UNIVERSITI PUTRA MALAYSIA YVONNE TEE YEE SIANG FPSK(p ...

UNIVERSITI PUTRA MALAYSIA

YVONNE TEE YEE SIANG

FPSK(p) 2013 14

DETERMINANTS OF BONE MINERAL DENSITY AND EFFECT OF SOY ISOFLAVONES IN PREMENOPAUSAL WOMEN IN THE KLANG

VALLEY

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DETERMINANTS OF BONE MINERAL DENSITY AND EFFECT OF SOY

ISOFLAVONES IN PREMENOPAUSAL WOMEN IN THE KLANG

VALLEY

By


Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia,

in Fulfilment of the Requirements for the Degree of Doctor of Philosophy

June 2013

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COPYRIGHT

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icons, photographs and all other artwork, is copyright material of Universiti Putra

Malaysia unless otherwise stated. Use may be made of any material contained within

the thesis for non-comercial purposes from the copyright holder. Commercial use of

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Putra Malaysia.

Copyright © Universiti Putra Malaysia

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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfilment

of the requirement for the degree of Doctor of Philosophy

DETERMINANTS OF BONE MINERAL DENSITY AND EFFECT OF SOY

ISOFLAVONES IN PREMENOPAUSAL WOMEN IN THE KLANG

VALLEY

By


June 2013

Chair: Assoc. Prof. Zaitun Yassin, PhD

Faculty: Medicine and Health Sciences

Isoflavones, a class of phytoestrogens or plant-derived compounds with estrogenic

activity found abundantly in soybeans and soy products, are purported to have

protective effects on bone health. A 12-month randomized-control trial was

conducted to determine the determinants of bone mineral density and effect of soy

isoflavones on bone mineral density (BMD) among 73 non-osteoporotic

premenopausal Chinese women.

The treatment group received 100 mg of soy isoflavones supplement daily containing

approximately 43.09 mg (86.2%) of the isoflavones in aglycone form. Changes in

BMD were assessed every 6 months using dual-energy X-ray absorptiometry

(DEXA). Weight and height were measured using appropriate instrument and fat

mass and lean mass were assessed by DEXA. Analysis on bone markers and several

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biochemical indicators such as lipid profile was carried out. Dietary intake and

selected lifestyle variables were also assessed.

At baseline, there was no significant difference between treatment and control group

for their socioeconomic background, anthropometric measurements, dietary intake,

biochemical parameters and physical activity level, except that the control group had

higher baseline BMD at the Ward’s triangle compared to the soy isoflavones group

(p<0.05). The mean age of the subjects was 39.3 ± 5.0 years. Their mean body mass

index (BMI) was 22.2 ± 3.4 kg/m2 and their average body fat percentage and lean

body mass were 33.9 ± 4.6% and 34.5 ± 4.4 kg, respectively. The mean BMD at the

spine, total hip, femoral neck, and total body were 1.025 ± 0.118 g/cm2, 0.876 ±

0.109 g/cm2, 0.739 ± 0.110 g/cm

2, and 1.061 ± 0.755 g/cm

2, respectively.

The mean caloric and calcium intake were 1506 ± 427 kcal / day and 534 ± 347 mg /

day, respectively. Their calcium intake only achieved 66.8% of the Recommended

Nutrient Intake (RNI) of Malaysia. The mean metabolic equivalent score (MET) was

771.4 ± 926.1 min / week. On average, the serum levels of most biochemical

indicators such as glucose, lipid profile, calcium, phosphorus, and magnesium were

within normal range. Mean serum parathyroid hormone (PTH) was 36.1 ± 18.2 pg/ml;

while mean serum beta-crosslaps was 0.21 ± 0.10 ng/ml. Conversely, mean serum

osteocalcin (8.5 ± 4.2 ng/ml) was lower than the reference value.

Age at menarche was negatively correlated with BMD at the femoral neck (r=-0.243,

p<0.05). Body weight and its related indices (BMI, lean mass, fat mass) were

significantly correlated with BMD at all skeletal sites. None of the dietary and

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physical activity factors were associated with BMD at various sites. Using the

repeated measure ANOVA analysis, soy isoflavones supplementation had no effect

on changes in BMD at all skeletal sites after 12 months. The findings of the study did

not show any significant gain or loss in BMD from baseline in both the

supplemented and control groups. Similarly, dietary intake, biochemical indicators

and physical activity did not change significantly with time and between soy

isoflavone and control group.

