Advertisement

Osteoporosis International

, Volume 29, Issue 4, pp 881–891 | Cite as

Tocotrienol supplementation suppressed bone resorption and oxidative stress in postmenopausal osteopenic women: a 12-week randomized double-blinded placebo-controlled trial

  • C.-L. ShenEmail author
  • S. Yang
  • M. D. Tomison
  • A. W. Romero
  • C. K. Felton
  • H. Mo
Original Article

Abstract

Summary

Tocotrienols have shown bone-protective effect in animals. This study showed that a 12-week tocotrienol supplementation decreased concentrations of bone resorption biomarker and bone remodeling regulators via suppressing oxidative stress in postmenopausal osteopenic women.

Introduction

Tocotrienols (TT) have been shown to benefit bone health in ovariectomized animals, a model of postmenopausal women. The purpose of this study was to evaluate the effect of 12-week TT supplementation on bone markers (serum bone-specific alkaline phosphatase (BALP), urine N-terminal telopeptide (NTX), serum soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and serum osteoprotegerin (OPG)), urine calcium, and an oxidative stress biomarker (8-hydroxy-2′-deoxyguanosine (8-OHdG)) in postmenopausal women with osteopenia.

Methods

Eighty-nine postmenopausal osteopenic women (59.7 ± 6.8 year, BMI 28.7 ± 5.7 kg/m2) were randomly assigned to three groups: (1) placebo (430 mg olive oil/day), (2) low TT (430 mg TT/day, 70% purity), and (3) high TT (860 mg TT/day, 70% purity). TT, an extract from annatto seed with 70% purity, consisted of 90% delta-TT and 10% gamma-TT. Overnight fasting blood and urine samples were collected at baseline, 6, and 12 weeks for biomarker analyses. Eighty-seven subjects completed the 12-week study.

Results

Relative to the placebo group, there were marginal decreases in serum BALP level in the TT-supplemented groups over the 12-week study period. Significant decreases in urine NTX levels, serum sRANKL, sRANKL/OPG ratio, and urine 8-OHdG concentrations and a significant increase in BALP/NTX ratio due to TT supplementation were observed. TT supplementation did not affect serum OPG concentrations or urine calcium levels throughout the study period. There were no significant differences in NTX level, BALP/NTX ratio, sRANKL level, and sRANKL/OPG ratio between low TT and high TT groups.

Conclusions

Twelve-week annatto-extracted TT supplementation decreased bone resorption and improved bone turnover rate via suppressing bone remodeling regulators in postmenopausal women with osteopenia. Such osteoprotective TT’s effects may be, in part, mediated by an inhibition of oxidative stress.

Trial registration

ClinicalTrials.gov identifier: NCT02058420. Title: Tocotrienols and bone health of postmenopausal women.

Keywords

Antioxidant Bone metabolism Osteoporosis Tocotrienols Women 8-OHdG 

Notes

Acknowledgements

This study was supported by American River Nutrition, Inc., Hadley, MA.

Funding information

This study is funded by American River Nutrition, Inc.

