Introduction
============

Osteoporosis affects one in three postmenopausal women but the nature of this generalized, initially asymptomatic, chronic disease means that many patients are unaware that they have this disease until they experience their first fracture. Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures ([@b63-cia-1-415]). Bone loss is the result of an imbalance in bone turnover, with bone resorption occurring at a faster rate than new bone formation. The resulting reduction in bone mass and accompanying damage to bone microarchitecture increases the risk of fracture. The most common form of osteoporosis, that experienced by postmenopausal women, results from reduced estrogen production following the menopause; by increasing bone resorption, estrogen deficiency disrupts the fine balance of the bone remodeling cycle. The spine (vertebral fractures), hips, and wrists (nonvertebral fractures) are the most common sites of osteoporosis-related bone fractures (ie, fractures that are out of proportion to the level of external trauma), although osteoporosis-related fractures can occur at almost any skeletal bone site.

Patients who suffer a vertebral fracture are subsequently at an increased risk of further fractures of all types, including hip fractures ([@b33-cia-1-415]). Large prospective fracture studies have demonstrated an increased mortality rate following vertebral fracture. In the Study of Osteoporotic Fractures (SOF), women with at least one prevalent vertebral fracture experienced a 23% greater age-adjusted mortality rate than age-matched controls in the general population ([@b32-cia-1-415]). In patients with postmenopausal osteoporosis in the Fracture Intervention Trial (FIT) ([@b42-cia-1-415]) and the European Prospective Osteoporosis Study (EPOS) ([@b34-cia-1-415]), it was demonstrated that the presence of a vertebral fracture increases the relative risk of mortality by approximately 60%.

In addition to mortality, vertebral fractures are associated with debilitating pain (lasting several weeks or months, with chronic pain lasting for many years), kyphosis (curvature of the spine, leading to height loss, abdominal protrusion, and a hump at the top of the spine), disability, and restricted movement ([@b53-cia-1-415]; [@b6-cia-1-415]; [@b38-cia-1-415]; [@b16-cia-1-415]; [@b25-cia-1-415]; [@b29-cia-1-415]; [@b37-cia-1-415]; [@b46-cia-1-415]). There are also psychological effects; patients may experience anxiety about their loss of independence, as well as having a fear of falls and further fractures. Nonvertebral fractures, especially hip fractures, are devastating; around half of the patients who experience a hip fracture will never be able to walk again without assistance ([@b31-cia-1-415]) and as many as 30% of hip fracture patients require permanent institutional care ([@b38-cia-1-415]).

Population-based outcome modeling estimates that Caucasian women over 50 years of age have a one-in-three risk of at least one vertebral fracture and a one-in-five risk of at least one hip fracture in their remaining lifetime ([@b8-cia-1-415]). The incidence of osteoporosis-related fractures increases with age, so as the population ages, the number of osteoporosis-related fractures is projected to increase dramatically ([@b10-cia-1-415]; [@b44-cia-1-415]). Overall, 40% of women with postmenopausal osteoporosis will suffer one or more fragility fractures during their remaining lifetime ([@b44-cia-1-415]). In the year 2000, an estimated 75 million people had osteoporosis in Europe, the US, and Japan ([@b40-cia-1-415]). During 2002, the direct impact of this disease translated to an estimated treatment cost in the US of \$17.5 billion ([@b43-cia-1-415]), and in 2003, in the EU, the estimated total direct cost of osteoporosis-related fractures was 25 billion ([@b26-cia-1-415]). Due to the increasing burden of osteoporosis, there is a real need for effective treatments.

Bisphosphonates for the treatment of osteoporosis
=================================================

