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Adherence, patient preference and dosing frequency: Understanding the relationship
Bone 38 (2006) S2 – S6 www.elsevier.com/locate/bone
Adherence, patient preference and dosing frequency: Understanding the relationship J.Y. Reginster ⁎, V. Rabenda, A. Neuprez WHO Collaborating Center for Public Health Aspects of Rheumatic Diseases, University of Liège, Liège, Belgium Received 25 October 2005; revised 2 November 2005; accepted 26 January 2006 Available online 7 March 2006
Abstract Adherence to treatment among patients with chronic diseases is currently suboptimal. Poor adherence leads to reduced clinical benefit, a raised incidence of secondary complications and therefore increased healthcare costs. For patients with osteoporosis, long-term adherence to therapy is further complicated by the asymptomatic nature of the disease and the lack of options for patient self-monitoring. Bone densitometry and biochemical markers of bone turnover are assessments that could be used by physicians to provide feedback to patients on the effectiveness of medication. However, these feedback systems are costly and not readily available. Oral bisphosphonates are currently the first-line therapy for postmenopausal osteoporosis. However, they are associated with stringent dosing procedures, and some patients may experience upper gastrointestinal side-effects following administration. Alarmingly, approximately 50% of patients discontinue daily bisphosphonate therapy within 1 year, which negatively impacts upon treatment outcomes, leading to a reduced antifracture effect. Thus, there is a need for an effective therapy that enhances patient adherence. The impact of reducing bisphosphonate dosing frequency on therapeutic adherence has been documented in several studies. Data have shown that, although weekly dosing improves adherence compared with daily administration, levels are still suboptimal. Results from two recent studies that have assessed patient preference for a once-monthly compared with a weekly dosing schedule have demonstrated that patients prefer a monthly regimen (67–71%). Their reasons for preferring once-monthly dosing were that it would fit better with their lifestyle (49–77%) and would be more convenient (75%). A novel once-monthly bisphosphonate regimen, such as the ibandronate regimen, may therefore help patients to follow dosing guidelines and encourage them to stay on therapy longer, thereby improving overall therapy effectiveness. © 2006 Elsevier Inc. All rights reserved. Keywords: Bisphosphonate; Ibandronate; Once-monthly; Osteoporosis; Postmenopausal; Adherence
Introduction Poor therapeutic adherence among patients suffering from chronic asymptomatic disease is a major issue facing physicians today [1]. Up to 50% of patients with chronic disease, such as hypertension, depression and asthma discontinue medication, with the rate rising in different therapeutic areas (up to 70% of patients prescribed preventive asthma medication stop treatment) and different countries (51% of patients in the USA continue with antihypertensives compared with 26% in the ⁎ Corresponding author. Unité d'Exploration du Metabolisme de l'Os et du Cartilage, CHU Centre Ville, Liège, Belgium. Fax: +32 4 270 32 53. E-mail address: [email protected] (J.Y. Reginster). 8756-3282/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2006.01.150
Seychelles). Poor adherence is considered to be ‘the primary reason for suboptimal clinical benefit’ of therapy [1]. Since the primary objective of treatment is not met, patients may experience complications. Furthermore, patients may experience reduced quality of life, which, in turn, leads to greater healthcare costs. Therefore, addressing poor adherence could potentially benefit both patients and society [1]. Therapeutic adherence In general terms, adherence is ‘the extent to which a person's behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health care provider’ [1]. Therapeutic adherence is
J.Y. Reginster et al. / Bone 38 (2006) S2–S6
a summary term determined by persistence and compliance of medication intake. Persistence describes the length of time a patient continues taking medication and is measured as the time from treatment initiation to treatment completion or discontinuation. Compliance describes how well a patient is taking his or her medication, that is, to what extent a patient follows a treatment regimen and any associated dosing requirements. Compliance is quantified using a surrogate measure: the medication possession ratio (MPR), which is the number of days of available medication (prescribed to and collected by the patient), divided by the number of days of study follow-up. The number of pills remaining at the end of a follow-up period is then counted to ascertain how many doses have been missed. Patients achieving an MPR of ≥80% are generally considered to be compliant to a clinically relevant level, as this has previously been associated with a reduction in the rate of fractures [2]. Adherence with therapy for the treatment of osteoporosis Osteoporosis is a chronic, asymptomatic condition characterized