Vitamin B₁₂, Folate, Homocysteine, and Bone Health in Adults and Elderly People: A Systematic Review with Meta-Analyses

Table 1

Studies regarding the association between vitamin B₁₂ and bone health.

Author; Year	Study characteristics; Duration of follow-up (when applicable); Country; Risk of bias	Population characteristics: N (% men); Age (y) ± SD	Vitamin B12 status pmol/L*; Mean ± SD	Outcome	Association type		Results*
Dhonukshe-Rutten et al.; 2005 [3]	Cohort (3 y); The Netherlands; High risk	1253 (48%); 75.5 ± 6.6	♀: 289 ± 99; ♂: 268 ± 89	Fracture; (verified by physician or radiograph)	β (SE) for association vitB12-fracture (per 50 pmol/L)		♀: −0.09 (0.06)^a, 1; ♂: 0.02 (0.08)^a, 1
Gjesdal et al. 2007 [24]	Cohort (12.6 y); Norway; Low risk	4761 (45%); 65–67 at baseline	♀: 386.4 ± 372.0; ♂: 359.3 ± 276.2	Hip fracture; (verified by hospital discharge diagnoses)	β (SE) for association vitB12-hip fracture (per 50 pmol/L)		♀: −0.03 (0.03)^b, 2; ♂: −0.06 (0.05)^b, 2
McLean et al. 2008 [25]	Cohort (16 y); USA; Low risk	823 (41%); 75.3 ± 4.9	Deficient (<148): ♀ 9%/♂14.0%; Low (148–257.9): ♀ 24.3%/♂32.5%; Normal (≥258): ♀ 66.7%/♂53.5%	Hip fracture; (verified by review medical records)	β (SE) for association vitB12-hip fracture (per 50 pmol/L)		♀: −0.09 (0.06)^c, 1; ♂: −0.09 (0.11)^c, 1
Ravaglia et al. 2005 [26]	Cohort (4 y); Italy; Moderate risk	702 (47%); 73.0 ± 6.0	Geometric mean (95% CI); 249.1 (203–272)	Fracture; (verified by review medical records)	β (SE) for association vitB12-fracture (per 50 pmol/L)		0.04 (0.08)^d, 2
Bozkurt et al. 2009 [32]	Cross-sectional; Turkey; High risk	178 (0%); 53.5 ± 8.0	247.7 ± 85.4	BMD: LS, FN; [DXA]	Logistic regression for FN, LS and FN + LS combined for vitB12 status under the quintile value. β (SE) + P value		LS: −2.3 (0.9) P = 0.017; FN: −0.4 (0.9) P = 0.669; LS + FN: 1.8 (0.8) P = 0.045^e
Bucciarelli et al. 2010 [33]	Cross-sectional; Italy; Moderate risk	446 (0%); 65.1 ± 9.4	(geometric mean ± SD); 399.1 ± 1.6	BMD: FN, LS, TH [DXA, Prodigy, GE, Lunar]	β for association vitB12-TH BMD β (SE) (per 50 pmol/L)		−0.00105 (0.939)^f, 2
Cagnacci et al. 2008 [34]	Cohort (5 y); Italy; Moderate risk	117 (0%); 54.4 ± 0.5	(Mean ± SE); 548.5 ± 40.5	BMD: LS; [DXA: Lunar DPX]	Regression for vitB12-BMD change β (SE) P value		−0.003 (0.012) P = 0.784^g
Dhonukshe-Rutten et al.; 2003 [35]	Cross-sectional; The Netherlands; Moderate risk	194 (26%); 78.3 ± 5.5	♀ 288 ± 131; ♂ 238 ± 95	BMD: whole body; [DXA, Lunar DPX-L]	Multivariate regression, β for association vitB12-BMD β (95% CI) in women		♀: 12.3·10^−5 (0.2·10^−5–2.4·10^−4)^h
Gjesdal et al. 2006 [10]	Cross-sectional; Norway; Moderate risk	5329 (43%); middle aged: 47–50; Older: 71–75	♀ 393.4 ± 235.8; ♂ 374.6 ± 230.7	BMD: TH; [DXA, Lunar EXPERT-XL]	OR (95% CI) for low BMD per category vitB12 status; 1: <230 pmol/L; 2: 230.0–279.9 pmol/L; 3: 280.0–414.9 pmol/L; 4: ≥415.0 pmol/L + P for trend		♀: 1: 0.97 (0.68–1.37); 2: 0.87 (0.63–1.21); 3: 1.02 (0.82–1.27); 4: 1.00 (reference); P for trend; = 0.61	♂: 1.22 (0.82–1.81); 1.14 (0.80–1.62); 0.97 (0.74–1.28); 1.00 (reference); P for trend; = 0.25^i
