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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:1458-1462 (2005)
© 2005 The Gerontological Society of America

Folate, But Not Homocysteine, Predicts the Risk of Fracture in Elderly Persons

Giovanni Ravaglia1,, Paola Forti1, Fabiola Maioli1, Lucia Servadei1, Mabel Martelli1, Nicoletta Brunetti1, Luciana Bastagli1, Domenico Cucinotta1 and Erminia Mariani2

1 Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy.
2 Laboratory of Immunology and Genetics, Codivilla Putti Research Institute, Rizzoli Orthopaedic Institute, Bologna, Italy.

Address correspondence to Prof. Giovanni Ravaglia, Department of Internal Medicine, Cardioangiology, and Hepatology-University Hospital S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy. E-mail: ravaglia{at}med.unibo.it


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. Recent prospective studies reported that increased plasma homocysteine levels are an independent predictor of osteoporotic fracture in elderly persons. These studies, however, did not take into account folate and vitamin B12, which are the major nutritional determinants of homocysteinemia.

Methods. Incident osteoporotic fractures were assessed in 702 Italian participants aged 65–94 years with a mean follow-up of 4 years (1999/2000–2003/2004). A multivariable logistic regression model was used to study the relation of baseline plasma homocysteine, serum folate, and serum vitamin B12 with risk of fracture.

Results. After adjustment for sociodemographic and clinical confounders, the odds ratio (OR) for each increase of 1 standard deviation in log-transformed plasma homocysteine was 1.39 (95% confidence interval [CI], 1.01–1.91), but decreased to 1.22 (95% CI, 0.85–1.74) after further adjustment for serum folate and vitamin B12. The corresponding multivariable-adjusted OR for hyperhomocysteinemia (plasma total homocysteine [tHcy] > 15 µmoL) was 1.58 (95% CI, 0.71–3.53). Participants in the lowest serum folate quartile (≤9.3 nmol/L) had an increased risk of fracture than did those in higher quartiles (multivariable-adjusted OR = 2.06; 95% CI. 1.02–4.18), but no dose-related protective effect for increasing serum folate levels was found (multivariable-adjusted OR = 0.84 for each increase of 1 standard deviation in log-transformed serum folate, 95% CI, 0.59–1.19). No independent association was found for serum vitamin B12.

Conclusions. Low serum folate is responsible for the association between homocysteine and risk of osteoporotic fracture in elderly persons.

MILDLY increased blood levels of the sulfur amino acid homocysteine are common in elderly persons (1,2), and are a risk factor for cardiovascular disease (3) and, perhaps, cognitive impairment (4). The increased prevalence of osteoporosis in homocystinuria, a rare autosomal recessive disease characterized by markedly elevated homocysteinemia (5), has led to hypotheses that homocysteine may also be involved in bone metabolism. In vitro, homocysteine may directly impair bone structure through inhibition of collagen cross-linking (6), and increased homocysteinemia appears to be a strong risk factor for osteoporotic fracture in elderly persons (7,8). This might have relevant diagnostic and therapeutic implications, because hyperhomocysteinemia could be used as an early marker of increased fracture risk and, even more important, is amenable to dietary treatment (9).

The studies reporting the association between homocysteine and risk of fracture, however, could not definitely establish homocysteine as an independent predictor of fracture in older age because they did not take into account folate and vitamin B12. These vitamins are the major nutritional determinants of fasting homocysteine blood levels (1), and their dietary deficit, along with the physiological age-related reduction in renal function (10), is responsible for the majority of cases of mild hyperhomocysteinemia in elderly persons (2).

Using data from the Conselice Study of Brain Aging (CSBA), an Italian population-based study of older persons, we investigated the independent contribution of baseline plasma homocysteine, serum folate, and serum vitamin B12 to the risk of osteoporotic fracture at 4 years of follow-up.


   METHODS
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 Methods
Results
 Discussion
 References
 
Study Population
The CSBA is a population-based survey, already described in detail elsewhere (11,12), the primary aim of which is to provide epidemiologic data on dementia in elderly persons. Briefly, in 1999 and 2000, 1016 (75%) of the 1353 individuals aged ≥65 years residing in the Italian municipality of Conselice (Ravenna province, Emilia Romagna region) participated in the prevalence study and underwent a standardized medical interview and examination, along with venous blood drawing. In 2003 and 2004, survivors were contacted again for a second examination. The study was approved by the local Institutional Review Board, and written informed consent was obtained from all participants.

