Medication-taking behaviour in Bulgarian women with postmenopausal osteoporosis treated with denosumab or monthly oral bisphosphonates

Osteoporosis is characterised by low bone mineral density (BMD) and disruption of bone architecture, which leads to an increased risk of fractures [1, 2]. The incidence and prevalence of osteoporosis are increasing as a consequence of ageing populations. In Bulgaria, a large epidemiological study by Borissova et al. (2011) found that in women aged 50 years or older, 16.8% had osteoporosis of the femoral neck, and approximately half had BMD T-scores at the femoral neck that indicated low bone mass or osteoporosis [3]. A more recent population-based study estimated that approximately 26.6% of Bulgarian women aged 50 years or older have osteoporosis of at least one bone site [4].

A consequence of the increasing prevalence of osteoporosis is that a growing number of women are at risk of fractures, which are associated with considerable pain and disability, as well as substantial healthcare costs [1, 5]. The estimated 10-year absolute fracture risk for women with osteoporosis in Bulgaria is 13.4% for major fractures and 2.8% for hip fractures [3]. This equated to 21,476 fractures among 1.6 million Bulgarian women aged 50 years or older in 2010 [1]. Therefore, osteoporosis is a major public health problem and imposes a huge financial burden [1]. In 2010, the economic burden of osteoporosis in Bulgaria was €42 million. Hip fractures were estimated to be the most expensive type of fracture, accounting for almost half of the economic burden associated with osteoporosis; although hip fractures were not the most frequent fracture type, costs were high at an estimated €1826 for each fracture. Pharmacological fracture prevention accounted for only 3.1% of the total cost [1]. Data on patient outcomes following antiresorptive therapy are required to improve understanding of their value, in terms of osteoporosis treatment and fracture prevention in Bulgaria.

Bisphosphonates, administered orally at daily, weekly or monthly intervals, are commonly used to treat osteoporosis and reduce the risk of fractures [1, 6, 7]. However, persistence and compliance with bisphosphonates are low [8]. Persistence can be defined as the extent to which treatment is continued for the prescribed duration, and compliance can be defined as the extent to which medication is taken correctly as per the prescribed dosage, timing and frequency of treatment. Approximately half of patients discontinue bisphosphonate treatment within 12–24 months [8, 9]. Additionally, over 2 to 5 years, fewer than half of women are compliant with treatment [10‐12], and only approximately 20% persist with it [11, 12].

Denosumab, a monoclonal antibody that inhibits RANK-L, is approved for the treatment of osteoporosis in patients with an increased risk of fractures [13]. Treatment with a subcutaneous (SC) injection of denosumab 60 mg every 6 months (Q6M) has been shown to result in a significant reduction in the risk of vertebral, non-vertebral and hip fractures in postmenopausal women [14]. Furthermore, persistence with denosumab has been shown to be high; in retrospective and prospective studies, the proportion of patients persistent at 12 and 24 months ranged from 81 to 95% and 75 to 86%, respectively [15‐19]. Also, better medication-taking behaviour has been reported in patients receiving denosumab than in those receiving oral bisphosphonates; in a 24-month randomised, crossover study in which women with osteoporosis received weekly oral alendronate for 12 months followed by denosumab SC Q6M for 12 months (or vice versa), significantly more patients were compliant and persistent with denosumab than with alendronate [20]. Increased persistence and compliance with osteoporosis treatment have been shown to improve BMD and reduce fracture risk [17, 21‐23]. A recent retrospective study found that patients who were compliant with osteoporosis medication (defined as a medication possession ratio of ≥ 80%) had a 23% greater reduction in fracture risk compared with patients who were non-compliant [17]. Poor medication-taking behaviour is, therefore, a major barrier to the effective management of osteoporosis.

There are no published data on persistence with denosumab in real-world Bulgarian clinical practice. Such data are critical to understand how therapies affect patient outcomes beyond the clinical trial setting. This study assessed medication-taking behaviour and clinical outcomes among postmenopausal women in Bulgaria who received denosumab or a monthly oral bisphosphonate (ibandronate), and estimated persistence with denosumab, in a real-world setting.

