ORIGINAL ARTICLE

Cost-effectiveness of raloxifene in the UK: an economic evaluationbased on the MORE study

J. A. Kanis Æ F. Borgstrom Æ O. Johnell Æ A. Oden

D. Sykes Æ B. Jonsson

Received: 4 February 2004 / Accepted: 4 June 2004 / Published online: 24 July 2004� International Osteoporosis Foundation and National Osteoporosis Foundation 2004

Abstract Raloxifene treatment has been shown to reducethe risk of vertebral fractures and breast cancer inpostmenopausal women. The long-term economicimplications of treatment with raloxifene have not yetbeen investigated. The aim of this study was to assess thecost-effectiveness of treating postmenopausal women inthe UK with raloxifene. A previously developedcomputer simulation model was used to estimate thecost-effectiveness of osteoporotic treatments with extraskeletal benefits. The model was populated with epide-miological data and cost data relevant for a UK femalepopulation. Data on the effect of treatment were takenfrom the Multiple Outcomes of Raloxifene (MORE)study, which recruited women with low bone mineraldensity or with a prior vertebral fracture. Cost-effec-

tiveness was estimated using Quality Adjusted LifeYears (QALYs) and life years gained as primary out-come measures. The cost per QALY gained of treatingpostmenopausal women without prior vertebral frac-tures was £18,000, £23,000, £18,000 and £21,000 at 50,60, 70 and 80 years of age. Corresponding estimates forwomen with prior vertebral fractures were £10,000,£24,000, £18,000 and £20,000. In relation to thresholdvalues that are recommended in the UK, the analysissuggests that raloxifene is cost-effective in the treatmentof postmenopausal women at an increased risk of ver-tebral fractures.

Keywords Breast cancer Æ Cost-effectiveness ÆRaloxifene Æ Vertebral fracture

Introduction

Osteoporosis is characterised by low bone density andhigh fracture risk and presents an increasing health careproblem. As the number of osteoporosis related frac-tures has increased over the last decades, so has thenumber of potential interventions for reducing fracturerisk. Raloxifene is a selective estrogen receptor modu-lator (SERM) that has been shown in a large clinicaltrial (the Multiple Outcomes of Raloxifene; MOREstudy) to reduce the risk of vertebral fractures in post-menopausal women [1]. The MORE study also showed areduction in the risk of invasive breast cancer [2]. Post-hoc analyses suggested that the risk of cardiovasculardisease might also be reduced in patients at high risk ofcoronary heart disease (CHD) [3].

With the introduction of a new treatment, it isimportant to evaluate both clinical and economicimplications. The clinical aspects of a treatment aretypically investigated in clinical trials within a controlledsetting and limited time frame, and do not address theshort-term and long-term impact of interventions interms of costs and health outcomes. These can be

Osteoporos Int (2005) 16: 15–25DOI 10.1007/s00198-004-1688-0

J. A. KanisWHO Collaborating Centre for Metabolic Bone Diseases,University of Sheffield Medical School, Sheffield, UK

F. BorgstromStockholm Health Economics, Stockholm, Sweden

O. JohnellDepartment of Orthopaedics, Malmo General Hospital,Malmo, Sweden

A. OdenConsulting Statistician, Gothenburg, Sweden

D. SykesLilly Research Centre, Erl Wood Manor, Windlesham,Surrey, UK

B. JonssonDepartment of Economics,Stockholm School of Economics, Stockholm,Sweden

J. A. Kanis (&)Centre for Metabolic Bone Diseases,University of Sheffield Medical School,Beech Hill Road,Sheffield, S10 2RX, UKE-mail: w.j.pontefract@shef.ac.ukTel.: +44-114-2851109Fax: +44-114-2851813

assessed by economic analyses that weigh costs ofintervention against the costs and effects of avoidedevents. Ideally, such analysis should take account ofconsequences in a longer term perspective than thatpossible in clinical trials which can be achieved by theuse of health outcomes modelling.