The aim of pharmacological intervention in postmenopausal osteoporosis is to reduce the frequency of fractures and, consequently, reduce the related burden on patients and healthcare services and improve patients' quality of life. The leading treatments for postmenopausal osteoporosis are the nitrogen-containing bisphosphonates. These antiresorptive agents reduce postmenopausal bone loss by inhibiting osteoclast activity and reducing the rate of bone resorption. This shifts the balance in favor of bone formation, so that bone mass is increased ([@b54-cia-1-415]). In numerous robust clinical trials, the nitrogen-containing bisphosphonates alendronate, risedronate, and ibandronate have consistently demonstrated considerable increases in bone mineral density (BMD) of the spine and hip and decreases in the biochemical markers of bone turnover together with substantial antifracture efficacy ([@b3-cia-1-415]; [@b15-cia-1-415]; [@b24-cia-1-415]; [@b51-cia-1-415]; [@b7-cia-1-415]). Additionally, the bisphosphonates are the only antiresorptive agents shown in a meta-analysis to significantly reduce the risk of nonvertebral fractures ([@b14-cia-1-415]) and, in a prospective analysis, risedronate was shown to reduce the risk of hip fracture ([@b41-cia-1-415]). All three of these bisphosphonates have favorable safety profiles, which have been shown in clinical studies to be similar to placebo. However, long-term treatment with bisphosphonates is required for optimal and sustained benefit and although oral bisphosphonates have proven efficacy in women with postmenopausal osteoporosis in clinical trials, the therapeutic benefits in clinical practice are often compromised by patients' low compliance to, and persistence with, their prescribed medication. Compliance describes the quality of intake of a given medication and considers the extent to which a dosing regimen and its associated instructions are followed. Compliance can often be quantified by a surrogate measure, the medication possession ratio, which is the number of days of available medication divided by the number of days of study follow-up. Persistence describes the length of time patients continue to take their medication, and is defined as the time from treatment initiation to treatment completion/discontinuation. Using the PHARMO Record Linkage System, which includes drug-dispensing records from community pharmacies serving more than 1 million community-dwelling patients in the Netherlands, [@b47-cia-1-415] showed that, overall, 1-year persistence with bisphosphonate therapy (daily or weekly) is low. Among 2124 new bisphosphonate users (alendronate daily or weekly, risedronate daily, etidronate daily), only 43% were persistent at 1 year. As few as 39% of patients may persist with weekly bisphosphonates at 1 year ([@b11-cia-1-415]) and persistence at 2 years could be as low as 18%--23% ([@b23-cia-1-415]; [@b60-cia-1-415]).

Impact of poor therapeutic adherence
====================================

Adherence is a summary term that is determined by compliance and persistence of medication intake. Adherence is thus used to describe the extent and the quality of medication intake. Adherence to medication in postmenopausal osteoporosis is in line with the general finding of low persistence rates in other chronic diseases. Following an inspection of several reviews, the World Health Organization estimated that long-term adherence in chronic disease averages only 50% ([@b62-cia-1-415]). In a recent meta-analysis of the association between adherence to drug therapy and mortality, nonadherent patients with chronic disorders had a higher mortality rate than their adherent counterparts ([@b59-cia-1-415]). It seems that this is particularly true for diseases like postmenopausal osteoporosis that have few or no clinical symptoms, as the patient does not experience ill effects from the disease or the subsequent benefit from treatment.

In the treatment of osteoporosis, nonadherence to bisphosphonate therapy negatively impacts upon treatment outcomes, for instance poor adherence is associated with a significantly higher rate of vertebral and nonvertebral fractures (see Figure [1](#f1-cia-1-415){ref-type="fig"}), which are in turn associated with a decreased quality of life ([@b5-cia-1-415]; [@b56-cia-1-415]; [@b23-cia-1-415]; [@b60-cia-1-415]). The antifracture efficacy of bisphosphonates has been demonstrated in clinical studies with 2--4 years of treatment, therefore if fewer than half of patients are adhering to therapy after just 1 year, it is unlikely that the same degree of antifracture efficacy will be achieved as has been shown in clinical trials. Nonadherent bisphosphonate use also increases the risk of hospitalization associated with osteoporotic fractures ([@b21-cia-1-415]). Thus, as would be expected, nonadherence with bisphosphonate therapy correlates with reduced gains in BMD and lower reductions in the levels of bone turnover markers ([@b18-cia-1-415]; [@b56-cia-1-415]). As well as adversely affecting these primary treatment outcomes, nonadherence leads to an increased incidence of secondary complications associated with fractures, such as pain, nosocomial infections, and pulmonary thromboembolism, and hence to increased healthcare costs.

Understanding the causes of poor adherence
==========================================