by low bone mass and an increased fragility for fracture [3]. Patients often experience few clinical symptoms prior to fracture and do not perceive the need for treatment [4]. Data from a study evaluating adherence to bisphosphonate therapy show that the probability of continuing daily oral treatment is approximately 50% at 1 year [5]. Even when diagnosed, patients may not perceive any direct benefit from taking medication as they are unable to self-monitor their condition. Furthermore, since measures of bone mineral density (BMD) or biochemical markers of bone turnover are not readily available, it is also difficult for physicians to provide feedback on the effectiveness of medication for individual patients. Oral bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. The need to comply with strict dosing requirements hinders patients' ability to adhere to bisphosphonate therapy [6,7]. Due to low bioavailability and the potential for gastrointestinal (GI) irritation, currently available daily or weekly nitrogen-containing bisphosphonates must be taken following an overnight fast with a glass of water, at least 30 min before ingesting either food, drink or medication. Patients are also required to remain sitting or standing upright for 30 min post-dose. To follow such a routine on a daily or weekly basis is inconvenient. However, to not comply with these instructions may lead to GI discomfort, another primary reason cited for patients discontinuing bisphosphonate therapy [4,5,8]. Although in clinical trials oral bisphosphonates have generally demonstrated a safety profile similar to placebo [9–16], in clinical practice, patients may experience upper GI adverse events, particularly following dosing [6,17–19]. Over a 4- to 12month period, of 366 patients commencing alendronate therapy, 19% discontinued treatment, with almost 15% stating sideeffects or safety concerns as a factor in their withdrawal [4]. Almost three quarters (73%) of the patients stopping alendronate therapy had experienced a side-effect, with a little less than half (46%) experiencing heartburn, nausea and stomach ache.
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Impact of poor adherence with bisphosphonates on treatment outcomes Suboptimal therapeutic adherence with oral bisphosphonates negatively impacts upon treatment outcomes. Compliance with risedronate and its influence on biochemical markers of bone turnover was assessed in a sub-analysis of patients from the IMPACT database (n = 2302) [20]. After 22 weeks of treatment, approximately 60% of compliant patients had a >50% decrease from baseline in serum C-telopeptide of the α-chain of type I collagen, compared with 20% of non-compliant patients. A second study reviewed a subset of patients (n = 1041) that had consistently attended follow-up visits over a 3-year period [21]. This study demonstrated that, although the majority of patients were compliant (88%), a significant difference existed between compliant and non-compliant patients with regard to BMD gains. The increase in BMD at 3 years for consistent users was 6.5% (95% CI: 3.7%, 9.3%), compared with 3.2% (95% CI: 0.03%, 6.3%) for inconsistent users (P = 0.002). The direct effect of therapeutic adherence on fracture risk has been evaluated in a study of almost 38,000 women with postmenopausal osteoporosis using data from the Medstat MarketScan® Research Database. Compliant patients (48%), with an MPR of ≥80%, had a statistically significantly better reduction in fracture risk compared with non-compliant patients over the 24-month study period (relative risk reduction: 0.74, P < 0.0001) [22]. The same pattern was demonstrated with persistent patients (patients who had no gap in refills >30 days) versus non-persistent patients (relative risk reduction: 0.79, P = 0.0069). With the majority of patients failing to achieve optimal fracture protection, improvement in bisphosphonate adherence has the potential to prevent many thousands of fractures each year. Can reducing dosing frequency improve therapeutic adherence? Since it is important for patients receiving bisphosphonates to remain on treatment in order to obtain maximum clinical benefit, any factors that could increase adherence are worthy of investigation. A report from the Surgeon General raises the question as to whether the currently available doses and schedules of osteoporosis medication are the most effective for encouraging adherence and therefore reducing fractures in the ‘real-world’ setting [23]. The report also asks whether increasing the between-dose interval could help the adherence issue. A study has been conducted using the German IMS Mediplus database comparing therapeutic adherence in osteoporotic women that were bisphosphonate naïve [24]. Over a 2year period, approximately 288 women were identified as receiving a new prescription for daily (10 mg) or weekly (70 mg) alendronate and were therefore included in the study. During the 12 months of observation, compliance with medication, measured using the MPR, was significantly greater in the group receiving weekly medication than the group receiving daily medication (51.7% vs. 37.7%, respectively,
