Skip to main content
Download PDF
  • Research article
  • Open access
  • Published:

Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study

BMC Musculoskeletal Disorders volume 14, Article number: 251 (2013) Cite this article

Abstract

Background

To describe changes in health-related quality of life (HRQoL) of postmenopausal women with osteoporosis treated with teriparatide for up to 18 months and followed-up for a further 18 months, and to assess the influence of recent prior and incident fractures.

Methods

The European Forsteo Observational Study (EFOS) is an observational, prospective, multinational study measuring HRQoL using the EQ-5D. The primary objective was to assess changes in HRQoL during 36 months in the whole study population. A secondary post-hoc analysis examined fracture impact on HRQoL in four subgroups classified based on recent prior fracture 12 months before baseline and incident clinical fractures during the study. Changes from baseline were analysed using a repeated measures model.

Results

Of the 1581 patients, 48.4% had a recent prior fracture and 15.6% of these patients had an incident fracture during follow-up. 10.9% of the 816 patients with no recent prior fracture had an incident fracture. Baseline mean EQ-VAS scores were similar across the subgroups. In the total study cohort (n = 1581), HRQoL (EQ-VAS and EQ-5D index scores) improved significantly from baseline to 18 months and this improvement was maintained over the 18-month post-teriparatide period. Improvements were seen across all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. Subjects with incident clinical fractures had significantly less improvement in EQ-VAS than those without incident fractures. Recent prior fracture did not influence the change in EQ-VAS during treatment.

Conclusions

EFOS is the first longitudinal study in women with severe postmenopausal osteoporosis in the real world setting to show a substantial improvement in HRQoL during teriparatide treatment that was sustained during subsequent treatment with other medications. The increase in HRQoL was lower in the subgroups with incident fracture but was not influenced by recent prior fracture. The results should be interpreted in the context of the design of an observational study.

Peer Review reports

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.

Methods

Study design and patients

EFOS was a multicentre, prospective, observational study of fracture outcomes, back pain and HRQoL in postmenopausal women with osteoporosis in eight European countries (Austria, Denmark, France, Germany, Greece, Ireland, the Netherlands, Sweden); the study design, sample size considerations, and characteristics of the patient population have been described in detail elsewhere [29]. Briefly, 1649 postmenopausal women with a diagnosis of osteoporosis who were about to initiate teriparatide treatment were enrolled. Patients were followed for the duration of their teriparatide treatment, which they could discontinue at any time, and were asked to return for two additional visits after they discontinued teriparatide. Patients were excluded from the study if they were currently being treated with an investigational drug or procedure, or had any contraindications as described in the teriparatide label. The observational study design meant there were no further restrictions for the selection of patients, reflecting routine practice. All patients gave written informed consent prior to enrolment and were able to withdraw without consequence at any time. The study was approved by local ethics committees or review boards, depending on local requirements. The study was conducted from April 2004 (first patient enrolled) until February 2009 (last patient completed).

Data collection

At the baseline visit, patient demographic characteristics, risk factors for osteoporosis and falls, osteoporosis therapies and disease status were recorded [29]. The women attended follow-up visits at approximately 3, 6, 12, and 18 months after teriparatide initiation, and at 6 and 18 months after discontinuing teriparatide treatment, during which time the majority of patients took other osteoporosis medication, mainly bisphosphonates [27].

HRQoL was measured at each visit using the EQ-5D, a generic self-administered health status questionnaire that consists of two parts [30]. In the first part, patients classify their own health status according to five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which is scored on a three-point scale (no problems, some problems, or extreme problems). From the scores of these five dimensions, a single index value is derived using a general UK population-based algorithm, where an index score of 0 represents a state equivalent to death and a score of 1 represents a state of perfect health [31, 32]. In the second part of the EQ-5D, patients complete a visual analogue scale (EQ-VAS), which assesses their perceived overall health status on the day of scoring on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

At the baseline assessment, a patient’s history of fragility fractures since the age of 40 years was collected by recording the fracture location and date of each fracture. From this information, a history of recent prior fracture within the last 12 months before starting teriparatide was determined and categorised as yes or no. Information on incident clinical vertebral and non-vertebral fragility fractures occurring during the study were collected at each follow-up visit as self-reported by the patient; these fractures were then diagnosed and confirmed by review of the original radiographs and/or the radiology or surgical reports at the investigational site. A new or worsened vertebral fracture was defined from the presence of a confirmed radiographic vertebral fracture associated with signs and/or symptoms suggestive of a vertebral fracture (such as acute or severe back pain). Incident morphometric spine fractures were not analysed in EFOS.

