Osteoporosis International

, Volume 19, Issue 8, pp 1153–1160

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women

  • P. D. Delmas
  • S. R. Davis
  • J. Hensen
  • S. Adami
  • S. van Os
  • E. A. Nijland
Original Article

DOI: 10.1007/s00198-007-0545-3

Cite this article as:
Delmas, P.D., Davis, S.R., Hensen, J. et al. Osteoporos Int (2008) 19: 1153. doi:10.1007/s00198-007-0545-3

Abstract

Summary

A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment.

Introduction

Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed.

Methods

A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60–79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism.

Results

Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p < 0.01 and at year 2: 3.8% versus 2.1%, p < 0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p < 0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline.

Conclusions

Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.

Keywords

Bone mineral density Menopause Osteoporosis Raloxifene Tibolone 

Introduction

Osteoporosis is a major public health concern resulting in significant morbidity and mortality. An estimated 75 million people in Europe, the USA and Japan currently suffer from osteoporosis and, if the present trend continues, the prevalence is expected to double by 2020 [1]. Loss of estrogen at the time of the menopause means that women are at increased risk, and around one third will suffer a fracture at some stage [2]. The lifetime risk of hip fracture in Caucasian women is 1 in 6, compared with 1 in 9 for breast cancer [3]. About 20% of elderly people die within a year of fracturing their hip and a further third become totally dependent [4].

Estrogen treatment is recognized to be effective in preventing osteoporosis [5, 6], but the role of hormone therapy (HT) has recently been revisited following reports by the Women’s Health Initiative of an increased risk of breast cancer and cardiovascular disease [7]. Other strategies are available to prevent osteoporosis, including the selective estrogen receptor modulators (SERMs), bisphosphonates and tibolone.

Tibolone is a selective tissue estrogenic activity regulator (STEAR) that has estrogenic effects on certain tissues, such as bone, brain and vagina, but not on others including endometrium and breast [8]. The bone preserving effects are mediated by direct activation of the estrogen receptor [9]. Randomized controlled studies in postmenopausal women have shown that the standard dose of tibolone (2.5 mg/day) prevents bone loss by reducing bone turnover, thus resulting in increased bone mineral density (BMD) [10, 11, 12, 13, 14]. A lower dose of 1.25 mg/day has also proved consistently effective on bone and has been recognized as the optimal dose for osteoporosis prevention [15, 16, 17, 18, 19, 20]. The SERM raloxifene has estrogen agonistic effects on bone, and estrogen antagonistic effects on the endometrium and breast, and has proved to be effective in the prevention and treatment of osteoporosis in postmenopausal women by increasing BMD and reducing vertebral fractures [21, 22, 23, 24, 25, 26, 27]. Preliminary results from the large scale randomized, placebo-controlled “Long-term Intervention on Fractures with Tibolone” (LIFT) trial have shown that tibolone 1.25 mg/day reduced fracture rates by 50% (P = 0.0003) in older (≥60 years) postmenopausal women with osteoporosis [28].

It is unknown, however, how tibolone compares to a standard regimen of raloxifene with respect to the effects on bone in elderly postmenopausal women with low bone mass.

The aim of the Study of Tibolone’s Effects on osteoPenia (STEP) study was to evaluate the effects of 2 years of treatment with tibolone 1.25 mg/day on BMD and biochemical markers of bone metabolism in osteopenic women and to compare these effects with those of raloxifene 60 mg/day. This is the first randomized controlled trial to directly compare the efficacy of tibolone and raloxifene in the prevention of osteoporosis.