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Wauquier F, Leotoing L, Coxam V, Guicheux J, Wittrant Y (2009) Oxidative stress in bone remodelling and disease. Trends Mol Med 15(10):468–477.  https://doi.org/10.1016/j.molmed.2009.08.004 CrossRefPubMedGoogle Scholar
  2. 2.
    NIH (2001) Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 285(6):785–795CrossRefGoogle Scholar
  3. 3.
    National Osteoporosis Foundation. American’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation, 2002;1–55Google Scholar
  4. 4.
    Rizzoli R, Reginster JY (2011) Adverse drug reactions to osteoporosis treatments. Expert Rev Clin Pharmacol 4(5):593–604.  https://doi.org/10.1586/ecp.11.42 CrossRefPubMedGoogle Scholar
  5. 5.
    Shahidi F, de Camargo AC (2016) Tocopherols and tocotrienols in common and emerging dietary sources: occurrence, applications, and health benefits. Int J Mol Sci 17(10):E1745CrossRefPubMedGoogle Scholar
  6. 6.
    Nizar AM, Nazrun AS, Norazlina M, Norliza M, Ima Nirwana S (2011) Low dose of tocotrienols protects osteoblasts against oxidative stress. Clin Ter 162(6):533–538PubMedGoogle Scholar
  7. 7.
    Ha H, Lee JH, Kim HN, Lee ZH (2011) Alpha-tocotrienol inhibits osteoclastic bone resorption by suppressing RANKL expression and signaling and bone resorbing activity. Biochem Biophys Res Commun 406(4):546–551.  https://doi.org/10.1016/j.bbrc.2011.02.085 CrossRefPubMedGoogle Scholar
  8. 8.
    Brooks R, Kalia P, Ireland DC, Beeton C, Rushton N (2011) Direct inhibition of osteoclast formation and activity by the vitamin E isomer gamma-tocotrienol. Int J Vitam Nutr Res 81(6):358–367.  https://doi.org/10.1024/0300-9831/a000087 CrossRefPubMedGoogle Scholar
  9. 9.
    Gürkan L, Ekeland A, Gautvik KM, Langeland N, Rønningen H, Solheim LF (1986) Bone changes after castration in rats. A model for osteoporosis. Acta Orthop Scand 57(1):67–70.  https://doi.org/10.3109/17453678608993219 CrossRefPubMedGoogle Scholar
  10. 10.
    Soelaiman IN, Ming W, Abu Bakar R, Hashnan NA, Mohd Ali H, Mohamed N, Muhammad N, Shuid AN (2012) Palm tocotrienol supplementation enhanced bone formation in oestrogen-deficient rats. Int J Endocrinol 2012:532862CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Deng L, Ding Y, Peng Y, Wu Y, Fan J, Li W, Yang R, Yang M, Fu Q (2014) γ-Tocotrienol protects against ovariectomy-induced bone loss via mevalonate pathway as HMG-CoA reductase inhibitor. Bone 67:200–207.  https://doi.org/10.1016/j.bone.2014.07.006 CrossRefPubMedGoogle Scholar
  12. 12.
    Abdul-Majeed S, Mohamed N, Soelaiman IN (2012) Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. Evid Based Complement Alternat Med 2012:960742CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Aktifanus AT, Shuid AN, Rashid NHA, Ling TH, Loong CY, Saat NM, Muhammad N, Mohamed N, Soelaiman IN (2012) Comparison of the effects of tocotrienol and estrogen on the bone markers and dynamic changes in postmenopausal osteoporosis rat model. Asian J Anim Vet Adv 7:225–234CrossRefGoogle Scholar
  14. 14.
    Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Asai A, Miyazawa T (2010) α-Tocopherol attenuates the cytotoxic effect of δ-tocotrienol in human colorectal adenocarcinoma cells. Biochem Biophys Res Commun 397(2):214–219.  https://doi.org/10.1016/j.bbrc.2010.05.087 CrossRefPubMedGoogle Scholar
  15. 15.
    Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, Chyu MC, Ima-Nirwana S (2017) Tocotrienols for bone health: a translational approach. Ann N Y Acad Sci 1401:150–165.Google Scholar
  16. 16.
    Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22(3):659–661.  https://doi.org/10.1096/fj.07-9574LSF CrossRefPubMedGoogle Scholar
  17. 17.