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P < 0.05) [24]. This is, however, still some way below the optimum MPR level of 80%. The level of persistence was also significantly improved in the weekly dosing group, with a greater proportion of patients persisting with therapy at the 12month point (46.5% vs. 27.8%, respectively, P < 0.05). The mean time to discontinuation was 227 days with weekly alendronate and 172 days with daily alendronate. Fewer patients discontinued weekly treatment after the first prescription compared with daily users (31.3% vs. 45.8%, respectively, P < 0.05). This study confirms that, although therapeutic adherence is improved with weekly compared with daily dosing, the weekly regimen still results in suboptimal levels of patient compliance and persistence, and bisphosphonate dosing requires further consideration. The findings from the IMS Mediplus study [24] correspond with those obtained in other studies of therapeutic adherence with oral bisphosphonates [25,26]. The NDCHealth study analyzed prescription data obtained from ∼25% of US retail pharmacies and included a large group of patients receiving bisphosphonates (daily treatment n = 33,767, weekly treatment n = 177,552) [25]. The IHCIS study included 2741 bisphosphonate naïve women from the USA using administrative claims data [26]. The level of compliance (MPR) was comparable across these studies and showed increased compliance with the weekly rather than the daily regimens (Fig. 1). Similarly, the number of patients persisting with therapy after 1 year was greater with the weekly regimens compared with the daily regimens (Fig. 2). Therefore, while the overall therapeutic adherence still remains suboptimal, these studies support the observation that reducing dosing frequency can improve adherence. Influence of patient preference on therapeutic adherence Patient's preferences for daily or weekly bisphosphonate therapy have been evaluated in a prospective, open-label studies [27,28]. Four hundred and six postmenopausal women with osteoporosis were randomized to receive daily and weekly alendronate for 4 weeks per regimen using a crossover design. A total of 396 participants received both regimens and completed a preference questionnaire. Of the 364 (92%) women who expressed a preference, a significant number of
Fig. 1. The proportion of patients achieving a clinically relevant MPR (≥80%) at 1 year across three adherence studies [24–26].
Fig. 2. The proportion of persistent patients at 1 year across three adherence studies [24–26].
patients (over 80%) expressed a preference for the weekly regimen, stating that it was more convenient than the daily regimen (P < 0.001) and that they would be more willing to continue with a weekly regimen over a longer time period than a daily regimen (P < 0.001). Subsequently, a preference survey has been completed of 393 women who were taking weekly bisphosphonate therapy. The participants were asked for their preference for a weekly or new, once-monthly bisphosphonate regimen [29]. A total of 367 (93%) women expressed a preference, with the majority preferring the once-monthly schedule (67% vs. 33%). The main reasons for preferring the once-monthly regimen (patients could choose more than one reason) were taking the medication less frequently (73%) and fitting better with lifestyle (49%). Significantly, 78% of patients considered less frequent dosing to be ‘very’ or ‘extremely’ important. For those patients who would prefer their weekly regimen, the primary reason given was ‘comfortable with current routine’ (64%). Additional clinical data regarding patient preference for a monthly compared with weekly bisphosphonate regimen have been obtained in an open-label study conducted in the USA among women with postmenopausal osteoporosis who were either bisphosphonate naïve or had discontinued daily bisphosphonate therapy at least 3 months previously [30]. Utilizing a crossover design, patients (n = 342) received either oncemonthly ibandronate (150 mg for 3 months) or weekly alendronate (70 mg for 12 weeks) before receiving the alternative treatment. Both study medications were taken in the morning after an overnight fast (≥6 h), and patients were required to remain upright (sitting or standing) and refrain from eating for 1 h following ibandronate administration and 30 min after alendronate administration. The primary endpoint of the study was patient preference as assessed by completion of the Preference Questionnaire at the end of the study or on withdrawal. The Preference Questionnaire was adapted from that used in a previous study [28] and was validated by MEDTAP International Inc. Of the 298 patients eligible for analysis, almost all (276; 92.6%) expressed a preference for one of the regimens [30]. Of the patients expressing a preference, a significant majority (71%) preferred once-monthly ibandronate rather than weekly alendronate (29%, P < 0.0001) (Fig. 3). Patient preference was
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Fig. 3. The proportion of patients expressing a preference for once-monthly ibandronate or weekly alendronate [30].
