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  1. Estranged
    Читатель Недуг.Ру
    Homocysteine and Fracture Prevention

    Joyce B. J. van Meurs, PhD; André G. Uitterlinden, PhD

    JAMA. 2005;293:1121-1122.

    Osteoporotic fractures are a major health problem in Western society and are associated with increased morbidity and mortality and substantial economic costs. Because the number of fractures will increase throughout the world as the population ages, prevention of fractures is becoming increasingly important. Recently, studies have identified a new and potentially modifiable risk factor for osteoporotic fracture—a mildly elevated circulating homocysteine level. These epidemiological studies showed that a relatively high homocysteine level predicts a higher fracture risk but they did not establish a causal relationship. The question remained whether the increase in fracture risk was due to homocysteine itself, or to other covarying factors.

    To establish a causal relationship between elevated homocysteine concentrations and osteoporosis, data from 2 types of studies are needed. One consists of randomized placebo-controlled trials studying the effect of lowering homocysteine levels on the incidence of fractures, the most important clinical end point of osteoporosis. In addition, cellular and molecular studies are required to elucidate the biological mechanism linking high homocysteine concentrations with factors that predispose to or cause fracture.

    In this issue of JAMA, Sato and colleagues present the first evidence that an elevated homocysteine level might indeed cause more brittle bones. In this randomized double-blind study, Japanese patients following stroke who were treated with folate and vitamin B12 had a 5 times lower risk for hip fracture over a follow-up period of 2 years compared with the placebo group. This is a very large risk reduction, but care should be taken in interpreting these results. As the authors note, the generalizability of the results is limited. The control patients had an unusually high incidence of hip fracture (4.3% per year) compared with the incidence in the average Japanese population of the same age (0.3% for women and 0.6% for men).5 In addition, the high mean levels of circulating homocysteine in the studied population (19.9 µmol/L) could explain the effectiveness of the therapy. Earlier studies suggested that there is a threshold above which homocysteine predicts increased fracture risk; the greater the percentage of the population above the threshold, the greater would be the expected effectiveness of treatment with a homocysteine-lowering therapy. The results of the study by Sato et al are also limited due to a relatively low power, with only 33 hip fractures during the study period of 2 years. This suggests that the 80% risk reduction reported in this study might not be detected in a larger study or with other (high-risk) populations, and the true relative risk might be as high as 0.5, which would translate to a 2-fold risk reduction.

    A wide spectrum of diseases is already associated with elevated circulating homocysteine concentrations, such as cardiovascular disease (including stroke) and cognitive impairment. Because these diseases are also associated with a high fracture risk, they could be confounding factors. However, Sato et al adjusted their risk estimates for cardiovascular events and presence of dementia without an effect on the study outcome. More important, the fall frequency was similar in both groups, which means that with the same number of falls, the placebo group fractured more easily. Because the recording of the falls was well-validated with a "fall calendar" in combination with a monthly visit to the clinic, cognitive impairment without dementia, which could affect recall of the falls, is an unlikely confounder. Nevertheless, similar intervention studies in patients other than those who have had a stroke will be necessary to show generalizability of the conclusions.

    Apart from showing that homocysteine levels were effectively reduced, Sato et al showed that vitamin B12 and folate levels were increased at the end of the study. It is possible that the observed effects on fracture are caused by increasing the levels of vitamin B12 rather than by lowering homocysteine. Vitamin B12 deficiency is common in the elderly population, ranging from 10% to 40%, depending on the diagnostic criteria. Vitamin B12 has been linked to bone health by a limited but growing number of studies. Patients with vitamin B12 deficiency (pernicious anemia) have a higher risk for fracture, and recent population-based studies suggest that vitamin B12 status is important for maintenance of bone mineral density (BMD). In addition, vitamin B12 has been found to affect osteoblast activity and bone formation. Because vitamin B12 plays an important role as a cofactor in metabolizing homocysteine, the levels of each are highly associated, making it difficult to separate the effects of vitamin B12 and homocysteine. This question can only be addressed by clarifying the biological mechanism linking homocysteine, vitamin B12, or both to fractures.

