Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin D deficiency is common. This review considers the role of vitamin D in skeletal and nonskeletal health and suggests strategies for the prevention and treatment of vitamin D deficiency.

Vitamin D Deficiency

Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.

/pdf/a-candidate-genetic-risk-factor-for-vascular-disease-a-28fnjdqen2.pdf

A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase

Objective. —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. Data Sources. —MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. Study Selection and Data Extraction. —Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. Data Synthesis. —Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact. Conclusions. —A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements. ( JAMA . 1995;274:1049-1057)

https://jamanetwork.com/journals/jama/articlepdf/389728/jama_274_13_028.pdf

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes

Recently, dietary pattern analysis has emerged as an alternative and complementary approach to examining the relationship between diet and the risk of chronic diseases. Instead of looking at individual nutrients or foods, pattern analysis examines the effects of overall diet. Conceptually, dietary patterns represent a broader picture of food and nutrient consumption, and may thus be more predictive of disease risk than individual foods or nutrients. Several studies have suggested that dietary patterns derived from factor or cluster analysis predict disease risk or mortality. In addition, there is growing interest in using dietary quality indices to evaluate whether adherence to a certain dietary pattern (e.g. Mediterranean pattern) or current dietary guidelines lowers the risk of disease. In this review, we describe the rationale for studying dietary patterns, and discuss quantitative methods for analysing dietary patterns and their reproducibility and validity, and the available evidence regarding the relationship between major dietary patterns and the risk of cardiovascular disease.

Dietary pattern analysis: a new direction in nutritional epidemiology.

Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. Methods A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease....

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011613

Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease

Objective. —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. Design. —Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. Setting. —Population-based cohort in Framingham, Mass. Participants. —A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. Main Outcome Measures. —Plasma homocysteine concentration correlated with plasma folate, vitamin B 12 , pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. Results. —Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B 12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B 6 , but not vitamin B 12 . Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Conclusions. —These results indicate a strong association between homocysteine concentration and folate, vitamin B 12 , and vitamin B 6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status. ( JAMA . 1993;270:2693-2698)

Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population

Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study.

Background: Evidence suggests that pathophysiologic processes in bone are important determinants of outcome in osteoarthritis of the knee Low intake and low serum levels of vitamin D may compromis

Relation of Dietary Intake and Serum Levels of Vitamin D to Progression of Osteoarthritis of the Knee among Participants in the Framingham Study

Nutrition and maternal mortality in the developing world

Objective. Cumulative damage to tissues, mediated by reactive oxygen species, has been implicated as a pathway that leads to many of the degenerative changes associated with aging. We hypothesized that increased intake of antioxidant micronutrients might be associated with decreased rates of osteoarthritis (OA) in the knees, a common age-related disorder.

Methods. Participants in the Framingham Osteoarthritis Cohort Study underwent knee evaluations by radiography at examinations 18 (1983–1985) and 22 (1992–1993). Usual dietary intake was assessed using the Food Frequency Questionnaire, administered at examination 20 (1988–1989). Knees without OA at baseline (Kellgren and Lawrence [K&L] grade ⩾1) were classified as having incident OA if they had a K&L grade ⩽2 at followup. Knees with OA at baseline were classified as having progressive OA if their score increased by ⩽1 at followup. Knees were also classified as having cartilage loss or osteophyte growth if their maximal joint space narrowing or osteophyte growth score increased by ⩽1 (range 0–3). The association of vitamin C, beta carotene, and vitamin E intake, ranked in sex-specific tertiles, with incidence and progression of OA was compared with that of a panel of nonantioxidant vitamins, B1, B6, niacin, and folate, using logistic regression and generalized estimation equations to adjust for correlation between fellow knees. The lowest tertile for each dietary exposure was used as the referent category. Odds ratios (OR) were adjusted for age, sex, body mass index, weight change, knee injury, physical activity, energy intake, and health status.

Results. Six hundred forty participants received complete assessments. Incident and progressive OA occurred in 81 and 68 knees, respectively. We found no significant association of incident OA with any nutrient. A 3-fold reduction in risk of OA progression was found for both the middle tertile (adjusted OR = 0.3, 95% confidence interval [95% CI] 0.1–0.8) and highest tertile (adjusted OR = 0.3, 95% CI 0.1–0.6) of vitamin C intake. This related predominantly to a reduced risk of cartilage loss (adjusted OR = 0.3, 95% CI 0.1–0.8). Those with high vitamin C intake also had a reduced risk of developing knee pain (adjusted OR = 0.3, 95% CI 0.1–0.8). A reduction in risk of OA progression was seen for beta carotene (adjusted OR = 0.4, 95% CI 0.2–0.9) and vitamin E intake (adjusted OR = 0.7, 95% CI 0.3–1.6), but was less consistent. No significant associations were observed for the nonantioxidant nutrients.

Conclusion. High intake of antioxidant micronutrients, especially vitamin C, may reduce the risk of cartilage loss and disease progression in people with OA. We found no effect of antioxidant nutrients on incident OA. These preliminary findings warrant confirmation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780390417

David Rush

Papers

Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population

Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study.

Relation of Dietary Intake and Serum Levels of Vitamin D to Progression of Osteoarthritis of the Knee among Participants in the Framingham Study

Nutrition and maternal mortality in the developing world

Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis