Homocysteine as a Predictive Factor for Hip Fracture in Older Persons
Robert R. McLean, M.P.H., Paul F. Jacques, D.Sc., Jacob Selhub, Ph.D., Katherine L. Tucker, Ph.D., Elizabeth J. Samelson, Ph.D., Kerry E. Broe, M.P.H., Marian T. Hannan, D.Sc., L. Adrienne Cupples, Ph.D., and Douglas P. Kiel, M.D.
Background The increased prevalence of osteoporosis among peoplewith homocystinuria suggests that a high serum homocysteineconcentration may weaken bone by interfering with collagen cross-linking,thereby increasing the risk of osteoporotic fracture. We examinedthe association between the total homocysteine concentrationand the risk of hip fracture in men and women enrolled in theFramingham Study.
Methods We studied 825 men and 1174 women, ranging in age from59 to 91 years, from whom blood samples had been obtained between1979 and 1982 to measure plasma total homocysteine. The participantsin our study were followed from the time that the sample wasobtained through June 1998 for incident hip fracture. Sex-specific,age-adjusted incidence rates of hip fracture were calculatedfor quartiles of total homocysteine concentrations. Cox proportional-hazardsregression was used to calculate hazard ratios for quartilesof homocysteine values.
Results The mean (±SD) plasma total homocysteine concentrationwas 13.4±9.1 µmol per liter in men and 12.1±5.3µmol per liter in women. The median duration of follow-upwas 12.3 years for men and 15.0 years for women. There were41 hip fractures among men and 146 among women. The age-adjustedincidence rates per 1000 person-years for hip fracture, fromthe lowest to the highest quartile for total homocysteine, were1.96 (95 percent confidence interval, 0.52 to 3.41), 3.24 (0.97to 5.52), 4.43 (1.80 to 7.07), and 8.14 (4.20 to 12.08) formen and 9.42 (5.72 to 13.12), 7.01 (4.29 to 9.72), 9.58 (6.42to 12.74), and 16.57 (11.84 to 21.30) for women. Men and womenin the highest quartile had a greater risk of hip fracture thanthose in the lowest quartile — the risk was almost fourtimes as high for men and 1.9 times as high for women.
Conclusions These findings suggest that the homocysteine concentration,which is easily modifiable by means of dietary intervention,is an important risk factor for hip fracture in older persons.
Homocysteine is an amino acid intermediate formed during themetabolism of methionine. Homocystinuria, a rare autosomal recessivebiochemical abnormality, causes elevated plasma concentrationsof homocysteine and severe occlusive vascular disease.1 Thisobservation has led to studies that implicate plasma homocysteineas a risk factor for cardiovascular disease.2,3 In patientswith homocystinuria, there is an increased prevalence of skeletaldeformities, including osteoporosis,1,4,5 which is a primaryrisk factor for hip fracture. Thus, elevated plasma homocysteineconcentrations may be associated with osteoporosis and may increasethe risk of hip fracture, which can lead to substantial disability,6high medical costs,7 and death.8 We examined the associationbetween plasma total homocysteine concentrations and the riskof hip fracture in a group of older men and women enrolled inthe Framingham Study.
Methods
Participants
The Framingham Study was begun in 1948 with the primary goalof evaluating risk factors for heart disease. A total of 5209men and women who ranged in age from 28 to 62 years were recruitedfrom a sample of two thirds of the residences in Framingham,Massachusetts, and have been examined biennially for more than50 years.9 The participants in the present study included 2043older subjects from whom blood samples were obtained at the16th biennial examination (between 1979 and 1982). Forty-foursubjects with prior hip fractures were excluded, leaving 1999participants (mean age, 70 years; range, 59 to 91) who werefollowed for an incident hip fracture from the date when theblood sample was obtained.
Homocysteine Measurement
Blood samples were collected while the subjects were in a nonfastingstate and were frozen immediately and stored at or below –20°C.In 1997, the samples were thawed and the plasma total homocysteineconcentrations were measured with the use of high-performanceliquid chromatography with fluorometric detection.10 The stabilityof measurements of total homocysteine from plasma or serum storedat temperatures at or below –20°C has been validatedpreviously.11 The coefficient of variation for this assay was9 percent.12
Assessment of Hip Fracture
As reported previously,13 all records of hospitalizations anddeaths for the study participants were systematically reviewedfor occurrences of hip fracture. Beginning in 1983 (18th biennialexamination in the Framingham Study), hip fractures were reportedby interview at each biennial examination or by telephone interviewfor participants unable to attend an examination. Reported hipfractures were confirmed by a review of medical records andradiographic and operative reports. Hip fracture was definedas a first-time fracture of the proximal femur that occurredin the absence of overwhelming trauma (e.g., a motor vehicleaccident).
