Effectiveness and Costs of Osteoporosis

Screening and Hormone Replacement

Therapy, Vol. I: Cost-Effectiveness Analysis

August 1995

OTA-BP-H-160

GPO stock #052-003-01423-8
Recommended Citation: U.S. Congress, Office of Technology Assessment, Effectiveness

and Costs of Osteoporosis Screening and Hormone Replacement Therapy, Volume I:

Cost-Effectiveness Analysis, OTA-BP-H-160 (Washington, DC: U.S. Government

Printing Office, August 1995).
iii

oreword

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
iv

dvisory 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, III

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
v

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 Permanente

Southern California Permanente

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
vi

roject 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 Associate

Douglas Teich

Senior Analyst

Laura Stricker

Research Assistant

William Adams

Research Assistant

Julia Bidwell

Research Assistant

Angela Schreiber

Research Assistant
vii

Summary of Findings 1

Cost-Effectiveness Analysis 5

Modeling the Cost Effectiveness of Osteoporosis

Screening/HRT Strategies 6

Results 23

Comparison of OTA’s Results with Other

Cost-Effectiveness Analyses 47

Screening Recommendations of Expert Groups 50

Conclusions and Policy Implications 51

References 53

ontents
ummary

of

Findings

his background paper assesses the costs and effectiveness

of screening women for bone density once, at the time of

menopause (age 50) or alternatively at age 65, and placing

those with low bone density on long-term hormonal replacement therapy (HRT).

Based on a review of the literature, OTA made assumptions

about the major adverse health events affected by HRT: hip fracture, coronary heart disease, breast cancer, endometrial cancer

and gallbladder disease. The base-case assumptions represent

OTA’s judgments about the most likely level of effects. OTA also

looked at the effect of best-case assumptions (those most favorable to osteoporosis screening and HRT) and worst-case assumptions (those least favorable to osteoporosis screening and HRT)

on the estimated cost effectiveness of screening and HRT.

OTA’s estimates include the costs (or savings) of hospital care,

nursing home care, and other long-term care due to diseaserelated disabilities as well as the costs of screening and HRT. OTA

did not include the cost of unpaid care provided by family and

friends.

Because evidence on the quality of life associated with HRT

and the diseases affected by it is scanty and even nonexistent for

some conditions, OTA estimated HRT’s impacts only on the

length of life, not on its quality. Yet, HRT may have a major impact on quality of life through its short-term side effects and relief

of menopausal symptoms and its long-term impact on fractures,

heart disease, breast cancer, and endometrial cancer. Many elderly women with hip fractures, for example, never regain full function or independence. This summary identifies the conditions

| 1
2 Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE A: Principal Effects of Hormone Replacement Therapy

ERT PERT

Base case Direction of Base case Direction

assumptions effecta

assumptions of effecta

Reduction in bone loss while on therapy 1OO% + 1OO% +

RR of heart disease while on therapy 0.5 + 0.8 +

RR of breast cancer after long-term therapy 1,35 1.35 —

RR of endometrial cancer after long-term therapy 7.0 1.0 0

RR of gallbladder disease while on therapy 2.5 2,5 —

a

Indicates whether the base case assumption does ( + ) or does not (-) Improve the cost-effectiveness ratios of the screening/ttreatment regimens

KEY: ERT = estrogen replacement therapy, PERT = progestin/estrogen replacement therapy, RR = relative risk

SOURCE Off ice of Technology Assessment, 1995

under which quality of life considerations could

alter judgments about the most appropriate

screening/HRT strategy.

HRT regimens consist either of estrogen given

alone (ERT) or estrogen given in combination

with a progestin (PERT). Evidence is strong that

ERT retards the rate of bone loss and reduces the

risk of hip fracture, but it also increases the incidence of endometrial cancer. Suggestive evidence

also exists for a reduced risk of coronary heart disease and an elevated risk of breast cancer and gallbladder disease in women on ERT for extended

periods of time. PERT eliminates the excess risk

of endometrial cancer, but it may also reduce the

heart disease benefits associated with ERT. OTA’s

base case assumptions regarding the impact of ERT

and PERT on each disease are shown in table A.

OTA examined a number of screening/HRT

strategies, defined by the age at which bone mineral density (BMD) measurement occurs, the

BMD threshold for initiation of a course of longterm HRT, and the duration of therapy. The

screening/HRT strategies examined are listed in

table B.

OTA’s cost-effectiveness analysis can be used

to guide overall public health policy, including decisions about educational programs or payment

for screening or HRT, but it is not intended to

guide individual decisions regarding BMD

screening or long-term HRT. Individual women’s

risks of the various conditions and diseases affected by HRT vary, as do their assessments of the

quality-of-life implications of various outcomes.

The findings of OTA’s cost-effectiveness analysis are summarized below:

■

■

■

Given base case assumptions, screening

women for osteoporosis at menopause and

placing those with low bone density on longterm ERT would deliver an additional year of

life for about $27,000, which is a reasonable

cost per added year of life compared with many

interventions currently paid for by public and

private third-party payers.

Given base case assumptions, placing all

women on long-term ERT at menopause, without screening for bone density, would deliver

an additional year of life for about the same

amount, roughly $23,000.

Although the cost per added year of life is about

the same for these two preventive strategies,

their aggregate costs and benefits differ. The

aggregate cost of the latter approach is higher

than the former because more women are

treated, and the aggregate benefits are also

higher because more lives are saved (about

11,000 years of life per 100,000 women entered

in the program vs. about 1,800 years of life per

100,000 women, respectively).
Summary of Findings 13

TABLE B: BMD Screening/HRT Strategies

Considered by OTA

Age at which BMD measurement occurs:

■ 50 years old

■ 65 years old

BMD threshold for initiating a course of therapy:

■ BMD 1 standard deviation below the mean

■ BMD below the mean of the population

■ Offer HRT to all women (no BMD screening)

Duration of therapy:

■ 10 years

■ 20 years

■ 30 years

■ 40 years

KEY: BMD = bone mineral density; HRT = hormone replacement

therapy,

SOURCE Off ice of Technology Assessment, 1995.

Regardless of the screening/treatment strategy

chosen, the cost per added year of life declines

dramatically with the duration of ERT, so that

a lifelong course of therapy delivers the greatest benefit per dollar spent. Shorter durations of

HRT—10 to 20 years-are less cost-effective

than are longer treatment durations, largely because substantial medical benefits accrue only

when women stay on the therapy into old age,

when hip fractures and heart disease would rise

dramatically. OTA’s model suggests that 10

years of HRT is extremely costly regardless of

whether or how HRT is targeted.

OTA’s estimated cost-effectiveness ratios are

most sensitive to assumptions about the effect

of ERT on heart disease. In the base case, OTA

assumed the existence of a substantial reduction in heart disease with ERT. This assumption

may be incorrect because the evidence of heart

disease benefits from ERT is based on observational studies, which may be biased. If ERT has

no heart disease benefit, the cost per added year

of life for all screening/ERT strategies would

be high. In this circumstance, putting all

women on a lifetime course of ERT would cost

roughly $450,000 per added year of life.

Screening women for osteoporosis at menopause and placing those with low bone density

on long-term ERT would cost less—roughly

$155,000 per added year of life—but it is substantially more costly per added year of life

than are most preventive technologies currently accepted for Medicare payment.

If ERT has no heart disease benefits, the quality-adjusted cost-effectiveness ratio of screening and long-term ERT for those with low bone

density would depend on the improvement in

quality of life from fewer fractures compared

with the decline in quality of life from increased risks of breast and endometrial cancer.

The impact on quality of life from fracture incidence reduction would occur relatively late in

life, because most fractures occur in the very

old, whereas the quality of life impacts of increased cancer incidence would occur earlier in

life. Depending on the value people place on

these impacts, the quality-adjusted cost-effectiveness ratio could be either higher or lower

than the unadjusted cost-effectiveness ratio

given above.

Current practice is to prescribe PERT for longterm therapy. Although PERT clearly eliminates the excess risk of endometrial cancer, it

may also reduce the magnitude of heart disease

benefits obtained from ERT. Clinical trials

have demonstrated that the addition of progestins reverses some or all of ERT’s favorable effects on lipoproteins. Under OTA’s base case

assumption that PERT has a small but significant effect on heart disease benefit of PERT,

placing all women on long-term PERT would

cost roughly $71,000 per added year of life.

Placing only those with low bone density on

long-term PERT would cost about the same

amount per added year of life.

If PERT has no heart disease benefit, the cost

per added year of life is very high for all screening and treatment strategies. For example, the

cost of putting all women on PERT would be

about $262,000 per added year of life. Quality4
4 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

of-life adjustments could change this ratio, but

the magnitude and direction of the change cannot be predicted with currently available evidence.

 OTA considered including the cost of vertebral

and other fractures associated with osteoporosis in the analysis, and did not do so. Good estimates of the health care costs associated with

these fractures are unavailable. As discussed in

the report, the costs of wrist and vertebral fractures are very low in comparison with the costs

of other adverse health conditions considered

in this analysis. OTA therefore concluded that

adding these costs would make no difference to

the basic conclusions of the study.

 OTA’s estimates of cost effectiveness assume

complete compliance with HRT, which may be

unrealistic. Studies have shown that long-term

compliance with HRT is low, usually below 20

percent. The effect of incomplete compliance is

to reduce the cost effectiveness of all screening/

HRT regimens considered. For example, OTA

found that, if 50 percent of women were to terminate ERT after only 10 years while the rest

of the population remained on therapy for life,

the cost per added year of life for this population as a whole would be $73,000. Although

new HRT regimens under development may

have fewer undesirable side effects, their ultimate impact on compliance is unknown.

 Beginning HRT at older ages (e.g., 65 years of

age) may be more cost-effective than beginning

it at the time of menopause, but such a conclusion depends on extrapolating the range of cardiac benefits seen in women who begin HRT at

menopause to women who begin therapy at

older ages.

 Some osteoporosis experts propose that HRT

should be targeted to those postmenopausal

women at highest risk of fracture, as determined by BMD screening. There may be other

methods, however, of selecting women who

would gain the most from HRT. If HRT is effective for prevention of heart disease, for example, then it may be less costly and more

effective to screen women for risk of heart disease and target HRT to those at highest risk.

Furthermore, targeting HRT to those postmenopausal women with low bone density may discourage those women with low risk of fracture

and high risk of heart disease from taking HRT.

 Bone density screening may increase uptake of

and continuous compliance with HRT. The effectiveness of osteoporosis screening as a tool

for improving compliance should be evaluated

against other methods for improving compliance. In addition, the use of bone mass

measurements in inducing other changes in

lifestyle needs evaluation in comparison with

other methods of inducing multiple lifestyle

changes.

 OTA analyzed the cost effectiveness of a hypothetical drug to maintain bone density without

any of the adverse or beneficial side effects

associated with HRT. OTA assumed that such

a drug would cost about $250 per year (the

annual cost of PERT today). Screening women

for BMD and placing those with the lowest

BMD levels on a targeted osteoporosis drug

would cost approximately $155,000 per added

year of life. Adjusting this ratio for improvements in the quality of life due to reduction in

the number of fractures would surely make

such a drug more cost-effective depending on

the value people place on these improvements.
ost-Effectiveness

Analysis

steoporosis is a disease characterized by low bone density and increased bone fragility, which reduce bone

strength. As a contributing factor in fractures of the hip

and other skeletal sites in older people, especially older

women, osteoporosis takes a high toll in lost years of independent

living and expenditures for health care. The major source of morbidity and mortality from osteoporosis arises from hip fractures.

OTA estimates that total societal expenditures for hip fractures,

not all osteoporosis-related, were $5 billion in 1990 (132).

The search for ways to prevent osteoporosis and its consequences has led some experts to espouse screening for women

around the age of menopause1 (about 50 years of age) to identify

those with low bone density who are at greater risk of fracture in

subsequent years. Several technologies that measure bone density have been proposed as good screening tools for predicting future bone density and, hence, future risk of fractures. These

available technologies include single photon absorptiometry

(SPA), dual photon absorptiometry (DPA), dual energy x-ray absorptiometry (DEXA), and quantitative computed tomography

(QCT). Proponents claim that such screening would allow clinicians and counselors to target preventive interventions to those at

highest risk and thus offer improved health at a reasonable cost

(94).

1 Menopause occurs naturally around age 50. Menopause is also a secondary consequence of surgical removal of the ovaries (bilateral oophorectomy) and of diseases causing premature failure of the ovaries.

| 5
6 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

The benefits of screening a population for high

risk of future disease or adverse events depend on

the availability of interventions that are effective

in preventing those events. In the case of fractures

associated with osteoporosis, many approaches to

prevention have been proposed, including patient

education, exercise, diet, dietary supplements,

and architectural modifications of living quarters

for those at risk. The evidence supporting the effectiveness of these alternatives is mixed (15, 22,

92).

Pharmacologic approaches have also been

sought. Although research is currently underway

on a number of compounds that might be effective

in altering bone strength or the speed of bone loss

as women age (53, 54, 77, 103, 111, 120), today

only one medicine has been recognized by the

U.S. Food and Drug Administration (FDA) as effective for the prevention of osteoporosis: the reproductive hormone estrogen.2

This background paper assesses the medical effectiveness, medical risks, and health care costs

associated with screening women for bone density

once, at age 50, or alternatively at age 65, and

placing those with low bone density on long-term

hormone replacement therapy (HRT).

Hormone replacement therapy refers to estrogen given alone or estrogen given sequentially or

in combination with a progestin. In this report,

HRT is a general term referring to either regimen,

where a distinction is not necessary. When we are

referring specifically to estrogen given alone, we

call it estrogen replacement therapy (ERT). When

a statement refers specifically to estrogen and progestin, it is called progestin/estrogen replacement

therapy (PERT).

OTA estimated the cost effectiveness of several

screening and treatment strategies by estimating

the net health care cost per year of life gained from

each strategy. In a cost-effectiveness analysis, the

multiple health effects of screening and preventive therapy are reduced to a single measure of effectiveness—the extra years of life, sometimes

adjusted for differences in their quality, that are

gained or lost as a result of the preventive strategy.

The average cost of achieving a given increase in

the length or quality of life is the cost-effectiveness ratio.

OTA developed a computer model of the costs,

risks, and effectiveness of bone-density screening

and HRT in women eligible for HRT. The model

predicts the cost of bone-density screening and the

incidence and costs of the major adverse health

events associated with osteoporosis and HRT.

These major events include hip fracture, heart attack, breast cancer, endometrial cancer and gallbladder disease.

This background paper contains two volumes.

This first volume describes the cost-effectiveness

model, including the assumptions regarding the

cost of screening and the effectiveness, risks, and

costs associated with various HRT strategies. It

presents OTA’s findings regarding the cost effectiveness of alternative strategies for screening and

HRT, and it analyzes the sensitivity of the findings

to uncertainty about the assumptions. The final

section compares the results of OTA’s cost-effectiveness analysis with those of previous analyses

and discusses the implications for health care

policy.

The evidence on the benefits, risks and costs of

HRT is summarized in Volume II of this report.

That volume also gives the rationale for the structure and assumptions underlying the OTA cost-effectiveness model.

MODELING THE COST EFFECTIVENESS

OF OSTEOPOROSIS SCREENING/HRT

STRATEGIES

OTA developed a computer simulation model of

a hypothetical sample of women eligible for bonedensity screening and HRT beginning at age 50

2 Estrogen has been approved for marketing for the prevention and treatment of osteoporosis. Calcitonin has been approved for treatment of

established osteoporosis, but its approval is qualified (106).
Cost-Effectiveness Analysis | 7

and ending either at death or at age 90, whichever

comes first. For each woman in the sample, the

model creates a fabricated health record that includes all relevant measures of each woman’s

health status (e.g., whether she has a condition or

disease of interest) and health-related events (e.g.,

whether she is diagnosed with or dies from a

condition or disease).3

Because many health states or events are governed by the laws of probability, the computer assigns health states and health-related events

randomly according to predetermined probability

distributions.4 When a computer model determines what happens to each member of a hypothetical sample by figurative spins of a roulette

wheel, it is referred to as a Monte Carlo simulation

(73).

OTA’s Monte Carlo simulation of a woman’s

health record begins with a random assignment of

bone mineral density (BMD) at age 50 (or other

starting age when appropriate). Preventive strategies correspond to specific BMD threshold values, i.e., BMD values below which HRT is

initiated. Whether the woman is placed on HRT

depends on whether her BMD falls below the specific threshold. Any woman whose measured

BMD is below the BMD threshold is placed on

HRT.

For those women placed on HRT, the probabilities of subsequent health-related events (e.g., hip

fracture, heart attack, death, etc.) are adjusted to

reflect the benefits or risks of hormone therapy.

