

Division of Vital Statistics, Tennessee

Department of Public Health.

Followup of study by Hoover, et al. (1976)

originally assembled for the evaluation of

cancer risk, to include mortality from all

causes. The medical records of all white

women seen in one private practice in

Louisville, KY, from 1939 to 1972, were

reviewed, Average age of women in the

cohort at baseline was 49 years. Mean

duration of followup was 12 years, Rates of

fatal CHD in the cohort were compared to the

age-specific death rates in the general

population.

Cohort included women receiving HRT

recruited between 1977 and 1982 from 21

menopause clinics around Britain. Subjects

were followed through 1988 and median

duration of followup was 8.0 years.

Sixty-three percent of cohort was 45 to 54

years of age upon entry into cohort. Mortality

rates in the cohort were compared to the

expected rates in the female population of

England and Wales. Information about deaths

was obtained through death registries, and

diagnosis was confirmed by review of

medical records.

1,016 women (all estrogen Fatal CHD Ever users:

users); 13 cases of fatal unadjusted relative riskc 0,37

CHD (p<o.oo5)

1,891 women (all estrogen Fatal CHD Current users:

users); 33 cases of fatal age-adjusted relative risk 0.30

CHD (0.21 -0,42)

4,544 women (2,726 Fatal IHD Ever users:

postmenopausal) (all HRT age-adjusted relative risk 0.41

users) (43% estrogen- (0.20-0.61)

progestin users); 36 cases

of fatal IHD
w

Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa

’

b

Falkeborn (1992) Cohort comprised 23,174 women aged 35 23,174 women (all HRT users, First Ml

and older (median age 54 at study entry) 21% current users), 227

from the Uppsala Health Care Region of cases of first Ml

Sweden, who had been treated with

estrogen/progestin. Subjects were identified

from pharmacy records as having been

prescribed non-contraceptive estrogens from

1977 to 1983, Subjects were followed for an

average of 5.8 years. Cases of Ml within

cohort were identified through a regional

hospital inpatient registry. A subcohort of 735

women were surveyed in 1980 and 1984 by

mailed questionnaire to further characterize

the cohort with respect to lifetime hormone

exposure and the presence of other risk

factors. The incidence of first Ml in the cohort

was compared with that in the general

population.

KEY: CHD = coronary heart disease, IHD = ischemic heart disease, Ml = myocardial infarction

Ever users.

age-adjusted relative risk estradiol/

conjugated estrogens 0.74

(0.61 -0.88)

other estrogens only 0.90 (0.74-1 .08)

estrogen/progestin combination 0.50

(0.28-0.80)

overall age-adjusted relative risk 0,81

(0.71 -0.92)

“The relative risk tended to decrease

with increased duration of followup, ”

from a relative risk of 0,96

(0,44-1 .83) during the first year to a

relative risk of 0.76 (0.55-1 .02)

during the last (6 years later).

0

a Estimates are of relative risk unless otherwise specified

b 95% confidence intervals are provided in parentheses.

C Figures obtained from reanalysis of data in text. Reanalysis of data was presented in M J Stampfer, and G A Colditz, “Estrogen Replacement Therapy and Coronary Heart Disease A

Quantitative Assessment of the Epidemiological Evidence,” Preventive Medicine 2047-63, 1991

SOURCE Off Ice of Technology Assessment, 1995
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa

Hammond (1979) Study subjects were identified through Duke 610 women (49% estrogen CHD Ever users:

University Medical Center’s (Durham, NC) users); 58 cases unadjusted odds ratiob

inpatient medical record retrieval system and 0.33 (0.1 9-0.56)

outpatient office records. All cohort subjects

received diagnoses related to

hypoestrogenism between 1940 and 1964,

who returned for followup for five or more

years after diagnosis, and had most recently

been seen at Duke after January 1, 1974.

Patients referred to Duke were excluded from

the sample. Mean age of subjects was 46.3

years at baseline.

Lafferty (1985) The cohort was recruited from 173 private 124 women (49% estrogen Ml

practice patients of the author for a users); 7 cases

prospective study between 1966-1981,

Candidates had been followed for not less

than 3 years and had periodic physical

exams and laboratory studies. The mean

duration of followup was 1.6 years. The mean

age of subjects was 53,7 years (range 45 to

60 years) at baseline.

Ever users:

unadjusted odds ratiob

0.17 (0.03-1 .06)

Wilson (1985) Patients considered for inclusion were 1,234 women (14Y0 past users All CVD Ever users:

members of the Framingham of estrogen, 1O% current relative risk for all CVD

(Massachusetts) Heart Study cohort who users); 194 cases of CVD, 1,76 (p< O.01) adjusted for age and

participated in the 12th biennial exam (index) 48 cases of CVD death, and HDL level;

between 1970 and 1972 and who were 51 cases of Ml relative risk for CVD death

postmenopausal and over 50 years of age at 1.94(p<0.05) adjusted for age and

that exam. The cohort was followed for 8 HDL level;

years. relative risk for Ml 1.87(p<0.05)

adjusted for age and HDL level —
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Eaker (1987) The author reanalyzed the data from the

cohort of the Framingham (Massachusetts)

Heart Study, described above (Wilson,

1985).The subjects included women in the

Framingham Study cohort who were 50-59

years of age or 60-69 years of age upon

exam 1 in 1950, exam 6 in 1960, or exam 11

in 1970. The cohort was divided on the basis

of the subject’s age at exam. Duration of

followup was 10 years.

Bush (1987a)

Pettiti (1987)

Criqui (1988)

The cohort consisted of 2,270 white women,

ages 40 to 69 at baseline, who were followed

for an average of 8.5 years. All women

included in the study were participants in the

Lipid Research Clinic (LRC) Prevalence Study

of CVD, that was conducted in 10 North

American clinics between 1972 and 1976.

Study was restricted to whites due to the

small number of minorities in the LRC study.

The cohort included women aged 18 to 54

during December 1968 through February

1972 who participated in the Walnut Creek

Contraceptive Drug Study who never used

any type of estrogens or used estrogens for

reasons other than contraception. Duration of

followup was 10 to 13 years.

Study subjects were followed between 1972

to 1986 when they participated in a

community survey of homogeneous, white,

upper-middle class residents of a planned,

small Southern California retirement

community (Rancho Bernardo). Women were

50 to 79 years of age at baseline. Average

duration of followup was 12 years.

1,297 women (14% past users,

10% current users)

695 women ages 50 to 59; 35

cases

602 women ages 60 to 69; 51

cases

2,270 women (26% ever

estrogen users); 50 cases

6,093 women (44% ever users);

40 cases of AM I

1,868 women (39% ever users),

87 cases

CHD except 50-59 years of age:

angina relative risk 0.26 (0.06-1 .22) adjusted

for age and HDL level

relative risk 0.4 (p< O.05)adjusted for

multiple risk-factors including HDL

level

50-69 years of age:

relative risk 1.68 (0.71 -4.00) adjusted

for age and HDL level

relative risk 2.2 (p< O.05) adjusted for

multiple risk-factors, including HDL

level

Fatal CVD Ever users:

age-adjusted relative risk

0.34 (0.12-0.81)

risk-factor adjusted

(0.16-0.88)

relative risk 0,37

Fatal CVD or Ever users:

fatal Ml age-adjusted relative risk 0.9 (0.2-3.3)

for fatal CVD

risk-factor adjusted relative risk 0.61

(0.3-1 .1) for fatal CVD

age-adjusted relative risk 0.3 (0.1 -1 .3)

for fatal Ml

Fatal CHD Ever users:

age-adjusted relative risk 0.75

(0.45-1 24)

risk-factor adjusted relative risk 0.99

(0.59-1 .67)
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpoints

Avila (1 990) The study cohort comprised all female

members of the Group Health Cooperative of

Puget Sound who were ages 50 to 64 years

upon entry to cohort between 1978 to 1984.

Cases were selected from women who were

hospitalized and later discharged with a first

occurrence of Ml. Average duration of

followup was 5 years.

Henderson (1991) The cohort comprised female residents of

Leisure World Retirement Community, Laguna

Hills, California, who responded to a health

questionnaire. The cohort was followed for

7.5 years using death certificate records of

the local health department. Female residents

were almost uniformly white, moderately

affluent, and well educated with a median

age of 73 years.

24,900 women (14% current Ml Current users,

users), 120 cases age-adjusted relative risk 0.07

(0.4-1 .3)

risk-factor adjusted relative risk 0,7

(0.4-1 .4)

8,853 women (41% past users, Fatal AM I or Current users:

17.3% current users), 203 fatal IHD age-adjusted relative risk 0.601

cases (p< O.001 ) for fatal AMI

age-adjusted relative risk of 0.79

(NS) for IHD

Duration (for a fatal AM I):

<3 years: 0.64 (p<0.05)

4-14 years: 0.60 (p<0.05)

>15 years: 0.52 (p<O.O1 )

There was a significant trend toward

decreased risk with increased

duration of use for both IHD and

AMI.

Recency (years since last use) for fatal

AMI.

>15 years, 0,73 (NS)

2-14 years. 0.47 (p<O.01 )

O-1 year. 0.51 (p< O.05)

There was a significant trend toward

decreased risk of both AMI and

IHD with increased recency of use,
Stampfer (1 991 ) The cohort includes participants in the

Nurses Health Study. The study cohort began

in 1976 when 121,700 female married

registered nurses in 11 large states

completed questionnaires about their medical

histories and postmenopausal hormone use.

Followup questionnaires were mailed at two

year intervals thereafter. The study population

includes participants ages 30 to 55 at

baseline who had no preexisting cancers or

CVD history that could be associated with

hormone use. Mean duration of followup was

7 years.

48,470 female registered Nonfatal Ml and Current users.

nurses (21.8% current fatal CHD age-adjusted relative risk

estrogen users; 25.2% past 0.51 (0.37-0.70)

users), 405 cases risk-factor adjusted relative risk

0.56 (0.40-0.80)

Past users:

age adjusted relative risk

0,91 (0.73-1 .14)

risk-factor adjusted relative risk

0.83 (0.65-1 .05)

Ever users:

risk-factor adjusted relative risk

0.72 (0.55-0.95)

There were no significant trends with

regard to duration of use or

recency of use (time since last

use).

Ever users:

risk-factor adjusted relative risk 0.66

(0.48-0.90)

wolf (1 991) This cohort consists of a natural sample of 1,944 women (21 % ever users); Fatal CVD

women from the National Health and Nutrition 347 cases

Examination (NHANES) followup study who

were at least 55 years of age and

menopausal at baseline survey between 1971

and 1975. The study was restricted to white

female participants. Followup occurred from

1982 to 1984, and again in 1986 and 1987.

Followup intervals ranged from 11,4 -16.3

years (mean 14.1 years) for survivors and 2

months to 16,3 years (mean 8.6 years) for the

descendants. Women were categorized as

either ever users or never users of HRT on the

basis of their response to the 1982-1984

followup questionnaire. HRT type was almost

exclusively conjugated equine estrogens

(Premarin). Mean age at baseline exam was

65.7 years.
Relationship of hormonal

Measured replacement therapy to heart

Author Description of study Number of study subjects endpoint disease endpointsa

Manolio (1 993) Cardiovascular Health Study participants Cases, 461 12% current users Definite CHD Ever versus never usersa

were recruited from a random sample of 39% ever users age adjusted relative risk

Health Care Financing Administration cohort size, 2,955 P = 0.4

Medicare eligibility lists in 4 U.S. 39% post menopausal

communities: Forsyth Co., NC; Sacramento,

CA, Washington Co., MD; and Allegheny Co.,

PA. The participants were females from 65 to

100 years of age with a mean age of 72.4

years.

KEY: AMI = acute myocardial infarction, CHD = coronary heart disease, CVD = cardiovascular disease, ERT = estrogen replacement therapy, HDL = high-density lipoprotein cholesterol, IHD = ischemic heart disease, Ml =

myocardial infarction

a Ninety-five percent confidence intervals are provided in parentheses, unless otherwise specified

b Estimates of crude odds ratio derived from reanalysis of data in the text or from meta-analysis by Stampfer and Colditz in M J, Stampfer and G.A Colditz, “Estrogen Replacement Therapy

and Coronary Heart Disease’ A Quantitative Assessment of the Epidemiological Evidence, ” Preventive Medicine 20:47-63, 1991

SOURCE: Office of Technology Assessment, 1995.
186 Cost Effectiveness of Screening for Osteoporosis

confounding factors (age, blood pressure, and

smoking) did not substantially change the finding

of a reduction in risk of cardiovascular death

among current estrogen users.

On the basis of multivariate analysis of the results of this study, the investigators concluded that

the beneficial effect of estrogens on cardiovascular disease risk was substantially mediated

through HDL levels. When the multivariate analysis included HDL, the benefit of cardiovascular

disease mortality among estrogen users compared

with nonusers was reduced and no longer statistically significant, a finding consistent with the hypothesis that the protective effect of estrogens is

substantially mediated through increased HDL

levels. Preliminary data from the 15-year follow

up of patients in the study demonstrated a 65-percent reduction in cardiovascular disease and an

approximately 50-percent reduction in all-cause

mortality (28). Even after adjusting for age, HDL,

and LDL, estrogen users continued to have a risk

of 60 percent that of nonusers.

A nationwide study of nurses also found postmenopausal estrogens to have a protective effect

on major coronary disease (102). The Nurses’

Health Study was established in 1976 with

121,700 female nurses ages 30 to 55 years old. By

1986,48,470 of these women were postmenopausal. Participants who reported ever using estrogens in the past had a statistically significant

relative risk for nonfatal and fatal coronary heart

disease of 0.51 after an average of 7 years’ followup. Adjustments for a variety of cardiac risk factors including high cholesterol, family history of

heart disease, hypertension, diabetes, obesity, and

smoking did not substantially change these relative risk estimates.