Covariables
Potential confounders obtained from data from the 16th biennialexamination (except where noted) included sex, age, height,weight, smoking status, caffeine consumption, alcohol consumption,educational level (12 years or <12 years),and current use or nonuse of estrogen among women. Height withoutshoes was measured to the nearest quarter inch (0.6 cm). Weightin pounds (without shoes) was measured with the use of a standardbalance-beam scale at each examination. Smoking was measuredat the 15th examination (between 1977 and 1979) as the averagenumber of cigarettes smoked per day in the previous two years.Caffeine consumption in the form of tea and coffee was quantifiedas previously described.14 At the 15th examination alcohol consumption(beer, wine, or spirits) was calculated as the number of ouncesconsumed per week, as previously reported.15 Participants wereclassified at baseline (16th biennial examination) as eitherhaving a prior diagnosis of cardiovascular disease or not, accordingto previously published diagnostic criteria.16 A score for physicalfunction was calculated as a weighted sum of the participants'self-reported responses to nine questions selected from thosedeveloped by Nagi to measure physical function,17 which wereasked at the 14th biennial examination (between 1975 and 1978),18and a score for cognitive status was obtained with the use ofthe Folstein Mini–Mental State Examination,19 which wasadministered at the 17th examination (between 1981 and 1984),as previously described.20
Statistical Analysis
Owing to a skewed distribution, total homocysteine concentrationswere analyzed as quartiles and as continuous, natural-log–transformedvalues. Incidence rates of hip fracture (the number of incidentcases divided by the number of person-years at risk for fracture)were calculated for quartiles and were standardized for agein five-year age groups on the basis of sex-specific age distributionsof all the study participants. For each participant, the accumulationof person-years at risk started from the collection of the bloodsample and continued until the first occurrence of hip fracture,death, last contact with the participant, or the end of follow-up(June 30, 1998, for all study participants). Cox proportional-hazardsregression was used to calculate the hazard ratios and the 95percent confidence intervals that were used to estimate therelative increase in the risk of hip fracture for each of thethree higher quartiles as compared with the lowest quartile(referent); it was also used to test for a linear trend in thehazard ratios across all the quartiles. To estimate the absoluteassociation between homocysteine concentrations and hip fracture,differences in risk between the highest and lowest quartileswere calculated with 95 percent confidence intervals.
The risk of hip fracture within each quartile was calculatedwith the use of the Cox regression model as 1 minus the probabilityof survival without a hip fracture to the median follow-up time.Cox regression was also used to estimate the hazard ratio forhip fracture for each increase of 1 SD in continuous, log-transformedtotal homocysteine values. All analyses were conducted separatelyfor men and women. Regression analyses used to calculate thehazard ratios were adjusted for potential confounders by includingdata on age, height, weight, smoking status, caffeine consumption,alcohol consumption, educational level, and current use or nonuseof estrogen among women. To estimate the risk of fracture withinquartiles in the Cox regression models, potential confounderswere assigned mean levels for continuous covariates and themost prevalent category for dichotomous variables.
People with higher homocysteine concentrations may have an increasedrisk of cardiovascular disease and cognitive dysfunction,21conditions that limit activity and result in greater frailtyand an increased risk of hip fracture. To address cardiovasculardisease as a potential confounder, we performed additional analysesadjusted for the presence or absence of cardiovascular diseaseand for measures of physical function and cognitive status.Because the scores for cognitive status were not collected untilthe 17th examination, analyses involving this covariate startedat that examination. To investigate the possible effect of changesin weight, we adjusted a model for time-varying weight. To determinewhether a subgroup of participants with extremely high homocysteineconcentrations who were in the highest quartile might be drivingthe association between homocysteine and hip fracture, we repeatedour original analysis but excluded subjects considered to haveextreme homocysteine values within the highest quartile. Forall statistical analyses, we used SAS/STAT software, version8.1 (SAS Institute).
Results
Table 1 lists the baseline characteristics of the participantsaccording to sex. The mean (±SD) age among the 825 menwas 69.5 years, and among the 1174 women it was 70.3 years.The men were taller than the women, weighed more, smoked morecigarettes, consumed more alcohol, and had higher mean totalhomocysteine concentrations. Among the men the median follow-upperiod was 12.3 years, and among the women it was 15.0 years.During follow-up, 41 of the men and 146 of the women sustainedhip fractures.
Table 1. Baseline Characteristics of the Study Participants.
The characteristics of the study participants across the quartilesof total homocysteine concentrations are shown in Table 2. Amongmen, the mean total homocysteine concentration in the lowestquartile (quartile 1) was 8.5±0.9 µmol per liter,and among women it was 7.6±1.0. In the highest quartile(quartile 4), among men the total homocysteine concentrationsranged from 15.01 to 219.80 µmol per liter, with a meanof 20.8±15.7. Among women in quartile 4, concentrationsranged from 13.47 to 59.27 µmol per liter, with a meanof 18.6±6.4. Mean age increased from the lowest to thehighest quartile among men (quartile 1, 67.9 years; and quartile4, 71.8) and among women (quartile 1, 68.3 years; and quartile4, 73.3). The age ranges for men and women were similar in allquartiles.
Table 2. Homocysteine Concentrations and Ages of Participants.
Table 3 lists the age-adjusted incidence rates of hip fractureaccording to the quartile of total homocysteine concentration.Among men, the number of hip fractures increased monotonicallyfrom 5 in quartile 1 to 17 in quartile 4. Among women, however,the number of hip fractures was similar from quartile 1 to quartile3 (range, 26 to 36) and then increased to 54 in quartile 4.Age-adjusted incidence rates among men increased across thequartiles, from 1.96 fractures per 1000 person-years in quartile1 to 8.14 per 1000 person-years in quartile 4. Among women,although the incidence rates were similar from quartile 1 toquartile 3 (range, 7.01 to 9.58 fractures per 1000 person-years),the rate of fracture was higher in quartile 4 (16.57 per 1000person-years).
Table 3. Age-Adjusted Incidence Rates of Hip Fracture According to Quartile of Homocysteine Level.
