Homocysteine and Osteoporotic Fractures — Culprit or Bystander?
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《新英格兰医药杂志》
Osteoporotic fractures are a major health problem in the industrialized nations, a problem that is likely to become even greater throughout the world as the population ages. One way to prevent osteoporotic fractures is to identify risk factors that can be readily reversed. Epidemiologic studies in the United States and Europe have identified many such factors. For example, supplementation with calcium and vitamin D has been shown to reduce the risk of fracture.
Two studies in this issue of the Journal introduce still another potentially reversible factor: increased circulating homocysteine levels.1,2 There is ample evidence that high homocysteine levels are associated with an increased risk of cardiovascular disease3; the degree of association between homocysteine levels and the risk of osteoporotic fracture as shown in these two studies is of similar magnitude. In the study by van Meurs and colleagues from the Netherlands,1 subjects in the highest quartile of homocysteine levels had a risk of nonvertebral osteoporotic fractures, of which half were hip and wrist fractures, that was twice the risk among the subjects in the other three quartiles. Using data from the Framingham Study,2 that seemingly inexhaustible source of new epidemiologic insight, McLean and colleagues found that the risk of hip fracture was increased by nearly a factor of four in men and a factor of two in women for the highest quartile of plasma homocysteine levels as compared with the lowest quartile. No spinal radiographs were obtained to assess the incidence of vertebral compression fractures in either study. Measurements of bone mineral density were performed in the study from the Netherlands; analysis of these data showed that homocysteine levels were not associated with bone mineral density at the femoral neck or lumbar spine.
Is homocysteine a true culprit? That is, does a high level directly affect bone fragility and hence increase the risk of fracture? Both groups of authors point out that homocystinuria, a rare autosomal recessive disease, has been associated with generalized osteoporosis. This finding has been attributed to an inhibition of collagen cross-linking by high homocysteine levels, but in vivo evidence of the link between homocysteine and generalized osteoporosis is limited.4 Missense mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) are a cause of homocystinuria.5 Moreover, a polymorphism of MTHFR, in which a substitution of valine for alanine results in decreased enzyme activity, is associated with higher-than-normal homocysteine levels. In some studies, this polymorphism has also been associated with either decreased bone mineral density or an increased risk of fracture.6,7 There may be an interaction between the MTHFR polymorphism and folic acid deficiency, since the highest homocysteine levels and the lowest values for bone mineral density in persons with the valine substitution are also associated with low folic acid levels.8
Could homocysteine be an "innocent bystander"? Homocysteine levels are dependent on nutritional status, not only with respect to folic acid, but also with respect to cobalamin and pyridoxine. A direct relation between folate levels and bone mineral density, as well as an association of low cobalamin levels with an increased rate of bone loss, has been reported in postmenopausal women.9,10 In persons with cardiovascular disease, high levels of homocysteine, related to either mutations in the gene for MTHFR or to nutritional deficits, are associated with increased risks of ischemic heart disease and stroke.3 Although nutritional supplements can lower homocysteine levels and such lowering may affect some cardiovascular outcomes,11 a recent study of supplementation with pyridoxine, cobalamin, and folic acid showed no reduction in cardiovascular events.12
Homocysteine might also be a bystander that simply reflects estrogen deficiency.13 Homocysteine levels increase during menopause and can be reduced by the oral administration of estrogen or raloxifene, a selective estrogen-receptor modulator.14 Postmenopausal women in the lowest quartile of serum estradiol concentrations have a risk of fracture that is twice that among women in the highest quartile and similar to the increase in risk reported with high homocysteine levels.15 It is important to determine whether there is an association between these low estrogen levels and high homocysteine levels. Low calcium and vitamin D intake, low initial body weight, and weight loss are also associated with an increased risk of fracture. It is possible that high homocysteine levels are simply a reflection of poor nutrition. However, when the data on the risk of fracture from one cohort of the Netherlands study were adjusted for either dietary intake or vitamin D levels, the risk estimates were not altered.1
Whatever the mechanism, the effect of high homocysteine levels on the risk of fracture could be substantial. In the Netherlands study, the effect of high homocysteine levels on the risk of fractures was similar in magnitude to that of low bone mineral density, cognitive impairment, and recent falls. A randomized, placebo-controlled clinical trial to determine whether reducing homocysteine levels with nutritional supplements decreases the incidence of fracture in patients with osteoporosis would not be ethical, since effective therapy is available for those patients. Instead, it would be possible to collect data on fractures from studies of the effects of altering homocysteine levels in cardiovascular disease. Additional biochemical data are needed; if homocysteine truly is a culprit, the effects are likely to come from alteration of collagen cross-linking. Thus, an analysis of the association between homocysteine levels and the proportion of collagen degradation products with or without cross-links might help in this determination. Furthermore, measurements of homocysteine could be added to ongoing epidemiologic studies of risk factors in osteoporosis, but these measurements should be combined with better nutritional analysis.