The aim of this study was to examine the healtheconomic implications of raloxifene treatment within aUK setting using the results of the MORE study. Sincethere are no data comparing the effects of raloxifenewith other treatments, raloxifene is compared with notreatment in patient groups similar to those patients inthe MORE study.

Materials and methods

Cost-effectiveness analysis

In cost-effectiveness analysis, differences in costs andeffects between two or more interventions are related toeach other. The incremental cost-effectiveness ratio(ICER), which is a measure of the cost per gained unit ofhealth effect, was in this study defined as:

ICER ¼ DCDD¼ Ctreat � Cnotreat

Etreat � Enotreatð1Þ

where the numerator is the difference in costs betweentreatment with raloxifene (Ctreat) and no treatment withraloxifene (Cnotreat) and the denominator is the differencein health effects (i.e. Etreat and Enotreat). Two measures ofhealth effect were used in this study, Quality-AdjustedLife Years (QALYs) and life years gained. The QALYmeasure is frequently used in cost-effectiveness studies,since it includes both effects on survival and quality of lifeand hence allows the integration of multiple outcomes, aswell as comparisons between different therapies.

In line with recommendations from the NationalInstitute of Clinical Excellence (NICE) £30,000 was usedas an upper threshold for an indication of cost-effec-tiveness [4].

The model

The model used to estimate cost-effectiveness in theanalysis was an incidence based Markov model, whereoccurrence of all events is based on yearly probabilities.The model originally stems from a model for the esti-mation of cardiovascular disease prevention [5] and wasat a later stage adapted to include fracture and breastcancer events [6]. The model has been used in severalstudies to predict fracture and mortality risks and forcost-effectiveness calculations, which makes it well vali-dated and calibrated [7,8,9,10]. In a review of modelsassessing the cost-effectiveness of osteoporosis, the

model was suggested as a reference model for the eco-nomic evaluation of osteoporosis [11].

In this study, the model was slightly revised to alsoinclude health states for vertebral fracture patients thesecond and following years after fracture and for venousthromboembolic events. It is also possible for patients toget breast cancer and CHD after all fracture healthstates. The model structure is illustrated in Fig. 1. Allother technical aspects of the model are the same asthose previously reported [6].

Effect of treatment

The MORE study was a multi-centre, randomised,blinded, placebo controlled trial including 7705 osteo-porotic postmenopausal women aged 31–80 years(mean age 67 years). Mean femoral neck T-score forbone mineral density (BMD) was )2.33 SD and forthe lumbar spine the BMD was )2.58 SD [1,3,12,13].Patients were randomly assigned to receive 60 mg or120 mg raloxifene daily or matching placebo for 4years. All participants were also given calcium andvitamin D supplements. The clinical trial included twogroups. The first (study group 1) included patientswithout prior fractures at baseline and the second(study group 2) included patients with prevalent ver-tebral fractures at baseline. These two groups wereused as base-case populations in this study. For thepatients without fractures we used a relative risk of0.52 (CI 0.35–0.78), and for patients with prior verte-bral fractures, a relative risk of 0.65 (CI 0.52 -0.81) ofvertebral fracture compared with placebo [13]. Theserelative risks are comparable to those found at 3 years[1]. In contrast to the effects on vertebral fracture,raloxifene was not shown to affect the risk of non-vertebral fractures (RR 0.9; CI 0.8–1.1) and in thisanalysis no effect was assumed. In the same study,raloxifene also reduced the risk of invasive breastcancer by 72% (CI 54–83%) [12]. The incidence ofbreast cancer regardless of invasiveness was reduced by62% (CI 42–76%) and this efficacy estimate was usedin a sensitivity analysis.

The upper and lower limits of the confidence intervalfor the effect of treatment on vertebral fracture andbreast cancer were used in a sensitivity analysis. In orderto further account for the uncertainty in the effect, astochastic analysis was performed. The risk reductionestimates were ascribed normal distributions (vertebralfracture: l=)0.65393 d=0.204429, breast cancer:l=)1.27297 d=0.253936) and the relative risk oftreatment was calculated as exp[sample(normdist)*d+l]. By running the model 5000 times, each timesampling from the distributions, an estimation of theuncertainty in the cost-effectiveness could be obtained.The results are presented as acceptability curves [14].