The results of the multivariable-adjusted Cox proportional-hazardsregressions for quartiles of homocysteine concentrations areshown in Figure 1. Whereas men in quartiles 2 and 3 tended tohave a higher risk of hip fracture than those in quartile 1(hazard ratio for quartile 2, 1.67; 95 percent confidence interval,0.54 to 5.14; hazard ratio for quartile 3, 2.07; 95 percentconfidence interval, 0.70 to 6.09), the risk of fracture amongmen in quartile 4 was almost four times the risk among men inquartile 1 (hazard ratio for quartile 4, 3.84; 95 percent confidenceinterval, 1.38 to 10.70). The test for a linear trend in hazardratios across the quartiles was statistically significant (P<0.01),suggesting a linear association between the quartile of homocysteineconcentration and the risk of hip fracture. In quartile 4 ascompared with quartile 1, there were 8.8 excess fractures per100 men (95 percent confidence interval, 0.4 to 17.3) for themean levels of the covariates at 14 years of follow-up.
Figure 1. Multivariable-Adjusted Hazard Ratios for the Risk of Hip Fracture, According to the Quartile of Total Homocysteine Concentration.
The y axis is on a log scale. The reference group is quartile 1. The I bars denote 95 percent confidence intervals.
Among the women, there was no apparent increase in the riskof fracture in quartiles 2 and 3 as compared with quartile 1(hazard ratio for quartile 2, 0.78; 95 percent confidence interval,0.45 to 1.33; hazard ratio for quartile 3, 1.07; 95 percentconfidence interval, 0.64 to 1.78) (Figure 1). Among women inquartile 4, however, the risk of fracture was nearly twice thatamong women in quartile 1 (hazard ratio for quartile 4, 1.92;95 percent confidence interval, 1.18 to 3.10). The test fora linear trend in hazard ratios was statistically significant(P<0.01). For women who were not currently receiving estrogentherapy, the difference in the risk of hip fracture betweenquartiles 4 and 1 for the mean levels of their covariates at14 years of follow-up was 9.5 excess fractures per 100 participants(95 percent confidence interval, 1.2 to 17.9).
For each increase of 1 SD in the log-transformed total homocysteineconcentration, the risk of hip fracture increased by 59 percentin men (1 SD in log-transformed homocysteine concentration,0.34; hazard ratio, 1.59; 95 percent confidence interval, 1.31to 1.94) and by 26 percent in women (1 SD, 0.35; hazard ratio,1.26; 95 percent confidence interval, 1.08 to 1.47). Additionaladjustments for cardiovascular disease, physical function, cognitivestatus, and weight modeled as a time-varying covariate did notchange the effect of the homocysteine concentration on the riskof hip fracture for men or women. Among the men in quartile4, two had homocysteine values (96 and 220 µmol per liter)that were more than double the next highest value. The effectof the homocysteine concentration on the risk of hip fracturewas essentially unchanged when our analysis was repeated withthese two outliers excluded. There were no extreme homocysteinevalues among the women.
Discussion
We found that plasma homocysteine concentrations were associatedwith the risk of hip fracture in both men and women. The studyparticipants in the highest quartile of values for total homocysteinehad a significantly higher risk of hip fracture than those inthe lowest quartile: by a factor of almost four in men and bya factor of 1.9 in women. The risk of hip fracture was elevatedby 59 percent in men and by 26 percent in women for each increaseof 1 SD in the log-transformed total homocysteine concentration.The increase in risk across quartiles in men appeared to bemonotonic. Despite the statistically significant test for alinear trend in the risk among women, only those in the highestquartile were at increased risk for hip fracture, which suggestsa possible threshold effect.
The apparent differences according to sex in the gradient ofrisk from the lowest to the highest quartile of homocysteineconcentrations may be explained by the lower background incidenceof hip fracture in men. Because the magnitude of the hazardratio depends on the risk in the reference group, we providedan absolute measure of the effect of the homocysteine concentrationon the risk of hip fracture. The differences in absolute riskbetween the highest and lowest quartiles for men and women weremore similar (8.8 and 9.5 fractures, respectively, per 100 participantsat 14 years of follow-up) than the hazard ratios (3.84 and 1.92,respectively). Therefore, the effect of the homocysteine concentrationon the risk of hip fracture is most likely very similar in menand women.
To explain the increased prevalence of osteoporosis among patientswith homocystinuria, McKusick first proposed that homocysteineinterferes with the cross-linking of collagen.22 Later studiessupported this hypothesis with evidence of reduced collagencross-linking in patients with homocystinuria.23,24 Whetherthese findings in studies of patients with the congenital conditionof homocystinuria are directly applicable to normal variationsin homocysteine concentrations among adults is unclear.
There is little evidence that homocysteine has a direct effecton bone. One study showed that chicks fed a homocysteine-supplementeddiet had altered bone growth, bone matrix, and bone compositionas compared with control chicks25 but had similar mechanicalstrength and indexes of bone formation. This finding suggestedthat changes in bone geometry may compensate for any weaknesscaused by possible defects in collagen cross-linking. Futurestudies are needed to examine the association between homocysteineand the material and structural properties of bone in humans.
Although one previous report failed to find a relation betweenhomocysteine concentrations and bone mineral density,26 studiesof genetic association support the concept that homocysteineis involved in the development of osteoporosis. The reducedactivity of the enzyme methylenetetrahydrofolate reductase (MTHFR),which is determined by the MTHFR gene, can interfere with themethylation of homocysteine to methionine, possibly resultingin abnormal plasma homocysteine concentrations. A common mutationin the MTHFR gene27 is associated with elevated plasma homocysteineconcentrations in patients with reduced plasma folate concentrations.28The results of studies of bone mass29,30,31,32 and fracture30are not consistent, yet they suggest that there may be a relationbetween the MTHFR gene and both bone mineral density and therisk of fracture.
