Persistence with Bisphosphonate Treatment for Osteoporosis: Finding the Root of the Problem

The American Journal of Medicine (2006) Vol 119 (4A), 12S-17S

Persistence with Bisphosphonate Treatment for Osteoporosis: Finding the Root of the Problem Joyce A. Cramer, BS,a Stuart Silverman, MDb a

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA; bDepartments of Rheumatology and Medicine, Cedars-Sinai Hospital, University of California, Los Angeles, California, USA ABSTRACT Poor compliance and persistence are among the most significant reasons for failed pharmacotherapy encountered in clinical practice. Consequences of poor compliance range from minor to serious, depending on drug characteristics, disease state, and severity of disease. Compliance and persistence are particular problems for patients with a disorder such as osteoporosis, which remains asymptomatic for long periods. Poor compliance with bisphosphonate therapy for osteoporosis has been associated with a smaller decrease in the rate of bone turnover and smaller improvements in bone mineral density, and may potentially result in a higher risk of fracture and disability. The compliance problem is additive; complex dosing guidelines may contribute to poor compliance with therapy, and the failure to follow these guidelines may result in treatment-related adverse events that further reduce compliance. In the long term, these issues often result in nonpersistence with treatment. In addition to direct consequences for the patient, poor compliance is associated with significant healthcare costs. Studies suggest that less-frequent dosing regimens improve compliance; however, even among patients receiving weekly bisphosphonates, persistence may remain suboptimal. Several strategies are available to improve compliance and persistence with osteoporosis therapies. Good communication between the healthcare provider and the patient—with continuous reinforcement of the importance of treatment—is a key approach to improving persistence. Patients should receive feedback to confirm that their treatment is having an effect, and individualized reminder systems should be recommended to help the patient adhere to the treatment plan. Potentially, every patient is liable to discontinue treatment even after a long period of regular dosing. It should be assumed that every patient receiving therapy for osteoporosis needs regular reinforcement of the importance of continuing therapy. © 2006 Elsevier Inc. All rights reserved. KEYWORDS: Bisphosphonates; Compliance; Dosing; Osteoporosis; Persistence

Across disease states, and regardless of severity, only 76% of medications are taken as prescribed.1 As a result, between 30% and 50% of all prescriptions fail to produce the desired results.2 Osteoporosis is no exception to this low rate of medication compliance. Despite the availability of effective, well-tolerated drugs for osteoporosis, fracture rates remain high, due in part to poor compliance and persistence with medication. Patient compliance is defined as the extent to which a person’s behavior—in terms of Requests for reprints should be addressed to Joyce A. Cramer, BS, Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue (G7E), West Haven, Connecticut 06516-2770. E-mail address: [email protected].

0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.12.018

taking prescribed medication, following dietary regimens, or instituting recommended lifestyle changes—is consistent with medical or health advice.3 Operationally, adequate compliance may be defined by the achievement of a desired outcome—for example, reduction in fracture risk or achieving blood pressure targets—not by the percentage of pills a patient takes. The term compliance is synonymous with adherence, but is used here because compliance is the medical subject heading term used by the National Library of Medicine. Compliance represents the patient’s actions in taking medication doses as prescribed. This includes the number of doses, the time interval between doses, and other special

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instructions related to taking doses. The term persistence represents the duration of treatment. Thus, nonpersistence is defined as treatment discontinuation without medical recommendation. There is no universal threshold above which patients may be considered compliant with medications. Although some investigators have suggested that taking 80% or more of recommended doses signifies compliance, this rate depends on the type of medication, dose, and patient characteristics (pharmacokinetic and pharmacodynamic). Compliance is a continuum from 0% to 100%. However, the clinical target is not necessarily to take 100% of doses, but rather to take enough doses to achieve the desired clinical outcome.4-6 For patients with osteoporosis, the desired outcome is to maintain or increase bone mineral density (BMD) and decrease markers of bone turnover to premenopausal levels. Good compliance with the dosing regimen is an important factor in reaching this goal, but treatment persistence is also necessary to retain the benefit over the long term. Partially compliant patients have accepted their diagnosis and the necessity of treatment, but do not receive the full effects of therapy.7 Reasons for partial compliance include forgetfulness, a change in dosage that is not fully explained and thus leads to misunderstanding, or medical events that cause the patient to believe the medication is not helping. In contrast to partial compliers, noncompliers do not believe in their diagnosis and either do not return for treatment or take their medication only infrequently.