The computer then constructs each woman’s

health record year by year. In subsequent years,

each woman is assigned to certain disease or death

states with given probabilities depending on her

age, current BMD, and whether she is currently on

or ever has been placed on HRT. As each woman’s

health record is compiled, the computer keeps

track of each health-related event, recording the

age at which the event occurred and the health

costs associated with it.

After the lifetime health record is constructed,

a woman’s total lifetime health care costs and

number of years of life lived are computed. The

estimated costs and effects incurred over time are

discounted to their net present value in the year the

program began.5 Across all women in the sample,

the mean lifetime health care cost and years of life

lived are estimates of the average experience

associated with the particular preventive strategy

(or no prevention) in the population of women

from which the simulated sample was drawn.

The effectiveness of a specific screening/HRT

strategy (defined by a specific BMD threshold and

duration of HRT) is estimated by computing the

3 The computer simulation model is written in the Mumps computer language (Micronetics Standard Mumps (MSM) version 3.0 published

by the Micronetics Design Corp.). Although MSM Mumps is a complete implementation of the ANSI standard implementation of Mumps, the

OTA model makes use of MSM functions and utilities that may not be compatible with other implementations of Mumps. Copies of the program

and documentation are available from the National Technical Information Service, Springfield, Virginia (NTIS # PB95-209805).

4 Computers generate random numbers which can be used to determine whether some characteristic or event is assigned to a subject. When a

program calls for a random number between 0 and 1, the computer generates a number which is equally likely to be anywhere in the interval

between 0 and 1. This randomly generated number is then used to determine whether an event occurs. Suppose, for example, that 3 per 1,000

70-year-old women die from heart attacks. When a hypothetical woman in the simulation reaches the age of 70, the computer generates a random

number with some value between 0 and 1. If the value of the random number is between 0 and 0.003, the health record is noted with the woman’s

death from heart attack, and the health record ends. If the random number generated by the computer is above 0.003, then no heart attack is

recorded for that year and the woman continues to be subjected to various risks until she either dies from an assigned health-related event or the

record closes at age 90.

5 To compare outlays occurring in different time periods, they must each be discounted to their present value in the year of program initiation.

The discounting of health effects as well as costs is necessary to ensure that programs whose benefits lie well in the future will not be found more

cost-effective if postponed indefinitely (69). A discount rate of 5 percent per year was used to convert both years of life lived (effects) and costs in

future years to their present value in the year the program begins. Although other discount rates may be used, a discount rate of 5 percent has

become a commonly accepted value in health cost-effectiveness research. Use of a standard discount rate permits comparison of the results of

this analysis with the results from the cost-effectiveness analyses of other health interventions.
8 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

difference in the net present value of years of life

lived by the sample of women who undergo the

strategy and the net present value of years of life

lived in a hypothetical sample of women not subjected to screening and HRT. The net costs of the

screening/HRT strategy are estimated as the difference in the net present value of lifetime health

care costs incurred by the sample of women undergoing the strategy and the net present value of

lifetime health care costs incurred by a sample of

women not subjected to the strategy. The cost effectiveness of the strategy—the ratio of the difference in costs to the difference in years of life

lived—is expressed as the net cost per year of life

gained from the preventive strategy.6

The validity of this kind of model as a true picture of the expected effects and costs of various

preventive strategies depends on the accuracy of

the underlying assumptions about costs, risk of

disease and death, the effects of therapy, etc.

These assumptions are of two kinds: structural

and parametric. Structural assumptions govern

the shape of the relationship among the various

measures of health status throughout a woman’s

life. For example, the model may assume that a

woman’s risk of breast cancer is altered by HRT

only after she has been exposed to the therapy for

a certain length of time. That the risk of breast cancer is altered only after a certain length of therapy

is a structural assumption. Parametric assumptions, or parameters, describe the magnitude of

the structural assumptions. Using the above example, the model may assume that the length of

therapy required before the risk of breast cancer is

elevated is 10 years. The assumption that 10 years

is required is a parameter of the model.7

Uncertainty about both structural assumptions

and specific parameters abounds in a model of the

complex set of diseases affected by bone-density

screening and HRT. OTA made base case assumptions, representing our best estimate of the true

structural relationship or parameter value. A standard technique for dealing with uncertainty about

parameters is to perform sensitivity analysis, that

is, to assess how sensitive estimates of cost and effectiveness are to changes in parameter values.

OTA analyzed the sensitivity of the cost-effectiveness results to alternative values of specific parameters. In addition, we constructed best case

and worst case sets of assumptions to test how simultaneously setting several uncertain parameters to their upper or lower limits would affect the

estimated cost effectiveness of the intervention.

Assessing the sensitivity of results to changes

in structural assumptions was not possible because it would require extensive reprogramming

of the computer model. In the next section, we

summarize all of the major structural and parametric assumptions (including the range of values

considered in sensitivity analyses) in the OTA

model of osteoporosis screening.

❚ Structure and Assumptions of OTA’s

Osteoporosis Screening Model

Table 1 lists the potential effects and costs brought

about by any particular osteoporosis screening

and HRT regimen. Screening and subsequent

HRT potentially affect both costs and health outcomes in both positive and negative ways.

The primary motive for bone-density screening

(and long-term HRT in those with low bone density) is to reduce hip and other fractures that are

more frequent in women with osteoporosis. By retarding the rate of decline in bone density after

menopause, HRT helps protect women from fractures.

6 The cost-effectiveness ratio is uninterpretable if it is negative. A negative cost-effectiveness ratio occurs either when the preventive strategy

actually reduces health care costs without reducing effectiveness (i.e., cost saving), or when the preventive strategy results in a net increase in

costs and reduction in health (i.e., a dominated strategy).

7 The assumption about the magnitude of the alteration in breast cancer risk is also a parameter of the model.
Cost-Effectiveness Analysis 19

TABLE 1: Effects and Costs of Osteoporosis Screening

Included in

Effects and costs of osteoporosis screening OTA’s model?

Effects

Longer life

■ Treatment with HRT may reduce the risk of death from hip fracture

● Treatment with HRT may reduce the risk of death from heart attack

Shorter Iife

● Treatment with HRT may increase the risk of death from breast cancer

■ Treatment with HRT may increase the risk of death from endometrial cancer

Higher quality of life

● Treatment with HRT may reduce the pain and disabiIity associated with hip fracture

■ Treatment with HRT may reduce risk of painful fractures of the spine and other sites

■ Treatment with HRT may reduce the pain and disabiIity associated with coronary

heart disease

■ Treatments with HRT relieve menopausal symptoms

Lower quality of Iife

yes

yes

yes

yes

no

no

no

no

Treatment with HRT may increase the risk of pain and disability associated with

breast cancer

Treatment with HRT may increase the risk of pain and disability associated with

endometrial cancer

Treatment with HRT may increase the risk of pain and temporary disability associated

with gallbladder disease

HRT itself may Involve side effects, such as vaginal bleeding, that involve pain

and discomfort.

costs

Higher costs

■ Screening for osteoporosis yes

■ HRT (Including followup physician visits and procedures) yes

no

no

no

no

■ Treatment of induced breast cancer

■ Treatment of induced endometrial cancer

● Treatment of induced gallbladder disease

Lower costs

● Prevention of hip fractures

■ Prevention of other fractures

■ Prevention of coronary heart disease

yes

yes

yes

yes

no

yes

SOURCE Off ice of Technology Assessment, 1995

HRT has other consequences, however, some

of which are good, others bad. The evidence is

strong that prolonged use of ERT increases the incidence of endometrial cancer. PERT, on the other

hand, appears to eliminate this increased risk.

More uncertain are the impacts of HRT on breast

cancer and heart disease, which may also differ between ERT and PERT. OTA assessed the available

evidence to arrive at a best estimate of these effects.
10 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

Excluded Impacts

OTA’s model includes estimates of each potential

category of cost and effect listed in table 1. These

estimates include costs of hospitalization, nursing

home care, and other long-term care due to disease-related disabilities. They do not include the

costs of unpaid care provided by family or friends.

The model also does not measure changes in the

quality of life associated with HRT. Finally, it

does not include changes in the incidence of fractures other than those of the hip. The reasons for

these omissions from the model are considered

below. The implications for the findings of the

study of omitting these costs and effects are discussed in the concluding section.

Impacts on quality of life

The consequences of bone-density screening and

HRT for women’s quality of life are not trivial.

HRT affects the incidence of all kinds of fractures,

and each kind of fracture involves some loss of

function or enjoyment for a short or long duration.

Box A summarizes the evidence on the effects of

three of the most common kinds of osteoporosisrelated fracture—hip, spine, and wrist—on short

and long-run functional status. Hip fracture takes

the greatest toll not only in terms of mortality

(which is accounted for in OTA’s model) but also

in terms of long-term effects on ability to function

independently.

Fractures are just one of the diseases or conditions affected by HRT. HRT also alters the incidence (and possibly severity) of heart disease,

breast cancer, endometrial cancer, and gallbladder

disease8. The impact of these diseases on functional status is also major. Data from the Framingham Heart Study suggest that in the aggregate,

heart disease has a greater impact on functional limitations in the elderly than do hip fractures (50).

In five of seven activities of daily living, heart disease accounted for a greater percentage of the total

disability discovered in elderly members of the

Framingham cohort than did hip fracture (50).

Finally, HRT relieves symptoms of menopause, such as hot flashes, painful intercourse, and

irritability. But HRT also has side effects such as

periodic bleeding, depression, bloating, weight

gain, and breast tenderness. Indeed, many women

stop HRT when they find the side effects of the

therapy intolerable (145).

The major problem with including quality-oflife impacts in a cost-effectiveness analysis is that

people’s preference for time spent in each possible

state of health resulting from HRT must be

compared with preferences for the same amount

of time in a disease-free state. To compare changes

in the length of life with changes in its quality, one

would have to know how many years of healthy

life consumers would be willing to give up to

avoid a certain period spent in a specific disease

state.9 The value of a year of life lived with a specific outcome (say, a hip fracture) would be expressed as a quality-adjusted-life-year (QALY), a

percentage of a year of healthy life. Although

abundant information exists on the impact of hip

fracture, heart disease, breast cancer, and other

diseases on functional ability and other aspects of

quality of life, the evidence is extremely sparse on

how these impacts translate into QALYs. 

In a study of QALYs in 67 patients who had survived a heart attack at some point in the previous

28 months, for example, the patients rated a year

of life lived in their current state of health as equivalent on average to 0.88 years of life in excellent

health (129). This valuation did not vary with time

since the heart attack and was uncorrelated with

changes in patients’ functional status over time.

Whether this value reflects those of people who

8 In a cost-effectiveness analysis, the quality of life impacts of hip fracture would be discounted relative to cancers, given that hip fractures

occur late in life and cancers much earlier (23).

9 There are many theoretical and practical issues in measuring consumers’ preferences for various states of health or disease. Whose preferences should be measured and when and how such preferences should be elicited are basic unresolved issues at present (133).
Cost-Effectiveness Analysis 111

BOX A: Impact of Fractures on Functional Limitations

Osteoporosis has been linked to an increase in the frequency of all kinds of fractures (14, 121)

The three most common osteoporosis-related fractures—those of the wrist, spine, and hip—have

unique profiles of effects on the severity and duration of functional limitations, Wrist fractures cause temporary partial disability and sometimes longer term loss of function Spinal fractures are frequent in

women with osteoporosis, but the majority do not cause symptoms severe enough to seek medical

care. Hip fractures not only involve a short-term risk of mortality, but they also have a major impact on

long-term function Each of the three major kinds of fractures is discussed below

Wrist Fractures: Wrist (Cones’) fractures occur frequently in postmenopausal women, Like other

fractures, the incidence of wrist fractures increases with age, For example, among white women in

Rochester, Minnesota, in the 1970s the annual incidence of wrist fracture increased from 3.6 per 1,000

in women ages 50-54 to 6.9 per 1,000 in women 85 years of age or older (1 00), At any age, women with

low bone mass have a higher Incidence of wrist fractures (14, 56, 121)

Although wrist fractures do not cause death, they are painful, usually require one or more reductions, and need 4 to 6 weeks in a plaster cast to heal (65). An estimated 20 to 31 percent of wrist fractures are accompanied by short-term complications, including damage to the skin, fascia, tendons, and

nerves (71 ).

Wrist fractures may also result in long-term functional impairment for a small percentage of patients. Full recovery generally takes a full year after fracture (35) In a Finnish study, 6 percent of patients had pain in the wrist area and 22 percent noted pain at the joint between the radius and ulna

bones of the forearm at 6 months after the fracture (68). OTA found no empirical evidence on wrist function beyond the first year following fracture, but a small proportion of women can be expected to have

permanent decline in wrist function.

Vertebral Fractures: Fractures of the spine (vertebra) are the most common kind of osteoporosisrelated fracture Estimating the relationship of bone mass to vertebral fractures IS much more complex

than with other fractures, in part because there is a lack of agreement among experts about the radioIogic definition of vertebral fractures (14), On x-ray, vertebral fractures appear as vertebral deformities,

rather than as a distinct fracture, The best evidence suggests that the risk of vertebral fractures increases two-fold with each standard deviation of bone mass below the mean BMD for a given age (14)

The prevalence of vertebral deformities in white women 50 years of age and older in Rochester,

Minnesota, is estimated at 25,3 percent (87), (Black women have a much lower incidence of osteoporotic fractures, ) Most vertebral fractures, however, do not cause symptoms and are never brought to

clinical attention In another study of almost 3,000 non-black women ages 65 to 70 recruited from the

community, 606 percent had vertebral deformities, but only those with the most severe deformities

(10,2 percent of the total population) had significantly higher levels of back pain, disability, or loss of

height compared to women with no vertebral deformities (39), Because women with back pain might be

more likely to volunteer for a study of osteoporosis, the prevalence of back pain in this group of women

is likely to be higher than in the general population, Whereas 66 percent of women with no vertebral

deformities had back pain at least rarely during the past year, 78 percent of women with severe deformities had back pain at least rarely; thus, about 12 percent more women with the most severe deformities were Iikely to experience back pain than those without any deformities. This suggests that under

1 3 percent of the total population of women 65 years of age and older suffers back pain as a consequence of severe vertebral deformities, most of which are due to osteoporosis (38) The same study

found that women with the most severe vertebral deformities tended to have more problems with overall

health, and did not rule out the possibility that other health conditions affecting pain and disability may
12 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

BOX A: Cent’d.

also be correlated with vertebral fractures. Consequently, these estimates represent the maximum independent effect of vertebral fractures on pain and disability.

Of women with severe vertebral deformities, about 16.4 percent reported having much difficulty

with one or more activities of daily living because of back pain within the past year, compared with 82

percent of women with no spinal deformities (39) This suggests that under 0.83 percent of the total

population of elderly women had some decline in function as a result of severe vertebral deformities

Other studies have found Impacts on functional abilities of about the same order of magnitude (124).

Hip Fractures: The risk that a 50-year-old woman will fracture her hip sometime during the rest of

her life is about 16 percent (14). The risk of hip fracture is reversely related to bone mass at all ages

above 50. (See appendix D )

Most of the recovery of functional abilities following a hip fracture occurs within the first 6 months

after the fracture (62, 79). Three studies found that after 6 months, only about one-third of all elderly hip

fracture patients regain their pre-fracture level of functioning (33, 62, 90).

A prospective study of a cohort of over 2,800 community-living elderly women traced the loss of

function in 120 who sustained a hip fracture during the 6-year study period (81) Of the 120 women with

hip fracture, 98 survived at least 6 months. Of the survivors, the percentages who could perform various

functions, compared with those able to perform them at the beginning of the study, are shown below

At baseline 6-month post-fracture

Dress independently 86% 49%

Transfer independently 90 32

Walk across room independently 7 5 15

Climb a flight of stairs 63 8

Walk 1/2 mile 41 6

Other studies of changes in functional abilities in older people also clearly illustrate the severe

impact of a hip fracture, One study of change in functional abilities over a 6-year period among 356

older people in California found that a hip fracture led to significantly greater loss of functional abilities

than any of the other acute medical conditions measured, including heart attack, stroke, and cancer

(66). Another study of change in mobility over a 6-year period among 7,000 older people in three locations found that the risk for loss of mobility was two to five times greater for people who had a fracture

than for people who did not (51). Moreover, the relative risk of loss of mobility was greater following a

hip fracture than a heart attack, stroke, or cancer. In the aggregate, however, heart disease may have a

greater effect on functional ability than hip fracture because of its much higher Incidence in elderly

women (50).1

1 Based on estimates of the age-specific heart attack death rate and estimates of the ratio of fatal to nonfatal heart attacks, OTA

estimates that the risk that a 50-year-old woman wiII have a heart attack sometime in her Iife is roughly 22 percent

have never had a heart attack is unknown, because Two studies of QALYs in breast cancer have

there are no other similar studies. 10 shown that the value of a year lived with breast

10 Measuring time trade-offs in healthy people who lack direct experience with the disease under study requires that they be informed about

the health states they are being asked to value. How such information is framed and how diseases are labeled can affect the values people assign to

them (46).
Cost-Effectiveness Analysis | 13

cancer varies greatly depending on the stage of the

disease at diagnosis, the prognosis for dying of

breast cancer (versus other causes), and other information provided to respondents about the disease (8, 52). As is generally true in most QALY

studies across diseases, women with breast cancer

gave a higher value to living a year of life with the

disease than did women without breast cancer. In

an Australian study, women over 40 years of age

rated a year with breast cancer with a favorable

prognosis as equivalent to 0.79 healthy years of

life and a year with breast cancer with a poor prognosis as equivalent to 0.3 healthy years of life

(52).

