cost-effective treatment strategies for osteoporosis

Cost-Effective Treatment Strategies for Osteoporosis

L. J. Melton IIISection of Clinical Epidemiology, Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester,Minnesota, USA

Introduction

There can be little doubt that osteoporosis is a majorpublic health problem [1]. The cost of caring forosteoporotic fractures in the United States in 1995 was$13.8 billion [2], and this figure is sure to rise as theelderly population grows and the number of fracturesincreases in the future [3,4]. It has been estimated that, inthe next 10 years alone, white women in the UnitedStates aged 45 years or over will experience 5.2 millionfractures of the hip, spine or distal forearm, which willlead to 2 million person-years of fracture-relateddisability and to over $45 billion in direct medicalexpenditures [5]. Surely something must be done to avertthis growing problem, but what is feasible? The problemis that osteoporosis is such a common disorder thatindividual clinical decisions whether to intervene or nothave, in either case, enormous economic consequences.For example, the potential cost of universal hormonereplacement therapy (HRT) in the United States couldexceed $10 billion annually (39 million postmenopausalwomen at $269 per year [6]). Given the large number ofpotential candidates for therapy, and the growingarmamentarium of diagnostic tests and drugs thatmight be used, it is necessary from the societalperspective at least to assure that huge expenditures forosteoporosis screening and treatment are rewarded withcommensurate benefits in terms of reducing the adverseoutcomes of osteoporotic fractures. This, in turn,requires knowledge about each of the issues delineatedin the sections that follow.

What Is the Target Population?

It is impossible to design a cost-effective program toprevent osteoporotic fractures without first deciding whoare the candidates for evaluation and treatment. Thus, asubstantial proportion of the entire population either has

osteoporosis already or is at high risk for developing thecondition. For example, recent data from the ThirdNational Health and Nutrition Examination Survey(NHANES III) indicate that, by World Health Organiza-tion criteria, 13–18% of women and 4–6% of men in theUnited States have osteoporosis of the hip, depending onthe particular site that is assessed, while another 37–50%of women and 28–47% of men have low bone mineraldensity (BMD) [7]. These data indicate that 10 millionAmericans have osteoporosis of the hip and nearly 19million more have low bone mass; by the year 2015,these numbers are expected to rise to 14 million and 27million, respectively [8]. However, the social conse-quences of osteoporosis derive from associated fractures,particularly those of the proximal femur [1]. The lifetimerisk of a hip fracture is about 17% in white womencompared with only 6% in white men [9]. Hip fracturesare considerably less frequent among African-Amer-icans, while the incidence among those of Asian ancestrylies between the rates for blacks and whites [1]. Thisdoes not mean, though, that nonwhite populations can beignored. Moreover, it is not clear which individualswithin each population are actually at high risk offracture. The most comprehensive study followed over9000 elderly white and Asian-American women andfound that, even after adjusting for age and calcaneusBMD, there was a long list of independent predictors ofhip fracture risk as shown in Table 1 [10]. Unfortunately,this information has not yet been distilled into a riskscore that could be used clinically, and comparable datado not exist for men or for nonwhite women.

What Is the Objective of Intervention?

Because so many people are potentially affected, publichealth measures are indicated. As illustrated in Fig. 1,public health measures are directed at the entirepopulation with the hope of improving some character-istic (e.g., bone density) in the population as a whole[11]. With this approach, it is unnecessary to test orclassify individuals with respect to their risk ofosteoporosis or fractures. Correspondingly, publichealth measures must be entirely safe since they are

Osteoporos Int (1999) Suppl. 2:S111–S116ß 1999 International Osteoporosis Foundation and National Osteoporosis Foundation Osteoporosis

International

Correspondenceand offprint requeststo: Dr L. JosephMelton III,Departmentof Health SciencesResearch,Mayo Clinic, 200 FirstStreetSW,Rochester,MN 55905,USA. Tel: +1 (507)2845550;Fax:+1 (507) 284 1516.

aimedat low-risk aswell ashigh-risk individuals.As acorollary, public health interventionsoften have onlymodestpotency,but evena small averageimprovementon a population-wide basiscould havea largepotentialeffect on fracture risk. For example, it has beensuggestedthat an increasein regular exercise couldreducethe numberof hip fracturesby half [12], but thisconclusionis basedon observationalstudiesof elderlyindividuals who havebeenable to remainactive ratherthan evaluation of a specific public health programcapable of assuring this result. Other public healthmeasuresfor osteoporosisinclude the promotion ofimprovedcalciumandvitamin D nutrition, but all theseinterventions must be very inexpensive to be cost-effective on a populationbasis[13]. UniversalHRT atthe menopausewould also be a public healthmeasure,directedmainly at reducingcoronaryheartdiseasewithosteoporosispreventionasan addedbenefit.

