Accepted Manuscript

Tibolone Decreases Lipoprotein(a) levels in Postmenopausal Women: A SystematicReview and Meta-Analysis of 12 studies with 1009 patients

Kazuhiko Kotani, Amirhossein Sahebkar, Corina Serban, Florina Andrica, Peter P.Toth, Steven R. Jones, Karam Kostner, Michael J. Blaha, Seth Martin, Jacek Rysz,Stephen Glasser, Kausik K. Ray, Gerald F. Watts, Dimitri P. Mikhailidis, Prof. MaciejBanach, MD, PhD, FNLA, FAHA, FESC; FASA, Head

PII: S0021-9150(15)30017-4

DOI: 10.1016/j.atherosclerosis.2015.06.056

Reference: ATH 14168

To appear in: Atherosclerosis

Received Date: 28 May 2015

Revised Date: 28 June 2015

Accepted Date: 29 June 2015

Please cite this article as: Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K,Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M, Lipid and BloodPressure Meta-analysis Collaboration (LBPMC) Group, Tibolone Decreases Lipoprotein(a) levels inPostmenopausal Women: A Systematic Review and Meta-Analysis of 12 studies with 1009 patients,Atherosclerosis (2015), doi: 10.1016/j.atherosclerosis.2015.06.056.

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Tibolone Decreases Lipoprotein(a) levels in Postmenopausal Women:

A Systematic Review and Meta-Analysis of 12 studies with 1009 patients

Kazuhiko Kotani1, Amirhossein Sahebkar2,3, Corina Serban4, Florina Andrica5,, Peter P. Toth6,7,

Steven R. Jones7, Karam Kostner8, Michael J. Blaha7, Seth Martin7, Jacek Rysz9, Stephen Glasser10,

Kausik K. Ray11, Gerald F. Watts12, Dimitri P. Mikhailidis13, Maciej Banach14;

Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

1Department of Clinical Laboratory Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Japan;

2Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 3Metabolic Research

Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth,

Australia; 4Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University of

Medicine and Pharmacy, Timisoara, Romania; 5Faculty of Pharmacy, Discipline of Pharmaceutical Chemistry

“Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 6Preventive Cardiology, CGH Medical

Center, Sterling, Illinois, USA; 7The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease,

Baltimore, MD, USA; 8Mater Hospital, University of Queensland, St Lucia, QLD, Australia; 9Chair of Nephrology

and Hypertension, Medical University of Lodz, Poland; 10Department of Preventive Medicine, University of

Alabama at Birmingham, Birmingham, AL, USA; 11Department of Primary Care and Public Health, Imperial

College London, London, UK; 12Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of

Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia; 13Department of Clinical

Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL),

London, UK; 14Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz,

Poland.

*Corresponding author: Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC; FASA, Head,

Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz,

Zeromskiego 113; 90-549 Lodz, Poland. Phone: +48 42 639 37 71; Fax: +48 42 639 37 71;

E-mail: maciejbanach@aol.co.uk

Conflict of Interest Disclosures: None

Number of words: 2625

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ABSTRACT

INTRODUCTION: Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for

cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however,

evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated

the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women.

METHODS: The search included PUBMED, Web of Science, Scopus, and Google Scholar (up

to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral

tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression

was performed using unrestricted maximum likelihood method for the association between

calculated weighted mean difference (WMD) and potential moderators.

RESULTS: Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant

reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval

[CI]: -36.50, -14.06; p<0.001). This result was robust in the sensitivity analysis and its

significance was not influenced after omitting each of the included studies from the meta-

analysis. When the studies were categorized according to the tibolone dose, there were consistent

significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD:

-17.00%, 95%CI: -30.22, -3.77; p<0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02,

-13.33; p<0.001). Likewise, there were similar reductions in the subsets of trials with follow-up

either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p<0.001) or ≥24 months (WMD: -

23.10%, 95%CI: -40.17, -6.03; p=0.008).

