GENDER MEDICINE/VOL. 5, No.4, 2008

Descriptive Analysis of Concomitant Prescription MedicationPatterns from 1999 to 2004 Among US Women ReceivingDaily or Weekly Oral Bisphosphonate TherapyDeborah T. Gold, PhD!; Sydney Lou Bonnick, MD2; Mayur M. Amonkar, PhD3;Hosam K. Kamel, MD, MPH4; Shuchita Agarwal, PhD5; and Mone Zaidi, MD6

1Duke University Medical Center, Durham, North Carolina; 2Clinical Research Center ofNorth Texas,Denton, Texas; 3GlaxoSmithKline pIc, Collegeville, PenllSylvania; 4University ofArkansas for MedicalSciences, Little Rock, ArkallSas; sWolters Kluwer Health, Yardley, PenllSylvania; and 6Mount Sinai SchoolofMedicine, New York, New York

ABSTRACTBackground: To improve medication-taking behavior, it is important to identify factors that may con­

tribute to suboptimal compliance and persistence with osteoporosis medications.Objective: The purpose of this descriptive analysis was to identify concurrent prescription medication

use (number and type) among women receiving daily or weekly oral bisphosphonate therapy.Methods: Patient prescription data were collected from November 1999 to June 2004 from a US patient

claims database accessed through Wolters Kluwer Health (formerly NDC Health), which represents >65 mil­lion patients annually. Women aged ~50 years who were receiving daily or weekly oral bisphosphonatemedication during the study months were included. Concomitant medications were defined based on~14 days of prescription supply in the same month as bisphosphonate therapy. Data were examined todetermine the frequency with which certain drugs and drug classes were prescribed concomitantly withbisphosphonates. Each study month was treated independently to assess concomitant medication use.

Results: Over the study period, the number of female bisphosphonate recipients in the databaseincreased from 78,909 to 250,286. At the end of the study, 16.2%, 12.2%, 8.7%, and 19.1% of bisphos­phonate recipients were prescribed 3, 4, 5, or ~6 concomitant medications, respectively. The most com­monly prescribed concomitant drug classes were cholesterol reducers, diuretics, 13-blockers, calcium chan­nel blockers, synthetic thyroid hormones, angiotensin-converting enzyme inhibitors, systemic analgesics/anti-inflammatory drugs, and antispasmodics/antisecretory drugs. From July 2001 until the end of thestudy, the number of concomitant medications was higher for women receiving daily bisphosphonatesthan for those receiving weekly bisphosphonates, 4.16 versus 3.77 as of June 2004. In addition, the meannumber of concomitant medications prescribed increased with age: in the aged 50 to 64 years cohort, theaged 65 to 74 years cohort, and the aged ~75 years cohort, the mean number was 3.09, 3.62, and 3.97,respectively, as of June 2004.

Conclusion: This analysis suggests that women prescribed bisphosphonates have a high medicationburden, with the majority of patients (56%) taking ~3 concomitant prescription medications. (GeJld Med.

2008;5:374-384) © 2008 Excerpta Medica Inc.Key words: bisphosphonates, alendronate, risedronate, osteoporosis, polypharmacy, prescriptions, com­

pliance, persistence, drug statistics, numerical data.

Accepted for publication August 8, 2008.© 2008 Excerpta Medica Inc. All rights reserved.

374

001:10.1 016/j.genm.2008.1 0.0041550-8579/$32.00

INTRODUCTIONOsteoporosis, defined as a skeletal disorder charac­terized by compromised bone strength predispos­ing a person to an increased risk of fracture,l is as­sociated with progressive reduction in bone massand often presents without symptoms. In additionto aging, primary osteoporosis in women may bethe result of bone loss due to menopause-relatedestrogen decreases.2 Certain medical conditions(eg, hypogonadism, hyperthyroidism), use of medi­cations (eg, glucocorticoids, antiepileptic drugs),and diseases (eg, celiac disease) may result in sec­ondary osteoporosis, which can occur in bothwomen and men.3-b In the United States, ~10 mil­lion people (80% women, 20% men) have osteo­porosis of the hip.7-

qIt has been predicted that

1 in 2 women and 1 in 5 men >50 years of age willexperience an osteoporosis-related fracture.7-

qFrac­

tures, in particular, hip fractures, can be debilitat­ing, are associated with increased morbidity andmortality, and are expensive. lO