If the homocysteine concentration truly is a causal mechanismfor the risk of fracture, the public health implications couldbe substantial. The 1996 mandate of the Food and Drug Administrationto fortify enriched grain products with folic acid33 has helpedto reduce the prevalence of low folate concentrations (<7nmol per liter) in persons who are not taking vitamin supplementsfrom 22.0 percent to 1.7 percent and to reduce the prevalenceof homocysteine concentrations higher than 13 µmol perliter from 18.7 percent to 9.8 percent.34 It remains to be seenwhether this intervention will affect future rates of hip fracturein the United States.
Our study has several potential limitations. First, our findingsin white men and women may not be generalizable to other racialand ethnic groups. Second, because blood samples obtained fromnonfasting subjects tend to yield higher total homocysteineconcentrations than samples from fasting subjects,35 the concentrationsin our study may not be comparable to those in other studiesin which samples were obtained from fasting subjects. Third,owing to the within-person variability of homocysteine concentrations,the use of a single measurement performed during the 20-yearfollow-up period may have led to regression dilution, resultingin an underestimate of the relative risk of hip fracture accordingto the homocysteine concentration.36 Fourth, we were unableto assess potential confounding due to dietary factors, becauseno dietary information was available at baseline. Because folateand vitamins B12 and B6 are major determinants of homocysteineconcentrations in older persons,12,37 the inadequacy of oneor more of these vitamins, rather than the homocysteine concentrationitself, may be responsible for the observed effect on the riskof hip fracture. Patients with pernicious anemia have decreasedbone mineral density at the lumbar spine,38 and in comparisonwith the general population they have almost double the riskof hip fracture.39 A recent, population-based study showed thatolder women, but not men, with low bone mineral density hadsignificantly lower vitamin B12 concentrations than older womenwith higher bone density.40
It is also possible that the effect of homocysteine on the riskof hip fracture is mediated through other nutrients, apart fromB vitamins, that we were unable to measure. If there is a directeffect of these dietary factors on the risk of hip fracture,the homocysteine concentration may simply reflect nutritionalstatus. Thus, dietary factors may explain the relation betweenthe plasma homocysteine concentration and the risk of hip fractureobserved in our study. Finally, because no data on bone mineraldensity were available for the study participants at baseline,we were unable to assess whether the effect of homocysteineon hip fracture may be mediated through bone mineral density.
We were not able to establish causality definitively, becauseplasma homocysteine concentrations may only be a marker fornutritional or metabolic differences that are the real causalfactors in hip fracture. Furthermore, we cannot determine whetherthe association observed in our study population is a resultof the same mechanisms that lead to an increased prevalenceof osteoporosis among patients with homocystinuria.
This study suggests that the total homocysteine concentrationis strongly associated with the risk of hip fracture. If therelationship proves to be one of cause and effect, this findingmay have important implications for the development of interventionsto prevent hip fractures, because total homocysteine concentrationscan be effectively and easily modified by dietary intake offolic acid and vitamins B6 and B12. Further population-basedresearch is needed to examine the role of homocysteine in osteoporosisand osteoporotic fracture and to determine whether nationwidefolic acid fortification of food will help to reduce rates ofhip fracture in the United States.
Supported by a grant from the National Institutes of Health(RO1 AR/AG 41398), a contract with the National Heart, Lung,and Blood Institute's Framingham Heart Study (N01-HC-25195),a grant from the National Heart, Lung, and Blood Institute (HL54776),and an agreement (58-1950-9-001) and a contract (53-3K06-01)with the Department of Agriculture Research Service.
Dr. Jacques reports having received consulting fees from AgeWaveand lecture fees from Syngenta and the Vitamin Nutrition InformationService. Dr. Selhub reports having received consulting feesfrom Eprova, Pamlab, Cooper Clinic, and VitaMed and holdinga U.S. patent (10/020,634) on methods of vitamin compositionin the treatment of osteoarthritis.
We are indebted to Dr. David T. Felson, who helped initiatethe Framingham Osteoporosis Study and who helped adjudicatehip fractures.
Source Information
From the Hebrew Rehabilitation Center for Aged Research and Training Institute (R.R.M., E.J.S., K.E.B., M.T.H., D.P.K.); the Jean Mayer Department of Agriculture Human Nutrition Research Center on Aging, Tufts University (P.F.J., J.S., K.L.T.); the Department of Biostatistics, Boston University School of Public Health (L.A.C.); and the Harvard Medical School Division on Aging (M.T.H., D.P.K.) — all in Boston.
Address reprint requests to Dr. McLean at the Framingham Study, 73 Mt. Wayte Ave., Framingham, MA 01702, or at rmclean{at}mail.hrca.harvard.edu.