Despite the abundant evidence that functional

dependency increases after a hip fracture, there are

no empirical estimates of QALYs associated with

hip fracture.11 It would be dangerous to speculate

on such values based on what we know about

functional status after a hip fracture, because

people’s willingness to pay to avoid a specific disease is not a straightforward function of such elements.

Other omissions

OTA did not estimate the savings in health care

costs associated with reductions in wrist, vertebral, or other fractures resulting from long-term

HRT because data on these costs are not available.

Because these fractures rarely lead to hospitalization or nursing home placement, the cost of treating them is likely to be very low compared with

the cost of hip fractures and other diseases affected

by HRT. Thus, the effect of this omission on costeffectiveness ratios is likely to be very small.

OTA also did not measure the costs of informal

(unpaid) assistance provided by family and

friends to patients with the conditions and diseases affected by HRT, because very little information is available on the amount of such care

provided to patients of various ages with hip fractures, heart attacks, breast cancer, endometrial

cancer, or gallbladder disease. The net effect of ignoring this dimension of cost on the cost effectiveness of various screening and HRT strategies is

unknown, because the savings in such care from

reductions in fractures and heart attacks are balanced to an unknown extent against extra costs

from the increased incidence of breast cancer, endometrial cancer, and gallbladder disease. However, the value of these services may not be very

important compared with the other health care

costs of these diseases.12

Bone Density, HRT, and Hip Fracture

The screening simulation model predicts, on the

basis of each woman’s measured BMD at age 50

(the typical age of onset of menopause) and her assigned HRT regimen, the probability of hip fracture in each subsequent year of life. Ideally, such

a prediction would be based on the results of controlled clinical trials comparing hip fractures in

women randomly assigned to HRT with those assigned a placebo or alternative therapy. Unfortunately, such studies do not exist.

Although several studies have consistently

found a relationship between HRT and the incidence of hip fractures (see appendix B for a summary of all such studies), none of the existing

studies of this relationship are randomized pro11 Several osteoporosis cost-effectiveness studies have used estimates based on the subjective judgment of an individual or a small group of

experts (23, 34, 127). Because such estimates have not been tested or validated, they serve only as exploratory studies.

12 For example, one study of hip fracture patients age 65 and over who were treated in seven Maryland hospitals found that, two months after

the fracture, 88 percent were receiving an average of 44 hours per week of informal care from family members and friends (67). However, before

the hip fracture, 82 percent of the patients had received an average of 41 hours of informal care, so the difference (which was not statistically

significant in the study) in the amount of family care given to hip fracture patients, particularly elderly patients, may not be great. A later report on

this cohort found that direct nonmedical and informal care costs were lower six months or more after fracture than they were during the six

months prior to the fracture (16). The investigators posited that this result may be due to chronic diseases in patients prior to hip fracture. Although OTA did not include the value of lost earnings, this value is also small, given that virtually all osteoporosis-related hip fractures occur in

persons past the age of retirement.
14 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

spective clinical trials. All existing studies are observational studies, where treatment and control

groups are not randomly assigned.13 The limitations of such observational studies as definitive

evidence of a causal relationship between an intervention and a clinical outcome are well known.

More importantly, none of the existing studies of

HRT and fracture examine a specific duration of

HRT; rather, they typically report on the average

experience of a sample of women whose HRT

lasted for varying lengths of time. Thus, while the

existing evidence relating HRT to a reduction in

hip and other fractures is supportive of the existence of such effects, it provides little direct evidence on which to build a quantitative estimate of

such effects.

In contrast, numerous prospective controlled

studies are available on the impact of HRT on

BMD. (See appendix C.) These studies show unequivocally that HRT reduces bone loss. For postmenopausal women treated with estrogen, bone

loss initially ceases almost completely, and some

studies show that bone mass may increase slightly

and then show either maintenance or a gradual

long-term decline. Long-term estrogen users have

been shown to have significantly more bone mineral than matched controls at all sites measured

(15). The reduction in the rate of bone loss continues as long as estrogens are taken (74, 75). Once

estrogen therapy is discontinued, bone loss accelerates at a rate similar to that seen immediately after menopause in untreated women (25, 76).14

Because the evidence on the causal relationship

between HRT and BMD is strong and consistent,

OTA estimated the effectiveness of HRT on hip

fracture in two steps. First, we estimated the impact of HRT on BMD at each age. Then we estimated the impact of BMD at each age on the

probability of a hip fracture at each age. Thus, all

effects of HRT on hip fracture were assumed to

work through its effects on BMD.15

The general framework and specific parameters

of a method to predict BMDs and hip fractures in

women at each age between 50 and 90 were developed by Dennis Black under contract to OTA (14).

The justification and details of the method are provided in appendix D. The method is described

briefly below.

Predicting BMDs

Data are available from a number of sources on the

distribution (means, variances, and shape of the

distribution) of BMDs, measured at the proximal

radius (wrist), with single photon absorptiometry

(SPA) at each age. (See appendix D.) Some data

are also available on the correlation between a

woman’s measured BMD at age 50 and her BMD

in subsequent years. On the basis of Black’s review of available data and estimates, OTA as13 Observational studies include both case-control and cohort studies. In case-control studies, the frequency of a suspected causative factor,

such as estrogen use, is compared in a group of people who have a disease (cases) with those who do not (controls). If this factor is found with

greater (or less) frequency in those with the disease, a causal association may be suspected. In cohort studies, 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 (external controls).

14 In the absence of hormone therapy, bone loss accelerates in the five years or so immediately following menopause and then proceeds more

gradually in subsequent years (14, 20, 24, 56, 72, 74, 75, 82, 84, 85, 86, 88, 95, 115, 140).

15 This assumption may either underestimate or overestimate the true number of hip fractures prevented by HRT. On the one hand, HRT may

reduce hip fracture risk through mechanisms in addition to increasing bone mass. For example, HRT may reduce hip fractures by improving

muscle strength and neuromuscular coordination, but this hypothesis is controversial (122). HRT may also prevent hip fractures by preventing

chronic conditions, such as heart disease, which make people prone to falling. On the other hand, the effect of bone mass on hip fracture risk may

be overstated because low bone mass may be correlated with other conditions predisposing people to hip fracture (30, 32, 42, 80, 107, 115).

Browner and colleagues analyzed deaths occurring after hip and pelvis fractures and found that most of the increase in mortality is due to underlying conditions that are unlikely to be much affected by reductions in the incidence of these fractures (17).
Cost-Effectiveness Analysis 115

FIGURE 1: Mean Bone Mineral Density

(gm/cm2

) by Age Predicted in OTA’s

Osteoporosis Model

0.9,

0.5 I I I I I I , I I , I , , I , , , , , , , , , , , ,

50 55 60 65 70 75 80 85 90

Age

SOURCE Off ice of Technology Assessment, 1995

sumed that at any age the BMD in a population of

women follows a normal (bell-shaped) distribution. Each woman’s BMD measured at the wrist

at age 50 is sampled from a normal distribution

with a meanBMDof0.814 gm/cm2 and a standard

deviation of 0.1 gm/cm2

. Although the mean

BMD declines with age as shown in figure 1, the

standard deviation is constant across ages. Subsequent BMDs are assigned on the basis of the starting BMD, age-specific correlation coefficients

relating BMDs in each pair of years, and the mean

and standard deviation of BMD in the population

of women at each age. (See appendix D for details.)

Predicting the impact of HRT on BMD

HRT clearly retards bone loss and, according to

most trials, may actually stop bone loss for the

duration of therapy. Although the optimal dose of

estrogen is uncertain, studies have consistently

shown that doses in the range of 0.625 mg per day

of conjugated estrogen or its equivalent are sufficient to protect bone mass during the course of

therapy. (See appendix E for a discussion of the

evidence on alternative HRT regimens. )

OTA assumed as a base case that the mean

BMD in a sample of women on HRT would not

change for the duration of therapy, although individual women’s measured BMD values will vary

randomly from year to year. 16 Thus, when a

woman is placed on HRT because of a low initial

BMD at age 50, her subsequent BMDs are assumed to be sampled from a population distribution whose mean and standard deviation do not

change for the duration of therapy. (See appendix

D.) When HRT ends, BMD is assumed to decline

at the rate observed in women immediately following menopause.

The BMD parameters in OTA’s model are

based on bone-mass measurements taken by SPA

in the wrist. Newer densitometry techniques,

which measure bone mass at other body sites, may

predict fracture with greater precision. For example, recent evidence suggests that DEXA measurements at the hip may predict the short-run risk

of hip fracture more accurately than does SPA at

the wrist (15). If such improved predictive accuracy were established over the long term, the effectiveness of screening would increase. (The cost

effectiveness of screening would depend on the

relative costs of different densitometry techniques.) Unfortunately, this possibility cannot be

explored at present, because data are unavailable

on either long-term prediction of hip fracture or

the correlation of BMD measurements over time

for any densitometry technique except for SPA at

the wrist.

Figure 2 shows the simulated BMD trajectory

of a woman whose initial BMD measured by SPA

at the wrist is 0.806 mg/cm2 and compares it with

the simulated BMD trajectories of two women

16 The relationship between a woman’s BMD values in any two consecutive years depends on the strength of the correlation between BMD

values measured over time. OTA’s contractor estimated the correlation coefficients based on data provided by Hui (56, 57, 58). See appendix D

for details.
16 Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

FIGURE 2: Bone Density in Three

Simulated Cases

1 I

20 years HRT-Case 2

/

, “

 20 years HRT-Case 1

>

.—

Baseline-No HRT - .

L

E

 0.4

0.2

0 I I 1 [ I 50 55 60 65 70 75 80 85 90

Age

SOURCE: Office of Technology Assessment, 1995

whose initial BMD values are similar but who are

placed on HRT for 20 years under the assumption

that BMD halts bone loss for the duration of therapy. Figure 3 shows the cumulative lifetime hip

fracture incidence predicted by the model for two

simulated samples of 100,000 women. In one

sample, none of the women is placed on therapy;

in the other, all women are placed on HRT for the

rest of their lives.

Because of uncertainty about the ability of HRT

to preserve bone mass in the long term (39), OTA

tested the sensitivity of the results to the assumption that HRT reduces the rate of bone loss by one

half during the course of therapy.

Predicting hip fractures

The relationship between measured BMD in each

year and the probability of hip fracture is based on

data from the Study of Osteoporotic Fractures

(SOF) on age-specific bone mass and hip fracture

rates (31 ). The simulation model determines

whether or not to assign a hip fracture to each

sampled woman at each age from 50 through 90

FIGURE 3: Cumulative Fractures per 100,000

Women Predicted in OTA’s Osteoporosis Model

20

16-

12- 8

8

4

Lifetime HRT

- -

0 [ I I I I I I I I I I I I I I 1 ) 1 I I I 1 I I ) 1 I I 1 I

50 55 60 65 70 75 80 85 90

Age

SOURCE: Off ice of Technology Assessment, 1995

based on the probability of hip fracture, which is

calculated as a function of both age and BMD.

(See appendix D.)

Predicting hip fracture mortality

A hip fracture increases mortality, morbidity, and

costs for the patient, her family, and society. In a

separate background paper, OTA examined the

evidence on the consequences of hip fracture

(132). OTA concluded that hip fracture increases

the risk of death in the year following fracture, but

after the first year, the risk of death is no greater

than that of the general population of women at

each age. For the purposes of the model, therefore,

OTA assumed that a woman with a hip fracture

would have a probability of death in the subsequent year as shown in table 2. Those who survive

beyond the first year are assumed to have a risk of

death equal to that of the general population of

women of the same age.

Breast Cancer and Hormone

Replacement Therapy

HRT increases breast cancer risk by a small

amount, if at all. Consequently, the evidence on
Cost-Effectiveness Analysis 117

TABLE 2: Mortality Rates Per 100 Women

in the First Year After Fracture

Age

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

Value

0.054

0.056

0.058

0.061

0.063

0.065

0.068

0.070

0.072

0.075

0.077

0079

0.082

0.084

0.086

0.088

0091

0,093

0.095

0098

0.100

0.107

0.114

Age

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

Value

0.121

0.128

0.135

0.142

0.149

0.156

0.163

0.170

0.183

0.196

0.209

0.221

0,234

0.247

0.260

0.276

0.292

0.308

0.324

0.340

0.356

0.372

SOURCE Off ice of Technology Assessment, 1995

the relationship is inconsistent: low risks are more

difficult to detect and estimate than are high risks.

For purposes of this model, OTA assumed that

the risk of breast cancer increases with HRT, but

only after a patient has been exposed to HRT for

a long period of time. In the base case, OTA assumed that women on HRT would have no increase in breast cancer risk until HRT therapy has

continued for 10 years; in subsequent years, the

relative risk of breast cancer in women on HRT

compared with the general population is 1.35.

OTA assumed treated women’s risk of breast cancer would remain elevated even after cessation of

therapy. Because of the uncertainty surrounding

these estimates, OTA investigated the sensitivity

of the estimates of cost and effectiveness to a best

case assumption that the relative risk of breast

cancer is 1.0 and a worst case assumption that the

relative risk is 2.0. HRT was assumed to have no

effect on the stage distribution of detected breast

cancers or on breast cancer prognosis. The basis

for these assumptions is presented in appendix F,

which summarizes the evidence on the relationship between HRT and breast cancer incidence.

Once a woman has breast cancer, the computer

assigns an age of death based on age and stage at

diagnosis. The probability of death as a function

of time since diagnosis was constructed from the

National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) tumor registry

data (108). 17 Because the assigned death age is

based on data on deaths in breast cancer patients

from all causes, once it is assigned, the death age

overrides all other possible mortal events in the

model. (That is, a woman cannot die earlier of

most other causes.18)

OTA also assumed, based on a review of the

epidemiologic evidence, that the addition of a progestin to estrogen replacement therapy does not

reduce the risk of breast cancer associated with

HRT.

Endometrial Cancer and Hormone

Replacement Therapy

The impact of HRT on endometrial cancer differs

widely between ERT and PERT. Endometrial cancer risk rises dramatically with the use of ERT and

increases with the duration of ERT. After ERT is

ended, however, evidence suggests that endometrial cancer risk rapidly returns to the pre-therapy

level (63, 101, 117, 123). OTA assumed that the

risk of endometrial cancer is elevated only with

17 NCI provided OTA with unpublished data on 1-, 5-, 10-, and 15-year all-cause survival rates by age and stage at the time of detection.

18 As explained later in this section, a death age is assigned if a woman contracts one of three conditions: breast cancer, endometrial cancer. or

hip fracture. If a woman is assigned one of these conditions after having had a death age assigned for another, the original and new death ages are

compared, and the youngest death age prevails.
18 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

current use of ERT and the risk increases with

longer duration of ERT. For the first 10 years of

therapy, the relative risk of endometrial cancer

compared with women on HRT is assumed to be

3.5. Once ERT has exceeded 10 years in duration,

the relative risk becomes 7.0. When ERT ceases,

the relative risk returns to 1. The basis for these assumptions is presented in appendix G.

OTA tested the sensitivity of the results to

changes in the relative risk of endometrial cancer.

In the best case, OTA assumed a relative risk of 1

for short-term ERT and 2 for long-term ERT. In

the worst case, OTA assumed a relative risk for

short-term ERT of 7.5; and for long-term ERT of

15. (See appendix G.)

Although endometrial cancer risk is clearly elevated by ERT, women diagnosed with endometrial cancer while on ERT have much lower

mortality rates than do those not on therapy at the

time of diagnosis. The evidence suggests that

women diagnosed with endometrial cancer while

on ERT rarely die of it; rather, they are treated with

a full hysterectomy, which is almost always curative (26, 28, 36, 37, 78, 113, 144).