The patients were assumed to be treated with raloxif-ene for 5 years. The effect of raloxifene on fracture riskafter the intervention period has not been investigated but

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the bone loss in the year after stopping treatment seems tobe no greater than that compared with placebo [15].Consistent with a long offset of effect seen with othertherapeutic agents including estrogens [16,17,18], we as-sumed that the effect of raloxifene on vertebral fracturerisk would not disappear immediately after stoppingtreatment, but would decline linearly for 5 years after theintervention period. Since the offset of effect after the endof treatment was not directly investigated in the MOREstudy, a sensitivity analysis was conducted where no effectafter treatment was assumed.

In a patient subgroup (13.4% of the patients in theMORE study) at high risk of cardiovascular events therewas a 40% reduction in the risk of cardiovascular events(CI 5–62%) [3]. In a sensitivity analysis the risk reducingeffect of CHD for this high-risk patient group (relativerisk of 3.5) was analysed. Raloxifene was only assumedto have effect on the risk of CHD and breast cancerduring the treatment period, as suggested by recentstudies [19].

Raloxifene has been reported to have a number ofother associated effects, some adverse and some poten-tially beneficial. Most seriously, it increases the risk forvenous thromboembolism (VTE) approximately 3-fold[1,13]. The increase in risk (relative risk=3.1, 95%CI=1.5–6.2), is comparable to that derived fromobservational studies on HRT. To account for this in the

analysis, VTE was included as a health state in themodel.

Risk of disease events

Vertebral fracture can be classified as clinically overtfracture, i.e symptomatic fractures that come to clinicalattention, or morphometric, which includes all fractures,both symptomatic and asymptomatic. For this study,the clinical definition of a vertebral fracture was used inthe base-case and the morphometric definition was usedin sensitivity analysis. Because data on vertebral fracturerisk in the UK are scarce, the clinical vertebral fractureincidence was calculated by assuming that the ratio ofclinical vertebral fracture to hip fracture would be sim-ilar in the UK compared with Sweden [9]. Swedishfracture risk data was taken from Kanis et al. [20]. Forthe sensitivity analysis on morphometric vertebral frac-tures, the risk were derived from the EVOS/EPOS study[21].

Low BMD and prior fractures are both indepen-dently associated with increases in fracture risk [22,23].Patients without prior vertebral fractures were assumedto have a doubled risk (RR=2) of vertebral fracturecompared with average population risk [22]. Patientswith prior vertebral fractures were assumed to have a3-fold increase in vertebral fracture risk [23]. In a sen-sitivity analysis, the relative risk of vertebral fracturewas varied between 1 and 5.

The risk of invasive and all breast cancer were basedon the 1998 incidence in England and Wales [24]. There

Fig. 1 Structure of the model. Note that it is possible to go to thedead state from all health states. However, to simplify the figures,the transition arrows have been left out

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are observational studies indicating that the risk ofbreast cancer decreases with diminishing bone density[25,26]. In the MORE population, however, the risk ofbreast cancer was not lower than expected for age [12].In sensitivity analysis, the risk of breast cancer wasreduced by 20%.

The risk of CHD events used in the model was basedon the Framingham study [27] and the risk of VTEevents from Silverstein et al. [28].

Costs and discounting

The analysis was carried out from a health care per-spective; thus only direct costs were included. All costsare in year 2002 values. As recommended by NICE [29],costs were discounted at a rate of 6% and effects at arate of 1.5%. In the sensitivity analysis a zero discountrate and 6% rate was used for both costs and effects.

Disease costs

Costs during the first year after clinical vertebral fracturewere derived from Dolan and Torgerson [30] and from areport by Kanis et al. [£446 (50–64 years), £555 (65–74years), £582 (75–84) and £629 (85 years and above)] [31].A study by De Laet [32] showed that vertebral fracturerelated costs persisted for longer than 1 year. In line withthese findings, the cost of a clinical vertebral fracturewas assumed to be £233 for subsequent years afterfracture event for all ages [31]. Morphometric vertebralfractures were assumed to be associated with costs onlythe first year after fracture (£233).