In an ongoing prospective study in a retirement

community near Los Angeles (Leisure World),

Henderson and colleagues found that women who

used ERT had a relative risk of fatal acute MI of

0.60 compared with nonusers (39). This study was

begun in 1981 to investigate the risks and benefits

of menopausal ERT. A questionnaire was mailed

to all 20,000 residents of this retirement community in 1981, and the two-thirds who completed

and returned the questionnaire became members

of the study cohort. About 9,000 of these were

women (77). After 7.5 years of followup, current

users had an age-adjusted relative risk of fatal ischemic heart disease of 0.46 compared with nonusers. Adjustment for several CHD risk factors

did not substantially change the results. Henderson also found that the overall mortality rate in

those who had ever used estrogen was 20 percent

lower than lifetime nonusers (95 percent confidence intervals 0.7 to 0.87) and the overall mortality in current users of estrogen with more than 15

years of estrogen use was 36 percent below that in

nonusers (95 percent confidence intervals 0.51 to

0.82) (39).

A cohort of 6,093 women ages 18 to 54 from

the Kaiser Permanence Medical Program was followed for an average of 10 to 13 years (80). The

mortality rate from heart disease and stroke was

slightly lower among estrogen users, with a relative risk of 0.9 (95 percent confidence intervals

0.2 to 3.3). After adjustment for a variety of cardiovascular risk factors, including age, hypertension, obesity, and smoking, the apparent benefit

was more marked, with a relative risk of 0.6 but

the reduction in risk remained statistically insignificant (95 percent confidence intervals 0.3 to

1.1).

In contrast to the other cohort studies, the Framingham Heart Study3 reported a 50 percent increased risk for all circulatory disorders in

postmenopausal estrogen users (120). An increased incidence of MI was observed among estrogen users, particularly those who smoked

cigarettes.

One criticism of the Framingham study’s conclusions with respect to postmenopausal ERT and

3 The Framingham Heart Study, named for the Boston suburb where residents have participated since 1948, began with 5,209 healthy men

and women ages 30 to 62. In 1971, the ongoing study was expanded to include the offspring of the original participants. The effects on diet,

medication, and life-style on health have been assessed every two years (biennial examinations).
Appendix I Evidence on HRT and Coronary Heart Disease 187

cardiovascular disease is that a reduction in cardiovascular disease risk in estrogen users may

have been obscured by including in the estrogen

user group women whose use was remote; in the

Framingham study, anyone who had used estrogen at some time in the eight years before the

twelfth biennial examination was counted as an

estrogen user (119).

Another criticism of the Framingham study is

that the investigators adjusted the results for HDL

levels. Because estrogen’s beneficial effects are

thought to be substantially mediated through its

effect on HDL level (15), the analysis may have

underestimated the cardiovascular benefits of

postmenopausal ERT.

The Framingham study has also been criticized

for the use of subjective measures of cardiovascular disease (29). In the Framingham study, the relative risk of cardiovascular disease was estimated

using a number of endpoints including angina

pectoris (chest pain due to inadequate oxygenation of the heart), coronary heart disease, intermittent claudication (symptom associated with

atherosclerosis and other occlusive arterial diseases characterized by leg pain with walking and

relieved by rest), transient ischemic attack (occlusive vascular disease symptom characterized by

brief periods of cerebral dysfunction, with no persistent necrologic deficit), myocardial infarction,

congestive heart failure, coronary heart disease

death, and sudden death. Chest pain can be due to

a wide variety of causes, some of which can be

mistakenly attributed to the presence of coronary

heart disease. In a reanalysis of the Framingham

data, excluding the nonspecific endpoint of angina pectoris, Eaker demonstrated a statistically

nonsignificant reduction in risk of coronary heart

disease among younger estrogen users (relative

risk 0.4,95 percent confidence interval 0.1 to 2.3)

and a statistically nonsignificant increase in risk

of coronary heart disease among older estrogen

users (relative risk 1.8, 95 percent confidence interval 0.5 to 6.9).

Although prospective cohort studies have important advantages over case-control studies in

avoiding bias from the subject recall of exposure

and the difficulties in selection of controls, a problem with some cohort studies is that estrogen use

was often ascertained only at the initiation of the

observation period and not reascertained at a later

point in the study ( 103). By failing to update estrogen use status, current and former users may be

misclassified, and an underestimate of the effect

of estrogen may result, particularly because the

benefits of estrogen use are most pronounced

among current or recent users.

❚ Cross-Sectional Studies

Recently, a number of cross-sectional surveys of

estrogen use in women who have had coronary angiography (heart catheterization) have been reported; these studies have found reduced

incidence of CHD in estrogen users (table I-5).

Angiographically demonstrated coronary artery

obstruction is thought to be a more specific endpoint for the presence of CHD than signs and

symptoms such as angina pectoris or MI. Coronary angiography involves the injection of x-ray

opaque dye into each artery of the heart (78). Xray images of the heart (cineangiograms) are recorded, and these images are then reviewed by the

cardiologist for evidence of obstructions of the

coronary arteries.

Cross-sectional studies are a subcategory of

case-control studies where the presence of disease

and the exposure to the agent are ascertained simultaneously (94). In the studies listed in table

I-5, the presence of angiographically demonstrated coronary artery obstruction and the patient’s history of estrogen exposure were

simultaneously ascertained. These studies have

found reduced disease in women who had taken

estrogen. For example, Gruchow et al. reports on a

series of 933 women ages 50 to 75 years who underwent coronary angiography (36). Estrogen users were one-half as likely as nonusers to have

moderate or severe occlusion of the coronary arteries. In nonusers, the likelihood of occlusion increased with age, whereas in users, no age trend

was evident.

Hong et al. reported on a series of 90 consecutive women 55 years old or older undergoing diagnostic coronary angiography (41). Only 22
188 Cost Effectiveness of Screening for Osteoporosis

percent of estrogen users had significant obstruction of a major coronary artery (defined as 25 percent or more luminal diameter narrowing),

whereas 68 percent of nonusers had significant

obstruction.

❚ Randomized Clinical Trials

In the only prospective randomized double-blind

clinical trial of estrogen use and heart disease,

Nachtigall and colleagues reported on the 10-year

followup of eighty-four pairs of chronically ill

women in a long-term-care hospital matched for

age and diagnosis, who were randomly assigned

to take estrogen opposed with progestin (PERT)

or placebo (73). PERT users had a lower relative

risk of myocardial infarction than nonusers, but

there were only four myocardial infarctions in the

study and the difference in risk was not statistically significant. In a study this small, however, one

would expect only very large differences in relative risk of disease to be capable of producing statistically significant results.

Some investigators have argued that much of

the reported heart disease benefit of HRT may be

due to “healthy user” bias—the selection of relatively healthy women with a lower risk of heart

disease for HRT. These investigators argue that estrogen users are generally of higher social class

than nonusers (8), and social class is inversely

associated with both heart disease and cancer

(51,65). They also argue that the lower heart disease incidence in ERT users maybe because doctors were reluctant to prescribe estrogens to

women with coronary risk factors 10 years ago,

because, at that time, estrogen was contraindicated in these women because earlier studies had

found increased risk of thrombosis and heart attack in young women taking oral contraceptives

and in older men treated with estrogen.

One investigator showed that cohort studies

that found a reduction of heart disease incidence in

ERT users also showed a reduction in risk of total

cancer incidence in ERT users, even though ERT

would not be expected to have a beneficial effect

on total cancer incidence (83).

Estrogen replacement therapy, however, has

been found to prolong survival even in women

who are not “healthy” women who already have

significant coronary artery disease. Recent studies have compared the later survival of estrogen users versus nonusers with previously documented coronary artery lesions demonstrated by

arteriography. Sullivan et al. recently found allcause mortality over a 10-year period to be lower

in women with coronary artery disease who used

ERT than in those who never used estrogen (1 07).

They reported a retrospective analysis of postmenopausal estrogen use, coronary artery obstruction (stenosis), and survival in 2,268 women 55

years or older who underwent coronary arteriography in the past. They compared overall survival in

estrogen users and nonusers who initially had various degrees of coronary artery obstruction as

demonstrated by arteriography. Over 10 years of

followup, there was no difference in survival between estrogen users and nonusers with no initial

evidence of coronary artery obstruction on arteriography. But in those with initially mild to moderate coronary artery occlusion (less than 70 percent

stenosis), 10-year survival was 85 percent in never

users versus 95.6 percent in ever users of estrogen.

And in those who initially had severe occlusion

(70 percent or greater stenosis), survival was 60

percent among those who never used estrogen and

97 percent among those who had ever used estrogen. One implication of these findings is that ERT

may have beneficial effects on the heart even

when started in older women with preexisting coronary heart disease.

Barrett-Connor found that, even within a group

of women from the same socioeconomic class,

women taking estrogen were different from nonusers with regard to health promotion and disease

prevention measures (6). In order to minimize the

bias introduced by differences in socioeconomic

status between estrogen users and nonusers, Barrett-Connor evaluated the estrogen use patterns of

1,057 postmenopausal women from the same socioeconomically upper-middle-class community

in California (6). The women were categorized as
Appendix I Evidence on HRT and Coronary Heart Disease 189

never users, past users, and current users. After an

average followup period of 4.4 years, 95 percent

of these women completed a mailed health survey

questionnaire that asked about lifestyle and health

care factors related to good health. In general,

women who never used estrogen were least likely

to have implemented healthy behavior changes,

and were least likely to have had screening evaluations. Seventy percent of the group of current estrogen users had had a mammogram in the last 12

months, whereas 45 percent of the never users had

had one (p< 0.001).

Other investigators have also argued that users

of ERT are relatively compliant, and that “compliance bias” may account for some of the apparent benefit of ERT on heart disease (79). To

examine the magnitude of “compliance bias,”

analyses of data from two randomized clinical

trials of drug treatments for heart disease have examined total mortality in persons who complied

with the taking of placebo (24,43). In these analyses, subjects who complied with the taking of a

placebo had significantly lower overall mortality.

The benefit of compliance with placebo was not

reduced by adjustment for a large number of variables, both medical and sociodemographic, that

might affect mortality.

The issue of selection bias will not be completely resolved until completion of randomized

controlled clinical trials of HRT and heart disease.

A number of randomized controlled clinical trials

have been performed that have examined the effect of HRT on lipids and lipoproteins. In women,

levels of high density lipoprotein (HDL) and triglycerides, and to a lesser extent, low density lipoproteins (LDL) predict cardiovascular death in

women (9). These studies have demonstrated that

ERT, and to a lesser extent, PERT, have induced

favorable changes in lipids and lipoproteins, consistent with a reduced risk of heart disease in HRT

users.

A controlled clinical trial that uses the endpoint

of coronary heart disease symptoms or mortality

would be expensive because of the large number

of study participants and the long duration of followup that would be required (71). Therefore,

many trials have been conducted that measure estrogen’s effect on various intermediate endpoints

for coronary heart disease, such as blood lipid and

lipoprotein levels. The first long-term large-scale

controlled clinical trial of HRT using coronary

heart disease endpoints was begun in fall 1993 as

part of the Women’s Health Initiative. This

15-year, $625 million study, sponsored by the National Institutes of Health, will examine the effect

of HRT, as well as low fat diets, calcium supplements, and vitamin D supplements on the incidence of heart disease, osteoporosis, and other

diseases. The study includes a clinical trial involving 57,000 women ages 50 to 79, and an observational study involving 100,000 women from 45

medical centers across the United States.

Randomized controlled clinical trials examining the effect of estrogen on heart disease risk factors have shown evidence of heart disease benefits

in users of estrogen. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial involved

875 women, 45 to 64 years old at study entry, who

were randomly assigned to either estrogen, one of

three estrogen/progestin combinations, or placebo (122). During this three-year multicenter trial,

the women were monitored for changes in a number of heart disease risk factors, including blood

pressure LDL, HDL, and hemostatic factors. At

the end of the three year trial period, women taking estrogen alone had significant increases in

HDL, decreases in LDL, and decreased fibrinogen

levels changes consistent with a decreased risk of

heart disease in estrogen users.

EVIDENCE ON PERT AND CHD

The primary indication for adding progestins to

the HRT regime is to reduce the risk of estrogeninduced irregular bleeding, endometrial hyperplasia (abnormal overgrowth of the inner lining of the

uterus, or endometrium), and endometrial cancer

(118). (See appendix G for more discussion.) But

an important unresolved issue is whether the

benefits of PERT in protecting the endometrium

are outweighed by the effect of progestins on the

risk of coronary artery disease. Studies of the relationship of HRT to coronary artery disease have

been largely limited to ERT. The effect of proges-
190 Cost Effectiveness of Screening for Osteoporosis

tin supplementation has not been extensively evaluated because the routine addition of progestins

to prevent estrogen-induced endometrial carcinoma has been recommended only recently (66).

Progestins are suspected to have an adverse impact on cardiovascular disease risk because progestins have opposite effects on lipid and

lipoprotein metabolism from estrogens (84). Progestins decrease HDL levels (40,76,99). Different

types of progestins, however, vary in their impact

on lipids and lipoproteins, with the more androgenic progestins, particularly those derived from

the male hormone testosterone, having a greater

adverse impact. For example, Hirvonen et al.

found that the progestins levonorgestrel and norethindrone in large doses (up to 10 mg) substantially reduced HDL, and the less androgenic

progestin medroxyprogesterone acetate (10 mg)

also reduced HDL levels, but not to as great an extent (40). Ottosson found that medroxyprogesterone acetate lowered HDL-2 cholesterol level,

negating the increase observed with oral estrogens

(76). Some evidence suggests that progestins may

also adversely affect vessel-wall physiology (62).

There is some evidence that lower doses of the

less androgenic progestins are sufficient to induce

endometrial transformation and not substantially

attenuate estrogen’s beneficial effect on lipoproteins (2,34,45,49, 100,113,116,1 17,123) and other

metabolic changes associated with heart disease

risk (69,97). Progestin’s effect on lipoproteins appears to be dose dependent, and lower doses of

progestins may not substantially reduce estrogen’s beneficial effect on HDL (45).

