a report by

V é r o n i q u e R a b e nd a and J e a n - Y v e s R e g i n s t e r

Department of Epidemiology and Public Health, University of Liège

Therapeut i c Adherence wi th B i sphosphonates in the Treatment o f Os teoporos i s

Osteoporosis

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The single most important public health problemfacing physicians today may be the failure of patientsto follow their prescribed treatment regimens, aphenomenon that results in treatment failures,increased morbidity and mortality and enormousburdens to society and the economy. As is the casewith many chronic diseases, the problem ofadherence to therapy has emerged as a significantchallenge to the successful management ofosteoporosis. Despite the availability of effective,well-tolerated drugs for osteoporosis, fracture ratesremain high, due in part to poor compliance andpersistence with medication.

Adh e r e n c e t o C u r r e n t B i s p h o s p h on a t eT h e r a p y

Bisphosphonates are usually the first-line treatmentoption for post-menopausal osteoporosis because oftheir ability to provide substantial increases in bonemineral density (BMD) at the lumbar spine andhip, and to significantly decrease bone turnover,which translates into reductions in the risk ofvertebral fractures of up to 65% and of non-vertebral fractures of up to 53%. However, long-term adherence to therapy is required for optimaltherapeutic benefit for patients with osteoporosis.

An open-label, observational, clinic-based study ofdaily oral alendronate, the most prescribedbisphosphonate, in post-menopausal women withosteoporosis or osteopenia investigated persistence.Of the 401 patients recruited, 13% did not even starttherapy, and of those who did start, the probability ofpersisting with therapy was 49% at 12 months and30% at 24 months. Similar findings were reported inanother study of more than 1,800 patients withosteoporosis. In this study, a fifth of patients stoppedtreatment in the first four months.

In the Canadian Database of Osteoporosis andOsteopenia (CANDOO), persistence with currentbisphosphonates decreases over time, with 29.9%and 35.8% of 477 patients discontinuing treatmentwith daily alendronate after one and two years oftreatment, respectively. Ettinger et al. reported that

the rate of discontinuation of alendronate treatmentincreased linearly over time, with almost half of thewomen followed (46.1%) having discontinuedtherapy by the end of 10 months of follow-up.

Although the introduction of weekly formulationsimproved adherence compared with daily regimens,levels still remain suboptimal.

The results of a US-based observational studyshowed that treatment adherence was significantlygreater in patients receiving once-weeklybisphosphonates than in those receiving daily therapyover one year. A total of 2,741 women wereidentified from administrative claims data. Patientshad been provided with a new prescription for dailyor weekly oral bisphosphonate. Compliance, asassessed by mean medication possession ratio (MPR),defined as the number of days the drug was supplieddivided by the number of follow-up days, wassignificantly higher in patients receiving once-weekly bisphosphonates than in those receiving dailytreatment (69.2% versus 57.6%; p<0.0001). At theend of the 12 months, more women receiving once-weekly bisphosphonates persisted with therapy thanthose receiving daily regimens (44.2% versus 31.7%),but the rates of persistence were suboptimal in bothdosing regimens.

An analysis of prescriptions from 25% of US retailpharmacies, recorded on a longitudinal patientdatabase performed in 211,319 patients receivingdaily or weekly bisphosphonates, showed thatadequate compliance (defined as MPR>80%) wassignificantly higher in patients receiving weeklytherapy compared to those receiving daily therapy.Over the year of follow-up, the worst adherence wasobserved for patients new to bisphosphonates (13.2%for daily and 25.2% for weekly regimens).

Van Staa et al. examined two databases containingmedical records of medical practitioners in the UKand identified 12,373 patients initiated on eitheralendronate or risedronate treatment. The one-yearpersistence was 68.7% with weekly and 57.5% withdaily regimens.

Jean-Yves Reginster is currently aProfessor of Epidemiology, PublicHealth and Health Economics andDirector of the Department ofEpidemiology and Public Health atthe University of Liège, Belgium.Professor Reginster is also Head ofthe University Center forInvestigation in Bone and ArticularCartilage Metabolism, Director ofthe World Health Organization(WHO) Collaborating Center forPublic Health Aspects of RheumaticDisorders. He is also President ofthe Group for the Respect of Ethicsand Excellence in Science (GREES),the General Secretary of theInternational OsteoporosisFoundation (IOF) and the BelgianBone Club (BBC). ProfessorReginster has published more than400 original articles in a variety ofreputable medical journals. He hasalso contributed to more than 60chapters in a variety of books.

Véronique Rabenda is a researcherat the Department of Public Health,Epidemiology and Health Economicsat the University of Liège, Belgium.Her specific research interestsinclude pharmacoepidemiology,adherence to medications, quality oflife and health economics inosteoarthritis and osteoporosis. Sheis a member of the World HealthOrganization (WHO) CollaboratingCenter for Public Health Aspects ofOsteo-articular Disorders andmember of the Group for theRespect of Ethics and Excellence inScience (GREES).