More potent pharmaceuticalagents,which may besomewhatmore hazardousand almost certainly moreexpensive,arebetteremployedin the clinical approachto osteoporosiscontrol,which is basedonearlydetectionand treatmentof high-risk individuals (Fig. 1). Riskassessments,and related treatments,could be directedtowardthosewith low BMD, excessiveboneturnoveroran increased likelihood of falling. The number ofaffected people is neverthelessvery large. A fifth ofthe populationfalls eachyear [14], while elevatedboneresorptionis seenin 25–42%of postmenopausalwomen,dependingon the assayused [15]. Most osteoporosistreatmentsarecurrentlyaimedat slowingboneloss.It isdifficult to predict BMD from known risk factors [16]but easy to measurebone density directly, and these

measurementshavebeenshownto predictfuturefracturerisk [17]. Such data can be used to describelifetimefracturerisk asa functionof ageandBMD asillustratedin Fig. 2 [18], and this information might be usedtoestablish treatment thresholds.As mentioned above,however, there are risk factors for fracture that areindependentof bonedensity[10], and it is not entirelyclear how theseadditional data could best be usedtoselect patients for therapy. Indeed, it is still debatedwhether bone density should be measuredat the hip,which providesthe best indication of hip fracture risk[17], or at a peripheralsite such as the wrist or heel.Additional debateconcernsthe technologies(e.g., dualenergyX-ray absorptiometryversusultrasounddensito-metry)usedto assessfracturerisk [19]. Consequently,ithas not been possible to achieve consensuson the

Table 1. Multivariate modelsof risk factorsfor hip fractureswith and without adjustmentfor a history of prior fracturesand calcanealbonedensityamong9516white women

Measurement(comparisonor unit) Relativerisk(95% confidenceinterval)

Basemodel Add fracturehistory andbonedensity

Age (per 5 years) 1.5 (1.3–1.7) 1.4 (1.2–1.6)History of maternalhip fracture(vs none) 2.0 (1.4–2.9) 1.8 (21.2–2.7)Increasein weight sinceage25 years(per 20%) 0.6 (0.5–0.7) 0.8 (0.6–0.9)Height at age25 years(per 6 cm) 1.2 (1.1–1.4) 1.3 (1.1–1.5)Self-ratedhealth(per 1-point decrease) 1.7 (1.3–2.2) 1.6 (1.2–2.1)Previoushyperthyroidism(vs none) 1.8 (1.2–2.6) 1.7 (1.2–2.5)Currentuseof long-actingbenzodiazepines(vs not) 1.6 (1.1–2.4) 1.6 (1.1–2.4)Currentuseof anticonvulsantdrugs(vs no currentuse) 2.8 (1.2–6.3) 2.0 (0.8–4.9)Currentcaffeineintake(per 190 mg/day) 1.3 (1.0–1.5) 1.2 (1.0–1.5)Walking for exercise(vs not walking for exercise) 0.7 (0.5–0.9) 0.7 (0.5–1.0)On feet54 h/day(vs 44 h/day) 1.7 (1.2–2.4) 1.7 (1.2–2.4)Inability to rise from chair (vs no inability) 2.1 (1.3–3.2) 1.7 (1.1–2.7)Lowestquartile for distantdepthperception(vs others) 1.5 (1.1–2.0) 1.4 (2.0–1.9)Low-frequencycontrastsensitivity (per 1 SD decrease) 1.2 (1.0–1.5) 1.2 (1.0–1.5)Restingpulserate480 beatsper min (vs 580 beats) 1.8 (1.3–2.5) 1.7 (1.2–2.4)Any fracturesinceage50 years(vs none) – 1.5 (1.1–2.0)Calcanealbonedensity(per 1 SD decrease) – 1.6 (1.3–1.9)

From Cummingset al. [10].