Given the impact of nonadherence to therapy on patient outcomes and healthcare resources, it is clearly important to improve adherence. However, to improve therapeutic adherence it is important to know why patients stop taking, or do not take adequate amounts of, their medication. Overall, the main reasons patients cite for not continuing to take their osteoporosis medication are the stringent dosing schedule, adverse events, not feeling that treatment is working, or not believing that they have a disease that needs treating (see Figure [2](#f2-cia-1-415){ref-type="fig"}) ([@b27-cia-1-415]). The most common of the reasons cited above for nonadherence is that patients find the strict dosing instructions for bisphosphonates difficult to follow; fasting (overnight for at least 6 hours prior to taking the medication and 30--60 minutes after administration), and posture (staying upright for 30--60 minutes after taking the medication) requirements can be inconvenient and often not feasible in the daily routine. The strict requirements interfere not only with eating and drinking, but also with taking other medications, especially if these need to be taken with food. The next most common reason for discontinuation of therapy is that despite clinical studies reporting side-effect profiles that are similar to placebo, many patients stop taking treatment due to adverse events. The main complaints with oral bisphosphonates are upper gastrointestinal irritation, dyspepsia, nausea, upper abdominal pain, vomiting, and gastroesophageal reflux. Finally, as patients often have no symptoms until they suffer a fracture, they do not feel that treatment is worth taking or do not believe they have a disease that needs treatment. This means they may consider the pill burden and inconvenience of the dosing requirements to be unnecessary. It has been suggested that, compared with other chronic diseases, adherence in osteoporosis is compromised because measures of therapeutic outcome (such as increases in BMD and reductions in the level of biochemical markers of bone turnover) are not readily available, therefore patients are unable to monitor their response to medication and thus gain feedback regarding the benefits of their medication ([@b27-cia-1-415]).

Many physicians believe that the main reason for patients not continuing to take their osteoporosis medication is a lack of understanding of the benefits of treatment. However, in the IOF adherence survey ([@b27-cia-1-415]), 71% of physicians questioned recognized that they did not know why their patients were discontinuing treatment. Almost half of the physicians surveyed believed that the best way to motivate patients to continue on treatment is to talk to them about risks and complications, however, the patients surveyed believed that it may be better to adopt a more positive approach that stresses the benefits of therapy.

Strategies to overcome the problem of nonadherence
==================================================

On the whole, patients with osteoporosis want an effective and well-tolerated treatment, however, even with the proven efficacy and safety profiles of the bisphosphonates from clinical trials, patients still do not remain on treatment. Therefore other strategies are needed to improve therapeutic adherence. Improved communication between physicians and their patients may be one way to help. During the IMPACT ([I]{.ul}mproving the [M]{.ul}easurements of [P]{.ul}ersistence on [Ac]{.ul}tonel [T]{.ul}reatment) study, patients were given verbal feedback regarding their bone turnover marker results ([@b17-cia-1-415]). The study showed that a significant improvement in persistence was achieved if patients were given a positive message regarding their response to treatment. It has also been shown that involving patients in treatment decisions and matching them with their preferences improves patient satisfaction, adherence, perception of health, and outcomes ([@b39-cia-1-415]; [@b30-cia-1-415]; [@b28-cia-1-415]; [@b36-cia-1-415]). With regards to pharmacological intervention, patients have identified key product attributes as being efficacy, side effects, formulation, costs, drug interactions, dosing procedure, and dosing frequency. For the bisphosphonates, it is acknowledged that most of these attributes cannot be altered. However, one attribute that can be changed is the dosing frequency. Several studies have evaluated patient preferences for different dosing schedules and the impact this has had on therapeutic adherence.

Patient preference for an increased dosing interval: weekly dosing
------------------------------------------------------------------

The registration studies, which showed antifracture efficacy for the oral bisphosphonates, were all conducted using a daily regimen ([@b3-cia-1-415]; [@b15-cia-1-415]; [@b24-cia-1-415]; [@b51-cia-1-415]; [@b7-cia-1-415]). The comparable antifracture efficacy of weekly oral bisphosphonate regimens of alendronate and risedronate with their respective daily regimens has been inferred based on equivalent increases in BMD (a validated surrogate marker for antifracture efficacy), and decreases in bone turnover markers ([@b55-cia-1-415]; [@b4-cia-1-415]). The weekly regimens of alendronate and risedronate are both licensed and are widely accepted as being at least as effective as the daily regimens with the added convenience of only one tablet a week. In several studies evaluating bisphosphonate regimen preference (using alendronate or risedronate), there was a strong preference for a weekly regimen versus daily dosing (see Table [1](#t1-cia-1-415){ref-type="table"}). The weekly regimen was considered by the patients to be more convenient, would allow them to achieve better long-term compliance, and was the regimen that most said they would be willing to take for an extended period of time, ie, would improve their adherence ([@b58-cia-1-415]; [@b1-cia-1-415]; [@b12-cia-1-415]; [@b35-cia-1-415]; [@b48-cia-1-415]; [@b2-cia-1-415]).