CONCLUSIONS: This meta-analysis shows that oral tibolone treatment significantly lowers

circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the

mechanism of this effect and the potential value and place of tibolone or its analogues in the

treatment of elevated Lp(a) in individuals at risk of CVD.

Keywords: cardiovascular disease, cardiovascular risk, lipoprotein(a), tibolone.

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INTRODUCTION

Lipoprotein(a) (Lp(a)) is a unique lipoprotein particle, which consists of an apolipoprotein B

containing lipoprotein moiety very similar to low-density lipoprotein (LDL) covalently linked to

the glycoprotein component apoprotein(a) [apo(a)] 1. Apo(a) is exclusively produced in the liver,

and its secretions highly correlated with circulating Lp(a) levels 2. Clinical and epidemiological

evidence reveals an increased level of Lp(a) to be a causal, independent risk factor for

cardiovascular disease (CVD) 3-6. The atherogenic properties of Lp(a) are associated with several

mechanisms, including the inhibition of the fibrinolitic system by homologous structure of

apo(a) with plasminogen 7, the interaction with extracellular matrix conjugates such as

glycoproteins 8, the binding to scavenger receptors on macrophages 9, 10, and the induction of

inflammatory molecules 11.

Given the above, there has been an interest in Lp(a) as a target for residual risk therapy 12-14.

In general, circulating Lp(a) levels are genetically determined 15, while the levels can change in

certain circumstances, such as under acute vascular and inflammatory pathologies 16-18. The

European Atherosclerosis Society (EAS) Consensus Panel recommends screening for elevated

Lp(a) in those at intermediate or high CVD/coronary heart disease (CHD) risk, a desirable level

<50 mg/dL as a function of global CV risk, and use of niacin for Lp(a) and CVD/CHD risk

reduction 19. Since currently available LDL cholesterol-lowering drugs, such as statins, have

little effects of Lp(a), and other, such as niacin is poorly tolerated and is not available in many

countries, there has been a continuous search for effective agents for lowering circulating Lp(a)

levels 20.

Tibolone (Livial, Org OD 14) is a synthetic steroid with estrogenic, androgenic and

progestogenic properties, and used orally for the prevention of osteoporotic bone loss and

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hormonal replacement treatment on climacteric symptoms in postmenopausal women 21, 22.

Tibolone itself has no activities, but two estrogenic metabolites (3α- and 3β-hydroxy [OH]

tibolone) and the third metabolite (∆4-tibolone) exert the effects on climacteric symptoms, and

the third metabolite also exerts additional progestogenic effects in endometrium 23, 24. Tibolone

treatment can modulate the lipid profile and its possible reduction of Lp(a) has been observed 25,

although the effects of tibolone on Lp(a) were not previously analysed within systematic review

and meta-analysis 22. Therefore, we performed a meta-analysis to evaluate the efficacy of

tibolone treatment on circulating Lp(a) levels in postmenopausal women.

MATERIAL AND METHODS

Search Strategy

This study was designed according to the guidelines of the 2009 preferred reporting items

for systematic reviews and meta-analysis (PRISMA) statement 26. PubMed

(http://www.ncbi.nlm.nih.gov/pubmed), Web of Science (http://apps.webofknowledge.com),

SCOPUS (http://www.scopus.com), and Google Scholar (http://www.scholar.google.com)

databases were searcher and the search was limited to the controlled studies (mainly randomized

controlled trials [RCTs], as well as controlled clinical trials, perspective and open-label studies)

carried out up to January 31, 2014, investigating the potential effects of tibolone treatment on

Lp(a) concentrations in the group of postmenopausal women. The databases were searched using

the following search terms in titles and abstracts (also in the combination with MESH terms):

(tibolone OR OrgOD14 OR “Org OD14” OR livial OR livial®) AND (lipoprotein(a) OR

“lipoprotein (a)” OR Lp(a) OR “Lp(a)”). The wild-card term ‘‘*’’ was used to increase the

sensitivity of the search strategy. No language restriction was used in the literature search. The

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search was limited to studies in humans. Selected articles were searched to identify further

relevant studies. Two reviewers (KK and AS) evaluated each article separately. Disagreements

were resolved by agreement and discussion with a third party (MB).