The excellent prognosis for women diagnosed

with endometrial cancer while on ERT is difficult

to explain. It may be partly due to annual surveillance with endometrial biopsy, a standard precaution for women on long-term ERT. Since

endometrial cancer is slow-growing, surveillance

may be sufficient even with lower frequency in

some women to detect endometrial cancers before

they spread beyond the uterus. Some experts have

suggested that the endometrial cancer induced by

ERT is much more indolent than that occurring in

other women (26, 28, 36, 37, 78, 113, 144). Regardless of the reasons for the excellent prognosis

in women with ERT-induced endometrial cancer,

the most realistic assumption is that women diagnosed with endometrial cancer while on ERT have

a negligible increase in mortality risk over those

without endometrial cancer.19 Thus, in this model, these women are subjected to hysterectomy,

with its attendant costs, but they are not assigned

a death age and remain at risk for death from unrelated causes in subsequent years.20 Women diagnosed with endometrial cancer who are not

currently on HRT are assigned a death age based

on stage distribution and survival probabilities reported in the NCI SEER database.21 (See appendix G for the rationale behind these assumptions.)

Today, PERT is the most frequently used HRT

regimen in women with intact uteri, precisely because it eliminates the excess risk of endometrial

cancer associated with ERT. It may even reduce

the incidence of endometrial cancer compared

with no therapy (40, 49, 152). OTA assumed that

the relative risk of endometrial cancer in women

on PERT is 1.0. 

Just as the prognosis for endometrial cancers in

women on ERT is more favorable than for endometrial cancers found in women not on therapy,

the prognosis for endometrial cancer in women on

PERT is also favorable (83). Although annual

monitoring with endometrial biopsy is not routine

in women on PERT, women on PERT are generally monitored more closely than others, and any incidents of unscheduled vaginal bleeding are

evaluated with endometrial biopsies. OTA assumed that endometrial cancers found in women

on PERT would not be fatal, requiring only pri19 This is an underestimate of the true mortality associated with endometrial cancers in women on HRT, because some epidemiological studies have identified late stage cancers in women on HRT; in addition, early stage endometrial cancers are treated with a hysterectomy, and there is

some mortality associated with any surgical procedure where anesthesia is used. Only a small number of deaths are associated with endometrial

cancers in HRT users, so the consequences of this underestimate are small.

20 Women who contract endometrial cancer while on therapy remain at risk for death from unrelated causes unless they have previously been

assigned a death age because of breast cancer or hip fracture.

21 It is possible for a woman not on therapy to contract both breast cancer and endometrial cancer. If a woman diagnosed with breast cancer

and assigned a death age by the computer is later diagnosed with endometrial cancer, the breast cancer death age is compared with the endometrial death age, and the lower age is maintained as the assigned death age.
Cost-Effectiveness Analysis | 19

mary treatment (hysterectomy) and involving no

excess mortality.22

As the results of OTA’s analysis will demonstrate, one implication of the above assumptions

about prognosis for women with endometrial cancer detected while on HRT is that endometrial cancer has very little effect on the principal outcome

measure: years of life lived. Indeed, despite the

high relative risk of endometrial cancer, the predicted years of life lived in women on ERT actually increase compared with the life expectancy of

women not on therapy. This is because we assumed no women on ERT will die of endometrial

cancer, whereas a certain percentage of the relatively smaller number of women not on therapy

who get endometrial cancer would be predicted to

die of the disease.23

The endometrial cancer assumptions also mean

that years of life lost from endometrial cancer under any screening-HRT strategy will not differ according to the specific HRT regimen (ERT or

PERT) adopted. The costs of treating endometrial

cancer will differ between ERT and PERT, however, because many more women are detected with

endometrial cancer under ERT than under PERT.

Gallstones and Hormone

Replacement Therapy

HRT taken by mouth has been linked to increased

risk of gallstones, which require surgical removal

(cholecystectomy) to relieve symptoms and prevent recurrence. Appendix H contains a review of

the evidence on HRT and gallstones. Based on that

review, OTA’s model assumes a relative risk of

gallstone disease while a woman is on HRT of 2.5.

We also assume that the only consequence of gallstone disease is a cholecystectomy and that no excess mortality arises from this condition.24

Coronary Heart Disease (CHD) and

Hormone Replacement Therapy

Cardiovascular disease is the leading cause of

death among U.S. women, surpassing the rates

from cancer and other disease (18). Any change in

the risk of cardiovascular disease due to HRT

could profoundly alter the risk-benefit trade-offs

of HRT. Most studies show that ERT reduces the

risk of CHD in postmenopausal women, but the

magnitude and post-therapy duration of the reduction in risk have not been established.25 Even less

information is available on the impact of PERT on

CHD. Appendix I contains a review of the evidence on HRT and CHD.

It has been estimated that between 25 and 50

percent of the beneficial effect of estrogen on heart

disease risk occurs through alteration of lipoprotein levels (12). Observational studies and randomized clinical trials have shown that estrogen

reduces low-density lipoproteins (LDL, the bad

cholesterol) and raises levels of high-density lipoproteins (HDL, the good cholesterol) (153). When

progestins are added to the HRT regimen, however, these lipoprotein effects may be reduced. The

rest of estrogen’s beneficial effects on heart disease are mediated by other factors, such as estrogen’s immediate effects on coronary artery

vasospasm and clot formation. (See appendix I.)

Evidence on actual heart disease outcomes

(e.g., fatal or nonfatal heart attacks, incidence of

unstable angina, etc.) is weak, because although

there are many studies of the relation between

ERT and heart disease (see appendix I), virtually

22 Not making this assumption for PERT, when it has been made for ERT, would lead to the anomalous result that PERT would cause more

endometrial cancer deaths (and years of life lost) than would ERT.

23 The OTA model is capable of analyzing different assumptions about stage and prognosis for endometrial cancer under HRT. We did not

analyze other assumptions in this paper, because the evidence supporting the favorable prognosis is strong.

24 This is an underestimate of the mortality associated with this procedure, as all surgical procedures requiring anesthesia carry a small risk of

death. The surgical death rate associated with cholecystectomy is very low, however, so the consequences of this underestimate are small.

25 HRT has been found not to increase the risk of stroke (59, 102, 104, 105, 114, 150).
20 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

none are randomized clinical trials. Results of 16

case-control studies, 16 cohort studies, and four

cross-sectional studies, mostly of postmenopausal women on ERT, generally support the contention that the heart disease benefits are

substantial—on the order of 20 to 80 percent reduction in risk during the therapy period. (See appendix I.) Several randomized trials have

established a link between ERT and intermediate

endpoints, such as short-term effects on cholesterol level. (See appendix I.)

Without randomized clinical trials linking ERT

use to the incidence of or mortality from CHD,

however, the very real possibility remains that

these differences were found because patients who

choose HRT are systematically healthier than or

otherwise different from those who do not.26

Because observational studies and controlled

clinical trials using intermediate endpoints suggest a CHD benefit from ERT, OTA assumed in

the base case that the risk of heart attacks in

women currently on ERT is 50 percent lower than

the risk in women not on HRT. Once ERT is terminated, however, OTA assumed the risk reduction

disappears and CHD incidence returns to that of

the general population of women of the same

age.27 OTA further assumed that the ratio of fatal

to nonfatal heart attacks would remain the same

regardless of the risk level.28

Because of the importance of heart disease to

both health outcomes and health care costs and the

uncertainty concerning the benefits of ERT for

heart disease, OTA studied the impact on the results of changing the relative risks associated with

ERT from 0.2 to 1.0.

As uncertain as the CHD benefits are in women

on ERT, CHD benefits in women on PERT are

even more uncertain. Few observational studies

have been reported to date on the relationship, but

observational studies and clinical trials of PERT’s

impact on lipoproteins suggest that the beneficial

effect of estrogens is attenuated when progestins

of the type and dose most commonly used in the

United States are added to the HRT regimen. A

randomized controlled clinical trial of HRT effects on CHD risk factors found that PERT eliminated about two-thirds to three-quarters of the

increase in HDL cholesterol (153), the lipoprotein

most closely linked to heart disease in women

(13). Consequently, OTA assumed that the relative risk of a heart attack in women on PERT is

0.8, but we also examined the sensitivity of the results to assuming no benefit (i.e., a relative risk of

1.0.).

Costs

OTA sought data on the health care costs of bone

densitometry, HRT,29 hip fracture, breast cancer,

endometrial cancer, heart attacks, and gallbladder

disease. When cost estimates were based on historical data, they were inflated by the medical expenditures component of the Consumer Price

Index to 1993 constant dollars. The methods used

to estimate each component of costs are described

in detail in appendix J.

26 The healthy user bias occurs when those who seek or use health services are in generally better health than those who do not and consequently have lower incidence of disease.

27 The lipid hypothesis of estrogen protection against heart disease contradicts the empirical evidence on the shape of the observed association between estrogen use and heart disease risk (12, 109). The evidence suggests that estrogen protects only current users, and the degree of

protection does not increase with longer durations of use. But the lipid hypothesis would predict that protective effects on the heart would come

with long durations of estrogen use, because atherosclerotic plaques (fatty deposits) that block the arteries of the heart take years to develop.

28 Epidemiological studies of HRT and heart disease incidence have found that the reductions in risk of fatal and nonfatal myocardial infarctions in HRT users are similar. See appendix I.

29 The costs of HRT included annual physician visits, HRT prescriptions, and, for ERT, annual endometrial biopsies, as well as the cost of

followup visits for problems associated with therapy.
Cost-Effectiveness Analysis 121

TABLE 3: Summary of Assumptions in OTA’s Osteoporosis Model

Assumptions about cost

HRT annual treatment cost

● (Estrogen only) $269

■ (Estrogen/progestin) $258

BMD screening cost (SPA at wrist) $100

Cost of fatal heart attack $14,470

Cost of nonfatal heart attack $74,217

Ratio of nonfatal to fatal heart attacks 2.6

Cost of hip fracture $22,912

Cost of cholecystectomy $11,160

Discount rate, costs 0.05

Discount rate, life years 0.05

Lifetime cost of breast cancer

■ Localized $78,153 (age 50)-$12,616 (age 90)a

■ Regional $67,274 (age 50)-$1 5,837 (age 90)a

■ Distant $45,043 (age 50)-$26,230 (age 90)a

Lifetime cost of endometrial cancer

■ If on HRT $6,000

■ If not on HRT

—Localized $15,702 (age 50)- $8,635 (age90)a

—Regional $20203 (age 50)-$1 3,418 (age 90)a

—Distant $21,552 (age 50)-$1 5,890 (age 90)a

Assumptions about risks

and benefits of HRT Base case Worst case Best case

Relative risk of breast cancer

● With less than 10 years’ therapy 1,0 1,0 1,0

■ After 10 or more years’ therapy 1.35 2,0 1.0

Relative risk of endometrial cancer

■ While on HRT, with less than 10 years’

therapy 3.5 7.5 1,0

■ While on HRT, with 10 or more years’

therapy 7.0 15,0 2.0

Relative risk of heart attack while on therapy 0.5 0.8 0.2

Relative risk of gallbladder disease, while on

therapy 2.5 — —

Impact of HRT on rate of bone loss, while on Stops loss of bone density Reduces rate of

therapy loss by 50

percent

a Variable by age and stage

SOURCE Off ice of Technology Assessment, 1995
22 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 4: Screening/HRT Strategies Examined by OTA

Duration of therapy (years)

Therapy threshold 10 20 30 40

50 years old

1 standard deviation

Below mean BMD

Everyone on therapy

65 years old

1 standard deviation

Below mean BMD

Everyone on therapy

below mean BMD

below mean BMD

x x x x

x x x x

x x x x

x

x

x

SOURCE Off ice of Technology Assessment, 1995

Summary of Model Assumptions

Table 3 summarizes the assumptions underlying

the simulation model. The base case assumptions

are best estimates of true parameter values. The

best case assumptions are the most favorable to

screening and HRT. The worst case assumptions

are least favorable to screening.

❚ Screening/HRT Strategies Examined

The costs and effects of an osteoporosis screening

strategy depend on three elements of program design:

■ the age at which BMD measurement occurs,

■ the BMD threshold for initiation of a course of

long-term HRT, and

■ the duration of HRT therapy.

Table 4 contains a summary of the screening/

HRT strategies tested by OTA.

Age of BMD Screening

OTA assumed that BMD screening would take

place once at age 50. This screening age corresponds approximately to the average age at which

natural menopause begins.

To examine the effect of delaying the initiation

of screening and HRT, OTA performed additional

simulations in which BMD screening is initiated

at age 65.

BMD Threshold for HRT

OTA examined alternative BMD thresholds for

initiation of HRT:

the lowest 16.7 percent of BMD values in the

population (corresponding to a BMD threshold

equal to 1 standard deviation below the mean

for the hypothetical cohort at age 50),30

the lowest 50 percent of measured BMD values

in the population (corresponding to a BMD

threshold value equal to the mean population

BMD value), and

all women regardless of BMD level at age 50.

In the third case—universal application of HRT

to all women eligible for HRT—BMD measurement would be unnecessary. Therefore, in the

third case, OTA assumed no screening would take

place.

Duration of HRT

OTA considered only those preventive strategies

involving long-term application of HRT—at least

10 years’ duration. Although short-term HRT is

30 A European osteoporosis consensus conference in 1993 defined low bone mass as BMD or bone mineral content (BMC) one standard

deviation below the mean for the adult population (41 ).
Cost-Effectiveness Analysis 123

TABLE 5: Simulation Results: Baseline (No Intervention) in 15 Samples of 100,000 Women ($ millions)

Coefficient of

Mean (standard variation

Outcome deviation) (percent)

Number of hip fractures

Total hip fracture costs

■ undiscounted

■ discounted c

Number of breast cancers

Total Iifetime breast cancer costs

■ undiscounted

■ discounted

Number of endometrial cancers

Total lifetime endometrial cancer costs

■ undiscounted

■ discounted

Number of fatal heart attacks

Total Iifetime heart attack costs

■ undiscounted

■ discounted

Number of gallbladder operations

Total Iifetime gallbladder costs

■ undiscounted

■ discounted

Number of women alive at age 90

Total lifetime cost

● undiscounted

■ discounted

Total years of life lived

■ undiscounted

■ discounted

16,985 (1 04)

$389 (2.4)

$114 (0.9)

10,135 (129)

$513 (7.0)

$264 (3.8)

2)378 (36)

$42 (0.7)

$19 (0.4)

8,570 (49)

$1,778 (10.2)

$533 (3.5)

12,576 (1 52)

$140 (1 .7)

$67 (0.8)

17,824 (1 00.2)

$2,862 (1 2.2)

$997 (5.9)

3,018,098 (2,576)

1,549,499 (846)

0.61 %

0.61

0.79

1,28

1.36

1.45

1,51

1,67

1.94

0.58

0.58

0.66

1.21

1.21

1,26

0.56

0.42

0.60

0.09

0.05

95 percent

confidence intervalb

16,928-17,043

379-391

113-114

10,064-10,207

510-517

509.5 -517,3

262-266

21358-2,398

41-42

19-19

8,542-8,597

1,772-1,783

531-535

12,492-12,660

139-141

66-67

17,769-17,880

2,855-2,869

993- 1,000,0

3,016,671-3,019,525

1,549,030-1,549,967

a The coefficient of variation IS a relative measure of variation in a statistic. It IS technically defined as the standard deviation of the statistic divided

by the mean value of the statistic.

b The 95 percent confidence Interval IS the range of values of a statistic that contains the true value of the statistic with 95 percent probability

Confidence Intervals were calculated using the appropriate t-distribution value with 14 degrees of freedom

c Costs occurring in future years are discounted to their net present value at age 50 at 5 percent per year (for example, costs recurred at age 60 are

multiplied by 1/(1.05)10 = 0.614 to arrive at their present value at age 50)

SOURCE Off ice of Technology Assessment, 1995

often indicated for relief of menopausal symptoms, the benefits of treatment for prevention ofhip fracture tend to accrue only with longer use

(43). OTA therefore examined the effects and

costs of HRT maintained for 10, 20, 30 and 40

years. (A 40-year strategy is equivalent to placing

a woman on a lifelong regimen of HRT.)

RESULTS

❚ Screening/HRT at age 50

OTA first ran the osteoporosis model under the

base case set of assumptions with no preventive

intervention. Fifteen separate samples of 100,000

women were used to estimate the mean and standard deviations of the major outcomes. Table 5
24 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

shows the estimated average values of these outcomes and measures of their variation for the no

intervention strategy. The standard deviation

across the 15 samples of every outcome measure

was very low from 0.01 to 2 percent of the estimated mean value of the measure for all outcome

measures.31

Most of the analyses were performed assuming

that the HRT strategy being tested involves ERT.