Fig. 1. Preventivestrategiesfor osteoporosis:A high-risk approach,B population-basedapproach.(From CooperandMelton [11]).

112 L. J. Melton III

specificpatientpopulationswho shouldbe targetedforpharmaceuticalintervention.

What Is the Effectivenessof Treatment?

It is generally held that the efficacy of a particulartherapy can be establishedonly by a randomizedcontrolled clinical trial, but such trials are typicallycarriedout on highly selectedsubsetsof patientsand,asa consequence,the generalizabilityof trial resultsto theunderlyingpatientpopulationis oftenquestionable[20].Moreover, most trials of osteoporosistreatmentshaveevaluatedintermediateendpoints(i.e., changesin BMD)rather than a reduction in fracturesor fracture-relateddisability. However,someagents(e.g.,sodiumfluoridetherapy) have antifractureefficacy less than expectedfrom impressive gains in BMD, while others (e.g.,estrogen or calcium/vitamin D) have antifractureefficacy disproportionateto small gains in bone mass;both discrepancieshavebeenattributedto the indepen-dent influence on fracture risk of excessive boneturnover[21]. Althoughtheantiresorptivedrugslicensedfor osteoporosisareeffective in reducingboneturnoveras well as slowing bone loss, fracture effects cannotconfidently be predicted from short-term changesinbone density. Even when trials are conductedwithfractureasanendpoint,therearesufficientdifferencesinpatientpopulation,drug regimenandoutcomethat it isdifficult to synthesizetheresults[22]. As summarizedinFig. 3, for example, the results of various trials ofsodiumfluoridetherapyrangefrom a strongreductioninfracturesto an exacerbationof fracturerisk.

In addition, there is growing worry that fractureprotectionmay be reverseduponcessationof treatment.For example, Cauley et al. [23] showed that post-menopausalwomen who were still on HRT after 10years or more experienceda substantialreduction infracture risk (Table 2). However,womenwho stopped

therapyearlier had no residualprotectioneven thoughthey had takenHRT for an averageof 14.6 years[23].This is importantbecauselifetime compliancewith anytherapyis likely to be modest;for example,a third ormore of womenbegin HRT at the menopausebut lessthan 10% continuewith treatmentto an advancedage[24,25]. Moreover, some fractures would continue tooccur even if treatmentwere completely effective instopping bone loss. This is due to extraskeletalriskfactorsfor fracture.Thus, in addition to low BMD, therisk of hip fracture amongelderly fallers in one studywasincreased6-fold by falling backwardsor to theside,3-fold by eachstandarddeviation increasein potentialenergyof thefall and2-fold by everystandarddeviationdecreasein body massindex, a marker for the energy-absorbingeffects of soft tissueover the hip [26]. Hipfracture risk is also influencedby height [10] and byvariousaspectsof femoralneckgeometry[27], noneofwhich canbe changedby treatment.

What Is the Outcome and Cost?

Neither the costsof osteoporoticfracturesnor the costsassociatedwith osteoporosistreatmentsareknown withanyprecision.In particular,thereis uncertaintyabouttheoutcomes of osteoporosisthat might be averted bytreatment.For example,manystudieshavefocusedonlyon hip fractures,but essentiallyall fracturesin elderly

Fig. 2. Estimatedlifetime risk of hip fractureamongwhite womenatdifferent ages and with different levels of bone mineral density(BMD) asassessedin the distal radius.(From Sumanet al. [18].)

Fig. 3. Probabilitydistributionsfrom randomizedcontrolledtrials ofsodiumfluoride therapy.(From Eddy et al. [22].)

Table 2. Relativerisk of fractureby durationof hormonereplacementtherapy(HRT) comparedwith neverusersof HRT

Use510 years Use510 years

Fracturesite Current Past Current Past

Hip 0.81 0.97 0.27* 1.67Wrist 0.75 0.79 0.25* 0.90All nonspine 0.67* 0.92 0.60* 1.00

Modified from Cauleyet al [23].)*p 50.05.