Whether it is a culprit or a bystander, homocysteine can now be added to the growing list of risk factors for fractures. Its use might increase the predictive power of an assessment based not just on bone mineral density, but on multiple risk factors. Such an assessment is sorely needed to provide realistic individualized estimates of the risk of fracture that can guide physicians and patients in planning prevention and treatment.
Source Information
From the University of Connecticut Center for Osteoporosis, University of Connecticut Health Center, Farmington.
References
van Meurs JBJ, Dhonukshe-Rutten RAM, Pluijm SMF, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004;350:2033-2041.
McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350:2042-2049.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-1202.
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.
Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet 1995;57:34-39.
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.
Bathum L, Von Bornemann Hjelmborg J, Christiansen L, Madsen JS, Skytthe A, Christensen K. Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int (in press).
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.
Cagnacci A, Baldassari F, Rivolta G, Arangino S, Volpe A. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003;33:956-959.
Stone KL, Bauer DC, Sellmeyer D, Cummings SR. Low serum vitamin B-12 levels are associated with increased hip bone loss in older women: a prospective study. J Clin Endocrinol Metab 2004;89:1217-1221.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
Dimitrova KR, DeGroot K, Myers AK, Kim YD. Estrogen and homocysteine. Cardiovasc Res 2002;53:577-588.
De Leo V, la Marca A, Morgante G, Lanzetta D, Setacci C, Petraglia F. Randomized control study of the effects of raloxifene on serum lipids and homocysteine in older women. Am J Obstet Gynecol 2001;184:350-353.
Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 1998;339:733-738.
Related Letters:
Homocysteine as a Predictive Factor for Hip Fracture in Older Persons
Auer J., Lamm G., Eber B., Bursztyn M., Pérez-Castrillón J. L., Arranz-Pe?a 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.
N Engl J Med 2004; 351:1027-1030, Sep 2, 2004. Correspondence(Lawrence G. Raisz, M.D.)
Two studies in this issue of the Journal introduce still another potentially reversible factor: increased circulating homocysteine levels.1,2 There is ample evidence that high homocysteine levels are associated with an increased risk of cardiovascular disease3; the degree of association between homocysteine levels and the risk of osteoporotic fracture as shown in these two studies is of similar magnitude. In the study by van Meurs and colleagues from the Netherlands,1 subjects in the highest quartile of homocysteine levels had a risk of nonvertebral osteoporotic fractures, of which half were hip and wrist fractures, that was twice the risk among the subjects in the other three quartiles. Using data from the Framingham Study,2 that seemingly inexhaustible source of new epidemiologic insight, McLean and colleagues found that the risk of hip fracture was increased by nearly a factor of four in men and a factor of two in women for the highest quartile of plasma homocysteine levels as compared with the lowest quartile. No spinal radiographs were obtained to assess the incidence of vertebral compression fractures in either study. Measurements of bone mineral density were performed in the study from the Netherlands; analysis of these data showed that homocysteine levels were not associated with bone mineral density at the femoral neck or lumbar spine.