To the best of our knowledge, this is the first retrospective, multicentre study examining medication-taking behaviour in women with postmenopausal osteoporosis treated with denosumab or a monthly oral bisphosphonate in real-world clinical practice in Bulgaria. Our data show that, over a 24-month observational period, fewer patients discontinued denosumab than discontinued ibandronate, and persistence with denosumab was high. Compared with ibandronate, treatment with denosumab was associated with significantly greater improvements in BMD T-scores at the femoral neck and lumbar spine. There were several notable differences in the baseline characteristics between the denosumab and ibandronate groups: a higher proportion of patients initiating denosumab had one or more previous fragility fracture or past exposure to postmenopausal osteoporosis therapy, baseline lumbar spine BMD and BMD T-scores were lower in patients treated with denosumab. These data suggest that patients initiating denosumab had a higher fracture risk than those initiating ibandronate and likely reflect real-world practice, whereby denosumab is prescribed to patients with severe osteoporosis, and commonly after suboptimal outcomes following bisphosphonate therapy. Although further studies are needed to determine whether this is indeed the case and which other factors may influence prescribing patterns, real-world studies in other European countries suggest that the favourable efficacy profile of denosumab may partly explain these behaviours. For example, in a recent prospective study evaluating the medication-taking behaviour of women with osteoporosis receiving denosumab in Germany, Austria, Greece and Belgium, the most common reason physicians gave for prescribing denosumab was that their patients had multiple risk factors for fracture or a history of osteoporotic fracture. Patients were also frequently prescribed denosumab owing to failure of, or intolerance to, their previous osteoporosis therapy [15].

This 24-month study demonstrated that few patients discontinue denosumab in real-world clinical practice in Bulgaria; only 4.5% of women initiating denosumab discontinued treatment within 24 months, compared with more than half of those initiating ibandronate. These data are in line with previous studies, which have shown that approximately half of patients discontinue oral bisphosphonate treatment within 12–24 months after initiation [8, 9]. The time to discontinuation for women treated with denosumab was also significantly longer than for those treated with ibandronate (median, 729 vs 367 days; p < 0.001). These data should, however, be interpreted with caution owing to the low number of patients discontinuing denosumab. Of the 10 women who discontinued denosumab, eight stopped therapy for unknown reasons and two did so for financial reasons. The main reason for discontinuation of ibandronate was poor compliance (34%); this is consistent with previous studies that have reported low compliance to bisphosphonates [20, 25]. The monthly oral administration of ibandronate is possibly a barrier to achieving compliance to therapy. Previous studies have shown that compliance to oral bisphosphonates is low owing to patient dissatisfaction with the route of administration and dosing frequency [20, 25]. Other reasons for patients discontinuing ibandronate therapy in this study were financial reasons (19%), lack of effect (16%) and adverse events (11%).

Over one third of patients who discontinued ibandronate switched to denosumab. Medication switching in chronic diseases is well documented [26]. Although the decision to switch from ibandronate to denosumab likely reflects the aforementioned reasons for discontinuation the impact of physician bias to switch from an older agent (ibandronate) to a newer agent (denosumab) cannot be ruled out. It should be noted, however, that the Bulgarian reimbursement committee require a medical reason, such as lack of effect of current medication, and consultation with a specialist endocrinologist or rheumatologist to support medication switching.