Fig. 4. The proportion of patients finding once-monthly ibandronate or weekly alendronate more convenient [30].
not affected by the sequence of medication administration (Gart-order effect, P = 0.1855). Similar proportions of patients with a preference stated their chosen regimen would be ‘easier to follow for a long time’, ‘fit better with their lifestyle’ and was associated with ‘less stomach discomfort’ (Table 1). Nine percent more patients stated that the side-effects were easier to tolerate with the once-monthly ibandronate regimen vs. the weekly alendronate regimen. Patients were also requested to indicate which regimen they found most convenient; 32 patients thought that the oncemonthly and weekly regimens were equally convenient. However, of the patients expressing an opinion, a significantly greater proportion found the once-monthly ibandronate regimen (75%) to be more convenient than the weekly alendronate regimen (25%; P < 0.0001) (Fig. 4). As with preference, the choice for convenience was not affected by the order of treatments (Gart-order effect P = 0.1570). The safety profiles of both study medications were generally comparable. Data from this study [30] therefore confirm the findings from the previously conducted survey [29]. In offering greater convenience and good tolerability, more women with postmenopausal osteoporosis prefer once-monthly oral ibandronate compared with weekly alendronate therapy. Ibandronate has been approved in the USA and Europe for the treatment and prevention of postmenopausal osteoporosis. It is anticipated that, as patients begin to be prescribed once-monthly iban-
dronate, this strong patient preference will be reflected in improved ‘real-world’ therapeutic adherence.
Table 1 Reasons given by the patients for treatment choice (patients could provide more than one reason) [30]
Easier to follow for a long time Dosing schedule fits lifestyle better Easier to tolerate side-effects Less stomach discomfort
Once-monthly ibandronate n (%)
Weekly alendronate n (%)
169 (85.8%) 152 (77.2%) 47 (23.9%) 46 (23.4%)
70 (88.6%) 59 (74.7%) 12 (15.2%) 16 (20.3%)
Discussion Poor adherence is a common cause of reduced patient benefit from therapies used in the ‘real-world’ setting compared with the benefits demonstrated in clinical trials. Inadequate therapeutic adherence to oral bisphosphonates in the treatment of osteoporosis compromises therapeutic outcomes, resulting in lower BMD gains, reduced effects on bone turnover and subsequently a lower antifracture effect. It has been shown that improving compliance and persistence enhances patient outcomes. Therefore, strategies need to be devised to provide therapies that patients can adhere to and obtain the most clinical benefit from. Dosing frequency and therapy preference are important factors in patients' adherence behavior. Numerous studies have demonstrated that reducing bisphosphonate dosing frequency from daily to weekly results in improved adherence rates. Unfortunately, however, the level of adherence remains low, with many patients falling short of the clinically relevant MPR of ≥80% and the majority failing to persist with treatment for longer than 1 year. The studies conducted by Simon and colleagues [29] and Emkey and colleagues [30] indicate that a strong patient preference exists for once-monthly over weekly dosing (67% vs. 33% and 71% vs. 29%, respectively). The majority of patients from both studies stated that they would prefer the once-monthly dosing regimen as it would fit better with their lifestyle. Patients also considered the once-monthly regimen to be more convenient. Further preference data will be available from studies in European patients in the near future. By offering greater convenience and a simple dosing regimen that complements patients' lifestyles, a once-monthly bisphosphonate regimen should help patients to follow the dosing guidelines and stay on therapy for a longer period of
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time. Improved therapeutic adherence should subsequently be reflected in enhanced therapy outcomes.