As noted above, adding progestin (PERT) to the

strategy alters the incidence but not the outcome

of endometrial cancer. The reduced incidence of

endometrial cancer with PERT does translate into

lower costs of endometrial cancer, but even when

the risk is elevated seven-fold with ERT, endometrial cancer is relatively rare compared with the

other diseases (breast cancer, hip fracture, and

CHD) affected by HRT. Also, the net annual costs

of ERT and PERT differ very little from one

another. Thus, if nothing else were affected by the

switch from ERT to PERT, the ratio of cost to effectiveness of any HRT strategy using PERT

would be slightly lower than the ratio of cost to effectiveness of the same HRT strategy using ERT,

and the cost effectiveness of ERT could be used as

a rough guide for the cost effectiveness of PERT.

PERT may have a major impact on the cost effectiveness of HRT, however, because it potentially has a less beneficial effect on heart disease than

ERT. This difference is reflected in a higher assumed relative risk of heart attack with PERT than

with ERT. We therefore directly compared the cost

effectiveness of several HRT strategies involving

PERT with those of ERT to calibrate the two therapeutic approaches with one another. These comparisons permit summary statements about the

relative cost effectiveness of alternative HRT

strategies using PERT.

Outcomes with ERT: Base Case Assumptions

Tables 6 through 10 show the results of sample

simulations of 100,000 women under different

ERT strategies for 50-year-old women. The lifetime incidence of hip fractures (table 6) declines

from approximately 17 percent with no intervention, to about 7 percent when all women are placed

on ERT for the rest of their lives. As expected, intermediate strategies in which fewer women are

provided ERT, or they stay on ERT for shorter periods, reduce the lifetime incidence of hip fractures by lesser amounts.

The lifetime incidence of fatal heart attacks

also decreases with intervention (table 7) from 8.5

per 100 with no therapy to 5.1 per 100 when everyone is placed on a lifelong regimen of ERT.32 The

gains from therapy accelerate in percentage terms

as the duration of ERT increases. With everyone

on therapy, for example, a 10-year ERT regimen

reduces the incidence of fatal heart attacks by 5

percent. An additional 10-years of therapy reduces fatal heart attacks by another 6 percent. Adding 10 more years of therapy (to arrive at a

30-year ERT regimen) reduces fatal heart attacks

by another 15 percent. Finally, going from 30 to

40 years of ERT means a further 23-percent reduction in heart attack deaths. This accelerating effect

of ERT on cardiac death rates reflects the rising

burden of CHD with age.

31 The low variation across the 15 samples of size 100,000 suggests that samples of this size are sufficient to produce highly stable outcomes

of the simulation model.

32 Although the relative risk of acute myocardial infarction is assumed to be 0.5 while a woman is under therapy, the lifetime incidence does

not decline by 50 percent with lifelong therapy, for two reasons. First, women on therapy have a much higher relative risk of endometrial cancer

than do women not on therapy. The model assumes that once a woman is diagnosed with endometrial cancer she is removed from therapy, and the

cardiac benefits of HRT are eliminated. Second, women diagnosed with breast cancer are also removed from therapy, and death rates from breast

cancer increase with therapy.
Cost-Effectiveness Analysis 125

TABLE 6: Lifetime Incidence of Hip Fractures per 100,000 Women Under Different Osteoporosis

prevention Strategies-Base Case Assumptionsa (number of samples of 100,000)

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT below mean BMD < mean at 50 yrs old

No ERT 16,985 (15) —

10 years — 15,978 (15) 14,374 (14) 12,865 (11)

20 years — 15,268 (15) 12,374 (10) 9,801 (15)

30 years — 14,796 (15) 11,229 (15) 7,833 (15)

—40 years — 14,653 (15) 10,871 (15) 7,184 (15)

a For base case assumptions, see table 3

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE: Office of Technology Assessment, 1995

TABLE 7: Lifetime Incidence of Fatal Heart Attacks per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptions (number of samples of 100,000)

—

BMD threshold —

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT ——— below mean BMD < mean at 50 yrs old

No ERT

----— .———— -.— — _.. -— — .-— .

8,570 . .— -—

10 years — 8,549 (15) 8,449 (14) 8,211 (11)

20 years — 8,496 (15) 8,214 (1 O) 7,784 (15)

30 years — 8,298 (15) 7,652 (15) 6,680 (15)

40 years — 8,054 (15) 6,888 (15) 5,149 (15)

- —-.. .—-. .—--.——-. -— —-— .—.—. -—— .- —— ..- —. —.—. .— ——.-_——— ——_— --- —— —.— —

a For base case assumptions, see table 3

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy; STD = standard deviation,

SOURCE: Off ice of Technology Assessment, 1995
26 Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 8: Lifetime Incidence of Breast Cancer per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptionsa (number of samples of 100,000)

BMD threshold

Baseline: Screen at 50 yrs old, Screen at 50 yrs DO NOT screen, all

no screening, ERT when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT — below mean BMD < mean at 50 yrs old .

No ERT 10,135 (15) — — —

10 years 10,670 (15) 11,492 (14) 12,911 (11)

20 years 16,630 (15) 11,567 (10) 12,813 (15)

30 years — 10,601 (15) 11,595 (15) 12,935 (15)

40 years — .

— 10,643 (15) 11,597 (15) 12,997 (15)

. — ———..——

a For base case assumptions, see table 3

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995

TABLE 9: Lifetime Incidence of Endometrial Cancer per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptionsa (number of samples of 100,000) —

BMD threshold

Baseline: Screen at 50 yrs old, Screen at 50 yrs DO NOT screen, all

no screening, ERT when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT below mean— BMD < mean at 50 yrs old

No ERT 2,378 — .

10 years — 2,589 (15) 3,092 (14) 3,826 (11 )

20 years — 3,332 (15) 5,360 (10) 8,399 (15)

30 years — 3,896 (15) 7,235 (15) 12)073 (15)

40 years — 4,136 (15) 7,997 (15) 13,558 (15) — —. —

a For base case assumptions, see table 3

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy; STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995

TABLE 10: Lifetime Incidence of Gallbladder Disease per 100,000 Womena Under Different

osteoporosis Prevention Strategies–Base Case Assumptionsb (number of samples of 100, 000)

BMD threshold

Baseline: Screen at 50 yrs old, Screen at 50 yrs

no screening, ERT when BMD <1 STD old, ERT when

Duration of ERT no ERT below mean BMD < mean

No ERT 12,576

10 years 13,233 (15) 14,585 (14)

20 years 14,024 (15) 17,112 (1 o)

30 years 14,708 (15) 19,054 (15)

40 years 14,932 (15) 19,819 (15)

a Incidence of gallbladder disease requiring cholecystectomy

b For base case assumptions, see tables

KEY: BMD - bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995

“DO NOT screen, all

women on ERT

— at 50 yrs old

16,559 (11 )

21,649 (15)

25,488 (15)

26,974 (15)
Cost-Effectiveness Analysis | 27

The lifetime incidence of breast cancer and endometrial cancer rises with ERT (tables 8 and 9).

The incidence of breast cancer increases by 28

percent when all women are put on HRT for the remainder of their lives. Intermediate strategies

have positive, but lower, effects on breast cancer

incidence.

The lifetime incidence of gallbladder disease

severe enough to require surgery increases from

about 12.6 percent without intervention, to almost

27 percent with lifelong HRT for everyone (table

10).33

Tables 11 through 17 show the lifetime health

care costs per 100,000 women of each cost component in the model: BMD measurement (screening), ERT, hip fracture, heart disease, breast

cancer, endometrial cancer, and gallbladder disease. These tables present both the undiscounted

and discounted costs of each component under the

12 screening/HRT strategies studied. Discounted

costs are substantially lower than undiscounted

costs in all categories except BMD measurement,

because that is the only cost component fully incurred in the first year of the program (at age 50).

As expected, the costs of hip fractures and heart

attacks decline as the number of people placed on

ERT or the duration of ERT increases. Conversely, the costs of ERT itself and of treating breast

cancer and gallbladder disease increase as the

number of people on ERT or the duration of ERT

increase. The costs of treating endometrial cancer

also increase as the number of women placed on

ERT or the duration of ERT increase, but the cost

increase is very small. This result reflects the

model’s assumption that the treatment cost of endometrial cancer ($6,000) diagnosed in a woman

on HRT is substantially less than the treatment

cost for a woman not on HRT at the time of diagnosis. (The lifetime cost of treating a localized endometrial cancer in a woman not on HRT ranges

from $8,635 to $15,702, depending on the age at

detection. (See appendix J.))

The net health care costs and years of life lived

across all components of the model are shown in

tables 18 and 19, respectively. Table 18 demonstrates that, compared with no intervention, any

screening/ERT strategy increases lifetime health

care costs. For example, placing all women on

ERT for the remainder of their lives increases net

lifetime undiscounted health care costs by 4.5 percent (from $2.86 billion to $2.99 billion per

100,000 women) and increases net lifetime discounted costs by 25 percent ($1 billion to $1.25

billion) compared with no intervention.

The net years of life gained from intervention

are positive, although small (table 19). Placing all

women on a lifelong course of ERT, for example,

adds approximately 42,000 years of life to a cohort of 100,000 women, an average of approximately five extra months of life per woman.34

When years of life lived are discounted to their

present value at age 50, the gains in life extension

are much more modest. ERT of 10 years’ duration

offers almost no net gain in discounted years of

life; placing all women on a course of ERT for 10

years gains only 11,000 discounted years of life

per 100,000 women, or slightly less than one additional month of life per woman on average.

Cost Effectiveness of ERT:

Base Case Assumptions

If a preventive intervention both increases net

health care costs and improves health outcomes,

the ratio of incremental costs to incremental

health effects is a useful measure of the improvements in the health outcomes of interest that each

dollar buys on average.

33 Although the relative risk of gallbladder disease is 2.5 with HRT, the actual incidence does not increase by that much because the model

takes women off therapy if they are newly diagnosed with either breast or endometrial cancer.

34 Of course, some women will die much earlier because of the adverse impacts of HRT (i.e., breast cancer), while others will die much later

because they avoid fatal heart attacks or hip fractures.
28 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 11: Lifetime Cost of BMD Screening per 100,000 Women Under Different Osteoporosis

Prevention Strategies–Base Case Assumptionsa ($ millions)

Duration of ERT

No ERT

undiscounted

discounted b

10 years

undiscounted

discounted

20 years

undiscounted

discounted

30 years

undiscounted

discounted

40 years

undiscounted

discounted

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs

no screening, when BMD <1 STD old, ERT when

no ERT below mean BMD < mean

$0.0

0.0

$10.0 $10.0

10,0 10,0

10,0 10.0

10.0 10,0

10,0 10,0

10,0 10.0

10.0 10,0

10,0 100

a For base case assumptions see table 3

DO NOT screen, all

women on ERT

at 50 yrs old

$0.0

0 0

0 0

0.0

0 0

0 0

0.0

0 0

b Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a

rate of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995
Cost-Effectiveness Analysis 129

TABLE 12: Lifetime Cost of ERT per 100,000 Women Under Different Osteoporosis Prevention

Strategies–Base Case Assumptions ($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD

Duration of ERT no ERT below mean

old, ERT when women on ERT

BMD < mean at 50 yrs old

No ERT

undiscounted

discounteda

10 years

undiscounted

discounted

20 years

undiscounted

discounted

30 years

undiscounted

discounted

40 years

undiscounted

discounted

$0.0

0.0

—

—

—.

—

—

—

—

$41,3

33.6

76,5

51.2

102,8

59.5

116.3

62.1

—

—

$129,8

105.6

241,6

161,8

323.3

187,2

366.1

195,4

—

$259.8

211,4

483,2

323.6

646.4

374.3

733.2

391.2

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program in initiation at a rate

of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995
30 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 13: Lifetime Cost of Treating Hip Fractures per 100,000 Women Under Different

Prevention Strategies-Base Case Assumptions ($ millions)

BMD threshold

Duration of ERT

No ERT

undiscounted

discounted a

10 years

undiscounted

discounted

20 years

undiscounted

discounted

30 years

undiscounted

discounted

40 years

undiscounted

discounted

Osteoporosis

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD old, ERT when women on ERT

no ERT below mean BMD < mean at 50 yrs old

$389.2

113.6

— $366.1

— 106.2

349.8

101,9

— 339.0

99.5

— 335.7

98.9

$329.3 $294.8

94.9 8 4 2

2835 2246

82.6 65.6

2573 179.5

7 6 8 55.7

249. 1 1646

75,3 5 3 2

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate

of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995
Cost-Effectiveness Analysis 131

TABLE 14: Lifetime Cost of Heart Attacks per 100,000 Women Under Different Osteoporosis

Prevention Strategies–Base Case Assumptions ($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT below mean BMD < mean at 50 yrs old

No E R T

—

undiscounted $1,777.6

discounted a

533.0

10 years

undiscounted $1,773,4 $1,752,6 $1,7033

discounted — 530,7 5164 493,0

20 years

undiscounted 1,762.3 1,703,8 1,6147

discounted 521.6 488,3 439.7

30 years

undiscounted — 1,721.3 1,587,3 1,385,6

discounted 508,3 453.1 367,5

40 years

undiscounted 1,670,7 1,4289 1,0681

discounted — 499.5 422,5 307,6

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate

of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation.

SOURCE Off ice of Technology Assessment, 1995
32 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 15: Lifetime Cost of Endometrial Cancer per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptions ($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs DO NOT screen, all

no screening, when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT below mean BMD < mean at 50 yrs old

No ERT

--

-undiscounted $41,5 —

discounted a

19,2 — —

10 years

undiscounted $41,7 $42.7 $437

discounted — 19,3 20.1 21.0

20 years

undiscounted 4 4 6 51.0 60.7

discounted 20.9 24,3 29,5

30 years

undiscounted — 46,8 58.7 75.9

discounted — 21,5 26.7 34.4

40 years

undiscounted — 47.8 62.3 82.5

discounted — 21,7 27.5 35.7 ————.— —————. - .— ——. .

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate

of 5 percent per annum.

KEY: BMD = bone mineral density: ERT = estrogen replacement therapy: STD = standard deviation

SOURCE: Office of Technology Assessment, 1995
Cost-Effectiveness Analysis 133

TABLE 16: Lifetime Cost of Breast Cancer per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptions ($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, ERT Screen at 50 yrs

no screening, when BMD <1 STD old, ERT when

Duration of ERT no ERT below mean BMD < mean

No ERT

undiscounted $513,4 — —

discounted a264,0

10 years

undiscounted — $539.1 $577,5

discounted 275,2 290.5

20 years

undiscounted — 537.2 579.5

discounted — 274,1 289,6

30 years

undiscounted 535.2 581.4

discounted — 272.7 291,4

40 years

undiscounted — 537.7 580.2

discounted — 274.4 290,1

DO NOT screen, all

women on ERT

at 50 yrs old

—

$644,4

317.3

638.4

314.0

6428

315.1

644.1

315.5

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate

of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995
34 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 17: Lifetime Cost of Gallbladder Disease per 100,000 Women Under Different Osteoporosis

Prevention Strategies–Base Case Assumptions ($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, Screen at 50 yrs

no screening, ERT when BMD <1 STD old, ERT when

Duration of ERT no ERT below mean BMD < mean

DO NOT screen, all

women on ERT

at 50 yrs old

No ERT

undiscounted

discounted a

10 years

undiscounted

discounted

20 years

undiscounted

discounted

30 years

undiscounted

discounted

40 years

undiscounted

discounted

$140.4

66.9

—

—

—

—

—

—

—

—

—

—

$147.7

73.0

156,5

77.5

164,1

80.0

166.6

80.7

—

—

$162,8

85.5

191,0

100,1

212.6

107.0

221.2

108.8

—

—

$184,8

104,3

241,6

133,3

284,4

146,9

301.0

150,4

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate

of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Office of Technology Assessment, 1995
Cost-Effectiveness Analysis 135

TABLE 18: Total Lifetime Cost per 100,000 Women of Different Osteoporosis Prevention Strategies

($ millions)

BMD threshold

Baseline: Screen at 50 yrs old, Screen at 50 yrs DO NOT screen, all

no screening, ERT when BMD <1 STD old, ERT when women on ERT

Duration of ERT no ERT below mean BMD < mean at 50 yrs old

No ERT

undiscounted $2,862,1 — —

discounted a

996.7 —

10 years

undiscounted $2,919,2 $3,004.7 $3,130.8

discounted — 1,048.0 1,122,8 1,231,3

20 years

undiscounted 2,936.9 3,060.4 3,263,1

discounted — 1,057.2 1,156,6 1,305,7

30 years

undiscounted 2,919.2 3,030.6 3,214.5

discounted — 1,051.6 1,152,2 1,293,8

40 years

undiscounted 2,884,8 2,917,7 2,9936

discounted 1,047,2 1,129,6 1,2536

a Costs occurring in years subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a

rate of 5 percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE: Office of Technology Assessment, 1995
36 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 19: Total Number of Years of Life Lived per 100,000 Women Under Different Osteoporosis

