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

Table 2

Studies regarding the association between folate and bone health.

Author; Year	Study characteristics; Duration of follow-up (when applicable); Country; Risk of bias	Population characteristics: N (%men); Age (y) ± SD	Folate status (nmol/L)*; Mean ± SD	Outcome	Association type	Results*
Gjesdal et al. 2007 [24]	Cohort (12.6 y); Norway; Low risk	4761 (45%); 65–67 at baseline	♀ 6.0 ± 3.5; ♂ 5.2 ± 2.7	Hip fracture; (verified by hospital discharge diagnoses)	HR for hip fracture according to folate status; 1: <2.9; 2: 2.9–3.8; 3: 3.9–6.5; 4: ≥6.6	♀: 1: 2.40 (1.50–3.84); 2: 1.15 (0.68–1.94); 3: 1.02 (0.68–1.54); 4: 1.00 (reference)^a	♂: 1.00 (0.48–2.12); 0.80 (0.39–1.62); 0.81 (0.45–1.46); 1.00 (reference)^a
McLean et al. 2008 [25]	Cohort (16 y); USA; Low risk	960 (41%); 75.3 ± 4.9	Not shown	Hip fracture; (verified by review medical records)	HR for hip fracture according to folate status; Normal: ≥11 Low: 7–10.9 Deficient: <7	Normal: 1.00 (reference); Low: 0.76 (0.43, 1.32); Deficient: 1.38 (0.91, 2.09)^b
Ravaglia et al. 2005 [26]	Cohort (4 y); Italy; Moderate risk	702 (47%); 73.0 ± 6.0	11.7 (9.0–12.2); mean (95% CI)	Fracture; (verified by review medical records)	OR (95% CI) for risk of fracture at follow-up for each increment of 1 sd in the log-transformed serum folate value	0.83 (0.59–1.19)^c
Baines et al. 2007 [41]	Cross-sectional; Great Britain; High risk	328 (0%); 67.5 (40–85); mean (range)	Osteoporosis: 8.1 ± 8.7^#; Osteopenia: 10.2 ± 4.6; Normal: 9.4 ± 6.3	BMD: os calcis/ heel bone [PIXI, GE Lunar]	ANOVA for difference between the normal, osteopenia and osteoporosis group	FA status was significantly different between osteroporotic and osteopenic group; (P = 0.049)
Bozkurt et al. 2009 [32]	Cross-sectional; Turkey; High risk	178 (0%); 53.5 ± 8.0	24.9 ± 7.9	BMD: FN, LS; [DXA]	Logistic regression for FN, LS and FN + LS combined. β (SE) + P value for assoc. BMD-folate status under the median value	LS: −0.2 (0.2) P = 0.417; FN: −0.04 (0.2) P = 0.835; LS + FN: −0.03 (0.2); P = 0.896^d
Bucciarelli et al. 2010 [33]	Cross-sectional; Italy; Moderate risk	446 (0%); 65.1 ± 9.4	(geometric mean ± SD); 3.8 ± 1.6	BMD: FN, LS, TH [DXA, Prodigy, GE, Lunar]	β for association folate-TH BMD β (SE)	0.004 (0.018)^e, 2
Cagnacci et al. 2008 [34]	Cohort (5 y); Italy; Moderate risk	117 (0%); 54.4 ± 0.5	(Mean ± SE); 20.6 ± 1.4	BMD: LS; [DXA: Lunar DPX]	Regression analysis for folate-BMD change β (SE) + P value	1.602 (0.803) P = 0.048^f
Cagnacci et al. 2003 [8]	Cross-sectional; Italy; Moderate risk	161 (0%); 53.3 ± 1.04	(Mean ± SE); 21.5 ± 4.3	BMD: LS; [DXA: Lunar DPX]	Regression analysis, r (P value) for association folate-BMD	r = 0.254	(P < 0.002)
Gjesdal et al. 2006 [10]	Cross-sectional; Norway; Moderate risk	5329 (43%); middle aged: 47–50; Older: 71–75	♀ 8.9 ± 7.1; ♂ 7.3 ± 4.6	BMD: TH [DXA, Lunar EXPERT-XL]	OR (95% CI) for low BMD per category folate status: 1: FA < 3.8 nmol/L; 2: FA 3.8–4.9 nmol/L; 3: FA 5.0–8.4 nmol/L; 4: FA ≥ 8.5 nmol/L + P for trend; Multivariate regression for folate-BMD β (SE) (per 50 nmol/L)	♀: 1: 1.55 (1.07–2.23); 2: 1.18 (0.86–1.63); 3: 1.24 (0.99–1.56); 4: 1.00 (reference); P for trend = 0.02	♂: 0.81 (0.53–1.24); 0.96 (0.67–1.38); 1.15 (0.87–1.53); 1.00 (reference); P for trend = 0.26^g
						Elderly women: β = 0.05 (0.02)^g, 2
Golbahar et al. 2004 [9]	Cross-sectional; Iran; Moderate risk	271 (0%); 60.8 ± 6.8	(geometric mean ± SD); 11.6 ± 6.5	BMD: FN, LS [DXA, Lunar DPX-L]	β for association folate-BMD β (SE)	FN: 0.008 (0.019)^h, 2; LS: 0.010 (0.018)^i, 2
Haliloglu et al. 2010 [36]	Cross-sectional; Turkey; Moderate risk	120 (0%); 54.4 ± 1.1	Osteoporotic: 12.2 ± 6.3; Osteopenic: 15.4 ± 7.4; Normal: 15.8 ± 8.3	BMD: LS; [DXA, Lunar DPX-L]	ANOVA for difference in folate status per BMD group (osteoporotic, osteopenic, compared to normal BMD group)	No significant differences in folate status between BMD groups
Krivosikova et al. 2010 [37]	Cross-sectional Slovakia; High risk	272 (0%); 41.3 ± 19.8	23.8 ± 9.6	BMD: FN, LS, trochanter, TH; [DXA, Lunar DPX-L]	Stepwise multivariate linear regression, β for association folate-BMD.; β (SE) P value	FN: −0.028 (0.054) P = 0.606 ^j, 2; LS: −0.001 (0.067) P = 0.988 ^j, 2; TH: −0.032 (0.060) P = 0.595^j, 2
Morris et al. 2005 [7]	Cross-sectional; USA; Low risk	1550 (47%); 68	Osteoporosis: 17.2 (15.4–19.2); Osteopenia: 17.2 (16.0–18.5); Normal: 16.7 (15.3–18.3) Geometric mean (95% CI)	BMD: Trochanter, intertrochanter, FN, Ward’s triangle, TH [DXA, Hologic QDR-1000]	OR (95% CI) for mean BMD in relation to quartile categories of folate status + P for trend; Category median (nmol/L): Q1: 8.0; Q2: 12.4; Q3: 20.3; Q4: 38.9	Q1: 1.1; Q2: 1.1; Q3: 1.5; Q4: 1.0; P for trend	(0.5–2.3); (0.0.5–2.9); (0.7–3.4); (reference); = 0.83^k
Naharci et al. 2012 [38]	Cross-sectional; Turkey; Moderate risk	264 (100%); 77.0 ± 6.0	low (<7.0, group I): 0.0%; borderline (7.0–10.9, group II): 9.2%; normal (>10.9, group III): 90.8%	BMD: FN, TH, trochanter, intertrochanter; [DXA, hologic QDR-4500]	Independent sample t-test for differences in FN BMD between group II and III of serum folate	No significant differences in BMD (all sites) between group II and III of folate status
Ouzzif et al. 2012 [39]	Cross-sectional; Morocco; Moderate risk	188 (0%); 57.8 ± 8.5	15.6 ± 6.8	BMD: FN, LS, TH, trochanter [DXA, Lunar prodigy]	Multivariate regression, β for association folate-BMD β (SE) + P value	LS: 0.007 (0.002) P = 0.808^L; TH: 0.006 (0.001) P = 0.834^L
Rumbak et al. 2012 [40]	Cross-sectional; Croatia; Low risk	131 (0%); 54.0 ± 4.9	22.4 ± 7.5	BMD: FN, LS, TH, radius; [DXA, Lunar-prodigy]	Stepwise multivariate regression, β for association folate-BMD; β + P value	Premenopausal: LS: 3.31 (4.73) P = 0.490^m, 2; FN: 1.32 (4.90) P = 0.791^m, 2; TH: 2.87 (4.35) P = 0.516^m, 2; Postmenopausal: LS: −3.75 (3.47) P = 0.284^m, 2; FN: −1.32 (3.15) P = 0.679^m, 2; TH: 0.66 (3.89) P = 0.862^m, 2

