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/cm2 at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm2 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. © 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).

Impact of Folate Intake on Bone Mineral Density in Patients with Inflammatory Bowel Disease

“…Additionally, the folic acid status may be affected by other factors—not only diet—such as the gut microbiota [ 44 ] or inflammation, which also may affect nutritional status [ 45 ]. Clements et al reported that low-dose vitamin B (folate, vitamins B2, B6, and B12) supplementation for two years did not affect the BMD in adults over 50 years old [ 46 ].…”

The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture—results of a large observational cohort study

“…The analysis may also have been underpowered to detect differences in serum PTH between PPI groups. Of interest, higher dose PPI use has been associated with vitamin B12 deficiency (through suppression of gastric acid secretion) [ 27 ], while supplementation of B12-deficient individuals with B vitamins may increase BMD [ 22 ]. However, no study has shown any association between hyperparathyroidism and serum B vitamin levels.…”

“…The mechanisms by which PPIs contribute to fracture risk are currently unknown, but a number of ideas have been postulated including inhibition of gastric acid secretion and reduced absorption of calcium and other nutrients (e.g., B vitamins) which may be important for bone health and hypergastrinaemia [ 8 , 9 , 22 ]. However, only a few small studies have previously explored the relationship between PPIs and serum PTH [ 23 – 25 ].…”

Role of vitamins beyond vitamin D3 in bone health and osteoporosis (Review)

“…Several studies have investigated combined group B vitamin supplementation. It was previously demonstrated shown that the 2-year group B vitamin (folic acid, B 6 , B 12 , B 2 ) supplementation in subjects with a low B 12 status prevented a significant reduction in BMD at the femoral neck and hip ( 280 ). In turn, circulating plasma folic acid and B12 levels have been shown to be directly associated with BMD and bone strength in post-menopausal Chinese-Singaporean women, respectively ( 281 ).…”