Plasma Homocysteine, Folate, and Vitamin B12 and the Risk of Hip Fracture: The Hordaland Homocysteine Study

Abstract

Homocysteine and related factors were evaluated as risk factors for subsequent hip fractures among 4766 elderly men and women. High levels of homocysteine and low levels of folate predicted fracture, whereas vitamin B 12 and genotypes were not related to fracture risk. High homocysteine may be a modifiable risk factor for hip fracture.Introduction: Elevated plasma total homocysteine (tHcy) and deficiencies of folate and vitamin B 12 are associated with risk of osteoporosis and fracture. We examined whether plasma levels of tHcy, folate, and vitamin B 12 and the methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298C→T polymorphisms predicted hip fracture. Materials and Methods:This was a population-based prospective study of 2639 women and 2127 men who were 65-67 yr at enrollment in 1992-1993. Information on hip fracture was obtained from computerized records of discharge diagnoses from all hospitalizations in the region in the period between enrollment and November 30, 2005. Cox proportional hazard regression was used to estimate fracture risk according to levels of plasma tHcy, folate, and vitamin B 12 and for different genotypes. Results: Over a median follow-up period of 12.6 yr, hip fracture was recorded in 184 (7.0%) women and 90 (4.2%) men. The adjusted hazard ratio (95% CI) for fracture in subjects with high (Ն15 M) compared with low levels (<9.0 M) of tHcy was 2.42 (1.43-4.09) among women and 1.37 (0.63-2.98) among men. Doseresponse analyses indicated a positive association between plasma tHcy and risk of fracture in both sexes and a negative association between plasma folate and risk of fracture among women only. Plasma vitamin B 12 level or MTHFR genotype was not significantly related to risk of fracture after adjustments for confounding factors. The association between tHcy and risk of hip fracture was only slightly weakened by adjustments for plasma levels of vitamin B 12 and folate. Conclusions: tHcy seems to be a predictor for hip fracture among elderly men and women. Folate was a predictor among women only, whereas vitamin B 12 and MTHFR genotype did not predict hip fracture. Our data corroborate the hypothesis that homocysteine may play a role in the pathogenesis of osteoporotic fractures.

B-vitamins and bone in health and disease: the current evidence

“…In 2004, two landmark studies performed in the Netherlands and the USA produced consistent findings in terms of the magnitude of increased risk of fracture associated with mild elevations in homocysteine (36,37) . In subsequent years, further studies from the USA, the Netherlands and Norway similarly demonstrated increases in fracture risk associated with elevated homocysteine concentrations (31)(32)(33)35) . Confirming these findings, a recent meta-analysis involving nine prospective studies and 14 863 participants reported a relative risk of 1.59 (95 % CI 1.30, 1.96) and 1.67 (95 % CI 1.17, 2.38) for all fractures and hip fractures, respectively, in those within the highest homocysteine quartile compared with the lowest (30) .…”

“…In the past decade, numerous large observational studies have provided evidence to support a role for homocysteine and/or low B-vitamin status in fracture risk (Table 1) (12,(29)(30)(31)(32)(33)(34)(35)(36)(37) . In 2004, two landmark studies performed in the Netherlands and the USA produced consistent findings in terms of the magnitude of increased risk of fracture associated with mild elevations in homocysteine (36,37) .…”

“…Most recently, a doseresponse meta-analysis including eight observational studies and 11 511 participants estimated a 4 % increase in fracture risk for every 1 μmol/l increase in homocysteine concentration (12) . Given the close metabolic relationship of the B-vitamins with homocysteine, studies have also demonstrated inverse associations between the status of the B-vitamins, folate, vitamins B 12 and B 6 and fracture risk in large cohorts of men and women (29,(33)(34)(35) .…”

Medical cost savings in Sakado City and worldwide achieved by preventing disease by folic acid fortification

“…For example, moderate hyperhomocysteinemia induced by low folate status is an independent risk factor for cardiovascular disease (CVD) (Ishihara et al 2008; Bentley et al 2009), stroke (Yang et al 2006; Huo et al 2015; Li et al 2016b), colon cancer (Bentley et al 2009), dementia (Jernerén et al 2015), fracture (Gjesdal et al 2007), kidney diseases (Massy 2003) and depression (Bottiglieri 2005; Hiraoka et al 2014). These diseases can be prevented or alleviated by increased folate intake, as shown by many epidemiological and interventional studies.…”

“…In contrast, the TT genotype of MTHFR C677T showed significantly lower serum folate and higher serum Hcy than the CC and CT genotypes (Hiraoka et al 2004). The TT genotype of the C677T polymorphism in MTHFR has been associated with CVD (Morita et al 1998), dementia (Kageyama et al 2008), osteoporosis (Gjesdal et al 2007), depression (Bottiglieri 2005) and kidney diseases (Sakamoto et al 2015). In addition, there are many risk SNPs of CVD, metabolic syndrome, and other chronic diseases (Kagawa 2012; Kagawa et al 2012) that affect the MTHFR genotypes and must be considered for disease prevention and the reduction of medical costs.…”