Prevention Strategies-Base Case Assumptions (thousands of years)

BMD threshold

Baseline: Screen at 50 yrs old, ERT

no screening, when BMD <1 STD

Duration of ERT no ERT below mean

No ERT

undiscounted 3,018.1 —

discounted a 1,549,5

10 years

undiscounted 3,018.5

discounted — 1,549,8

20 years

undiscounted — 3,021.5

discounted — 1,550,6

30 years

undiscounted 3,025.1

discounted 1,551,4

40 years

undiscounted — 3,025.4

discounted 1,551,3

Screen at 50 yrs

old, ERT when

BMD < mean

—

3,020.2

1,550.4

3,029.6

1,553,2

3,036.9

1,554.8

3,040.8

1,555.4

DO NOT screen, all

women on ERT

at 50 yrs old

—

3,021.5

1,551.4

3,038.5

1,556.3

3,052.4

1,5591

3,060.6

1,560,5

a Years of life Iived subsequent to program initiation (at age 50) are discounted to their present value in the year of program initiation at a rate of 5

percent per annum

KEY: BMD = bone mineral density, ERT = estrogen replacement therapy, STD = standard deviation

SOURCE Off ice of Technology Assessment, 1995
Cost-Effectiveness Analysis 137

TABLE 20: Cost Per Added Year of Life for 12 Osteoporosis Prevention Strategies–

Base Case Assumptions (95% confidence interval)a

Number of years on ERT

BMD screening

threshold 10 years 20 years 30 years 40 years —

1 S.D, below mean $151,392 $53,610

($45,783-Undefined)

$28,257 —$27,486

($31,432-$165,262) ($19,777-$47,240) ($18,865-$47,815)

Below the mean $134,644 $42,724 $29,357 $22,431

($73,364-$758,436) ($34,606-

$55,524) ($25490-$34,484) ($19,687-$25,954)

Everyone on therapy $126,876 $45,761 $31,059 $23,334

($87,643-$228,472) ($41 ,061-$51 ,633) ($28)700-$33,815) ($21,744-$25,151)

a Confidence Intervals computed based on Fieller’s Theorem as cited in A.R. Willan and B J O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada, August 1994

KEY: ERT = estrogen replacement therapy

SOURCE Off ice of Technology Assessment, 1995

Table 20 contains the ratios of cost to years of

life gained for each of the 12 osteoporosis prevention strategies under study. Regardless of the

BMD threshold for ERT, the cost per added year

of life declines dramatically with the duration of

ERT. Forty years of ERT (a lifelong course) delivers an additional year of life for between $22,000

and $27,000 depending on the number of women

placed on therapy.

The components of the cost effectiveness ratio

(cost and years of life lived) were estimated from

simulated samples of hypothetical women subjected to either a given preventive strategy or no

intervention. The 95-percent confidence intervals

for these components were very narrow. (See table

5 above.) Although the confidence intervals for

the underlying components of the cost effectiveness ratio are very narrow, the cost effectiveness

ratio is based on differences in costs and outcomes, which vary more widely. And because the

net effects (years of life gained) are very small in

relation to the added costs (tens of thousands of

years of life gained versus hundreds of millions

additional dollars in costs), the ratio of net added

costs to net effects has even greater variability.

No exact method exists for determining the

confidence interval for a ratio of random variables

such as the cost-effectiveness ratio (97, 148). OTA

estimated the 95-percent confidence intervals for

the cost-effectiveness ratios using two approximation methods recently reported in the literature. 35 Table 20 shows the approximate 95-

percent confidence intervals for the cost-effectiveness ratio of each strategy under study.

The approximate confidence intervals for the

cost-effectiveness ratio of strategies involving

only 10 years of therapy are very wide. These results are to be expected given the low number of

years of life gained under these strategies (table 18

above). 36 Thus. not only are the mean cost-effectiveness ratios associated with the shortest ERT

35 One method, referred to as Taylor’s Approximation (7), is useful when the estimate of net effectiveness is positive and statistically significant ( 148, 149). When effectiveness is near zero, a more exact method based on Fieller’s Theorem should be used (149). OTA estimated the

confidence intervals in table 20 and in selected cases (as noted) in tables 21 through 26 using Fieller’s method. All other confidence intervals

were estimated using Taylor Approximation.

36 When the value of the denominator is low relative to the numerator, small changes in the denominator make for very large changes in the

ratio.
38 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 21: Cost Per Added Year of Life for Two Osteoporosis Prevention Strategiesa

Best- and Worst-Case Assumptions About Relative Risks of Coronary Heart Disease

Everyone on Therapy

(95% confidence interval)

Number of years on ERT

20 years 40 years — —

Base case assumptions $45,761 $23,334

($41,061-$51,633) b

($21,744-$25,151 )b

Best case assumptions—CHD $28,431 $7,153

($25,218-$31,643) ($6,703-$7,604)

Worst case assumptions—CHD $118,196 $78,860

($83,162 -$203,109)b

— ($57)962-$99758).- —.

a All women are placed on therapy for either 20 or 40 years

b Confidence Intervals computed based on Fieller's Theorem as cited in A.R. Willan and B.J. O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada August 1994

KEY: CHD = coronary heart disease

SOURCE Off ice of Technology Assessment, 1995

duration much higher than those of all other strategies, but the wide confidence intervals suggest

that the true ratio may be very different from the

estimate.

Together, these results imply that if a woman is

to be placed on ERT, a lifelong course of therapy

delivers the greatest benefit per dollar spent.

Whether all women should be placed on therapy,

or whether the ERT decision should be based on

a BMD measurement at age 50, is more debatable.

The cost-effectiveness ratios for the three 40-year

ERT strategies are very close and are not significantly different from one another.

The estimated additional discounted lifetime

cost of each BMD measurement strategy

compared with no intervention rises as the number

of women placed on therapy increases. The lifetime cost ranges from $50 million per 100,000

when the 16 percent of women with the lowest

measured BMD values are placed on HRT to $257

million per 100,000 women when no BMD

screening takes place and all women are placed on

therapy. But the net measured health benefits also

rise as the proportion of women on therapy increases. Placing women on ERT whose measured

BMDs lie in the lowest 16 percent of the population delivers about 1,800 additional discounted

years of life per 100,000 screened women, while

placing all women on ERT delivers 11,000 years

of life per 100,000 women.

Sensitivity Analyses with ERT

OTA tested the effects of varying key parameters

individually and together on the results of the

cost-effectiveness analysis of screening/ERT

strategies. The critical assumptions subjected to a

sensitivity analysis were:

1. the relative risk of heart attack under ERT;

2. the relative risk of breast cancer after long-term

ERT;

3. the relative risk of endometrial cancer under

ERT; and

4. the degree to which ERT affects the rate of

bone loss.

Analyses were conducted on the impact of

changes in these assumptions on the cost-effectiveness ratios of two strategies: everyone on therapy for 20 years and everyone on therapy for 40

years.

Relative risk of heart attack

Table 21 shows the cost-effectiveness ratios for

two strategies (everyone on ERT for either 20 or

40 years) under the base case and the best and
Cost-Effectiveness Analysis 139

FIGURE 4: Impact of Coronary Heart Disease

Benefits on the Cost Effectiveness of Lifetime

ERT in 50-Year-Old Women

0.2 0.4 0.6 0.8

Relative risk of acute myocardial

infarction in women on ERT

SOURCE Office of Technology Assessment, 1995

worst case assumptions regarding the relative risk

of heart attack while on ERT. Under the best case

assumption, the relative risk of AMI is 0.20. Under the worst case assumption, it is 0.80.

As expected, assuming a smaller beneficial effect of HRT on heart attacks raises the cost per year

of life gained from about $23,000 to almost

$79,000 for a lifelong course of ERT. But if ERT

follows the best case assumption, the cost per added year of life is reduced to slightly more than

$7,000, a very low cost-effectiveness ratio

compared with that of other clinical preventive interventions.

Figure 4 shows the cost effectiveness of lifetime ERT in all women under a range of assumptions (0.2-1 .0) regarding the relative risk of heart

attack under ERT. The sensitivity of the cost-effectiveness ratio to changes in assumptions about

HRT’s effect on heart disease reflects the high incidence and lethality of heart disease and the high

costs of treating it, If the suggestive evidence from

clinical trials on cardiac risk factors and from observational studies is correct, the cost per additional year of life from lifelong ERT lies within

commonly used benchmarks for acceptability of

clinical preventive services. Conversely, if the

true heart disease benefit from ERT is small or

nonexistent, the cost of ERT for each year of life

gained is very high.

If heart disease benefits do not exist, limiting

ERT to those with low bone mass would still be

very costly for each year of life gained. For example, under the assumption of no heart disease

benefits, placing on lifelong ERT only those

whose measured BMD at age 50 lies more than 1

standard deviation below the mean results in a

cost-per-added-year-of-life equal to $157,041.

This amount is substantially less than the cost-effectiveness ratio of placing all women on lifelong

ERT ($443,884), but it is still much higher than

the ratio predicted for screening and selective ERT

under the base case assumptions ($27,486).

Relative risk of breast cancer

Table 22 shows the cost-effectiveness ratios for

the best case and worst case assumptions regarding the relative risk of breast cancer after an extended duration of ERT. Under the best case

assumption, HRT was assumed not to alter the relative risk of breast cancer, while under the worst

case assumption, 10 or more years of HRT was assumed to increase the relative risk of breast cancer

to 2.0.

Assuming the worst about the relative risk of

breast cancer with HRT raises the cost per year of

life gained for lifelong ERT for all women from

$23,000 to about $44,000. Under the best case assumptions, the cost-effectiveness ratio is about

$16,000 per year of life gained.

Relative risk of endometrial cancer

Changing the assumptions about the relative risk

of endometrial cancer does not alter cost-effectiveness ratios very much, (table 23) largely because the model assumes that endometrial cancer

induced by ERT has an excellent prognosis and

relatively low treatment cost.
40 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 22: Cost Per Added Year of Life for Two Osteoporosis Prevention Strategiesa

Best- and Worst-Case Assumptions About Relative Risks of Breast Cancer

Everyone on Therapy

(9570 confidence interval)

Number of years on ERT

20 years 40 years

Base case assumptions $45,761

($41,061-$51,633) b

$23,334

($21,744-$25,151) b

Best case assumptions—breast cancer $37,734 $16,105

($31,042-$44,427) ($14,473-$1 7,737)

Worst case assumptions—breast cancer $158,378 $43,765

($105,494-$316,054)b

($37,808-$49,723)

a All women are placed on therapy for either 20 or 40 years

b Confidence Intervals computed based on Fieller’s Theorem as cited in A.R. Willan and B.J. O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada, August 1994

SOURCE Off ice of Technology Assessment, 1995

TABLE 23: Cost Per Added Year of Life for Two Osteoporosis Prevention Strategiesa

Best- and Worst-Case Assumptions About Relative Risks of Endometrial Cancer

Everyone on Therapy

 (95% confidence interval)

Number of years on ERT

20 years 40 years

Base case assumptions $45,761 $23,334

($41,061-$51,633) b

($21,744-$25,151) b

Best case assumptions—endometrial cancer $42,496 $21,039

($35,304-$49)689) ($19,061-$23,01 7)

Worst case assumptions—endometrial cancer $49,304 $29,718

($39,694-$58)914) ($25,810-$33,625)

a All women are placed on therapy for either 20 or 40 years

b Confidence intervals computed based on Fieller’s Theorem as cited in A.R. Willan and B.J. O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada, August 1994

SOURCE Off ice of Technology Assessment, 1995

Relationship of HRT to bone loss bone density hardly affects the estimated cost per

Table 24 shows how assuming that HRT reduces year of life gained. Because all other assumptions

bone loss by 50 percent, rather than 100 percent as are the same as those in the base case, the large

assumed in the base case, changes the cost-effec- gains in years of life resulting from lower risk of

tiveness ratios for the two ERT strategies. Under heart attack overwhelm other dimensions of effecthe lifetime ERT strategy, the assumption that tiveness and maintain the cost-effectiveness ratio

ERT is only partially effective in maintaining at a moderately low level.
Cost-Effectiveness Analysis 141

TABLE 24: Cost Per Added Year of Life for Two Osteoporosis Prevention Strategiesa

Worst-Case Assumptions About Effects of ERT on Bone Loss

Everyone on Therapy

(95% confidence interval)

Number of years on ERT

20 years 40 years —

Base case assumptions $45,761 $23,334

($41,061-$51,633) b

($21,744 -$25,151)b

Worst case assumptions—ERT and bone loss $62,342 $27$994

($48,295-$76,390) ($24,721 -$31 ,267)

a All women are placed on therapy for elf her 20 or 40 years

b Confidence intervals computed based on Fieller’s Theorem as cited in A.R. Willan and B.J. O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada, August 1994

SOURCE: Office of Technology Assessment, 1995

TABLE 25: Cost Per Added Year of Life for Two Osteoporosis Prevention Strategiesa

Best- and Worst-Case Assumptions About Four Uncertain Parameters

Everyone on Therapy

(95°/0 confidence interval)

Number of years on ERT

20 years 40 years

Base case assumptions $45,761 $23,334

($41,061-$51,633) b

($21 ,744-$25,151 )b

Best case assumptions—four uncertain parameters $17,427 $1,559

($15,915--

$18,939) ($1 ,467-$1 ,650)

Worst case assumptions—four uncertain parameters neg. effect., pos. costs $1,465,434

($436,834-undefined) b

a All women are placed on therapy for either 20 or 40 years

b Confidence intervals computed based on Fieller’s Theorem as cited in A.R. Willan and B.J. O’Brien, “Cost-Effectiveness Ratios in Clinical Trials

From Deterministic to Stochastic Models, ” presented at the American Statistical Association meeting, Toronto, Canada, August 1994

SOURCE Off ice of Technology Assessment, 1995

Simultaneous changes in four

uncertain parameters

OTA analyzed how the cost-effectiveness ratios

change if all four of the parameters are held simultaneously to their worst case values or to their best

case values. Table 25 presents the results for the

two preventive strategies. The range of cost-effectiveness values widens dramatically to span a very

low ratio ($1,559 per year of life gained for 40

years of therapy) and a prohibitively high ratio

($1.5 million per year of life gained for 40 years

HRT). Because the estimated mean years of life

gained are very small under the worst case scenario, the approximate 95-percent confidence interval for the estimate is very wide. Again, when the

effects of an intervention are close to zero, one can

have little confidence in the mean reported costeffectiveness ratio.

The best case/worst case analysis gives an extremely wide envelope of potential cost-effectiveness ratios for ERT. Because our base case
42 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

assumptions predicted cost-effectiveness ratios

for lifelong ERT strategies that were reasonably

low (i.e., reasonably cost effective) compared

with other accepted clinical preventive services,

any uncertainty favoring the best case merely reinforces the cost effectiveness of lifelong ERT. The

very high cost-effectiveness ratio in the worst case

scenario, however, means that we cannot rule out

the possibility that any ERT strategy (with or

without BMD screening) would be a very poor investment for society.

Outcomes with PERT

PERT reduces the excess risk of endometrial cancer in women on HRT, but it may also reduce

HRT’s heart disease benefits. OTA analyzed the

cost effectiveness of a lifelong regimen of PERT

assuming that 1) the risk of endometrial cancer

with PERT, is not elevated over population levels

and 2) the relative risk of heart attack in women on

PERT compared with those not on therapy is 0.8.

All other assumptions followed the base case.

(See table 2 above.) Figure 5 compares the resulting cost-effectiveness ratios of two preventive

strategies with those of the same strategy using

ERT.

The PERT strategies are less cost effective be--

cause assumptions about heart disease have a big

impact on the analysis. 37 Although PERT reduces

incidence and lowers treatment costs of endometrial cancer, it also lowers heart disease benefits,

which far outweigh the consequences of endometrial cancer. Of course, if ERT itself has no heart

disease benefits, the addition of progestins to the

HRT regimen improves the cost-effectiveness ratio, but the cost-effectiveness ratios of either regimen would be very high. (For a 40-year course of

HRT in all women, the cost per added year of life

FIGURE 5: Cost Effectiveness of PERT v. ERT

 ■ Everyone on therapy

❏ 1 STD below mean

PERT ERT

Type of HRT

SOURCE: Off ice of Technology Assessment 1995

assuming no heart disease benefits is $443,884 for

ERT and $262,673 for PERT.)

❚ Initiating Osteoporosis Screening/HRT

at Age 65

Is osteoporosis prevention at menopause better or

worse than initiating prevention at a later age,

when the risk of hip fracture and heart disease

have increased? Beginning HRT in elderly

women has been proposed as a way to reduce the

total duration of exposure to HRT in these women,

thus reducing the risks of breast and endometrial

cancer, while having HRT present during the ages

of highest risk of heart disease and hip fracture.