The first year cost of breast cancer was estimated tobe £10,014 [33]. Breast cancer was assumed not to beassociated with any long-term costs beyond the first yearafter event.

The cost of recognised acute myocardial infarction(AMI) in the first year was £2861 for all ages [34]. Thecost for ischaemic heart disease (£4001) was derivedfrom Daly et al. [35] and was used as the first year costafter angina and coronary events. Costs for subsequentyears for all CHD states were £1340 [35]. No estimate ofthe cost for unrecognised AMI was found, and wastherefore conservatively assumed to be associated withno costs. VTE was assumed to be associated with costsin the first year after event only and was derived fromthe National Schedule of Reference Costs for pulmonaryembolism (HRG codes D10 and D11) and deep veinthrombosis (HRG codes E20 and E21). The cost of VTEin the first year after event for patients aged £ 69 yearswas estimated as £1412, and £977 for patients aged ‡70years.

Cost of intervention

The yearly cost of 60 mg raloxifene treatment in the UKis £257. Standard monitoring of treatment was assumed

to comprise one physician consultation (£27) [36] everyyear and a BMD measurement (£30) [31] every secondyear, giving a yearly intervention cost of £299. All pa-tients in the MORE study received calcium and vitaminD supplements, which made it possible to exclude thecosts of these agents.

Quality of life

The utility loss in the year after osteoporosis relatedfractures were estimated in a study based on patients re-cruited at the orthopaedic department at the MalmoUniversity Hospital in the south of Sweden [37]. Byrelating the utility loss during the year after fracture topopulation utility [38] values, the proportionate utility ofeach fracture relative to the population can be calculated[39]. For a patient having a vertebral fracture, the qualityof life was found to be 0.63 of that of a healthy individualin the first year after fracture. Corresponding estimatesfor hip andwrist fracture were 0.79 and 0.98, respectively.In order to obtain age-differentiated quality of life esti-mates in different fracture health states, the proportion-ate utilities were related to population utility values forwomen in the UK [0.82 (50–64 years), 0.78 (65–74 years),0.72 (75–84 years) and 0.69 (85 years and above)] [40].

The quality of life in subsequent years after vertebralfractures was assumed to be 0.93 of that of healthyindividuals [39].

Morphometric vertebral fractures were assumed tohave a disutility value of 0.82 in the first year afterfracture and 0.97 all subsequent years [39].

The reduction in quality of life of 37% after a ver-tebral fracture, based on empirical observations, is highcompared with those based on expert opinion, whichestimate a utility loss of 5–10% [41,42]. A 10% reduc-tion in the quality of life first year after a vertebralfracture and no loss in subsequent years was tested in asensitivity analysis.

Breast cancer in the first year after event was assumedto have the same utility value as estimated in Huttonet al. [33] for stable breast cancer disease, i.e. 0.62. Forthe second and following years after breast cancer,utility was assumed to decrease by 0.1 [6].

CHD events were assumed to be associated with autility loss of 0.1 in all years after the event [43]. Therewas no appropriate estimate found on the utility lossafter a VTE event in the literature, and it was assumedthat VTE was associated with a loss in utility of 0.1 forthe first year and no loss in subsequent years after event.

Mortality

The age-specific normal mortality rates for the generalpopulation in the UK were based on the years 1998–2001 [44]. These were adjusted in the model to take intoaccount mortality from fractures, breast cancer andcardiovascular events.

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A clinical vertebral fracture is associated with an in-crease in mortality [45,46,47]. Based on a study includingfracture patients in Malmo, the relative risk of deathafter a vertebral fracture was estimated to be 2.5 in thefirst year and 1.3 in the subsequent years after fracture[48]. These estimates, adjusted for co-morbidity, wereused in the base-case analysis. In the sensitivity analysis,a scenario assuming no excess mortality after vertebralfractures was tested. In the sensitivity analysis when themorphometric definition of a vertebral fracture wasused, the relative risk of death was assumed to be 1.5during the first year after fracture and no excess mor-tality in the following years.