*Serum/plasma folate concentrations were converted to nmol/L if applicable, using the following equation: 1 ng/ml = 2.266 nmol/L. Subsequent outcomes were also converted. Where possible, subgroups were combined. BMD sites—LS: Lumbar Spine, FN: Femoral Neck, TH: Total Hip ^#data presented in article as μmol/L, this is presumably a typing error and should be nmol/L.
¹β (SE) as calculated from data provided by author; ²β (SE) as calculated from presented data.
^aadjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; ^badjusted for sex, age, height, weight, estrogen use in women; ^cadjusted for age, gender, education, osteoporosis drug, serum creatinine, tHcy; ^dAdjusted for duration of menopause, smoking, BMI, B₁₂, tHcy; ^eadjusted for age, BMI, logtHcy, logB₁₂, creatinine clearance, smoking, alcohol intake;
^fAdjusted for age, weight, weight change; ^gAdjusted for smoking, BMI, creatinin, coffee intake, physical activity, use of estrogen therapy; ^hadjusted for age, BMI, alkaline phosphatase; ⁱadjusted for years since menopause, BMI, alkaline phosphatase, creatinine; ^jadjusted for age, B₁₂, 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, B₁₂; ^madjusted for Age, BMI, smoking, alcohol, physical activity, tHcy, B₁₂.