Nabulsi and colleagues found in a cross-sectional analysis of postmenopausal women that the

addition of progestins did not attenuate estrogen’s

beneficial effects on heart disease risk factors; users of estrogen with progestin actually had a better

profile of heart disease risk factors than users of

estrogen alone (72). The investigators examined

heart disease risk factors among 4,958 postmenopausal women, ages 45 to 64, from four regions of

the United States, who were participating in the

Atherosclerosis Risk in Communities study. They

examined the associations of HRT with blood

pressure, concentrations of plasma lipids and hemostatic factors, and fasting serum concentrations

of glucose and insulin. Approximately 63 percent

of the women had never used HRT, 16 percent had

formerly used HRT, and 21 percent currently used

HRT. Among current users of HRT, 83 percent

were using estrogen alone (primarily conjugated

equine estrogens (CEE)), and 17 percent were using PERT (primarily CEE with low dose medroxyprogesterone acetate).

The investigators found that, after adjusting for

differences in other heart disease risk factors, current users of estrogen had significantly increased

levels of HDL and decreased levels of LDL than

did nonusers (72). They also found no significant

difference in levels of HDL and LDL between users of ERT and users of PERT. Users of ERT had

significantly higher plasma triglyceride levels

than users of PERT. As elevated triglyceride levels are thought to increase heart disease risk, users

of estrogen alone had a somewhat poorer plasma

lipid profile than users of estrogen with progestin,

but both groups of current users had better lipid

profiles than nonusers. Finally, current HRT users

had significantly lower levels of lipoprotein(a)

than nonusers, with users of PERT having significantly lower levels of lipoprotein(a) than users of

estrogen alone. Lipoprotein(a) concentrations

may be inversely related to heart disease risk (98).

Other changes were observed in the two groups of

current users that would be predicted to lower the

risk of coronary artery disease: a decline in fibrinogen levels (a serum protein involved in coagulation) and a decrease in glucose and insulin levels.

Users of ERT had higher levels of coagulation factor VII and protein C than users of PERT and nonusers. This would suggest that PERT would have a

better hemostatic profile than ERT.

These findings confirm three other populationbased studies in which HDL levels in women who

received ERT were similar to those in women who

received PERT (8,32,1 14).

Recently, Falkeborn et al. reported the results

of a study of first MI among a cohort of 23,174

postmenopausal estrogen/progestin users compared with postmenopausal women in the community (31). They found an age-adjusted relative
Appendix I Evidence on HRT and Coronary Heart Disease 191

risk of first MI among current users of CEE (or estradiol) with progestin of 0.74 (0.61 to 0.81).

Results from the PEPI trial have also shown evidence of heart disease benefits in users of PERT,

although the benefits are not as great as those in

users of ERT (122). At the end of the three year

trial period, women taking estrogen plus a synthetic progestin (medroxy progesterone) had a 2

milligram per deciliter (mg/dL) increase in HDL,

whereas users of estrogen alone or estrogen plus a

natural progestin (micronized progesterone,

available in Europe) had about a 6 milligram per

deciliter (mg/dL) increase in HDL, and the

women assigned to the placebo group experienced

no increase in HDL. Both the ERT group and the

PERT group had significantly lower LDL than the

placebo group. Both treatment groups experienced improvements in hemostatic factors and no

change in blood pressure compared with the placebo group.

CONCLUSIONS

The conclusion of authors of several recent reviews of the evidence is that ERT reduces the risk

of coronary heart disease (30,38,59). Both Stampfer and Bush, in recent meta-analyses of the data,

concluded that the evidence strongly suggests that

women taking estrogen therapy are at a risk for

coronary heart disease about half that of nonusers

(13,102). Several authors have found that the consistency of findings is stronger in the better designed and analyzed studies (13,56,59,84,93,

102).

Several studies demonstrated that women who

currently use estrogen (current users) had a lower

risk of coronary heart disease than women who

had used them in the past (past users) (4,39,

64,81,88,90,91,102,111). Few data are available

about whether dose, length of use, and type of estrogen affect risk. One study that examined the effect of estrogen duration on CHD risk failed to

detect any effect of duration (102). However, Henderson et al. showed that women with a history of

use showed a decrease in relative risk of fatal acute

MI and fatal ischemic heart disease with increased

duration of use (39). Rosenberg et al., in a casecontrol study, also found a significant trend toward decreased risk of first MI with increased

duration of use of HRT, but only among current

users (90).

Studies that examined dose failed to demonstrate a decreased risk of coronary heart disease

with greater doses (39,102). But Ross found a

nonsignificant trend toward decreased risk with

higher doses of conjugated equine estrogens (92).

Studies have not examined whether there are differences in efficacy with different estrogen preparations. Further study is needed on whether dose,

length of use, and type of estrogen used affect risk.

There is evidence that HRT’s heart disease

benefits will continue into women’s later years.

Epidemiologic studies have demonstrated HRT’s

heart disease benefits in elderly women (15,39,

88,107,108).

OTA’s review of the evidence concurs with

those of other reviewers: there is both a theoretical

rationale and empirical evidence to support a reduced risk of heart disease in women who use estrogens.

OTA chose a relative risk of 0.5 as the base case

estimate of heart disease risk in current users of estrogen. In formulating this estimate, OTA placed

greater emphasis on cohort studies than case-control studies, because cohort studies are less prone

to bias. In general, cohort studies have demonstrated a greater heart protective effect of ERT

than case control studies. Among cohort studies,

10 of 17 estimated relative risks of heart disease of

0.5 or below, and 13 of 17 were consistent with the

hypothesis that ERT reduces heart disease risk in

current users by half (confidence intervals included 0.5).4 The major disadvantage of cohort

studies without internal controls is that the “control” group may not be comparable to the clinic

4 0TA relied on the results of the Framingham cohort published by Eaker (29), because the results of the major paper on heart disease in the

Framingham cohort did not report the crude or age-adjusted cardiovascular disease rates.
Number Risk–factor

of Type of Percentage of adjusted

Study Patient’s age patients estrogen use estrogen users Age-adjusted relative riska

relative riska

Sullivan, et al. (1988) Mean age 62.8 2,188 Current use 4.4% 0.44 (0.29-0.67) for 70+ percent 0.58 (0.35-0.97)

occlusion vs. no steriosls

0.50 C

Gruchow, et al. (1988) Age range 50 to 75 933 Current use 15,5 0.59 (0.48-0.73) moderate vs. low b

occlusion score

0.37 (0.29-0.46) severe vs. low

occlusion score

McFarland, et al. (1989) Age range 35 to 59 283 Ever use 41 0.5 (0.3-0.8) for 70+ percent

occlusion vs. no stenosis

Hong (1992) Mean age 62.3 90 Current use 20 OR for coronary artery disease =

0.13 (p < 0.001) in estrogen

users vs. nonusers.

KEY OR = odds ratio

a 95 percent confidence intervals are given in parentheses

b Value not provided.

c Confidence interval not provided.

o

Adapted from: M.J. Stampfer, and G.A. Colditz, “Estrogen Replacement Therapy and Coronary Heart Disease: A Quantitative Assessment of the Epidemiological Evidence,” Preventive

Medicine 20:47-63, 1991.

II
Appendix I Evidence on HRT and Coronary Heart Disease 193

population. Among cohort studies with internal

controls, seven of 12 reported reductions in heart

disease risk greater than 0.5 in ERT users.

OTA’s base case estimate of heart disease risk

in ERT users is also consistent with all of the angiographic studies, which show 50-to 60-percent

reductions in the amount of coronary artery stenosis in ERT users (table I-5). These studies of angiographically defined coronary artery disease

should provide more precise estimates of heart

disease risk than studies using clinical endpoints

of heart attack or ischemic heart disease symptoms. This is because many postmenopausal

women with significant coronary artery occlusions have no symptoms, and these women will be

misclassified as having no heart disease. This misclassification diminishes the ability of an epidemiologic study of ERT users and nonusers to

detect differences in risk of heart disease between

the groups.

OTA’s base case estimate of heart disease risk

in ERT users is consistent with that of the metaanalyses by Barrett-Connor and Bush (7) (approximately 50-percent reduction in risk of heart

disease in ERT users), Bush (13) (a reduction in

risk of 40- to 50-percent), and Mack (60) (an estimated 50-percent reduction in risk). This is also

consistent with the meta-analysis by Stampfer et

al. of cohort studies with internal controls and

cross-sectional angiographic studies (102). Stampfer et al. obtained a somewhat higher estimate of

heart disease in ERT users when the results of cohort studies without internal controls and case

control studies were also factored in to the estimate (102). OTA’s estimate of relative risk of heart

disease in ERT users was less than the meta-analysis of Grady et al., who calculated a relative risk of

heart disease in ERT users of 0.65 (35).

Because of the uncertainty about the magnitude

of the heart protective effect of ERT, OTA tested

the sensitivity of the model to a wide range of estimates of heart disease risk in ERT users. Although

most cohort studies have demonstrated a reduced

risk of heart disease in ERT users, the range of estimates of the relative risk varies widely, to as low

as 0.17. In addition, cohort studies of current ERT

users have, on average, estimated a lower risk of

heart disease than studies of ever users or past users of ERT. To encompass the range of estimates

from these studies in our sensitivity analysis, OTA

chose a relative risk of 0.2 as a best case estimate

of heart disease risk in ERT users, and a relative

risk of 0.8 as a worst case estimate.

OTA assumed as a base case that users of PERT

would have no heart disease benefit, and as a best

case, that estrogen/progestin users would have a

20-percent lower risk of heart disease than nonusers (relative risk 0.8). Randomized clinical trials

examining estrogen with progestin’s effect on lipids and lipoproteins suggest that the heart disease

benefits of estrogen would be reduced when progestins are added, although this reduction maybe

minimized by using the lowest effective dose of

the least androgenic progestins.

OTA’s estimates of the relative risk of heart disease in PERT users are consistent with recent epidemiologic studies. Because the addition of a

progestin to ERT has become standard medical

practice only relatively recently, there are few epidemiologic studies with sufficient numbers of estrogen/progestin users to estimate its impact on

heart disease risk.

The evidence is weak to support a protective effect extending beyond the period of use. In the absence of such evidence, a reasonably conservative

assumption is that ERT (when not combined with

progestins) reduces heart disease rates by onehalf, but only during the therapy period. Once

HRT ceases, heart disease rates can be assumed to

return quickly to the rates in the general population of women of the same age.

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T

his appendix describes the methods and

sources used in estimating cost parameters

for the OTA model. The components of

cost required for the model include those

of bone mineral density (BMD) measurement,

hormone replacement therapy (HRT), heart disease, hip fractures, gall bladder disease, endometrial cancer, and breast cancer.

The OTA model considers only those health

care costs that are directly attributable to the specific conditions whose incidence or severity are

affected by osteoporosis prevention strategies.

They do not include any health care costs unrelated to these conditions. When an osteoporosis

prevention strategy increases life spans, people

are likely to use more health care simply because

they are living longer. These increases in “unrelated costs” are not included in OTA’s analysis, because they are assumed to be part of the portfolio

of both costs and benefits embodied in the effectiveness measure (years of life gained). The basis

for OTA’s assumptions concerning each component is described below.

BMD SCREENING COST

The cost of screening for BMD was based on

the cost of single photon absorptiometry (SPA).

This is the only method of bone densitometry curAppendix J:

Methods for

Estimating

costs J

rently covered by Medicare (18). It is also the

method used in OTA’s model to estimate the distribution of BMD levels at various ages. Other

BMD measurement technologies are available,

generally at higher cost than SPA. The estimate of

$100 used for this analysis is consistent with estimates from a variety of sources. Table J- 1 summarizes the cost estimates used in various studies of

BMD screening.

HRT COST

The components of the treatment costs are summarized in table J-2. HRT regimens vary, sometimes including estrogen (ERT) alone and

sometimes estrogen in combination with (or followed by) progestin (PERT).

❚ Estrogen-Only Therapy

The annual cost of ERT, $75, was based on the retail price of PremarinTM (0.625 mg daily for 273

days per year). To arrive at this estimate OTA surveyed retail pharmacy costs in the Washington,

DC area in 1991.

The American College of Obstetricians and

Gynecologists recommends annual mammograms and endometrial biopsies for all women on

ERT ( 1). However, annual mammograms are gen201
Data Cost of screening Constant

Author/article year SPA DPA QCT Other dollar year

Health Care Financing

Administration, 1993

National Osteoporosis

Foundation, 1990

Vogel et al., 1991

Cummings and Black,

1986

American Osteoporosis

Alliance, 1990

Health Insurance

Association of America,

1991

1990

1990

1990

1984

1987

1988

Claim

dates:

11/1/89 to

1 0/31/90

$1 18a

$97a

7 1

b

6 9

b

75.50C75.50C

50-150 150-300 150-400 $ 50-$150d

150-300 e

75-00f

50-1509

40-120 150-300 100-300 —

75 78 86 —

75 68 81 —

.51h54 h — —

116i159 i — —

1990

1990

1990

NG

1987-1988

1989-1990

Source Comments

Medicare

Estimate based on

Medicare fee screens

Based on information

obtained from hospital,

clinic, and private

settings

American College of

Physicians

HCFA

Health Insurance

Association of America’s

Medical Prevailing

Healthcare Charges

System

a Average submitted

charges

b Average allowed

charges

C Average Medicare

reimbursement for SPA

and DPA

d SXA (single photon

x-ray absorptiometry)

e DXA (dual energy x-ray

absorptiometry

f Lumbar spine series

g Radiogrammetry

Medicare average

allowable amounts.