CHD mortality was taken from the Framinghamstudy [27]. Breast cancer mortality in the first and sub-sequent years were derived by taking the ratio of the UKage-standardised breast cancer mortality to the corre-sponding mortality in Sweden (36.1/24.2=1.492) andmultiplying by Swedish age-specific breast cancer mor-tality rates. In Heit et al. [49], the survival after all VTEevents was estimated to 74.8%. About 20% of thedeaths can be related to the VTE event itself [50]. Byrelating the excess mortality to normal mortality, a rel-ative risk of mortality after an occurred VTE of 6 wasestimated.

Results

Base-case simulations

The costs-per QALY gained for patients with low BMDbut without vertebral fractures at the start of treatmentwere £18,000, £23,000, £18,000 and £21,000 at startingages of 50, 60, 70 and 80 years, respectively (Table 1).The risk of vertebral fractures among patients withprevalent vertebral fractures was higher compared withthose without fractures, but the effect of treatment wasless. This gave cost-effectiveness estimates that did notdiffer substantially between patients with and withoutvertebral fractures. In all base-case scenarios the cost-effectiveness fell below the assumed threshold value of£30,000.

The results from the stochastic analysis for patientswithout prior vertebral fractures are shown in the form

of acceptability curves (Fig. 2). Acceptability curvesindicate the proportion of simulations (the y-axis) thatgive a result below different threshold cost-effectivenessratios (x-axis). For a 50-year-old, the proportion oftimes the cost-effectiveness ratio lay below the thresholdvalue was 0.999. Corresponding proportions for 60-, 70-and 80-year-olds were 0.988, 0.992 and 0.980. Using amore modest threshold of £20,000/QALY gained gavethe corresponding proportions: 0.50, 0.04, 0.82 and 0.62.

Depending on the starting age, the driving factorbehind the incremental outcome measures differed. Atyounger ages, the breast cancer effect was the mainfactor that affected the cost-effectiveness, whereas inolder patients the effect on vertebral fracture risk was themain factor. The separate impact of the effect on ver-tebral fracture and breast cancer on cost-effectiveness isshown in Table 2. As the fracture risk increased withage, so did the benefits of intervention for vertebralfracture. Because the outcome of breast cancer was moresevere (a higher relative mortality) at younger ages, thebenefits of intervention decreased with age for breastcancer. When these two effects were combined the cost-effectiveness was rather stable over all ages studied.

Sensitivity analysis

The sensitivity analyses were based on patients with lowBMD but without prior vertebral fractures (Table 3).

Morphometric vertebral fracture

Using a morphometric definition of vertebral fracturegave cost-effectiveness ratios that were somewhat higher(except for 60-year-olds) compared to the clinical ver-tebral definition. However, the estimates lay below thethreshold value of £30,000 at all ages.

Risk of events

With increasing risk of vertebral fracture the cost perQALY gained improved (Fig. 3). The gradient of thecurves became steeper at higher ages. When the vertebral

Table 1 Cost-effectiveness of treatment with raloxifene for the base case

Age (years) QALYs Life-years Incremental Cost/QALY Cost/life-yeargained gained cost (£) gained (£) gained (£)

No prior vertebral fracture50 0.069 0.070 1265 18,268 18,15560 0.053 0.051 1248 23,604 24,51070 0.067 0.062 1190 17,626 19,20580 0.054 0.052 1106 20,609 21,113

Prior vertebral fracture50 0.069 0.069 1264 18,234 18,20960 0.053 0.051 1247 23,622 24,65370 0.068 0.062 1187 17,503 19,18480 0.054 0.053 1104 20,402 20,963

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fracture was set to be the same as for the population(relative risk=1) the cost-effectiveness fell below thethreshold value at all ages except for 80-year-oldwomen.

Cost-effectiveness did not vary markedly when theincidence for all breast cancer instead of the invasive riskwas used, since the risk of event was higher and theeffect of treatment lower (Table 3). Lowering the inci-dence of breast cancer by 20% reduced cost-effectiveness

somewhat, but was still below the £30,000 threshold atall ages.