Study Selection

Original studies (all in postmenopausal women) were included if they met the following

inclusion criteria: (i) being a controlled clinical study (RCT, controlled perspective or open-label

study), (ii) investigating the impact of tibolone on plasma/serum concentrations of Lp(a), (iii)

presentation of sufficient information on Lp(a) concentrations at baseline and at the end of

follow-up in each group or providing the net change values.

Exclusion criteria were: (i) lack of a an appropriate control group in the study design, (ii)

non-clinical observational studies with case-control, cross-sectional or cohort design, (iii) lack of

sufficient information on baseline or follow-up Lp(a) concentrations, (iv) inability to obtain

adequate details of study methodology or results from the article or the investigators, and, (v) the

study was ongoing.

Data extraction

Eligible studies were reviewed and the following data were abstracted: 1) first author's

name; 2) year of publication; 3) study location; 4) study design; 5) tibolone dose and the route of

administration; 6) number of participants in the tibolone and control groups; 7) inclusion and

exclusion criteria; 8) age, gender and body mass index (BMI) of study participants; 9) prevalence

of diabetes mellitus; and 10) baseline and follow-up plasma concentrations of Lp(a).

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Quality assessment

A systematic assessment of bias in the included studies was performed using the Cochrane

criteria 27. The items used for the assessment of each study were as follows: adequacy of

sequence generation, allocation concealment, blinding, addressing of dropouts (incomplete

outcome data), selective outcome reporting, and other potential sources of bias. According to the

recommendations of the Cochrane Handbook, a judgment of “yes” indicated low risk of bias,

while “no” indicated high risk of bias. Labeling an item as “unclear” indicated an unclear or

unknown risk of bias.

Quantitative Data Synthesis

Meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) V2 software

(Biostat, NJ) 28. Net changes in measurements (change scores) were calculated as follows:

measure at end of follow-up − measure at baseline. For cross-over trials, net change in plasma

concentrations of Lp(a) were calculated by subtracting the value after control intervention from

that reported after treatment. All values were collated in percentage changes from baseline

levels. Standard deviations (SDs) of the mean difference were calculated using the following

formula: SD = square root [(SDpre-treatment)2 + (SDpost-treatment)

2 – (2R × SDpre-treatment × SDpost-

treatment)], assuming a correlation coefficient (R) = 0.5. If the outcome measures were reported in

median and inter-quartile range, mean and standard SD values were estimated using the method

described by Hozo et al. 29. Where standard error of the mean (SEM) was only reported, standard

deviation (SD) was estimated using the following formula: SD = SEM × square root (n), where n

is the number of subjects. When the results were presented in multiple time points, only data

relating to the longest duration of treatment were considered.

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A random-effects model (using DerSimonian-Laird method) and the generic inverse

variance method were used to compensate for the heterogeneity of studies in terms of

demographic characteristics of populations being studied and also differences in study design.

Heterogeneity was quantitatively assessed using I2 index. Effect sizes were expressed as

weighted mean difference (WMD) and 95% confidence interval (CI). In order to evaluate the

influence of each study on the overall effect size, sensitivity analysis was conducted using leave-

one-out method, i.e. removing one study each time and repeating the analysis 30, 31.

Meta-regression

Random-effects meta-regression was performed using unrestricted maximum likelihood

method to evaluate the association between calculated WMD and potential moderators including

duration of treatment with tibolone.

Publication bias

Potential publication bias was explored using visual inspection of Begg’s funnel plot

asymmetry, fail-safe N test, and Begg’s rank correlation and Egger’s weighted regression tests.

Duval & Tweedie “trim and fill” method was used to adjust the analysis for the effects of

publication bias 32.