‘Professional

Component

‘Total Component

ABBREVIATIONS: DPA = dual photon absorptiometry, NG = not given, QCT = quantitative computed tomography, SPA = single photon absorptiometry

SOURCES National Osteoporosis Foundation, Medicare Reimbursement for Bone Mass Measurement:Costs and savings executive summary (Washington, DC August 1990); J Petrie,

U S Department of Health and Human Services, Health Care Financing Administration, personal communication, July 1993, J M Vogel, P D Ross, J W Davis, et al , Hawaii Osteoporosis

Center, Honolulu, Hl, “Technologies to Detect Osteoporosis” Final Report, unpublished contractor report prepared for the Office of Technology Assessment, U S Congress, Washington,

DC, Mar 25, 1991 S Cummings and D Black, “Should Perimenopausal Women Be Screened for Osteoporosis?’’ Annals of Internal Medicine 104(6) 817-823, 1986, American Osteoporosis Alliance memorandum to U S House Select Committee on Aging, Subcommittee on Human Services, Washington, DC, 1990, Health Insurance Association of America, B L Harris,

Associate Director, Washington, DC, letter to R C Herdman, Office of Technology Assessment, U S Congress, Washington, DC, Aug 30, 1991
Appendix J: Methods for Estimating Costs 203

erally recommended for all women over 50, so endometrial biopsy is the only cost recognized in the

model. The cost of this procedure was estimated

from average submitted physician charges in 40

Blue Cross/Blue Shield plans (10).

In a certain percentage of women on ERT, adenomatous or atypical endometrial hyperplasia

would be detected, requiring dilatation and curettage (D&C) of the uterus. Weinstein and Schiff estimated that 7.5 percent of estrogen users would

be diagnosed with endometrial hyperplasia (19).

The average submitted physician charge for D&C

in 40 Blue Cross/Blue Shield plans was $526 (10);

therefore, the expected additional annual cost

associated with this procedure for estrogen therapy users would be $39.

Most women who experience unscheduled

bleeding while on estrogen replacement therapy

would be given an additional endometrial biopsy.

Weinstein and Schiff have estimated the incidence

of bleeding in estrogen users at 2.5 percent (19).

Therefore, $3 per year is added to the yearly treatment cost to account for this procedure.

On the basis of all of these estimated components of HRT cost, the total annual cost of ERT in

the OTA model is $269.

❚ Estrogen-Progestin Therapy

In PERT, a progestin is added to the estrogen regimen. The price of the progestin used in our analysis was based on Provera ( 10 mg daily dosage) for

12 days per four-week cycle. From a survey of retail pharmacy costs in the Washington, DC area,

we estimated the annual prescription drug cost of

PERT at $119.

An annual endometrial biopsy is not usually required for women on PERT, but they would have a

yearly physician visit. The cost of the doctor visit,

$38, was based on the Medicare charge for an established patient who receives limited service.

Most observers believe that women on PERT

are not at increased risk of endometrial hyperplasia. Therefore, extra D&C procedures would not

occur. PERT does result in increased frequency of

abnormal vaginal bleeding, however. Ettinger and

ERT

Prescription drug $ 98a,b

Endometrial biopsy 129d

Dilation and curettage 3 9

e

Additional endometrial biopsy 3

f

Total $269

PERT

Estrogen $ 98 a,b

Progestin 1 19b,c

Doctor visit 3 8

g

Endometrial biopsy 3

d , h

Total $258

KEY: ERT = estrogen replacement therapy; HRT = hormone replacement therapy; PERT = progestin/estrogen replacement therapy

aDrug cost IS from a survey conducted in 1993 by OTA of retail pharmacies in the Washington, DC area

bBased on PremarinTM (0.625 mg daily) for 273 days/year.

cBased on ProveraTM (1 O mg daily) for 156 days/year.

dAverage submitted physician charges from 40 Blue Cross & Blue

Shield plans.

e Weinstein and Schiff estimated that 7.5 percent of patients on estrogen alone would need a dilation and curettage The cost of $526 for

this procedure was obtained from Blue Cross & Blue Shield average

submitted physician charges.

f 2.5 percent of Patients on estrogen alone are assumed to need an

additional endometrial biopsy due to increased risk of unscheduled

bleeding.

g Charge is based on the 1993 Medicare average submitted charge

for an established patient requiring limited service (CPT code 90050

in Physicians’ Current Procedural Terminology).

h Unscheduled bleeding in estrogen-progestin therapy Patients

would require an endometrial biopsy. The incidence of bleeding in

this group is assumed to be 2,5 percent.

SOURCES: Office of Technology Assessment, 1995. R. Lapp, Manager for Provider Strategy, Blue Cross&Blue Shield Association, Chicago, IL, personal communications, July 18, 1993, and July 23, 1993.

M.C, Weinstein and I. Schiff, “Cost-Effectiveness of Hormone Replacement Therapy in the Menopause,” Obstetrical and Gynecological Survey 38(8):445-455, 1983.

colleagues recently compared the frequency of

abnormal vaginal bleeding in post-menopausal

women taking cyclic PERT with a cohort of

women not on HRT of any kind (8). They found a

relative risk of abnormal bleeding of approximately 3.1 in women on therapy. The frequency of

abnormal bleeding declined with age, however.

About 60 extra events per 1,000 patient-years
204 Cost Effectiveness of Screening for Osteoporosis

Fatal acute myocardial infarction $14,470-31 ,397a

Nonfatal acute myocardial infarction 74,217

a,b

Ratio of nonfatal to fatal acute myocardial infarction 2.6/1 c

Total heart attack costs per fatal heart attack $ 2 0

7

,

4

3

4 -

$

2 2 4

, 3 6

1

a E. Wittels, J Hay, and A. Gotto, "Medical Costs of Coronary Artery Disease in the United States, ” American Journal of Cardiology 65 ”432-440,

1990,

b Flve_year costs discounted to their net present value at the time of the heart attack at an annual rate Of 5 perCent.

C M. Stampfer, G. Colditz, W. Willett, et al , “Postmenopausal Estrogen Therapy and Cardiovascular Disease Ten-Year Follow-Up from the Nurses’

Health Study, ” New England Journal of Medicine 325(11):756-762, 1991

SOURCES” Based on data from sources cited in the footnotes

(6%) occurred in women, aged 50-54; 40 extra

events per 1,000 patient-years (470) occurred in

women aged 55-59; and about 5 extra events per

1,000 patient-years (0.5%) occurred in women

aged 60-67. In an early cost-effectiveness study,

Weinstein and Schiff estimated that PERT would

induce abnormal bleeding in approximately 2.5

percent of patients (19). This estimate is similar to

the data from the Ettinger study, if a single estimate of relative risk is used for all ages.5 We therefore adopted 2.5 percent as an estimate of the

number of cases of abnormal bleeding that would

require an endometrial biopsy. Thus, $3 is added

to the annual cost of HRT with progestin therapy.

The total cost of estrogen/progestin treatment is

therefore $258.

The components of HRT (i.e., drugs, doctor

visits, tests) used in this model are similar to those

used in other analyses of HRT and osteoporosis

(5,15,16,19). Some analyses included only drug

costs (5,15) or used drug costs plus the costs of

physician visits to monitor treatment without

itemizing the costs of specific diagnostic procedures included in the treatment (16). Our cost

components and total cost estimates for HRT—

$269 per year for ERT and $258 for PERT—are

consistent with these cost estimates.

COST OF HEART DISEASE

The major cardiovascular impact of HRT is a potential reduction in the number of acute myocardial infarctions (AMIs) (i.e., heart attacks). The cost

of AMI used in our analysis, shown in table J-3,

reflects that of both fatal and nonfatal heart attacks.

The model assumes that there is a fixed ratio of

fatal to nonfatal heart attacks. Thus, for every

heart attack death assigned by the model, costs

would accrue both for that woman and for a given

number of additional women who would have

nonfatal heart attacks.

OTA used data from the Nurses’ Health Study

to estimate the ratio of fatal to nonfatal heart attacks (13). That study reported the incidence of

both fatal and nonfatal (confirmed and probable)

AMIs in 48,470 postmenopausal nurses followed

for 10 years. The observed ratio of nonfatal to fatal

AMIs in that sample was 2.6.

Data from the Framingham Heart Study, a large

ongoing study of heart disease incidence and outcome, gave cost estimates for fatal and nonfatal

heart attacks. The study categorizes coronary

artery disease into five events: acute myocardial

infarction, angina pectoris, unstable angina pectoris, sudden death, and nonsudden death. Using

these outcomes, Wittels and colleagues analyzed

1 If Ettinger’s estimates for the 60-67 year-old population is assumed to hold for older women as well, the average frequency across all ages

would be approximately 16 per 1000 patient-years ( 1.6%). But as the population ages, fewer women in the cohort are alive, so this simple average

underestimates the true average.
Appendix J: Methods for Estimating Costs 205

Medicare cost data, a pharmaceutical price survey,

and Houston area surveys to estimate five-year

costs including those for hospitalization, emergency room care, monitoring and testing, heart catheterization, and thrombolytic therapy resulting

from acute myocardial infarction (20). The final

cost estimates were based on these charges,

weighted by their frequency of occurrence.

In the Framingham study, sudden death was defined as a change within a l-hour period from a

stable clinical status to death. Nonsudden death

occurs when a patient admitted with a diagnosis of

AMI dies in the hospital. We used the costs of sudden and nonsudden death as the endpoints of the

range of estimates for the cost of a fatal AMI. In

1993 dollars, the costs of sudden and nonsudden

death from AMI were $14,470 and $31,397, respectively.

AMI patients in the Framingham Heart Study

who survived hospitalization had a five-year cost

(in 1993 dollars) of $81,630. This estimate was

not discounted over the five-year period, and it

also did not include costs incurred in years beyond

the five-year period of study. To better estimate

costs spread out over five years, the total was divided into five equal amounts, which were then

discounted to their present value at the time of the

heart attack at an annual discount rate of 5 percent.

We used this discounted cost—$74,217—as the

estimate of the cost of a nonfatal AMI.

Together, these estimates imply that for every

heart attack death, a cost of between $207,434 and

$224,361 is incurred in treating heart attacks, both

fatal and nonfatal. These estimates are consistent

with the few analyses that identify costs of AMI

by fatal and nonfatal outcomes (9).

The costs calculated for the Framingham study

included those for both men and women. If the

cost of treating a female AMI patient is different

from the cost of treating a male AMI patient, then

the estimates used in our model may be inaccurate. Also, the expected frequencies of events or

resource used in the Framingham study (based on

a cohort of Massachusetts residents) may not represent the national population of coronary artery

disease patients.

COST OF HIP FRACTURE

An analysis of the health care costs attributed to

hip fractures is provided in a separate OTA background paper (18). The total cost includes in-hospital and post-hospital expenses as shown in table

J-4. OTA used the inpatient hospital costs for patients between 50 and 64 years of age as the basis

for our estimate, because it is higher than the cost

for older women and therefore gives an optimistic

estimate of the cost savings associated with reductions in hip fractures. The total estimated cost (including long-term care costs) is $21,189 in 1990

dollars, or $22,914 in 1993 dollars (after adjusting

for inflation using the CPI-U for all items).

COST OF CHOLECYSTECTOMY

The cost of a cholecystectomy was obtained from

the rates (physician and hospital costs) allowed by

Blue Cross and Blue Shield of the Washington,

DC region (1 1). Open cholecystectomy, which

costs $11,160, was used as the basis for procedure

cost estimation. Laparoscopic cholecystectomy is

an increasingly frequent procedure costing

approximately $9,000. This estimate is consistent

with a previous analysis of gallstone treatments,

which calculated the costs for a cholecystectomy -

based on a 45-year-old female patient at between

$6,024 and $18,072 in 1993 dollars (3).

BREAST CANCER COSTS

There are no accurate data on the lifetime cost of

treating breast cancer. The existing literature provides estimates of some parts of cancer treatment,

but for this analysis we constructed age- and

stage-specific lifetime breast cancer cost estimates.
206 Cost Effectiveness of Screening for Osteoporosis

Hospital services

In-hospital physician

Anesthesia services

Radiologic services

Physical therapy

Total

$ 7,732

services 1,946

576

298

785

$11,337

In-hospital for persons age 65 and over

Hospital services

In-hospital physician services

Anesthesia services

Radiologic services

Physical therapy

Total

Post-hospital for persons of all ages

Nursing home care

Care in a rehabilitation facility or other short-stay hospital

Readmission to a short-stay hospital

Home health care

Nonmedical home care

Outpatient physician services

Emergency room and ambulance services

Total

Total cost of hip fracture for patients 50 to 64

Total cost of hip fracture for patients 65 and over

7,623

1,236

319

116

28

$9,32 2

7,054

742

440

453

329

550

284

$ 9,852

$21,189

$19,174

SOURCE U.S. Congress, Office of Technology Assessment, Hip Fracture Outcomes in People Age Fifty and Over-Background Paper, OTA-BPH-120 (Washington, DC U S. Government Printing Off Ice, July 1994).

The expected lifetime cost of treating breast

cancer varies with the number of years of survival

after detection, which is itself a function of both

age and stage at detection. Age-and stage-specific

l-year, 5-year, 10-year, and 15-year all-cause survival rates were provided to OTA by the National

Cancer Institute from its Surveillance, Epidemiol-ogy, and End Results (SEER) tumor registry

data6 (12). These data were used to estimate the

proportion of women who would live for 1 year, 3

years, 8 years, and 13 years (the midpoints of the

surviv-al intervals available in the SEER data).

Women who survive for at least 15 years were assumed to live 15 years plus the average life expectancy of U.S. women who reach an age equal to

their age of detection plus 15 years. For example, a

65-year-old who survives 15 years to age 80 is assumed to live the average life expectancy of other

80-year-olds.

2 The SEER data on cancer incidence, stage, and survival is based on tumor registries maintained in 10 cities.
Appendix J: Methods for Estimating Costs 207

Treatment Unadjusted cost Comorbidity costa Net attributable cost

Initial care

local 13,500 1,369 12,131

regional 14,470 1,369 13,101

distant 14,470 1,369 13,101

Continuing care 10,620/yr. 5,477/yr. 5,143/yr.

Terminal care 27,744 2,739 25,005

aComorbidity cost refers to the cost of treating patients for diseases unrelated to breast cancer.

