Introduction
Osteoporosis is a disease characterized by excessive bone resorption leading to reduced bone strength and an increased risk of fracture. In women, reduced oestrogen levels during or after menopause can lead to postmenopausal osteoporosis (PMO) [
1].
There are several treatments available for osteoporosis, which have the primary aim of reducing the risk of fracture [
2,
3]. For optimal outcomes, patients need to take their treatment according to the dosing instructions and for the prescribed duration (i.e., they need to be both compliant and persistent with therapy) [
4]. Studies in both the USA and Europe have shown that persistence with osteoporosis treatment is important for reducing the risk of fracture [
5‐
7]. The data indicate that, compared with treatment lasting for less than 1-month, treatment must extend beyond 1 year in order to significantly reduce 3-year fracture incidence [
6]. Evidence suggests, however, that approximately 50 % of women do not follow their prescribed osteoporosis treatment regimen and 50 % discontinue treatment within 1 year [
8,
9]. Hence, persistence is an important consideration in the overall management of patients with osteoporosis. Moreover, modelling studies have shown that the incorporation of persistence in health economic evaluations can have a considerable impact on the estimated cost-effectiveness of an intervention [
10,
11].
Oral bisphosphonates (BPs), including both alendronate and risedronate, are the current mainstay of anti-osteoporosis treatment in Europe [
12]. Oral BPs can be administered daily, weekly, or monthly. An alternative treatment option is denosumab, a fully human monoclonal antibody that inhibits the RANK ligand, which is administered as a 60-mg subcutaneous injection once every 6 months. Denosumab 60 mg is indicated for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fracture [
13]. Denosumab 60 mg has also been shown to increase bone mass in women with bone loss associated with adjuvant aromatase inhibitor therapy [
14].
In patients with osteoporosis, the long-interval subcutaneous dosing regimen of denosumab could enable higher persistence with therapy than that observed with other anti-osteoporosis treatments [
7,
9]. Indeed, levels of 12-month persistence have been reported with denosumab that vastly exceed the 50 % rate cited above. In a randomized, cross-over trial comparing denosumab with alendronate, 91 % of patients were persistent with treatment over 12 months, whilst in two single-arm, prospective, observational studies conducted in the USA, Canada, Austria, Belgium, Greece, and Germany, 12-month persistence rates varied from 82 to 94 % across countries [
15‐
17]. To our knowledge, however, no study of real-world persistence with denosumab therapy in Sweden has yet been published.
This study had two objectives. The first was to estimate persistence in Swedish women in whom denosumab treatment was initiated for PMO and to explore patient characteristics that might affect persistence. The second was to put the findings regarding persistence with denosumab into context by conducting a literature review and meta-analysis of published, retrospective data on persistence with oral BPs.
Discussion
For optimal clinical outcomes, women with PMO need to persist with anti-osteoporosis medications for the prescribed treatment duration. To the best of our knowledge, this is the first retrospective register study of persistence among Swedish women in whom denosumab therapy was initiated for the treatment of PMO. Twelve-month persistence with denosumab treatment was 83 %. This result is similar to previously reported estimates of persistence with denosumab [
15‐
17] and is higher than previously published estimates of persistence with oral BPs. Indeed, this study’s pooled estimate from 39 studies of oral BPs showed that only 45 % of patients were persistent with treatment after 12 months.
Persistence with denosumab
The women included in our database study were slightly older than those included in a study of treatment-naïve users of oral BPs which also used the same database [
6,
47]. Additionally, the majority of women in our study had previously received other anti-osteoporosis therapies; this is not surprising given that most women are prescribed oral BPs as their first line of treatment and subsequently switch to another treatment if they do not respond or experience intolerable side effects or dosing inconvenience. We estimated 12- and 24-month persistence with denosumab therapy to be 83 and 62 %, respectively, using a permissible gap of 56 days (8 weeks). The length of this gap is somewhat arbitrary and was chosen to be consistent with that used in previous studies of persistence using the same database [
6,
47]. Varying the permissible gap to 30, 90, and 180 days resulted in estimated persistence rates of 78, 84, and 87 %, respectively, at 12 months, indicating that the estimates were robust.