Materials and methods

Subjects

This randomized, double-blind, double-dummy, parallel group comparative trial was conducted in eight centers in five countries (Australia, France, Germany, Italy and the USA). Subjects were osteopenic, but otherwise healthy, postmenopausal women aged 60–79 years. The women were required to have been amenorrheic for at least one year (if the date of last menstruation was unclear due to perimenopausal HT use, HT had to have been used for at least 2 years), to have a lumbar vertebrae (L1–L4) BMD between −2.5 and −1.0 standard deviations and a body mass index >19 and ≤30 kg/m2. Women were excluded if they were not ambulatory or if they had a spinal X-ray showing a symptomatic vertebral fracture (i.e., more than 20% reduction in expected vertebral height), a history of bilateral hip replacement or bone disease other than osteoporosis. Other exclusion criteria included history or presence of malignancy (except non-melanoma skin cancer), an abnormal Pap smear or transvaginal ultrasound finding, undiagnosed abnormal vaginal bleeding in the previous year, mammography or physical examination findings suggestive of malignancy, uncontrolled hypertension, type I diabetes mellitus, presence or history of thromboembolic disorders, serious decompensated renal or hepatic disease, abnormal laboratory values, and the use of more than 20 cigarettes or four alcoholic drinks per day. Current or recent prolonged use of hepatic microsomal enzyme-inducing anticonvulsants (or other drugs known to affect the pharmacokinetics of steroids), use of anabolic steroids, calcitonin or raloxifene in the last 6 months, treatment with alendronate or risedronate for more than 6 months (12 month washout required if >6 months), treatment with etidronate (washout of 6 or 12 months required if used for ≤1 year or >1 year, respectively), use of fluoride treatment for ≥2 weeks, systemic glucocorticoid treatment for more than 1 month in the past 6 months, a change in thyroid medication in the last 6 weeks, and history of use of estrogen and/or progestin implants were all reasons for exclusion. Washout periods included 8 weeks for oral estrogen and/or progestin therapy, 4 weeks for transdermal HT or local estrogen, and 20 weeks for medroxyprogesterone acetate-containing contraceptives.

The study was conducted in compliance with the Declaration of Helsinki, ICH guidelines and Good Clinical Practice; the protocol was approved by the independent ethics committee or institutional review board of each center. All women provided written informed consent.

Treatment

The women were randomized to treatment with oral tibolone 1.25 mg or raloxifene 60 mg once daily for 2 years. Treatment was taken in the evening and a double-dummy technique was used to preserve blinding. Concomitant use of sex hormones or anabolics, hepatic enzyme inducing drugs, cholestyramine, colestipol, coumarin products or medication for osteoporosis (except calcium/vitamin D) was not permitted.

Assessments

Following screening and baseline visits, the women returned for assessments after 4, 12, 24, 52, 76 and 104 weeks of treatment. At screening, BMD of the lumbar vertebrae (L1–L4) and total hip (neck, trochanter and intertrochanteric region) was measured using dual X-ray absorptiometry (DEXA), and lateral lumbar and thoracic spinal X-rays were performed. The baseline visit, at which biochemical markers of bone metabolism—serum osteocalcin and type I collagen C-telopeptides (CTX-1)—were determined, was performed no more than 42 days after screening. Assessments of lumbar vertebrae and hip BMD were repeated after 52 and 104 weeks of treatment, spinal X-rays after 104 weeks, and biochemical markers of bone metabolism after 12, 24, 52 and 104 weeks. Spinal X-rays were read centrally by one contract research organization (Synarc, France).

Bone mineral density of the lumbar vertebrae was measured using DXA scanners from Hologic (QDR-1000, −1000W, −1500, −2000 or −4500 absorptiometers) or comparable Lunar DEXA scanners. Due to the different scanner brands and types within one site, all BMD assessments were adjusted to the scanner brand Hologic type QDR 2000 used by one of the largest participating centers. The adjustments as described were performed by one contract research organization specialized in BMD measurement (Synarc, France). Blood samples for analysis of biochemical markers of bone metabolism were taken after the subjects had fasted for at least 10 hours. The samples were sent to a central laboratory for analysis (Synarc, Lyon, France).

Safety was assessed throughout the study by evaluation of signs and symptoms, adverse events (AEs), laboratory parameters, physical examination, vital signs, gynecological examination, endometrial safety evaluation and mammography.

Statistical analyses

Standard deviations of the percentage change from baseline in BMD after 2 years have been shown to vary between 3% and 4%. The number of subjects per group needed to detect a difference of 1.5% between the groups, with a two-sided significance level of 5%, a standard deviation of 4% and a power of 80% was calculated to be 113. Because it is estimated that approximately 30% of subjects will discontinue early in a 2-year study, the total number of subjects needed was 324.