Modeling the impact of BMD screening and/or

HRT on bone loss, heart disease, breast cancer, endometrial cancer, and gallbladder disease is even

more uncertain for a population of 65-year-old

37 If the relative risk of CHD were the same for both ERT and PERT then the cost-effectiveness ratios would be similar. For example, if the

relative risk of CHD is 0.8 for both ERT and PERT, the cost per added year of life of a lifetime course of ERT for all women is $78.860 and the cost

per added year of life for the same strategy using PERT is $64.376.
Cost-Effectiveness Analysis | 43

women than it is for a population of 50-year-old

women, because there is much less information

available on effectiveness and risks of HRT in

women who begin therapy at 65 years of age.38

OTA analyzed the cost effectiveness of initiating a screening program in women at age 65 under

the base case assumptions regarding the effect of

ERT on disease. Specifically, OTA assumed that:

1. ERT will stop further bone loss while a woman

is on therapy;

2. the relative risk of heart attack is 0.5 while on

therapy;

3. the relative risk of breast cancer is 1.35 after 10

years of therapy;

4. the relative risk of endometrial cancer is 3.5 as

soon as therapy begins and 7.0 after 10 years for

the duration of therapy; and

5. the relative risk of gallbladder disease is 2.5

while on therapy.

Table 26 shows the results of the analysis for

strategies in which women are screened at age 65

and placed on ERT for 20 years. Regardless of the

BMD threshold for ERT, prevention is cost saving. That is, it not only lengthens life on average

but also reduces health care costs. Putting all

women on therapy both provides the greatest cost

saving and adds the greatest number of years of

life to the cohort.

Much of the medical benefit and reduced cost

predicted by the model stems from assumed reductions in the risk of heart attacks for women on

ERT. Since there is no evidence that women first

placed on ERT at age 65 do indeed have a reduced

heart attack risk, OTA examined the sensitivity of

the results of assuming the relative risk of heart attack is 1.0.

Placing on ERT for 20 years only those women

whose BMDs are below the mean costs almost

$184 million per 100,000 women screened and

adds about 2,000 years of life to the cohort.39 The

mean cost per discounted year of life gained is

$90,117 (approximate confidence interval is

$45,191 to $135,033). Thus, if there are no cardiac

benefits to HRT when it is begun at 65 years of

age, an osteoporosis screening and HRT program

that begins at age 65 will deliver health benefits at

a cost that lies above commonly accepted benchmarks for preventive interventions. The risks and

benefits of initiating HRT at older ages need more

study.

❚ Cost Effectiveness of A Hypothetical

Targeted Osteoporosis Drug

HRT is at present the only therapy approved for

marketing to prevent the reduction in bone mass

that accelerates in women around menopause and

eventually contributes to fractures. Other classes

of drugs are currently under investigation as targeted approaches to maintaining or increasing

bone mass in women with osteoporosis (19, 54,

61, 98, 110). One drug approved today for the

treatment of women with established osteoporosis

is injectable calcitonin, although questions remain about calcitonin’s long-term efficacy on

bone and fracture. Calcitonin is approved for

treatment of osteoporosis, but it has not been approved for prevention of osteoporosis (29, 70).

The bisphosphonate class of drugs has received

considerable development effort. The most wellstudied bisphosphonate, etidronate, was recommended for rejection by an FDA medical advisory

panel in November 1994. Researchers today are

focusing on the bisphosphonate alendronate,

38 Although studies of HRT’s impact on heart disease, osteoporosis, and other disease have included elderly women, few of these women

began HRT in old age. The benefits of HRT initiated many years after menopause may differ from the benefits in those who have been on HRT for

many years. For example, the benefit of HRT on heart disease may be lower in women who already have substantial atherosclerosis. The ability

of HRT to reduce hip fracture risk may be limited in women with already compromised bone structure.

39 Both costs and effectiveness are discounted to their present value in the screening year at an annual rate of 5 percent.
44 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 26: Cost Effectiveness of Screening/HRT Beginning at 65 Years of Agea

per 100,000 women screened

($ millions)

Number who complete therapy “

Fatal heart attacks

Number of breast cancer cases

Number of endometrial cancer cases

Number of hip fractures

Number of gallbladder removals

Cost of treating breast cancer

(undiscounted)

Cost of treating breast cancer (discounted)

Cost of treating endometrial cancer

(undiscounted)

Cost of treating endometrial cancer

(discounted)

Cost of heart attacks (undiscounted)

Cost of heart attacks (discounted)

Cost of treating hip fractures

(undiscounted)

Cost of treating hip fractures (discounted)

Cost of treating gallbladder disease

(undiscounted)

Cost of treating gallbladder disease

(discounted)

Cost of hormone replacement therapy

(undiscounted)

Cost of hormone replacement therapy

(discounted)

Cost of BMD screening (undiscounted)

Cost of BMD screening (discounted)

Total lifetime costs (undiscounted)

Total lifetime costs (discounted)

Years of life lived per 100,000

(undiscounted)

Years of life lived per 100,000 (discounted)

Dollars saved

Baseline:

no therapy

o

8,929

7,292

1,679

17,190

8,929

$313

$216

$29

$20

$1,852

$983

$394

$201

$100

$67

$0

$0

$0

$0

$2,688

$1,487

1,773,287

1,155,306

BMD threshold for therapy

1 STD

below mean

13,540

8,380

7,549

2,625

15,918

10,633

$322

$221

$32

$22

$1,738

$915

$365

$187

$119

$81

$64

$44

$10

$10

$2,650

$1,480

1,779,926

1,158,286

$7

2,981

Below mean

42,828

7,458

7,965

4,488

14,102

14,239

$336

$227

$37

$25

$1,547

$797

$323

$168

$159

$110

$202

$141

$10

$10

$2,615

$1,478

1,791,992

1,163,942

$8

Years of life gained 8,637

a 20 years of therapy.

KEY: BMD = bone mineral density; HRT = hormone replacement therapy, STD = standard deviation

NOTE: Discount rate = 5% for both years of life and costs Costs discounted to present value at age 65 years Base case assumptions

SOURCE: Office of Technology Assessment, 1995

Everyone

on therapy

85,564

5,972

8,677

7,297

11,781

19,581

$361

$240

$45

$29

$1,239

$609

$270

$144

$219

$153

$405

$281

$0

$0

$2,538

$1,456

1,811,804

1,173,341

$31

18,035
Cost-Effectiveness Analysis | 45

which has been shown to be effective in preventing bone loss (10, 143).

What would OTA’s cost-effectiveness model

predict about a hypothetical drug targeted to bonemass maintenance without the side-effects attributed to HRT? We analyzed two osteoporosis

prevention strategies for 50-year-old women:

screening for BMD and placing all women whose

BMD lies below the mean on preventive doses of

the drug; and placing all women (regardless of

BMD) on the drug. We assumed the following

about the intervention: 1) it would preserve bone

mass for the duration of therapy; 2) it would involve no increased risks of cancer, gallbladder disease, or any other unintended side effects; and 3)

it would have no beneficial effect on heart disease.40

The analysis was based on two alternative assumptions about the annual cost of such a medication: 1) that it would cost the same as PERT; and

2) that it would cost $1,000 per year. The latter assumption is probably more realistic about a new

drug for the prevention of a chronic illness with

major morbidity.41

Table 27 describes the results of the analysis.

Regardless of the annual cost of the drug or whether BMD screening is used to target the drug to

those at highest risk of osteoporosis, the lifetime

cost per added year of life is well above $100,000.

If the drug is introduced at a total annual cost of

$1,000, the lifetime cost would be very high relative to the gains in years of life, particularly if all

women are placed on therapy.

Were a new drug to be approved that meets the

assumptions laid out above, the case for limiting

therapy to those at highest risk for osteoporosis

would be strong. Even then, a strategy of BMD

screening and selective therapy would be difficult

to justify on cost-effectiveness grounds without

better information about dimensions of effectiveness that have not been included in the present

model—the quality-of-life impacts associated

with osteoporosis-related fractures. OTA’s model

included only length-of-life and cost impacts of

hip fractures. Whether the decrements in the quality of life associated with hip fractures and other

fractures would bring a quality-adjusted cost-effectiveness ratio into line with customary benchmarks is a research issue that may be worth careful

exploration in anticipation of the development of

a targeted osteoporosis drug sometime in the future.

❚ Low Compliance with HRT:

Implications for Cost Effectiveness

OTA’s analysis assumed that women who enter a

screening or HRT program would stick with the

therapy for its entire course. Although the proportion of post-menopausal U.S. women who use

HRT has increased in the past two decades (21),

until recently the duration of use and the average

dose actually declined (116). This is due in part to

the growing evidence that risk of cancer may be

related to the dose and duration of HRT. Even

when women are prescribed HRT, a substantial

proportion (20 to 60 percent) never have their prescriptions filled (125). The five-year full compliance rate for women who begin postmenopausal HRT is between 5 and 34 percent

(125).42

Recently introduced HRT regimens, such as

continuous-combined HRT or estrogen patches,

may increase compliance in the future, and better

40 Calcitonin and the bisphosphonates appear to have no major effects other than on bone.

41 Commonly prescribed preventive medications for cholesterol reduction cost on the order of $750 to $2,000 per year (45). In 1994, the

average wholesale price of a yearly dose of injectable calcitonin for treatment of osteoporosis was $3,545.98 (1).

42 Low compliance with HRT has many reasons. In general, compliance with a drug regimen is lower when patients suffer no physical symptoms, patients are not convinced the medication will help, patients are afraid of side effects, or symptoms disappear before the end of treatment

(138). Many women may be resistant to taking HRT because it is not natural (91). They also discontinue HRT because of side effects they find

unacceptable, such as resumed menstruation, breast tenderness, weight gain, headaches, and abdominal bloating (93).
46 I Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

TABLE 27: Cost Effectiveness of a Lifetime Course of a Hypothetical Osteoporosis Preventive Therapy in

Women Beginning at 50 Years of Agea

per 100,000 women

($ millions)

Baseline: 1 STD Everyone

no therapy below mean on therapy

For therapy = $258/year

Number who complete therapy

Fatal heart attacks

Number of breast cancer cases

Number of endometrial cancer cases

Number of hip fractures

Number of gallbladder removals

Years of life lived per 100,000 (undiscounted)

Years of life Iived per 100,000 (discounted)

Total lifetime costs (undiscounted)

Total lifetime costs (discounted)

Extra costs incurred

Gain in years of life lived

Cost effectiveness ratio (dollars per year of life added)

For therapy = $1000/year

Total lifetime costs (undiscounted)

Total Iifetime costs (discounted)

Extra costs recurred (undiscounted)

Gain in years of life Iived

Cost effectiveness ratio (dollars per year of life added)

o

8,570

10$135

2,378

16,985

12,576

3,018,098

1,549,499

$2,862

$997

13,897

8,619

10,220

2,398

14,633

12,596

3,020,287

1,549,958

$2,975

$1,067

$70

459

$152,288

$3,279

$1,234

$237

650

$363,752

87,727

8,675

1o,199

2,379

6,588

12,678

3,028,149

1,551,618

$3,389

$1,327

$330

2,119

$155,816

$5,523

$2,412

$1,445

1,932

$747,894

a Therapy IS assumed to stop bone loss at the age of initiation with no other health effects

NOTE Discount rate = 5% for both years of Iife and costs. Costs discounted to present value at age 50 years

SOURCE Off ice of Technology Assessment, 1995

information about risks and benefits of therapy

may help as well (93), but it is unrealistic to assume that most women who begin HRT will remain on it for the rest of their life.

What does low long-term compliance with

therapy mean for the cost effectiveness of HRT?

The data in table 20 show clearly that HRT is substantially less cost effective with lower rates of

compliance. If 50 percent of women were to terminate therapy after only 10 years while the rest of

the population remains on therapy for 40 years, for

example, the cost effectiveness of ERT in the population as a whole would rise to about $73,000.

Thus, unless present compliance rates can be substantially increased, an HRT strategy is not likely

to be very cost-effective.

Because low bone density does not have obvious symptoms unless fracture occurs, bone-density measurement may increase commencement

and maintenance compliance with HRT. Physicians could use densitometry to help patients who

are undecided about initiating HRT to visualize

their low bone density (96). In addition, maintenance compliance might be improved by the use

of densitometry in following patients’ bone density over time.
Cost-Effectiveness Analysis | 47

Recent evidence suggests that women who

have had below-average bone density confirmed

by densitometry may be more likely to commence

HRT as a preventive measure for osteoporosis

(118). In a study of a random sample of women

who had undergone densitometry, 38 percent of

those who were told their BMD was below normal

began taking HRT, compared with 8 percent of

those who were told their BMD was normal or

high.43

Given the very real barriers to compliance with

HRT that exist in the general population and the

evidence that BMD screening may increase compliance among those at highest risk of osteoporosis, a strategy of BMD screening coupled with

HRT only in those at highest risk of fracture may

be more cost-effective in practice than a strategy

that encourages all women to commence HRT.

The cost per added year of life may still be very

high if the compliance obtained from such a strategy is incomplete.44 Thus, even if screening and selective HRT can substantially increase long-term

rates of compliance, the cost of prevention may

still be high compared with its medical benefits.

Furthermore, the use of BMD screening as a tool

to increase compliance must be evaluated against

other methods of improving long-term compliance.

COMPARISON OF OTA’S RESULTS

WITH OTHER COST-EFFECTIVENESS

ANALYSES

Several earlier studies examined the health and

cost impacts of long-term HRT, with or without

BMD screening. None of these studies included

the same components of effect, and each made different assumptions about the benefits, risks, and

costs of screening and HRT.

Weinstein analyzed the cost effectiveness of

placing women on estrogen therapy for 15 years

beginning at age 50 (141, 142). Unlike OTA,

Weinstein attributed no beneficial cardiovascular

effects to HRT. On the other hand, he assumed that

HRT would reduce the frequency of wrist fractures (and therefore the cost of treating them) as

well as those of hip fractures. Weinstein’s assumptions about patterns of risk of hip fracture, endometrial cancer, and breast cancer in women placed

on HRT also differed from those of OTA. Finally,

Weinstein assigned subjective quality-of-life

weights to years of life lived in the presence of the

diseases and conditions affected by HRT. These

quality-of-life weights were based on the authors’

best judgment about the value of one year of life

lived with hip fracture compared with a year of life

lived in perfect health.

The estimated cost per quality-adjusted year of

life gained under a 15-year-long regimen of HRT

in all women was $24,000 (in 1980 dollars). This

is somewhat lower than OTA’s estimate for a

15-year course of therapy, whose estimated average cost lies between $46,000 (20 years’ therapy)

and $127,000 (10 years’ therapy).

Tosteson and colleagues examined the cost effectiveness of estrogen/progestin therapy and

BMD screening using more recent data on hip

fracture risks than was available to Weinstein

(127). Some of the assumptions in that analysis

more closely approximate those of OTA. For example, they assumed that HRT would stop bone

loss for the duration of therapy. Because the HRT

tested in their analysis included progestin, Toste43 This study is difficult to interpret, because it did not control for differences in the level of BMD. The study investigators did not state how

many women were already planning to begin HRT before BMD screening. How much higher compliance would be in low-BMD women who are

given bone-density information than in low-BMD women who are not told their BMD levels remains an open question. There is also no information about what physicians recommended to their patients, or whether HRT was prescribed. Studies of compliance with HRT have shown that it is

strongly affected by what people are told by their physicians and what women believe about HRT’s risk and benefits.

44 For example, under a strategy of screening and ERT for women whose BMD is in the lowest 16 percent of the population, if 50 percent of

the high-risk women stop ERT after 10 years of therapy, the average cost would be $90 thousand per added year of life, compared with $27

thousand if all high-risk women stayed on therapy for the rest of their life. (See table 20).
48 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

son and colleagues assumed neither beneficial

heart disease effects nor increased risks of endometrial or breast cancer in women on HRT. Thus,

the Tosteson analysis rests primarily on the beneficial effects of HRT on osteoporotic fractures.

Tosteson presented results both in terms of cost

per added year of life and cost per year of life, adjusted for the quality of life in various health

states. The quality adjustment weights were based

on subjective estimates developed by Hillner and

colleagues based on the judgement of a small

group of experts (55).45 OTA did not apply quality-of-life weights, but how such weighting would

affect OTA’s results is unclear, since the deleterious effects on the quality of life with breast or endometrial cancer, or of HRT itself, are

accompanied by improvements in the quality of

life when hip fractures and heart disease are

avoided. Tosteson did not address the negative effects of HRT on breast cancer, endometrial cancer

and gallbladder disease; hence, their quality adjustments decreased the cost-effectiveness ratio.