    Kruger MC, Ha PC, Todd JM, Kuhn-Sherlock B, Schollum LM, Ma J, Qin G, Lau E (2012) High-calcium, vitamin D fortified milk is effective in improving bone turnover markers and vitamin D status in healthy postmenopausal Chinese women. Eur J Clin Nutr 66(7):856–861.  https://doi.org/10.1038/ejcn.2012.54 CrossRefPubMedGoogle Scholar
  18. 18.
    Li Z, Karp H, Zerlin A, Lee TY, Carpenter C, Heber D (2010) Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study. Nutr J 9(1):44.  https://doi.org/10.1186/1475-2891-9-44 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Shen CL, Mo H, Yang S, Wang S, Felton CK, Tomison MD, Soelaiman IN (2016) Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial. BMJ Open 6(12):e012572.  https://doi.org/10.1136/bmjopen-2016-012572 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Iwamoto J, Takada T (2015) Effect of minodronate on the speed of sound of the calcaneus in postmenopausal women with an increased risk of fractures: a clinical practice-based observational study. J Chin Med Assoc 78(10):591–596.  https://doi.org/10.1016/j.jcma.2015.06.010 CrossRefPubMedGoogle Scholar
  21. 21.
    Naylor KE, Jacques RM, Peel NF, Gossiel F, Eastell R (2016) Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia. Osteoporos Int 27(8):2585–2592.  https://doi.org/10.1007/s00198-016-3573-z CrossRefPubMedGoogle Scholar
  22. 22.
    Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BA (2000) Palm vitamin E is comparable to alpha-tocopherol in maintaining bone mineral density in ovariectomised female rats. Exp Clin Endocrinol Diabetes 108(04):305–310.  https://doi.org/10.1055/s-2000-7758 CrossRefPubMedGoogle Scholar
  23. 23.
    Zittermann A, Geppert J, Baier S, Zehn N, Gouni-Berthold I, Berthold HK, Reinsberg J, Stehle P (2004) Short-term effects of high soy supplementation on sex hormones, bone markers, and lipid parameters in young female adults. Eur J Nutr 43(2):100–108.  https://doi.org/10.1007/s00394-004-0447-5 CrossRefPubMedGoogle Scholar
  24. 24.
    Shen CL, Chyu MC, Yeh JK, Zhang Y, Pence BC, Felton CK, Brismée JM, Arjmandi BH, Doctolero S, Wang JS (2012) Effect of green tea and Tai Chi on bone health in postmenopausal osteopenic women: a 6-month randomized placebo-controlled trial. Osteoporos Int 23(5):1541–1552.  https://doi.org/10.1007/s00198-011-1731-x CrossRefPubMedGoogle Scholar
  25. 25.
    Clarke BL, Khosla S (2010) Physiology of bone loss. Radiol Clin N Am 48(3):483–495.  https://doi.org/10.1016/j.rcl.2010.02.014 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tchernof A, Poehlman ET, Després JP (2000) Body fat distribution, the menopause transition, and hormone replacement therapy. Diabetes Metab 26(1):12–20PubMedGoogle Scholar
  27. 27.
    Maltais ML, Desroches J, Dionne IJ (2009) Changes in muscle mass and strength after menopause. J Musculoskelet Neuronal Interact 9(4):186–197PubMedGoogle Scholar
  28. 28.
    Fu X, Ma X, Lu H, He W, Wang Z, Zhu S (2011) Associations of fat mass and fat distribution with bone mineral density in pre- and postmenopausal Chinese women. Osteoporos Int 22(1):113–119.  https://doi.org/10.1007/s00198-010-1210-9 CrossRefPubMedGoogle Scholar
  29. 29.
    Nelson CA, Warren JT, Wang MWH, Teitelbaum SL, Fremont DH (2012) RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. Structure 20(11):1971–1982.  https://doi.org/10.1016/j.str.2012.08.030 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12(1):17–25.  https://doi.org/10.1016/j.molmed.2005.11.007 CrossRefPubMedGoogle Scholar
  31. 31.
    Weichhaus M, Segaran P, Renaud A, Geerts D, Connelly L (2014) Osteoprotegerin expression in triple-negative breast cancer cells promotes metastasis. Cancer Med 3(5):1112–1125.  https://doi.org/10.1002/cam4.277 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473(2):139–146.  https://doi.org/10.1016/j.abb.2008.03.018 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Boyce BF, Xing L (2007) Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 9 Suppl 1:S1. ReviewGoogle Scholar
