Original Full Length ArticleHomocysteine level and risk of fracture: A meta-analysis and systematic review
Highlights
► Inconsistent findings regarding the association between elevated plasma Hcy levels and fracture risk. ► We performed a meta-analysis and systematic review on plasma Hcy levels and fracture risk. ► Hcy significantly increased the risk of fracture, and the increase was independent of risk factors. ► Routine Hcy assays will be helpful in identifying fracture risk among elderly people.
Introduction
Osteoporotic fractures are a major health problem in Western countries and are associated with increased morbidity and mortality [1]. The most common consequences of osteoporosis are fractures of the hip, wrist and vertebrae [2]. More than 40% of women and 14% of men older than 50 years of age experience fractures related to osteoporosis [3]. So, prevention of fractures by identifying the modifiable risk factors, as well as the development of new treatment strategies, is becoming increasingly urgent.
Homocysteine (Hcy), a sulfur amino acid, has been found to accumulate in the bone, thereby affecting the bone metabolism. Hcy metabolism consists of the intersection of two pathways: remethylation to methionine, which requires folic acid and B12 coenzymes; and transsulfuration to cysteine, which requires pyridoxal-5′-phosphate, the B6 coenzyme. Several studies reported that the elevated Hcy concentrations were identified as a potentially modifiable risk factor for fractures [4], [5], [6], [7], [8], [9]. These findings suggested that the total Hcy levels were strongly associated with the risk of fractures. High plasma Hcy levels can be effectively and easily modified by supplementation of folate, vitamins B6 and B12 [10], [11], [12]. Moreover, randomized clinical trials (RCTs) of Hcy-lowering therapy on the fractures suggested that folate and vitamin B12 supplement could reduce the incidence of fractures [13], [14].
However, previous studies have reported inconsistent findings regarding the association between elevated plasma Hcy levels and fracture risk. Hcy levels were not independently associated with fractures [15], [16], [17], [18], [19], [20]. Low folate levels but not Hcy levels predicted the fracture risk [21]. Importantly, two-thirds of cases of Hcy elevation were ascribable to low vitamin B12 and folate status or intake [22]. Taken together, available data suggest that high Hcy levels, low plasma folate and B12 levels may be related to an increased fracture risk. Furthermore, elevated Hcy levels are also associated with other high fracture risks of diseases, such as cardiovascular disease and cognitive impairment. Hence, whether the fracture is affected by elevated plasma Hcy itself or by a deficiency of the other confounding factors remains unclear.
To our knowledge, no systematic evaluation of such studies has been conducted on the association between plasma Hcy level and fractures. Given these reasons, a meta-analysis and systematic review may help clarify this issue. The aim of the current meta-analysis and systematic review was to quantitatively evaluate findings from observational studies on the plasma level of Hcy and the incidence of fracture. We also looked for the RCTs that evaluated the beneficial effects of Hcy-lowering therapy in such patients, and to conclude the associations of plasma Hcy levels with fracture risk.
Section snippets
Search strategy
We conducted a PubMed database and Embase search (up to April 2012) for studies assessing the association between fractures and Hcy. Papers could be published in English and Chinese. Potentially relevant studies included the word ‘fracture’, plus at least one of the following terms: hyperhomocysteinemia, homocysteine, folate, folic acid, vitamin B6, and pyridoxine. In addition, we also manually searched the reference lists to detect additional eligible studies.
Study selection
Studies satisfying the following
Literature search
After the application of search strategy, a total of 165 potentially relevant citations were identified in our initial literature search. After screening the abstracts or titles, 153 studies were excluded, mainly because they were reviews, case–control studies, or not relevant to our analysis. After reviewing the full texts, 9 studies met the inclusion criteria [4], [5], [15], [16], [18], [19], [20], [21], [28]. Three trials were included in systematic review [13], [14], [29]. A flow chart
Discussion
The findings of the current meta-analysis provided prospective evidence that Hcy was prospectively associated with a significantly increased risk of incident fracture. Subjects with elevated Hcy increased risk of all fractures (RR 1.59, 95% CI 1.30–1.96) and hip fracture (RR 1.67, 95% CI 1.17–2.38). The risk appeared more pronounced in men.
Osteoporotic fractures affect both sexes, but primarily postmenopausal women, because of the substantial decline in bone mass and changes in bone
Conclusions
In conclusion, this meta-analysis and systematic review provided strong evidence that Hcy was associated with an increased future risk of incident fracture, and the increase might be probably independent of conventional risk factors. The risk appeared more pronounced in men. Whether this link is causal remained to be clarified further by future studies. More well-design RCTs on the effect of Hcy-lowering therapy on the prevention or treatment of fracture would be helpful to clarify this
Conflict of interest
There were no conflicts of interest for each named author.
Acknowledgments
This work was supported by Nature Science Foundation of China (81070254, 30872527). We gratefully thank Shijun Wang for his assistance in preparing the manuscript.
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