RESULTS

The search provided 82 articles excluding duplicates. Of those, 67 were excluded after initial

screening and the remaining 15 full text papers were reviewed. Finally 12 were scrutinized as

full texts and were selected to be included in the analysis 33-44. The reasons for excluding the

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remaining 3 articles were: not controlled for tibolone (n=2) and no tibolone treatment arm (n=1)

(Figure 1). In total, 1009 participants were randomized, of whom 634 were allocated to tibolone

supplementation group and 375 to control group in the selected studies. The number of

participants in these studies ranged from 6 to 136. They were published between 1996 and 2009,

and were conducted in USA, Greece, Ireland, the Netherlands (3 trials), Italy (2 trials), UK,

Serbia and Turkey. A range of tibolone doses from 0.3 to 2.5 mg/day was administered in the

included trials. Duration of supplementation with tibolone ranged between 3 and 60 months.

Tibolone was safe and well-tolerated in all included studies with no report of any drug-related

adverse events. Baseline parameters of the included studies are shown in Table 1.

Risk of bias assessment

According to the Cochrane Collaboration 45, a specific tool for assessing risk of bias in each

involved study comprises judgment of specific features of the study. This involves evaluating the

risk of bias as ‘low risk’, ‘high risk or ‘unclear risk’. The last category shows either lack of

information or uncertainty over the potential for bias. There are seven analyzed domains

comprising: sequence generation (selection bias), allocation sequence concealment (selection

bias), blinding of participants and personnel (performance bias), blinding of outcome assessment

(detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting

bias) and other potential sources of bias (Table 2).

Effect of tibolone on plasma Lp(a) concentrations

Overall, the impact of tibolone on plasma Lp(a) concentrations were reported in 12 trials

comprising 16 treatment arms with 1009 women-patients. The results suggested a significant

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reduction of Lp(a) levels following treatment with tibolone (WMD: -25.28%, 95%CI: -36.50, -

14.06; p < 0.001), which are robust in the sensitivity analysis, and their significance was not

influenced after omitting each of the included studies from meta-analysis (Figure 2). When the

studies were categorized according to the dose of treatment, there was consistent significant

reduction in Lp(a) concentrations in the subsets of trials with doses <2.5 mg/day (WMD: -

17.00%, 95%CI: -30.22, -3.77; p < 0.012) and =2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -

13.33; p < 0.001) (Figure 3). Likewise, there were similar reductions in the subsets of trials

lasting either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p<0.001) or ≥24 months

(WMD: -23.10%, 95%CI: -40.17, -6.03; p=0.008) (Figure 4).

Meta-regression

Random-effects meta-regression was performed to assess if the Lp(a) response to tibolone is

associated with administered dose and duration of treatment. The results did not suggest any

significant association between the changes in plasma concentrations of Lp(a) with dose (slope:

-6.07; 95%CI: -20.16, 8.02; p = 0.399) and duration of treatment (slope: 0.27; 95%CI: -0.53,

1.08; p = 0.505).

Publication bias

The funnel plot of the study standard error by effect size (WMD) was symmetric, suggesting

lack of publication bias in the analysis of the effect tibolone on plasma Lp(a) concentrations.

This finding was confirmed by the results of Egger’s linear regression (intercept = -3.04,

standard error = 1.72; 95%CI: -6.73, 0.65, t = 1.77, df = 14, two-tailed p = 0.099) and Begg’s

rank correlation tests (Kendall’s Tau with continuity correction = -0.24, z = 1.31, two-tailed

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p-value = 0.192) (Figure 5). The “fail-safe N” test suggested that 523 studies would be needed to

bring the effect size down to a non-significant (p > 0.05) value.

DISCUSSION

The present meta-analysis of data from 12 trials comprising 16 treatment arms revealed that

oral tibolone treatment significantly reduced circulating Lp(a) levels in postmenopausal women.

These results are of high importance because Lp(a) is an independent risk factor for CVD, there

are no effective and safe treatments for high Lp(a) levels, and postmenopausal women are at

higher CVD risk 3-5.