References
Grieco AJ. Homocystinuria: pathogenetic mechanisms. Am J Med Sci 1977;273:120-132. [Web of Science][Medline]
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-1057. [Free Full Text]
Clarke R. An updated review of the published studies of homocysteine and cardiovascular disease. Int J Epidemiol 2002;31:70-71. [Free Full Text]
Morreels CL Jr, Fletcher BD, Weilbaecher RG, Dorst JP. The roentgenographic features of homocystinuria. Radiology 1968;90:1150-1158. [Web of Science][Medline]
Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37:1-31. [Web of Science][Medline]
Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med 1997;103:Suppl 2A:12S-19S. [Medline]
Ray NF, Chan JK, Thamer M, Melton LJ III. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:24-35. [CrossRef][Web of Science][Medline]
Browner WS, Pressman AR, Nevitt MC, Cummings SR. Mortality following fractures in older women: the Study of Osteoporotic Fractures. Arch Intern Med 1996;156:1521-1525. [Free Full Text]
Dawber TR, Meadors GF, Moore FE Jr. Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951;41:279-281. [Free Full Text]
Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;422:43-52. [Web of Science][Medline]
Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993;39:1764-1779. [Abstract]
Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-2698. [Free Full Text]
Kiel DP, Felson DT, Anderson JJ, Wilson PWF, Moskowitz MA. Hip fracture and the use of estrogens in postmenopausal women: the Framingham Study. N Engl J Med 1987;317:1169-1174. [Abstract]
Kiel DP, Felson DT, Hannan MT, Anderson JJ, Wilson PW. Caffeine and the risk of hip fracture: the Framingham Study. Am J Epidemiol 1990;132:675-684. [Free Full Text]
Felson DT, Kiel DP, Anderson JJ, Kannel WB. Alcohol consumption and hip fractures: the Framingham Study. Am J Epidemiol 1988;128:1102-1110. [Free Full Text]
Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Heart Study: an epidemiological investigation of cardiovascular disease. Section 35. Survival following cardiovascular events: 30 year follow-up. Bethesda, Md.: National Heart, Lung, and Blood Institute, May 1988. (NIH publication no. 88-2969.)
Nagi SZ. An epidemiology of disability among adults in the United States. Milbank Mem Fund Q Health Soc 1976;54:439-467. [Web of Science][Medline]
Jette AM, Pinsky JL, Branch LG, Wolf PA, Feinleib M. The Framingham Disability Study: physical disability among commu-nity-dwelling survivors of stroke. J Clin Epidemiol 1988;41:719-726. [CrossRef][Web of Science][Medline]
Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198. [CrossRef][Web of Science][Medline]
Bachman DL, Wolf PA, Linn RT, et al. Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology 1993;43:515-519. [Free Full Text]
Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-483. [Free Full Text]
McKusick VA. Heritable disorders of connective tissue. 3rd ed. St. Louis: C.V. Mosby, 1966:150.
Kang AH, Trelstad RL. A collagen defect in homocystinuria. J Clin Invest 1973;52:2571-2578. [Web of Science][Medline]
Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH. Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1996;1315:159-162. [Medline]
Masse PG, Boskey AL, Ziv I, et al. Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model. BMC Musculoskelet Disord 2003;4:2-2. [CrossRef][Medline]
Browner WS, Malinow MR. Homocyst(e)inaemia and bone density in elderly women. Lancet 1991;338:1470-1470. [Web of Science][Medline]
Goyette P, Sumner JS, Milos R, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994;7:195-200. [Erratum, Nat Genet 1994;7:551.] [CrossRef][Web of Science][Medline]
Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9. [Free Full Text]
Miyao M, Morita H, Hosoi T, et al. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 2000;66:190-194. [CrossRef][Web of Science][Medline]
Abrahamsen B, Madsen JS, Tofteng CL, et al. A common methylenetetrahydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish Osteoporosis Prevention Study. J Bone Miner Res 2003;18:723-729. [CrossRef][Web of Science][Medline]
Jorgensen HL, Madsen JS, Madsen B, et al. Association of a common allelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures: a case control study in Danish postmenopausal women. Calcif Tissue Int 2002;71:386-392. [CrossRef][Web of Science][Medline]
McLean RR, Karasik D, Selhub J, et al. Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. J Bone Miner Res 2004;19:410-418. [CrossRef][Web of Science][Medline]
Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 1996;61:8781-8797.
Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454. [Free Full Text]
Nurk E, Tell GS, Nygard O, Refsum H, Ueland PM, Vollset SE. Plasma total homocysteine is influenced by prandial status in humans: the Hordaland Homocysteine Study. J Nutr 2001;131:1214-1216. [Free Full Text]
Clarke R, Lewington S, Donald A, et al. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk 2001;8:363-369. [CrossRef][Web of Science][Medline]
Johnson MA, Hawthorne NA, Brackett WR, et al. Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services. Am J Clin Nutr 2003;77:211-220. [Free Full Text]
Eastell R, Vieira NE, Yergey AL, et al. Pernicious anaemia as a risk factor for osteoporosis. Clin Sci (Lond) 1992;82:681-685. [Medline]
Goerss JB, Kim CH, Atkinson EJ, Eastell R, O'Fallon WM, Melton LJ III. Risk of fractures in patients with pernicious anemia. J Bone Miner Res 1992;7:573-579. [Web of Science][Medline]
Dhonukshe-Rutten RA, Lips M, de Jong N, et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr 2003;133:801-807. [Free Full Text]
Homocysteine as a Predictive Factor for Hip Fracture in Older Persons
Auer J., Lamm G., Eber B., Bursztyn M., Pérez-Castrillón J. L., Arranz-Peña M. L., Luis D. D., Ellenberg S. S., Orloff D. G., Temple R. J., McLean R. R., Kiel D. P., van Meurs J. B.J., Pols H. A.P., Uitterlinden A. G., Raisz L. G.
Extract |
Full Text |
PDF
N Engl J Med 2004;
351:1027-1030, Sep 2, 2004.