CONSEQUENCES OF INADEQUATE COMPLIANCE The consequences of noncompliance may range from inconsequential to severe, depending on drug characteristics, disease state, and severity of disease. Approximately 10% of all hospitalizations and 23% of all nursing home admissions are attributable to a patient’s inability to follow drug therapy.2 For example, poor compliance with asthma medication regimens is associated with significantly more wheezing, greater variability in peak flow rates, lower asthma control scores, and a higher risk of death.8 Among patients with epilepsy, nearly 50% report having a seizure as a consequence of a missed dose.9 Research has shown that patients may have clinically significant increases in blood pressure within 24 to 48 hours of missing a dose of a calcium-channel blocker or ␤-blocker, and that even patients taking their blood pressure medications 80% to 99% of the time can experience up to a 2-fold increase in risk for a cardiovascular event as a result of the occasional missed dose.10 Poor compliance and persistence with medication dosing are significant contributors to the costs of medical care in every therapeutic area. Inadequate response to therapy may result in additional office visits and increases in the frequency of laboratory and physiologic testing.4 Unnecessary dosage changes or therapeutic substitutions further increase the cost of treatment. In a study conducted by McCoombs and colleagues,11 nearly 86% of newly treated patients with

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hypertension interrupted or discontinued purchasing antihypertensive medication during the first year of therapy. This resulted in an additional $873 in healthcare costs per patient during the first year, even though there was a $281 reduction in the cost of prescriptions. The increased costs were primarily attributable to a $637 increase in hospital expenditures. Among patients with asthma, the largest proportion of disease-related costs results from emergency room visits and hospitalizations; poorly compliant patients are much more likely to require emergency care or to be hospitalized than patients who comply with medication regimens.8

COMPLIANCE WITH OSTEOPOROSIS MEDICATIONS Poor compliance with osteoporosis medications has been shown to be associated with smaller decreases in the rate of bone turnover, lower gains in BMD, and a significantly greater risk of fracture. In addition, poor compliance with osteoporosis therapy increases both direct and indirect medical costs, and ultimately leads to decreased quality of life when fractures occur.12 Individuals who are compliant with bisphosphonate treatment have lower fracture rates. A study of 11,252 Canadian women who took an osteoporosis medication between 1996 and 2001 examined the relation between compliance with osteoporosis medication and fracture in actual practice.13 The overall fracture rate was 4.5% per year. Patients who refilled ⱖ80% of their prescriptions (considered good compliers) had a 16% lower fracture rate compared with those who obtained fewer refills (considered poor compliers). This result likely underestimates the impact of full compliance with therapy because the pattern of dose-taking was not assessed. Individuals who are compliant have greater decreases in bone turnover. Short-term (3- to 6-month) changes in levels of bone turnover markers such as the urinary N-terminal cross-linking telopeptide of type I collagen (uNTX) and serum type 1 collagen C-telopeptide (sCTX) have been shown to be significantly correlated with reduced vertebral fracture risk in patients receiving bisphosphonate therapy.14 In a study by Eastell and colleagues,15 bone turnover marker levels were measured in 2,302 postmenopausal women with osteoporosis, and compliance with bisphosphonate treatment was assessed using electronic monitoring. Improvements in levels of these markers, as well as BMD, were directly correlated with the level of compliance. For example, after 22 weeks of therapy, a decrease of ⱖ50% (improvement) in levels of sCTX from baseline was observed in ⱖ60% of compliant patients. In contrast, only 20% of noncompliant patients achieved a similar suppression of sCTX levels. Compliant individuals also have greater increases in BMD. Yood and colleagues16 studied the effect of medication compliance (including estrogen, bisphosphonates, calcitonin, or ⬎1 of these therapies) on changes in BMD in previously untreated women with osteoporosis. After ⬎1

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Figure 1 Compliance influences change in bone mineral density (BMD) in patients treated with bisphosphonates. (Adapted with permission from Osteoporos Int.16)

year of therapy, 70.7% of patients who were prescribed estrogen and 69.2% of patients who were prescribed bisphosphonates continued to take their medication. Among participants whose compliance with therapy was at ⱖ66%, the mean increase in spine BMD was 3.80% per year, compared with 2.11% per year for those whose compliance was ⬍66% (P ⬍0.0056) (Figure 1). Similar results were observed for hip BMD. Similarly, in a study conducted by Sebalt and colleagues,17 patients who reported that they consistently took their prescribed bisphosphonate (ⱖ80% of the time) experienced a significant increase in lumbar spine BMD from baseline after 1, 2, and 3 years of therapy (3.3%, 4.9%, and 6.5%, respectively). In contrast, no significant improvement in spine BMD was observed in those who reported inconsistent use until year 3, at which time a modest gain of 3.2% was achieved relative to baseline. There was a trend toward a 27% greater 10-year fracture risk in patients who were inconsistent users compared with consistent users. It should be noted that these results are based on self-report and may overestimate consistent use.