Tibolone treatment can reduce circulating Lp(a) levels by 25% (42-44). More recently,

significant reductions of Lp(a) have been shown with a range of new therapies, including

cholesteryl ester transfer protein (CETP) inhibitors, sequence-specific antisense oligonucleotides

against apoB, inhibitory monoclonal antibodies to proprotein convertase subtilisin/kexin type-9

(PCSK9), thyroid hormone analogues, and synthetic inhibitors of microsomal triglyceride

transfer protein 46-51. The magnitude of reductions of Lp(a) by these drugs appears to be similar

to the ones with tibolone, while the overall magnitude of these recent drugs is still not

established 46-48, 52. The magnitude of reduction of Lp(a) with tibolone is similar to that of niacin.

The influences of the dose and duration of used drugs on Lp(a) is also of concern 25. Niacin can

reduce Lp(a) in a dose-dependent manner 53. Whereas, the present meta-analysis did not find a

dose- or duration-dependent manner of tibolone treatment on Lp(a). This may be an advantage in

using tibolone to decrease Lp(a) levels.

The reduction of circulating Lp(a) by tibolone is still incompletely explained. The estrogenic

property of tibolone is a possible explanation of the reduction of Lp(a) 25; however, the details in

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the involvement of estrogens in the Lp(a) regulation still remain to be fully clarified 54. One of

the mechanism potentially responsible might be the fact that Lp(a) gene has an estrogen response

element and tibolone may active this and reduce hepatic output of Apo(a) 55. Lp(a) is also

decreased by testosterone and the androgenic component of tibolone may have a dual effect 56.

However, further studies of the mechanism of action of tibolone on Lp(a) metabolism are still

required.

The present meta-analysis has limitations. First, the studies included in the present meta-

analysis were not always interventional studies focused on the Lp(a) levels, as a main endpoint,

therefore well-designed interventional trials specific for Lp(a) are still necessary. Next, the

included studies did not evaluate the long-term CVD outcomes associated with Lp(a) reduction.

The reduction of Lp(a) is theoretically thought to be favorable for the prevention of the events,

but whether the reduction of Lp(a) with Lp(a)-targeted therapies can lead to the favorable

outcomes still needs to be proven, especially that available long-term controlled studies with a

Lp(a)-lowering drug (nicotinic acid plus laropiprant) have failed to find a positive impact of the

Lp(a) reduction on CV events 19. Some studies have also indicated that very low Lp(a) levels

might be harmful 57, 58, however Mendelian randomization studies did not confirm that low Lp(a)

increases the risk of diabetes 59. However, tibolone can improve not only Lp(a) level but also

vascular functions (e.g. vasodilation) with its estrogenic property 21. Additionally, tibolone is

reported to modulate other lipoprotein factors, i.e. the drug with its androgenic properties can

reduce high-density lipoprotein cholesterol (HDL-C) as an unfavorable change 25. However,

there are findings that the change of HDL-C is usually transient 33; on the other hand there are

more and more data that we should not focus on HDL-C as it is not main target of the lipid-

lowering therapy, also due to the lasting debate on HDL functionality in different patients’

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groups 42, 60, 61. It should be emphasized that data on circulating Lp(a) levels were obtained from

studies using different assays for Lp(a). It would be also necessary to look at the tibolone effects

in general, including the influence on inflammatory markers, and other risk factors of CVD (e.g.

blood pressure) 62, in order to finally confirm the possible benefits of its therapy. Finally, the

included studies did not particularly focus on tibolone therapy-related side effects. One should

notice that the side effects after tibolone therapy with doses ≤2.5 mg/day are uncommon 63. In

the Long-Term Intervention on Fractures with Tibolone (LIFT) trial 64 in older postmenopausal

women (aged 60-85 years) tibolone therapy (in comparison to placebo) significantly reduced the

risk of vertebral and nonvertebral fractures, invasive breast cancer and colon cancer, however,

increased of the stroke risk. There were also no significant differences in the risk of either CHD

or venous thromboembolism 64. However the above mentioned stroke risk was not observed in

other studies with younger postmenopausal women 65, 66.

