Real-world Management of Women with Postmenopausal Osteoporosis Treated with Denosumab: A Prospective Observational Study in the Czech Republic and Slovakia

Osteoporosis is a common disease, characterized by low bone mineral density (BMD), leading to fragile bones and an increased fracture risk [1]. An estimated 27.5 million people were living with osteoporosis in 27 European countries in 2010, including more than half a million people in the Czech Republic and almost a quarter of a million in Slovakia [1]. This is equivalent to 5.0% and 4.2% of the total population in each country, respectively [1].

Osteoporosis and the consequent fractures are associated with increased mortality and significant patient morbidity, including an increased risk of pain [2, 3] and disability [1, 4‐7]. In 2010, an estimated 44,000 and 22,000 incident fractures occurred in women aged 50 years or older in the Czech Republic and Slovakia, respectively [7]. Osteoporosis also results in a substantial healthcare burden, driven primarily by the costs associated with fractures [7]. The economic burden of incident and previous osteoporotic fractures in 2010 was estimated at €273 million in the Czech Republic and €107 million in Slovakia, with incident fractures representing 60% and 71% of these costs, respectively [7]. Thus, there is a clear need to improve the management of osteoporosis in postmenopausal women in these countries to reduce the significant morbidity and social and economic costs associated with this disease.

Bisphosphonates are prescribed widely to treat osteoporosis [6, 8], but suboptimal persistence and adherence to treatment have been reported [9‐12]. Denosumab, a fully human monoclonal antibody targeted against the receptor activator of nuclear factor kappa B ligand, is an alternative osteoporosis treatment indicated in postmenopausal women and in men who have an increased risk of fractures [13]. In a pivotal phase 3 study, denosumab (60 mg subcutaneously) administered every 6 months (Q6M) for 3 years in postmenopausal women resulted in a significant reduction in the risk of vertebral, non-vertebral, and hip fractures compared with placebo [14]. Additionally, in patients with suboptimal adherence to daily or weekly oral bisphosphonates, switching to denosumab was well tolerated and more effective at increasing BMD than switching to monthly oral bisphosphonate treatment [15‐17]. Several studies have shown that persistence with and adherence to denosumab are high: 81–95% of patients persist with treatment at 1 year [18‐21] and 91% at 3 years [22]. Furthermore, persistence is 1.5–2.0 times higher with denosumab than with bisphosphonates [12, 19]. Poor persistence and adherence to osteoporosis treatment have been shown to increase fracture risk [23]. Thus, the reduction in fracture risk reported in clinical trials of osteoporosis medications may not be achieved in real-world clinical practice without good adherence to and persistence with treatment.

Denosumab was approved for use in patients with postmenopausal osteoporosis in Europe in 2010 [13]. Following the approval and launch of a new pharmaceutical, assessment of its use in the real-world setting is recommended. The approved dose of denosumab is 60 mg administered subcutaneously Q6M; it should only be administered by an individual who has been adequately trained. Patients prescribed denosumab should also receive concurrent calcium and vitamin D supplementation, unless contraindicated [13, 24, 25]. It should be noted that denosumab reimbursement criteria differ between the Czech Republic and Slovakia. In both countries, patients must have a baseline BMD T score of − 2.5 or lower at the femoral neck, lumbar spine, or total hip. For reimbursement in the Czech Republic, patients must also have experienced a previous osteoporosis fracture, be intolerant to other osteoporosis treatments, or have not responded to other available osteoporosis therapies [26]. In Slovakia, denosumab is reimbursed as first-line treatment in patients who have been diagnosed with osteoporosis by dual-energy X-ray absorptiometry (DXA) assessment of BMD or who have sustained an osteoporotic fracture. It is therefore not possible to directly compare the real-world management of patients with osteoporosis in the two countries.

In this 24-month real-world observational study of postmenopausal women with osteoporosis, conducted in the Czech Republic and Slovakia, most patients were prescribed denosumab according to the reimbursement criteria in their country. In both countries, denosumab was always administered by a healthcare professional, treatment discontinuation was low, as was the incidence of new fractures, and no new safety issues were identified.

The baseline characteristics and patient outcomes (specifically BMD) in this real-world study reflect those of the broad population of women with osteoporosis, some of whom are often excluded from clinical trials. There were some notable differences in baseline characteristics between patients from the two countries; patients in the Czech Republic were older, had a higher prevalence of previous osteoporotic fracture, were more likely to have previously received an osteoporosis medication, and had lower mean BMD T scores. This most likely reflects differences in the reimbursement criteria for denosumab between the two countries. Indeed, for most patients, the reasons for prescribing denosumab were in line with the local reimbursement criteria, namely ‘low BMD T score,’ ‘a history of osteoporotic fracture,’ ‘multiple risk factors for fracture,’ ‘failure to respond to other available osteoporosis therapy,’ and ‘intolerance to other osteoporosis therapy.’ The fact that DXA assessments were performed in at least 99% of patients prior to prescription of denosumab suggests that the results of these tests influence the treatment decision. Indeed, in the Czech Republic, DXA criteria for diagnosis and treatment must be fulfilled before treatment for osteoporosis is started.