Discount rate

Treatment costs occurred only during the interventionperiod whilst the effect of treatment has more long-termconsequences. Thus, when costs and effects were not

Table 3 Sensitivity analyses inwomen with low BMD but noprior vertebral fractures: cost(£) per QALY gained

*Both costs and effects

Age (years)

Scenario 50 60 70 80Base-case 18,268 23,604 17,626 20,609Morphometric vertebral fracture 19,430 22,689 25,769 23,112All breast cancer 20,493 25,404 17,646 20,261Lower breast cancer incidence 21,960 28,043 19,308 22,274CHD-effect 10,157 7352 5197 70040% discount rate* 15,408 21,127 16,752 20,5806% discount rate* 39,504 44,512 28,117 28,870No effect after treatment period 20,144 27,437 23,524 29,445QoL-vertebral fracture 18,608 24,357 19,318 23,512No excess mortality for vertebral fractures 19,430 26,599 27,165 41,574

Fig. 2 Acceptability curves, inpopulations with low BMD andno prior vertebral fractures

Table 2 Base case: the separateimpact of risk reduction forvertebral fracture and breastcancer, respectively, in womenwith low BMD and no priorfracture

Age (years) QALY:s Life-years Incremental Cost/QALY Cost/life-yeargained gained cost (£) gained (£) gained (£)

Effect on vertebral fracture50 0.011 0.004 1316 119,353 291,03260 0.011 0.005 1303 115,499 244,29870 0.039 0.029 1240 31,991 42,93880 0.035 0.030 1157 33,366 38,514

Effect on breast cancer50 0.056 0.063 1280 23,056 20,45060 0.037 0.041 1264 33,861 30,98170 0.022 0.024 1228 56,360 50,70380 0.009 0.008 1122 123,832 129,611

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discounted, the cost-effectiveness improved whilst at adiscount rate of 6%, the cost-effectiveness ratio in-creased significantly over £30,000 at the age of 50 and 60years.

Effect of treatment

Cost-effectiveness using all combinations of the meanand confidence interval estimates of the risk reductionfor vertebral fracture and breast cancer are shown inFig. 4. Changes in the effect of raloxifene on breastcancer risk had larger impact at younger ages comparedwith older age groups, whilst the effect of varying ver-tebral fracture risk had a greater impact on cost-effec-tiveness at higher ages than at lower ages.

When it was assumed that treatment only had aneffect on vertebral fracture risk during the interventionperiod, the cost-effectiveness ratios increased, but theestimates remained below £30,000 (see Table 3).

When estimating the cost-effectiveness for patientswho also had an increased risk of cardiovascular disease,and thereby a 40% risk reducing effect of treatment onCHD events, cost-effectiveness improved markedly(£10,000 and below) compared with the estimates in thebase-case scenarios.

Quality of life

The cost per QALY gained was somewhat higher com-pared to base-case when more conservative values forthe utility loss after vertebral fractures were tested.

Mortality

When it was assumed that vertebral fractures were notassociated with any excess mortality the cost-effective-ness ratio became greater with advancing age, because ofthe increasing risk of vertebral fractures with age. At the

Fig. 3 Sensitivity analysis:relative risk of vertebralfracture in women with lowBMD but no prior vertebralfractures

Fig. 4 Sensitivity analysis:combinations of the mean andconfidence interval of the riskreduction for vertebral fractureand breast cancer

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age of 80 years, cost-effectiveness lay above the £30,000threshold value.

Discussion

The present analysis examines the cost-effectiveness ofraloxifene against no intervention with raloxifene incohorts of women at moderately increased risk of ver-tebral fracture. The model, based on the UK population,utilized information on effectiveness derived from a verylarge double blind prospective study (the MORE study)that forms by far the largest data resource on its efficacyand safety. The results of this study indicate that ra-loxifene is cost-effective in the treatment and preventionof osteoporosis. Our base-case analysis shows that thecost-effectiveness ratio is below £30,000, the thresholdvalue used by NICE [4], for all starting ages of treatmentbetween 50 and 80 years.