    The reduced fracture risk observed by Sato et al could not be explained by BMD, which suggests that bone quality rather than bone quantity explains the difference in fracture risk. Previous studies did not find a relationship between homocysteine levels and femoral neck BMD,2 supporting the present findings. A mechanism underlying the deleterious effect of homocysteine on bone quality might involve inhibition of collagen cross-linking by high homocysteine concentrations. This hypothesis is based on observations in patients with homocystinuria, a rare autosomal recessive disease characterized by very high homocysteine levels and early generalized osteoporosis. In vivo evidence for this hypothesis is limited, and it remains to be determined whether disturbed collagen cross-linking is also involved when homocysteine levels are only mildly elevated.

    Another way to prove a causal relationship between increased homocysteine and fracture risk is by studying mendelian randomization (ie, performing genetic association studies with polymorphisms known to increase homocysteine levels). This approach was recently successfully applied to examine the relationship between homocysteine and stroke. The most frequently studied related polymorphism is Ala222Val, a common functional polymorphism in the gene encoding for methylenetetrahydrofolate reductase, which has been found to cause higher homocysteine levels. A number of studies have found a relationship between this polymorphism and BMD and fracture. However, definitive answers about the relationship with fracture will require larger studies and possibly meta-analysis.

    Despite the potential limitations of the study by Sato et al, the results show that—at least in patients following stroke—folate and vitamin B12 supplementation is effective in preventing hip fracture. Whether a similar effect can also be obtained in other (high fracture risk) patients can only be answered by other intervention studies. After the initial observation of association between circulating homocysteine levels and fracture risk less than 1 year ago, these results now support a causal link. However, final proof of causality will have to come from elucidation of the biological mechanism underlying this relationship.

  2. joker
    Читатель Недуг.Ру
    Effect of Folate and Mecobalamin on Hip Fractures in Patients With Stroke

    A Randomized Controlled Trial

    Yoshihiro Sato, MD; Yoshiaki Honda, MD; Jun Iwamoto, MD; Tomohiro Kanoko, PhD; Kei Satoh, MD

    JAMA. 2005;293:1082-1088.


    Stroke increases the risk of subsequent hip fracture by 2 to 4 times. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women. Treatment with folate and mecobalamin (vitamin B12) may improve hyperhomocysteinemia.


    To investigate whether treatment with folate and vitamin B12 reduces the incidence of hip fractures in patients with hemiplegia following stroke.

    Design, Setting, and Patients

    A double-blind, randomized controlled study of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year following first ischemic stroke, who were recruited from a single Japanese hospital from April 1, 2000, to May 31, 2001. Patients were assigned to daily oral treatment with 5 mg of folate and 1500 µg of mecobalamin, or double placebo; 559 completed the 2-year follow-up.

    Main Outcome Measure

    Incidence of hip fractures in the 2 patient groups during the 2-year follow-up.


    At baseline, patients in both groups had high levels of plasma homocysteine and low levels of serum cobalamin and serum folate. After 2 years, plasma homocysteine levels decreased by 38% in the treatment group and increased by 31% in the placebo group (P<.001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (P<.001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment vs placebo groups were 0.20 (95% confidence interval [CI], 0.08-0.50), 7.1% (95% CI, 3.6%-10.8%), and 14 (95% CI, 9-28), respectively. No significant adverse effects were reported.


    In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B12 is safe and effective in reducing the risk of a hip fracture in elderly patients following stroke.

  3. лара
    Читатель Недуг.Ру
    Очень интересное сообщение, но, думаю, вряд ли оно найдёт практическое применение, т.к. больным после инсульта итак есть от чего умирать .

  4. Seduction
    Читатель Недуг.Ру
    И почти универсальной причиной всех страданий видеть анемию тоже перебор...

  5. Катя Петрова
    Читатель Недуг.Ру
    Уважаемый Вадим Валерьевич, спасибо за сообщение, но давайте ближе к практике. Что же предлагается? Прием 5 мг фолата и 1500 мкг витамина В12 ежедневно в течение 2 лет? А какой пенсионер согласится в течение такого периода ежедневно принимать указанные препараты? Или можно ограничиться, например месяцем терапии. И не велика ли доза в 1500 мкг В-12 ежедневно в течение длительного времени?

  6. Katty2002
    Читатель Недуг.Ру
    И почти универсальной причиной всех страданий видеть анемию тоже перебор...

    Уважаемый коллега Галлен!