Several osteoporosis treatments have been foundto be efficaciousll- 13 and cost effective1-±-lbi how­ever, studies have reported that refill complianceand persistence with osteoporosis medications aresuboptimal. 17-1 q It has been estimated that up to

40% of patients prematurely withdraw from treat­ment within 6 to 7 months of initiating therapy.20-2.,1Although there are many factors that could nega­tively influence medication persistence and com­pliance, the lack of visible symptoms early in thedisease process and the lack of perceptible treat­ment benefits may be partly responsible.2s Patientsmay not perceive osteoporosis as a meaningfulthreat to their health or recognize a need fortherapy.2b-28

Nitrogen-containing bisphosphonates are high­ly effective agents for the treatment of postmeno­pausal osteoporosis,ll.12.2q,30 and a consistentlyhigh level of compliance (a medication possessionratio [MPR] of ~80%) with bisphosphonates hasbeen linked to decreased risk of fracture (relativerisk reductions of 160/0-45%).17.1q,31 To achieve maxi­

mal effectiveness, it is necessary for patients toadhere closely to the dosing instructions for oralbisphosphonates, which some patients may per­ceive as inconvenient. For example, all oral bis-

D.T. Gold et al.

phosphonates must be taken with only water afteran overnight fast to ensure proper absorption.32

The patient must remain upright for 30 to 60 min­utes after dosing and continue to fast for 30 to60 minutes before ingesting food, liquids otherthan plain water, or other oral medications.33-3s

When oral bisphosphonates are not taken as rec­ommended, their potency is reduced by decreasedabsorption, and the risk of local esophageal irrita­tion is increased.33-3 7

Recognition that simplified dosing regimensand reduced frequency of administration areimportant factors for improving compliance andpersistence has led to the development of oralbisphosphonates with less-frequent dosing regi­mens.38 Their high antiresorptive potency andpersistence in bone have allowed for the develop­ment of extended-dosing formulations. 3QAO Oralbisphosphonates currently approved by the USFood and Drug Administration are available indaily, weekly, and monthly dosing options. Less­frequent administration of bisphosphonates hasbeen associated with greater patient preference23

and improved persistence and refill compliance.-±lHowever, overall rates of persistence and compli­ance with weekly bisphosphonate therapies arestill inadequate, with reported MPRs ranging from65% to 69% after 1 year of follow-Up.18A1 Thesefindings suggest that even a weekly oral bisphos­phonate dosing regimen may present substantialdifficulties and inconvenience to the patient.-±2

It has been estimated that two thirds of medica­tion recipients aged ~70 years take 2 to 4 medi­cations, and one fifth take ~5 medications.-±3 Asurvey of the US community-dwelling adult popu­lation revealed that the prevalence of the use ofmultiple concurrent medications was highest inwomen aged ~65 years, of whom 12% took at least10 medications (including vitamins, minerals, andherbal preparations/natural supplements) and23% took at least 5 prescription drugs.-±-! The useof multiple medications has been associated withmedication errors, increased likelihood of adversedrug reactions, and poor persistence and com­pliance.-±sAb Dosing instructions that vary acrossconcomitant prescriptions may contribute to thisproblem. Increased complexity of the drug regi-

375

Gender Medicine

men can exacerbate difficulties in comprehendinginstructions, resulting in increased confusion.-±? Toaccommodate the dosing requirements for bis­phosphonates, patients may need to alter theirestablished drug regimen.

This study assessed the use of multiple concur­rent medications among women receiving bisphos­phonate therapy. A descriptive analysis was per­formed to identify and compare the number andtype of concomitant medications taken by womenprescribed daily or weekly bisphosphonates.

