From EFOS to ExFOS
Baseline findings of both observational studies suggested that Greek patients suitable for teriparatide treatment tended to be elderly, have severe osteoporosis and be at high risk of new fractures. They also had relatively frequent and severe back pain, which can affect mobility and consequently quality of life [
20‐
22]. A descriptive comparison between the two studies (Table
1) suggests that women initiating treatment with teriparatide more recently (ExFOS) were relatively healthier, more active, exercised more frequently, could rise from a chair more easily and had fewer previous fractures than their counterparts from EFOS.
In Greece, teriparatide treatment is usually only initiated following prior treatment with anti-osteoporotic medications. While the use of prior osteoporosis medication was high in the total ExFOS cohort, a considerable proportion of patients (19.8 %) were treatment naïve, in common with the EFOS cohort (16.9 %). Since experience with all osteoporosis medications has increased in the period between these two studies and the insurance needs for teriparatide reimbursement include failure of prior osteoporosis treatments, we can only speculate that the treatment naïve patients have been first diagnosed with osteoporosis after a severe event, such as clinical fracture. Our observations indicate there has been a decrease in calcitonin use in recent years, which may reflect concerns of Greek health care practitioners concerning the benefits and risks of calcitonin-containing medicines. These concerns would have been manifest before the final recommendation of the European Medicines Agency (EMA) that calcitonin use should be limited for the treatment of osteoporosis (this recommendation was made in July 2012, 2 months after enrolment into ExFOS was completed, and stated that calcitonin-containing medicines should only be used for short-term treatment because of evidence that long-term use is associated with an increased risk of cancer, and further that they should no longer be prescribed as nasal sprays for the treatment of osteoporosis) [
23].
The study enrolment rate appeared to increase by about 45 % in ExFOS compared to EFOS. This may be explained by the increased familiarity of health care practitioners with teriparatide, and its benefits and risks, and greater awareness of observational studies and the benefits of enrolment. Indeed, many sites were common in both Greek studies, which ameliorates a possible bias due to differing investigators’ perceptions in each study.
The proportions of patients enrolled without a history of fracture increased considerably between the two studies (in EFOS 15.9 % had confirmed no fracture history and 9.6 % did not provide data versus 46.2 % with no fracture history in the female Greek ExFOS subgroup); this discrepancy may be explained in part by changes to reimbursement criteria. A criterion for teriparatide use—only after sustained fracture—was in place during EFOS, but was removed after May 2007. Thus, in ExFOS, committees were able to approve treatment with teriparatide regardless of fracture history.
Impact of changes in health reimbursement system on prescription habits
The Greek health system is complex and based on interplay between a national system financed by the state, and medical expenses financed by social insurance organisations for insured patients. Funding for health services and products comes primarily from the state budget and social insurance funds [
24].
Teriparatide was almost exclusively reimbursed via public insurance institutes. Public reimbursement criteria as well as reimbursement coverage rates have been amended in many occasions during the ExFOS enrolment period.
Since the economic crisis caused a deterioration of health care [
16,
17] and considering the problems faced regarding drug provision by private pharmacies, particularly for teriparatide we were anticipating enrolment delays, especially at milestones of important health care changes. Nevertheless, these factors did not negatively affect enrolment into ExFOS, since the enrolment rate pattern per month was similar to that of other observational studies performed before the economic crisis.
Results from ExFOS show that, at present, teriparatide-treated patients are largely elderly patients. As this segment of the population usually comprises insured pensioners, and since teriparatide is, currently, 100 % reimbursed after being approved by a specialized committee, few patients are currently affected financially. In addition, most patients suitable for teriparatide treatment still visit their healthcare practitioner. In the future, this picture could change. Indeed a growing portion of the Greek population no longer seek preventive care. Whether this will affect consulting patterns during ExFOS and the long-term outcomes of the study remains to be seen.
Impact of EU license changes on prescription habits
The most important change in the EU label of teriparatide, the extension of teriparatide treatment for up to 24 months, has been incorporated into the ExFOS protocol. This longer duration of therapy has been associated with an increase in non-vertebral fracture protection and a reduction in back pain [
25]. Observational studies, such as DANCE (Direct Assessment of Non-vertebral Fractures in the Community Experience), have shown that the reduction in the risk of non-vertebral fractures during 24 months of teriparatide treatment in men and women with osteoporosis stabilises during the last 6-month treatment period [
26]. Furthermore, improvements in the severity of back pain and quality of life have also been recorded after 24 months of teriparatide treatment in postmenopausal women with osteoporosis [
27]. ExFOS may provide data on the effect of this extended period of teriparatide treatment on the risk of fracture and the reduction in back pain.