[17]
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Adherence, patient preference and dosing frequency: Understanding the relationship J.Y. Reginster ⁎, V. Rabenda, A. Neuprez WHO Collaborating Center for Public Health Aspects of Rheumatic Diseases, University of Liège, Liège, Belgium Received 25 October 2005; revised 2 November 2005; accepted 26 January 2006 Available online 7 March 2006
Abstract Adherence to treatment among patients with chronic diseases is currently suboptimal. Poor adherence leads to reduced clinical benefit, a raised incidence of secondary complications and therefore increased healthcare costs. For patients with osteoporosis, long-term adherence to therapy is further complicated by the asymptomatic nature of the disease and the lack of options for patient self-monitoring. Bone densitometry and biochemical markers of bone turnover are assessments that could be used by physicians to provide feedback to patients on the effectiveness of medication. However, these feedback systems are costly and not readily available. Oral bisphosphonates are currently the first-line therapy for postmenopausal osteoporosis. However, they are associated with stringent dosing procedures, and some patients may experience upper gastrointestinal side-effects following administration. Alarmingly, approximately 50% of patients discontinue daily bisphosphonate therapy within 1 year, which negatively impacts upon treatment outcomes, leading to a reduced antifracture effect. Thus, there is a need for an effective therapy that enhances patient adherence. The impact of reducing bisphosphonate dosing frequency on therapeutic adherence has been documented in several studies. Data have shown that, although weekly dosing improves adherence compared with daily administration, levels are still suboptimal. Results from two recent studies that have assessed patient preference for a once-monthly compared with a weekly dosing schedule have demonstrated that patients prefer a monthly regimen (67–71%). Their reasons for preferring once-monthly dosing were that it would fit better with their lifestyle (49–77%) and would be more convenient (75%). A novel once-monthly bisphosphonate regimen, such as the ibandronate regimen, may therefore help patients to follow dosing guidelines and encourage them to stay on therapy longer, thereby improving overall therapy effectiveness. © 2006 Elsevier Inc. All rights reserved. Keywords: Bisphosphonate; Ibandronate; Once-monthly; Osteoporosis; Postmenopausal; Adherence
Introduction Poor therapeutic adherence among patients suffering from chronic asymptomatic disease is a major issue facing physicians today [1]. Up to 50% of patients with chronic disease, such as hypertension, depression and asthma discontinue medication, with the rate rising in different therapeutic areas (up to 70% of patients prescribed preventive asthma medication stop treatment) and different countries (51% of patients in the USA continue with antihypertensives compared with 26% in the ⁎ Corresponding author. Unité d'Exploration du Metabolisme de l'Os et du Cartilage, CHU Centre Ville, Liège, Belgium. Fax: +32 4 270 32 53. E-mail address: [email protected] (J.Y. Reginster). 8756-3282/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2006.01.150
Seychelles). Poor adherence is considered to be ‘the primary reason for suboptimal clinical benefit’ of therapy [1]. Since the primary objective of treatment is not met, patients may experience complications. Furthermore, patients may experience reduced quality of life, which, in turn, leads to greater healthcare costs. Therefore, addressing poor adherence could potentially benefit both patients and society [1]. Therapeutic adherence In general terms, adherence is ‘the extent to which a person's behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health care provider’ [1]. Therapeutic adherence is
J.Y. Reginster et al. / Bone 38 (2006) S2–S6
a summary term determined by persistence and compliance of medication intake. Persistence describes the length of time a patient continues taking medication and is measured as the time from treatment initiation to treatment completion or discontinuation. Compliance describes how well a patient is taking his or her medication, that is, to what extent a patient follows a treatment regimen and any associated dosing requirements. Compliance is quantified using a surrogate measure: the medication possession ratio (MPR), which is the number of days of available medication (prescribed to and collected by the patient), divided by the number of days of study follow-up. The number of pills remaining at the end of a follow-up period is then counted to ascertain how many doses have been missed. Patients achieving an MPR of ≥80% are generally considered to be compliant to a clinically relevant level, as this has previously been associated with a reduction in the rate of fractures [2]. Adherence with therapy for the treatment of osteoporosis Osteoporosis is a chronic, asymptomatic condition characterized by low bone mass and an increased fragility for fracture [3]. Patients