Statistical analysis

Data were analysed for the total study cohort, which included all patients with a baseline visit and at least one follow-up visit. The impact of fractures on patient HRQoL was assessed in a post-hoc analysis by classifying the total study population into four mutually exclusive subgroups based on recent prior fracture in the 12 months before baseline (yes/no) and incident fracture during the study (yes/no).

Descriptive statistics (e.g. frequencies and percentages for categorical variables; means and standard deviations (SD) or medians with 25th and 75th percentiles for continuous variables) were used to describe the total study population and subgroups by recent prior and incident fracture status. For EQ-VAS and EQ-5D index scores, a last observation carried forward (LOCF) approach was used for missing data.

Baseline characteristics between subgroups were compared using Fisher exact tests for categorical variables, Wilcoxon rank sum tests for time since most recent fracture and number of previous fractures, and t-tests for other continuous variables. The p-values of the pairwise comparisons were Bonferroni adjusted.

EQ-VAS changes from baseline were analysed using a mixed model for repeated measures (MMRM) with an unstructured correlation matrix and adjusting for age, duration of prior bisphosphonate treatment and a diagnosis of rheumatoid arthritis at baseline. We adjusted for age because it is associated with HRQoL [31]. Likewise, we adjusted for rheumatoid arthritis because it was the most prevalent comorbidity in the patient cohort and is associated with worse HRQoL regardless of fracture status. Duration of prior bisphosphonate use was included in the model as a surrogate of the severity of osteoporosis and for consistency with the model used in the primary analysis of the study (incident fractures). Missing values are taken into account using this method. The data are presented as adjusted mean changes from baseline obtained after controlling for the covariates (least-squares mean changes) with standard errors. P-values for the within-group change from baseline represent the unique influence of the corresponding factor after adjustment for the other factors in the model. Pairwise comparisons between subgroups (by fracture status) in the adjusted least-squares mean change from baseline at each follow-up visit were calculated, and the p-values for the comparisons are presented.

For the EQ-5D index score, which was not normally distributed, Wilcoxon signed-rank test was used to assess within-group changes from baseline. Between-group comparisons used Wilcoxon rank-sum tests and Bonferroni adjusted p-values within each visit are reported.

All p-values presented are two-sided and the level of significance is set to 5%. All data were analysed using SAS software version 9.2.

Results

Patients

Of the 1649 postmenopausal women enrolled in the study, 1581 were analysed at baseline and returned for at least one post-baseline visit (the total study cohort). Figure 1 presents the patient distribution for the secondary analysis according to recent prior fracture status in the 12 months before study entry and incident clinical fracture during the study. Of the 1581 patients, 765 (48.4%) had a recent prior fracture in the 12 months before study entry. Of these, 119 (15.6%) patients had an incident fracture during the study. In the group of patients with no prior fracture in the 12 months before baseline (n = 816), 89 (10.9%) patients had an incident fracture during the study. Across the subgroups, 79–94% of patients remained in the study at 18 months and 62–78% were observed at the 36-month visit.

Figure 1
figure 1

Study disposition. Patient distribution by recent prior fracture in the 12 months before study entry and by incident fracture during the study.

Full size image

Table 1 summarises the baseline characteristics of the total study cohort and the four subgroups by recent prior and incident fracture status. There were few differences in baseline characteristics between the subgroups. As expected (because of how the subgroups were defined), the time since recent fracture and number of previous fractures after age 40 differed between groups. However, for the time since most recent fracture, no difference was detected between patients with and without incident fractures in the subgroups with recent prior fracture in the 12 months before baseline (groups A and B); the same was true for the subgroups without recent prior fracture (groups C and D). Among the patients with recent prior fracture, those with an incident fracture (group A) had a significantly higher number of previous fractures than those without incident fracture (group B, p < 0.05); no difference was seen between patients with and without incident fracture in the groups with no recent prior fracture (groups C and D).