    Если Вы посмотрите более внимательнее на ред. комментарий, то увидите, что кобаламин влияет на остеобластическую активность и костеобразование непосредственно, а не через поддержание гемоглобина на физиологическом уровне:

    "vitamin B12 has been found to affect osteoblast activity and bone formation"

    И к сожалению, пока доподлинно не установлено, почему у отдельных пациентов дефицит кобаламина приводит k развитию мегалобластной анемии, а у других дефицит проявляется преимущественно в ПНС (вплоть до параличей) или в ЦНС (вплоть до старческого слабоумия), тогда как нарушения со стороны крови минимальны.

    Если же говорить об анемиях у пожилых, то простая американская статистика оценивает ее как 10% среди старше 65 лет и 20% - после 85 лет и является неблагоприятным прогностическим фактором для заболеваемости и выживаемости:

    Curr Opin Hematol. 2005 Mar;12(2):123-128.

    Anemia in older adults.

    Woodman R, Ferrucci L, Guralnik J.

    In persons 65 years and older, anemia was present in 11.0% of men and 10.2% of women, with the prevalence rising to over 20% in people 85 years and older. One third of the cases were due to nutritional deficiencies, and one third was due to chronic illness, including but not limited to chronic kidney disease. About one third of the cases of anemia remain unexplained. Anemia is also prognostic for diminished physical performance and loss of mobility in people 65 years and older. A recent report suggests that the prevalence of anemia is even higher in elderly persons living in nursing homes. The data suggest that the risk of mortality and loss of mobility even extends to levels of hemoglobin normally considered low normal by WHO criteria, raising the question about optimal hemoglobin levels in the elderly.

    Дефицит кобаламина у пожилых тоже не редкость:

    Vitamin B12 deficiency affects about 5% of people aged 65–74 years and over 10% of people aged 75 years or older.

    Age Ageing. 2004 Jan;33(1):34-41. Vitamin B12 and folate deficiency in later life. Clarke R и соавт.

    Единственно, прав коллега под ником Algor говоря, что "вряд ли [все это] найдёт практическое применение" особенно на нашей территории, ведь пожилых старше 65 все меньше и меньше в России:

    Circulatory diseases exacerbated by stress are a major killer. Life expectancy for a Russian man has sunk to 58.4 years, the lowest of the 53 countries in the WHO European Region.

    Russia's population crisis

    Tom Parfitt

    The Lancet

    Volume 365, Issue 9461 , 26 February 2005, Pages 743-744

  7. Svetik79
    Читатель Недуг.Ру
    Уважаемый Вадим Валерьевич.

    Ни в коей мере не хотел умалить прямое положительное воздействие кобаламина на остеобластическую активность и костеобразование. Просто не сдержался увидев знакомые "антианемичные" слова в очередной теме, весьма далёкой от анемии, на мой взгляд простого хирурга...

  8. маринав
    Читатель Недуг.Ру
    Уважаемый коллега И.Н. Ефимов!

    В отношении дозы кобаламина - выбирается следующая из-за того, что у нормальных субьектов длительный прием не вызывает токсического действия вследствие кумуляции, а у пациентов с отсутствием внутреннего фактора Касла (наиболее частой причиной мегалобластной анемии в пожилом возрасте) данная дозировка способна ликвидировать кобаламино-дефицит (после того как было обнаружено, что 0,5-1% поступающего кобаламина может усваиваться фактор-независимым путем).

    Для сравнения доз - фрагмент идущего В-витаминного трайла по профилактике инсульта:

    The VITATOPS study is a multicenter, randomized, double-blind, placebo-controlled secondary stroke prevention trial to determine whether the addition of vitamin supplements (B12, 500 µg; B6, 25 mg; and folate, 2 mg) will reduce the combined incidence of recurrent vascular events (stroke, myocardial infarction) and vascular death in patients with recent stroke or transient ischemic attack (TIA)...target is to recruit a total of 8000 patients over the next 2 years, with a median follow-up of 2.5 years.

    Не помню названий, но аналогичные идут и по ССЗ с примерно такими же дозами витаминов: кобаламин 500-1500 мкг, фолиевая - 2-4 мг.

    В отношении будет или не будет принимать пациент эти витамины длительно - это вопрос комплайенса - будет ли принимать аспирин, статин, ИАПФ, ББ после инсульта пожизненно или ограничится 3-мя месяцами?

Клиника стоматологии и косметологии в Москве

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