often experience few clinical symptoms prior to fracture and do not perceive the need for treatment [4]. Data from a study evaluating adherence to bisphosphonate therapy show that the probability of continuing daily oral treatment is approximately 50% at 1 year [5]. Even when diagnosed, patients may not perceive any direct benefit from taking medication as they are unable to self-monitor their condition. Furthermore, since measures of bone mineral density (BMD) or biochemical markers of bone turnover are not readily available, it is also difficult for physicians to provide feedback on the effectiveness of medication for individual patients. Oral bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. The need to comply with strict dosing requirements hinders patients' ability to adhere to bisphosphonate therapy [6,7]. Due to low bioavailability and the potential for gastrointestinal (GI) irritation, currently available daily or weekly nitrogen-containing bisphosphonates must be taken following an overnight fast with a glass of water, at least 30 min before ingesting either food, drink or medication. Patients are also required to remain sitting or standing upright for 30 min post-dose. To follow such a routine on a daily or weekly basis is inconvenient. However, to not comply with these instructions may lead to GI discomfort, another primary reason cited for patients discontinuing bisphosphonate therapy [4,5,8]. Although in clinical trials oral bisphosphonates have generally demonstrated a safety profile similar to placebo [9–16], in clinical practice, patients may experience upper GI adverse events, particularly following dosing [6,17–19]. Over a 4- to 12month period, of 366 patients commencing alendronate therapy, 19% discontinued treatment, with almost 15% stating sideeffects or safety concerns as a factor in their withdrawal [4]. Almost three quarters (73%) of the patients stopping alendronate therapy had experienced a side-effect, with a little less than half (46%) experiencing heartburn, nausea and stomach ache.
S3
Impact of poor adherence with bisphosphonates on treatment outcomes Suboptimal therapeutic adherence with oral bisphosphonates negatively impacts upon treatment outcomes. Compliance with risedronate and its influence on biochemical markers of bone turnover was assessed in a sub-analysis of patients from the IMPACT database (n = 2302) [20]. After 22 weeks of treatment, approximately 60% of compliant patients had a >50% decrease from baseline in serum C-telopeptide of the α-chain of type I collagen, compared with 20% of non-compliant patients. A second study reviewed a subset of patients (n = 1041) that had consistently attended follow-up visits over a 3-year period [21]. This study demonstrated that, although the majority of patients were compliant (88%), a significant difference existed between compliant and non-compliant patients with regard to BMD gains. The increase in BMD at 3 years for consistent users was 6.5% (95% CI: 3.7%, 9.3%), compared with 3.2% (95% CI: 0.03%, 6.3%) for inconsistent users (P = 0.002). The direct effect of therapeutic adherence on fracture risk has been evaluated in a study of almost 38,000 women with postmenopausal osteoporosis using data from the Medstat MarketScan® Research Database. Compliant patients (48%), with an MPR of ≥80%, had a statistically significantly better reduction in fracture risk compared with non-compliant patients over the 24-month study period (relative risk reduction: 0.74, P < 0.0001) [22]. The same pattern was demonstrated with persistent patients (patients who had no gap in refills >30 days) versus non-persistent patients (relative risk reduction: 0.79, P = 0.0069). With the majority of patients failing to achieve optimal fracture protection, improvement in bisphosphonate adherence has the potential to prevent many thousands of fractures each year. Can reducing dosing frequency improve therapeutic adherence? Since it is important for patients receiving bisphosphonates to remain on treatment in order to obtain maximum clinical benefit, any factors that could increase adherence are worthy of investigation. A report from the Surgeon General raises the question as to whether the currently available doses and schedules of osteoporosis medication are the most effective for encouraging adherence and therefore reducing fractures in the ‘real-world’ setting [23]. The report also asks whether increasing the between-dose interval could help the adherence issue. A study has been conducted using the German IMS Mediplus database comparing therapeutic adherence in osteoporotic women that were bisphosphonate naïve [24]. Over a 2year period, approximately 288 women were identified as receiving a new prescription for daily (10 mg) or weekly (70 mg) alendronate and were therefore included in the study. During the 12 months of observation, compliance with medication, measured using the MPR, was significantly greater in the group receiving weekly medication than the group receiving daily medication (51.7% vs. 37.7%, respectively,