Correspondence
This article has been cited by other articles:
Holstein, J. H, Herrmann, M., Splett, C., Herrmann, W., Garcia, P., Histing, T., Graeber, S., Ong, M. F., Kurz, K., Siebel, T., Menger, M. D, Pohlemann, T.
(2009). Low serum folate and vitamin B-6 are associated with an altered cancellous bone structure in humans. Am. J. Clin. Nutr.
90: 1440-1445
[Abstract][Full Text]
Collins, T. C., Ewing, S. K., Diem, S. J., Taylor, B. C., Orwoll, E. S., Cummings, S. R., Strotmeyer, E. S., Ensrud, K. E., for the Osteoporotic Fractures in Men (MrOS) Study,
(2009). Peripheral Arterial Disease Is Associated With Higher Rates of Hip Bone Loss and Increased Fracture Risk in Older Men. Circulation
119: 2305-2312
[Abstract][Full Text]
Nitsch, D., Mylne, A., Roderick, P. J., Smeeth, L., Hubbard, R., Fletcher, A.
(2009). Chronic kidney disease and hip fracture-related mortality in older people in the UK. Nephrol Dial Transplant
24: 1539-1544
[Abstract][Full Text]
LeBoff, M. S., Narweker, R., LaCroix, A., Wu, L., Jackson, R., Lee, J., Bauer, D. C., Cauley, J., Kooperberg, C., Lewis, C., Thomas, A. M., Cummings, S.
(2009). Homocysteine Levels and Risk of Hip Fracture in Postmenopausal Women. J. Clin. Endocrinol. Metab.
94: 1207-1213
[Abstract][Full Text]
Hyder, J. A., Allison, M. A., Wong, N., Papa, A., Lang, T. F., Sirlin, C., Gapstur, S. M., Ouyang, P., Carr, J. J., Criqui, M. H.
(2009). Association of Coronary Artery and Aortic Calcium With Lumbar Bone Density: The MESA Abdominal Aortic Calcium Study. Am J Epidemiol
169: 186-194
[Abstract][Full Text]
Badiou, S., Bariolet, S., Dupuy, A.-M., Sultan, A., Avignon, A., Cristol, J.-P.
(2009). A New DiaSys Colorimetric Assay for Plasma Homocysteine: Application in Diabetic Patients. Annals of Clinical & Laboratory Science
39: 233-240
[Abstract][Full Text]
van Staveren, W. A., Steijns, J. M., de Groot, L. C.P.G.M.
(2008). Dairy Products as Essential Contributors of (Micro-) Nutrients in Reference Food Patterns: An Outline for Elderly People. J. Am. Coll. Nutr.
27: 747S-754S
[Abstract][Full Text]
Dowd, J. B., Aiello, A. E
(2008). Did national folic acid fortification reduce socioeconomic and racial disparities in folate status in the US?. Int J Epidemiol
37: 1059-1066
[Abstract][Full Text]
Borrell, L. N
(2008). Commentary: Health policies in the US: can they increase or decrease the gap between subgroups of the population? The case of folic acid. Int J Epidemiol
37: 1067-1068
[Full Text]
Zoehrer, R., Dempster, D. W., Bilezikian, J. P., Zhou, H., Silverberg, S. J., Shane, E., Roschger, P., Paschalis, E. P., Klaushofer, K.
(2008). Bone Quality determined by Fourier Transform Infrared Imaging Analysis in Mild Primary Hyperparathyroidism. J. Clin. Endocrinol. Metab.
93: 3484-3489
[Abstract][Full Text]
Szulc, P, Montella, A, Delmas, P D
(2008). High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study. Ann Rheum Dis
67: 1249-1255
[Abstract][Full Text]
Yang, Q.-H., Botto, L. D, Gallagher, M., Friedman, J., Sanders, C. L, Koontz, D., Nikolova, S., Erickson, J D., Steinberg, K.
(2008). Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank. Am. J. Clin. Nutr.
88: 232-246
[Abstract][Full Text]
McLean, R. R., Jacques, P. F., Selhub, J., Fredman, L., Tucker, K. L., Samelson, E. J., Kiel, D. P., Cupples, L. A., Hannan, M. T.
(2008). Plasma B Vitamins, Homocysteine, and Their Relation with Bone Loss and Hip Fracture in Elderly Men and Women. J. Clin. Endocrinol. Metab.
93: 2206-2212
[Abstract][Full Text]
Garnero, P.
(2008). New Biochemical Markers of Bone Turnover. IBMS BoneKEy
5: 84-102
[Abstract][Full Text]
Jadoul, M.
(2007). Towards the prevention of bone fractures in dialysed patients?. Nephrol Dial Transplant
22: 3377-3380
[Full Text]
Vance, D. E., Li, Z., Jacobs, R. L.
(2007). Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology. J. Biol. Chem.
282: 33237-33241
[Full Text]
Sawka, A. M., Ray, J. G., Yi, Q., Josse, R. G., Lonn, E.
(2007). Randomized Clinical Trial of Homocysteine Level Lowering Therapy and Fractures. Arch Intern Med
167: 2136-2139
[Full Text]
Herrmann, M., Wildemann, B., Claes, L., Klohs, S., Ohnmacht, M., Taban-Shomal, O., Hubner, U., Pexa, A., Umanskaya, N., Herrmann, W.
(2007). Experimental Hyperhomocysteinemia Reduces Bone Quality in Rats. Clin. Chem.
53: 1455-1461
[Abstract][Full Text]
Yang, Q.-H., Carter, H. K, Mulinare, J., Berry, R., Friedman, J., Erickson, J D.