In conclusion, the present meta-analysis revealed that oral tibolone treatment significantly

reduced circulating Lp(a) levels in postmenopausal women. The significance of this metabolic

effect for the prevention of CVD needs to be weighed against other effects of tibolone and

requires further investigations. Large-scale, well-designed studies may then be justified to

explore the value of tibolone treatment in high risk subjects with elevated plasma Lp(a) levels 19.

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DECLARATION OF INTEREST

This meta-analysis was written independently; no company or institution supported it

financially. No authors have any conflict of interest concerning the preparation of this analysis.

Some of the authors have given talks, attended conferences and participated in trials and

advisory boards sponsored by various pharmaceutical companies. No professional writer was

involved in the preparation of this meta-analysis.

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TABLES

Table 1. Demographic characteristics of the included studies

Study

Bjarnason et al. 33

Gallagher et al. 34

Kalogeropou-los et al. 35

Kroiss et al.36

Lloyd et al. 37

Milner et al. 38

Ostberg et al. 39

Perrone et al.40

Von Eckardstein

et al. 41

Von Eckardstein

et al. 42

Anedda et al.43

Demirol et al. 44

Year 1997 2001 2004 2005 2000 1996 2004 2009 2001 2003 2003 2007

Location Netherlands

USA Greece Netherlands UK Ireland Serbia Italy Netherlands Germany Italy Turkey

Design Randomized

double-blind,

placebo controlled

study

Randomized,

double-blind,

placebo controlled

, dose-finding studies

Clinical controlled trial

Randomized, double-

blind, placebo-

controlled, pilot study

Randomized double-blind,

placebo-controlled

study

Randomized placebo-

controlled, pilot study

One-year open-label controlled

study

Prospective

controlled study

Randomized, double-blind and placebo-

controlled study

Randomized, double-

blind, placebo-

controlled study

Randomized double-blind,

placebo controlled

study

Randomized double-

blind, placebo-

controlled study

Duration of study

24 month 24 month 60 month 12 months 6 month 24 month 12 month 12 month 3 month (84 days)

3 month (84 days)

6 month 6 month

Inclusion criteria

Healthy women

not being treated

with any medication known to affect coagulati

on fibrinolysis lipid or

bone metabolis

m and with more than 10 years of

spontaneous

Healthy Caucasian or Asian women

45years of age or older, within

80–130% of ideal body

weight,1year or

more but 4 years or less past natural

menopaus

Non-smoking women,

undergoing menopause with

normal BP, without

cardiovascular problems and

osteopenia, but with mild

hypercholesterolemia (TC 241+7 mg/dl; LDL-C 153+9 mg/dl)

Postmenopausal women

(≤75 years old; BMI

18–30 kg/m2) with

newly diagnosed

and histologically confirmed invasive or

non-invasive early stage

breast cancer, with

surgical treatment

Hypertensive patients on or off treatment

with antihypertensive, with 1 or more years of postmenopau

sal on clinical grounds

Patients at least 45

years of age, postmenopausal for 12 month or

more, within 15% of ideal body weight

or height and had

intact uteri and ovaries

Postmenopausal women undergoing

chronic hemodialysi

s, with at least 6

months of amenorrhea, age less than

65 years, and serum

FSH (>20 mIU/L)

