A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status

Michelle Clements; Maria Heffernan; Mary Ward; Leane Hoey; Leanne C Doherty; Roberta Hack Mendes; Michelle M Clarke; Catherine F Hughes; Ingrid Love; Shauna Murphy; Eilish McDermott; Jennifer Grehan; Adrian McCann; Liadhan B McAnena; JJ Strain; Lorraine Brennan; Helene McNulty

doi:10.1002/jbmr.4709

A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status

Michelle Clements, Maria Heffernan, Mary Ward, Leane Hoey, Leanne C Doherty, Roberta Hack Mendes, Michelle M Clarke, Catherine F Hughes, Ingrid Love, Shauna Murphy, Eilish McDermott, Jennifer Grehan, Adrian McCann, Liadhan B McAnena, JJ Strain, Lorraine Brennan, Helene McNulty

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Abstract

Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5 mg), or “active” placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from −0.7% to −1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of −0.003 (−0.008, 0.002) versus −0.015 (−0.021, −0.010) g/cm ² at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm ² at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status.

Original language	English
Pages (from-to)	2443-2455
Number of pages	13
Journal	Journal of Bone and Mineral Research
Volume	37
Issue number	12
Early online date	21 Sept 2022
DOIs	https://doi.org/10.1002/jbmr.4709
Publication status	Published (in print/issue) - 31 Dec 2022

Bibliographical note

Funding Information:
This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland.

Funding Information:
The authors thank all the study participants for taking part in this research. We acknowledge the contributions of Advanced Orthomolecular Research (AOR; https://aor.ca/about/), Alberta, Canada, for providing the study supplements. This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland. Authors’ roles: HMN, LB, MW, MMC, and JJS designed the research. MC, MH, LCD, and RHM contributed equally to the recruitment of participants, execution of the trial, and collection of data across study centers in Northern Ireland and Republic of Ireland. IL, SM, EMD, and JG supported DXA scanning. AMC, LBM, and MC conducted laboratory analysis. MC analyzed the data. MC, CFH, MW, LH, and HMN drafted the manuscript. LB, JJS, MH, LCD, RHM, LBM, AMC, and MMC provided critical feedback to improve the intellectual content. HMN had primary responsibility for the final content. All authors approved the final manuscript.

Publisher Copyright:
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords

B-vitamins
One-carbon metabolism
Bone mineral density
Osteoporosis
Aging
BONE MINERAL DENSITY
AGING
B-VITAMINS
ONE-CARBON METABOLISM
OSTEOPOROSIS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/jbmr.4709

J of Bone Mineral Res - 2022 - Clements - A 2‐Year Randomized Controlled Trial With Low‐Dose B‐Vitamin SupplementFinal published version, 727 KBLicence: CC BY

Cite this

Clements, M., Heffernan, M., Ward, M., Hoey, L., Doherty, L. C., Hack Mendes, R., Clarke, M. M., Hughes, C. F., Love, I., Murphy, S., McDermott, E., Grehan, J., McCann, A., McAnena, L. B., Strain, JJ., Brennan, L., & McNulty, H. (2022). A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status. Journal of Bone and Mineral Research, 37(12), 2443-2455. https://doi.org/10.1002/jbmr.4709

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title = "A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status",

abstract = "Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5 mg), or “active” placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from −0.7% to −1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of −0.003 (−0.008, 0.002) versus −0.015 (−0.021, −0.010) g/cm 2 at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm 2 at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status.",

keywords = "B-vitamins, One-carbon metabolism, Bone mineral density, Osteoporosis, Aging, BONE MINERAL DENSITY, AGING, B-VITAMINS, ONE-CARBON METABOLISM, OSTEOPOROSIS",

author = "Michelle Clements and Maria Heffernan and Mary Ward and Leane Hoey and Doherty, {Leanne C} and {Hack Mendes}, Roberta and Clarke, {Michelle M} and Hughes, {Catherine F} and Ingrid Love and Shauna Murphy and Eilish McDermott and Jennifer Grehan and Adrian McCann and McAnena, {Liadhan B} and JJ Strain and Lorraine Brennan and Helene McNulty",