In conclusion, daily supplementation with 100 mg of soy isoflavones did not show a

bone-sparing effect in healthy premenopausal women. Although the soy isoflavones

tablets in this study were well-tolerated and did not result in any adverse effects, the

long-term safety of very high supplemental doses of soy isoflavones is not yet known.

Therefore, consumption of diets rich in soy and soy products may be the preferred

option to gain the beneficial effects of isoflavones on bone health in both

premenopausal and postmenopausal women.

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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai

memenuhi keperluan untuk ijazah Doktor Falsafah

PENENTU KETUMPATAN MINERAL TULANG DAN KESAN ISOFLAVON

SOYA KE ATAS WANITA PRA-MENOPAUS DI KLANG VALLEY

Oleh


Jun 2013

Pengerusi: Prof. Madya Zaitun Yassin, PhD

Fakulti: Perubatan dan Sains Kesihatan

Isoflavon, salah satu kelas fitoestrogen atau sejenis komponen yang terhasil dari

tumbuh-tumbuhan yang mempunyai aktiviti estrogenik dan banyak terdapat dalam

kacang soya atau produk soya, telah dikatakan mempunyai kesan perlindungan

terhadap kesihatan tulang. Satu kajian reka bentuk kajian kawalan rawak yang

mengambil masa 12 bulan telah dijalankan untuk menentukan penentu ketumpatan

mineral tulang dan keberkesanan isoflavon soya terhadap ketumpatan mineral tulang

di kalangan 73 wanita Cina pra-menopaus yang tidak mengalami osteoporosis.

Kumpulan eksperimen menerima 100 mg supplemen isoflavon soya setiap hari yang

mengandungi 43.09 mg (86.2%) isoflavon dalam bentuk aglycone. Perubahan dalam

ketumpatan mineral tulang diukur setiap 6 bulan dengan menggunakan X-ray

absortiometri dua tenaga (DEXA). Berat badan dan ketinggian diukur dengan

menggunakan alat yang sesuai. Analisis untuk penanda tulang dan beberapa

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penunjuk biokimia seperti profil lemak badan telah dijalankan. Pengambilan

makanan dan pembolehubah terpilih gayahidup juga dinilai.

Pada awal kajian, tiada perbezaan signifikan di antara kumpulan eksperimen dan

kawalan dari segi latar belakang sosio-ekonomi, ukuran antropometri, pengambilan

makanan, parameter biokimia dan tahap aktiviti fizikal, kecuali ketumpatan mineral

tulang yang lebih tinggi dalam kumpulan kawalan pada Ward. Purata umur subjek

adalah 39.3 ± 5.0 tahun. Purata Indeks Jisim Tubuh (IJT) mereka adalah 22.2 ± 3.4

kg/m2, dan purata peratusan lemak badan dan jisim otot tanpa lemak mereka adalah

33.9 ± 4.6% and 34.5 ± 4.4 kg, masing-masing. Purata ketumpatan mineral tulang

mereka pada tulang belakang, keseluruhan pinggul, leher femur, dan keseluruhan

badan adalah 1.025 ± 0.118 g/cm2, 0.876 ± 0.109 g/cm

2, 0.739 ± 0.110 g/cm

2, dan

1.061 ± 0.755 g/cm2, masing-masing.

Min pengambilan kalori dan kalsium adalah 1506 ± 427 kcal dan 534 ± 347 mg

sehari. Pengambilan kalsium mereka hanya mencapai 66.8% daripada Saranan

Pengambilan Nutrien (RNI) Malaysia. Min skor metabolik setara (MET) mereka

adalah 771.4 ± 926.1 min / minggu. Secara purata, paras serum kebanyakan

penunjuk biokimia seperti glukosa, profil lipid, kalsium, fosforus, dan magnesium

adalah dalam julat yang normal. Min serum hormon paratiroid (PTH) adalah 36.1 ±

18.2 pg/ml manakala min serum beta-crosslaps adalah 0.21 ± 0.10 ng/ml. Sebaliknya,

min serum osteocalcin (8.5 ± 4.2 ng/ml) adalah lebih rendah rendah daripada nilai

rujukan.