Table 1 Baseline characteristics of the four subgroups and total study cohort
Full size table

EQ-VAS

Table 2 presents the unadjusted EQ-VAS scores at each visit for the total study population and for the four subgroups by recent prior and incident fracture status. These unadjusted results are derived from the available data at the visits and support the adjusted analysis from the MMRM (adjusted for age, duration of prior bisphosphonate treatment and a diagnosis of rheumatoid arthritis) shown in Figure 2. For the total study cohort, the unadjusted mean EQ-VAS score was 52.0 (SD 22.0) at baseline, increasing to 67.5 (SD 21.4) at 18 months and maintained at this level at 24 and 36 months (Table 2). The within-group change from baseline was significant at all visits (p < 0.001, Wilcoxon signed rank test). Figure 2 shows an improvement in adjusted mean EQ-VAS from baseline at all visits in the total study cohort (p < 0.001 from MMRM); the increase from baseline at 18 months was 11.3 (95%CI 9.7–12.8) and this was maintained during the post-teriparatide treatment period: 10.0 (95%CI 8.3–11.7) at 24 months and 10.7 (95%CI 8.9–12.5) at 36 months.

Table 2 Unadjusted EQ-VAS and EQ-5D index scores at each study visit
Full size table
Figure 2
figure 2

EQ-VAS changes from baseline. Adjusted mean (SE) change in EQ-VAS from baseline during and after teriparatide treatment in the total study cohort and according to recent prior fracture (within last 12 months) and incident fracture status. Data presented is from the MMRM analysis (adjusted for age, duration of prior bisphosphonate treatment and a diagnosis of rheumatoid arthritis at baseline). All p < 0.05 for within-group change from baseline (except for no recent prior/incident fracture at 6, 24 and 36 months). Significant pairwise comparisons between subgroups at 18 and 36 months are shown in the figure but the same pairwise comparisons were significant (p < 0.05) at 6, 12 and 24 months. *p < 0.05 for recent prior/incident fracture (group A) versus recent prior/no incident fracture (group B); †p < 0.05 for recent prior/incident fracture (group A) versus no recent prior/no incident fracture (group D); ‡ p < 0.001 for recent prior/no incident fracture (group B) versus no recent prior/incident fracture (group C); X p < 0.001 for no recent prior/incident fracture (group C) versus no recent prior/no incident fracture (group D). Note: variability (standard error bars) only added to the graph at two time points (18 and 36 months) for clarity.

Full size image

In the secondary post-hoc analysis, the four subgroups of patients according to recent prior and incident fracture status did not differ in their baseline mean EQ-VAS scores (Table 2). Figure 2 shows significant within-group changes from baseline in the adjusted mean EQ-VAS for all subgroups (p < 0.05 from MMRM), except for the no recent prior/incident fracture subgroup at 6, 24 and 36 months. Figure 2 also shows that the two subgroups with incident fracture (dotted lines) had significantly less improvement in adjusted mean EQ-VAS (irrespective of recent prior fracture) than the two subgroups without incident fracture (solid lines, p < 0.05 for all comparisons at 18 and 36 months). Notably, the no recent prior fracture plus no incident fracture subgroup showed a clear increase in EQ-VAS from baseline to 18 months that was maintained at 36 months (as did the recent fracture plus no incident fracture subgroup). Pairwise comparisons revealed no significant differences at any visit in the change in EQ-VAS between the two subgroups with incident fractures (Groups A and C) or between the two subgroups with no incident fracture (Groups B and D) (Figure 2), indicating that recent prior fracture does not influence the change in HRQoL.

EQ-5D index scores

Median (Q1, Q3) EQ-5D index scores for the total study cohort increased from 0.59 (0.08, 0.73) at baseline to 0.73 (0.59, 0.85) at 18 months and were maintained at this median value after teriparatide discontinuation (Table 2). The median (Q1, Q3) change from baseline in EQ-5D index scores for the total study cohort (Table 3) was significant at each follow-up visit (p < 0.001, Wilcoxon signed rank test for within-group change).