No natural

menstruation for at least 12 months,

FSH >60

pg/ml, estradiol

<20 µg/ml and

the presence

of menopaus

al symptoms

Postmenopausal women (absence of

any menstrual

bleeding for 12 months

�and FSH > 50 IU/l

and estradiol < 20 pg/ml),

45 to 60 years of age with a BMI

ranging between 20

and 28 kg/m2

Healthy postmenopausal women

with previous

oophorectomy or 12 months

passed after the last

menstrual bleed, FSH > 50 IU/l and serum levels of

estradiol < 70 pmol,

aged 45–60

Healthy women (mean

age 52.0 ± 0.34 years) who were at

least 6 months beyond a 12 month period

of hypergonadotr

opic amenorrhea

and had never begun HRT

Healthy menopausal women

45–50 years of age who

had undergone hysterecto

my and bilateral salpingo-oophorec-tomy as a result of benign diseases

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menopause

e and without

osteoporosis

followed by tamoxifen

years, BMI 20–28 kg/m2

Route of administrat

ion

oral oral oral oral oral oral oral oral oral oral oral oral

Tibolone dose

1.25 mg/day or

2.5 mg/day

0.3 mg/day

or 0.625

mg/day or

1.25 mg/day

or 2.5

mg/day

2.5 mg/day

2.5 mg/ day 2.5 mg/day 2.5 mg/day 2.5 mg three times per

week

2.5 mg/day

2.5 mg /day 2.5 mg /day 2.5 mg/day 2.5 mg/day

Partici-pants

Case 29a 132c 53 35e 19 31f 13 20g 12 34 11 28h

136d

28b 127a 32b 21b 28b

131b

Control

13 130 29 35 11 50 13 19 6 31 11 27

Age (years) Case 66.4 (7.0)a

52.3 (2.9)c 49.6±5 58 (6.1)e 60.11 (1.28) 52.4±0.74f 54.5 (4.6) 51.1 ± 4.1g

45 - 60 54.5 ± 3.7 51.6±0.49 48±0.6h

52.8 (3.5)d

65.5 (7.5)b

52.4 (3.2)a 53.6±0.77b 53.4 ± 3.6b

46±3b

52.1 (3.3)b

Control

68.4 (6.1) 52.6 (3.4) 48.4±4 59 (5.5) 62.73 (1.79) 55.6±0.61 56.0 (7.4) 52.7 ± 3.3

45 - 60 53·5 ± 3·7 52.1±0.44 47± 0.6

Male (%) Case 0a 0c 0 0e 0 0f 0 0g 0 0 0 0h

0d

0b 0a 0b 0b 0b

0b

Control

0 0 0 0 0 0 0 0 0 0 0 0

BMI (kg/m2)

Case 24.5 (3.4)a

24.8 (3.8)c 22–26 24.8 (3.2)e* 33.90 (5.99) 41.1± 0.6f 23.9 (4.0) 24 ± 2.7g 20-28 24.5 ± 2.5 21.2±0.32 25.4± 0.3h

24.8 (3.6)d

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23.1 (2.8)b

25.5 (3.5)a 39.6± 0.7b 25.2 ± 2.6b

24.4± 0.7b

25.2 (3.7)b

Control

24.7 (3.2) 25.4 (3.8) 22–25 25.4 (3.7) 29.60 (1.30) 39.2± 0.5 21.2 (3.0) 23.2 8 2.6

20-28 23.7 ± 2.7 20.9±0.22 25.1± 0.1

prevalence of diabetes

mellitus (%)

Case NSa 0c NS NSe NS NSf 0 NSg NS 0 NS 0h

0d

NSb 0a NSb NSb 0b

0b

Control

NS 0 NS NS NS NS 0 NS NS 0 NS 0

Lp(a) (mg/dL)

Case 23.1 (12.6–44.9)a

NSc 25±4 20.4 (25.1)e**

10 (7.5–23) 14.1 (0.9-106.1)f

19 (8–117) 28.0 (24.4)g

45 (2-229) 27 ± 32

37.5±3.3 35.9 ± 20.8 h

NSd

25.8 (8.95–36.9)b

NSa 39.4 (1.6-122.4)b

26.7 (17.1)b

38.5± 17.8 b NSb

Control

24.3 (16.6–51.2)

NS 26±5 17.8 (23.9)**

14 (5–66) 12.6 (0.6-87.5)

16 (8–84) 28.6 (22.0)

17 (3-84) 27 ± 34 35.8±5.6 39.8 ± 18.2

Values are expressed as mean ± SD or median (25–75 percentiles).

