Sunday, November 22, 2009

Management of Vitamin D Deficiency Reviewed

Am Fam Physician. 2009;80:841-846. Abstract

Clinical Context

Skeletal development, bone health, and neuromuscular function all require vitamin D. There are 2 forms of vitamin D: vitamin D2 (ergocalciferol), produced by irradiating ergosterol found in yeast and plants; and vitamin D3 (cholecalciferol), found in oily fish and synthesized in the skin in response to sunlight.

Because few foods contain vitamin D2, it is difficult to maintain adequate levels of vitamin D from dietary sources alone, and humans typically obtain 90% of vitamin D from sunlight. Because milk and other foods have been fortified with vitamin D, the rickets epidemic has subsided, but vitamin D deficiency and insufficiency are still linked to other pathologic conditions affecting persons of all ages.


Study Highlights

Signs and symptoms of vitamin D deficiency develop slowly or are nonspecific.
These may include symmetric low back pain in women, proximal muscle weakness, muscle aches, and throbbing bone pain.
Vitamin D deficiency is defined as a 25-hydroxyvitamin D level of less than 20 ng/mL (50 nmol/L).
Vitamin D insufficiency is defined as a serum 25-hydroxyvitamin D level of 20 to 30 ng/mL (50 - 75 nmol/L).
To prevent vitamin D deficiency, infants and children should have vitamin D intake of at least 400 IU/day from diet and supplements.
Unless infants are ingesting at least 1 L/day (33.8 fl oz) of vitamin D-fortified formula or milk, they should receive supplementation of 400 IU/day.
Vitamin D supplementation, 400 IU/day, is recommended for all children and adolescents who do not get regular sunlight exposure, who do not consume 1 L/day or more of vitamin D-fortified formula or milk, or who do not take a daily multivitamin supplement containing at least 400 IU of vitamin D.
In adults, vitamin D supplementation of 700 to 800 IU or more per day may reduce rates of falls and fractures.
Contraindications to vitamin D supplementation include tuberculosis or other granulomatous diseases, metastatic bone disease, sarcoidosis, or Williams syndrome.
Patients with vitamin D deficiency should receive oral ergocalciferol (vitamin D2), 50,000 IU per week for 8 weeks.
Serum 25-hydroxyvitamin D levels should be checked when this 8-week course is completed, and if these levels are not at least 30 ng/mL, the most likely cause is nonadherence to therapy or malabsorption.
A second 8-week course of ergocalciferol should be given if the level is not at least 30 ng/mL. Patients with suspected malabsorption may need gastroenterologic consultation.
Once vitamin D levels normalize in patients who were deficient, patients should receive maintenance dosages of cholecalciferol (vitamin D3), 800 to 1000 IU per day from dietary sources and/or supplements.
Because vitamin D is fat soluble, toxicity may result from excessive supplementation.
Signs and symptoms of vitamin D toxicity may include headache, metallic taste, nephrocalcinosis or vascular calcinosis, pancreatitis, nausea, and/or vomiting.

Clinical Implications

The diagnosis of vitamin D deficiency is often missed because the signs and symptoms develop slowly or are nonspecific, such as symmetric low back pain, proximal muscle weakness, muscle aches, and throbbing bone pain. Diagnosis of suspected vitamin D deficiency or insufficiency is confirmed with measurement of 25-hydroxyvitamin D levels.
In older adults, vitamin D supplementation of 700 to 800 IU per day is associated with a lower risk for falls and fractures. Suggested treatment in patients with vitamin D deficiency is oral ergocalciferol, 50,000 IU per week for 8 weeks. Adults with vitamin D deficiency, except for those with malabsorption syndromes, should receive maintenance dosages of 800 to 1000 IU of vitamin D per day.

Thursday, November 19, 2009

Folate Supplementation Linked to Increased Cancer Incidence and Mortality

From Medscape Medical News

Zosia Chustecka

November 18, 2009 — Folic acid and vitamin B supplementation was associated with an increase in cancer incidence, cancer mortality, and all-cause mortality in a new analysis with long-term follow-up of data from 2 trials conducted in Norway, where there is no folic acid fortification of foods.

The results are reported in the November 18 issue of the Journal of the American Medical Association.

The authors, led by Marta Ebbing, MD, from Haukeland University Hospital in Bergen, Norway, say that these results, although in need of confirmation, suggest that there is a need for "safety monitoring" because there is now widespread folic acid fortification of foods and increasing use of folic acid in dietary supplements.

