- Email: [email protected]
Therapeutic adherence to bisphosphonates
Biomedicine & Pharmacotherapy 61 (2007) 191e193 www.elsevier.com/locate/biopha
Review
Therapeutic adherence to bisphosphonates Juraj Payer a, Zdenko Killinger a, Ivana Sˇulkova´ b, Peter Celec b,c,* a
5th Department of Internal Medicine, Faculty Hospital, Comenius University, Bratislava, Slovakia b Institute of Pathophysiology, Comenius University, Bratislava, Slovakia c Department of Molecular Biology, Comenius University, Bratislava, Slovakia Received 23 January 2007; accepted 6 February 2007 Available online 12 March 2007
Abstract Therapeutic adherence of patients is a key factor of treatment success in clinical praxis, although it is often neglected. Several studies have shown that insufficient persistence and compliance cause differences in the efficiency of treatments in clinical studies and clinical praxis. A recent meta-analysis even showed a clear inverse relationship between therapeutic adherence and mortality. Factors influencing the adherence to treatment include explanations by the physician, characteristics of the disease, patient’s attitudes, but also the therapeutic regime. Osteoporosis as a chronic disorder with relatively long asymptomatic initial course represents a major problem. In addition, the currently available therapeutic regimes are discomfortable and, thus, contribute to the low therapeutic adherence of the patient. One of the factors causing discomfort in bisphosphonates therapy is the frequency of application e once daily or once weekly. Several questionnaire-based studies have shown that patients clearly prefer the new alternative once monthly regime available for ibandronate. Although the efficiency of the drug is proven in large clinical trials, the effects of the once monthly regime itself on hard clinical end-points like mortality can only be analyzed in long-term follow-up studies. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Adherence; Osteoporosis; Bisphosphonates; Dosing regimen; Ibandronate
1. What is therapeutic adherence? Therapeutic adherence is a key factor influencing the effectiveness of treatment in chronic diseases. Nevertheless, adherence, its control and consequences are often overlooked in the clinical practice. Similarly, scientific interest into the topic of therapeutic adherence is minimal. Recently, this situation is beginning to change. According to the WHO adherence represents an analysis of the real behavior of a patient in the relationship to treatment in comparison to the recommendations of the health care provider. The term adherence to treatment covers two aspects e qualitative and quantitative (Table 1). Persistence is the quantitative component * Corresponding author. Institute of Pathophysiology, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia. Tel.: þ421 2 5935 7296; fax: þ421 2 5935 7601. E-mail address: [email protected] (P. Celec). URL: http://www.biomed.szm.com 0753-3322/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2007.02.003
of adherence e it is a measure of time, during that the patient takes the prescribed therapy, while it starts at the beginning of the treatment and ends at the completion or discontinuation of the treatment. Complementary to persistence the measure of correctness of treatment use is compliance e an often misinterpreted term. It covers the issue of correct timing, but also other conditions that must be followed during the treatment [1]. Although the terms adherence, compliance and persistence seem to be of academic nature, the methodology of their measurement and analysis is well-known and generally accepted; an excellent review article has been published in the New England Journal of Medicine recently [2]. The analysis of adherence to treatment can be realized using direct methods (direct monitoring of patients, measurement of applied drug levels or other biological markers in plasma of patients) or using easier, but less informative indirect methods (questionnaires, counting of unused pills, classic or electronic treatment diaries of patients, tracing the somatic response to the therapy). The latter indirect methods are, of course, used mostly.