Tosteson found that the cost per additional year

of life lived (before adjusting for quality of life)

was $86,100 (in 1990 dollars) for a 15-year course

of HRT. This compares with OTA’s estimate in the

range of $46,000 (20 years’ therapy) to $127,000

(10 years’ therapy).

Screening women for BMD and placing on

HRT only those at high risk of fracture was more

cost effective than treating all women with estrogen-progestin therapy. For example, placing on

HRT only those women whose BMD values were

below 0.9 gm/cm2 resulted in a cost per year of life

gained of $14,620 (in 1990 dollars). The relatively

low costs of selective HRT (compared with those

of universal HRT) are to be expected in a model

that predicts no heart disease benefits.

A recent Australian study provides estimates of

the cost per QALY of various HRT strategies initiated at menopause (23). The authors adopted the

subjective quality weights developed by Weinstein (142). In contrast to Weinstein, they included

heart disease benefits, valuing each year of life

following a heart attack at the same value as a year

of life following hip fracture. They also assumed

that HRT would have no impact on breast cancer

incidence. The study did not include the costs of

nursing home stays following hip fracture and

made assumptions about the risks and costs of endometrial cancer that differed from those of OTA.

These authors concluded that a 15-year course of

HRT would cost approximately $46,000 (1988

Australian dollars) per QALY with ERT and

$40,000 per QALY with PERT if the relative risk

of heart attack is 0.5 with ERT and 0.75 with

PERT.

Other analysts have also estimated the cost impacts of osteoporosis screening and treatment, but

their work is less directly comparable with OTA’s

study. Ross and colleagues evaluated the potential

annual costs and savings associated with screening all women at age 50 and a lifetime course of

HRT (116). They assumed that HRT would reduce

bone loss by 50 percent throughout the period and

predicted the impact of HRT on the incidence of

fractures using data from a sample of 2,000

women. Placing all women on HRT for their lifetimes would reduce lifetime fracture frequency by

43 percent (compared with a reduction of 53 percent predicted under OTA’s base case assumptions).

45 For example, one year spent in a nursing home following a hip fracture was assumed to be worth 0.36 years of life without disease.
Cost-Effectiveness Analysis | 49

Ross and Wasnich estimated the national cost

of osteoporotic fractures in women at $5.69 billion (in 1987 dollars).46 They assumed that BMD

screening would cost $60 (compared with OTA’s

estimate of $100) and that annual HRT would cost

$75 (compared with OTA’s estimate of $269). Assuming a proportional reduction in national fracture costs with reductions in fracture incidence,

Ross and Wasnich predicted that placing all

women on HRT would save $2.43 billion per year

(1987 dollars) in fracture costs, which would just

pay for the costs of HRT. Screening for bone mineral content and placing only those women with

the lowest 50 percent on HRT would reduce the

national costs of osteoporotic fractures by $1.88

billion per year which, when combined with the

costs of screening and selective HRT, would lead

to a net savings of $760 million per year.

The finding that the national cost of illness actually declines with HRT, even when cardiac

benefits are not considered, is due to several aspects of the approach taken by Ross and his colleagues. First, the costs of screening and therapy

assumed in that study are substantially lower than

those assumed by OTA and other investigators.

Second, the national cost of osteoporotic fractures

includes cost items that are excluded from OTA’s

analysis.47 Third, Ross and Wasnich did not include the costs of treating other diseases induced

by HRT, such as gallbladder disease, endometrial

cancer, and breast cancer.

It is also worth noting that the conclusion that

BMD screening and selective HRT in those at

high risk will actually increase savings associated

with osteoporosis prevention compared with universal HRT is based on the exclusion of heart disease benefits from the model. In OTA’s analysis,

heart disease benefits are in large part responsible

for the greater cost effectiveness of a lifelong regimen of HRT for all women.

Clark and Schuttinga recently analyzed the

present value of net direct and indirect health care

costs of screening for BMD at 50 years of age and

placing high and moderate-risk women on a

15-year estrogen/progestin strategy (27). They assumed that a 15-year course of HRT would reduce

fracture risk by 50 percent after the first five years

and through the rest of the woman’s lifetime. They

estimated the average cost of hip fracture at

$41,723 (compared with approximately $23,000

assumed by OTA).48

Slightly less than 10 percent of total hip fracture costs estimated by Clark and Schuttinga are

lost earnings. Clark and Schuttinga included the

net costs of vertebral fractures (assumed to result

in hospitalization in 50 percent of cases) and of all

other fractures.49 Assuming that 1) 90 percent of

46 This estimate was taken from a 1984 study of the costs of musculoskeletal conditions conducted by the American Academy of Orthopedic

Surgeons (3). The authors of that study estimated the annual national costs associated with osteoporosis at $6.14 billion in 1984 dollars. Ross and

colleagues updated the cost estimate to 1987 dollars and multiplied the result by 80 percent to account for the proportion of osteoporotic fractures

assumed to occur in women (80%).

 Because it is difficult to identify the true contribution of osteoporosis to fracture incidence, the authors of the 1984 study had to estimate the

proportion of fractures attributable to osteoporosis. The 1984 report does not specify these assumptions, but in the report 32 percent of total

fracture-related inpatient hospital costs across all ages was attributed to osteoporosis and more than 50 percent of all nursing home cost

associated with fractures was attributed to osteoporosis.

47 The 1984 estimate of osteoporosis costs includes several items that are excluded from OTA’s estimate of the costs of osteoporotic fractures.

First, the study includes the costs of all fractures, whereas OTA’s analysis is limited to hip fractures (3). Even within hip fractures, however, about

16 percent of the 1984 estimate is for cost items excluded by OTA. In particular, 7 percent was attributed to nonhealth sector goods and service

(e.g., the value of unpaid family care); 2 percent was attributed to administration of the system; and 7 percent was attributed to indirect costs (i.e.,

lost earnings). OTA excluded these cost items either because data were not accurate or the cost item is inappropriate for a cost-effectiveness

analysis. See OTA’s background paper on hip fractures for a detailed discussion (132).

48 Clark’s higher hip fracture costs are due principally to two factors: 1) a higher estimate of hospital costs ($11,600 vs. $7,623 for OTA); and

2) the use of an estimate for nursing home costs implies that all hip fracture patients spend a full year in a nursing home.

49 The source of data on the incidence of different kinds of fractures is not given in the paper by Clark and Schuttinga.
50 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

the high risk group and 70 percent of the mid-risk

group would comply with HRT therapy; 2) BMD

measurement would cost $150 (compared with

$100 in OTA’s model); and 3) HRT would cost

$190 per year (compared with $269 in OTA’s

model), Clark and Schuttinga concluded that the

program would save $5.1 million in net national

costs per 100,000 women screened.

The optimistic forecast of net national cost savings for BMD screening and HRT in this analysis,

compared with that of both OTA and Tosteson and

Weinstein, is explained in large part by the relatively low annual HRT costs and the assumption

that HRT would reduce fracture risk by 50 percent

throughout the rest of a woman’s life despite the

discontinuation of therapy (compared with OTA’s

estimate of a lifetime decrease of roughly 35 percent for HRT of similar duration). Inclusion of indirect costs (lost earnings) and the costs of

vertebral and other fractures in the national cost of

osteoporosis also raises the potential cost savings

associated with HRT. And the assumption that 50

percent of vertebral fractures would result in hospitalization, an assumption that is not supported

by data, clearly increases the cost savings attributable to HRT.

On the other hand, Clark and Schuttinga assumed higher BMD screening costs than those of

OTA. They also assumed lower compliance with

therapy, which depresses net cost savings, and

they assumed a higher discount rate (6 percent

versus 5 percent used by both OTA and Tosteson

and Weinstein.) These differences have a relatively small impact on the resulting estimates of cost

savings compared with the differences in impacts

on fracture rates and HRT cost assumptions.

As with all other analyses that assumed no heart

disease benefits, Clark and Schuttinga’s study

found that BMD screening and selective placement on HRT of those at highest risk of fracture

saves more money than placing all women on

HRT.

SCREENING RECOMMENDATIONS

OF EXPERT GROUPS

A number of technology assessment agencies of

other governments have recommended against

bone-density measurement as a routine procedure

for screening of osteoporosis in all postmenopausal women, including France (2); Germany (47);

Britain (128, 130, 139); Spain (60, 99, 119); Australia (9); Finland (44); and Canada (48). The

World Health Organization (WHO) also recommended against general screening of postmenopausal women for osteoporosis (147). Some of

these groups did recommend BMD measurements

in menopausal women with multiple risk factors

(2, 9, 137, 147). Other government agencies are

planning an assessment, including the Netherlands (89) and Sweden (126).

In the United States, the U.S. Preventive Services Task Force (137) and the National Center for

Health Services Research (135, 136) have not recommended general screening of bone density in

menopausal women. Both the OHTA and

USPSTF have new assessments near completion.

The new USPSTF recommendations, due out this

year, are not likely to change regarding bone density screening (64).

Several medical organizations in the United

States have also issued recommendations regarding BMD screening. The American College of

Obstetrics and Gynecology does not recommend

routine BMD screening for all postmenopausal

women, but densitometry has a place in screening

women who are at increased risk for osteoporosis

(4). They also mention that BMD screening may

improve compliance with HRT.

The American College of Physicians does not

recommend screening of all postmenopausal

women for osteoporosis, but recognizes a role for

BMD measurements in women who are undecided about HRT (5). The American College of

Rheumatology recommends BMD measurements

in women who have risk factors for osteoporosis:
Cost-Effectiveness Analysis | 51

a family history of osteoporosis, early onset of

menopause, and low body weight. They also recommend BMD screening in women with other

medical conditions that predispose to osteoporosis, such as primary hyperparathyroidism and

long-term glucocorticoid therapy (6).

A consensus conference sponsored by the European Foundation for Osteoporosis and Bone

Disease, the National Osteoporosis Foundation,

and the National Institute of Arthritis and Musculoskeletal Diseases concluded that bone-mass

measurement is the best approach to screen individuals for their risk of developing osteoporosis

(41).

CONCLUSIONS AND

POLICY IMPLICATIONS

OTA’s analysis of the costs and effectiveness of

osteoporosis screening and HRT, under base case

assumptions, suggests that it would be reasonably

cost effective to offer ERT at age 50 (the time of

menopause) to all women who commit to a lifelong course of ERT. Entering all eligible women

on lifelong ERT would cost roughly $257 million

per 100,000 women entered in the program and

provide about 11,000 extra years of life (discounted to their present value) to the program enrollees. The net cost per added year of life is

$21,600 to $25,000 (in 1993 dollars). These estimated costs per added year of life are comparable

to other preventive interventions currently paid

for by public and private third-party payers.

Biannual screening mammograms, for example,

were legislated as a covered Medicare benefit

based in part on evidence that showed a cost of

$34,000 per added year of life (in 1987 dollars)

(131).

Screening women for low BMD and targeting

those at highest risk of osteoporosis for ERT is

also reasonably cost effective. Entering eligible

women with BMD values one standard deviation

below the mean on lifelong ERT would cost

roughly $50.5 million per 100,000 women entered in the program and provide 1,800 extra years

of life (discounted to their net present value) to the

program enrollees. The net cost per added year of

life is $18,900 to $47,800 (in 1993 dollars).

Though aggregate program costs decline with

fewer people on therapy, aggregate benefits also

decline, and the net cost per added year of life does

not change much. Screening may help to identify

those women who would stand to gain the most in

life extension benefits from HRT, but other methods of selecting women who would gain the most

from HRT, such as identifying those at highest

risk of heart disease or at lowest risk of breast cancer, might be less costly and more effective than

BMD screening.

Shorter durations of HRT use—10 to 20

years—are much less cost-effective than are longer treatment durations, largely because substantial

medical benefits accrue only when women stay on

the therapy into old age, when the frequency of hip

fractures and heart disease rise dramatically.

OTA’s model suggests that taking HRT for only 10

years after menopause is extremely costly, regardless of whether BMD screening is used to target

therapy.

OTA’s conclusions about the costs and effectiveness of osteoporosis screening and HRT are

tempered by substantial uncertainty about the

benefits and risks of HRT. The impacts of HRT on

breast cancer, hip fracture, heart disease, gallbladder disease, and endometrial cancer have not been

estimated in adequate randomized controlled clinical trials. Because almost all studies of HRT’s impacts on these diseases are observational, one

cannot exclude the possibility that selection bias

affects their results. The most important factor affecting the tentativeness of OTA’s conclusions is

the uncertainty about HRT’s impact on heart disease, because the estimated cost effectiveness of

screening and HRT is especially sensitive to assumptions about heart disease risk.

OTA’s estimated cost-effectiveness ratios assume the existence of substantial reductions in

heart disease incidence in women on HRT. Without such benefits, the net life-extending effects of

HRT are substantially reduced, and the cost of

achieving such benefits may be extremely high.

Unfortunately, the evidence of heart disease benefits is based principally on observational studies
52 | Effectiveness and Costs of Osteoporosis Screening and Hormone Replacement Therapy

which, though they are largely consistent in showing a protective effect of HRT, could be substantially confounded by selection bias.

If HRT proves to have little or no heart disease

benefit, screening women for BMD and limiting

HRT to those with low BMD values would be

more cost-effective than giving HRT to all

women, but the costs of screening and HRT would

still be extremely high relative to the life-extension benefits received. If HRT has little or no heart

disease benefit, BMD screening might meet commonly accepted cost-effectiveness benchmarks

for clinical preventive services only if it were

shown that the improvements in quality of life

from prevention of hip fracture substantially outweighed the loss of quality of life from HRT-induced breast cancer.

Estimates of the cost effectiveness of osteoporosis screening and HRT are very sensitive to assumptions about women’s compliance with HRT.

Realistic expectations about compliance with

HRT, especially over a lifetime of treatment, reduce the cost effectiveness that can be expected of

the osteoporosis prevention strategies examined

in this paper. If compliance remains as low as it

has been, all of the screening/HRT strategies

would be very costly for the benefits they convey.

Long-term compliance with HRT might improve

if physicians became more aggressive in recommending the therapy. Newer HRT regimens currently under development may reduce the

incidence of bleeding and other adverse effects

that tend to discourage long-term compliance with

HRT. Nevertheless, policymakers must consider

whether encouraging women to embark on a lifelong HRT regimen through education programs or

payment for preventive HRT is likely to be effective in delivering the benefits that such a regimen

promises.

Some experts have suggested that BMD

screening has a role in the assessment of menopausal women who would accept HRT if it were

shown that they were at high risk of osteoporosis

(5). Experts have suggested that BMD screening

may also be useful in improving women’s longterm compliance with HRT (118), because a

woman’s awareness that her bone density is low

may encourage that woman to remain on HRT.

But the results of BMD screening could also discourage those with high measured bone densities

from remaining on HRT. The costs and long-term

effectiveness of using BMD screening for increasing uptake and compliance with HRT needs to be

evaluated. The use of BMD screening for these

purposes needs to be judged against other methods of increasing HRT uptake and compliance.

OTA’s analysis suggests that it would be even

more cost-effective to offer ERT to women at age

65 than at age 50. This conclusion, however, depends on extrapolating the heart disease benefits

seen in women who begin ERT at menopause to

women who begin therapy at older ages. Conclusions about the costs and effectiveness of initiating HRT in the elderly are even more tentative

because there is far less information about the effects of HRT initiated at age 65 than there is about

HRT initiated at age 50. If, in fact, HRT has substantially less effect on heart disease when initiated at age 65 than when initiated at age 50,

beginning HRT at older ages would be less costeffective than beginning it at age 50.

The OTA cost-effectiveness analysis is intended to guide overall public health policy, including decisions about educational programs or

payment for screening or HRT. This analysis is not

intended to guide individual decisions regarding

BMD screening or long-term HRT. Individual

women’s risks of the various conditions and diseases affected by HRT vary, as do their assessments of the quality-of-life implications of

various outcomes. For example, some women

may wish to avoid increasing their risk of cancer

regardless of the achievable heart disease benefits

or hip fracture risk reduction.

To summarize, if OTA’s best estimates of the

impacts of screening and HRT on health outcomes

and costs are accurate, a life-long course of ERT

for all women beginning at menopause is a good

investment for society compared with other accepted preventive services. The uncertainty surrounding critical parameters, however, means that

we cannot be absolutely assured that HRT is rela-
Cost-Effectiveness Analysis | 53

tively cost-effective. And barriers to compliance

with long-term therapy cast doubt on whether the

potential benefits, even if they are accurately forecast, will be achieved in practice.

The only condition under which BMD screening would become more cost-effective than giving

HRT to everyone would be if it were shown, first,

that there are no heart disease benefits from HRT

and, second, that hip fractures and other osteoporotic fractures had a dramatic effect on quality of

life. There are no data on quality-adjusted life

years in persons with hip fracture or other osteoporotic fractures.

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