SOURCES: M. Baker, L. Kessler, N. Urban, et al., “Estimating the Treatment Costs of Breast and Lung Cancer, ” Medical Care 29(1) 40-49, 1991

U.S. Congress, Office of Technology Assessment, Breast Cancer Screening for Medicare Beneficiaries: Effectiveness, Costs to Medicare and

Medical Resources Required (Washington, DC U.S. Government Printing Off Ice, November 1987)

For each combination of age and stage of cancer at detection, we assumed that a patient would

incur an initial cost in the year of cancer onset,

continuing care costs in each remaining year of

life, and terminal care costs in the final year of life.

Initial costs were assumed to vary with the stage of

cancer at detection, whereas continuing and terminal care costs were assumed constant across allages and stages. The age- and stage-specific

schedule of costs was constructed by combining

these cost parameters with the age- and stage-specific survival times and discounting the costs incurred over time to their present value in the year

of cancer detection at an annual rate of 5 percent.

Estimates of the cost of initial, continuing, and

terminal breast cancer care are available from a

study conducted by researchers at the National

Cancer Institute (2). That study used data on a

sample of Medicare patients to estimate the net

health care costs of each kind (initial, continuing,

and terminal) attributable to breast cancer.

The costs of initial care were not estimated by

stage in that study, however, so OTA broke down

the initial care cost into stage-specific costs using

information on initial care costs by stage provided

in another study (7,17). The resulting estimates of

initial, continuing, and terminal care costs used in

the construction of the age- and stage-specific

breast cancer costs are shown in table J-5.

The resulting age- and stage-specific lifetime

discounted costs are shown in table J-6.

ENDOMETRIAL CANCER COSTS

The osteoporosis prevention strategies tested in

this analysis are relevant to women with intact

uteri who are therefore at risk of endometrial cancer. The risk, prognosis, and treatments vary, depending on whether the woman is currently on

ERT or PERT at the time of diagnosis.

OTA assumed that endometrial cancer found

during HRT would have no excess associated

mortality. The woman would undergo a hysterectomy and face no permanent loss of vitality. The

procedure would affect costs only, not the length

of life. (See appendix G for the rationale underlying this assumption.)

The cost of a hysterectomy was estimated from

several published articles shown in table J-7. We

used a mid-range estimate (updated to 1993 dollars) of $6,000 to include all costs (physician fees

and hospitalization) associated with a hysterectomy.

If a woman is not on HRT at the time of diagnosis, the mortality risk depends on age and stage at

diagnosis. The costs for this scenario were estimated in a manner similar to that used for breast

cancer.
208 I Cost Effectiveness of Screening for Osteoporosis

Age

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

Stage A

$78,153

76,671

75,385

73,861

73,181

71,727

70,049

69,310

67,765

66,299

65,717

64,300

63,810

62,019

60,296

59,417

57,742

57,028

54,947

53,831

51,885

Stage B

$67,274

66,228

65,237

63,966

63,338

62,183

61,107

60,503

59,525

58,668

58,209

57,394

57,135

56,132

55,256

54,851

53,863

53,356

52,001

51,277

50,091

Stage C

$45,043

44,855

44,823

44,490

44,357

44,176

43,985

43,996

43,720

43,545

43,394

43,220

43,163

42,814

42,653

42,516

42,336

42,268

41,951

41,856

41,601

Age

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

Stage A

$50,849

49,250

47,340

45,605

43,951

42,293

40,825

39,127

37,542

35,414

33,403

31,637

29,572

27,703

24,941

22,334

20,056

18,209

16,673

12,616

Stage B

$48,598

47,527

46,161

44,911

43,818

42,685

41,824

40,514

38,638

37,169

35,869

34,781

33,515

30,667

28,835

27,156

25,791

24,528

19,099

15,837

Stage C

$41,285

41,173

40,893

40,679

40,619

40,375

40,352

39,778

39,071

38,497

37,960

37,433

36,655

35,044

34,364

33,643

33,089

32,533

27,503

26,230

aCosts recurred in years after detection are discounted to their present value at the age of detection at a rate of 5 percent per annum

SOURCE: Office of Technology Assessment, 1995

The initial, continuing, and terminal care costs

used in the estimation procedure are summarized

in table J-8. We used the endometrial cancer treatment guidelines described in a cancer textbook(6)

to determine the components of the cost model.

The initial cost was the cost of a hysterectomy if

the cancer was detected at stage I or stage 11. We

used $6,000 for the cost of a hysterectomy as described above. Endometrial cancers found at more

advanced stages (III or IV) are usually treated initially with intense radiation therapy. This cost was

obtained from Blue Cross & Blue Shield average

submitted charges for several clinical brachytherapy treatments (CPT codes 77750,77761,77762,

77776, 77777) (10). The average cost of these procedures was about $600, and assuming that the

cost of radiation therapy increases with increasing

dosage, we estimated that the initial treatment cost

would be $1,200. The continuing cost was the

annual cost of radiation therapy, $600, for no more

than eight years of treatment, and the cost of annual doctor visits, $200. After consulting with an

analyst at the National Cancer Institute (4), we assumed that the terminal care cost for endometrial

cancer is the same as the terminal care cost of

breast cancer, or $25,005.

These endometrial cancer costs were used in estimating discounted lifetime cancer costs by age

and stage of onset in a cost model similar to the
Appendix J: Methods for Estimating Costs 209

Source Treatment costs Data

Summitt et al., 1992

Kovac et al., 1991

Health Care

Financing

Administration, 1991

Blue Cross & Blue

Shield, 1990 (Lapp,

1 993)

Tosteson et al., 1990

Average hospital charge for a laparoscopyassisted vaginal hysterectomy: $7,905

Average hospital vaginal hysterectomy

charge: $2,831.05

Average hospital abdominal hysterectomy

charge: $3,584.82

Average hospital vaginal hysterectomy

charge: $2,831.05

Average physician charge for an abdominal

hysterectomy: $2,020 (submitted) $890

(allowed)

Average submitted charges for physician

services for a total abdominal hysterectomy:

$1,906

Abdominal hysterectomy: $4,900 (based on

stage 1, charge includes hospital care and

Cost data collected from women undergoing

vaginal hysterectomies at the University of

Tennessee, Memphis Gynecological Clinic.

Based on data collected from all patients

undergoing hysterectomies in a St. Louis

Missouri hospital between January 1, 1986

and December 31, 1986.

Medicare Part B data, Office of Research and

Demonstrations

Based on data gathered from 40 Blue Cross

plans (New York and California not included.)

Physician fees based on Medicare prevailing

charges or charges at selected Boston-area

professional fees) teaching hospitals

SOURCES: R.L. Summitt, Jr., T.G. Stovell, G.H. Lipscomb, et al., “Randomized Comparison of Laparoscopy-Assisted Vaginal Hysterectomy with

Standard Vaginal Hysterectomy in an Outpatient Setting,” Obstetrics and Gynecology 80(6):895-901, 1992, S R Kovac, S.J. Christie and G.A.

Bindbeutel, “Abdominal Versus Vaginal Hysterectomy’ A Statistical Model for Determining Physician Decision Making and Patient Outcome, ” Medical Decision Making 11(1):19-28, 1991, J. Petrie, U S Department of Health and Human Services, Health Care Financing Administration, personal

communication, July 1993; R. Lapp, Manager for Provider Strategy, Blue Cross&Blue Shield Association, Center for Health Economics and POIicy

Research, Chicago, IL, personal communications, July 18, 1993, and July 23, 1993; A.N.A. Tosteson, D.I. Rosenthal, J Melton, Ill, et al., “Cost

Effectiveness of Screening Perimenopausal White Women for Osteoporosis: Bone Densitometry and Hormone Replacement Therapy, ” Anna/s of

Internal Medicine 113(8):594-603, 1990.

Initial care:

All stages

(hysterectomy) $6,00 0

Stages Ill and IV (radiation treatment) 1,200

Continuing care:

Annual doctor visits 200

Annual radiation therapy 600

Terminal care 25,005

one for breast cancer. The lifetime costs due to endometrial cancer were discounted by 5 percent per

year to the age of onset and weighted by the probability of surviving for different lengths of time,

based on age- and stage-specific all-cause survival

rates provided to OTA by the National Cancer

Institute (12). These costs are shown in table J-9

(see page 210).

SOURCE: Office of Technology Assessment, 1995
210 I Cost Effectiveness of Screening for Osteoporosis

Age Stage A Stage B Stage C Age Stage A Stage B Stage C

50 $15,702 $20,203 $21,552 71 $15,178 $21,482 $22,964

51 15,796 20,467 21,679 72 15,297 21,677 23,064

52 15,925 20,635 21,804 73 15,418 21,891 23,166

53 16,018 20,888 21,964 74 15,599 21,993 23,220

54 16,053 20,985 22,027 75 15,780 21,177 23,322

55 16,207 21,241 22,227 76 15,837 22,119 23,151

56 16,286 21,370 22,317 77 15,941 22,136 23,005

57 16,317 21,509 22,376 78 16,048 22,167 22,863

58 16,394 21,681 22,521 79 14,949 21,015 21,970

59 16,491 21,862 22,623 80 15,114 21,178 21,927

60 16,519 21,932 22,713 81 15,254 21,291 21,882

61 16,581 22,138 22,810 82 15,401 21,474 21,848

62 16,610 22,154 22,860 83 15,742 21,588 21,806

63 16,670 22,351 22,988 84 13,643 19,375 21,028

64 16,733 22,473 23,055 85 13,605 19,438 20,993

65 16,781 22,549 23,165 86 13,525 19,443 20,935

66 16,807 22,660 23,158 87 13,505 19,509 20,892

67 16,831 22,726 23,177 88 13,517 19,648 20,880

68 16,898 22,851 23,224 89 8,990 13,546 15,996

69 16,920 22,907 23,238 90 8,635 13,418 15,890

70 17,014 23,021 23,292 —

aCosts incurred in years after detection are discounted to their present value at the age of detection at a rate of 5 percent per annum

SOURCE: Office of Technology Assessment, 1995

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4.

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Appendix J: Methods for Estimating Costs 211

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(Washington, DC: U.S. Government Printing

Office, November 1987).

18. U.S. Congress, Office of Technology Assessment, Hip Fracture Outcomes in People Age

Fifty and Over—Background Paper, OTABP-H-120 (Washington, DC: U.S. Government Printing Office, July 1994).

19. Weinstein, M. C., and Schiff, I., “Cost-Effectiveness of Hormone Replacement Therapy in

the Menopause,” Obstetrical and Gynecological Survey 38(8):445-455, 1983.

20. Wittels, E. H., Hay, J.W., and Gotto, A. M., Jr.,

“Medical Costs of Coronary Artery Disease in

the United States,” American Journal of Cardiology 65(7):432-440, 1990.
1,25 OH2D3

ACOG

AHCPR

AMI

BMC

BMD

CEA

CHD

CVA

CVD

DES

DEXA

DHHS

DPA

ERT

FDA

HCFA

HDL

HRT

IHD

IU

IV

calcitriol or 1,25

dihydroxyvitamin D3

American College of

Obstetricians and Gynecologists

Agency for Health Care Policy

and Research (DHHS)

acute myocardial infarction

bone mineral content

bone mineral density

cost-effectiveness analysis

coronary heart disease

cerebrovascular accident

cardiovascular disease

diethylstilbestrol

dual energy x-ray absorptiometry

U.S. Department of Health and

Human Services

dual photon absorptiometry

estrogen replacement therapy

Food and Drug Administration

(DHHS)

Health Care Financing

Administration (DHHS)

high-density lipoprotein

cholesterol

hormone replacement therapy

ischemic heart disease

international units

intravenous

Appendix K:

Abbreviations

and

Glossary K

LDL

MI

MPA

MRI

NCI

NHLBI

NIA

NIAMS

NIDDK

NIH

NOF

OB-GYN

OHTA

OTA

PEPI

PERT

PHS

QALY

low-density lipoprotein

cholesterol

myocardial infarction

medroxyprogesterone acetate

magnetic resonance imaging

National Cancer Institute (NIH)

National Heart, Lung, and Blood

Institute (NIH)

National Institute on Aging (NIH)

National Institute of Arthritis,

Musculoskeletal and Skin

Diseases (NIH)

National Institute of Diabetes and

Digestive and Kidney Diseases

(NIH)

National Institutes of Health

(DHHS)

National Osteoporosis Foundation

obstetrics and gynecology

Office of Health Technology

Assessment (AHCPR)

Office of Technology Assessment

Postmenopausal Estrogen/

Progestin Interventions Trial

combined estrogen/progestin

replacement therapy

Public Health Service

quality-adjusted life year

1213
214 Cost Effectiveness of Screening for Osteoporosis

QCT quantitative computed

tomography

SC subcutaneous

SPA single photon absorptiometry

SXA single photon x-ray

absorptiometry

19-nortestosterone

A form of progestin.

Amenorrhea

The absence or abnormal cessation of menstruation.

Anabolic steroid

Any of a group of synthetic derivatives of the androgen testosterone (a sex steroid or hormone)

having pronounced anabolic properties and relatively weak androgenic properties. Anabolic steroids such as dromostanolone, ethylestrenol,

nandrolone, oxandrolone, oxymetholone, and stanozolol are used clinically mainly to promote

growth and repair of body tissues in senility, debilitating illness, and convalescence.

Androgen (or androgenic hormone)

Naturally occurring male sex hormones (e.g., testosterone, androsterone, and dehydroepiandrosterone) and substances that exert biological effects

characteristic of these hormones (e.g., the synthetic compound methyltestosterone). Androgens inhibit bone resorption and increase calcium

absorption in the intestine, but also have serious

side effects.

Androgenic

Any substance, e.g., androsterone and testosterone, that stimulates male characteristics.

Angina

Any spasmodic, choking, or suffocating pain. The

term is often used to denote angina pectoris—a

condition characterized by severe, transient chest

pain, accompanied by a feeling of suffocation, is

due to a deficiency in blood supply to the heart.

Angiography

See arteriography.

USP DI U.S. Pharmacopoeia Dispensing

Information

VLDL very low-density lipoprotein

cholesterol

Anovulation

The absence of ovulation (development and release of an ovum from the ovary).

Appendicular skeleton

The bones of the extremities, including all of the

bones of the limb girdles.