Table 3 Median change from baseline in EQ-5D index score
Full size table

In the secondary post-hoc analysis, the baseline median EQ-5D index scores differed significantly between the subgroup with recent prior and incident fractures (group A) and the subgroup without recent prior and incident fractures (group D) (0.23 [Q1, Q3: -0.02, 0.67] vs. 0.59 [Q1, Q3: 0.09, 0.73]; p < 0.001); all other pairwise comparisons at baseline were non-significant (Table 2). The median (Q1, Q3) changes from baseline in EQ-5D index scores for the four subgroups by recent prior and incident fracture status (Table 3) shows large variability at each visit, but there was a trend for improvement to 18 months that was maintained to 36 months (p < 0.05 for within-group change from baseline for each subgroup, Wilcoxon signed rank test). Pairwise comparisons in the change from baseline at the 18 and 36 month visits showed there was significantly less improvement in EQ-5D index score in the subgroup with no recent prior/incident fracture (group C) compared with the recent prior/no incident fracture subgroup (group B) (Bonferroni adjusted p values; p < 0.05 at both time points); all other pairwise comparisons at these two time points were non-significant (Table 3).

EQ-5D domains

For the total study cohort, there were improvements from baseline in all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. The percentage of women reporting extreme problems in the five domains was reduced at all post-baseline visits and Figure 3 shows the results at 18 and 36 months. The highest frequency of extreme problems was in the usual activities and pain/discomfort domains.

Figure 3
figure 3

Extreme problems in EQ-5D domains. Patients (%) reporting extreme problems at baseline and at 18- and 36-months follow-up in the five domains of EQ-5D for (a) the total study cohort, (b) group A with recent prior fracture and incident fracture; (c) group B with recent prior fracture and no incident fracture; (d) group C with no recent prior fracture and incident fracture; and (e) group D with no recent prior fracture and no incident fracture. The remaining patients in each group reported either no problems or some problems for each domain.

Full size image

Figure 3 also shows the percentage of women reporting extreme problems in the five EQ-5D domains at baseline and 18 and 36 months follow-up for the four subgroups according to recent prior and incident fracture status. As expected, for all five domains the frequency of extreme problems was higher at baseline for the two subgroups with recent prior fracture (groups A and B) than the two groups with no recent prior fracture (groups C and D). Also, the frequency of extreme problems was higher at 18- and 36-months follow-up in the subgroups with incident fractures (groups A and C) than in the subgroups with no incident fractures (groups B and D). Thus, the proportion with extreme problems was highest at baseline and during follow-up in the subgroup of women with both recent prior and incident fractures (group A). The proportion of patients reporting extreme problems in the two subgroups with no incident fractures (groups B and D) decreased during 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.

Conclusions

In this large pragmatic study of postmenopausal women with severe osteoporosis, we have observed a clinically meaningful improvement in HRQoL during teriparatide treatment that is maintained after teriparatide is discontinued when most patients are receiving other osteoporosis medications. We have demonstrated that the improvement in HRQoL is unaffected by a previous history of a recent fracture in the last 12 months before starting treatment but, as expected, was attenuated by incident clinical fractures. Further studies will be needed to understand the underlying mechanisms; however, this study for the first time demonstrated that a clinically-relevant improvement in HRQoL was maintained after stopping teriparatide treatment in addition to previously demonstrated positive effects on clinical fracture. However, because of the open label and non-comparative nature of the present study, our findings need confirmation through a randomised, controlled, double-blind study.

Abbreviations

BMD:

Bone mineral density

CI:

Confidence interval

CNS:

Central nervous system

EFOS:

European Forsteo Observational Study

FPT:

Fracture Prevention Trial

EQ-5D:

EuroQol 5-Dimensions questionnaire

EQ-VAS:

EuroQol Visual Analogue Scale

HRQol:

Health-related quality of life

LOCF:

Last observation carried forward

MMRM:

Mixed model for repeated measures

OSSO:

Observational Study of Severe Osteoporosis

RCT:

Randomised controlled trial

rhPTH:

Recombinant human parathyroid hormone

SD:

Standard deviation.

References

  1. Lips P, van Schoor NM: Quality of life in patients with osteoporosis. Osteoporos Int. 2005, 16: 447-455. 10.1007/s00198-004-1762-7.