Efficacy was analyzed in the intent-to-treat (ITT) group (i.e., all randomized women who received at least one dose of study medication and who had at least one post-baseline BMD assessment). Statistical analyses of BMD were performed by an Analysis of Variance (ANOVA) model, with factors for treatment and center using the last observation carried forward (LOCF) approach. Treatment by center interaction was tested at the 10% level. The spinal X-ray findings were analyzed by Chi-square and Fisher exact tests and the biochemical markers of bone metabolism were analyzed using an ANOVA model or a non-parametric Cochran–Mantel–Haenszel test.

Results

A total of 310 women were enrolled and randomized, 154 in the tibolone group and 156 in the raloxifene group. The disposition of the subjects is shown in Fig. 1. Two randomized subjects did not start medication (one because she thought medication intake was not tolerable and one quoted personal reasons). All 308 subjects (153 on tibolone and 155 on raloxifene) who received at least one dose of treatment are included in the all-subjects-treated (AST) population and are used for the safety analysis; their demographic characteristics are presented in Table 1. Baseline characteristics were comparable for both groups and no differences existed in previous use of anti-osteoporotic treatment such as HRT, bisphosphonates or others. All subjects with at least one post-baseline BMD assessment (115 on tibolone and 120 on raloxifene) are included in the intent-to-treat (ITT) population and are used for the efficacy analysis. The study was discontinued prematurely by 33% of the AST population: 52 subjects in the tibolone group and 50 subjects in the raloxifene group, resulting in 101 completers on tibolone and 105 on raloxifene. Treatment compliance, assessed by pill count, was high in both groups: 93.3% with tibolone and 92.8% with raloxifene. Concomitant use of calcium and/or vitamin D preparations was 20% for the total trial population with no differences between groups.
Fig. 1

Subject disposition

Table 1

Demographic characteristics (all-subjects-treated population)

 

Tibolone (n = 153)

Raloxifene (n = 155)

Mean (±SD) age (years)

66.0 ± 4.6

65.9 ± 4.4

Mean (±SD) weight (kg)

66.1 ± 8.7

64.8 ± 8.3

Mean (±SD) height (cm)

160.1 ± 6.0

160.7 ± 5.7

Mean (±SD) body mass index (kg/m2)

25.8 ± 2.8

25.1 ± 2.9

Mean (±SD) time since menopause (years)

17.4 ± 6.5

17.8 ± 7.0

Number (%) of women who have ever used HT and/or bone agents

65 (42.5%)

63 (40.9%)

Number (%) of hysterectomized women

40 (26.1%)

41 (26.5%)

Data missing for one subject

Bone mineral density

Mean baseline lumbar spine BMD was 0.87 (SD ± 0.06) and 0.88 (SD ± 0.05) g/cm2 in the tibolone and raloxifene groups, respectively. Significant (p < 0.001) increases in lumbar spine BMD compared with baseline occurred in both the tibolone and raloxifene groups after 1 year (2.2% and 1.2%) and 2 years (3.8% and 2.1%) (Fig. 2). A significant treatment difference in favor of tibolone was already present after 1 year (p < 0.01) and was maintained after 2 years (p < 0.001). The percentage of women who did not lose bone at the lumbar spine bone after both 1 year and 2 years was larger in the tibolone group than in the raloxifene group at year one (81.7% vs. 62.5% for tibolone versus raloxifene respectively p < 0.01) and at year 2 (90.4% vs. 70.8%; p < 0.0001).
Fig. 2

Percentage change from baseline in mean lumbar spine BMD (±SEM) with tibolone and raloxifene after 1 and 2 years (ITT population). * p < 0.01 vs. raloxifene. ** p < 0.001 vs. raloxifene