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Osteoporosis

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Imp a c t o f S u b op t ima l A d h e r e n c e t oB i s p h o s p h on a t e s o n C l i n i c a l a n dE c o n om i c O u t c ome s

Regular use of bisphosphonate therapy is importantto prevent fractures and chronic disability. Indeed,inadequate use of bisphosphonates leads toinadequate reduction of biochemical markers of boneturnover, insufficient increases in BMD andincreased fracture risk.

A subanalysis of the IMPACT study database,including 2,302 osteoporotic women, showed that aclinically significant decrease (>50%) in thebiochemical marker of bone resorption was found inmore than 60% of patients who take their risedronatetreatment consistently, compared with only 20% ofpoorly compliant patients. The relationship betweensuboptimal use of bisphosphonates and adverse impacton BMD has been demonstrated in several studies. Ina study including 176 new users of bisphosphonates,it was found that patients who took at least two-thirdsof their bisphosphonate medication showedsignificantly higher increases in BMD at the lumbarspine (3.8%) and hip (2.6%), than patients who wereless compliant (2.1% and 2.3%, respectively;p<0.006). Similar findings from a questionnaire thatincluded 240 patients showed that compliant patientsachieved BMD gains of 4.3% and 1.2% at the lumbarspine and hip, while women taking less medicationdemonstrated modest gains of only 2.8% and 0.3%,respectively. In the CANDOO study, a statisticallysignificant difference was observed betweenconsistent and inconsistent bisphosphonate users forincreases in lumbar spine BMD after one, two andthree years. The consistent users group had significantincreases in BMD during each year of the study,whereas there were no significant increases in BMDfor the inconsistent user group until year three, whena modest gain of 3.2% was recorded.

Many studies have also demonstrated that patientswho do not take adequate amounts of bisphosphonateare at greater risk of fracture. In an analysis of a USclaims database, it was demonstrated that thelikelihood of fracture was reduced if compliance wasmaintained for one year, compared with patientsswitching or discontinuing therapy. Adherent patientshad a significantly lower risk of fractures at the spine(odds ratio (OR)=0.6; p<0.05) and hip (OR=0.38;p<0.01), compared to non-adherent patients. Similarfindings from a Canadian database that included11,249 women showed that highly compliant patients(MPR>80%) had a 16% lower fracture rate (hazardratio=0.84; p<0.005) than low compliant patients. Inthe CANDOO study, there was a non-significanttrend towards a 27% greater 10-year fracture riskamong patients taking therapy inconsistently.

Most importantly, Siris et al. estimated theprobability of fracture along a gradient of adherence.This retrospective study used two largepharmaceutical databases. The overall fracture ratewas 29% lower for women without a refill gap thanfor those who were not persistent with therapy. Atan MPR from 0% to 50%, the probability of fractureduring a period of 24 months remained consistent atabout 11%. These results are supported byHuybrechts et al. In this study, relative risk offracture in patients with 80–90% adherence was 9.1%higher than in those with adherence greater than90%, whereas relative risk of fracture in patients withless than 50% adherence was 21% higher than inthose with adherence greater than 90%. Eventually,there is a significant association between poorcompliance and economic outcomes. McCombs,using a large medical claims database, found thatgood compliance with therapy was associated withdecreased fracture risk and decreased healthcare costs.

F a c t o r s A f f e c t i n g A d h e r e n c e t oB i s p h o s p h on a t e T r e a tmen t

Although bisphosphonates improve the outcomes ofosteoporosis, many patients are reluctant to takethem. A major reason is because osteoporosis is anasymptomatic, chronic condition. This difficulty iscompounded further by the fact that, inasymptomatic condition, the benefits of treatment arenot immediately apparent and, consequently, patientsdo not consider themselves in need of medication.

Patients with concurrent illnesses and conditionsrequiring multiple medications may be at a greaterrisk of discontinuing with therapy. In a recent studyconducted by Curtis et al., it was shown that anincreased burden of medical comorbidity decreasedthe likelihood to persist with therapy. The authorsalso demonstrated that younger age and lack of BMDtesting were associated with discontinuation.

Adherence to medications is complicated by the lackof options for patients’ self-monitoring.Measurement of BMD or biochemical markers ofbone turnover could be used by physicians toprovide feedback to patients on the effectiveness ofmedication, but feedback systems are costly and notreadily available. An additional barrier to treatmentadherence is that current oral bisphosphonates needto be administered according to strict treatmentguidelines, including remaining upright and noteating, drinking or taking other medications for upto 60 minutes after the bisphosphonate intake. Thesecomplex dosing instructions are necessary tomaximise the bioavailability of bisphosphonates andreduce the risk of adverse events. However, theserequirements can be inconvenient for patients,

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Prescribing Information Bonviva (ibandronic acid) 150mg FilmCoated Tablet Please refer to the Summary of Product Characteristics

(SPC) before prescribing. Indications: Treatment of osteoporosis in

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fractures has not been established. Dosage andadministration: 150mg once a month swallowed

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use. Side effects: See SPC for full details. Dyspepsia, nausea, abdominal

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AL7 1TW, United Kingdom. Bonviva is a registered trade mark. Date of Preparation: March 2006. Print code: BON/FPA/06/25800/2

P117629a August 2006. References: 1. Chesnut CH

et al. J Bone Miner Res 2004; 19(8): 1241-1249.