(2007). Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002. Am. J. Clin. Nutr.
85: 1409-1416
[Abstract][Full Text]
Kuo, H.-K., Liao, K.-C., Leveille, S. G., Bean, J. F., Yen, C.-J., Chen, J.-H., Yu, Y.-H., Tai, T.-Y.
(2007). Relationship of Homocysteine Levels to Quadriceps Strength, Gait Speed, and Late-Life Disability in Older Adults. J Gerontol A Biol Sci Med Sci
62: 434-439
[Abstract][Full Text]
Green, T. J, McMahon, J. A, Skeaff, C M., Williams, S. M, Whiting, S. J
(2007). Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-y randomized controlled trial. Am. J. Clin. Nutr.
85: 460-464
[Abstract][Full Text]
Ruiz, J. R., Sola, R., Gonzalez-Gross, M., Ortega, F. B., Vicente-Rodriguez, G., Garcia-Fuentes, M., Gutierrez, A., Sjostrom, M., Pietrzik, K., Castillo, M. J.
(2007). Cardiovascular Fitness Is Negatively Associated With Homocysteine Levels in Female Adolescents. Arch Pediatr Adolesc Med
161: 166-171
[Abstract][Full Text]
Fried, L. F., Biggs, M. L., Shlipak, M. G., Seliger, S., Kestenbaum, B., Stehman-Breen, C., Sarnak, M., Siscovick, D., Harris, T., Cauley, J., Newman, A. B., Robbins, J.
(2007). Association of Kidney Function with Incident Hip Fracture in Older Adults. J. Am. Soc. Nephrol.
18: 282-286
[Abstract][Full Text]
Jensen, G. L.
(2006). Inflammation as the Key Interface of the Medical and Nutrition Universes: A Provocative Examination of the Future of Clinical Nutrition and Medicine. JPEN J Parenter Enteral Nutr
30: 453-463
[Abstract][Full Text]
Wildschut, H. I.J., Peters, T.J., Weiner, C. P.
(2006). Screening in women's health, with emphasis on fetal Down's syndrome, breast cancer and osteoporosis. Hum Reprod Update
12: 499-512
[Abstract][Full Text]
Fried, L. F., Shlipak, M. G., Stehman-Breen, C., Mittalhenkle, A., Seliger, S., Sarnak, M., Robbins, J., Siscovick, D., Harris, T. B., Newman, A. B., Cauley, J. A.
(2006). Kidney Function Predicts the Rate of Bone Loss in Older Individuals: The Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci
61: 743-748
[Abstract][Full Text]
Selhub, J.
(2006). The Many Facets of Hyperhomocysteinemia: Studies from the Framingham Cohorts. J. Nutr.
136: 1726S-1730S
[Abstract][Full Text]
Refsum, H., Nurk, E., Smith, A. D., Ueland, P. M., Gjesdal, C. G., Bjelland, I., Tverdal, A., Tell, G. S., Nygard, O., Vollset, S. E.
(2006). The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease. J. Nutr.
136: 1731S-1740S
[Abstract][Full Text]
Woo, C. W.H., Siow, Y. L., O, K.
(2006). Homocysteine Activates cAMP-response Element Binding Protein in HepG2 Through cAMP/PKA Signaling Pathway. Arterioscler. Thromb. Vasc. Bio.
26: 1043-1050
[Abstract][Full Text]
Ratnam, S., Wijekoon, E. P., Hall, B., Garrow, T. A., Brosnan, M. E., Brosnan, J. T.
(2006). Effects of diabetes and insulin on betaine-homocysteine S-methyltransferase expression in rat liver. Am. J. Physiol. Endocrinol. Metab.
290: E933-E939
[Abstract][Full Text]
LEVINE, J., BELMAKER, R. H.
(2006). Osteoporosis and Schizophrenia. Am. J. Psychiatry
163: 549-550
[Full Text]
Gjesdal, C. G., Vollset, S. E., Ueland, P. M., Refsum, H., Drevon, C. A., Gjessing, H. K., Tell, G. S.
(2006). Plasma Total Homocysteine Level and Bone Mineral Density: The Hordaland Homocysteine Study. Arch Intern Med
166: 88-94
[Abstract][Full Text]
Stead, L. M, Brosnan, J. T, Brosnan, M. E, Vance, D. E, Jacobs, R. L
(2006). Is it time to reevaluate methyl balance in humans?. Am. J. Clin. Nutr.
83: 5-10
[Abstract][Full Text]
Herrmann, M., Widmann, T., Colaianni, G., Colucci, S., Zallone, A., Herrmann, W.
(2005). Increased Osteoclast Activity in the Presence of Increased Homocysteine Concentrations. Clin. Chem.
51: 2348-2353
[Abstract][Full Text]
Ravaglia, G., Forti, P., Maioli, F., Servadei, L., Martelli, M., Brunetti, N., Bastagli, L., Cucinotta, D., Mariani, E.
(2005). Folate, But Not Homocysteine, Predicts the Risk of Fracture in Elderly Persons. J Gerontol A Biol Sci Med Sci
60: 1458-1462
[Abstract][Full Text]
Dou, C., Xia, D., Zhang, L., Chen, X., Flores, P., Datta, A., Yuan, C.
(2005). Development of a Novel Enzymatic Cycling Assay for Total Homocysteine. Clin. Chem.