    Article  PubMed  Google Scholar 

  2. Cooper C, Jakob F, Chinn C, Martin-Mola E, Fardellone P, Adami S, Thalassinos NC, Melo-Gomes J, Torgerson D, Gibson A, Marin F: Fracture incidence and changes in quality of life in women with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO). Osteoporos Int. 2008, 19: 493-501. 10.1007/s00198-007-0488-8.

    Article  CAS  PubMed  Google Scholar 

  3. Francis RM, Aspray TJ, Hide G, Sutcliffe AM, Wilkinson P: Back pain in osteoporotic vertebral fractures. Osteoporos Int. 2008, 19: 895-903. 10.1007/s00198-007-0530-x.

    Article  CAS  PubMed  Google Scholar 

  4. Oleksik A, Lips P, Dawson A, Minshall ME, Shen W, Cooper C, Kanis J: Health-related quality of life in postmenopausal women with low BMD with or without prevalent fractures. J Bone Miner Res. 2000, 15: 1384-1392. 10.1359/jbmr.2000.15.7.1384.

    Article  CAS  PubMed  Google Scholar 

  5. Salaffi F, Cimmino MA, Malavolta N, Carotti M, Di Matteo L, Scendoni P, Grassi W, Italian Multicenter Osteoporotic Fracture Study Group: The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study. J Rheumatol. 2007, 34: 1551-1560.

    PubMed  Google Scholar 

  6. Silverman SL, Minshall ME, Shen W, Harper KD, Xie S: The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum. 2001, 44: 2611-2619. 10.1002/1529-0131(200111)44:11<2611::AID-ART441>3.0.CO;2-N.

    Article  CAS  PubMed  Google Scholar 

  7. Adachi JD, Ioannidis G, Berger C, Joseph L, Papaioannou A, Pickard L, Papadimiropoulos EA, Hopman W, Poliquin S, Prior JC, Hanley DA, Olszynski WP, Anastassiades T, Brown JP, Murray T, Jackson SA, Tenenhouse A, and the Canadian Multicentre Osteoporosis Study (CaMos) Research Group: The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada. Osteoporos Int. 2001, 12: 903-908. 10.1007/s001980170017.

    Article  CAS  PubMed  Google Scholar 

  8. Brenneman SK, Barrett-Connor E, Sajjan S, Markson LE, Siris ES: Impact of recent fracture on health-related quality of life in postmenopausal women. J Bone Miner Res. 2006, 21: 809-816. 10.1359/jbmr.060301.

    Article  PubMed  Google Scholar 

  9. Hallberg I, Rosenqvist AM, Kartous L, Löfman O, Wahlström O, Toss G: Health-related quality of life after osteoporotic fractures. Osteoporos Int. 2004, 15: 834-841.

    Article  CAS  PubMed  Google Scholar 

  10. Crans GG, Silverman SL, Genant HK, Glass EV, Krege JH: Association of severe vertebral fractures with reduce quality of life. Reduction in the incidence of severe vertebral fractures by teriparatide. Arthritis Rheum. 2004, 50: 4028-4034. 10.1002/art.20671.

    Article  CAS  PubMed  Google Scholar 

  11. Fechtenbaum J, Cropet C, Kolta S, Horlait S, Orcel P, Roux C: The severity of vertebral fractures and health-related quality of life in osteoporotic postmenopausal women. Osteoporos Int. 2005, 16: 2175-2179. 10.1007/s00198-005-2023-0.

    Article  CAS  PubMed  Google Scholar 

  12. Begerow B, Pfeifer M, Pospeschilli M, Scholz M, Schlotthauer T, Lazarescu A, Pollaehne W, Minne HW: Time since vertebral fracture: an important variable concerning quality of life in patients with postmenopausal osteoporosis. Osteoporos Int. 1999, 10: 26-33. 10.1007/s001980050190.

    Article  CAS  PubMed  Google Scholar 

  13. Romagnoli E, Carnevale V, Nofroni I, D’Erasmp E, Paglia F, De Geronimo S, Pepe J, Raejntroph N, Maraanghi M, Minisola S: Quality of life in ambulatory postmenopausal women: the impact of reduced bone mineral density and subclinical vertebral fractures. Osteoporos Int. 2004, 15: 975-980. 10.1007/s00198-004-1633-2.