ABBREVIATIONS: BMI: body mass index; BP: blood pressure; NS: not stated; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; DM: diabetes mellitus; FSH: serum levels of follicle stimulating hormone; HRT: hormonal replacement therapy; adenotes 1.25 mg/day tibolone; bdenotes 2.5 mg/day tibolone; cdenotes 0.3 mg/day tibolone; ddenotes 0.625 mg/day tibolone; edenotes 20 mg/day oral tamoxifen (Nolvadex-D; Astra-Zeneca) plus either 2.5 mg/ day oral tibolone (Livial; NVOrganon), fdenotes a combined estrogen (0.625 mg/day) – progestin (0.15 mg for 12 days in 28) preparation; g denotes oral medroxyprogesterone acetate (MPA; 10 mg/day for 12 days); hdenotes conjugated ET (Premarin, 0.625 mg/d oral tablets; Wyeth, Istanbul, Turkey); *denotes patients belonging to tibolone group n = 34; ** denotes patients belonging to tibolone group or placebo group n = 29.

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Table 2. Risk of bias assessment in the studies considered for meta-analysis.

Study Ref SEQUENCE GENERATION

ALLOCATION CONCEALMENT

BLINDING OF PARTICIPANTS

AND PERSONNEL

BLINDING OF OUTCOME

ASSESSMENT

INCOMPLETE OUTCOME

DATA

SELECTIVE OUTCOME

REPORTING

OTHER POTENTIAL

THREATS TO VALIDITY

Bjarnason et al. 33 U U L L L L L Gallagher et al. 34 U H L L L L L Kalogeropoulos et al. 35 U U U U L L L Kroiss et al. 36 L L L L L L L Lloyd et al. 37 U U L L L L L Milner et al. 38 L U U U L L L Ostberg et al. 39 U U U U L L L Perrone et al. 40 U U U U L L L von Eckardstein et al. 41 U U L L L L L von Eckardstein et al. 42 U U L L L L L Anedda et al. 43 U U L L L L L Demirol et al. 44 U U L L L L L L: low risk of bias; H: high risk of bias; U: unclear risk of bias

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FIGURE LEGENDS

Figure 1. Flow chart of the number of studies included to the meta-analysis.

Figure 2. Forest plot displaying weighted mean difference and 95% confidence intervals for the

impact of tibolone on circulating Lp(a) levels. Lower plot shows leave-one-out sensitivity analysis.

Figure 3. Forest plot displaying weighted mean difference and 95% confidence intervals for the

impact of tibolone on circulating Lp(a) levels in trials administering doses < 2.5 mg/day (upper

plot) and ≥ 2.5 mg/day (lower plot).

Figure 4. Forest plot displaying weighted mean difference and 95% confidence intervals for the

impact of tibolone on circulating Lp(a) levels in trials lasting < 24 months (upper plot) and ≥ 24

months (lower plot).

Figure 5. Meta-regression plots of the association between mean changes in circulating Lp(a)

levels s and dose and duration of treatment with tibolone. The size of each circle is inversely

proportional to the variance of change.

Figure 6. Funnel plot detailing publication bias in the studies reporting the impact of tibolone on

circulating Lp(a) levels. Open diamond represents observed effect size; closed diamond represents

imputed effect size.

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ACCEPTED MANUSCRIPTHIGHLIGHTS:

• Circulating Lp(a) is a recognized risk factor for cardiovascular disease (CVD).

• Tibolone may lower Lp(a), however, evidence of this effect remains to be confirmed.

• Meta-analysis suggests a significant Lp(a) reduction following tibolone (by 25.28%).

• Further studies are warranted to explore the mechanism of this effect.

• A place of tibolone in individuals at CVD risk needs to be further investigated.