Golbahar et al. 2004 [9]	Cross-sectional; Iran; Moderate risk	271 (0%); 60.8 ± 6.8	(geometric mean ± SD); 339.5 ± 247.6	BMD: FN, LS; [DXA, Lunar DPX-L]	β (SE) for association vitB12-BMD (per 50 pmol/L)		FN: 0.0002 (0.07)^2; LS: 0.0114 (0.14)^2
Haliloglu et al. 2010 [36]	Cross-sectional; Turkey; Moderate risk	120 (0%); 54.4 ± 1.1	Osteoporotic: 216.0 ± 135.1; Osteopenic: 190.8 ± 97.4; Normal BMD: 251.0 ± 205.8	BMD: LS; [DXA, Lunar DPX-L]	ANOVA for difference in vitB12 status per BMD group compared to normal BMD group		No sign differences in vitB12 status between BMD groups
Krivosikova et al. 2010 [37]	Cross-sectional; Slovakia; High risk	272 (0%); 41.3 ± 19.8	273.2 ± 152.7	BMD: FN, LS, trochanter, TH; [DXA, Lunar DPX-L]	Stepwise multivariate linear regression, β for association vitB12-BMD. β (SE) P value (per 50 pmol/L)		FN: −2.0 (2.73) ^j, 2; LS: −1.15 (1.42)^j, 2; TH: −0.5 (3.03) ^j, 2
Morris et al. 2005 [7]	Cross-sectional; USA; Low risk	1550 (48%); 68	Geometric mean (95% CI) Osteoporosis: 271 (243–302); Osteopenia: 309 (293–325); Normal: 310 (297–323); Serum MMA (nmol/L); Osteoporosis: 305 (276–337); Osteopenia: 251 (234–269); Normal: 241 (212–274)	BMD: Trochanter, intertrochanter, FN, Ward’s triangle, TH [DXA, Hologic QDR-1000]	OR (95% CI) for mean BMD in relation to quartile categories of vitB12 and MMA status + P for trend. Category medians:		Vit B12: Q1: 2.0 (1.0–3.9); Q2: 1.3 (0.6–2.7); Q3: 1.7 (0.8–3.3); Q4: 1.0 (reference); P for trend = 0.09	MMA: 1.0; (reference); 3.5; (1.4–8.5); 5.2; (2.0–13.1); 7.2; (3.4–15.2); P for trend <0.001^k
					B12 (pmol/L): Q1: 182; Q2: 268; Q3: 349; Q4: 495	MMA (nmol/L): 157; 206; 272; 415	Among subjects with vitB12 <220 pmol/L mean BMD increased sign with increasing vitB12 (𝑃=0.01)
Naharci et al. 2012 [38]	Cross-sectional; Turkey; Moderate risk	264 (100%); 77.0 ± 6.0	26.7% low (<148, group I); 39.1% borderline (148–221, group II); 34.2% normal (>221, group III)	BMD: FN, TH, trochanter, inter-trochanter [DXA, hologic QDR-4500]	Anova for differences in FN BMD between groups of serum vitB12		Sign differences FN BMD; group I and II (𝑃=0.013); group I and III (𝑃<0.001); group II and III (𝑃=0.003); FN BMD was positively correlated with serum vitB12 (𝑟=0.362, 𝑃<0.001)
Ouzzif et al. 2012 [39]	Cross-sectional; Morocco; Moderate risk	188 (0%); 57.8 ± 8.5	360.4 ± 149.2	BMD: FN, LS, TH, trochanter [DXA, Lunar prodigy]	Multivariate regression, β for association vitB12-BMD β (SE) (per 50 pmol/L) P value		LS: −7.85 (0.25); TH: −11.65 (0.02)	𝑃=0.160^L, 2; 𝑃=0.007^L, 2