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Usia mendapat haid dikaitkan secara negatif dengan ketumpatan mineral tulang pada

leher femur (r=-0.243, p<0.05). Berat badan dan indeks yang berkaitan dengan berat

badan (IJT, jisim otot tanpa lemak, jisim lemak badan) menunjukkan perkaitan yang

signifikan dengan ketumpatan mineral tulang pada semua kawasan tulang. Tiada satu

pun faktor diet dan aktiviti fizikal dikaitkan dengan ketumpatan tulang mineral.

Dengan menggunakan ujian analisis repeated measure ANOVA, pemberian soya

isoflavon tidak mempunyai kesan ke atas perubahan ketumpatan mineral tulang pada

semua kawasan tulang selepas 12 bulan. Hasil kajian ini tidak menunjukkan sebarang

peningkatan atau kehilangan jisim tulang berbanding dengan data pada awal kajian

dalam kedua-dua kumpulan eksperimen dan kawalan. Begitu juga dengan

pengambilan makanan, penunjuk biokimia dan aktiviti fizikal yang tidak berubah

secara signifikan dengan masa dan antara kumpulan isoflavon soya dan kawalan.

Kesimpulannya, pemberian supplemen 100 mg soya isoflavon setiap hari tidak

menunjukkan kesan perlindungan terhadap tulang dalam kalangan wanita pra-

menopaus yang sihat. Walaupun wanita dalam kajian ini mempunyai toleransi yang

baik terhadap tablet isoflavon soya dan tidak mengakibatkan apa-apa kesan buruk,

keselamatan supplemen isoflavon soya dalam dos yang sangat tinggi untuk jangka

masa panjang adalah belum diketahui. Oleh itu, pengambilan diet yang kaya dengan

kacang soya dan produk soya mungkin merupakan pilihan yang lebih bijak untuk

mendapatkan kebaikan isoflavon terhadap kesihatan tulang dalam kalangan kedua-

dua wanita pra-menopaus dan menopaus.

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ACKNOWLEDGEMENTS

This dissertation would not have been possible without the support and help of

several individuals who contributed in one way or another to the completion of this

study.

First and foremost, I would like to extend my heartfelt gratitude and appreciation to

my supervisor Assoc. Prof. Zaitun Yassin for her guidance, support, and advice

throughout the study. I am grateful for her encouragement as I hurdled all the

obstacles in the completion of the research.

I am truly indebted and thankful to Assoc. Prof. Chan Yoke Mun, Assoc. Prof.

Norhaizan, and Assoc. Prof. Zanariah for their unselfish and unfailing support, as

well as their valuable advice.

A special thanks to Ms. Lesley who had gone the extra mile to assist me throughout

the study period and we became friends in the end. I want to thank Dr JK Lee for

giving me permission to commence the study at his clinic. I would also like to thank

the support from the churches and Buddhist association. Especially, I would like to

thank each of the ladies whose participation enabled me to complete the dissertation.

Last but not least, to my family members for their faith in me. Thank you all for the

continuous love and patience. Words alone cannot express what I owe them for their

unending support to help me survived the challenges.

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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been

accepted as fulfilment of the requirement for the degree of Doctor of Philosophy.

The members of the Supervisory Committee were as follows:

Zaitun Yassin, PhD

Associate Professor

Faculty of Medicine and Health Sciences

Universiti Putra Malaysia

(Chairman)

Chan Yoke Mun, PhD

Senior Lecturer



(Member)

Norhaizan Mohd. Esa, PhD

Associate Professor



(Member)

Zanariah Othman, PhD

Associate Professor



(Member)

____________________________

BUJANG BIN KIM HUAT, PhD

Professor and Dean

School of Graduate Studies


Date:

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DECLARATION

Declaration by graduate student

I hereby confirm that:

this thesis is my original work

quotations, illustrations and citations have been duly referenced

this thesis has not been submitted previously or concurrently for any other degree

at any other institutions

intellectual property from the thesis and copyright of thesis are fully-owned by


written permission must be obtained from supervisor and Deputy Vice-

Chancellor (Research and Innovation) before thesis is published in book form

there is no plagiarism or data falsification/fabrication in the thesis, and scholarly

integrity was upheld as according to Rule 59 in Rules 2003 (Revision 2012-2013).