J. Payer et al. / Biomedicine & Pharmacotherapy 61 (2007) 191e193
192 Table 1 Adherence and its components
However, their bias probability related to the subjectivity considerably decreases their accuracy. 2. What influences the therapeutic adherence? Adherence to treatment is mainly depending on the individual patient. But, the physician prescribing drugs can considerably affect the adherence of the patient to the therapy, both, positively and negatively. Some of the main influencing factors are shown in Table 2. Besides human factors an important role has the treatment itself. The appearance, shape and consistence of the medicine are interesting not only for marketing purposes, but also from the view of adherence. A well-known and important factor is that many patients simply forget to take the pill [3]. Mistakes in application of treatment are influenced by the therapeutic regime. In a systemic meta-analysis authors show that the theoretic frequency of drug application is inversely correlated with the measured therapeutic adherence, while monitored treatments had a frequency of drug application once daily or higher. In regimes with 4 pills during a day the adherence reached alarming levels of only 50% [4]. 3. How is the adherence to treatment in osteoporosis? Adherence to treatment is crucial especially in chronic diseases like ischemic heart disease, diabetes mellitus etc., where Table 2 Selected factors negatively influencing the therapeutic adherence to a drug therapy Physician
Disease
Therapy
Patient
No explanation of disease seriousness No explanation of adverse effects Misbehavior to the patient
Weak or none symptoms Chronicity
Application discomfort Ineffectiveness
Low level of education Disease neglect
Disabling disease
Cost of medication
Fear of adverse effects
the effects of the therapy can only be seen after a long-term application of drugs or are subjectively not perceived at all. The situation is even more complicated in chronic asymptomatic diseases like hypertension or osteoporosis. Studies have shown that the treatment with bisphosphonates is significantly affected by a weak adherence. After one year the probability of continuing of treatment decreases to one half and after two years even to one third or one fifth [5]. The therapy with oral bisphosphonates is highly demanding to the patient. The therapeutic regime must be followed strictly to reach the desired high level of efficiency but also the low level of adverse side effects. Currently available bisphosphonates are applied in the morning after an overnight fast, while the patient must stay fasting for further 30 min after application. In addition, the patient must stay standing or sitting. This application once daily or once weekly represents an important discomfort for the patients, which can lead to discontinuation of the treatment. Failure to adhere to the regime and conditions of application leads to an increased frequency of adverse effects in the gut and these might shortened the persistence of patients on treatment. These specifics cause the very low adherence of patients to treatment with bisphosphonates. The consequences of low adherence are serious. Analysis of the relationship between mortality in clinical studies and adherence to treatment regardless of indication and diagnosis has proved that good adherence is connected with lower mortality and vice versa [6]. Monitoring of markers of treatment efficiency in osteoporosis e bone density and bone turnover has shown that good compliance results in a 100% higher treatment efficiency in comparison to patients with worse compliance [7,8]. 4. How to increase the therapeutic adherence? Prof. Robiner from the Minnesota University divides the possibilities how to influence adherence to treatment into several groups [9]: physician e patient relationship (the basis of success is to explain all details related to the application, efficiency and adverse effects right at the time of prescription of the drug, to increase the interaction between the physician and the patients, more frequent treatment controls), social aspects (involvement of family members in the adherence control, to offer a positive feedback during the treatment), the therapeutic regime (integration of the drug administration into daily activities of the patient, decrease the number of taken pills, decrease the frequency of application), logistic support (reminding of application using several different communication media). One of the most challenging ways how to increase adherence is the regular monitoring of treatment. In clinical studies results have clearly shown that visits of nurses and medics in patients to control treatment adherence once in 3 months increase the cumulative adherence to treatment with bisphosphonates by 57% [10]. Another interesting result of this study was the finding, that additional measurement of biochemical markers of treatment success did not further increase the adherence. In general, results have proved the value of direct personal interaction between the patient and the health care personnel.
J. Payer et al. / Biomedicine & Pharmacotherapy 61 (2007) 191e193