    Article  PubMed  Google Scholar 

  14. Dhillon V, Hurst N, Hannan J, Nuki G: Association of low general health status, measured prospectively by Euroqol EQ5D, with osteoporosis, independent of a history of prior fracture. Osteoporos Int. 2005, 16: 483-489. 10.1007/s00198-004-1705-3.

    Article  PubMed  Google Scholar 

  15. Silverman SL, Piziak VK, Chen P, Misurski DA, Wagman RB: Relationship of health related quality of life to prevalent and new or worsening back pain in postmenopausal women with osteoporosis. J Rheumatol. 2005, 32: 2405-2409.

    PubMed  Google Scholar 

  16. Adachi JD, Lyles KW, Colón-Emeric CS, Boonen S, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Bucci-Rechtweg C, Su G, Eriksen EF, Magaziner JS: Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-Recurrent Fracture Trial. Osteoporos Int. 2011, 22: 2539-2549. 10.1007/s00198-010-1514-9.

    Article  CAS  PubMed  Google Scholar 

  17. Sambrook PN, Silverman SL, Cauley JA, Recknor C, Olson M, Su G, Boonen S, Black D, Adachi JD, HORIZON Pivotal Fracture Trial: Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT. Bone. 2011, 48: 1298-1304. 10.1016/j.bone.2011.03.719.

    Article  PubMed  Google Scholar 

  18. Dursun N, Dursun E, Yalcin S: Comparison of alendronate, calcitonin and calcium treatments in postmenopausal osteoporosis. Int J Clin Pract. 2001, 55: 505-509.

    CAS  PubMed  Google Scholar 

  19. Kawate H, Ohnaka K, Adachi M, Kono S, Ikematsu H, Matsuo H, Higuchi K, Takayama T, Takayanagi R: Alendronate improved QOL of postmenopausal women with osteoporosis. Clin Interv Aging. 2010, 5: 123-131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Marquis P, Roux C, de la Loge C, Diaz-Curiel M, Cormier C, Isaia G, Badurski J, Wark J, Meunier PJ: Strontium ranelate prevents quality of life impairment in post-menopausal women with established vertebral osteoporosis. Osteoporos Int. 2008, 19: 503-510. 10.1007/s00198-007-0464-3.

    Article  CAS  PubMed  Google Scholar 

  21. Bolland MJ, Grey AB, Gamble GD, Reid IR: Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab. 2010, 95: 1174-1181. 10.1210/jc.2009-0852.

    Article  CAS  PubMed  Google Scholar 

  22. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH: Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001, 344: 1434-1441. 10.1056/NEJM200105103441904.

    Article  CAS  PubMed  Google Scholar 

  23. Confavreux CB, Canoui-Poitrine F, Schott AM, Ambrosi V, Tainturier V, Chapurlat RD: Persistence at 1 year of oral antiosteoporotic drugs: a prospective study in a comprehensive health insurance database. Eur J Endocrinol. 2012, 166: 735-741. 10.1530/EJE-11-0959.

    Article  CAS  PubMed  Google Scholar 

  24. Ziller V, Kostev K, Kyvernitakis I, Boeckhoff J, Hadji P: Persistence and compliance of medications used in the treatment of osteoporosis–analysis using a large scale, representative, longitudinal German database. Int J Clin Pharmacol Ther. 2012, 50: 315-322.

    Article  CAS  PubMed  Google Scholar 

  25. Silverman S: From randomized controlled trials to observational studies. Am J Med. 2009, 122: 114-120. 10.1016/j.amjmed.2008.09.030.

    Article  PubMed  Google Scholar 

  26. Barbagello M, Dominguez LJ, Maugeri D, Isaia G, Silverstri S, Bevilacqua M, Adami S, ICARO Study Group: Quality of life in osteoporotic women with inadequate clinical response to antiresorptive drugs: results from the ICARO study. Aging Clin Exp Res. 2007, 19 (3 Suppl): 24-27.

    Google Scholar 

  27. Langdahl BL, Rajzbaum G, Jakob F, Karras D, Ljunggren O, Lems WF, Fahrleitner-Pammer A, Walsh JB, Barker C, Kutahov A, Marin F: Reduction in fracture rate and back pain and increased quality of life in postmenopausal women treated with teriparatide: 18-month data from the European Forsteo Observational Study (EFOS). Calcif Tissue Int. 2009, 85: 484-493. 10.1007/s00223-009-9299-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fahrleitner-Pammer A, Langdahl BL, Marin F, Jakob F, Karras D, Barrett A, Ljunggren O, Walsh JB, Rajzbaum G, Barker C, Lems WF: Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS). Osteoporos Int. 2011, 22: 2709-2719. 10.1007/s00198-010-1498-5.

