Background
The quality of life of postmenopausal women with osteoporosis is adversely affected if they have bone fractures and pain [
1‐
6]. Health-related quality of life (HRQoL) has become an important outcome measure in osteoporosis clinical trials and covers physical, emotional and social functioning and well-being, which can be assessed using generic or osteoporosis-specific questionnaires [
1]. A decreased HRQoL is well documented in postmenopausal women with osteoporosis-related fractures, and this can vary according to type of fracture [
7‐
9], number and severity of fractures [
4,
10,
11], and time since fracture [
12]. Some aspects of HRQoL are reduced in patients with subclinical vertebral fractures or reduced bone mineral density [
13], although low BMD is generally regarded as asymptomatic. Additional factors, such as comorbidities and back pain, may also influence HRQoL, especially in older women [
14,
15].
Osteoporosis treatment aims to prevent fractures and, in turn, to reduce morbidity and mortality. The efficacy of osteoporosis medications in reducing the risk of fragility fractures in postmenopausal women with osteoporosis has been demonstrated in randomised controlled trials (RCTs), but there is only limited data that they are capable of improving patient quality of life [
16‐
20] or reduce mortality [
21]. Teriparatide is a bone anabolic agent that reduces the risk of vertebral and non-vertebral fractures in postmenopausal women [
22], but its effect on patient quality of life has not been thoroughly investigated. Moreover, RCTs are conducted using carefully selected patients and there is limited data on HRQoL in routine clinical practice, where patients with osteoporosis can have multiple comorbidities, more severe disease, and receive sequential treatment regimens. In addition, patient adherence or persistence with anti-osteoporosis therapies is poor in everyday clinical practice [
23,
24] and may lead to an increased fracture risk and reduced quality of life. Therefore, data from observational studies can complement RCTs [
25].
Results from the ICARO observational study showed that osteoporotic women who sustained a new fragility fracture during antiresorptive therapy had a lower HRQoL score compared with patients without an incident fracture [
26]. Similarly, in the Observational Study of Severe Osteoporosis (OSSO), women with an inadequate response to osteoporosis therapy had a high rate of incident fractures during 12 months’ treatment with any osteoporosis medication, and this was associated with worse HRQoL regardless of prior fracture status [
2]. An improvement in HRQoL during 18 months of teriparatide treatment in the European Forsteo Observational Study (EFOS) has been reported [
27]. However, changes in HRQoL both during and after teriparatide treatment in routine clinical practice have not been described, nor has the influence of prior and incident fractures on HRQoL during such treatment.
EFOS was a large 36-month, prospective, observational study designed to evaluate fracture outcomes, back pain and HRQoL in postmenopausal women with severe osteoporosis treated with teriparatide in the outpatient setting for a maximum of 18 months, followed by a post-teriparatide treatment observational period of a further 18 months. A reduced incidence of clinical vertebral and non-vertebral fractures and reduction in back pain over 36 months has been reported elsewhere [
28].
The primary aim of this paper is to present a pre-planned analysis of the HRQoL results in the EFOS study population, both during teriparatide treatment for up to 18 months and in the subsequent 18-month period after teriparatide discontinuation when patients were receiving other osteoporosis medications. In addition, we perform a secondary post-hoc analysis to examine the HRQoL changes in patients grouped according to recent prior fracture in the 12 months before the baseline assessment and incident clinical fracture during 36 months follow-up.
Discussion
EFOS is the first study to longitudinally examine health-related quality of life in postmenopausal women with severe osteoporosis in routine clinical practice both during and after teriparatide treatment. The results show that HRQoL (measured using the EQ-5D) is substantially improved during teriparatide treatment for up to 18 months and, importantly, is maintained during the 18-month post-teriparatide period while patients are receiving other osteoporosis treatments (mainly bisphosphonates, as described previously by Fahrleitner-Pammer et al. [
27]). Notably, improvements were seen across all five EQ-5D domains during teriparatide treatment. The HRQoL results are consistent with the back pain results already reported for this study cohort [
27]. Our analysis also shows that when the quality of life data are broken down according to recent prior and incident clinical fracture status, all four subgroups have a comparable but low EQ-VAS at baseline and show a trend for improvement during the study. However, the increase in EQ-VAS is smaller in patients who had an incident fracture at some point during the study compared with those without an incident fracture. Recent prior fracture in the 12 months before the study does not appear to influence the change in EQ-VAS during the study.