Assessment of Fractures
Survivors who agreed to be reassessed in the 2003–2004 period were requested to present all medical documentation pertaining to the time period between baseline and follow-up examination. Participants were also specifically asked about the occurrence of bone fractures in the same interval. For participants unable to answer because of sensory-motor or mental impairment, information was sought from relatives and/or caregivers. A fracture in any skeletal location was considered to be osteoporotic except for hand, foot, and skull-facial fractures. Fractures due to cancer or to an overwhelming trauma such as a road accident were also excluded.

Laboratory
Baseline venous blood samples were taken after an overnight fast. Plasma samples for determination of plasma total homocysteine (tHcy) and plasma pyridoxal-5'-phosphate (the active coenzyme form of vitamin B6), and EDTA-treated blood samples for methylenetetrahydrofolate reductase (MTHFR) 677 (C -> T) polymorphism screening were stored at –70°C until the analysis was performed. The duration of storage was up to 12 months. The fully automatized IMx assay (Abbott Laboratories, Abbott Park, IL) was used to measure plasma tHcy. Intra- and interassay coefficients of variation (CV) were 2.1% and 3.2%. Plasma vitamin B6 was measured by high performance liquid chromatography (HPLC) (13). Intra- and interassay CV were 4.5% and 4.8%. Genomic DNA was obtained using a commercial DNA extraction kit (QIAmp DNA Blood Mini Kit; QIAGEN GmbH, Hilden, Germany) and for MTHFR 677 polymorphism genotyping was performed according to standardized polymerase chain reactions protocols (14).

Serum samples for folate and vitamin B12 determination were sent to the biochemical laboratory for immediate immuno-electrochemiluminescence analysis (Elecsys Folate Immunoassay and Elecsys B12 Immunoassay for Elecsys 2010 System; Roche Diagnostics Italia S.p.A. Monza, Milano, Italy). For serum folate, intra- and interassay CV were 3.1% and 3.8%. For vitamin B12, intra- and interassay CV were 4.3% and 4.6%. Serum creatinine was measured by the Jaffé method, adapted for autoanalyzers.

Covariates
Sociodemographic, lifestyle, and clinical confounders were defined using data collected at baseline. Educational status was categorized as 5 versus ≥6 years of formal education, because only a small number of CSBA participants had completed the 5 years of mandatory education provided for in the old Italian school system. Smoking status was dichotomized as never smokers versus ex-and current smokers. Physical activity was classified as sedentary vs active lifestyle (defined as performing at least moderate activity [≥3 metabolic equivalents] for ≥4 hours/week). Caffeine (coffee or tea) and alcohol consumption (beer, wine, or spirits) were classified according to the number of cups or drinks consumed per day. Diagnosis of cardiovascular disease (myocardial infarction, angina, peripheral vascular disease, and congestive heart failure) was based on medical history as provided by the patients and confirmed by their general practitioner. Whenever available, previous medical records were also reviewed. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Current consumption of osteoporosis drugs (calcium, vitamin D, and bisphosphonates) and, for women, current or previous consumption of estrogen-replacement therapy was also recorded.

The Italian version of the Mini-Mental State Examination (MMSE) (15) was used as a measure of global cognitive function, because cognitive impairment is associated with both increased propensity to fall and hyperhomocysteinemia.

Statistical Analysis
Variables are presented as mean (standard deviation [SD]) or number and percentage except for plasma homocysteine, serum folate, serum vitamin B12, and plasma vitamin B6. Owing to their skewed distribution, these variables were analyzed as both categorical and continuous natural log-transformed values, and were reported as geometric mean and 95% confidence interval (CI). Hyperhomocysteinemia was defined as plasma tHcy >15 µmol/L, corresponding to the 75th percentile of plasma tHcy distribution. The 25th percentile was used to dichotomize folate (≤9.3 nmol/L), vitamin B12 (≤190 pmol/L), and vitamin B6 (≤14 nmol/L) levels. Student t tests and chi-square tests were used for comparisons between groups. Logistic regression analysis was used to evaluate the effect of selected variables (age, gender, education, hyperhomocysteinemia, low folate, and low vitamin B12) as predictors of noninclusion in the actual study. The independent associations of homocysteine, folate, and vitamin B12 (both as a categorical and log-transformed continuous variable) with risk of fracture at follow-up were also examined with logistic regression. A first model provided sequential adjustment for age, gender, education, serum creatinine, and osteoporosis drugs. A second model included additional adjustment for low vitamin B6 and MTHFR 677 T/T genotype, which are known causes of hyperhomocysteinemia (1), and might also affect bone metabolism (16–18). A third model included all the first model's covariates plus smoking, sedentary lifestyle, alcohol and caffeine intake, cardiovascular disease, BMI, and MMSE score. In supplementary analyses, we adjusted for other potential confounders. All p values are two-sided. Statistical analyses were performed using SYSTAT10 (SPSS, Inc., Chicago, IL).