2. Meunier PJ et al. Clin Ther 1999; 21(6): 1025-1044.

Information about adverse event reporting can be foundat www.yellowcard.gov.uk. Adverse events shouldbe reported to Roche Products Limited. Pleasecontact UK Drug Safety Centre on: 01707 367554.

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Hoffman_ad.qxp 24/10/06 4:46 pm Page 85

especially those taking daily therapy, and may reducecompliance. The impact of failure to follow dosingguidelines is illustrated in a study of 219 womenreceiving alendronate. Despite receiving counsellingand written instructions, almost 26% of women werenot compliant with instructions.

Tolerability is another factor to consider in this field.Although in clinical trials oral bisphosphonates havegenerally demonstrated a safety profile similar toplacebo, in clinical practice patients may experienceupper gastro-intestinal adverse events, anotherprimary reason cited for patients discontinuingbisphosphonates treatment. A telephone surveyconducted in 956 women receiving hormonereplacement therapy (HRT), raloxifene oralendronate, explored this issue. At the time ofinterview, 19% had stopped therapy. Side effects andsafety concerns were the primary reasons stated fordiscontinuing therapy, with 46% experiencing uppergastro-intestinal events.

Another important factor influencing adherence isthe cost of medication. On the basis of an evaluationof claims data, Caro et al. suggest that adherence andpersistence may be strongly influenced by cost andavailability of insurance coverage. A study conductedin Israel showed that the number of women onosteoporosis medication and persistence with therapyincreased when co-pays were eliminated forosteoporosis medication specifically. However, evengood insurance prescription coverage does notnecessarily guarantee that people with a chronic,asymptomatic disease will take their medications overthe long term.

S t r a t e g i e s t o E n h a n c e A d h e r e n c e t oO s t e o p o r o s i s M ed i c a t i o n

One strategy to improve compliance is to increasepatient convenience by decreasing the frequency ofdosing regimens. In a review of 76 studies across avariety of therapeutic areas, Claxton et al. concludedthat less frequent dosing regimens significantlyimprove compliance. Alendronate and risedronatewere initially introduced as once-daily formulations,but are now both available as once-weeklyformulations. These formulations reduce theinconvenience of having to take the bisphosphonatein the morning, fasting and remaining upright afterdosing, to once-weekly instead of daily. However,and as mentioned above, the adherence to weeklyregimens remains suboptimal. Less frequentregimens, such as once-monthly or once-yearlyadministration may increase patient convenience andtherefore potentially improve compliance andachieve the full potential benefit of bisphosphonatetherapy. Two clinical studies (Boniva Alendronate

Trial in Osteoporosis (BALTO I and II)) of patientpreference demonstrated that more than 70% ofpatients preferred treatment with the monthlyregimen of ibandronate versus the weekly regimen ofalendronate. The results from the PERSIST(Persistence Study of Ibandronate verSusalendronaTe) trial showed that once-monthlyibandronate, coupled with a patient supportprogramme, improved persistence on treatment,compared with once-weekly alendronate.

Enhancing communication between the physicianand the patient is a key and effective strategy inboosting the patient’s ability to follow a medicationregimen. However, it was highlighted that there is aserious and widespread lack of communicationbetween physicians and patients about the need tostay on long-term treatment in order to effectivelytreat osteoporosis and reduce the risk of fractures.

Data from the IMPACT study showed increasedpersistence in those patients receiving a positivemessage based on bone resorption markermonitoring. In a study conducted by Silverman etal., 140 women were randomised to receiveeducational information and a voucher forimmediate BMD testing in one year. Amongwomen who received an immediate BMD test,63.4% filled their prescription immediately. Incontrast, only 20% of those who received a BMDtest one year later filled their prescription. In arecent UK study, both nurse monitoring alone andnurse plus bone turnover measurement monitoringimproved adherence by 57%. This demonstratesthat discussion with a healthcare professional toreinforce the need for long-term therapy may be ofequal value for patient compliance as informationabout response to biochemical markers. Similarly,Cooper et al. reported the success of patient supportprogrammes plus monthly ibandronate inimproving persistence compared to a weeklybisphosphonate only.

Con c l u s i o n

Adherence to osteoporosis medications remains poorand is associated with long-term consequences suchas increased osteoporotic fractures and healthcarecosts. Pursuing interventions that could improveadherence is worthwhile. The development of newmedications with extended dosing intervals andinterventions to involve patients in the treatment oftheir diseases may promote compliance and enhancepatient satisfaction and outcomes. ■

A longer version of this article containing references can befound in the Reference Section on the website supportingthis briefing (www.touchbriefings.com).

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