The thesis has undergone plagiarism detection software

Signature: ___________________________ Date: ________________

Yvonne Tee Yee Siang (GS 19763)

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Declaration by Members of Supervisory Committee

This is to confirm that:

the research conducted and the writing of this thesis was under our supervision;

supervision responsibilities as stated in Rule 41 in Rules 2003 (Revision 2012-

2013) were adhered to.

Signature: ___________________ Signature: __________________

Assoc. Prof. Zaitun Yassin Dr. Chan Yoke Mun

Signature: ___________________

Assoc. Prof. Norhaizan Mohd. Esa

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TABLE OF CONTENTS

Page

ABSTRACT ii

ABSTRAK v

ACKNOWLEDGEMENTS viii

sAPPROVAL ix

DECLARATION x

LIST OF TABLES xv

LIST OF FIGURES xvii

LIST OF ABBREVIATIONS xviii

CHAPTER

1 INTRODUCTION

1.1 Introduction

1.2 Problem statement

1.3 Significance of study

1.4 Objectives of study

1.5 Hypotheses

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1

4

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2 LITERATURE REVIEW

2.1 Bone structure and composition

2.2 Bone remodeling

2.3 Peak bone mass

2.4 Loss of bone mass

2.4.1 Premenopausal bone loss

2.4.2 Postmenopausal bone loss

2.4.3 Age-related bone loss

2.5 Osteoporosis

2.6 Measurement with DEXA

2.7 Biochemical markers of bone remodeling

2.8 Low bone mineral density in premenopausal

women

2.8 Risk factors related to Premenopausal Bone

Mineral Status

2.8.1 Race and ethnicity

2.8.2 Body composition

2.8.3 Familial resemblance

2.8.4 Hormonal characteristics

2.8.5 Physical activity

2.8.6 Smoking

2.8.7 Alcohol

2.9 Dietary factors

2.9.1 Calcium

2.9.2 Vitamin D

2.9.3 Protein

2.9.4 Other nutrients

2.10 Soybean

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2.10.1 Soy Isoflavones

2.10.2 Mechanism of action

2.10.3 Studies of the effects of soy isoflavones

on bone mass

2.10.4 Bioavailability of soy isoflavones

2.10.5 Safety of soy isoflavones

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3 MATERIALS AND METHODS /

METHODOLOGY

3.1 Study design

3.1.1 General design

3.1.2 Study population

3.1.3 Subject recruitment

3.1.4 Randomization

3.1.5 Interventions

3.1.6 Controls

3.2 Study Methodologies

3.2.1 Bone mineral density measurement

3.2.2 Anthropometric measurements

3.2.3 Biochemical measurement

3.2.4 Dietary assessment

3.2.5 Questionnaires

3.2.6 Compliance

3.2.7 Data collection

3.2.8 Data analysis

3.2.9 Limitations of study

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4 RESULTS AND DISCUSSION

4.1 Randomization and subject disposition

4.2 Baseline characteristics of subjects

4.2.1 Demographic and socioeconomic background

4.2.2 Lifestyle habits

4.2.3 Family history of bone fractures

4.2.4 Anthropometry measurement

4.2.5 Bone mineral density

4.2.6 Reproductive history

4.2.7 Dietary intake

4.2.8 Biochemical profile

4.2.9 Physical activity

4.2.10 Determinants of BMD

4.3 Effects of soy isoflavones supplementation

4.3.1 Baseline characteristics comparison between

treatment and control groups

4.3.2 Changes in anthropometry indices

4.3.3 Changes in physical activity level

4.3.4 Changes in biochemical indices

4.3.5 Changes in dietary intake

4.3.6 Changes in bone mineral density

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5 CONCLUSION AND RECOMMENDATIONS

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REFERENCES/BIBLIOGRAPHY 201

APPENDICES 250

BIODATA OF STUDENT

LIST OF PUBLICATIONS

279

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