Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B₁₂ with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B₁₂ concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk. Introduction: Hyperhomocysteinemia may contribute to the development of osteoporosis. Vitamin B₁₂ is closely correlated to homocysteine (Hcy). The main objective of our study was to examine the association of Hcy and vitamin B₁₂ status and the combined effect of these two with broadband ultrasound attenuation (BUA), bone turnover markers, and fracture. Materials and Methods: Subjects were 615 men and 652 women with a mean age of 76 ± 6.6 (SD) years of the Longitudinal Aging Study Amsterdam (LASA). At baseline (1995/1996), blood samples were taken after an overnight fast for dairy products. Plasma Hcy was measured with IMx, serum vitamin B₁₂ with competitive immunoassay (IA) luminescence, serum osteocalcin (OC) with immunoradiometric assay (IRMA), and urinary excretion of deoxypyridinoline (DPD) with competitive IA and corrected for creatinine (Cr) concentration. CVs were 4%, 5%, 8%, and 5%, respectively. BUA was assessed in the heel bone twice in both the right and left calcaneus. Mean BUA value was calculated from these four measurements. CV was 3.4%. After baseline measurements in 1995, a 3‐year prospective follow‐up of fractures was carried out until 1998/1999. Subjects were grouped by using two different approaches on the basis of their vitamin B₁₂ concentration, normal versus low (15 μM) or highest quartile (Q4) versus normal quartiles (Q1‐Q3). Analysis of covariance was performed to calculate mean values of BUA, OC, and DPD/Cr_urine based on the specified categories of Hcy and vitamin B₁₂ and adjusted for several confounders (potential confounders were age, sex, body weight, body height, current smoking [yes/no], mobility, cognition). The relative risk (RR) of any fracture was assessed with Cox regression analysis. Quartiles were used when Hcy and vitamin B₁₂ were separately studied in their relationship with fracture incidence. Results: Fourteen percent of the men and 9% of the women had high Hcy (>15 μM) and low vitamin B₁₂ (<200 pM) concentrations. Women with vitamin B₁₂ levels 15 μM had lower BUA, higher DPD/Cr, and higher OC concentrations than their counterparts. In men, no differences were found between the different Hcy and vitamin B₁₂ categories in adjusted means of BUA, OC, or DPD/Cr_urine. Twenty‐eight men and 43 women sustained a fracture during the 3‐year follow‐up period. The adjusted RR for fractures (95% CI) for men with high Hcy and/or low vitamin B₁₂ concentrations was 3.8 (1.2‐11.6) compared with men with normal Hcy and vitamin B₁₂ concentrations. Women with high Hcy and/or low vitamin B₁₂ concentrations had an adjusted RR for fractures of 2.8 (1.3‐5.7). Conclusions: High Hcy and low vitamin B₁₂ concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.

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