REASONS FOR POOR COMPLIANCE WITH OSTEOPOROSIS THERAPY It is likely that failure to comply with osteoporosis therapy is a consequence of the lack of noticeable symptoms associated with the condition. Without obvious evidence of disease, patients may not believe their diagnosis, or they may accept the diagnosis but fail to perceive a sufficient threat to their health. Tolerability is another important factor to consider: studies suggest that upper gastrointestinal side effects are the major reason for discontinuation of bisphosphonate therapy. A systematic study of reasons for early discontinuation of treatment for osteoporosis was conducted in women with

osteoporosis or osteopenia who had initiated treatment with hormone replacement therapy, raloxifene, or alendronate.18 Among the 956 women interviewed an average of 7 months after therapy initiation, discontinuation of therapy had occurred in 26% of patients taking hormone therapy, 19% of those taking raloxifene, and 19% of those taking alendronate. Those who thought their bone density test did not show osteoporosis or were unsure about the results were 1.6 times more likely to discontinue therapy than were those who thought their report did show the condition. Regardless of therapy, side effects were the major reason for treatment discontinuation. In all, 71% of women who characterized the side effects they experienced as “very” or “extremely” bothersome discontinued therapy. Safety concerns were another important reason for patients to discontinue therapy. The reasons for failure to start therapy and failure to continue an existing regimen differ somewhat. Lombas and colleagues19 examined reasons for failure to initiate or continue treatment in 401 postmenopausal women with osteopenia or osteoporosis (Table 1). Of these, 52 (13%) never initiated treatment. The most common reasons for failure to start treatment were lack of acceptance of the need for treatment (48%), conflicting advice from healthcare providers (11.5%), fear after reading the product insert (9.6%), dosing regimen complexity (9.6%), other health problems (5.7%), and cost of therapy (5.7%). Among the 349 patients who started treatment, only 45.4% persisted with therapy. Common reasons for discontinuation of therapy were gastrointestinal disorders (12.9%), physician’s advice (11.7%), dosing complexity (4.3%), and cost of therapy (3.7%). In contrast to those who failed to initiate therapy, only 1.4% of patients discontinued because they believed therapy was not necessary. Age, number of concomitant medications, Tscore, and the presence of fracture did not influence risk of discontinuation.

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Table 1 Most common reasons for failure to initiate and continue alendronate therapy in 401 postmenopausal women

Reason Lack of acceptance of need for treatment Conflicting advice Physician’s advice Fear after reading product insert Dosing regimen complexity Gastrointestinal disorders Cost of therapy Other health problems

Failure to Initiate Therapy 48%

Failure to Continue Therapy 1.4%

11.5% — 9.6%

— 11.7% —

9.6% — 5.7% 5.7%

4.3% 12.9% 3.7% —

Reprinted from “Compliance with alendronate in an osteoporosis clinic.”19

Bisphosphonates must be administered according to strict dosing guidelines to achieve optimum absorption and tolerability. Patients are instructed to avoid food and drink for 30 minutes to 1 hour after morning dosing and to take their medication with water. Patients must remain upright for ⱖ30 minutes and until after their first meal of the day. Failure to follow these guidelines increases the risk of esophageal side effects and reduces absorption.20-22 The impact of failure to follow dosing guidelines is illustrated in a study of 219 women receiving alendronate for osteoporosis.23 Despite receiving counseling and written instructions, approximately 26% of women overall were not compliant with dosing instructions. Gastrointestinal adverse events were most common among the patients studied, occurring in 76% who discontinued treatment. Adverse events among those who discontinued therapy were most often the result of not staying upright long enough (43% of dropouts), not fasting long enough (19%), or not taking enough water during dosing (3%). These data underscore the need not only to emphasize compliance with the dosing schedule, but also to focus on ensuring that patients take their medications according to dosing requirements.