Cost-EffectiveTreatmentStrategiesfor Osteoporosis 113

white womenare due in part to low bonedensity[28],and these other fractures contribute substantially toexpendituresfor the careof osteoporosis[2]. It is alsoimportant to know the psychosocial impact of thevarious fractures.Thus, an estimated10% of womenbecomefunctionally dependentfollowing hip fracture,and19%requirelong-termnursinghomecare[29]. Fewforearmfracturepatientsare disabledas a result of thefracture [29], but nearly half report unsatisfactoryfunctional outcomes at 6 months [30]. Likewise,vertebralfracturesrarely causeinstitutionalization [29]but may leadto heightloss,kyphosisandpersistentpainthat interfere with the activities of daily living [31].Indeed,the adverseinfluenceof vertebral fracturesonmostactivities of daily living is almostasgreatas thatseen for hip fractures [32], and even wrist fracturesinterfere significantly with some activities (Table 3).However,the meaningof theseeventsto the patient isessentiallyunknown.Most analysesrequireestimatesofthe impactof eachevent(healthstate)on patientqualityof life, but theseestimateshavetypically beenmadebythe investigators rather than the patients who haveactually experienced such outcomes. Because thedistribution of fracture outcomesis not known, totalexpendituresfor osteoporosishave usually been esti-matedfrom administrativedatabases(e.g.,[2,33]).Thereis even less quantitative data about the patterns ofosteoporosistreatmentin the community – neither thedrug regimens used nor the services employed tomonitor treatment.Therefore,only roughestimatescanbe made of the actual costs associatedwith differenttreatments.

What Is Treatment Cost-Effectiveness?

There is also lack of agreementabout the bestway toassessthebalanceof treatmentbenefitsversustreatmentcosts. In one analysis, screening 50-year-old whitewomenwith BMD measurementsof thehip, andtreatingwomenwhosebonedensitywas more than 1 standarddeviationbelowthemean(about16%of thepopulation)with HRT for 20 years,cost over $53000 per life-yearsaved [6]. Cost-effectivenessimproved with longerdurationof treatmentsincemost of the adverseeventspreventedby HRT occur late in life, but the modelwasdominatedby the extraskeletaleffects of therapy.Forexample, the cost per life-year saved increasedfromabout$23000 for universalHRT treatmentfor 40 yearsto nearly$44000if treatmentdoubledbreastcancerriskratherthanraising it by 35%,but fell to about$7000ifmyocardialinfarctionswerereducedby 80% insteadof50%. Becausescreening at the menopauserequirestreatmentfor manyyearsduringwhich time fractureriskis low, it is difficult to demonstratethat any suchprogram is cost-effective [22,34–36]. Therefore, thefocusof screeningprogramsshouldprobablybeon olderindividuals [37]. Furthermore,since osteoporoticfrac-turesare more closely linked with morbidity than with

mortality, a more appropriatemetric is the impact oftreatment on the quality-adjustedlife-years (QALY)savedratherthanthe life-yearsper se.

In a comprehensiveassessmentin Sweden,the cost-effectivenessof 5 years of treatment to prevent hipfractureswas$13375(US $ = 8 SEK) perQALY savedfor a62-year-oldwomanwith BMD 1 standarddeviationbelow the mean,while the costper life-year savedwas$27500 and the cost per hip fracture avoided was$43750 [38]. However, this presumedsome residualbenefit after treatmentceased.If, instead,10 yearsoftreatmentwererequiredto achievethe sameresult,thenthe cost per QALY saved rose to nearly $27000comparedwith thecost-effectivenessof antihypertensivetherapyfor strokeof lessthan$13000perQALY saved[38]. In addition,if the osteoporosistreatmentitself hadeven a tiny negativeimpact on patient quality of life,then the cost per QALY savedrosefurther to $62500.This illustration wasbasedon a hypotheticaltreatment,much like HRT, that reducedfracture risk by half. A

Table 3. Functional impairment associatedwith minimal traumafracturesamongwomenin RanchoBernardo,California

Oddsof impairmenta

Activi ties Hip fracture Spinefracture Wrist fracture

Put sockson 1.6 1.7 1.1Cook meals 11.1 6.9 10.2Shop 4.6 5.2 3.3Heavyhousework 2.8 2.1 1.6

Modified from Greendaleet al. [32].aLikelihood of having the impaired activity following fracture afteradjustingfor age,body massindex, estrogenuse,visual impairmentandreducedmentalstatus.