    Article  CAS  PubMed  Google Scholar 

  29. Rajzbaum G, Jakob F, Karras D, Ljunggren O, Lems WF, Langdahl BL, Fahrleitner-Pammer A, Walsh JB, Gibsob A, Tynan AJ, Marin F: Characterization of patients in the European Forsteo Observational Study (EFOS): postmenopausal women entering teriparatide treatment in a community setting. Curr Med Res Opin. 2007, 24: 377-384.

    Article  Google Scholar 

  30. The EuroQol Group: EuroQoL: a new facility for the measurement of health-related quality of life. Health Policy. 1990, 16: 199-208.

    Article  Google Scholar 

  31. Szende A, Williams A: Measuring self-reported population health: an international perspective based on EQ-5D. 2004, Hungary: SpringMed Publishing Ltd

    Google Scholar 

  32. Dolan P: Modeling valuations for EuroQol health states. Med Care. 1997, 35: 1095-1108. 10.1097/00005650-199711000-00002.

    Article  CAS  PubMed  Google Scholar 

  33. Wilson S, Sharp CA, Davie MWJ: Health-related quality of life in patients with osteoporosis in the absence of vertebral fracture: a systematic review. Osteoporos Int. 2012, 23: 2749-2768. 10.1007/s00198-012-2050-6.

    Article  CAS  PubMed  Google Scholar 

  34. Majumdar SR, Kim N, Colman I, Chahal AM, Raymond G, Siminoski KG, Hanley DA, Rower BH: Incidental vertebral fractures discovered with chest radiography in the emergency department. Arch Intern Med. 2005, 165: 905-909. 10.1001/archinte.165.8.905.

    Article  PubMed  Google Scholar 

  35. Nevitt MC, Chen P, Dore RK, Reginster J-Y, Kiel DP, Zanchetta JR, Glass EV, Krege JH: Reduced risk of back pain following teriparatide treatment: a meta-analysis. Osteoporos Int. 2006, 17: 273-280. 10.1007/s00198-005-2013-2.

    Article  PubMed  Google Scholar 

  36. Lyritis G, Marin F, Barker C, Pfeifer M, Farrerons J, Brixen K, del Pino J, Keen R, Nickelsen TN, for the EUROFORS Study Group: Back pain during different sequential treatment regimens of teriparatide: results from EUROFORS. Curr Med Res Opin. 2010, 26: 1799-1807. 10.1185/03007995.2010.488516.

    Article  CAS  PubMed  Google Scholar 

  37. Genant HK, Halse J, Briney WG, Xie L, Glass EV, Krege JH: The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis. Curr Med Res Opin. 2005, 21: 1027-1034. 10.1185/030079905X49671.

    Article  CAS  PubMed  Google Scholar 

  38. Oglesby AK, Minshall ME, Shen W, Xie S, Silverman SL: The impact of incidence vertebral and non-vertebral fragility fractures on health-related quality of life in established postmenopausal osteoporosis: results from the teriparatide randomized, placebo-controlled trial in postmenopausal women. J Rheumatol. 2003, 30: 1579-1583.

    PubMed  Google Scholar 

  39. Silverman S, Viswanathan HN, Yang YC, Wang A, Boonen S, Ragi-Eis S, Fardellone P, Gilchrist N, Lips P, Nevitt M, Palacios Gil-Antuñano S, Pavelka K, Revicki D, Simon J, Macarios D, Siris ES: Impact of clinical fractures on health-related quality of life is dependent on time of assessment since fracture: results from the FREEDOM trial. Osteoporos Int. 2012, 23: 1361-1369. 10.1007/s00198-011-1720-0.

    Article  CAS  PubMed  Google Scholar 

  40. Hagino H, Nakamura T, Fujiwara S, Oeki M, Okano T, Teshima R: Sequential change in quality of life for patients with incident clinical fractures: a prospective study. Osteoporos Int. 2009, 20: 695-702. 10.1007/s00198-008-0761-5.

