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

Table 3

Studies regarding the association between homocysteine and bone health.

Author; Year	Study characteristics; Duration of follow-up (when applicable); Country; Risk of bias	Population characteristics: N (%men); Age (y) ± SD	Homocysteine status (μmol/L); Mean ± SD	Outcome	Association type		Results
Dhonukshe-Rutten et al. 2005 [3]	Cohort (3y); The Netherlands; High risk	1253 (48%); 75.5 ± 6.6	geometric mean (10–90 percentile); ♀: 13.0 (8.6–19.7); ♂: 14.9 (10.2–22.8)	Fracture (verified by physician or radiograph)	β (SE) for association tHcy-fracture		♀: 0.07 (0.05)^a, 2; ♂: 0.11 (0.05)^a, 2
Enneman et al. 2012 [30]	Cohort (7 y); The Netherlands; Moderate risk	503 (0%); 68.5 (61.3–74.9); Median (range)	Median (range); 9.3 (3.5–29.7)	Fracture (verified by physician)	β (SE) for association tHcy-fracture		0.05 (0.02)^b, 2
Gerdhem et al. 2007 [29]	Cohort (7 y); Sweden; Low risk	996 (0%); 75	Median (IQR); 14.1 (11.6–17.3)	Hip fracture (verified by radiograph)	β (SE) for association tHcy-hip fracture		0.07 (0.03)^c, 2
Gjesdal et al. 2007 [24]	Cohort (12.6 y); Norway; Low risk	4761 (45%); 65–67 at baseline	♀: 11.6 ± 4.2; ♂: 13.1 ± 5.8	Hip fracture (verified by hospital discharge diagnoses)	β (SE) for association tHcy-hip fracture		♀: 0.05 (0.02)^d, 2; ♂: 0.03 (0.03)^d, 2
Leboff et al. 2009 [28]	Nested case-control; USA; Moderate risk	800 (0%); 70.8 ± 6.2	11.2 ± 4.1	Hip fracture (verified by radiograph)	β (SE) for association tHcy-Hip fracture		0.07 (0.03)^e, 2
					HR (95% CI) for hip fracture risk by quartiles of tHcy. Mean tHcy per quartile:
McLean et al. 2004 [4]	Cohort (♀ 15 y; ♂12.3 y); USA; Moderate risk	1999 (41%); 70.0 ± 7.0	♀: 12.1 ± 5.3; ♂: 13.4 ± 9.1	Hip fracture (verified by review medical records)	♀: Q1: 7.6 ± 1.0; Q2: 9.9 ± 0.7; Q3: 12.2 ± 0.7; Q4: 18.6 ± 6.4	♂: 8.5 ± 0.9; 11.0 ± 0.6; 13.4 ± 0.9; 20.8 ± 15.7	♀: 1: 1.00 (reference); 2: 0.78 (0.45–1.33); 3: 1.07 (0.64–1.78); 4: 1.92 (1.18–3.10)	♂: 1.00 (reference); 1.57 (0.54–5.14); 2.07 (0.70–6.09); 3.84 (1.38–10.70)
					HR (95% CI) for each increase of 1 SD in log-transformed tHcy concentration		♀/♂ Test for trend: P < 0.01; ♂ HR per SD 1.59 (1.31–1.94)^f; ♀ HR per SD 1.26 (1.08–1.47)^f
McLean et al. 2008 [25]	Cohort (16 y); USA; Low risk	979 (41%); 75.3 ± 4.9	73.7% normal (≤14 μmol/l); 26.3% high (>14)	Hip fracture (verified by review medical records)	HR (95% CI) for high plasma tHcy (≥14 μmol/L) versus normal tHcy		Normal 1.00; High 1.69	(reference); (1.12–2.55)^g
Van Meurs et al. 2004 [5]	Cohort (4.7 y); The Netherlands; High risk	2406 (47%); 73.9 ± 7.8	14.3 ± 5.8	Fracture (verified by physician)	RR (95% CI) for fracture for each increment of 1 SD in the natural log-transformed tHcy value.		1.4 (1.2–1.6)^h
Périer et al. 2007 [27]	Cohort (10 y); France; Moderate risk	671 (0%); 61.6 ± 8.4	10.6 ± 3.5	Fracture (verified by radiograph or surgical report)	β (SE) for association tHcy-fracture		0.02 (0.02)^i, 3
Ravaglia et al. 2005 [26]	Cohort (4 y); Italy; Moderate risk	702 (47%); 73.0 ± 6.0	Geometric mean (95% CI); 12.7 (11.3–15.1)	Fracture (verified by review medical records)	β (SE) for association tHcy-fracture		0.09 (0.05)^j, 2
Zhu et al. 2009 [31]	Cohort (5 y); Australia; Moderate risk	1213 (0%); 75.2 ± 2.7	12.1 ± 4.6	Fracture (verified by radiograph)	β (SE) for association tHcy-fracture		−0.002 (0.006)^k, 2