Arteriography

A diagnostic procedure that allows blood vessels

to be seen on X-ray film after the injection of contrast material into the bloodstream; used to detect

abnormalities such as obstructions, aneurysms,

clots, tumors, and injured organs.

Arteriosclerosis

A general term that describes thickened and hardened arteries, the condition that leads to most

cases of heart disease and a significant proportion

of cerebrovascular disease in the United States.

Atherogenesis

The formulation of patchy plaques of fatty or lipid

material on the inner lining of the arteries, restricting blood flow and encouraging the development

of blood clots; can result in sudden stoppage of

blood flow to the heart.

Atherosclerosis

A descriptive term for thickened and hardened lipid-rich lesions of the medium and large muscular

arteries; classified into two forms: early lesions,

consisting of fatty streaks, and advanced lesions,

consisting of fibrous plaques; commonly occurs

in arteriosclerosis, in which deposits of fibrous

and cellular tissue, cholesterol, and fat accumulate

in large and medium-sized arteries, impeding

blood flow; responsible for the majority of cases

of myocardial and cerebral infarction.

Axial skeleton

The spine, ribs, sternum, and skull.
Appendix K Abbreviations and Glossary 1215

Bilateral oophorectomy

Surgical removal of both ovaries.

Bioavailability

The degree to which a drug or other substance becomes available to the target tissue after administration.

Bioequivalence

The requirement that a generic product include the

same therapeutic ingredient, and that its rate and

extent of absorption be the same as the innovative

product.

Bisphosphonates

Chemical compounds developed during the past

20 years for treatment of various bone diseases.

Basically, they are carbon-substituted analogues

of pyrophosphate (an endogenous physiologic inhibitor of bone mineralization).

Several bisphosphonates are under investigation as therapeutic agents for osteoporosis, among

them etidronate, clodronate, tiludronate, pamidronate, risedronate, and alendronate. Bisphosphonates are considered experimental

(investigational) in the prevention and treatment

of osteoporosis in the United States.

Blinding

A technique used in a randomized clinical trial

(RCT) to prevent bias by preventing the patients

and/or investigators involved in the trial from

knowing which participants are receiving which

treatment. In a single-blind RCT, the patients in

the trial are “blind” as to which individuals in the

study are receiving the experimental or control

treatment. In a double-blind RCT, both the investigators and the patients are “blind” as to which

individuals in the study are receiving the experimental treatment and which are receiving control

treatment. Additional layers of blinding can be

added, as, for example, when a third individual

(usually the evaluator of outcomes, the individual

analyzing the data) also is unaware of treatment

assignments.

Body mass index (BMI)

Weight in kilograms divided by height in meters

squared. A measure used to define normal ranges

of body weight.

Bone

A specialized connective tissue in which a matrix

consisting of collagen fibers, a large variety of

other proteins and ground substances is impregnated with a solid mineral. Bone is the dynamic

and complex tissue of which the bones in the adult

skeleton of humans and other vertebrates is largely composed. The skeleton is composed of two

kinds of bone: an outer, dense shell of cortical (or

compact or haversian) bone and an inner, open,

sponge-like region of cancellous (or trabecular)

bone. About 80 percent of the mass of the skeleton

is cortical bone, and 20 percent is cancellous bone.

Bone densitometry

A term used to refer to a range of noninvasive

techniques that use a densitometer to measure the

density of bone (e.g., SPA, DEXA, DPA, SXA)

and is used to detect osteoporosis.

Bone density

The mass of bone substance per unit volume

(g/cm3

).

Bone mineral content (BMC)

The mass of bone divided by the one dimensional

length of bone measured expressed as grams per

cm.

Bone mineral density (BMD)

The mass of bone divided by the two dimensional

projected area of the bone measured, expressed as

mass per unit area (g/cm2).

Calcaneus

The heel bone.

Calcitonin, human

One of the three calcium-regulating hormones in

humans, the others being human parathyroid hormone (hPTH) and calcitriol.

Calcitriol (1,25 OH2D3

, 1,25-dihydroxyvitamin D3 or 1,25-dihydroxycholecalciferol)

One of several vitamin D metabolizes.

Calcium

The most abundant mineral element in the human

body. In humans, calcium is an essential nutrient

not only for the normal mineralization of bones
216 Cost Effectiveness of Screening for Osteoporosis

and teeth but also for regulating intracellular

events in most, if not all body tissues.

Cancellous (or trabecular) bone

The inner, open, sponge-like region of bone prevalent in the vertebrae and in the pelvis, the main

sites of osteoporotic fractures. About 20 percent

of the mass of the skeleton is cancellous bone.

Compare cortical bone.

Carcinogen

An agent that causes cancer (e.g., certain chemicals, ionizing radiation, tobacco smoke, asbestos

fibers, and estrogen).

Carcinoma

A cancer arising from epithelial cells, including

the external epitheliums (mainly skin and linings

of the gastrointestinal tract, lungs, and cervix) and

the internal epitheliums that lines various glands

(e.g., breast, pancreas, uterus, and thyroid).

Cardiac arrhythmias

Variations from the normal rate or rhythm of heart

beats.

Cardiac catheterization

Passage of a small catheter through a vein or artery

into the heart for the purpose of securing blood

samples, determining intracardiac pressures, and

detecting cardiac anomalies.

Cardiovascular disease (CVD)

Any of a diverse group of diseases affecting the

heart, blood vessels, and/or blood circulation.

CVD includes diseases of the heart muscle itself,

ischemic heart disease, hypertension, cerebrovascular diseases, and various other conditions.

Case-control study

A type of observational study, where the frequency of a suspected causative factor, such as estrogen

use, is compared in a group of people who have a

disease (cases) and those who do not (controls). If

this factor is found with greater frequency in those

with disease, a causal association may be suspected. Results of the comparison may be expressed as the relative risk. See relative risk.

Cerebral infarction

An area of dead tissue in the cerebrum caused by

an interruption of blood circulation due to functional constriction or actual obstruction of a blood

vessel, hemorrhage, etc. Also known as a stroke

or cerebrovascular accident (CVA).

Cerebrovascular disease

Any disease of the blood vessels supplying blood

to the brain or of the brain’s covering membranes

(meninges), characterized by rupture of the blood

vessels or inadequacy of blood to the brain. Common causes include atheroma, hypertension, cerebral thrombosis, or embolism.

Cholecystectomy

Surgical removal of the gall bladder.

Cholesterol

A sterol present in animal tissues (e.g., cell membranes, blood plasma, and lipoproteins), involved

in physiological processes, such as the manufacture of bile acids, sex hormones, and adrenocorticoid hormones; also involved in the development

of pathological processes such as atherosclerosis.

See also high-density lipoprotein cholesterol and

low-density lipoprotein cholesterol.

Climacteric

The syndrome of endocrine, somatic, and psychic

changes occurring at the end of the female reproductive period (menopause).

Clinical trial (also called therapeutic

trial)

A research activity that involves the administration of an experimental prophylactic, diagnostic,

or therapeutic agent, device, regimen, procedure,

etc. to humans to evaluate its safety and effectiveness. The term is subject to wide variation in

usage, from the first use in humans without any

control treatment to a rigorously designed and

executed experiment involving test and control

treatments and randomization. See also randomized clinical trial (RCT).

Coagulation

The process of certain particles joining together to

form larger masses.
Appendix K Abbreviations and Glossary 1217

Coagulation proteins

Proteins found in the plasma that aid in the coagulation process of blood (e.g., Factor VIII, Factor

IX. antihemophilic factor, or prothrombin). Also

called “clotting factors.”

Cohort study

A type of observational study, where the investigator begins with a group of subjects (the “COhort”), some or all of whom are exposed to a

suspected causative factor, and follows this cohort

over time for development of a disease. Comparison is made with a control group composed of unexposed members of the cohort (internal

controls), or to subjects outside the cohort who

are similar to members of the cohort, but who have

not been exposed to the suspect factor (population, community, or external controls).

Cones fracture

Fracture of the wrist.

Compact bone

See cortical bone

Comparison group

In a cohort study, the group of unexposed members to which the exposed members are compared.

In case-control studies, the group of subjects without disease to which the subjects with disease (the

cases) are compared.

Confidence interval

Conventionally, a 95-percent confidence interval

is used, which implies that there is a 95-percent

chance that the true relative risk being measured

falls within the interval, and a 5-percent risk that

it does not.

Confounding variables

Variables related to both the disease and the exposure under study that can explain or alter all or part

of an observed association.

Conjugated estrogens

An amorphous preparation of naturally occurring,

water-soluble, conjugated forms of mixed estrogens, chiefly sodium estrone sulfate, extracted

from the urine of pregnant mares; suitable for parenteral, oral, and topical administration and used

in estrogen hormone therapy. The conjugated estrogens have pharmacologic effects similar to

those of endogenous estrogens.

Consensus conference

A meeting of scientists, medical practitioners, and

informed lay people to review scientific information about biomedical technologies and to

develop a consensus statement on the clinical application of current medical findings.

Coronary artery bypass graft (CABG)

surgery

A surgical procedure in which a vein or an artery

is used to bypass a constricted portion of one or

more coronary arteries. This procedure has become the primary surgical approach to the treatment of coronary artery disease.

Coronary artery disease (CAD)

Narrowing or blockage of the coronary arteries,

which usually results in reduced blood flow to the

heart muscle.

Coronary perfusion

The pumping of a fluid through the heart by way

of an artery.

Cortical (or compact or haversian) bone

The dense outer shell of bone. One of the two general structural categories of the bone tissue making up the skeleton, cortical bone consists of

tightly packed layers of bone. It forms the outer

shell of all bones and is prevalent in the shafts of

the long bones of the arms and legs. About 80 percent of the mass of the skeleton is cortical bone.

Compare cancellous bone.

Cost-effectiveness analysis (CEA)

An analytical technique that compares the costs of

a project or of alternative projects to the resultant

benefits, with costs and benefits/effectiveness expressed by different measures. Costs are usually

expressed in dollars, but benefits/effectiveness are

ordinarily expressed in terms such as “lives

saved,” “disability avoided,” “quality-adjusted

life-years saved,” or any other relevant objectives.

Cross-sectional study

In epidemiology, an observational study that examines the relationship between diseases (or other

health-related characteristics) and other variables
218 Cost Effectiveness of Screening for Osteoporosis

of interest as they exist in a defined population at

one particular time. The temporal sequence of

cause and effect cannot necessarily be determined

in a cross-sectional study.

Cyclic regimen

Interrupted episodes with ongoing medication. In

cyclic regimens of estrogen and progestin, estrogen is usually given for 21 days each month, and

a progestin is given with estrogen for the last 7 to

14 days of those 21 days.

Densitometry

See bone densitometry

Diethylstilbestrol (DES)

A synthetic estrogenic compound used to treat

menopausal symptoms, vaginitis, and suppressed

lactation.

Discounting

A procedure used in economic analysis to express

as “present values” those costs and benefits that

will occur in future years. Discounting is based on

two premises: 1) individuals prefer to receive

benefits today rather than in the future; and 2) resources invested today in alternative programs

could earn a return over time.

Double blind

See randomized clinical trial (R CT) and blinding.

Dual energy x-ray absorptiometry

(DEXA)

A bone densitometry technique similar to DPA

but uses an x-ray machine rather than a radioactive

material to produce a dual-energy radiation beam.

Different manufacturers use different terms for

this technology (e.g., quantitative digital radiography (QDR), dual-energy radiography (DER),

dual energy radiographic absorptiometry (DRA),

and dual x-ray absorptiometry (DXA).

Dual photon absorptiometry (DPA)

A bone densitometry technique that uses a dualenergy radioactive material (usually gadolinium- 153) as the source of a dual-energy radiation

beam; the dual-energy beam allows measurement

of bone and soft tissue without the necessity of encasement in water required in SPA or SXA. The

site of measurement for DPA is typically the hip

or spine. DPA is sometimes used to measure bone

mass in the whole body and can be used to measure bone mass in the forearm, distal radius

(wrist), and calcaneus (heel).

Duration of exposure

The length of time a person or test animal is exposed to a chemical.

Dysmenorrhea

Difficult and painful menstruation.

Dyspareunia

Difficult or painful coitus/intercourse in women.

Dysuria

Painful or difficult urination.

Effectiveness

The same as efficacy (see below) except that it refers to “. . . average or actual conditions of use.”

Efficacy

The probability of benefit to individuals in a defined population from a medical technology applied for a given medical problem under ideal

conditions of use. Efficacy is generally evaluated

in controlled trials of an experimental therapy and

a control condition. Compare to effectiveness.

Endogenous

Produced within or caused by factors within the

organism.

Endometrial biopsy

The microscopic examination of a sample of cells,

obtained from the lining of the uterus, in order to

evaluate ovulatory function and/or to detect the

presence of hyperplasia, dysplasia, or cancer.

Endometrium

The tissue lining the inner uterus, the thickness

and structure of which vary with the phase of the

menstrual cycle.

Endothelium

The layer of epithelial cells that lines the cavities

of the heart and of the blood and lymph vessels,

and the serious cavities of the body.

Epidemiological studies

Studies concerned with the relationships of various factors determining the frequency and dis-
Appendix K Abbreviations and Glossary 219

tribution of specific diseases in a human

community.

Epidemiology

The scientific study of the distribution and occurrence of human diseases and health conditions,

and their determinants.

Equine estrogen

Estrogen pertaining to, characteristic of, or

derived from the horse. See conjugated estrogens.

Erythema

Redness of skin due to congestion of the capillaries.

Esterified estrogen

A mixture of the sodium salts of sulfate esters of

estrogenic substances; used for oral estrogen therapy.

Estradiol

The most potent naturally occurring estrogen in

humans.

Estrogen

A generic term for estrus-producing compounds;

the naturally occurring female sex hormones, including estradiol, estriol, and estrone. The term

also refers to substances occurring in plants or

made synthetically (as benzestrol or diethylstilbestrol) that have biologic activity similar to that

of estrogens produced in the ovaries of female

mammals.