SAMPLE AND METHODSData Source

Patient prescription data were collected from alarge US patient database accessed through WoltersKluwer Health, Yardley, Pennsylvania (formerlyNDC Health), which represents >65 million pa­tients annually. The database stored prescriptioninformation from ~14,000 geographically dispersedUS retail pharmacies (~25% of all US retail phar­macies) and included brand name, generic name,strength, quantity, date of fill/refill, age, sex, andpayment method. The database was compliantwith the Health Insurance Portability and Account­ability Act-±8 and consisted of a rolling 60 monthsof historical data that track patients' prescriptionactivity longitudinally. Furthermore, the databasecovered a broad range of patient ages, includingthe elderly, and of incomes, but excluded hospitaland military prescriptions and had only minimaldata on mail-order prescriptions. Informationabout payment methods (cash, third-party payers,and Medicaid) and retail pharmacy types (chain,independent, food store, mass merchandiser, anddiscount store pharmacies) was also recorded.

SampleThis study examined concomitant prescription

medication use among women receiving eitherdaily or weekly bisphosphonate therapy (monthlydosing was not yet available during the studyperiod). The study population included womenaged ~50 years who received bisphosphonatemedication during the study month. Each studymonth was treated independently to assess con­comitant medication use. Based on availability,

376

56 months of data were evaluated (November1999-June 2004). Bisphosphonate therapy permonth was defined as at least 14 days of prescrip­tion supply. Patients taking daily bisphosphonatetherapy received 5 mg or 10 mg of alendronate or5 mg of risedronate. Weekly doses were 35 mg or70 mg of alendronate or 35 mg of risedronate. Con­comitant prescription medications were definedbased on ~14 days of prescription supply in thesame month as bisphosphonate therapy, andincluded those medications that were intended tobe administered either orally, as inhaled or intra­nasal medications, or as self-administered paren­teral injections.

Outcome MeasuresData from November 1999 to June 2004 were

analyzed to determine the frequency with whichcertain drugs and drug classes were used concomi­tantly with bisphosphonates. The primary analy­sis, descriptive only, included comparisons betweendaily and weekly bisphosphonate recipients withI, 2, 3, 4, 5, or ~6 concomitant therapies. Patientsalso were categorized by age group as follows: 50 to64 years, 65 to 74 years, and ~75 years.

RESULTSThe total number of women included in this studyincreased from 78,909 to 250,286 by the end ofthe 56-month study period. At the beginning ofthe study (November 1999), all patients took bis­phosphonates on a daily basis because, at thattime, only daily bisphosphonates were availablefor prescription (alendronate was marketed in 1995,risedronate in 1998-±q). At the conclusion of thestudy Gune 2004), most patients were receivingweekly bisphosphonates (234,402 [93.7%]) versusdaily bisphosphonates (15,884 [6.3%]) (Figure 1).

Weekly formulations ofalendronate and risedronatewere marketed in 2000 and 2002, respectively.-±Q

Daily bisphosphonate recipients were prescribed3.14 to 4.16 concomitant medications betweenNovember 1999 and June 2004. Weekly bisphos­phonate recipients were prescribed 3.64 to 3.77 con­comitant medications between November 2000and June 2004. From May 2001 until the end ofthe study, patients receiving a daily bisphospho-

D.T. Gold et al.

--I:s- Daily blsphosphonate use-. Weekly blsphosphonate use

lul-Ol Dec-01 May-02 Oct-02 Mar-03 Aug-03 lan-04 lun-04

Date

260,000

240,000

220,000

200,000

180,000

160,000

140,000

120,000

100,000

80,000 ---<N-"~­

60,000

40,000

20,000

0-+------,-----,-----=::..,---,--------,----,---------,---,--------,------,,--------,

Nov-99 Apr-OO Sep-OO Feb-Ol

~

iiJ~c

~-ooZ

Figure 1. Number of women receiving daily versus weekly bisphosphonates from November 1999 to June 2004.

nate had a higher mean number of concomitantmedications than those receiving a weekly bisphos­phonate (Figure 2A).

At the end of the study, 16.2%, 12.2%, and8.7% ofbisphosphonate recipients were prescribed3, 4, or 5 concomitant medications, respectively(Figure 2B). Furthermore, the proportion of wom­en filling ~6 additional prescriptions increasedfrom 11.9% to 19.1% from November 1999 to theend of the study. Thus, 56% of women receivingbisphosphonate treatment were prescribed ~3 con­comitant medications as of June 2004.