Is homocysteine a true culprit? That is, does a high level directly affect bone fragility and hence increase the risk of fracture? Both groups of authors point out that homocystinuria, a rare autosomal recessive disease, has been associated with generalized osteoporosis. This finding has been attributed to an inhibition of collagen cross-linking by high homocysteine levels, but in vivo evidence of the link between homocysteine and generalized osteoporosis is limited.4 Missense mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) are a cause of homocystinuria.5 Moreover, a polymorphism of MTHFR, in which a substitution of valine for alanine results in decreased enzyme activity, is associated with higher-than-normal homocysteine levels. In some studies, this polymorphism has also been associated with either decreased bone mineral density or an increased risk of fracture.6,7 There may be an interaction between the MTHFR polymorphism and folic acid deficiency, since the highest homocysteine levels and the lowest values for bone mineral density in persons with the valine substitution are also associated with low folic acid levels.8
Could homocysteine be an "innocent bystander"? Homocysteine levels are dependent on nutritional status, not only with respect to folic acid, but also with respect to cobalamin and pyridoxine. A direct relation between folate levels and bone mineral density, as well as an association of low cobalamin levels with an increased rate of bone loss, has been reported in postmenopausal women.9,10 In persons with cardiovascular disease, high levels of homocysteine, related to either mutations in the gene for MTHFR or to nutritional deficits, are associated with increased risks of ischemic heart disease and stroke.3 Although nutritional supplements can lower homocysteine levels and such lowering may affect some cardiovascular outcomes,11 a recent study of supplementation with pyridoxine, cobalamin, and folic acid showed no reduction in cardiovascular events.12
Homocysteine might also be a bystander that simply reflects estrogen deficiency.13 Homocysteine levels increase during menopause and can be reduced by the oral administration of estrogen or raloxifene, a selective estrogen-receptor modulator.14 Postmenopausal women in the lowest quartile of serum estradiol concentrations have a risk of fracture that is twice that among women in the highest quartile and similar to the increase in risk reported with high homocysteine levels.15 It is important to determine whether there is an association between these low estrogen levels and high homocysteine levels. Low calcium and vitamin D intake, low initial body weight, and weight loss are also associated with an increased risk of fracture. It is possible that high homocysteine levels are simply a reflection of poor nutrition. However, when the data on the risk of fracture from one cohort of the Netherlands study were adjusted for either dietary intake or vitamin D levels, the risk estimates were not altered.1
Whatever the mechanism, the effect of high homocysteine levels on the risk of fracture could be substantial. In the Netherlands study, the effect of high homocysteine levels on the risk of fractures was similar in magnitude to that of low bone mineral density, cognitive impairment, and recent falls. A randomized, placebo-controlled clinical trial to determine whether reducing homocysteine levels with nutritional supplements decreases the incidence of fracture in patients with osteoporosis would not be ethical, since effective therapy is available for those patients. Instead, it would be possible to collect data on fractures from studies of the effects of altering homocysteine levels in cardiovascular disease. Additional biochemical data are needed; if homocysteine truly is a culprit, the effects are likely to come from alteration of collagen cross-linking. Thus, an analysis of the association between homocysteine levels and the proportion of collagen degradation products with or without cross-links might help in this determination. Furthermore, measurements of homocysteine could be added to ongoing epidemiologic studies of risk factors in osteoporosis, but these measurements should be combined with better nutritional analysis.
Whether it is a culprit or a bystander, homocysteine can now be added to the growing list of risk factors for fractures. Its use might increase the predictive power of an assessment based not just on bone mineral density, but on multiple risk factors. Such an assessment is sorely needed to provide realistic individualized estimates of the risk of fracture that can guide physicians and patients in planning prevention and treatment.
Source Information
From the University of Connecticut Center for Osteoporosis, University of Connecticut Health Center, Farmington.
References
van Meurs JBJ, Dhonukshe-Rutten RAM, Pluijm SMF, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004;350:2033-2041.
McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350:2042-2049.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-1202.
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.
Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet 1995;57:34-39.
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.
Bathum L, Von Bornemann Hjelmborg J, Christiansen L, Madsen JS, Skytthe A, Christensen K. Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int (in press).
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.
Cagnacci A, Baldassari F, Rivolta G, Arangino S, Volpe A. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003;33:956-959.
Stone KL, Bauer DC, Sellmeyer D, Cummings SR. Low serum vitamin B-12 levels are associated with increased hip bone loss in older women: a prospective study. J Clin Endocrinol Metab 2004;89:1217-1221.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
Dimitrova KR, DeGroot K, Myers AK, Kim YD. Estrogen and homocysteine. Cardiovasc Res 2002;53:577-588.
De Leo V, la Marca A, Morgante G, Lanzetta D, Setacci C, Petraglia F. Randomized control study of the effects of raloxifene on serum lipids and homocysteine in older women. Am J Obstet Gynecol 2001;184:350-353.
Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 1998;339:733-738.
Related Letters:
Homocysteine as a Predictive Factor for Hip Fracture in Older Persons
Auer J., Lamm G., Eber B., Bursztyn M., Pérez-Castrillón J. L., Arranz-Pe?a 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.
N Engl J Med 2004; 351:1027-1030, Sep 2, 2004. Correspondence(Lawrence G. Raisz, M.D.)