Mean total hip BMD at baseline was 0.81 g/cm2 in both groups (T-score of −1.1). Tibolone significantly increased total hip BMD after 1 year (change from baseline 0.79 g/cm2p < 0.05) and 2 years (change from baseline 1.15 g/cm2p < 0.0001) (Fig. 3) achieving a statistical significant difference when compared to raloxifene after 2 years (percentage change from baseline 1.26% and 0.44% for tibolone and raloxifene respectively p < 0.05) (Fig. 3). The percentage of women who did not lose bone at the hip was similar in the tibolone and raloxifene groups after 1 year (60.9% vs. 60%) and 2 years (60.9% vs. 59.2%) of treatment. The mean increase in BMD in tibolone and raloxifene treated patients at 2 years were 1.51% (p = 0.01) and 1.32% (p = 0.056), respectively, at the femoral neck. There was no significant difference in the increase in femoral neck BMD between the two groups. The mean increase in BMD in tibolone and raloxifene treated patients at 2 years were 2.28% (p < 0.0001)and 1.01% (p = 0.05), respectively, at the trochanter. The increase was significantly greater (p = 0.015) in the tibolone group than in the raloxifene group at 2 years.
Fig. 3

Percentage change from baseline in mean total hip BMD (±SEM) with tibolone and raloxifene after 1 and 2 years (ITT population). * p < 0.05 vs. raloxifene

Bone turnover markers

The percentage changes from baseline in biochemical markers of bone turnover are shown in Table 2. Tibolone and raloxifene both resulted in a significant reduction in type I collagen C-telopeptides and osteocalcin levels. The reduction in type I collagen C-telopeptides was significantly (p < 0.05) greater with tibolone than with raloxifene after weeks 24, 52 and 104, whilst the reduction in osteocalcin was significantly (p < 0.0001) greater with raloxifene at week 12.
Table 2

Percentage change from baseline (mean±SD) in serum type I collagen C-telopeptides and osteocalcin during treatment with tibolone and raloxifene (ITT population)

 

Tibolone (n = 115)

Raloxifene (n = 120)

Type I collagen C-telopeptides (ng/mL)

Baseline

0.42 ± 0.19

0.42 ± 0.19

Week 12

−22.01 ± 30.01c

−15.55 ± 32.73d

Week 24

−29.68 ± 36.30c,d

−17.45 ± 40.85b

Week 52

−28.06 ± 38.33b,d

−18.27 ± 40.44a

Week 104

−20.17 ± 46.15b,d

−8.01 ± 48.19

Osteocalcin (μg/L)

Baseline

27.42 ± 9.12

27.63 ± 8.53

Week 12

−1.78 ± 19.95

−13.77 ± 17.42c,e

Week 24

−12.25 ± 23.10c

−16.98 ± 17.21c

Week 52

−14.98 ± 26.31c

−20.26 ± 16.82c

Week 104

−17.68 ± 23.91c

−15.57 ± 19.10c

Data evaluable for 111 women in the tibolone group and 113 in the raloxifene group

ap < 0.05 vs. baseline; bp < 0.01 vs. baseline; cp < 0.0001 vs. baseline dp < 0.05 vs. raloxifene; ep < 0.0001 vs. tibolone

Spinal X-rays

Most changes in vertebral body shape from “normal” to “abnormal” at 2 years were described as related to osteoarthritis and qualified as “clinically insignificant” except for one patient with an incident vertebral fracture and one with a deformation compatible with a mild vertebral fracture, both in the raloxifene treated group.

Safety and tolerability

Tibolone and raloxifene were well tolerated, with generally no differences between the groups in the prevalence of subjects reporting AEs, serious AEs or withdrawals due to AEs (Table 3). One subject in the raloxifene group died after a fall that resulted in a fatal subarachnoid bleeding. Drug-related (defined as definitely, probably or possibly related to the trial medication by the investigator blunted to treatment allocation) serious AEs reported for seven subjects in the tibolone group were: postmenopausal bleeding (n = 1), uterine polyp and vaginal bleeding (n = 1), endometrial disorder (n = 1), hydrometra (n = 1), meningioma (n = 1), breast cancer (n = 1) and transient ischemic attack (n = 1). Three drug-related serious AEs were reported for the raloxifene group: benign breast neoplasm (n = 1), dystonia (n = 1) and exanthema and pruritis (n = 1).
Table 3