Women who had received previous anti-osteoporosis therapies were more likely to persist with denosumab than treatment-naïve women. One possible explanation for this finding is that treatment-experienced women are more informed about their disease and receive more information from their prescriber. Filling a prescription for calcium and/or vitamin D supplementation in the first 6 months after initiating denosumab was significantly associated with persistence, with those who filled prescriptions having a higher persistence rate than those who did not. Similar results were reported by Cotte et al. [
33], who found that the rate of persistence was higher in women taking calcium and vitamin D supplementation than in those who did not take such supplements. While the reason for this is not clear, a possible explanation is that calcium and vitamin D supplementation is an indicator of high risk and, therefore, high disease awareness. Finally, women receiving glucocorticoids before initiating denosumab had lower rates of persistence than those who had no experience of glucocorticoids. Similar results have been reported elsewhere for other anti-osteoporosis treatments [
6,
44,
53], and further study is warranted to elucidate the reasons for the association between persistence and glucocorticoid use.
Persistence with oral bisphosphonates
The literature review identified 40 retrospective studies reporting at least one estimate of 12- or 24-month persistence with oral BPs, using varying methodologies. While all studies were similar in terms of how persistence was defined, they varied in the size of the permissible gap, which is directly related to the probability of being defined as non-persistent. Other study design heterogeneities concerned the possibility of a patient accumulating prescriptions or switching between dosages, dosing intervals, types of BP, and differences in study population. Less obvious differences, which were not systematically captured in our review, related to data quality and completeness, under-reporting by family physicians, and administrative hurdles. As well as methodological heterogeneity, the results are likely to have been influenced by other factors, such as types of healthcare organization, approaches to patient monitoring, drug reimbursement levels, and population disease awareness.
The pooled estimate from our literature review showed that 45 % of patients were persistent with oral BP therapy after 12 months. This relatively low persistence can possibly be explained by the asymptomatic nature of osteoporosis [
68] and the complicated administration of oral BPs, whereby the tablet is taken under fasting conditions and with the patient remaining in an upright position for about an hour to avoid oesophageal reflux and oesophagitis, which, although infrequent, has been reported [
69].
The two Swedish studies identified in the literature review were based on the Swedish Prescribed Drug Register. They estimated 12-month persistence with oral BPs to be 51 and 67 %, and 24-month persistence to be 25 % [
6,
47]. It is worth noting that the estimate of 67 % was derived before the introduction of generic alendronate, which is likely to have caused a drop in persistence. These estimates for persistence with oral BP therapy are lower than the rates observed with denosumab using the same database. The permissible gap was identical to that in the present study (56 days); the only major difference was that patients were allowed to accumulate medicine in the studies of oral BPs.
Limitations
While retrospective register studies are based on historical prescription data and, hence, avoid the reporting bias that can arise in prospective studies, pharmaceuticals administered in hospitals are not captured by the Swedish Prescribed Drug Register and thus have not been included in our analysis. It is estimated that less than 10 % of sold denosumab doses have been administered in hospitals. By not including denosumab administered in hospitals, we may have not identified women who started treatment earlier than was recorded in the database and so we may have underestimated the true persistence rate; however, these women may be atypical and, to a large extent, may have been given denosumab for reasons related to cancer diagnoses. A register of prescriptions does not provide any assurance that the dose was actually taken; therefore, persistence with denosumab may have been overestimated in this study. Another limitation of retrospective data is that all variables of interest may not be available, and it was not possible in this database analysis to control for bone mineral density, concomitant medicine use, comorbidities, lifestyle factors, and socioeconomic variables, all of which may be important predictors of persistence [
57].
The literature review included all identified retrospective studies on oral BPs that reported at least one estimate of either 12- or 24-month persistence, with no other quality requirement for inclusion. Some persistence estimates may consequently have been derived from data of insufficient quality for a robust analysis. In addition, there was heterogeneity between the studies. With this in mind, the pooled estimates and the comparisons between the studies need to be interpreted with some caution. Moreover, the analysis did not consider persistence with other anti-osteoporosis drugs such as zoledronic acid and intravenous bisphosphonates. Persistence with these treatments, which are administered less frequently than oral BPs, has previously been shown to be higher than with oral BPs [
62].
Conclusion
Persistence with denosumab in women with PMO in Sweden was found to be approximately two-fold higher than pooled persistence rates from a meta-analysis of retrospective data on oral BPs. Our results from clinical practice are consistent with previous reports of persistence with denosumab, in both a clinical trial setting and studies of routine practice.
Acknowledgments
Editing support was provided by Claire Desborough, Amgen (Europe) GmbH, and Oxford PharmaGenesis Ltd, Oxford, UK (funded by Amgen). The authors also thank Fereshte Ebrahim, National Board of Health and Welfare, Sweden, for sample extraction. The study was sponsored by Amgen Inc.
Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.