note = "Funding Information: This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland. Funding Information: The authors thank all the study participants for taking part in this research. We acknowledge the contributions of Advanced Orthomolecular Research (AOR; https://aor.ca/about/), Alberta, Canada, for providing the study supplements. This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland. Authors{\textquoteright} roles: HMN, LB, MW, MMC, and JJS designed the research. MC, MH, LCD, and RHM contributed equally to the recruitment of participants, execution of the trial, and collection of data across study centers in Northern Ireland and Republic of Ireland. IL, SM, EMD, and JG supported DXA scanning. AMC, LBM, and MC conducted laboratory analysis. MC analyzed the data. MC, CFH, MW, LH, and HMN drafted the manuscript. LB, JJS, MH, LCD, RHM, LBM, AMC, and MMC provided critical feedback to improve the intellectual content. HMN had primary responsibility for the final content. All authors approved the final manuscript. Publisher Copyright: {\textcopyright} 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).",

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doi = "10.1002/jbmr.4709",

language = "English",

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Clements, M, Heffernan, M, Ward, M , Hoey, L , Doherty, LC, Hack Mendes, R, Clarke, MM, Hughes, CF, Love, I, Murphy, S, McDermott, E, Grehan, J, McCann, A, McAnena, LB , Strain, JJ, Brennan, L & McNulty, H 2022, 'A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status', Journal of Bone and Mineral Research, vol. 37, no. 12, pp. 2443-2455. https://doi.org/10.1002/jbmr.4709

TY - JOUR

T1 - A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status

AU - Clements, Michelle

AU - Heffernan, Maria

AU - Ward, Mary

AU - Hoey, Leane

AU - Doherty, Leanne C

AU - Hack Mendes, Roberta

AU - Clarke, Michelle M

AU - Hughes, Catherine F

AU - Love, Ingrid

AU - Murphy, Shauna

AU - McDermott, Eilish

AU - Grehan, Jennifer

AU - McCann, Adrian

AU - McAnena, Liadhan B

AU - Strain, JJ

AU - Brennan, Lorraine

AU - McNulty, Helene

N1 - Funding Information: This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland. Funding Information: The authors thank all the study participants for taking part in this research. We acknowledge the contributions of Advanced Orthomolecular Research (AOR; https://aor.ca/about/), Alberta, Canada, for providing the study supplements. This article was supported by governmental funding from the Department of Agriculture, Environment and Rural Affairs (DAERA) in Northern Ireland and the Department of Agriculture, Food and the Marine in the Republic of Ireland. Authors’ roles: HMN, LB, MW, MMC, and JJS designed the research. MC, MH, LCD, and RHM contributed equally to the recruitment of participants, execution of the trial, and collection of data across study centers in Northern Ireland and Republic of Ireland. IL, SM, EMD, and JG supported DXA scanning. AMC, LBM, and MC conducted laboratory analysis. MC analyzed the data. MC, CFH, MW, LH, and HMN drafted the manuscript. LB, JJS, MH, LCD, RHM, LBM, AMC, and MMC provided critical feedback to improve the intellectual content. HMN had primary responsibility for the final content. All authors approved the final manuscript. Publisher Copyright: © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PY - 2022/12/31

Y1 - 2022/12/31

N2 - Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5 mg), or “active” placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from −0.7% to −1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of −0.003 (−0.008, 0.002) versus −0.015 (−0.021, −0.010) g/cm 2 at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm 2 at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status.

AB - Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5 mg), or “active” placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from −0.7% to −1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of −0.003 (−0.008, 0.002) versus −0.015 (−0.021, −0.010) g/cm 2 at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm 2 at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status.

KW - B-vitamins

KW - One-carbon metabolism

KW - Bone mineral density

KW - Osteoporosis

KW - Aging

KW - BONE MINERAL DENSITY

KW - AGING

KW - B-VITAMINS

KW - ONE-CARBON METABOLISM

KW - OSTEOPOROSIS

UR - http://www.scopus.com/inward/record.url?scp=85140097356&partnerID=8YFLogxK

U2 - 10.1002/jbmr.4709

DO - 10.1002/jbmr.4709

M3 - Article

C2 - 36128889

SN - 0884-0431

VL - 37

SP - 2443

EP - 2455

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 12

ER -

A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status

Abstract

Bibliographical note

Keywords

UN SDGs

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