51: 1987-1989
[Full Text]
Kuo, H.-K., Sorond, F. A., Chen, J.-H., Hashmi, A., Milberg, W. P., Lipsitz, L. A.
(2005). The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review. J Gerontol A Biol Sci Med Sci
60: 1190-1201
[Abstract][Full Text]
Dayal, S., Devlin, A. M., McCaw, R. B., Liu, M.-L., Arning, E., Bottiglieri, T., Shane, B., Faraci, F. M., Lentz, S. R.
(2005). Cerebral Vascular Dysfunction in Methionine Synthase-Deficient Mice. Circulation
112: 737-744
[Abstract][Full Text]
Gori, A. M., Corsi, A. M., Fedi, S., Gazzini, A., Sofi, F., Bartali, B., Bandinelli, S., Gensini, G. F., Abbate, R., Ferrucci, L.
(2005). A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am. J. Clin. Nutr.
82: 335-341
[Abstract][Full Text]
Pfeiffer, C. M, Caudill, S. P, Gunter, E. W, Osterloh, J., Sampson, E. J
(2005). Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am. J. Clin. Nutr.
82: 442-450
[Abstract][Full Text]
Jamal, S.A., Leiter, R.E., Bauer, D.C.
(2005). Hyperhomocysteinaemia and aortic calcification are associated with fractures in patients on haemodialysis. QJM
98: 575-579
[Abstract][Full Text]
Ernest, S., Hosack, A., O'Brien, W. E., Rosenblatt, D. S., Nadeau, J. H.
(2005). Homocysteine levels in A/J and C57BL/6J mice: genetic, diet, gender, and parental effects. Physiol. Genomics
21: 404-410
[Abstract][Full Text]
Sato, Y., Honda, Y., Iwamoto, J., Kanoko, T., Satoh, K.
(2005). Effect of Folate and Mecobalamin on Hip Fractures in Patients With Stroke: A Randomized Controlled Trial. JAMA
293: 1082-1088
[Abstract][Full Text]
van Meurs, J. B. J., Uitterlinden, A. G.
(2005). Homocysteine and Fracture Prevention. JAMA
293: 1121-1122
[Full Text]
Seeman, E., Strewler, G. J.
(2005). Clinical and Basic Research Papers - February 2005 Selections. IBMS BoneKEy
2: 1-5
[Full Text]
Suliman, M. E., Barany, P., Kalantar-Zadeh, K., Lindholm, B., Stenvinkel, P.
(2005). Homocysteine in uraemia--a puzzling and conflicting story. Nephrol Dial Transplant
20: 16-21
[Full Text]
Chen, X., Jhee, K.-H., Kruger, W. D.
(2004). Production of the Neuromodulator H2S by Cystathionine {beta}-Synthase via the Condensation of Cysteine and Homocysteine. J. Biol. Chem.
279: 52082-52086
[Abstract][Full Text]
(2004). 23 Apr 2004 to 23 Jul 2004. Evid. Based Nurs.
7: e4-e4
[Full Text]
Auer, J., Lamm, G., Eber, B., Bursztyn, M., Perez-Castrillon, J. L., Arranz-Pena, M. L., Luis, D. D., Ellenberg, S. S., Orloff, D. G., Temple, R. J., McLean, R. R., Kiel, D. P., van Meurs, J. B.J., Pols, H. A.P., Uitterlinden, A. G., Raisz, L. G.
(2004). Homocysteine as a Predictive Factor for Hip Fracture in Older Persons. NEJM
351: 1027-1030
[Full Text]
Stone, K., Sellmeyer, D., Bauer, D. C., Cummings, S. R.
(2004). Authors' Response: Low Vitamin B12 and Bone Loss: A Role for Folate Deficiency. J. Clin. Endocrinol. Metab.
89: 4771-4772
[Full Text]
Cagnacci, A., Cannoletta, M., Baldassari, F., Volpe, A.
(2004). Low Vitamin B12 and Bone Loss: A Role for Folate Deficiency. J. Clin. Endocrinol. Metab.
89: 4770-4771
[Full Text]
Seeman, E., Strewler, G. J.
(2004). Clinical and Basic Research Papers - May and June 2004 Selections. IBMS BoneKEy
1: 1-3
[Full Text]
(2004). An Association Between Homocysteine and Fractures. JWatch General
2004: 1-1
[Full Text]
Raisz, L. G.
(2004). Homocysteine and Osteoporotic Fractures -- Culprit or Bystander?. NEJM
350: 2089-2090
[Full Text]
12 years or <12 years), and current use or nonuse of estrogen among women. Height without shoes was measured to the nearest quarter inch (0.6 cm). Weight in pounds (without shoes) was measured with the use of a standard balance-beam scale at each examination. Smoking was measured at the 15th examination (between 1977 and 1979) as the average number of cigarettes smoked per day in the previous two years. Caffeine consumption in the form of tea and coffee was quantified as previously described.14 At the 15th examination alcohol consumption (beer, wine, or spirits) was calculated as the number of ounces consumed per week, as previously reported.15 Participants were classified at baseline (16th biennial examination) as either having a prior diagnosis of cardiovascular disease or not, according to previously published diagnostic criteria.16 A score for physical function was calculated as a weighted sum of the participants' self-reported responses to nine questions selected from those developed by Nagi to measure physical function,17 which were asked at the 14th biennial examination (between 1975 and 1978),18 and a score for cognitive status was obtained with the use of the Folstein Mini–Mental State Examination,19 which was administered at the 17th examination (between 1981 and 1984), as previously described.20 
Previous