In this study, a high proportion of women were persistent with denosumab therapy; persistence was 100% at 12 months and exceeded 98% at 18 and 24 months. Numerous studies have reported on real-world persistence with denosumab [15, 16, 18, 19, 27]. In two prospective studies, one conducted in Europe by Hadji and colleagues and one conducted in North American by Silverman and co-workers, denosumab persistence ranged from 82 to 95% at 12 months and 75 to 86% at 24 months [15, 18, 19]. In a retrospective study by Karlsson and colleagues that analysed real-world data from the Swedish Prescribed Drug Register (n = 2315), denosumab persistence was 83% at 12 months and 62% at 24 months [16]. However, compared to the aforementioned studies, a retrospective study by Fuksa and colleagues that analysed data from the General Health Insurance Company of the Czech Republic (n = 7904) reported lower persistence rates for denosumab; persistence was 59% at 12 months and 35% at 24 months [27]. The differences in reported persistence between these studies may reflect the use of different definitions of persistence. In the studies by Hadji, Silverman and Karlsson, persistence at 12 months was defined as patients having received their second dose of denosumab within 6 months plus 56 days of their previous dose [15, 18]. Whereas, Fuksa and colleagues defined 12-month persistence as patients having received their third dose of denosumab within 6 months and 30 days of their previous dose [27]. Persistence with denosumab in our real-world study was higher than that previously reported in the literature. This may reflect the specialist physicians who participated in our study who were likely to provide good patient education, which has been shown to increase persistence [28].

While persistence with ibandronate could not be calculated in this study, persistence with oral bisphosphonates in the real-world setting has been shown to be low. In a meta-analysis of 40 retrospective studies assessing persistence with oral bisphosphonates, estimates of 24-month persistence ranged from 16 to 46%, with a pooled estimate of 30% [16]. It must be noted that most of these studies examined persistence of either daily or weekly oral bisphosphonates, rather than those with monthly dosing. Studies investigating the differences between oral bisphosphonates regimens have reported that monthly administration is associated with higher persistence that daily or weekly administration [29, 30]. In a randomised open-label multicentre study of persistence with osteoporosis medication, 6-month persistence was 57 and 39% with monthly ibandronate and weekly alendronate, respectively [29]. In a retrospective study that analysed data from the CISA prescription database in Japan, 24-month persistence was significantly higher with monthly oral bisphosphonates than with daily or weekly bisphosphonates (p < 0.001) [30]. Real-world persistence with monthly bisphosphonate regimens have, however, been reported to be low. In a large, Hungarian, retrospective, cohort study conducted in 296,300 women with postmenopausal osteoporosis, among 16,862 women receiving monthly oral bisphosphonates, persistence was at 27% at 12 months and 10% at 24 months [17]. In the same study, 12- and 24-month persistence with 6-monthly parenteral therapies was higher (81 and 38%, respectively) than persistence with daily/weekly/monthly oral therapies (32 and 16%, respectively) [17]. Therefore, the short interval between doses of oral bisphosphonates is likely to account, in part, for the poor persistence observed with bisphosphonates compared with denosumab, which is administered at 6-month intervals.

The importance of persistence in increasing BMD and reducing fracture risk is well established [11, 22, 31, 32]. At 24 months of follow-up, we observed significantly greater improvements in lumbar spine and femoral neck BMD and BMD T-scores for denosumab compared with ibandronate. Consequently, more patients in the denosumab group achieved a BMD T-score higher than − 2.5 SD. While our study was not powered to test for statistically significant differences in BMD changes between denosumab and ibandronate, and this analysis was exploratory, the increase in BMD and BMD T-scores observed for denosumab support data from other observational studies [24, 33]. The beneficial effect of denosumab on BMD has also been demonstrated over longer follow-up periods in clinical trial settings. The phase 3 Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) extension study reported cumulative 10-year increases of 21.6% at the lumbar spine and 9.1% for total hip BMD [34]. Sustained improvements in BMD with denosumab have also been shown in an 8-year, phase 2 study in which lumbar spine BMD was increased by 16.5% and total hip BMD by 6.8% [35]. Improvements in BMD with ibandronate have also been reported in clinical trial settings; in an extension of the Monthly Oral iBandronate In LadiEs (MOBILE) ibandronate study, BMD at the lumbar spine increased by 8.4% after 5 years of follow-up [36].