It has been demonstrated that patient preference for reduced bisphosphonate dosing frequency has impacted on therapeutic adherence. Studies that compared daily and weekly regimens found that a weekly regimen of alendronate or risedronate significantly increased rates of compliance versus a daily treatment (see Table [2](#t2-cia-1-415){ref-type="table"}) ([@b13-cia-1-415]; [@b49-cia-1-415]; [@b2-cia-1-415]). Patients receiving daily bisphosphonates filled prescriptions for only 33%--58% of their prescribed medication, while patients receiving a weekly regimen obtained more of their prescribed medication (46%--69%). Around half (41%--55%) of patients receiving a weekly regimen were highly compliant (at least 80% of prescribed medication taken) compared with only 23%--40% of patients taking a daily treatment. Preference for less frequently dosed bisphosphonate regimens also translates to improved therapeutic persistence (see Table [3](#t3-cia-1-415){ref-type="table"}). Analyses of a number of health databases of patients in the clinical setting show that 1-year persistence increases with weekly bisphosphonate dosing regimens by 12%--29% versus daily dosing ([@b20-cia-1-415]; [@b47-cia-1-415]; [@b61-cia-1-415]; [@b13-cia-1-415]; [@b2-cia-1-415]). However, fewer than half of patients receiving a weekly regimen persist with their therapy for 12 months so, even though adherence has been improved with weekly regimens versus daily, it is still suboptimal. Adherence, and therefore potentially quality of life, may be improved by further increasing the dosing interval, for instance from daily or weekly to monthly ([@b57-cia-1-415]).

Increasing the dosing interval further: monthly dosing
======================================================

Ibandronate is the first nitrogen-containing oral bisphosphonate for osteoporosis that can be administered in a monthly regimen, and it is anticipated that this regimen may have a positive impact on adherence, and therefore ultimately on fracture prevention. Similarly to the other currently licensed oral bisphosphonates for postmenopausal osteoporosis, daily ibandronate has well documented clinical efficacy ([@b52-cia-1-415]; [@b7-cia-1-415]; [@b45-cia-1-415]). When given in an intermittent schedule (dosing interval \>2 months), oral ibandronate also provides significant vertebral antifracture efficacy (relative risk reduction 50%, p=0.0006 versus placebo), which represents the first prospective demonstration of antifracture efficacy with a bisphosphonate administered less frequently than daily ([@b7-cia-1-415]). It is important to note that when the treatment-free interval is increased, the cumulative bisphosphonate dose must also be increased. Daily and intermittent ibandronate of the same cumulative dose provided comparable efficacy, however, similar to studies of daily and weekly bisphosphonates, a small, yet consistent, efficacy advantage was seen in favor of the daily regimen. Hence, in studies to evaluate a monthly regimen, oral doses beyond the cumulative monthly dose provided by the daily regimen were explored to compensate for the greater between-dose interval. As with the weekly regimens of alendronate and risedronate, a comparable vertebral antifracture profile for the monthly regimen of ibandronate with the daily regimen is inferred based on increases in BMD at all bone sites that are at least equivalent to those observed with the daily regimen ([@b45-cia-1-415]; [@b50-cia-1-415]). Trial data from the MOBILE ([M]{.ul}onthly [O]{.ul}ral I[b]{.ul}andronate [I]{.ul}n [L]{.ul}adi[e]{.ul}s) study showed that monthly ibandronate increased lumbar spine BMD and decreased markers of bone turnover and that the 150 mg monthly regimen was superior to the daily regimen ([@b45-cia-1-415]; [@b50-cia-1-415]). After both 1 and 2 years of the study, the monthly regimen showed a good tolerability profile, similar to that of the daily regimen ([@b7-cia-1-415]).

Patient preference for a monthly regimen
========================================

Two robust clinical studies with almost 700 patients using patient surveys have demonstrated a strong patient preference for a monthly versus a weekly oral bisphosphonate regimen ([@b19-cia-1-415]; [@b22-cia-1-415]). The BALTO ([B]{.ul}onviva [AL]{.ul}endronate [T]{.ul}rial in [O]{.ul}steoporosis) studies evaluated patients' preference for monthly oral ibandronate or weekly oral alendronate. BALTO I ([@b19-cia-1-415]) and BALTO II ([@b22-cia-1-415]) comprised two separate studies of identical design; both were 6-month, randomized, multicenter, two-sequence, open-label, cross-over studies conducted in bisphosphonate-naïve or -lapsed women with postmenopausal osteoporosis as determined by the treating physician. BALTO I (n=342) was a US only study, whereas BALTO II (n=350) included centers in the USA and Europe. Postmenopausal women were randomized to receive either monthly oral ibandronate (150 mg) for 3 months followed by weekly oral alendronate (70 mg) for 12 weeks, or weekly oral alendronate (70 mg) for 12 weeks followed by monthly oral ibandronate (150 mg) for 3 months. All patients were informed that both drugs are indicated for the treatment of osteoporosis. Patient preference and opinions on convenience were assessed using a subject-completed questionnaire.