Throughout the study, older women took moreconcomitant prescription medications than didyounger women (Figure 3). On examination ofthe data as a function of age group, patients in theaged 50 to 64 years cohort were taking 2.74 and3.09 concomitant medications at the start and endof the study, respectively; patients in the aged 65to 74 years cohort were taking 2.95 and 3.62 con­comitant medications at the start and end; andpatients in the aged ~75 years cohort were taking3.16 and 3.97 concomitant medications at thestart and end. The most commonly prescribedconcomitant medications and drug classes areshown in Table I.

The most frequently prescribed nonbisphospho­nate drugs were predominantly used for the treat­ment of cardiovascular-related comorbidities suchas high cholesterol and high blood pressure. Ad­ditionally, in the beginning of the study, the useof conjugated estrogens was prevalent, with 12.8%of both daily and weekly bisphosphonate recipi­ents filling prescriptions for conjugated estrogens.However, by June 2004, these percentages weregreatly reduced, with only 4.9% of daily and 4.8%of weekly bisphosphonate recipients filling pre­scriptions for conjugated estrogens.

DISCUSSIONThe current descriptive study assessing the num­ber and type of concomitant medications utilizedby women receiving daily or weekly bisphospho­nate therapy found that medication use increasedwith age. Once the weekly bisphosphonate regi­men was available, our findings indicated a strongpreference for this less-frequent regimen versusthe daily bisphosphonate regimen. Weekly bis­phosphonate treatment was associated with fewerconcomitant medications compared with dailytreatment, albeit that the number of prescribedmedications taken by both groups of bisphospho-

377

Gender Medicine

--Is- Daily blsphosphonate use-. Weekly blsphosphonate use

A4.2

<f> 4.0b.I)

20.... 3.8~

[3~c0 3.6u~

0U-0 3.4ciZ

3.2

3.143.0

4.16

Nov-99 Apr-OO Sep-OO Feb-01 lul-01 Dec-01 May-02 Oct-02 Mar-03 Aug-03 lan-04Iun-04

Date

B

30

25

20

15

~~o 10

~=.. -----..... -...... - ­• ••• • ................

5+---,--------,---,--------,-----,----,--------,---,--------,-----,----,-

Nov-99 Apr-OO Sep-OO Feb-01 lul-01 Dec-01 May-02 Oct-02 Mar-03Aug-03 lan-04 lun-04

Date

Figure 2. (A) The mean number of concomitant prescribed drugs taken, by daily versus weekly bisphosphonate use; and(B) the percentage share of the number of concomitant prescribed drugs taken per month (November 1999-June2004) among women receiving oral bisphosphonates.

378

~coi:!ou-ooZ

4.0

3.8

3.6

3.4

3.2

3.0

2.8

--I':r- Aged 50-64 years• Aged 65-74 years-... Aged ;>75 years

D.T. Gold et al.

2.6 +-------,------,,------,--------,------,---,--------,-----,--,-------,-----,­

Nov-99Apr-00 Sep-OO Feb-Ol lul-Ol Dec-01May-020ct-02 Mar-03Aug-03 lan-04 lun-04

Date

Figure 3. Mean number of concomitant prescribed drugs taken by women who also took bisphosphonates, per month(November 1999-June 2004) by age group.

Table I. Percentage of women taking daily or weekly bisphosphonates in June 2004 who also took concomitant drugsfrom the most prescribed therapeutic classes.

Drug Class

Cholesterol reducersDiuretics*13-BlockersCalcium channel blockersSynthetic thyroid hormonesACE inhibitorsSystemic analgesics/anti-inflammatory drugsAntispasmodics/antisecretory drugs

ACE = angiotensin-converting enzyme.*Includes thiazide, thiazide-related, potassium-sparing, and other types.

Dai Iy BisphosphonateRecipients

31.626.421.020.019.819.118.016.9

Weekly BisphosphonateRecipients

30.222.419.816.019.914.716.515.9

nate recipients was still substantial. The reasonsfor this difference are currently unknown. To ourknowledge, this observation of fewer medicationswith weekly treatment has not been noted previ­ously, and it is unclear whether these findings arespecific to this study.