Interestingly, the results for the subgroup with no recent prior fracture plus no incident clinical fracture showed a low level of HRQoL at baseline and an increase during treatment. Our finding of a low baseline HRQoL even in the subgroup with no recent prior fracture is consistent with a recent systematic review, which reported that HRQoL is adversely affected by osteoporosis in the absence of vertebral fracture [
33]. However, it may also be a consequence of our patient stratification. We have previously reported that, at baseline, 91.9% of the women in the EFOS study had a previous fracture since the age of 40 years and 70% had two or more vertebral deformities [
28]. As those with prior fractures older than 12 months at baseline were included in the no recent prior fracture group, the improved HRQoL in the no recent prior/no incident fracture subgroup may be due to teriparatide effects on these older fractures. Teriparatide effects on other factors may also be involved in driving the quality of life improvement. These include relief of back pain, which is a major contributor to disability and has a negative impact on HRQoL [
15]. Also, only clinical fractures were considered in EFOS and, as it has been shown that only about 30% of vertebral fractures are clinically diagnosed [
34], patients may have undiagnosed fractures that are impacting on their quality of life [
1]. It is possible that improvements in microfractures are contributing to the improved HRQoL and the beneficial effects of teriparatide on back pain may be related to the prevention and healing of microfractures [
35,
36], but this remains to be proven. The reduced risk of back pain in teriparatide-treated patients has been associated with a reduction in the severity and number of new vertebral fractures [
37]. However, the anti-pain effect of teriparatide cannot be fully explained by vertebral fracture reduction or accelerated fracture healing, although there are very few publications suggesting what the possible reasons could be. A potential CNS effect of teriparatide cannot be excluded, but has not been shown so far [
36]. Another possible explanation for the improvement in HRQoL is that it is a placebo effect resulting from the regular contact with study investigators. Further work is needed to identify other possible factors associated with the observed improvement in HRQoL during and after teriparatide treatment.
Our results are consistent with a substudy from the placebo-controlled Fracture Prevention Trial (FPT) of teriparatide treatment in postmenopausal women with severe osteoporosis, which examined the associations between fractures and HRQoL measured using the Osteoporosis Assessment Questionnaire [
10,
38]. All women in the FPT had a prevalent vertebral fracture at baseline and were at risk of subsequent fractures. Those with more severe vertebral fractures at baseline had a lower baseline HRQoL [
10]. Women with incident fractures (vertebral and non-vertebral) had a worse HRQoL (physical function, symptoms and emotional status dimensions) during the study than women without incident fractures, regardless of treatment group [
38]. Another large RCT evaluating denosumab treatment also demonstrated that incident clinical fractures have an adverse impact on HRQoL in postmenopausal women with osteoporosis [
39].
We measured HRQoL using the generic EQ-5D questionnaire rather than an osteoporosis-specific questionnaire. EQ-5D is a validated standardised instrument for the measurement of health status. A generic instrument has advantages because it enables comparison of health effects between diseases and is the instrument of choice in health technology assessment. Previous studies using EQ-5D have shown an impaired quality of life status after fracture together with gradual improvements over the subsequent year [
40]. Thus, EQ-5D is sensitive to change in patients with osteoporosis-related fractures. Although there have been no reports of what constitutes a clinically-relevant change in EQ-VAS scores for patients with osteoporosis, studies in other diseases indicate that EQ-VAS is responsive to changes in health and that a mean change in the score of 10.9 to 12.1 is a meaningful difference for improved health [
41,
42]. A change of 0.03 in the EQ-5D index score is considered a minimum clinically important difference in patients with osteoporosis [
43].
At baseline, the unadjusted mean EQ-VAS score of 52.0 for the total study cohort indicated that patients had worse quality of life compared with the German population norm for women aged 70–79 years old (mean 75.5) [
31]. We compared our results with population norms for Germany because this country provided 25% of the patients taking part in EFOS [
29]. The mean EQ-VAS values at 18 and 36 months (67.5 and 68.7, respectively) showed improvement in HRQoL. Although HRQoL decreases with age in the general population [
31], the EQ-VAS scores of patients participating in the present study increased over time; however, EQ-VAS was still lower than in an age-matched general German female population. In agreement with Dhillon et al. [
14], we found the most problematic EQ-5D domains were pain/discomfort and usual activities; these two domains were also the most improved during teriparatide treatment.
Our results of an improvement in HRQoL during teriparatide treatment are consistent with a small retrospective single centre study of 57 patients with osteoporosis, which showed that HRQoL (assessed using the mini-Osteoporosis Quality of Life Questionnaire) improved with teriparatide treatment in a clinical practice setting [
44]. Also, the PROPOSE observational study has shown HRQoL improvements during treatment with rhPTH(1–84) [
45]. Although several randomised clinical trials have shown that other osteoporosis treatments (alendronate, strontium ranelate and zoledronic acid) have some beneficial effects on HRQoL in postmenopausal women [
16‐
20], it is difficult to make comparisons between studies because of differences in study design, patient populations and methods used. Nevertheless, despite receiving previous osteoporosis treatment(s) and having multiple comorbidities, the patients in EFOS experienced substantial improvements in HRQoL during teriparatide treatment. As they received other osteoporosis medications after discontinuing teriparatide, those medications may have contributed to the maintenance of HRQoL enhancement associated with teriparatide treatment.