In BALTO I ([@b19-cia-1-415]), of those women who expressed a preference (92.6% of 298 participants), the majority (71.4%) preferred the monthly ibandronate regimen to the weekly alendronate regimen (p\<0.0001; see Figure [3](#f3-cia-1-415){ref-type="fig"}). Similarly, in those patients expressing an opinion on convenience, the monthly regimen of ibandronate was assessed as being more convenient for patients than the weekly regimen of alendronate (74.6% vs 25.4%, respectively; p\<0.0001; see Figure [4](#f4-cia-1-415){ref-type="fig"}). More women reported that the monthly regimen would be easier to follow for a long time (61% vs 25%), was better suited to their lifestyle (55% vs 21%), and was easier to tolerate (17% vs 4%) than the weekly regimen. In addition, patients indicated that there was a greater likelihood of long-term adherence and better tolerance of adverse events with the monthly regimen than the weekly regimen. The findings from BALTO I were confirmed by BALTO II. In BALTO II ([@b22-cia-1-415]), of those patients expressing a preference (93.1%), the majority (70.6%) preferred the monthly ibandronate regimen to the weekly alendronate regimen (see Figure [3](#f3-cia-1-415){ref-type="fig"}). Again the difference in preference rate between weekly alendronate and monthly ibandronate was statistically significant (p\<0.0001). Of the patients expressing an opinion on convenience, three-quarters found the monthly regimen more convenient than the weekly regimen (76.6% vs 23.4%, respectively; see Figure [4](#f4-cia-1-415){ref-type="fig"}). As in BALTO I, the most common reasons for preferring the monthly ibandronate regimen were ease of long-term adherence (81.5%) and better fit to lifestyle (75.4%).

Patient preference for a medication may encourage therapeutic adherence, but further studies are needed to determine how well preference and convenience translate into prolonged adherence. The UK [PER]{.ul}sistence [S]{.ul}tudy of [I]{.ul}bandronate ver[S]{.ul}us alendrona[T]{.ul}e (PERSIST) is the first trial to investigate persistence with 6 months of a monthly bisphosphonate regimen versus a weekly bisphosphonate regimen. Patients were randomized to receive either a monthly ibandronate regimen (plus a patient support program) or a weekly alendronate regimen ([@b9-cia-1-415]). A patient support program is available to all patients who are prescribed monthly ibandronate in the UK, however, there is no equivalent support program available to patients who are prescribed weekly alendronate. Therefore, to reflect current UK practice, only patients randomized to the ibandronate arm were enrolled into the program. The 6-month data show that compared with alendronate there was a 47% relative improvement in the proportion of patients persisting with treatment in the ibandronate/patient support program group. This compares well with the reported relative improvements in 1-year persistence of 12%--29% with weekly versus daily dosing ([@b20-cia-1-415]; [@b47-cia-1-415]; [@b61-cia-1-415]; [@b13-cia-1-415]; [@b2-cia-1-415]). Secondary endpoints, ie, proportion of patients remaining on treatment at study end and proportion of patients discontinuing from the study, were also in favor of the monthly regimen. The data from the UK PERSIST study suggest that this less frequent dosing schedule may provide improved adherence.

Conclusions
===========

To achieve maximum treatment benefits for patients with osteoporosis, it is important that physicians discuss all options with their patients before a treatment choice is made. It has been shown that the majority of patients prefer weekly to daily therapy, although adherence with weekly regimens remains suboptimal. As adherence with daily or weekly bisphosphonates is suboptimal, patients and physicians feel there is a need for bisphosphonates with extended dosing intervals. Given the reported strong patient preference for a monthly regimen, and the impact of patient preference on adherence, it is anticipated that monthly ibandronate will offer patients an alternative convenient regimen that may improve adherence over weekly regimens and thereby enhance outcomes. The nitrogen-containing bisphosphonates are effective therapies for osteoporosis, but if patients are more likely to adhere to a monthly regimen than a daily or weekly regimen, then this may be the treatment of choice. An effective bisphosphonate that combines a good tolerability profile with a convenient dosing regimen would be beneficial for patients and it is important that physicians consider patient preference when prescribing the appropriate treatment for osteoporosis to ensure that the disease is effectively managed for the long-term benefit of the patient.