Baines et al. 2007 [41]	Cross-sectional; Great Britain; High risk	328 (0%); 67.5 (40–85); mean (range)	12.3 ± 5.4	BMD: os calcis/heel bone [PIXI, GELunar]	Stepwise multivariate linear regression β (SE) + P value for association log tHcy-BMD		−1.548 (0.607) P = 0.011^L
Bozkurt et al. 2009 [32]	Cross-sectional; Turkey; High risk	178 (0%); 53.5 ± 8.0	10.4 ± 3.0^#	BMD: FN/LS [DXA]	Logistic regression for FN, LS and FN + LS combined. β (SE) + P value for association hcy level under the median value-BMD		LS: −0.8 (0.5) P = 0.140; FN: −0.5 (0.6) P = 0.408; LS + FN: −1.3 (0.6) P = 0.032^m
Bucciarelli et al. 2010 [33]	Cross-sectional; Italy; Moderate risk	446 (0%); 65.1 ± 9.4	(geometric mean ± SD); 10.6 ± 1.3	BMD: FN, LS, TH [DXA, Prodigy, GE, Lunar]	Multivariate linear regression β for association log tHcy-total femur BMD. β (SE) P value		−0.050 (0.025) P = 0.048^n, 2
Cagnacci et al. 2008 [34]	Cohort; Italy; Moderate risk	117 (0%); 54.4 ± 0.5	(Mean ± SE); 10.7 ± 0.5	BMD: LS; [DXA: Lunar DPX]	Regression analysis for Hcy-BMD change β (SE) + P value		−0.825 (1.09) P = 0.449^o
Cagnacci et al. 2003 [8]	Cross-sectional; Italy; Moderate risk	161 (0%); 53.3 ± 1.0	10.5 ± 0.9	BMD: LS; [DXA: Lunar DPX]	Regression analysis, β for association Hcy-BMD		β = −0.002^p, 1
Gerdhem et al. 2007 [29]	Cohort (cross sect data); Sweden; Low risk	996 (0%); 75	Median (IQR); 14.1 (11.6–17.3)	BMD: FN, LS, TH; [DXA: Lunar DPX-L]	t-test for difference in BMD (P value); between highest quartile of hcy versus all others		FN: Q4 versus; LS: Q4 versus; TH: Q4 versus	Q1–3: P = 0.032; Q1–3: P = 0.821; Q1–3: P = 0.001
Gjesdal et al. 2006 [10]	Cross-sectional; Norway; Moderate risk	5329 (43%); middle aged: 47–50; Older: 71–75	♀: 10.2 ± 4.5; ♂: 11.8 ± 3.9	BMD: TH; [DXA, Lunar EXPERT-XL]	Multivariate regression, β for association tHcy-BMD (P value) for middle aged and elderly women. (Data men not shown); OR (95% CI) for low BMD per category tHcy status + P for trend:		Mid. aged women: β = 0.004 (P < 0.001); elderly women: β = 0.003 (P < 0.001)^q
					1: <9.0 μmol/L; 2: 9.0–11.9 μmol/L; 3: 12.0–14.9 μmol/L; 4: ≥15 μmol/L		♀: 1: 1.00 (reference); 2: 1.14 (0.90–1.44); 3: 1.30 (0.95–1.79); 4: 2.19 (1.48–3.25); P for trend <0.001	♂: 1.00 (reference); 1.01 (0.74–1.37); 1.12 (0.79–1.60); 1.02 (0.66–1.56); P for trend = 0.72^q
Golbahar et al. 2004 [9]	Cross-sectional; Iran; Moderate risk	271 (0%); 60.8 ± 6.8	geometric mean (95% CI); 13.7 (7–14)	BMD: FN, LS [DXA, Lunar DPX-L]	β for association tHcy-BMD β (SE)		FN: −0.012 (0.023)^2; LS: −0.010 (0.024)^2
Haliloglu et al. 2010 [36]	Cross-sectional; Turkey; Moderate risk	120 (0%); 54.4 ± 1.1	Osteoporotic: 15.0 ± 4.6; Osteopenic: 14.2 ± 3.7; Normal: 11.2 ± 2.6	BMD: LS; [DXA, Lunar DPX-L]	ANOVA for difference in tHcy status per BMD group		tHcy was sign. higher in the osteoporotic group versus normal group (P < 0.05)
Krivosikova et al. 2010 [37]	Cross-sectional Slovakia; High risk	272 (0%); 41.3 ± 19.8	(μmol/L); 14.6 ± 5.5	BMD: FN, LS, trochanter, TH; [DXA, Lunar DPX-L]	Stepwise multivariate linear regression, β for association tHcy-BMD. β (SE) P value		FN: −0.093 (0.06) P = 0.100^r, 2; LS: 0.003 (0.07) P = 0.965^r, 2; TH: −0.134 (0.06) P = 0.033^r, 2
Morris et al. 2005 [7]	Cross-sectional; USA; Low risk	1550 (47%); 68	Osteoporosis: 11.5 (10.3–12.7); Osteopenia: 10.2 (9.5–10.8); Normal: 10.0 (9.6–10.5); 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 tHcy status + P for trend; Category median (μmol/L): Q1: 6.9; Q2: 8.9; Q3: 10.8; Q4: 14.8		Q1: 1.0 (reference); Q2: 0.9 (0.4–1.9); Q3: 2.0 (0.7–5.1); Q4: 2.0 (0.8–4.9); P for trend = 0.09 ^sDose response analysis: subjects with tHcy level >20 μmol/L had sign lower BMD than subj with tHcy level <10 μmol/L