In the therapeutic regime the most important factor is the frequency of drug application. A study using the German Mediplus database compared the adherence of patients to daily and weekly treatment with bisphosphonates. Adherence quantified using the parameter MPR (medication possession ratio) was in the weekly regime group 51.7% vs. 37.7% in the daily regime group [11]. This result shows the importance of dosing frequency of bisphosphonates and its influence on the adherence to the therapy of osteoporosis. On the other hand, it also shows that even the patients on once weekly regime had only a poor adherence to treatment with bisphosphonates (good adherence has a MPR of above 80%. Similar results were found in other studies in the USA [12,13]. 5. What are the preferences of the patients? Several questionnaire and interventional studies have been published concentrating on the preferences of patients in the relationship to the frequency of dosing of bisphosphonates. In a comparison between once daily and once weekly regime of alendronate application the patients clearly preferred (more than 80% of patients) dosing regime once weekly [14,15]. The issue of adherence to treatment with bisphosphonates was one of the main reasons for the development of a new bisphosphonate formulation (ibandronate) with a once monthly dosing regime. The vast majority of patients taking bisphosphonates once weekly would prefer the once monthly regime according to a questionnaire study [16]. The preferences of patients in relationship to the dosing of bisphosphonates were analyzed also on a group of women with postmenopausal osteoporosis (n ¼ 342) taking once weekly alendronate for three months and once monthly ibandronate for 3 months or vice versa. The resulting 71% preference for the monthly regime was a clear confirmation of previous studies [17]. Similar unpublished results were obtained in a recent questionnaire VIVA study in Slovakia. 6. Conclusion The therapeutic adherence represents a serious problem for evidence based medicine. If the decision-making process in clinical medicine is based on the results of clinical trials, it is based on results in nearly ideal conditions, where as part of the clinical research patients are often and thoroughly monitored, controlled, and, thus, the adherence to treatment is very high in these studies. It is much higher than in the real praxis, where especially in chronic asymptomatic diseases the persistence and compliance of patients reaches very poor levels. The safety and efficiency of oral once monthly bisphosphonates were proved in many clinical studies meeting highest criteria for evidence based medicine [18,19]. The complexity and difficulties related to the use of bisphosphonates are a major discomfort for the patients, which lead to a decreased efficiency and safety profile of the corresponding formulations. Once monthly dosing as a new alternative in the therapy of osteoporosis is requested by the patients and represents an important
193
step towards an improvement in the adherence to treatment. Long-term follow up studies in the future will show, whether these advances will result in a long-term benefit for the patients, their health status and quality of life. References [1] Reginster JY, Rabenda V, Neuprez A. Adherence, patient preference and dosing frequency: understanding the relationship. Bone 2006;38(4 Suppl. 1):S2e6. [2] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487e97. [3] Vlasnik JJ, Aliotta SL, DeLor B. Medication adherence: factors influencing compliance with prescribed medication plans. Case Manager 2005; 16(2):47e51. [4] Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23(8):1296e310. [5] Reginster JY. Adherence and persistence: impact on outcomes and health care resources. Bone 2006;38(2 Suppl. 2):S18e21. [6] Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 2006;333(7557):15. [7] Eastell R, Garnero P, Vrijens L, van de Langerijt L, Pols HAP, Ringe JD, 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. [8] Sebaldt RJ, Shane LG, Pham B, Cook R, Thabane L, Petrie A, et al. Longer-term effectiveness outcomes of non-compliance and nonpersistence with daily-regimen bisphosphonate therapy in patients with osteoporosis treated in tertiary specialist care. Osteoporos Int 2004;15(Suppl. 1):S107. [9] Robiner WN. Enhancing adherence in clinical research. Contemp Clin Trials 2005;26(1):59e77. [10] 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(3):1117e23. [11] Bartl R, Goette S, Hadji P, Hammerschmidt T. Persistence and compliance with daily and weekly-administered bisphosphonates for osteoporosis treatment in Germany. Osteoporos Int 2005;16(Suppl. 3):S45. [12] Cramer JA, Amonkar MM, Hebborn A, Suppapanya N. Does dosing regimen impact persistence with bisphosphonate therapy among postmenopausal osteoporotic women? J Bone Miner Res 2004;19(Suppl. 1):S448. [13] Ettinger MP, Gallagher R, Amonkar M, Mahoney PM, Gilbride J. Medication persistence is improved with less frequent dosing of bisphosphonates, but remains inadequate. Arthritis Rheum 2004;50:S513. [14] Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmissano JJ. Patient preference for once-weekly alendronate 70 mg versus oncedaily alendronate 10 mg; a multicenter, randomized, openlabel, crossover study. Clin Ther 2002;24:1871e86. [15] Kendler D, Kung AW, Fuleihan G-H, Gonzalez-Gonzalez JG, Gaines KA, Verbruggen M, et al. Patients with osteoporosis prefer once weekly to once daily dosing with alendronate. Maturitas 2004;48:243e51. [16] Simon J, Beusterien KM, Kline Leidy N, Hebborn A. Women with postmenopausal osteoporosis express a preference for once-monthly versus once-weekly bisphosphonate treatment. Female Patient 2005;30:31e6. [17] Emkey R, Koltun W, Beusterien K, Seidman L, Kivitz A, Devas V, et al. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin 2005; 21(12):1895e903. [18] Pyon EY. Once-monthly ibandronate for postmenopausal osteoporosis: review of a new dosing regimen. Clin Ther 2006;28(4):475e90. [19] Reid DM. Once-monthly dosing: an effective step forward. Bone 2006;38(4 Suppl. 1):S18e22.
Review
Therapeutic adherence to bisphosphonates Juraj Payer a, Zdenko Killinger a, Ivana Sˇulkova´ b, Peter Celec b,c,* a
5th Department of Internal Medicine, Faculty Hospital, Comenius University, Bratislava, Slovakia b Institute of Pathophysiology, Comenius University, Bratislava, Slovakia c Department of Molecular Biology, Comenius University, Bratislava, Slovakia Received 23 January 2007; accepted 6 February 2007 Available online 12 March 2007
Abstract Therapeutic adherence of patients is a key factor of treatment success in clinical praxis, although it is often neglected. Several studies have shown that insufficient persistence and compliance cause differences in the efficiency of treatments in clinical studies and clinical praxis. A recent meta-analysis even showed a clear inverse relationship between therapeutic adherence and mortality. Factors influencing the adherence to treatment include explanations by the physician, characteristics of the disease, patient’s attitudes, but also the therapeutic regime. Osteoporosis as a chronic disorder with relatively long asymptomatic initial course represents a major problem. In addition, the currently available therapeutic regimes are discomfortable and, thus, contribute to the low therapeutic adherence of the patient. One of the factors causing discomfort in bisphosphonates therapy is the frequency of application e once daily or once weekly. Several questionnaire-based studies have shown that patients clearly prefer the new alternative once monthly regime available for ibandronate. Although the efficiency of the drug is proven in large clinical trials, the effects of the once monthly regime itself on hard clinical end-points like mortality can only be analyzed in long-term follow-up studies. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Adherence; Osteoporosis; Bisphosphonates; Dosing regimen; Ibandronate
1. What is therapeutic adherence? Therapeutic adherence is a key factor influencing the effectiveness of treatment in chronic diseases. Nevertheless, adherence, its control and consequences are often overlooked in the clinical practice. Similarly, scientific interest into the topic of therapeutic adherence is minimal. Recently, this situation is beginning to change. According to the WHO adherence represents an analysis of the real behavior of a patient in the relationship to treatment in comparison to the recommendations of the health care provider. The term adherence to treatment covers two aspects e qualitative and quantitative (Table 1). Persistence is the quantitative component * Corresponding author. Institute of Pathophysiology, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia. Tel.: þ421 2 5935 7296; fax: þ421 2 5935 7601. E-mail address: [email protected] (P. Celec). URL: http://www.biomed.szm.com 0753-3322/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2007.02.003
of adherence e it is a measure of time, during that the patient takes the prescribed therapy, while it starts at the beginning of the treatment and ends at the completion or discontinuation of the treatment. Complementary to persistence the measure of correctness of treatment use is compliance e an often misinterpreted term. It covers the issue of correct timing, but also other conditions that must be followed during the treatment [1]. Although the terms adherence, compliance and persistence seem to be of academic nature, the methodology of their measurement and analysis is well-known and generally accepted; an excellent review article has been published in the New England Journal of Medicine recently [2]. The analysis of adherence to treatment can be realized using direct methods (direct monitoring of patients, measurement of applied drug levels or other biological markers in plasma of patients) or using easier, but less informative indirect methods (questionnaires, counting of unused pills, classic or electronic treatment diaries of patients, tracing the somatic response to the therapy). The latter indirect methods are, of course, used mostly.