Reporting of adverse events with tibolone 1.25 mg and raloxifene (all-subjects-treated population)

 

Tibolone (n = 153)

Raloxifene (n = 155)

Deaths

0

1 (0.6%)

Subjects with AEs

143 (93.5%)

147 (94.8%)

Subjects with SAEs

31 (20.3%)

23 (14.8%)

Discontinuations due to (S)AEs

42 (27.5%

36 (23.2%)

Subjects with drug-related AEs

108 (70.6%)

92 (59.4%)

Subjects with AEs of known severe intensity

34 (22.2%)

34 (21.9%)

AEs: Adverse events

SAEs: Serious adverse events

AEs that were reported in >10% of subjects in the tibolone group were: muscle spasms (25.5%), arthralgia (16.3%), hyperhidrosis (13.7%), back pain (13.1%), weight increase (12.4%), hypertension (11.8%), nasopharyngitis (11.1%) and menopausal symptoms (10.5%). In the raloxifene group, AEs with a prevalence >10% were: muscle spasms (26.5%), menopausal symptoms (18.1%), hyperhidrosis (16.1%), weight increase (13.5%), arthralgia (12.9%), back pain (11.6%) and nasopharyngitis (11.6%).

Overall, early discontinuation due to adverse events was 25.3% (similarly divided over the two groups). Most often reported reasons for discontinuation in the tibolone group were reproductive system and breast disorders (9.2%), body weight increase (3.3%) and gastrointestinal disorders (3.9%). In the raloxifene group, the most often reported reasons for discontinuations were vascular disorders (4.5%) body weight increase (3.2%) and musculoskeletal and connective tissue disorders (2.9%). Discontinuation due to menopausal symptoms occurred twice as often in the raloxifene group versus the tibolone group (5% vs. 2%). There were no between-group differences in laboratory parameters, physical parameters, gynecological examinations, mammograms or vital signs.

Discussion

This study was performed to compare the effects of tibolone 1.25 mg with raloxifene 10 mg on lumbar spine and hip BMD in osteopenic postmenopausal women. Our results show that tibolone increases BMD in both lumbar spine as well as in the total hip significantly more than raloxifene after two years of treatment (lumbar spine: 3.8% vs. 2.1% for tibolone and raloxifene, respectively, p < 0.001; and hip 1.26% vs. 0.44%, respectively, p < 0.05). Tibolone and raloxifene were generally well tolerated in this population of older postmenopausal women and adverse event rates were comparable between the groups during the two years of the STEP study. The number of early discontinuations was higher than reported for previous raloxifene studies [26]; however, it was comparable to what is commonly seen in HRT trials [7].

Discontinuations in the tibolone group were mainly due to reproductive system and breast disorders including vaginal bleeding and breast pain. In the tibolone group, no pattern of serious AEs was observed; in particular, there was no increased risk of stroke. This finding is relevant since a preliminary analysis of the LIFT trial has reported an increased risk of stroke in older women treated with tibolone for osteoporosis [28, 29]. In line with previous studies, treatment with raloxifene appeared to result in an increase in hot flushes [26, 30]. No cases of venous thromboembolism (VTE) in the raloxifene group were seen in this trial. It must be emphasized, however, that the current trial was not powered to identify the significance of less common serious AEs, such as VTE and stroke.

These findings in our study add on to the current available knowledge about tibolone’s bone preserving effect in both early and late postmenopausal women [15, 17, 18] and in those with established osteoporosis [16, 31, 32]. Several studies have focused on the lower dose of tibolone (1.25 mg/day) that was selected for the present study [15, 19]. Moreover, several direct comparative clinical trials as well as one meta-analysis have confirmed that the effect of tibolone on BMD is comparable to estrogens [10, 12, 33]. The effect of estrogens on fracture rate reduction has been established among other trials, in the prospective randomized controlled WHI study and preliminary results of a beneficial effect of tibolone on fracture incidence has been presented recently [28].