  34. 34.
    Raisz LG (2005) Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 115(12):3318–3325.  https://doi.org/10.1172/JCI27071 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor кB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocrine Rev 29(2):155–928.  https://doi.org/10.1210/er.2007-0014
  36. 36.
    Vega D, Maalouf NM, Sakhaee K (2007) The role of receptor activator of nuclear factor-휅B (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 92(12):4514–4521.  https://doi.org/10.1210/jc.2007-0646 CrossRefPubMedGoogle Scholar
  37. 37.
    Nabipour I, Larijani B, Vahdat K, Assadi M, Jafari SM, Ahmadi E, Movahed A, Moradhaseli F, Sanjdideh Z, Obeidi N, Amiri Z (2009) Relationships among serum receptor of nuclear factor-kappaB ligand, osteoprotegerin, high-sensitivity C-reactive protein, and bone mineral density in postmenopausal women: osteoimmunity versus osteoinflammatory. Menopause 16(5):950–955.  https://doi.org/10.1097/gme.0b013e3181a181b8 CrossRefPubMedGoogle Scholar
  38. 38.
    Garrett JR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR (1990) Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest 85(3):632–639.  https://doi.org/10.1172/JCI114485 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ (2004) Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 314(1):197–207.  https://doi.org/10.1016/j.bbrc.2003.12.073 CrossRefPubMedGoogle Scholar
  40. 40.
    Cervellati C, Romani A, Cremonini E, Bergamini CM, Fila E, Squerzanti M, Greco P, Massari L, Bonaccorsi G (2016) Higher urinary levels of 8-hydroxy-2′-deoxyguanosine are associated with a worse RANKL/OPG ratio in postmenopausal women with osteopenia. Oxidative Med Cell Longev 2016:6038798CrossRefGoogle Scholar
  41. 41.
    Wang Y, Park NY, Jang Y, Ma A, Jiang Q (2015) Vitamin E γ-tocotrienol inhibits cytokine-stimulated NF-κB activation by induction of anti-inflammatory A20 via stress adaptive response due to modulation of sphingolipids. J Immunol 195(1):126–133.  https://doi.org/10.4049/jimmunol.1403149 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Abd Manan N, Mohamed N, Shuid AN (2012) Effects of low-dose versus high-dose γ-tocotrienol on the bone cells exposed to the hydrogen peroxide-induced oxidative stress and apoptosis. Evid Based Complement Alternat Med 2012:680834CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Qureshi AA, Khan DA, Mahjabeen W, Trias AM, Silswal N, Qureshi N (2015) Impact of δ-Tocotrienol on inflammatory biomarkers and oxidative stress in hypercholesterolemic subjects. J Clin Exp Cardiolog 6(4):1000367Google Scholar
  44. 44.
    Qureshi AA, Khan DA, Mahjabeen W, Qureshi N (2015) Dose-dependent modulation of lipid parameters, cytokines and RNA by δ-tocotrienol in hypercholesterolemic subjects restricted to AHA Step-1 diet. Br J Med Medical Res 6(4):351–366.  https://doi.org/10.9734/BJMMR/2015/13820 CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • C.-L. Shen
    • 1
    Email author
  • S. Yang
    • 1
  • M. D. Tomison
    • 1
  • A. W. Romero
    • 2
  • C. K. Felton
    • 3
  • H. Mo
    • 4
  1. 1.Department of Pathology, School of MedicineTexas Tech University Health Sciences CenterLubbockUSA
  2. 2.Clinical Research InstituteTexas Tech University Health Sciences CenterLubbockUSA
  3. 3.Department of Obstetrics and Gynecology, School of MedicineTexas Tech University Health Sciences CenterLubbockUSA
  4. 4.Department of Nutrition, Byrdine F. Lewis College of Nursing and Health ProfessionsGeorgia State UniversityAtlantaUSA

Personalised recommendations