The author would like to thank Charlotte Kennerley (medical writer) for her editorial assistance.

![Fractures are increased as a result of suboptimal adherence: trend of a 33% greater fracture rate in inconsistent^a^ versus consistent users ([@b56-cia-1-415]).\
**Note:** ^a^Inconsistent = early discontinuation or self-reported taking of therapy \<80% of the time over the follow-up interval.](cia-1-415f1){#f1-cia-1-415}

![Reasons given by patients for not adhering to bisphosphonate therapy for osteoporosis ([@b27-cia-1-415]).](cia-1-415f2){#f2-cia-1-415}

![The majority of patients expressing a preference prefer monthly bisphosphonate treatment to weekly ([@b19-cia-1-415]; [@b22-cia-1-415]).\
**Note:** Modified intent-to-treat populations = 298 (BALTO I), 321 (BALTO II); ^a^Preference rate for monthly was significant in both studies (p\<0.0001).](cia-1-415f3){#f3-cia-1-415}

![The majority of patients expressing an opinion perceived a monthly bisphosphonate regimen to be more convenient than a weekly regimen ([@b19-cia-1-415]; [@b22-cia-1-415]).\
**Note:** Modified intent-to-treat populations = 298 (BALTO I), 321 (BALTO II); ^a^Perception that the monthly regimen was more convenient than the weekly regimen was statistically significant (p\<0.0001).](cia-1-415f4){#f4-cia-1-415}

###### 

Patients' preference for weekly versus daily dosing of bisphosphonates

  Study                                                                       Dose regimens                                                Outcome
  --------------------------------------------------------------------------- ------------------------------------------------------------ ------------------------
  Multicenter randomized crossover (n=287) ([@b58-cia-1-415])                 4 weeks of daily alendronate                                 86.4% preferred weekly
  1 week washout                                                              89.0% thought weekly convenient                              
  4 weeks of weekly alendronate                                               87.5% expected weekly to improve compliance                  
  Multicenter randomized crossover observational (n=406) ([@b35-cia-1-415])   4 weeks of daily alendronate                                 84.0% preferred weekly
  1 week washout                                                              87.0% thought weekly convenient                              
  4 weeks of weekly alendronate                                               84.0% would receive weekly long term                         
  Multicenter observational switchover (n=2997) ([@b1-cia-1-415])             6 months of daily calcitonin, raloxifene or bisphosphonate   99.5% preferred weekly
  99.8% thought weekly convenient                                                                                                          
  24 weeks of weekly alendronate                                              99.8% willing to use weekly long term                        

###### 

Studies of compliance with weekly compared with daily bisphosphonate regimens

  Study                                                 Dose regimens (n)                          MPR (%)           MPR ≥80% (%)
  ----------------------------------------------------- ------------------------------------------ ----------------- --------------
  IHCIS database (1997--2002) ([@b13-cia-1-415])        Daily alendronate or risedronate (2010)    58                40
  Weekly alendronate (731)                              69 (p\<0.0001)                             55 (p\<0.0001)    
  IMS Mediplus ([@b2-cia-1-415])                        Daily alendronate (144)                    38                19
  Weekly alendronate (144)                              51                                         31 (p\<0.05)      
  NDCHealth retrospective database ([@b48-cia-1-415])   Daily alendronate or risedronate (33767)   54                \~33
  Weekly alendronate or risedronate (177552)            65 (p\<0.001)                              \~45 (p\<0.001)   

**Abbreviations:** MPR, medication possession ratio.

###### 

Studies of persistence with weekly compared with daily bisphosphonate regimens

  Study                                                                   Dose regimens (n)                         Days to treatment discontinuation   Days of treatment duration
  ----------------------------------------------------------------------- ----------------------------------------- ----------------------------------- ----------------------------
  IHCIS database (1997--2002) ([@b13-cia-1-415])                          Daily alendronate or risedronate (2010)   185                                 134
  Weekly alendronate (731)                                                227                                       269                                 
  IMS Mediplus([@b2-cia-1-415])                                           Daily alendronate (144)                   153                                 --
  Weekly alendronate (144)                                                212                                       --                                  
  NDCHealth retrospective database ([@b20-cia-1-415]; [@b61-cia-1-415])   Daily alendronate or                      --                                  198
  risedronate (33767)                                                                                                                                   
  Weekly alendronate or risedronate (177552)                              --                                        238                                 