Raloxifene is an established therapy for the prevention and treatment of osteoporosis. Raloxifene significantly reduces the incidence of new vertebral fractures (relative risk 0.7 to 0.5 with 60 mg/day vs. placebo according to the baseline risk of fracture) although the increases in BMD were relatively small compared to other anti-bone resorptive agents [26]. There is no evidence that raloxifene can reduce the risk of hip and other non-spine fractures [34] except for a small subset of high risk patients in a post-hoc analysis of the MORE study [35].

Direct comparative studies on bone remodeling between tibolone and raloxifene are lacking, but experimental data suggest that raloxifene differs from estrogen exhibiting less bone remodeling suppression than estrogen, especially with continued use [36, 37]. In contrast, in animal models, clinical trials, and in one meta-analysis, tibolone showed similar a effect on bone remodeling as did estrogen. A previous analysis of clinical trials in a similar population has suggested that the effects of raloxifene on BMD may be less than those observed with estrogen or tibolone [38]. The findings from our study, that use of tibolone results in a statistically significant greater increase in BMD than raloxifene and a trend towards a greater decrease in bone turnover, confirm these previous anecdotal observations. Whether this between-group difference for BMD and bone turnover also translates into a differential effect on fracture prevention is not known.

A limitation of this study is the relatively low number of patients in the study. Although an 80% power was achieved for the primary endpoint on the ITT population, a larger population might have been useful for the analysis of the secondary endpoints. Another limitation is that we selected BMD as the primary endpoint. As the mechanism of action of raloxifene and tibolone on bone tissue of different sites is not identical and as raloxifene exerts its anti fracture efficacy by both an increase in BMD and an enhancement of the mechanical properties of vertebral bone independent of BMD [39], other endpoints such as analysis of iliac crest biopsies might be useful to compare the effects of both anti-osteoporotic drugs. In addition, comparative trials on anti-fracture efficacy are needed.

The strength of our study is that it is the only available head-to-head comparison between raloxifene and tibolone on bone. Both treatments are being prescribed in postmenopausal women and our study results provide further insight into their effects. Treatment decision depends not only on their effects on bone but also on the non-skeletal effects, including effects on climacteric symptoms, breast cancer, and cardiovascular disease.

In conclusion, treatment with tibolone 1.25 mg/day for 2 years effectively prevents postmenopausal bone loss and results in a larger increase of BMD at the lumbar spine and the hip than a standard dose of raloxifene. Tibolone therefore not only provides a comprehensive treatment for climacteric symptom relief, but may also be an attractive option for the prevention of postmenopausal bone loss.

Acknowledgements

The authors would like to thank Ellemiek von Mauw (Global Clinical Development, Organon, Oss) and Sabine Braat (Biometrics Department, Organon, Oss) for their contributions to the execution, statistical analysis and reporting of this study. The editorial contribution of Jane Irons (JSI Communications) to this manuscript is also acknowledged.

Conflicts of interest

P. Delmas has consulted for and received speaker fees from Organon. E. Nijland was an employee of Organon at the time of the study. S. Davis has been an investigator for Organon and has received honoraria for lectures from Organon. S. Adami and J. Hensen report no relevant conflicts of interest.

Funding source

This study was funded by NV Organon, Oss, The Netherlands.

Manufacturer names

Tibolone (Livial®): NV Organon

Raloxifene (Evista®): Eli Lilly

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Authors and Affiliations

  • P. D. Delmas
    • 1
    • 7
  • S. R. Davis
    • 2
  • J. Hensen
    • 3
  • S. Adami
    • 4
  • S. van Os
    • 5
  • E. A. Nijland
    • 6
  1. 1.INSERM Research Unit 831 and University of LyonLyonFrance
  2. 2.Monash Medical SchoolPrahranAustralia
  3. 3.University of ErlangenErlangenGermany
  4. 4.University of VeronaValeggio sul MincioItaly
  5. 5.Global Clinical Development, NV OrganonOssThe Netherlands
  6. 6.Rugpoli TwenteDeldenThe Netherlands
  7. 7.INSERM Research Unit 831, Hôpital E. HerriotLyonFrance

Personalised recommendations