   RESULTS
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Discussion
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Blood samples for laboratory measurements were not available for 38 of the 1016 participants at baseline. Of the remaining 978 individuals, 138 died before follow-up, 106 refused to be reassessed, and 26 underwent the 2003–2004 examination but were excluded because of missing information about incident fractures, thus leaving 708 eligible participants. Age (OR for 1-year increment of age = 1.12 [95% CI, 1.09–1.14], p <.001), female gender (OR = 1.33 [95% CI, 1.01–1.74], p =.041), poor education (OR for 1-year increment of education = 0.84 [95% CI, 0.79–0.90], p <.001), hyperhomocysteinemia (OR = 2.54 [95% CI, 1.89–3.41], p <.001), low folate (OR = 2.04 [95% CI, 1.53–2.72], p <.001), and low vitamin B12 (OR = 1.38 [95% CI, 1.02–1.86], p =.038) were all significant predictors of noninclusion in the present study.

During follow-up, osteoporotic fractures occurred in 44 participants: 23 (52.3%) hip, 8 (18.2%) wrist, 7 (15.9%) vertebrae, 3 (6.8%) rib or sternum, and 3 (6.8%) extremities (leg, arm, or ankle). Six individuals with incident nonosteoporotic fractures were excluded from the study population. Medical records confirming the event of interest were available for 30 osteoporotic fracture cases and five nonosteoporotic fracture cases. Table 1 lists the baseline characteristics of the 702 remaining participants grouped according to occurrence of fractures. Fractures were more frequent in older individuals, in women, in baseline users of osteoporotic drugs, and in those with low serum folate. The other variables did not differ between the groups.


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  		Table 1. Baseline Characteristics of Study Participants According to Occurrence of Fractures at Follow-Up.

 
Table 2 shows the results of the multivariable-adjusted logistic models for homocysteine. After adjustment for sociodemographic confounders and serum creatinine, the risk of fracture increased by 39% for each increase of 1 SD in log-transformed plasma tHcy and was unaffected by further adjustment for use of osteoporosis drugs. However, the association decreased appreciably when also controlling for serum folate and vitamin B12. A similar, but statistically weaker trend was observed for hyperhomocysteinemia. Additional adjustments for plasma vitamin B6, MTHFR 677 genotype, lifestyle habits, cardiovascular disease, BMI, and MMSE did not affect the results (results did not change when adjusting the models for serum folate and vitamin B12 considered as log-transformed continuous variables).


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  		Table 2. Multivariable Logistic Models Examining the Relation of Baseline Homocysteinemia With Risk of Fracture at Follow-Up.

 
The separate contribution of baseline serum folate and vitamin B12 to risk of fracture is shown in Table 3. Multivariable-adjusted risk of fracture decreased only by a marginal 17% for each increase of 1 SD in log-transformed serum folate levels, but doubled for the persons in the lowest serum folate quartile with respect to the persons in the higher quartiles (results did not change when adjusting for homocysteine considered as a categorical variable and vitamin B12 as a log-transformed continuous variable). By contrast, the same multivariable-adjusted model did not yield any significant association between risk of fracture and vitamin B12 analyzed either as a categorical (OR = 1.24; 95% CI, 0.57–2.64) or a continuous variable (OR for each increase of 1 SD in serum vitamin B12 = 0.86; 95% CI, 0.62–1.20).


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  		Table 3. Multivariable Logistic Models Examining the Relation of Baseline Serum Folate With Risk of Fracture at Follow-Up.

 
Among the participants, one had serum folate >100 nmoL, six had serum vitamin B12 >1000 pmol/L, and 10 women reported previous or current use of estrogen-replacement therapy at baseline. However, results were unchanged when analyses were repeated with these individuals excluded. Serum cholesterol, serum thyrotropin, disability with instrumental activities of daily living, and number of servings per day of dairy products were also measured at baseline, but adjustment for these additional variables did not affect results (data not shown).