In sensitivity analysis, the cost-effectiveness ratio re-mained fairly stable below £30,000. The risk of vertebralfracture was found to be the most sensitive parameter inthe model, especially at higher ages. The cost per QALYgained was above the threshold value at the populationrisk of vertebral fracture for 80-year-olds. Cost-effec-tiveness was also above the threshold value for higherages when the lower limit of the confidence interval forvertebral fracture efficacy was used.

In the stochastic analysis where distributions wereascribed to the treatment effects to characterize some ofthe surrounding uncertainty, the vast majority of simu-lated cost-effectiveness ratios fell below the assumedthreshold value. However, the analysis only tested thevariability in the risk reduction of treatment. Otherparameters with uncertainties were not included such ascosts and health state values, due to the lack of goodmeasures of spread for these estimates.

Our conclusions need to be placed in the context ofthe assumptions required for modeling. Issues of po-tential importance concern the epidemiology, morbidityand mortality associated with vertebral fracture andbreast cancer, as well as assumptions concerning treat-ment effects. Where possible, we have addressed theseeither by sensitivity analyses or by assuming conserva-tive scenarios.

The general conclusions about the cost-effectiveness ofraloxifene are based primarily on breast cancer and ver-tebral fracture outcomes. Whereas our conclusions arerelatively robust to modeling at the confidence estimatesof these outcomes, it is apparent that the effect of treat-ment on breast cancer risk is an important driver of thecost effectiveness. The impact of breast cancer on cost-effectiveness decreased with age, whereas the impact onvertebral fracture increased with age. A major uncer-tainty concerns the baseline risk of breast cancer. In thebase-case, we assumed that breast cancer risk would besimilar to that of the general population. This assumptionaccords with findings in the MORE study but not withthe two epidemiological studies mentioned from North

America [25,26]. When lower baseline risks of breastcancer were assumed, cost-effectiveness ratios increased,but treatment remained cost-effective. We conservativelyassumed no effect of treatment on non-vertebralfractures, since the estimate of effect in the MORE studydid not differ significantly from unity (RR=0.92; 95%confidence interval=0.79–1.07). The inclusion of effectson non-vertebral fractures, particularly hip fracture,would further improve cost-effectiveness.

In the base-case, we set the relative risk of vertebralfracture at 2 for patients without prevalent vertebralfractures and 3 for patients with existing vertebralfractures. We chose to express fracture risks as relativerisks, but it is of importance to place this in a clinicalcontext, since intervention is often targeted on the basisof BMD tests or absolute probability of fracture.Although surrounded with some uncertainty the relativerisk of a vertebral fracture can be calculated by relatingthe distribution of bone mineral density in the UK [51]to the increase in risk with a given T-score [52]. The riskratio at a T-score of )2.5 SD (the threshold of osteo-porosis) decreases with age from about 3 between theages of 50 and 55 years to 1.0 in the elderly [10]. Thereason that the risk ratio decreases with age is that theaverage T-score decreases with age. Relating this type ofrelative risk computations to our base-case assumptionsimplies that we may have underestimated the risk ofvertebral fracture at younger ages, and thereby also thecost-effectiveness, and overestimated this at higher ages.However, the sensitivity analysis showed that cost-effectiveness was below the threshold value at all valuesbelow the average population risk (RR of vertebralfracture=1) at all ages.

These considerations suggest that a prior fragilityfracture or moderate decreases in BMD provide suffi-cient fracture risk to make treatment worthwhile. Thisview needs to be tempered by the knowledge that asignificant component of the cost-effectiveness is due tothe reduction in breast cancer risk. The view also as-sumes that raloxifene is as effective in patients with os-teopenia as in women with osteoporosis. In this regard,analysis of the MORE study found no significantinteraction between treatment effects and baseline BMD[53], suggesting that effectiveness is expected in womenwith osteopenia.