Rumbak et al. 2012 [40]	Cross-sectional; Croatia; Low risk	131 (0%); 54.0 ± 4.9	239.6 ± 97.0	BMD: FN, LS, TH, radius; [DXA, Lunar-prodigy]	Stepwise multivariate regression, β for association vitB12-BMD for pre- and postmenopausal women β (SE) P value (per 50 pmol/L)		Premenopausal: LS: −3.39 (8.91) 𝑃=0.709^m, 2; FN: 7.45 (10.07) 𝑃=0.467^m, 2; TH: −1.36 (7.53) 𝑃=0.862^m, 2; Postmenopausal: LS: 7.45 (8.98) 𝑃=0.411^m, 2; FN: 12.20 (8.97) 𝑃=0.180^m, 2; TH: 8.81 (8.63) 𝑃=0.314^m, 2
Stone et al. 2004 [11]	Cohort (5.9 y); USA; Low risk	83 (0%); 71.1 ± 4.4	352 ± 174	BMD: TH, FN (change) [DXA, Hologic QDR-1000]	t-test for difference in BMD change between low and normal vitB12 status		Participants with low vitB12 (≤207 pmol/L) had a more rapid decline in BMD (−1.91%/year) than part. with normal vitB12 (−0.10%/year), P < 0.05
Tucker et al. 2005 [6]	Cross-sectional; USA; Low risk	2576 (44%); 58.8 ± 9.5	Distribution per category of plasma vitB12 status; 1: ♀ 4.4%/♂4.7% ≤148; 2: ♀ 6.9%/♂7.8%; >148–185; 3: ♀ 25.4%/♂28.2%; >185–259; 4: ♀ 63.3%/♂ 59.3% >259	BMD: FN, LS, TH, Trochanter, Ward; [DXA, Lunar DPX-L]	Differences in BMD per category of plasma vitB12 level, relative to category 1		♀: FN: no differences; ♀: LS: vitB12 in cat 2 (P < 0.10), 3, 4 (P < 0.05) was assoc. with better BMD; ♀: TH: vitB12 in cat 3, 4 (P < 0.10) was assoc. with better BMD; ♂: FN: vitB12 in cat 2, 3, 4 was assoc. with better BMD (P < 0.05); ♂ LS: no differences; ♂ TH: vitB12 in cat 2 (P < 0.10), 3, 4 (P < 0.05) was assoc. with better BMD^n

*Serum/plasma vitamin B₁₂ concentrations were converted to pmol/L if applicable, using the following equation: 1 pg/mL = 1 ng/L = 0.738 pmol/L. subsequent outcomes were also converted. Where possible, subgroups were combined. BMD sites: LS: Lumbar Spine, FN: Femoral Neck, TH: Total Hip.
¹β(SE) as calculated from data provided by author; ²β (SE) as calculated from presented data.
^aadjusted for age, BMI, smoking, recurrent falling; ^badjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; ^cadjusted for sex, age, height, weight, estrogen use in women; ^dadjusted for age, sex, education, osteoporosis drugs, creatinine, tHcy; ^eadjusted for duration of menopause, smoking, BMI, folic acid levels, tHcy levels; ^fadjusted for age, BMI, logtHcy, logFolate, creatinine clearance, smoking, alcohol intake; ^gAdjusted for age, weight, weight change; ^hadjusted for weight, height, energy intake; ⁱadjusted for smoking, BMI, creatinin, coffee intake, physical activity, use of estrogen therapy; ^jadjusted for age, folate, tHcy, PTH, CTx, Ca, Cr; ^kAdjusted for age, sex, ethnicity, BMI, smoking, physical activity, creatinin, alcohol, coffee, energy, calcium, vitamin D zinc intake; ^Ladjusted for age, BMI, tHcy and folate; ^madjusted for Age, BMI, smoking, alcohol, physical activity, tHcy, Folate; ⁿadjusted for energy, calcium, vitamin D intake, BMI, height, smoking, age, physical activity, calcium supplement, vitamin D supplement, alcohol, osteoporosis medication, season of measurement.