Estrogen replacement therapy (ERT)

The use of estrogen for the relief of menopausal

symptoms, e.g., hot flashes, the prevention of

heart disease, and the prevention of osteoporosis.

Estrone

An estrogen isolated from pregnancy urine, the

human placenta, and palm kernel oil, and also prepared synthetically.

Etidronate

A bisphosphonate (C2H6NA207P2) that was patented as a therapeutic agent for calcium disorders

in 1972 by Procter& Gamble, parent company of

Norwich Eaton Pharmaceuticals, Inc. Oral etidronate is indicated for the treatment of Paget’s disease and some other conditions, but it has not been

approved by FDA for osteoporosis. As of 1995,

etidronate was the only bisphosphonate available

on the U.S. market. Neither etidronate nor any

other bisphosphonates have been approved by

FDA for indications related to osteoporosis.

Etiology

The cause or origin of disease.

Exogenous estrogen

Estrogen that is not produced within the body but

is provided by other means, e.g., tablets, injection,

cream.

External controls

In a cohort study, individuals not part of the cohort

and who have not been exposed, with which the

exposed members of the cohort are compared. In

a clinical trial, individuals not formally enrolled

in the trial who have had an alternative treatment,

with which the experimentally treated group is

compared. External controls may be historical or

concurrent.

External validity

A measure of the extent to which study results can

be generalized to the population that is represented by individuals in the study, assuming that

the characteristics of that population are accurately specified.

Femur

The thigh bone, the bone that extends from the hip

to the knee. It is the longest and largest bone in the

body.

Fibrin

A white insoluble protein formed at the site of an

injury from fibrinogen that becomes the foundation of a blood clot.

Fibrinogen

A soluble plasma protein synthesized in the liver,

which is involved in blood coagulation as the precursor of fibrin. Also called “Factor I.”

Fibroblast

A connective tissue cell, found in the skin.

First-pass hepatic effect

See hepatic effect.
220 Cost Effectiveness of Screening for Osteoporosis

Functional impairment

A deficit in an individual’s ability to function independently. Functional impairments in elderly

people are often described in terms of deficits in

activities of daily living (ADLs) and instrumental

activities of daily living (IADLs).

Grade

The histological appearance of a cancer cell. In

oncology, the classification of cancer according to

the degree of differentiation of the cancer cell.

More differentiated cell types are generally less

malignant.

Haversian bone

See cortical bone.

Healthy user effect

A phenomenon in epidemiologic studies in which

subject participants exhibit lower incidence of

morbidity or mortality than the general population

because they are generally in good health while

the less healthy either choose not to participate in

the study or are excluded.

Hemostatic

The arrest of bleeding, whether by the physiological properties of vasoconstriction and coagulation

or by surgical means.

Hepatic effect

Pertaining to the liver, the metabolism of estrogen

by the liver.

Hepatobiliary

Related to the gallbladder.

High-density lipoprotein cholesterol

(HDL)

A class of cholesterol; low levels of HDL are

associated with an increased risk of heart attack.

Histology

Microscopic anatomy. The study of the minute

anatomical structure, composition, and function

of the tissues.

Historical controls

In nonrandomized clinical trials, individuals

treated with a “control treatment” outside the

study proper, at some time previous to the trial,

against which the experimentally treated individuals are compared. In a cohort study, unexposed

individuals outside of the cohort, at some time

previous to the cohort observation period, against

which the exposed members of the cohort are

compared.

Hormone

A specific organic product of living cells that,

transported by body fluids, produces a specific effect on the activity of cells remote from its point

of origin (e.g., metabolism, growth, and the development of secondary sex characteristics, such as

breasts and facial hair). Examples of such hormones include insulin, estrogen, progestin, testosterone, adrenaline, and thyroxine. Also a

synthetic substance that resembles a naturally occurring hormone in producing a specific biological effect.

Hormone replacement therapy (HRT)

This term describes either estrogen replacement

therapy or combined estrogen and progestin replacement therapy when a distinction is not necessary.

Hospital-based case-control studies

In this type of study, all cases diagnosed with the

disease under study in one or more hospitals are

compared with patients in the same hospitals who

do not have the disease.

Hot flash

Sudden sensations of heat and flushing of the face

and torso, associated with menopause.

Hypermenorrhea

Excessive menstrual bleeding, but occurring at

regular intervals and being of usual duration.

Hyperplasia

Abnormal increase in the number of normal cells

in normal arrangement in an organ or tissue,

which increases its volume.

Hypertension

Elevated pressure, usually referring to high blood

pressure—a common and significant cardiovascular disorder characterized by persistently high

arterial blood pressure, usually greater that

140mm Hg systolic and 90mm Hg diastolic pressure.
Appendix K Abbreviations and Glossary 122I

Hypertriglyceridemia

An excess of triglycerides in the blood.

Hysterectomy

Surgical removal of the uterus, in some cases also

including the cervix, ovaries, oviducts, and pelvic

lymph nodes.

In vitro

Literally “in glass”; pertaining to a biological process or reaction taking place in an artificial environment, usually a laboratory.

In vivo

Literally “in the living”; pertaining to a biological

process or reaction taking place in a living cell or

organism.

Incidence

In epidemiology, the number of new cases of disease, infection, or some other event having their

onset during a prescribed period of time in relation

to the unit of population in which they occur. The

incidence rate is the number of new cases of specified disease divided by the number of people in

a population over a specified period of time, usually 1 year.

Infarction

Necrosis (death) of tissue, resulting from the interruption of blood supply (e.g., as in a heart attack

(myocardial infarction)).

Internal controls

A control group composed of unexposed members of a cohort. See cohort study.

Internal validity

A measure of the extent to which study results reflect the true relationship of a “risk factor” (e.g.,

treatment or technology) to the outcome of interest in study subjects.

Ischemia

Insufficient blood supply to meet the full physiologic needs of the tissue for oxygen (but short of

the degree of ischemia that results in necrosis),

usually due to atherosclerosis, but also due to injury to blood vessels, muscle spasm, or inefficient

pumping of the heart.

Ischemic heart disease (IHD)

A spectrum of conditions caused by insufficient

oxygen supply to the heart muscle, and the leading

cause of death in the United states. The most common manifestations of IHD are angina. acute

myocardial infarction (heart attack), and sudden

death.

Latency

Time since first exposure to a suspected causative

factor.

Latent effect

A reaction to a substance that is not immediately

evident but that appears later in life; also referred

to as a silent effect.

Life expectancy

An expected number of years of life based on statistical probability.

Lipids

A group of organic compounds, classified into

complex lipids (e.g., fatty acids, phospholipids,

cholesterol) and simple lipids (e.g., steroids). Lipids are central to a wide variety of metabolic and

structural functions in the body, such as energy

storage, formation of hormones and bile acids,

and structure of cell membranes.

Lipoprotein

Compounds consisting of lipids (fatty substances

such as cholesterol) and proteins, the form in

which lipids are transported in the blood and

lymph fluid. Lipoproteins form the main structural components of cell membranes and cell organelles. They are classified as very low-density

(VLDL), low-density (LDL), and high-density

(HDL) lipoprotein cholesterol.

Low-density lipoprotein cholesterol

(LDL)

A class of cholesterol; high levels of LDL are

associated with a greater risk of heart attack.

Magnetic resonance imaging (MRI)

A diagnostic technique that produces cross-sectional images of organs and structures in the body

by measuring the reaction of nuclei (typically of

hydrogen protons) in magnetic fields to radio fre-
222 Cost Effectiveness of Screening for Osteoporosis

quency waves. MRI has also been used to measure

bone density.

Matching

A method of minimizing the impact of confounding factors. Controls may be matched to cases to

try to minimize other differences between groups.

Matching may be done with groups of subjects

(stratification) or with individuals, and may be

done with highly specific characteristics, such as

age, age at menopause, family history of the disease, etc.

Medicare

A nationwide, Federally administered health insurance program authorized by Title XVIII of the

Social Security Act in 1965 to cover the cost of

hospitalization, medical care, and some related

services for eligible persons over age 65, persons

receiving Social Security Disability Insurance

payments for 2 years, and persons with end-stage

renal disease. Medicare consists of two separate

but coordinated programs—hospital insurance

(Part A) and supplementary medical insurance

(Part B). Health insurance protection is available

to insured persons without regard to income.

MEDLINE database

The original, largest, and most utilized database in

the National Library of Medicine’s computerized

retrieval and technical processing system. MEDLINE contains references to biomedical and other

literature relevant to health and health services.

Medroxyprogesterone acetate (MPA)

A form of progestin. Also known as Provera

(Wyeth-Ayerst). In the United States, MPA is the

most commonly used progestin in combined estrogen/progestin replacement therapy.

Membership bias

Bias introduced when the group or cohort being

studied is unrepresentative of the population at

large, so that comparisons and extrapolations to

the population group are unjustified.

Menarche

The onset of menses at puberty.

Menopausal syndrome

Symptoms associated with menopause, e.g., hot

flashes, vaginal dryness, osteoporosis.

Menopause

Cessation of menstruation; the immediate postreproductive phase of a woman’s life, when

menstrual function ceases due to failure to form

ovarian follicles and ova. Menopause occurs naturally around the age of 50. Menopause is also a

secondary consequence of surgical removal of the

ovaries, and of certain illnesses (e.g., premature

ovarian failure).

Menorrhagia

Excessive menstruation.

Menses

The monthly flow of blood from the female genital tract.

Meta-analysis

A statistical process used to pool results from a

number of studies (e.g., from many small randomized clinical trials) to enable the demonstration of

statistically significant differences when the results are combined.

Metastasis

The process by which malignant cells spread to

distant body sites via the lymphatic circulation

of the bloodstream; also, a secondary malignant

tumor.

Metrorrhagia

Uterine bleeding, usually of normal amount, occurring at completely irregular intervals, the period of flow sometimes being prolonged.

Morbidity

The condition of being ill or otherwise afflicted

with an unhealthful condition.

Morbidity rate

The rate of illness in a population, calculated as

the number of people ill during a time period divided by the number of people in the total population; used to refer to incidence or prevalence rates

of disease.

Mortality rate

The death rate, often made explicit for a particular

characteristic; e.g., age, sex, or specific cause of
Appendix K Abbreviations and Glossary 223

death. A mortality rate contains three essential

elements: 1 ) the number of people in a population

group exposed to the risk of death (the denominator); 2) a time factor; and 3) the number of deaths

occurring in the exposed population during a certain time period (the numerator).

Myocardial infarction (Ml)

Heart attack. Sudden necrosis (death) of tissue in

the myocardium (heart muscle) characterized by

severe, unremitting chest pain. leading to arrhythmias and/or heart failure; in most cases, caused by

coronary atherosclerosis (obstruction of coronary

vessels, leading to insufficient blood supply to the

heart muscle).

Myocardium

Muscle of the heart.

Natural estrogen

An estrogen derived from natural sources, (i.e.,

not synthetic), such as conjugated equine estrogens, estradiol, or estriol.

Natural menopause

Menopause that occurs as a natural part of the aging process; not surgically induced.

Naturally occurring estrogenic

hormones

Female sex hormones produced by the ovaries, the

placenta, testes, and possibly the adrenal cortex.

Neoplasm

Uncontrolled and progressive growth of tissue, either benign or malignant; a tumor.

Nested case-control studies

Case-control studies conducted, or “nested,”

within a cohort group.

Nonischemic heart disease

Heart disease from causes other than coronary

artery disease (e.g., congenital heart disease, myocardiopathy).

Norethidrone acetate

.4 progestational agent similar in action to progesterone.

(e.g., case-control studies, cross-sectional studies,

and cohort studies). Such studies are the traditional source of information on suggestive associations in epidemiology.

Occlusion

In the context of the vascular system, the blocking

off or obstruction of blood flow through a vessel.

Odds ratio

A measure of association closely related to relative risk; the ratio of the odds of a disease occurring in individuals exposed to the risk compared

to those unexposed. For large samples, the odds

ratio is essentially equal to the relative risk.

Oligomenorrhea

Abnormally infrequent menstruation.

Oophorectomy

Excision of one or both ovaries.

Opposed estrogen

Estrogen used in conjunction with progestin.

Osteoblast

A cell arising from a fibroblast, which, as it matures, is associated with bone production.

Osteopenia

A reduction in the amount of bone mass, leading

to fractures after only minimal trauma.

Osteoporosis

A systemic skeletal disease characterized by low

bone mass and microarchitectural deterioration of

bone tissue, with a consequent increase in bone

fragility and susceptibility to fracture.

P value

In epidemiologic studies, the probability of concluding that a statistical association exists between, for instance, a risk factor and a health

endpoint, when, in fact, there is no real association; the likelihood that an observed association in

a study is due to the play of chance. Also called

“Type I error” or “alpha,” and commonly called

the level of significance. See significance level.

Observational study

An epidemiologic study in which the experiences

of the groups being compared are simply observed
224 Cost Effectiveness of Screening for Osteoporosis

Parathyroid hormone (PTH) or human

parathyroid hormone (hPTH)

A polypeptide hormone which regulates the concentration of extracellular fluid calcium.

Parenteral

Administration through routes other than the alimentary canal. Parenteral administration includes

intravenous. subcutaneous, transdermal, intraocular, and intranasal administration.

Pathophysiology

The physiology of disordered function.

Percutaneous

Literally, “through the skin”; refers to a surgical

procedure that requires only a very small incision,

such as a biopsy, or aspiration of fluid beneath the

skin using a needle, catheter, or syringe.

Perimenopause

The time around the menopause.

Peripheral conversion

Conversion of estrogen outside of the liver, in peripheral tissues.

Peripheral nervous system

The autonomic nervous system, the cranial

nerves, and the spinal nerves including associated

receptors.

Pharmacodynamics

The study of the actions of drugs on living systems.

Pharmacokinetics

The rate of change in a physical or chemical system, specifically in relation to drugs.

Placebo

A drug or procedure with no intrinsic therapeutic

value. In a placebo-controlled randomized clinical trial, a placebo is given to patients in control

groups as a means to blind investigators and patients as to whether an individual is receiving the

experimental or control treatment. See randomized clinical trial (RCT).