J. Payer et al. / Biomedicine & Pharmacotherapy 61 (2007) 191e193
192 Table 1 Adherence and its components
However, their bias probability related to the subjectivity considerably decreases their accuracy. 2. What influences the therapeutic adherence? Adherence to treatment is mainly depending on the individual patient. But, the physician prescribing drugs can considerably affect the adherence of the patient to the therapy, both, positively and negatively. Some of the main influencing factors are shown in Table 2. Besides human factors an important role has the treatment itself. The appearance, shape and consistence of the medicine are interesting not only for marketing purposes, but also from the view of adherence. A well-known and important factor is that many patients simply forget to take the pill [3]. Mistakes in application of treatment are influenced by the therapeutic regime. In a systemic meta-analysis authors show that the theoretic frequency of drug application is inversely correlated with the measured therapeutic adherence, while monitored treatments had a frequency of drug application once daily or higher. In regimes with 4 pills during a day the adherence reached alarming levels of only 50% [4]. 3. How is the adherence to treatment in osteoporosis? Adherence to treatment is crucial especially in chronic diseases like ischemic heart disease, diabetes mellitus etc., where Table 2 Selected factors negatively influencing the therapeutic adherence to a drug therapy Physician
Disease
Therapy
Patient
No explanation of disease seriousness No explanation of adverse effects Misbehavior to the patient
Weak or none symptoms Chronicity
Application discomfort Ineffectiveness
Low level of education Disease neglect
Disabling disease
Cost of medication
Fear of adverse effects
the effects of the therapy can only be seen after a long-term application of drugs or are subjectively not perceived at all. The situation is even more complicated in chronic asymptomatic diseases like hypertension or osteoporosis. Studies have shown that the treatment with bisphosphonates is significantly affected by a weak adherence. After one year the probability of continuing of treatment decreases to one half and after two years even to one third or one fifth [5]. The therapy with oral bisphosphonates is highly demanding to the patient. The therapeutic regime must be followed strictly to reach the desired high level of efficiency but also the low level of adverse side effects. Currently available bisphosphonates are applied in the morning after an overnight fast, while the patient must stay fasting for further 30 min after application. In addition, the patient must stay standing or sitting. This application once daily or once weekly represents an important discomfort for the patients, which can lead to discontinuation of the treatment. Failure to adhere to the regime and conditions of application leads to an increased frequency of adverse effects in the gut and these might shortened the persistence of patients on treatment. These specifics cause the very low adherence of patients to treatment with bisphosphonates. The consequences of low adherence are serious. Analysis of the relationship between mortality in clinical studies and adherence to treatment regardless of indication and diagnosis has proved that good adherence is connected with lower mortality and vice versa [6]. Monitoring of markers of treatment efficiency in osteoporosis e bone density and bone turnover has shown that good compliance results in a 100% higher treatment efficiency in comparison to patients with worse compliance [7,8]. 4. How to increase the therapeutic adherence? Prof. Robiner from the Minnesota University divides the possibilities how to influence adherence to treatment into several groups [9]: physician e patient relationship (the basis of success is to explain all details related to the application, efficiency and adverse effects right at the time of prescription of the drug, to increase the interaction between the physician and the patients, more frequent treatment controls), social aspects (involvement of family members in the adherence control, to offer a positive feedback during the treatment), the therapeutic regime (integration of the drug administration into daily activities of the patient, decrease the number of taken pills, decrease the frequency of application), logistic support (reminding of application using several different communication media). One of the most challenging ways how to increase adherence is the regular monitoring of treatment. In clinical studies results have clearly shown that visits of nurses and medics in patients to control treatment adherence once in 3 months increase the cumulative adherence to treatment with bisphosphonates by 57% [10]. Another interesting result of this study was the finding, that additional measurement of biochemical markers of treatment success did not further increase the adherence. In general, results have proved the value of direct personal interaction between the patient and the health care personnel.
J. Payer et al. / Biomedicine & Pharmacotherapy 61 (2007) 191e193