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P < 0.05) [24]. This is, however, still some way below the optimum MPR level of 80%. The level of persistence was also significantly improved in the weekly dosing group, with a greater proportion of patients persisting with therapy at the 12month point (46.5% vs. 27.8%, respectively, P < 0.05). The mean time to discontinuation was 227 days with weekly alendronate and 172 days with daily alendronate. Fewer patients discontinued weekly treatment after the first prescription compared with daily users (31.3% vs. 45.8%, respectively, P < 0.05). This study confirms that, although therapeutic adherence is improved with weekly compared with daily dosing, the weekly regimen still results in suboptimal levels of patient compliance and persistence, and bisphosphonate dosing requires further consideration. The findings from the IMS Mediplus study [24] correspond with those obtained in other studies of therapeutic adherence with oral bisphosphonates [25,26]. The NDCHealth study analyzed prescription data obtained from ∼25% of US retail pharmacies and included a large group of patients receiving bisphosphonates (daily treatment n = 33,767, weekly treatment n = 177,552) [25]. The IHCIS study included 2741 bisphosphonate naïve women from the USA using administrative claims data [26]. The level of compliance (MPR) was comparable across these studies and showed increased compliance with the weekly rather than the daily regimens (Fig. 1). Similarly, the number of patients persisting with therapy after 1 year was greater with the weekly regimens compared with the daily regimens (Fig. 2). Therefore, while the overall therapeutic adherence still remains suboptimal, these studies support the observation that reducing dosing frequency can improve adherence. Influence of patient preference on therapeutic adherence Patient's preferences for daily or weekly bisphosphonate therapy have been evaluated in a prospective, open-label studies [27,28]. Four hundred and six postmenopausal women with osteoporosis were randomized to receive daily and weekly alendronate for 4 weeks per regimen using a crossover design. A total of 396 participants received both regimens and completed a preference questionnaire. Of the 364 (92%) women who expressed a preference, a significant number of
Fig. 1. The proportion of patients achieving a clinically relevant MPR (≥80%) at 1 year across three adherence studies [24–26].
Fig. 2. The proportion of persistent patients at 1 year across three adherence studies [24–26].
patients (over 80%) expressed a preference for the weekly regimen, stating that it was more convenient than the daily regimen (P < 0.001) and that they would be more willing to continue with a weekly regimen over a longer time period than a daily regimen (P < 0.001). Subsequently, a preference survey has been completed of 393 women who were taking weekly bisphosphonate therapy. The participants were asked for their preference for a weekly or new, once-monthly bisphosphonate regimen [29]. A total of 367 (93%) women expressed a preference, with the majority preferring the once-monthly schedule (67% vs. 33%). The main reasons for preferring the once-monthly regimen (patients could choose more than one reason) were taking the medication less frequently (73%) and fitting better with lifestyle (49%). Significantly, 78% of patients considered less frequent dosing to be ‘very’ or ‘extremely’ important. For those patients who would prefer their weekly regimen, the primary reason given was ‘comfortable with current routine’ (64%). Additional clinical data regarding patient preference for a monthly compared with weekly bisphosphonate regimen have been obtained in an open-label study conducted in the USA among women with postmenopausal osteoporosis who were either bisphosphonate naïve or had discontinued daily bisphosphonate therapy at least 3 months previously [30]. Utilizing a crossover design, patients (n = 342) received either oncemonthly ibandronate (150 mg for 3 months) or weekly alendronate (70 mg for 12 weeks) before receiving the alternative treatment. Both study medications were taken in the morning after an overnight fast (≥6 h), and patients were required to remain upright (sitting or standing) and refrain from eating for 1 h following ibandronate administration and 30 min after alendronate administration. The primary endpoint of the study was patient preference as assessed by completion of the Preference Questionnaire at the end of the study or on withdrawal. The Preference Questionnaire was adapted from that used in a previous study [28] and was validated by MEDTAP International Inc. Of the 298 patients eligible for analysis, almost all (276; 92.6%) expressed a preference for one of the regimens [30]. Of the patients expressing a preference, a significant majority (71%) preferred once-monthly ibandronate rather than weekly alendronate (29%, P < 0.0001) (Fig. 3). Patient preference was
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Fig. 3. The proportion of patients expressing a preference for once-monthly ibandronate or weekly alendronate [30].