    Article  CAS  PubMed  Google Scholar 

  41. Stark RG, Reitmer P, Leidl R, Konig HH: Validity, reliability, and responsiveness of the EQ-5D in inflammatory bowel disease in Germany. Inflamm Bowel Dis. 2010, 16: 42-51. 10.1002/ibd.20989.

    Article  PubMed  Google Scholar 

  42. Kimman ML, Dirksen CD, Lambin P, Boersma LJ: Responsiveness of the EQ-5D in breast cancer patients in their first year after treatment. Health Qual Life Outcomes. 2009, 7: 11-10.1186/1477-7525-7-11.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Adachi JD, Adami S, Gehlbach S, Anderson FA, Boonen S, Chapurlat RD, Compston JE, Cooper C, Delmas P, Díez-Pérez A, Greenspan SL, Hooven FH, LaCroix AZ, Lindsay R, Netelenbos JC, Wu O, Pfeilschifter J, Roux C, Saag KG, Sambrook PN, Silverman S, Siris ES, Nika G, Watts NB, GLOW Investigators: Impact of prevalent fractures on quality of life: baseline results from the Global Longitudinal study of Osteoporosis in women. Mayo Clin Proc. 2010, 85: 806-813. 10.4065/mcp.2010.0082.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lau AN, Ali SH, Sawka AM, Thabane L, Papaioannou A, Gafni A, Adachi JD: Improvement in health-related quality of life in osteoporosis patients treated with teriparatide. BMC Musculoskelet Disord. 2008, 9: 151-10.1186/1471-2474-9-151.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Möricke R, Rettig K, Bethke TD: Use of recombinant human parathyroid hormone(1–84) in patients with postmenopausal osteoporosis. A prospective, open-label, single-arm, multicentre, observational cohort study of the effects of treatment on quality of life and pain – the PROPOSE study. Clin Drug Investig. 2011, 31: 87-99. 10.1007/BF03256936.

    Article  PubMed  Google Scholar 

  46. Papaioannou A, Kennedy CC, Ioannidis G, Brown JP, Pathak A, Hanley DA, Josse RG, Sebaldt RJ, Olszynski WP, Tenenhouse A, Murray TM, Petrie A, Goldsmith CH, Adachi JD: Determinants of health-related quality of life in women with vertebral fracture. Osteoporos Int. 2006, 17: 355-363. 10.1007/s00198-005-2020-3.

    Article  PubMed  Google Scholar 

Pre-publication history

Download references

Acknowledgements

The authors thank all the physicians and patients who participated in EFOS. The authors also thank Christine Jones, Lilly Germany, for central study coordination; Clare Barker for the development of the statistical analysis plan and the study analysis; Helmut Peto and Phil Smith for additional statistical support and Dr Deirdre Elmhirst for medical writing assistance, funded by Eli Lilly and Company.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, S-751 85, Sweden

    Östen Ljunggren

  2. Lilly Research Centre, Windlesham, UK

    Annabel Barrett, Ivaylo Stoykov & Fernando Marin

  3. Aarhus University Hospital, Aarhus, Denmark

    Bente L Langdahl

  4. VU University Medical Centre, Amsterdam, The Netherlands

    Willem F Lems

  5. Trinity College, Dublin, Ireland

    J Bernard Walsh

  6. Medical University, Graz, Austria

    Astrid Fahrleitner-Pammer

  7. Hôpital St. Joseph, Paris, France

    Gerald Rajzbaum

  8. Julius-Maximilians-Universitaet, Wuerzburg, Germany

    Franz Jakob

  9. Veterans Administration Hospital, Athens, Greece

    Dimitrios Karras

Authors
  1. Östen Ljunggren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annabel Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivaylo Stoykov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bente L Langdahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Willem F Lems
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Bernard Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Astrid Fahrleitner-Pammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gerald Rajzbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Franz Jakob
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dimitrios Karras
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fernando Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Östen Ljunggren.

Additional information

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.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Ljunggren, Ö., Barrett, A., Stoykov, I. et al. Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study. BMC Musculoskelet Disord 14, 251 (2013). https://doi.org/10.1186/1471-2474-14-251

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1471-2474-14-251

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

Contact us