IMPROVING COMPLIANCE WITH OSTEOPOROSIS THERAPY Monitoring and feedback are particularly important in patients receiving treatment for a disease such as osteoporosis, which remains asymptomatic for long periods. Regular reinforcement of therapeutic progress demonstrates to patients that their osteoporosis therapy is having a beneficial effect. In a study conducted by Silverman and colleagues,24 140 women were randomized to receive educational information and a voucher for immediate BMD testing or educational information plus a voucher for BMD testing in 1 year. Among women who received an immediate BMD test, 63.4% immediately filled their prescription. In contrast, only 20% of those who received a BMD test 1 year later

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filled their prescription. This study shows that physicians can engage patients in treatment by demonstrating the immediacy of the need to treat based on the diagnosis. Clowes and colleagues25 randomized 75 women with osteopenia who were receiving raloxifene to nurse monitoring, nurse monitoring plus baseline and follow-up bone turnover measurements (uNTX), or routine follow-up without the nurse or marker interventions. The primary end point was 1-year compliance with raloxifene as assessed by electronic monitors. Both nurse monitoring alone and nurse plus uNTX monitoring resulted in a significant 57% increase in compliance with therapy (P ⫽ 0.04), demonstrating that discussion with a healthcare professional to reinforce the need for long-term treatment may be of equal value for patient compliance as information about response to biochemical markers.

ROLE OF PHYSICIAN–PATIENT COMMUNICATION Obstetricians/gynecologists and other primary care providers are ideally placed to ensure that patients initiate and persist with therapy. In addition to supplying frequent feedback on treatment progress, the clinician should continually reinforce the need for therapy. The Medication Usage Skills for Effectiveness (MUSE) program was developed as a simple behavioral intervention for clinicians to enhance medication compliance.26 This short, simple intervention takes 5 minutes to introduce and requires approximately 2 minutes during follow-up visits. MUSE can be introduced by the healthcare provider saying to the patient, “I’d like to have you take your medication at a set time that is good for you. What would fit in with your lifestyle?” This type of interaction shows the patient that the healthcare provider is concerned about the patient’s well-being and involves the patient in treatment decisions.4 Reliable cues should be identified that remind patients to take their medications. Selection of appropriate cues is particularly important in patients receiving weekly or monthly therapy because the consequences of missing a dose can be greater. Agents that are taken intermittently may be linked to dependable actions—for example, weekly events— or to particular days of the week. Monthly agents may be taken on the first of the month, the patient’s birth date, or the day bills are paid. Dosing requirements are another important factor to consider when deciding when a patient should take the medication. Because the dosing requirements for bisphosphonates are complicated and may interfere with daily activities, administration on the weekend may be desirable in patients who take weekly or monthly formulations, particularly among those who work during the week.

DOSING REGIMEN Less-frequent dosing reduces disruption in patients’ lifestyles and may substantially enhance compliance and per-

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Figure 2 (A) Medication persistence: percentage of persistent patients on daily and weekly bisphosphonates as a function of time. (B) Mean medication possession ratios (⫾ confidence interval) for daily and weekly bisphosphonate cohorts. *P ⫽ 0.0001; †P ⫽ 0.002. (Reprinted with permission from Curr Med Res Opin.28)

sistence with therapy. Weekly bisphosphonate regimens are preferred to daily regimens. In a 9-week crossover study, 86% of 266 women with postmenopausal osteoporosis preferred weekly over daily alendronate.27 The majority of patients perceived the weekly regimen as more convenient than the daily regimen and thought it would allow them to be more compliant with treatment (89% vs. 88%).27 Persistence with weekly bisphosphonates is better than with daily regimens, although it remains suboptimal. Cramer and colleagues28 studied administrative claims data from 30 health plans to identify 2,741 postmenopausal osteoporotic women who were newly prescribed a once-weekly or once-daily bisphosphonate. During 12 months of follow-up, patients taking the daily regimen discontinued after an average of 185 days and patients taking weekly bisphosphonates discontinued after 227

days (P ⬍0.0001). After 12 months of therapy, only 44.2% of women taking a weekly bisphosphonate and 31.7% on daily therapy persisted with therapy (Figure 2A). Overall, women obtained ⬍66% of prescribed medication from their pharmacies; however, patients who received weekly formulations obtained significantly more medication compared with those who received once-daily formulations (69.2% vs. 57.6%; P ⬍0.0001) (Figure 2B).28 Also, patients new to bisphosphonates may have medication possession ratios (MPR)—i.e. days of supply divided by 365 days) that are less than adequate (MPR ⬍80%).28 Using a retail pharmacy database, Recker and colleagues29 found that only 25.2% of weekly and 13.2% of daily bisphosphonate users had adequate MPRs (P ⬍0.001). These data clearly indicate that less frequent bisphosphonate dosing regimens are associated

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with improved persistence compared with more frequent dosing.