Plaques

Yellowish fatty deposits formed within the intima

and inner media (innermost and middle coats of

the blood vessels) of large and medium-sized

veins.

Platelets

Disk-shaped tissue, found in the blood of mammals, which responds to injury elsewhere in the

body. Platelets are known for their role in blood

coagulation (clotting). Also called “thrombocytes.”

Population-based case-control studies

In this type of study, all cases diagnosed in the

community or in a sample of the general population are compared with controls selected from the

community or a sample of the general population.

Postmenopause

The period of time after the menopause.

Power

The power of the study refers to the chance of finding a true difference in risk and labeling it as statistically significant. Thus the power of the study is

equal to 0.80 when the sensitivity level is 0.20

(i.e., 1- 0.20= 0.80).

Predictive test

A medical test generally applied to asymptomatic

individuals to provide information regarding the

future occurrence of disease.

Premarin

Wyeth-Ayerst’s brand of conjugated estrogen.

The most commonly used estrogen for HRT in the

United States. See conjugated estrogens.

Premature ovarian failure

Condition characterized by the failure to ovulate

before the normal age of menopause.

Premenopause

The stage of life before menstruation stops.

Premenstrual syndrome

The pattern of symptoms related to the menstrual

cycle.

Preovulation

The first 14 days of a woman’s menstrual cycle,

when estrogen levels are rising before ovulation

takes place.
Appendix K Abbreviations and Glossary 225

Prevalence prevention of osteoporosis; progestin opposes the

A measure of the number of individuals in a given carcinogenic effects of estrogen on the endomepopulation who have a specific disease or other trium.

condition at a designated time (or during a particular period).

Primary prevention

A category of health and/or related interventions

that aim to eliminate a disease or disordered state

before it can occur. Compare secondary prevention.

Progestational

Favoring pregnancy; conducive to gestation; having a stimulating effect upon the uterine changes

essential for the implantation and growth of the

fertilized ovum. Referring to progesterone, or to

a drug with progesterone-like properties.

Progesterone (also called progestational

hormone)

An antiestrogenic female sex hormone secreted by

the ovaries (specifically by the corpus lutetium,

formed immediately after ovulation), by the placenta during pregnancy to prepare the inner lining

of the uterus for implantation of an ovum, and in

small amounts by the adrenal glands and testes,

and prepares the inner lining of the uterus for pregnancy. Receptors for progesterone have been identified on osteoblasts, and although the data are not

Progestogen

See progestin.

Prospective study

An epidemiologic study in which data are gathered after a hypothesis has been generated and the

study approved. In a prospective study, the investigator first identifies the subjects and then follows them over time for development of disease.

Compare retrospective study.

Provera

Wyeth-Ayerst’s brand of the progestin medroxyprogesterone acetate (MPA). The most commonly

used progestin for HRT in the United States. See

progestin, progesterone.

Quality-adjusted life-year (QALY)

In cost-effectiveness analysis, a measure of health

impact used to compare the benefit or effectiveness of alternative health interventions, such as

the value of an extra year of life gained through

kidney transplantation versus dialysis for patients

with end stage renal disease; involves some degree of arbitrary valuation and weighting of different conditions.

entirely clear, it appears that progesterone may Quantitative computerized tomography

stimulate bone formation. Progesterone and other (QCT)

agents capable of producing some or all of the bio- A bone densitometry technique similar to DEXA

logical effects similar to those of progesterone are which measures the central, trabecular portion of

called progestins (or progestogens). the vertebral body, the spongiosa. Techniques

Progestin have been developed to allow for quantitative

Originally, the crude hormone of the corpus lute- measurement on most commercially available CT

tium of the ovary; it has since been isolated in pure scanners.

form and is now known as progesterone. The ge- Radiographic densitometry

neric term for any substance, natural or synthetic, Noninvasive measurement of bone mass in vivo

that effects some or all of the biological changes was first performed by quantifying radiographs

produced by the hormone progesterone. See pro- with an optical densitometer. The film densitv

gesterone. . .

over the bone is compared to that over the soft tisProgestin/estrogen replacement therapy sue, and the resultant absorption is related to that

(PERT) obtained over a series of standards with known

The use of estrogen combined with progestin for mineral content. Because of technical errors rethe treatment of menopausal symptoms, e.g., hot lated to the polychromate nature of the radiation

flashes, the prevention of heart disease, and/or the source and differences in x-ray film characteris-
226 Cost Effectiveness of Screening for Osteoporosis

tics, this technique has many errors and is rarely

used clinically today.

Radiogrammetry

X-rays of the hand and radius, using fine grain industrial film, have been used to measure the cortical thickness of these tubular bones as an indicator

of cortical bone mass. Although the proximal radius and ulna and the six middle metacarpal of

both hands have been used, the mid-shaft of the

second metacarpal is the usual measurement site.

Radius

The bone on the outer or thumb side of the forearm. The distal radius is the end of the radius

bone adjacent to the wrist. The proximal radius

is the end of the radius adjacent to the elbow.

Random allocation

In a randomized clinical trial, allocation of individuals to treatment groups such that each individual has an equal probability of being assigned to

any group.

Randomized clinical trial (RCT) (also

called randomized controlled clinical

trial or controlled clinical trial)

In epidemiology, a clinical trial of a prophylactic,

diagnostic, or therapeutic agent, device, regimen,

procedure, etc. in which human (or animal) subjects are randomly allocated into groups, usually

called “the experimental group” (in which subjects receive the treatment being studied) and “the

control group” (in which subjects do not receive

the treatment being studied), and outcomes are

compared.

Recall bias

Bias caused by differences in abilities of two

groups to remember exposure to suspected causative factors.

Recency

Time since last exposure to a suspected causative

factor.

Regression analysis

A statistical procedure for determining the best

approximation of the relationship between variables. Multiple regression analysis is a method for

measuring the effects of several factors concurrently.

Relative risk

A measure of a relationship, defined as the chance

of an outcome, such as breast cancer, among a

group of persons having a suspected causative factor, divided by the chance of this outcome among

a similar group without this suspect factor.

Reliability

The reproducibility of results over repeated measurements, and relates to the lack of random error

over these repeated measurements. Reliability is

a prerequisite to validity.

Retrospective study

An epidemiologic study in which data that are already available are analyzed to test a hypothesis

(e.g., inferences about exposure to a possible

causal factor are derived from data on subjects

who already have the disease in question,

compared to other subjects who do not have the

disease).

Risk factor

An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or inheritance

characteristic, which on the basis of epidemiologic evidence is known to be associated with health

related conditions considered important to prevent.

Route of administration

In pharmacology, refers to the means by which a

drug is administered: namely intravenous (injected into the bloodstream), inhalation (through

the lungs), oral (through ingestion), and dermal

(through the skin).

Secondary preventions

An intervention that strives to shorten the course

of an illness by early identification and rapid intervention.

Selection bias

A distortion in the estimate of effect resulting

from the manner in which subjects are selected for

a study population.
Appendix K Abbreviations and Glossary 227

Sensitivity

The percentage of all those who actually have the

condition being tested who are currently identified as positive by the test.

Sensitivity analysis

In cost-effectiveness and cost-benefit analysis, an

analysis of the effect of changes in key assumptions or uncertainties on the findings and outcome

of the overall study.

Serum lipid profiles

A quantitative representation of the level of serum

lipids.

Serum triglycerides

Esters formed from glycerol and one to three fatty

acids; fats and oils are triglycerides.

Significance level

The significance level, or “p” value, is the probability of concluding that a relative risk is different

from 1.0 when it is not. By convention, a difference in risk is said to be statistically significant if

there is less than a five percent chance of making

this type of error (i.e., p < 0.05). The significance

can also be expressed as a confidence interval.

Single photon absorptiometry (SPA)

A bone densitometry technique that employs a

sealed source of radioactive material that emits a

single energy radiation (photon), and a detector

that measures the amount of photons transmitted

through bone and soft tissue. The radius and calcareous can be measured with this device.

Single photon x-ray absorptiometry

(SXA)

A bone densitometry technique similar to SPA but

using an x-ray source rather than a radioactive

source. Both the radius and calcareous can be

measured with this device.

Specificity

One measure of the validity (or accuracy) of a

diagnostic or screening test: the percentage of all

those who do not have the condition being tested

or who are correctly identified as negative by the

test. Operationally, it is the number of negative

test results divided by the number of patients that

actually have the disease (true-negatives divided

by the sum of true-negatives plus false-positives).

Compare sensitivity.

Statistically significant

The likelihood that an observed association is not

due to chance. See P value.

Steroid hormone

Any of numerous hormones characterized by steroid structure (i.e., four carbon rings interlocked

to forma hydrogenated cyclopentophenanthrenering system). Steroid hormones include the sex

hormones estrogen, progestin, and androgen; they

also include cortisone and adrenocortical hormones.

Steroids

Any of a class of compounds characterized by a

polycyclic structure like that of the sterols and that

usually include the sterols (e.g., cholesterol) and

vitamin D, as well as many other naturally occurring compounds (e.g., bile acids).

Stratification

In randomized clinical trials, the categorization of

individuals for the purpose of adjusting the groups

to take into account unequal distribution of characteristics of prognostic importance. Stratification may be used during patient allocation,

creating subgroups within which individuals are

randomized to treatments; or stratification maybe

applied during data analysis to statistically adjust

for differences between the groups.

Stress incontinence

See urinary stress incontinence.

Stroke

Loss of sensation, movement, or function caused

by a sudden interruption of the blood supply or a

leakage of blood in the brain. This can be caused

by heart failure, blockage of arteries (cerebral

thrombosis or cerebral embolism), or hemorrhage

in the brain.

Subcutaneous

Beneath the skin.

Subgroup analysis

A separate analysis performed on a subgroup of

the population being studied to identify important

differences in risk. Such differences in risk maybe
228 Cost Effectiveness of Screening for Osteoporosis

due to interactions of the purported causative factor with other risk factors

Surgical menopause

Menopause following the

ovaries.

Symptomatology

The combined symptoms

Synthetic calcitonin

for the disease.

surgical removal of the

of a disease.

A synthetically produced/manufactured form of

the hormone calcitonin, a 32 amino acid polypeptide, one of the three calcium regulating hormones

found in humans. The FDA has granted qualified

approval for both natural and synthetic calcitonin

for the treatment but not the prevention of osteoporosis.

Synthetic estrogen

A synthetically produced/manufactured estrogen

product.

Systemic circulation

Channels through which nutrient fluids of the

body flow: often restricted to the vessels conveying blood.

Testosterone

An androgen or steroid hormone secreted by the

interstitial cells of the testes, which functions in

the induction and maintenance of male secondary

sex characteristics and affects sperm production;

testosterone and its cypionate, enanthate, and propionate esters are used in palliative therapy in inoperable carcinoma of the female breast and

certain gynecologic conditions.

Thromboembolitic disease

Disease related to blood vessel obstruction.

Thrombosis

The abnormal development of a blood clot

(thrombus) inside an intact blood vessel, which

can be life-threatening if it obstructs the blood

supply to the brain (leading to stroke), heart (leading to myocardial infarction), the lungs (leading to

pulmonary embolism), or other organs (leading to

tissue damage or loss of function); the presence of

such clots also raises the risk that part of the clot

(an embolus) may break off and travel to a distant

artery or vein, causing thrombophlebitis or deep

vein thrombosis. Factors contributing to thrombosis include atherosclerosis, an increase in coagulation factors, or a deficiency of anticlotting

factors in the blood.

Total cumulative exposure

The total dose, which is related both to the level

and to the duration of exposure. For example, for

estrogen replacement therapy, total dose is related

to how much and for how long the estrogen is

given.

Trabecular bone

See cancellous bone.

Transdermal

Through the skin.

Transmenopausal

Occurring across the time period of the menopause.

Treatment group

In a randomized clinical trial, the group receiving

the treatment being evaluated for safety and efficacy. Also known as the experimental group. See

randomized clinical trial (RCT).

Tumor

A new growth of tissue in which the multiplication of cells is uncontrolled and progressive. Also

called neoplasm.

Ultrasound

Predictor of fracture risk using sound velocity and

sound attenuation to measure both bone mass and

altered bone architecture.

Unopposed estrogen

Estrogen used alone, without a progestin. Also

known as estrogen replacement therapy (ERT).

Unopposed progestin

Progestin used alone. Progestins alone have been

used to relieve menopausal symptoms.

Urinary bladder

The hollow, muscular organ that collects urine

from the ureters and stores it until the urine is discharged through the urethra during urination.
Appendix K Abbreviations and Glossary 229

Urinary incontinence

An involuntary loss of urine sufficient in quantity

and/or frequency to be a social or health problem.

Urinary stress incontinence

Involuntary escape of urine due to strain on the

orifice of the bladder, as in coughing or sneezing.

Urodynamics

A process that evaluates characteristics of the

urine stream and the pelvic musculature, and the

activity of the bladder.

Uterine prolapse

Descension of the uterus down into the vagina,

caused by weakening of the support ligaments and

muscles that hold the uterus in place.

Uterus

The hollow muscular organ in the female in which

the fertilized ovum normally becomes embedded

and in which the developing embryo and fetus are

nourished. Its cavity opens into the vagina below

and into a fallopian tube on either side.

Vagina

The canal in the female, from the vulva to the cervix uteri, that receives the penis in copulation and

is the birth canal.

Vaginal atrophy

The wasting or diminution in size of the vagina.

Vaginismus

Painful, involuntary contraction or spasm of the

muscles around the outer third of the vagina, interfering with sexual intercourse.

Validity

A measure of the extent to which an observed situation reflects the “true” situation.

Vertebra

In the human body, any of the 33 bones of the spinal column, comprising the 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 4 coccygeal vertebrae.

Withdrawal bleeding

Bleeding, associated with hormone replacement

therapy, caused by the sloughing of the endometrium due to withdrawal of estrogen stimulation.

*U.S. G.P. O. : 1995-387-789:47402