Fig. 4. The proportion of patients finding once-monthly ibandronate or weekly alendronate more convenient [30].
not affected by the sequence of medication administration (Gart-order effect, P = 0.1855). Similar proportions of patients with a preference stated their chosen regimen would be ‘easier to follow for a long time’, ‘fit better with their lifestyle’ and was associated with ‘less stomach discomfort’ (Table 1). Nine percent more patients stated that the side-effects were easier to tolerate with the once-monthly ibandronate regimen vs. the weekly alendronate regimen. Patients were also requested to indicate which regimen they found most convenient; 32 patients thought that the oncemonthly and weekly regimens were equally convenient. However, of the patients expressing an opinion, a significantly greater proportion found the once-monthly ibandronate regimen (75%) to be more convenient than the weekly alendronate regimen (25%; P < 0.0001) (Fig. 4). As with preference, the choice for convenience was not affected by the order of treatments (Gart-order effect P = 0.1570). The safety profiles of both study medications were generally comparable. Data from this study [30] therefore confirm the findings from the previously conducted survey [29]. In offering greater convenience and good tolerability, more women with postmenopausal osteoporosis prefer once-monthly oral ibandronate compared with weekly alendronate therapy. Ibandronate has been approved in the USA and Europe for the treatment and prevention of postmenopausal osteoporosis. It is anticipated that, as patients begin to be prescribed once-monthly iban-
dronate, this strong patient preference will be reflected in improved ‘real-world’ therapeutic adherence.
Table 1 Reasons given by the patients for treatment choice (patients could provide more than one reason) [30]
Easier to follow for a long time Dosing schedule fits lifestyle better Easier to tolerate side-effects Less stomach discomfort
Once-monthly ibandronate n (%)
Weekly alendronate n (%)
169 (85.8%) 152 (77.2%) 47 (23.9%) 46 (23.4%)
70 (88.6%) 59 (74.7%) 12 (15.2%) 16 (20.3%)
Discussion Poor adherence is a common cause of reduced patient benefit from therapies used in the ‘real-world’ setting compared with the benefits demonstrated in clinical trials. Inadequate therapeutic adherence to oral bisphosphonates in the treatment of osteoporosis compromises therapeutic outcomes, resulting in lower BMD gains, reduced effects on bone turnover and subsequently a lower antifracture effect. It has been shown that improving compliance and persistence enhances patient outcomes. Therefore, strategies need to be devised to provide therapies that patients can adhere to and obtain the most clinical benefit from. Dosing frequency and therapy preference are important factors in patients' adherence behavior. Numerous studies have demonstrated that reducing bisphosphonate dosing frequency from daily to weekly results in improved adherence rates. Unfortunately, however, the level of adherence remains low, with many patients falling short of the clinically relevant MPR of ≥80% and the majority failing to persist with treatment for longer than 1 year. The studies conducted by Simon and colleagues [29] and Emkey and colleagues [30] indicate that a strong patient preference exists for once-monthly over weekly dosing (67% vs. 33% and 71% vs. 29%, respectively). The majority of patients from both studies stated that they would prefer the once-monthly dosing regimen as it would fit better with their lifestyle. Patients also considered the once-monthly regimen to be more convenient. Further preference data will be available from studies in European patients in the near future. By offering greater convenience and a simple dosing regimen that complements patients' lifestyles, a once-monthly bisphosphonate regimen should help patients to follow the dosing guidelines and stay on therapy for a longer period of
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time. Improved therapeutic adherence should subsequently be reflected in enhanced therapy outcomes.
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