SUMMARY Poor compliance and persistence are among the most important reasons for failed pharmacotherapy in clinical practice, particularly in disease states that may remain asymptomatic for long periods, such as osteoporosis. Thus, compliance may be a particular problem in patients with osteoporosis, because it is considered a “silent” disease. Poor compliance with osteoporosis medications has been shown to be associated with smaller decreases in the rate of bone turnover, smaller gains in BMD, and a significantly greater risk of fracture. Furthermore, failure to comply with osteoporosis medication increases direct and indirect medical costs and substantially compromises patient quality of life when fractures occur. In the clinic, compliance and persistence with osteoporosis therapies are poor for a variety of reasons, including complex dosing requirements, tolerability (particularly in patients who fail to follow dosing guidelines), and patient beliefs. No questionnaire or interview has been reliable in predicting poor compliance. Every patient should be considered a potential poor complier, liable to discontinue treatment even after a long period of regular dosing. It should therefore be assumed that every patient needs continuous reinforcement and feedback to persist with therapy. Several strategies are available to improve compliance and persistence with osteoporosis therapies. Studies suggest that less frequent dosing regimens improve compliance; however, even among patients receiving weekly bisphosphonates, persistence may remain suboptimal. Healthcare provider– patient communication and continuous reinforcement of the importance of treatment are key to improving persistence. Individualized reminder systems should be recommended to help the patient comply with therapy, and patients should be provided with feedback to demonstrate that their treatment is having an effect.

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7. Cramer JA. Practical issues in medication compliance. Transplant Proc. 1999;31(suppl 4A):7S-9S. 8. Bender B, Milgrom H, Rand C. Nonadherence in asthmatic patients: is there a solution to the problem? Ann Allergy Asthma Immunol. 1997; 79:177-185. 9. Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3:338-342. 10. Psaty BM, Koepsell TD, Wagner EH, LoGerfo JP, Inui TS. The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers. JAMA. 1990;263:1653-1657. 11. McCombs JS, Nichol MB, Newman CM, Sclar DA. The costs of interrupting antihypertensive drug therapy in a Medicaid population. Med Care. 1994;32:214-226. 12. Silverman SL, Azria M. The analgesic role of calcitonin following osteoporotic fracture. Osteoporos Int. 2002;13:858-867. 13. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 2004;15:1003-1008. 14. Bonnick SL, Johnston CC Jr, Kleerekoper M, et al. Importance of precision in bone density measurements. J Clin Densitom. 2001;4:105110. 15. Eastell R, Garnero P, Vrijens B, et al. Influence of patient compliance with risedronate therapy on bone turnover marker and bone mineral density response: the IMPACT study. Calcif Tissue Int 2003;72:408. Abstract p-297. 16. Yood RA, Emani S, Reed JI, Lewis BE, Charpentier M, Lydick E. Compliance with pharmacologic therapy for osteoporosis. Osteoporos Int. 2003;14:965-968. 17. Sebalt RJ, Shane LG, Pham BZ. Impact of non-compliance and nonpersistence with daily bisphosphonates on longer-term effectiveness outcomes in patients with osteoporosis treated in tertiary specialist care [abstract]. J Bone Miner Res 2004;19(suppl 1):S445. 18. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of treatment for osteoporosis. Am J Med. 2003;115:209-216. 19. Lombas C, Hakim C, Zanchetta JR. Compliance with alendronate treatment in an osteoporosis clinic. Presented at the American Society for Bone and Mineral Research (ASBMR) 23rd Annual Meeting; October 12-16, 2001; Phoenix, AZ. Abstract M406. 20. Fosamax (alendronate sodium) tablet and oral solution [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; 2004. 21. Boniva (ibandronate sodium) tablets [prescribing information]. Nutley, NJ: Roche Laboratories, Inc.; 2005. 22. Actonel (risedronate sodium tablets) [prescribing information]. Kansas City, MO: Aventis Pharmaceuticals, Inc.; 2004. 23. Hamilton B, McCoy K, Taggart H. Tolerability and compliance with risedronate in clinical practice. Osteoporos Int. 2003;1:259-262. 24. Silverman SL, Greenwald M, Klein RA, Drinkwater BL. Effect of bone density information on decisions about hormone replacement therapy: a randomized trial. Obstet Gynecol. 1997;89:321-325. 25. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117-1123. 26. Cramer JA, Rosenheck R. Enhancing medication compliance for people with serious mental illness. J Nerv Ment Dis. 1999;187:53-55. 27. Simon JA, Lewiecki EM, Smith ME, Petruschka RA, Wang L, Palmisano JJ. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: a multicenter, randomized, open-label, crossover study. Clin Ther. 2002;24:1871-1886. 28. Cramer JA, Amonkar MM, Hebborn A, Altman RD. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin. 2005;21:14531460. 29. Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women. Mayo Clin Proc. 2005;80:856-861.