In the therapeutic regime the most important factor is the frequency of drug application. A study using the German Mediplus database compared the adherence of patients to daily and weekly treatment with bisphosphonates. Adherence quantified using the parameter MPR (medication possession ratio) was in the weekly regime group 51.7% vs. 37.7% in the daily regime group [11]. This result shows the importance of dosing frequency of bisphosphonates and its influence on the adherence to the therapy of osteoporosis. On the other hand, it also shows that even the patients on once weekly regime had only a poor adherence to treatment with bisphosphonates (good adherence has a MPR of above 80%. Similar results were found in other studies in the USA [12,13]. 5. What are the preferences of the patients? Several questionnaire and interventional studies have been published concentrating on the preferences of patients in the relationship to the frequency of dosing of bisphosphonates. In a comparison between once daily and once weekly regime of alendronate application the patients clearly preferred (more than 80% of patients) dosing regime once weekly [14,15]. The issue of adherence to treatment with bisphosphonates was one of the main reasons for the development of a new bisphosphonate formulation (ibandronate) with a once monthly dosing regime. The vast majority of patients taking bisphosphonates once weekly would prefer the once monthly regime according to a questionnaire study [16]. The preferences of patients in relationship to the dosing of bisphosphonates were analyzed also on a group of women with postmenopausal osteoporosis (n ¼ 342) taking once weekly alendronate for three months and once monthly ibandronate for 3 months or vice versa. The resulting 71% preference for the monthly regime was a clear confirmation of previous studies [17]. Similar unpublished results were obtained in a recent questionnaire VIVA study in Slovakia. 6. Conclusion The therapeutic adherence represents a serious problem for evidence based medicine. If the decision-making process in clinical medicine is based on the results of clinical trials, it is based on results in nearly ideal conditions, where as part of the clinical research patients are often and thoroughly monitored, controlled, and, thus, the adherence to treatment is very high in these studies. It is much higher than in the real praxis, where especially in chronic asymptomatic diseases the persistence and compliance of patients reaches very poor levels. The safety and efficiency of oral once monthly bisphosphonates were proved in many clinical studies meeting highest criteria for evidence based medicine [18,19]. The complexity and difficulties related to the use of bisphosphonates are a major discomfort for the patients, which lead to a decreased efficiency and safety profile of the corresponding formulations. Once monthly dosing as a new alternative in the therapy of osteoporosis is requested by the patients and represents an important
193
step towards an improvement in the adherence to treatment. Long-term follow up studies in the future will show, whether these advances will result in a long-term benefit for the patients, their health status and quality of life. References [1] Reginster JY, Rabenda V, Neuprez A. Adherence, patient preference and dosing frequency: understanding the relationship. Bone 2006;38(4 Suppl. 1):S2e6. [2] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487e97. [3] Vlasnik JJ, Aliotta SL, DeLor B. Medication adherence: factors influencing compliance with prescribed medication plans. Case Manager 2005; 16(2):47e51. [4] Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23(8):1296e310. [5] Reginster JY. Adherence and persistence: impact on outcomes and health care resources. Bone 2006;38(2 Suppl. 2):S18e21. [6] Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 2006;333(7557):15. [7] Eastell R, Garnero P, Vrijens L, van de Langerijt L, Pols HAP, Ringe JD, 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. [8] Sebaldt RJ, Shane LG, Pham B, Cook R, Thabane L, Petrie A, et al. Longer-term effectiveness outcomes of non-compliance and nonpersistence with daily-regimen bisphosphonate therapy in patients with osteoporosis treated in tertiary specialist care. Osteoporos Int 2004;15(Suppl. 1):S107. [9] Robiner WN. Enhancing adherence in clinical research. Contemp Clin Trials 2005;26(1):59e77. [10] 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(3):1117e23. [11] Bartl R, Goette S, Hadji P, Hammerschmidt T. Persistence and compliance with daily and weekly-administered bisphosphonates for osteoporosis treatment in Germany. Osteoporos Int 2005;16(Suppl. 3):S45. [12] Cramer JA, Amonkar MM, Hebborn A, Suppapanya N. Does dosing regimen impact persistence with bisphosphonate therapy among postmenopausal osteoporotic women? J Bone Miner Res 2004;19(Suppl. 1):S448. [13] Ettinger MP, Gallagher R, Amonkar M, Mahoney PM, Gilbride J. Medication persistence is improved with less frequent dosing of bisphosphonates, but remains inadequate. Arthritis Rheum 2004;50:S513. [14] Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmissano JJ. Patient preference for once-weekly alendronate 70 mg versus oncedaily alendronate 10 mg; a multicenter, randomized, openlabel, crossover study. Clin Ther 2002;24:1871e86. [15] Kendler D, Kung AW, Fuleihan G-H, Gonzalez-Gonzalez JG, Gaines KA, Verbruggen M, et al. Patients with osteoporosis prefer once weekly to once daily dosing with alendronate. Maturitas 2004;48:243e51. [16] Simon J, Beusterien KM, Kline Leidy N, Hebborn A. Women with postmenopausal osteoporosis express a preference for once-monthly versus once-weekly bisphosphonate treatment. Female Patient 2005;30:31e6. [17] Emkey R, Koltun W, Beusterien K, Seidman L, Kivitz A, Devas V, et al. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin 2005; 21(12):1895e903. [18] Pyon EY. Once-monthly ibandronate for postmenopausal osteoporosis: review of a new dosing regimen. Clin Ther 2006;28(4):475e90. [19] Reid DM. Once-monthly dosing: an effective step forward. Bone 2006;38(4 Suppl. 1):S18e22.