A further 72–84% of women also had DXA scans while receiving denosumab, indicating that, in both countries, many patients continued to be monitored for changes in BMD during treatment. In total, 89% of patients in the Czech Republic met the reimbursement criteria for denosumab. Equivalent data were not collected in Slovakia because these reimbursement requirements do not apply.

Treatment discontinuation rates (11.3–14.3%) were slightly higher than study withdrawal rates (7.0–11.7%) but were relatively low overall; most individuals in both countries received all four post-baseline injections of denosumab (82.0% and 81.0% of patients in the Czech Republic and Slovakia, respectively). The relatively low discontinuation rates observed in the real-world clinical settings are important because, while many patients with osteoporosis are treated with bisphosphonates, results from systematic reviews show that persistence with and adherence to therapy with these agents can be suboptimal [9, 10]. Adherence to bisphosphonates and osteoporosis treatments has also been shown to be poor in studies carried out in postmenopausal women in the Czech Republic [27] and Slovakia [28]. Thus, denosumab may help to improve persistence with therapy compared with bisphosphonates in the real-world setting in these countries. Nevertheless, persistence-enhancing strategies should still be used to optimize medication-taking and clinical outcomes. Results of further studies examining such strategies would be of great interest.

Irrespective of the total number of injections received on study, more than 98% of patients in both countries received all their denosumab injections at the center where the initial injection was prescribed, suggesting similarities in management practices in the two countries. Regular contact with healthcare professionals at the prescribing center may have contributed to the low discontinuation rates in this study. It has previously been shown that regular interaction with nurses improves persistence with osteoporosis therapy [29, 30].

Persistence with denosumab has been reported to be high: in retrospective and prospective studies, 81–95% of patients were persistent with denosumab after 1 year of treatment and 75–86% were persistent after 2 years [18‐21, 31]. However, an analysis of prescription data from the General Health Insurance Company of the Czech Republic showed that, although 93.8% of postmenopausal women with osteoporosis were compliant with denosumab treatment (defined as a medication possession ratio ≥ 0.8), persistence (defined as a refill gap ≤ 30 days) was only 59.1% after 12 months and 34.8% after 24 months [32]. The disparity between the persistence rate reported from the retrospective database study and the high proportion of women receiving all four doses of denosumab in our study may, in part, be explained by differences in study design. The 30-day refill gap used to define persistence in the retrospective database study could be considered restrictive. Previous retrospective and prospective studies of persistence with denosumab have used a 60-day or 8-week refill gap [18‐21]; therefore, a refill gap longer than 30 days may be appropriate for assessing denosumab persistence. Our study measured discontinuation rather than persistence so refill gaps are not relevant. In addition, the prospective design of our study may have led to more rigorous recording of medication-taking behavior; furthermore, patients were aware that they were being observed, which may have influenced their behavior [33].

The rate of new fractures in Slovakia in our study (1.3%) was in line with the rate reported during clinical trials of denosumab in postmenopausal women with osteoporosis in which the proportion of patients experiencing new fractures ranged from 2.3 to 6.5% during a 3-year study [14], and the annual incidence of new fractures was 0.8–2.6% in the 10-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study and extension [34]. However, the proportion of patients in the Czech Republic who experienced new fractures was higher (6.0%) than that reported in clinical studies [14]. Differences in the baseline characteristics of the patients at the Czech Republic centers in our study and those of the FREEDOM study must be considered. The FREEDOM study included women aged 60–90 years who had a BMD T score of − 2.5 or less at the lumbar spine or total hip but no less than − 4.0 at both sites; women who had taken oral bisphosphonates for more than 3 years were excluded [14]. In addition, differences in the reimbursement criteria in the Czech Republic and Slovakia mean that patients receiving denosumab in the Czech Republic were likely to have more severe disease than those in Slovakia. Indeed, in our study the proportion of patients who had had a previous osteoporotic fracture in the Czech Republic (67.7%) was more than double that reported in Slovakia (30.0%) or among participants in the FREEDOM trial (45.0%) [35]. If previous fracture is considered a strong predictor of future osteoporotic fractures [36], a higher rate of new fractures would be expected in the Czech Republic population studied here. Given the severity of osteoporosis and the risk factors for fracture in the population in the Czech Republic in this study, the proportion of women experiencing new fractures could be considered relatively low.

No new safety signals were identified, and the ADRs that occurred during the study were consistent with the known safety profile of denosumab or reflected diseases that are common in older women [16, 17, 37, 38]. Given that more than half of patients from the Czech Republic were prescribed denosumab because of intolerance to previous osteoporosis medications, this suggests that denosumab has an acceptable safety profile in patients who are intolerant of other osteoporosis medications.

Furthermore, no new safety risks were identified, and ADRs were consistent with the known safety profile of denosumab. The findings of our study in patients who are at high risk for fracture are consistent with the growing body of evidence demonstrating the effectiveness of denosumab in real-world clinical practice.