It has previously been shown that denosumab increases BMD significantly more than bisphosphonates. In post hoc analysis of patients at high fracture risk enrolled in two multicentre, open-label studies, denosumab was associated with greater increases in BMD at 12 months than monthly oral ibandronate or risedronate (femoral neck 1.8 vs 0.3%, lumbar spine 3.7 vs 1.4%, total hip 2.2 vs 0.8%, respectively; p < 0.0001 for all comparisons) [37]. Furthermore, in a phase 3, randomised, double-blind study, BMD increases were significantly greater with denosumab than with alendronate (lumbar spine 5.3 vs 4.2%, p < 0.0001; total hip 3.5 vs 2.6%, p < 0.0001; femoral neck 2.4 vs 1.8%, respectively; p = 0.0001) [38]. Denosumab has also been shown to provide greater improvements in BMD than the parenteral bisphosphonate, zoledronic acid. In a randomised, double-blind trial, 643 women with osteoporosis, previously treated with oral bisphosphonates, were randomised to receive SC denosumab every 6 months plus intravenous (IV) placebo once, or IV zoledronic acid once plus SC placebo every 6 months. At 12 months, changes in BMD from baseline were significantly greater with denosumab compared with zoledronic acid (lumbar spine 3.2 vs 1.1%, p < 0.0001; total hip 1.9 vs 0.6%, p < 0.0001; femoral neck 1.2 vs − 0.1%, p < 0.0001; one-third radius 0.6 vs 0.0%, p < 0.05) [39]. The significant increases in BMD and BMD T-scores reported with denosumab in our study may, in part, explain the high persistence rates that we observed for denosumab; indeed, in real-world settings, it has been shown that significant increases in BMD increase patient compliance to therapy [40]. Conversely, the high persistence rates for denosumab may, in part, account for the greater improvements in BMD seen with this agent compared with ibandronate. Although it was beyond the scope of this study to assess changes in BMD only in patients who were persistent with treatment, the results of such analyses would be of interest and are recommended for future studies.

There are several limitations to our study. BMD was not measured in all patients at all skeletal sites throughout follow-up, limiting the patient sample for which changes in BMD could be calculated. However, this reflects real-world clinical practice. This was a retrospective study and patients were not randomised; thus, any comparisons between groups should be made with caution, and the different baseline characteristics of the enrolled patients should be considered, in addition to the prescribing habits and preferences of the physicians. The differences in the baseline characteristics of the patients receiving denosumab and those receiving ibandronate may have influenced the rate of treatment discontinuation in each group. However, the differences in patient characteristics between the denosumab and ibandronate groups reflect the differing patient populations who are likely to receive these agents in real-world practice. Additionally, because this study was conducted in centres specialised in the treatment of osteoporosis, results may not be reflective of medication-taking behaviour of patients treated in general practice. Moreover, because denosumab was a new agent at the time the study was conducted, some physicians may have been biased towards switching patients in the ibandronate group to denosumab, thus inflating discontinuation rates for ibandronate. However, this is reflective of real-world clinical practice. The small patient number may limit the interpretation of the results. Finally, although the 24-month follow-up period is in line with several other studies assessing medication-taking behaviour in women with postmenopausal osteoporosis [17, 20, 41, 42], a longer follow-up would be valuable in understanding the long-term discontinuation rates with these agents.

This is the first real-world chart review study of medication-taking behaviour in women with postmenopausal osteoporosis receiving denosumab or ibandronate in Bulgaria. In real-world clinical practice, denosumab is frequently prescribed to patients with severe osteoporosis who are at a high risk of fracture. This was reflected in our study. Denosumab treatment was associated with significantly greater increases in BMD when compared with ibandronate. In addition, very few patients receiving denosumab discontinued therapy compared with patients receiving ibandronate. At 24 months, persistence with denosumab exceeded 98%. Consistent with the greater BMD increases observed, the low discontinuation rate and high persistence among women initiating denosumab could lead to improved clinical outcomes, including fracture risk reduction.