The rationale for the assumptions concerning ver-tebral fracture risk appear to be appropriate, though itshould be acknowledged that there are no robust epi-demiological data on vertebral fracture risk availablefrom the UK. Such information as is available indi-cates that the risks we used are appropriate [31].Moreover, it is not possible in the present construct ofthe model to have more than one vertebral fracture.The risk of further fractures is, however, high and inthis regard the model can be viewed as constructedconservatively.

In the base-case a 5-year treatment and 5-year offset ofeffect after stopping treatment was assumed. The 5-yeartreatment period is arbitrary, but has been previously

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used in health economic analysis [7,9,31] because itapproximates the duration of exposure available for mostinterventions. The offset of effect was not investigated inthe MORE study. However other anti-resorptive drugsshowing comparable trial results have shown that theeffect of treatment persists for several years after treat-ment is stopped [54,55,56]. When no reduction in fracturerisk after the treatment period was assumed, there wereonly modest adverse effects on cost-effectiveness.

The relative risks of mortality after vertebral frac-tures were derived from a Swedish population. Severalstudies have shown a relationship between vertebralfracture event and increase in mortality. Recently,Jalava et al. [57] showed that osteoporotic patients withvertebral fractures from the UK had a significantlyhigher mortality, adjusted for BMD, compared withosteoporotic patients without fracture. The estimate thatwe used was more conservative. When vertebral frac-tures were assumed not to be associated with an in-creased mortality, there was a marked adverse impact oncost-effectiveness, especially in older age groups.

With regard to health state values for vertebral frac-ture, these are based on empirical estimates and yieldvalues substantially lower than those used previously inhealth economic modeling [58,59]. Assuming more con-servative values of the utility loss after vertebral fracturesdid not significantly worsen the cost-effectiveness.

For the purposes of this paper, we have not examinedthe effects of poor compliance. In the MORE study 92%of women took more than 80% of study medication [1].The estimate of effectiveness thus assumes a high degree ofcompliance. Compliance in clinical practice is likely to beless which will lead to lower effectiveness, balancedsomewhat by lower intervention costs andhas been shownto have a small effect only on cost-effectiveness [31].

We conclude that, in relation to suggested thresholdvalues for cost-effectiveness, the results in this studyindicate that raloxifene is a cost-effective interventionfor the treatment of postmenopausal women at in-creased risk of vertebral fractures in the UK. In thiscontext, raloxifene can be added to the range of inter-ventions where cost-effective scenarios have been foundfor the UK [31,60,61]. It is important, however, to rec-ognise that the present analysis was undertaken in a UKsetting, and that the conclusions are not necessarilyapplicable elsewhere, since the risk of fracture, breastcancer, death and costs may differ. A recent analysis in aSwedish setting also found that raloxifene was cost-effective when the results of the MORE study weremodelled [62]. In other settings it will be important toacquire country-specific data on cost-effectiveness andintervention thresholds.

Appendix

Economic evaluation: techniques developed to assesscosts and benefits of alternative health strategies toprovide a decision-making framework

Direct costs: costs related to the use of resources dueto the disease or treatment in question. They include costto the health care system, costs to social services and topatients themselves or their relatives.

Indirect costs: costs related to loss of production dueto the disease or the treatment.

Incremental cost: the additional cost that one treat-ment alternative imposes over another.

Life-years gained: an effectiveness measure includingonly the quantity of the years of life a patient is expectedto have.

Quality adjusted life-years (QALY): an effectivenessmeasure including both the quantity and quality of theyears of life a patient is expected to have.

Sensitivity analysis: a technique used in economicevaluation to account for uncertainty by testing howchanges in the main parameters affect the results of theanalysis.

Discounting: the adjustment of future costs and ben-efits to render those occurring in different years com-parable with each other and with current cost andbenefits.

Stochastic analysis: a technique used to explore theimpact of uncertainty around the estimates of the inputparameters.

Markov analysis: a modelling technique to handledecision problems involving risks that are potentiallyvariable over time and where timing of events isimportant

Acknowledgements We are grateful to Eli Lilly and Co. for theirunrestricted support of this work.

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