   DISCUSSION
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 Abstract
 Methods
 Results
 Discussion
References
 
This study shows that low serum folate is responsible for the prospective association between homocysteine and risk of osteoporotic fracture in elderly persons previously reported in subsamples from the Framingham Study (7) and from the Longitudinal Aging Study Amsterdam and the Rotterdam Study (8). Although the sample size and follow-up time of the CSBA population are rather small compared to the Framingham cohort (7) and the two Dutch cohorts (8), we do not believe that our failure in confirming homocysteine as an independent predictor of fracture is due to an insufficient statistical power. Indeed, the association between plasma tHcy and risk of fracture was actually present in the models not including serum folate, and lost significance only after adjustment for the latter. By contrast, measurement of serum folate was not available for either the U.S. (7) or the Dutch cohort (8), and an indirect estimation of vitamin dietary intake was performed only for the Rotterdam Study subsample.

In the CSBA sample, risk of fracture doubled for the lowest serum folate quartile compared to the other quartiles, and the association remained significant even when adjusting for homocysteine and several other confounders associated with age-related bone loss and increased risk of fall, including the MTHFR 677 genotype. This agrees with cross-sectional data by McLean and colleagues (19), showing how the association between risk of fracture and the MTHFR 677 polymorphism reported by some authors (16,17), actually depends on low folate status. In this sample, MTHFR 677 genotype distribution did not differ between individuals with and without incident fractures and did not significantly affect the relationship between folate and fracture risk. However, due to the small number of fracture cases, we could not reliably estimate whether low folate levels modified risk of fracture across the different MTFHR genotypes. A similar lack of effect on fracture risk was found for vitamin B6, although animal studies suggest that it may act as a cofactor to build up collagen cross-links in bone (18).

Finally, our findings agree with two cross-sectional studies of older women showing an inverse association of bone mineral density with serum folate, but not hyperhomocysteinemia or decreased serum vitamin B12 (20,21). Both a cross-sectional (22) and a prospective study (23) reported an association between vitamin B12 deficit and bone loss in elderly persons, but they did not take into account serum folate levels, so the possible relevance of vitamin B12 to bone metabolism remains doubtful.

Folate can have a direct effect on bone because of its involvement in several intracellular processes through the methylation pathway (24). However, we could not find any evidence that increasing levels of serum folate conferred any additional protection against risk of fracture. An explanation for this lack of dose-response association might be that folate deficit in bone tissue occurs only when circulating folate levels fall below a specific threshold. If this were the case, having higher serum folate levels would provide no additional benefit. It cannot be excluded, however, that serum folate, as plasma homocysteine, is only an innocent bystander, reflecting other nutritional factors that were not measured in this study but actually modify the risk of fracture, such as poor calcium or vitamin D status (25), reduced protein and/or calorie intake (26), or deficit of other micronutrients such as riboflavin (27). In the Framingham cohort (7), however, the association between homocysteine and risk of fracture was unaffected by adjustment for either serum levels of 25-hydroxyvitamin D or dietary intake of calories, proteins, calcium, and vitamin D. Moreover, in a recent randomized controlled trial of elderly patients with stroke, combined treatment with folate and vitamin B12 was found to be effective in reducing risk of hip fractures (28).

The major strengths of this study are its prospective design and the large number of potential confounders taken into account. The study has also several major limitations. First, serum concentrations are widely used indicators of vitamin status, but other blood tests (e.g., red blood cell folate, serum methylmalonic acid) are deemed superior for diagnosis of B vitamin deficit (1). Second, only a one-time measurement was available, and duration of vitamin deficiency could not be estimated. Third, no spinal radiographs were obtained to assess the incidence of clinically silent vertebral fractures, bone densitometry was not performed, and diagnosis of fracture relied on self-report for about 32% of cases. Finally, individuals lost to follow-up were exactly those at higher risk of B vitamin deficit and fracture.

Conclusion
This study suggests that low serum folate, but not increased plasma homocysteine, is associated with increased risk of osteoporotic fracture in elderly persons. Our findings do not prove that the relationship is causal or dose-related and, therefore, cannot be used as a basis for treatment recommendations in the general elderly population. However, they prompt further research on the role of folate in bone metabolism and its potential clinical usefulness as a predictor of fracture in older age.


   Acknowledgments
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 Results
 Discussion
 References
 
This study was supported by grants from the Italian Ministry of University and Scientific Research (60% fund) and from "Ricerca Corrente Istituti Ortopedici Rizzoli."


   Footnotes
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Decision Editor: John E. Morley, MB, BCh

Received December 17, 2004

Accepted March 3, 2005


   References
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