Following the new indication for teriparatide of male osteoporosis
, 34 Greek men (7.3 %) were enrolled in ExFOS; however, women still out-numbered men by more than 10-fold in the study cohort. This is accordance with Greek epidemiological studies, showing that the prevalence of osteoporosis is more than 10-fold higher in Greek women than in Greek men [
28]. The number of treated Greek men in ExFOS could be perceived as lower than expected. However, despite causing significant morbidity and mortality [
29], male osteoporosis is still under-diagnosed, even in those with vertebral deformities [
30]. Male patients treated with teriparatide were also in the minority in other observational studies, which included a similar percentage of males to that in our study (ISSO study: 9.5 % [
31], DANCE study: 9.6 % [
32], Yu et al.: 9 % [
33]). As reported by Wong et al., in the DANCE study, patient gender may influence a physician’s decision to initiate teriparatide therapy, despite a similar proportion of men and women having prior fragility fractures at baseline and comorbid conditions that increase the risk of fracture [
32]. Frailty, low body mass index and inadequate response or intolerance to previous osteoporosis therapy were reasons for physicians prescribing teriparatide more often in women than in men, whereas chronic glucocorticoid therapy was given as a reason for initiating teriparatide more often in men than women [
32]. Likewise, in our study population, twice as many men as women had a history of glucocorticoid use. These results suggest a preference for prescribing teriparatide in females, regardless of the baseline risk of fracture. However, it is also possible that men were less likely than women to consent to participate in an observational study of a widely perceived ‘female’ health problem, even though men are generally more likely than women to enrol in clinical trials [
34].
In our cohort, only about half of the enrolled men had received prior osteoporosis treatment. It is possible that our study included patients (especially men) who sustained fractures in the past but were never treated for osteoporosis, since data support low osteoporosis treatment rates in patients with a prevalent fracture [
35]. In addition, the observation that men had experienced almost triple the number of hip fractures experienced by women, may provide further support for the finding that, in this study, teriparatide was used in men with more severe osteoporosis and newly diagnosed osteoporosis already complicated by fractures. We should note, however, that the low number (n = 34) of the males in the study population could be challenging in some respects and is a major limitation of the current per gender subanalysis.
Data on the use of teriparatide in GIOP are not available for our population from ExFOS. It is estimated that 2.5 % of the elderly population aged 70–79 years in Britain are prescribed oral glucocorticoid therapy [
36]. Our population has the same age range, yet past glucocorticoid use was reported in a higher percentage of patients (8.9 %). Interestingly, oral glucocorticoid use was reported in an even higher percentage of patients from the EFOS Greek cohort (Table
1). Nevertheless, we consider it unlikely that GIOP was an important factor for teriparatide treatment, at least in patients enrolled in the current ExFOS study. The lack of specific recommendations for teriparatide treatment in GIOP due to cost, the absence of long-term data (due to the restricted duration of administration), and the actual or perceived inconvenience of a daily injection for 24 months [
36] may explain the apparent decrease in the numbers of these patients in a study (ExFOS) in which a specific relevant indication has been incorporated. However, we know from the full EFOS cohort [
37] that for the 18.6 % of women who were glucocorticoid users at any time during the study and who were treated with teriparatide for up to 18 months, analysis of fracture data in 6-month segments revealed that the adjusted odds of fracture were significantly decreased during the last year of follow-up (i.e., during the two 6-month periods covering 24–36 months after teriparatide was discontinued) compared with the first 6 months of teriparatide treatment: an 81 % decrease in the 24 to <30-month period (p < 0.05), and an 89 % decrease in the 30 to < 36-month period (p < 0.05). In addition, the glucocorticoid user group in EFOS demonstrated significant reductions in back pain and improvements in quality of life during teriparatide treatment that were maintained after the drug was discontinued [
37]. It will be interesting to see the impact of a longer duration of teriparatide treatment (i.e. 24 months) on this specific population in the ExFOS cohort.
Regarding back pain, which is a very common symptom in the elderly in the absence of osteoporosis, its evolution during treatment is of great interest to us, considering the favourable effects shown in EFOS [
4,
5,
38] as well as other studies [
39], in contrast to the lack of differences in back pain-related endpoints in a head-tohead trial with risendronate [
40]. Since these patients seem to have lower rates of fractures at treatment initiation, it will be of interest to observe self-reported back pain validation as a consequence of teriparatide treatment.