Table 4. Cost-effectivenessof treating 70-year-oldDanish womenwith agentswhoseeffectivenessdiminishesafter cessationof therapycomparinguniversalusewith a screeningstrategy

Agent Costper hip fractureaverted

100%compliancewith therapy

50% compliancewith therapy

Hormonereplacementtherapya

Population-wide DK 178100 –Calciumb

Population-wide DK 228300 –(Low-costpreparation) (DK 49422) –

Screening DK 81300 DK 128300Etidronatec

Population-wide DK 24414 –Screening DK –15450 DK 8000

Calcitonind

Population-wide DK 866950 –Screening DK 417700 DK 464400

Modified from Ankjaer-JensenandJohnell[39].aFifty percentreductionin fracturerisk over 10 years.bTwenty-fivepercentreductionin fracturerisk over 5 years.cFifty percentreductionin fracturerisk over 5 years.dThirty percentreductionin fracturerisk over 5 years.


similar analysisin Denmark[39] comparedHRT withother treatments(Table 4). Universal HRT was morecost-effectivethan universal calcium supplementation,but it was assumedthat the cost of calcium was $395(US $ = 6 DK) per year, and it can be obtainedmuchmore cheaply than that. At half the price, the cost ofuniversalcalcium supplementationfell from $38000 to$8200per hip fractureaverted.At a high cost,calciumsupplementationwas more cost-effectivetreatinghigh-risk individuals in a screening program than useduniversally as a public health measure,as found alsoby others [13]. The samewas true of etidronateandcalcitonin,but no onesuggeststhat suchagentsbe usedindiscriminatelyin thegeneralpopulation.As might alsobe expected,the estimatedcostper hip fractureavertedincreasedas compliancewith therapydecreased(Table4).

How Is This Information Useful?

If onecanestablishanacceptablecostperQALY saved,it is thenpossibleto definetreatmentthresholdsthat arecost-effective.In a recentreview,Tengset al. [40] foundthat the averagecost per life-year savedby medicalinterventionswas$19000,but the rangewasvery wide.Using a figure of $30000 per QALY, a recentanalysisby the NationalOsteoporosisFoundation[22] produceda series of recommendedtreatment nomograms,anexample of which is shown in Fig. 4. However,limitations with respect to the data neededfor cost-effectivenessanalysesraisequestionsabout the useful-nessof this approach.Whether balancedformally incost-effectivenessanalyses or informally, however,patients and physiciansmust make inevitable judge-mentsaboutthetrade-offbetweenrisksandbenefits,andsociety must consider the costs. While authoritativetreatmentrecommendationsmay suffice for uncommonclinical problemssuchas idiopathic osteoporosisin theyoung,suchrecommendationshavesignificanteconomic

implicationsfor a condition suchas involutional osteo-porosis, which might require screeningand lifetimetreatmentof a majorproportionof theentirepopulation.Giventhespottytrackrecordof authoritativepronounce-ments [41], as well as variations in routine clinicalpracticewhich suggestthat manywidely usedinterven-tionshaveuncertainintellectualunderpinnings[42], it isunlikely that payorsor governmentpolicymakerswillevergive clinicianscarteblanche.While somefear thatformal cost-effectivenessanalyseswill be usedto limittheir clinical prerogatives,governmentalagenciesareperformingtheseanalysesanywayandsuchanalysesareoften naive and unduly strict in the absence ofinvolvement by knowledgeableclinicians. Therefore,practitioners must contribute to the developmentofevidence that will ensure that new pharmaceuticaladvancesareavailableto the patientswho needthem.

Acknowledgements.This work was supportedin part by researchgrants AG 04875 and AR 27065 from the National Institutes ofHealth,U.S. Public HealthService.

Theauthorwould like to thankMrs Mary Robertsfor assistanceinpreparingthe manuscript.

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cost-effective treatment strategies for osteoporosis

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