Ouzzif et al. 2012 [39]	Cross-sectional; Morocco; Moderate risk	188 (0%); 57.8 ± 8.5	12.4 ± 4.1	BMD: FN, LS, TH, trochanter [DXA, Lunar prodigy]	Multivariate regression, β for association tHcy-BMD β (SE) + P value		LS: −0.089 (0.003) P = 0.200^t; TH: −0.155 (0.002) P = 0.021^t
Périer et al. 2007 [27]	Cohort (cross-sect data); France; Moderate risk	671 (0%); 61.6 ± 8.4	10.6 ± 3.5	BMD: FN, LS,TH [DXA, Hologic QDR-2000]	β for association tHcy-BMD β (SE)		LS: −0.000065 (0.004); FN: −0.006 (0.004); TH: −0.006 (0.004)^2
Rumbak et al. 2012 [40]	Cross-sectional; Croatia; Low risk	131 (0%); 54.0 ± 4.9	9.9 ± 2.0	BMD: FN, LS, TH, radius; [DXA, Lunar-prodigy]	Stepwise multivariate regression, β for association tHcy-BMD. β (SE) for premenopausal and postmenopausal women		Premenopausal women^u, 2: LS: 0.20 (0.14) P = 0.176; FN: 0.17 (0.15) P = 0.253; TH: 0.20 (0.14) P = 0.170; Postmenopausal women^u, 2: LS: 0.12 (0.15) P = 0.439; FN: 0.20 (0.15) P = 0.181; TH: 0.12 (0.14) P = 0.391
Zhu et al. 2009 [31]	Cohort (5 y); Australia; Moderate risk	1213 (0%); 75.2 ± 2.7	12.1 ± 4.6	BMD: TH [DXA, Hologic Acclaim 4500A]	Change in hip BMD from 1 to 5 years per tertile of tHcy (μmol/L) ANOVA		Tertile 1 and 3 differ significantly (P < 0.05)

BMD sites—LS: Lumbar Spine, FN: Femoral Neck ^#data presented in article as nmol/L, this is presumably a typing error and should be μmol/L.
¹data as provided by author on our request, ²β (SE) as calculated from presented data, ³β (SE) as calculated from data provided by author on our request.
^aadjusted for age, BMI, smoking status, recurrent falling, serum creatinine; ^badjusted for age and BMI; ^cadjusted for serum creatinine (natural log), B₁₂ level, folic acid level, BMI, smoking, walking speed, BMD, LnPTH; ^dadjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; ^ecase-control matched for age and ethnicity. Adjusted for BMI, parental history of hip fracture, treated diabetes, alcohol use, smoking, history of stroke, total calcium intake; ^fadjusted for sex, age, height, weight, smoking status, caffeine intake, alcohol intake, education level, estrogen use in women; ^gadjusted for sex, age, height, weight, estrogen use in women; ^hadjusted for age, sex, BMI, changes in BMI before entry in the study, smoking, fall history, serum creatinine; ⁱadjusted for age, prevalent fractures, BMD, calcium intake, physical activity, vitamin D level, creatinine, albumin, estradiol; ^jadjusted for age, gender, education, serum creatinine, osteoporosis drugs; ^kadjusted for age, weight, hip BMD, prevalent fracture, calcium treatment; ^Ladjusted for weight, cysteine, smoking and height; ^mAdjusted for duration of menopause, smoking, BMI, folic acid levels, homocysteine levels; ⁿadjusted for age, BMI, logFolate, logB₁₂, creatinine clearance; ^oAdjusted for age, weight, weight change; ^pAdjusted for BMI, smoking, age; ^qAdjusted for smoking, BMI, creatinine, coffee intake, physical activity, use of estrogen therapy; ^radjusted for age, B₁₂, folate, PTH, CTx, Ca, Cr; ^sadjusted for age, sex, ethnicity, BMI, smoking, physical activity, creatinin, alcohol, coffee, energy, calcium, vitamin D zinc intake; ^tadjusted for age, BMI, folate, B₁₂; ^uadjusted for age, BMI, smoking, alcohol intake, physical activity, duration of menopause, HRT, levels of hcy, vitB₁₂ and folate.