One of the most interesting findings of the study is the influence of recent prior and incident fracture on HRQoL. We observed that women with an incident fracture had less improvement in EQ-VAS during the study than patients with no incident fracture. However, recent prior fracture in the 12 months before baseline did not seem to influence the change in HRQoL either during or after teriparatide treatment. These findings are consistent with the OSSO study, which assessed the impact of fracture on HRQoL (EQ-5D and QUALEFFO) at baseline and at 6 and 12 months of treatment with any osteoporosis medication [
2]. As in our study, HRQoL was worse in patients with an incident fracture regardless of recent prior fracture status [
2]. Recent prior fracture in the months before baseline was associated with an increased risk of incident fracture and worse HRQoL at baseline compared with no recent prior fracture [
2]. In contrast, however, Dhillon et al. [
14] found no significant difference in EQ-5D scores between patients with and without a history of prior fracture.
Although incident fracture is associated with worse HRQoL, we cannot assume a causal relationship. In our analysis of EQ-VAS we adjusted for patient age, duration of prior bisphosphonate treatment and a diagnosis of rheumatoid arthritis, but many other factors may influence HRQoL, including other comorbidities, back pain, and lifestyle [
46].
Our study has several limitations. First, this is a non-comparative study without a control group, and the subgroups of patients with incident fractures were small. The difference in sample size between the subgroups may limit the results. Second, incident fractures were those that were clinically recognised and patients could have had morphometric spine fractures not detected clinically. Third, EQ-5D assesses health status on the day of measurement and there were significant time gaps between HRQoL measurements. Fourth, the EQ-5D results may be influenced by patient drop-outs during the study. For EQ-VAS, this problem was reduced by applying the MMRM. For the other EQ-5D variables (EQ-5D index scores and domain scores), the LOCF method may have overestimated the improvement over time. Finally, comorbidities can impact on patient quality of life; although the baseline data suggests that the subgroups were reasonably well balanced regarding comorbidities.
The strengths of our study include the large sample size with few eligibility restrictions, allowing recruitment of a diverse range of subjects, many of whom had comorbidities and were taking concomitant medications. Other strengths include the prospective assessment of HRQoL both during and after teriparatide discontinuation in the normal clinical practice setting, and adjustment in the analysis for factors that may influence HRQoL, such as age, duration of prior bisphosphonate treatment and a diagnosis of rheumatoid arthritis. It also shows a clinically meaningful improvement in a relevant, patient-related outcome that is consistent across all patient groups.
Competing interests
O Ljunggren has received lecture fees from, participates as a clinical investigator and is on advisory boards for Lilly, Amgen, Astra Zeneca and Nycomed. BL Langdahl has participated on advisory boards for Eli Lilly and Company, MSD, Amgen, Nycomed and Novartis, has received research grants from Eli Lilly and Company, MSD, Amgen and Novartis, and serves on Speaker’s Bureaus with Eli Lilly and Company, MSD and Amgen. WF Lems has received fees for speaking/advisory boards from MSD, Warner Chilcott, Eli Lilly, Amgen and Servier. JB Walsh has received honoraria for lectures from Servier, Eli Lilly and Company, MSD and Amgen. A Fahrleitner-Pammer has received research grants from Amgen, Eli Lilly and Company, Nycomed, Roche and Servier, and has contributed to Speaker’s Bureaus for Amgen, Daiichi Sankyo, Eli Lilly and Company, Genzyme, GSK, MSD, Novartis, Nycomed, Roche, Sanofi-Aventis and Servier. F Jakob has received honoraria for lectures and advice from Lilly, Amgen, Novartis, MSD, Nycomed, Servier and Roche, has received unrestricted research grants from Novartis, and is involved in clinical studies related to osteoporosis drugs initiated by Lilly, Amgen, Servier and Novartis. F Marin is a full-time employee and stock holder of Eli Lilly and Company. A Barrett and I Stoykov are employees of Eli Lilly and Company. D Karras and G Rajzbaum have nothing to disclose.
Authors’ contributions
OL, BL, WL, JW, AF, GR, FJ, DK and FM contributed to the study design, revised and approved the final version of the manuscript. AB, IS and FM contributed to the analysis plan, drafted the manuscript and read and approved the final version. All authors read and approved the final manuscript.