However, the authors of an accompanying editorial points out that data from the United States, where there has been mandatory folic acid fortification of flour and other foods since 1998, have been showing a significant decrease in cancer incidence. "These national incidence rates do not support a substantial population-wide adverse effect of the magnitude suggested in the study," write the editorialists, Bettina F. Drake, PhD, MPH, and Graham Colditz, MD, DrPH, both from the Washington University School of Medicine in St Louis, Missouri.

"The population data from the United States do not suggest that there is a problem," Dr. Drake said in an interview with Medscape Oncology. She pointed out that folate supplementation used in the study resulted in much higher blood levels than would be seen after eating foods fortified with folic acid. In addition, the study was conducted in individuals with heart disease and was of limited duration.

The findings from this study "do not nullify the potential long-term benefits that folic acid fortification may have on population health," Dr. Drake explained. The measure was introduced to reduce neural tube defects in newborns (which arise from folate deficiency during pregnancy). A reduction was seen within a "few years," the editorialists note.

Concerns about a link between cancer and folic acid supplementation have been raised previously, most recently with regard to colorectal cancer, as reported by Medscape Oncology. At that time, leading expert on nutrition and cancer Walter Willet MD, DrPH, from the Harvard School of Public Health in Boston, Massachusetts, said: "I am certain that we are not causing an epidemic of colorectal cancer with folic acid fortification of flour." He added that there was a small increase in the incidence of this cancer soon after fortification was introduced, but this coincided with an increase in colonoscopy, and he pointed out that mortality rates from this cancer have been declining steadily.

Latest Results from Norway

The latest results come from 2 trials conducted in 6837 patients with ischemic heart disease, in which half the participants took supplements of vitamin B (including folic acid) to lower homocysteine levels to see if this would reduce cardiovascular outcomes. It did not, and these results are in line with other large trials.

At the same time, both trials showed — independently — an increase in cancer in the supplementation group, compared with the placebo group, but this was not statistically significant.

In these 2 trials, participants took supplements containing folic acid (0.8 mg/d), vitamin B12 (0.4 mg/d), and B6 (40 mg/d), or various combinations of these. This dose of folic acid is 4 to 6 times higher than the average dose delivered by the mandatory fortification in the United States, and is twice the recommended daily allowance, the authors note, although they add that it is below the tolerable upper intake level of 1 mg/d set by the US Institute of Medicine.

The current analysis pooled results from the 2 trials, which had a median participation of 39 months, and added data from an observational posttrial follow-up of 38 months, giving a total duration of around 5.5 years. The authors note that pooling the data from the 2 trials is "justified" because they were nearly identical.

This pooled analysis found a statistically significant increase in cancer incidence, cancer mortality, and all-cause mortality.

These results for cancer outcomes are not supported by other studies of homocysteine-lowering vitamin B trials, the authors note.

Cancer Decreasing Significantly

In their editorial, Drs. Drake and Colditz write that these results indicate an excess of approximately 3.5 new cases of cancer per 1000 people per year, and 1 excess case of lung cancer per 1000 people per year. The excess deaths correspond to 1.7 cancer deaths per 1000 people per year.

"These numbers, if generalizable to the United States, would be substantial at the overall levels of total cancer incidence and mortality," they write. In addition, an increase in lung cancer incidence would be expected.

"However, the rates of total cancer incidence decreased significantly from 2001 to 2005, and the lung cancer incidence has also declined significantly," they point out.

Although the study suggests there is an association between folic acid supplementation and an increase in cancer, the US population data suggest that there isn't a problem with folic acid fortification of foods and cancer, Dr. Drake told Medscape Oncology. Folic acid fortification has been mandatory in the United States for more than 10 years and, given the results of this study, we would have expected a significant increase in the incidence of cancer by now, she suggested.

One of the issues with clinical trials is that observations are reported with a short time frame after the implementation of an intervention, the editorialists note. This can often lead to "looking for effects that fit the time frame," they add. "By analogy, when keys are missing it is common to look for them under the lamppost where the light is, rather than in the murky location where the keys were more likely to have been dropped."

One of the coauthors on the paper, Klaus Meyer, PhD, is employed at the laboratory of Bevital AS. The other authors and both editorialists have disclosed no relevant financial relationships.

JAMA. 2009;302:2119-2126, 2152-2153.