The most commonly prescribed concomitantdrug classes included cholesterol reducers, diuret­ics, 13-blockers, calcium channel blockers, syntheticthyroid hormones, angiotensin-converting enzyme

inhibitors, systemic analgesics/anti-inflammatorydrugs, and antispasmodics/antisecretory drugs. Theuse of estrogen in our study population was greatlyreduced (~620/0 decrease) by the end of the studyperiod. It is likely that the findings of the Women'sHealth Initiative study in August 2002, whichraised concerns that the use of estrogen therapyincreased the risks of breast cancer, stroke, andmyocardial infarction, may have influenced drug­taking behavior among this cohort of women.so,s 1

379

Gender Medicine

Despite their proven efficacy, bisphosphonatesare associated with inadequate persistence andrefill compliance.25 It is possible that multiple con­comitant medications may contribute to poor per­sistence and compliance because of the individualrequirements of the different medications. Dosinginstructions for the commonly used concomitantmedications are shown in Table 1I.52-b1 Bisphos­phonate dosing restrictions are rarely convenientand may cause difficulties with the dosing instruc­tions of concomitant medications, especially forelderly patients receiving daily concurrent treat­ments. Many medications commonly used in con­junction with bisphosphonates specify dosingtimes, and some provide food ingestion guidelines.For example, many patients-almost 20% of thedaily and weekly bisphosphonate recipients includ­ed in this study-took oral thyroid medications.Guidelines for thyroid medications state that theyshould be taken in the morning before breakfast,followed by a 30- to 60-minute fast,58 thus conflict­ing with the recommended guidelines for bisphos­phonates. If both medications must be taken daily,combining these regimens could present additionalcomplexities for patients.

By prescribing the least complex regimen andsimplifying a patient's medication schedule andinstructions, convenience and, ultimately, persis­tence and compliance may be improved.21 Thiscould be achieved by decreasing the number ofmedications, minimizing the number of dailydoses, and tailoring the dosing schedule to thepatient's lifestyle. Simplification of the medicationregimen is unlikely to completely solve the prob­lem of nonpersistence and noncompliance withbisphosphonate therapy, but should be one com­ponent of a multifactorial strategy. As stated previ­ously, clinical trials have found that persistenceand compliance were higher with weekly dosingversus daily dosing. 18 ,b2 A review of administrativeclaims database analyses of persistence and com­pliance, by Silverman et al,31 reported an associa­tion between persistence and compliance (MPR~0.80) and reduced fracture incidence. Recently,one analysis found better persistence with month­ly bisphosphonates compared with weekly bispho­sphonates after 9 months of therapy (P = 0.003).b3

The database used in our study included a verylarge sample size and covered a wide geographicalareai as such, it provided robust information about

Table II. Recommended dosing instructions for the concomitant drugs most commonly used by women takingbisphosphonates.

Top 10 Therapeutic Recommended Recommended RecommendedConcomitant Drugs Category Dosing Frequency Dosing Restriction Time of Dose

Amlodipine besylate52 CCB Once daily With or without food Same time daily

Atenolol53 13-Blocker Once daily Not specified Same time daily

Atorvastatin calcium54 Lipid-lowering agent Once daily With or without food Anytime

Celecoxib55 NSAID Once daily With or without food Anytime

Furosemide56 Diuretic Once or twice daily Not specified Morning

Hydrochloroth iazide57 Diuretic Once daily Not specified Morning

Levothyroxine Synthetic thyroid Once daily Without food, take 30-60 minutes Morningsodium58 hormone before breakfast and 4 hours

apart from interfering medications

Lisi nopri 159 ACE inhibitor Once daily With or without food, Morningfull glass of water

Potassium chloride6O Potassium supplement Once or twice daily With food, full glass of water Not specified

Simvastatin 61 Lipid-lowering agent Once daily Not specified Evening

CCB = calCium channel blocker; ACE = angiotensin-converting enzyme.

380

the types and numbers of concomitant medica­tions prescribed to women receiving oral bisphos­phonate therapy. Point-of-sale information ondispensed prescriptions provided good correlationwith drug exposure. Information regarding all pay­ment types, including Medicaid, also was includedin the database, and therefore represented patientswith a broad range of ages and incomes.

It is important to note the limitations of thecurrent study. The dispensing of prescriptions wasused as a surrogate measure to estimate actualmedication usage. It was assumed that the pre­scriptions sold were being taken and the dosinginstructions were being followed. Also, the data­base used in this study included patients withprescriptions dispensed in retail pharmacies, con­tained minimal mail-order prescriptions, and didnot follow patients obtaining prescriptions fromhospitals, military, or other institutions. Furtherconsiderations include the fact that patients visit­ing more than one pharmacy were counted sepa­rately in each store, and these patients appeared asif they had ceased therapy. As a result, completepatient activity for patients switching pharmacieswas not captured. The current study was also notdesigned to assess the potential differences inpolypharmacy, such as age and prescribing habits,between daily and weekly bisphosphonate recipi­ents. Lastly, the database used did not provideinformation on over-the-counter (OTC) medica­tions. Treating physicians should be aware of anyOTC products their patients may be taking; forinstance, some commonly used OTC antacidscan interfere with the efficacy of bisphosphonatesas well as other medications (eg, celecoxib andlevothyroxine sodium).

The high level of concomitant medication useand the severity of the other conditions com­monly being treated (including hypercholester­olemia, hypothyroidism, heart failure, and hyper­tension) highlight the importance of consideringmedication options that are more convenient forosteoporosis patients. The high medication bur­den borne by these patients increases drug admin­istration constraints and may partially explainwhy compliance and persistence with bisphos­phonate therapy remain poor. The availability of

D.T. Gold et al.

even less frequent bisphosphonate regimens, suchas monthly dosing, may decrease the medicationburden and contribute to improved persistenceand refill compliance. These relationships shouldbe explored further in future studies.

CONCLUSIONSIn this study, women receiving either once-dailyor once-weekly bisphosphonate therapy were oftenbeing treated concurrently for other chronic con­ditions, and hence were taking multiple pres­criptions daily. The number of concomitant medi­cations prescribed to these women receivingbisphosphonates increased with age. Furthermore,women receiving daily bisphosphonate therapyappeared to be prescribed more concomitantmedications compared with those receiving week­ly bisphosphonates, but the reasons for this differ­ence are unknown.

ACKNOWLEDGMENTSFinancial support for this study was provided byRoche and GlaxoSmithKline pIc. The authors ac­knowledge the assistance of Rebecca Jarvis, PhD,in the preparation of this manuscript.

Dr. Gold is on the speakers' and advisory boardsat Amgen Inc., Eli Lilly and Company, Glaxo­SmithKline, Merck & Co., Inc., Procter & Gamble,Roche, and sanofi-aventis U.S. LLC, and hasreceived grants for other research projects fromProcter & Gamble and sanofi-aventis. Dr. Bonnickis on the speakers' boards at Novartis AG, Wyeth,Roche, and Merck; is a consultant for Roche,Merck, Wyeth, and Amgen; and has receivedgrants for other research projects from Roche,Wyeth, and Amgen. Dr. Amonkar is an employeeof GlaxoSmithKline. Dr. Kamel is on the speakers'boards at Roche, GlaxoSmithKline, Novartis, Procter& Gamble, and Merck; and is a consultant forRoche, GlaxoSmithKline, Principia Pharmaceu­tical Corporation, Ortho-McNeil-Janssen Pharma­ceuticals, Inc., Bio-Technology General Corp.,Procter & Gamble, Shire Pharmaceuticals GrouppIc, USB Pharma, Novartis, and Schwartz PharmaAG. Dr. Kamel also has received grants for otherresearch projects from Merck, Procter & Gamble,and Novartis. Dr. Agarwal is formerly an employee

Gender Medicine

of Wolters Kluwer Health (formerly NDC Health).Dr. Zaidi is on the speakers' boards at Procter &

Gamble, Merck, GlaxoSmithKline, Roche, andsanofi-aventisi is on the advisory boards at Roche,GlaxoSmithKline, Procter & Gamble, and sanofi­aventisi and has received grants for other researchprojects from Procter & Gamble.

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Address correspondence to: Deborah T. Gold, PhD, Duke University Medical Center, Box 3003, Durham, NC27710-0001. E-mail: dtg@gerLduke.eduAlternate corresponding author: Sydney Lou Bonnick, MD, Clinical Research Center of North Texas, 2921Country Club Road, Suite 101, Denton, TX 76210. E-mail: sbonnick@msn.com

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