Literature Review and Commentary

By Alan R. Gaby, MD

Vitamin D and for Osteoporosis Prevention: More Is Worse, Not Better

Three hundred thirty-one adults in Calgary, Canada, (53% male, 47% female; mean age, 62 years) who did not have osteoporosis were randomly assigned to receive, in double-blind fashion, 400, 4,000, or 10,000 IU per day of vitamin D for three years. Calcium supplements were given, if needed, to bring total calcium intake to around 1,200 mg per day. The mean serum 25-hydroxyvitamin D level at baseline was 31.5 ng/ml, indicating normal vitamin D status. The primary outcome measures were changes in total volumetric bone mineral density (BMD) at the radius and tibia, assessed by high resolution peripheral quantitative computed tomography, and bone strength (failure load) at the radius and tibia, estimated by finite element analysis. Ninety-two percent of the participants completed the study. At the end of the trial, mean serum 25-hydroxyvitamin D levels with 400, 4,000, and 10,000 IU per day of vitamin D were 31 ng/ml, 53 ng/ml, and 58 ng/ml, respectively.

Compared with baseline, the mean change in BMD at the radius was -1.2% with 400 IU per day, -2.4% with 4,000 IU per day, and -3.5% with 10,000 IU per day (p < 0.001 for 10,000 vs. 400 IU per day; p < 0.05 for 4,000 vs. 400 IU per day). Compared with baseline, the mean change in BMD at the tibia was -0.4%, -1.0%, and -1.7% for 400, 4,000, and 10,000 IU per day, respectively (p < 0.001 for 10,000 vs. 400 IU per day; p > 0.05 for 4,000 vs. 400 IU per day). Mean bone strength decreased to a greater extent in both high-dose groups than in the low-dose group, but the differences were not statistically significant.

Comment: In this study of healthy adults with a mean 25-hydroxyvitamin D level in the normal range at baseline, treatment with 4,000 or 10,000 IU per day of vitamin D, as compared with 400 IU per day, significantly decreased BMD of the lower radius, and significantly (10,000 IU per day) or nonsignificantly (4,000 IU per day) decreased BMD of the tibia. There was also a nonsignificant trend toward reduced bone strength with the two higher doses of vitamin D. The adverse effect of high-dose vitamin D would probably have been even greater if it had been compared with 800-1,000 IU per day, rather than with 400 IU per day. That is because previous studies have shown that 800-1,000 IU per day is effective for preventing fractures¹ and decreasing bone loss,² whereas 400 IU per day is not effective.

In previous randomized controlled trials, high-dose vitamin D was either nonsignificantly less effective or similarly effective for preventing bone loss, when compared with moderate-dose vitamin D (such as 800 IU per day). I am not aware of any studies that found high-dose vitamin D to be more effective than moderate doses. Based on the available evidence, high-dose vitamin D (such as more than 2,000 IU per day) should not be recommended for osteoporosis prevention unless there are extenuating circumstances such as malabsorption.

Burt LA, et al. Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength: a randomized clinical trial. JAMA. 2019;322:736-745.

Pregnant Smokers Need More Folic Acid

Three hundred forty-five cigarette-smoking women in Tampa, Florida, who were pregnant at less than 21 weeks of gestation, were randomly assigned to receive 0.8 mg per day or 4.0 mg per day of folic acid. All women were given smoking cessation counseling. Small for gestational age (SGA) was defined as below the 10th percentile of birth weight for gestational age. Fetal growth restriction (FGR) was defined as less than 85% of the expected mean birth weight for gestational age. The overall incidence of SGA and FGR was 23.7% and 29.2%, respectively. Mean birth weight was significantly higher by 140 g with 4.0 mg per day of folic acid than with 0.8 mg per day. The incidence of FGR was significantly lower by 35% with 4.0 mg per day than with 0.8 mg per day (p value not stated). The incidence of SGA was 31% lower with 4.0 mg per day than with 0.8 g per day (borderline statistical significance; p value not stated). The higher dose of folic acid was not associated with an increased risk of adverse events.

Comment: Serum and erythrocyte folate levels are lower in women who smoke cigarettes than in nonsmokers.³ Low maternal folate status, in addition to increasing the risk of neural tube defects, may lead to a reduction in fetal weight. The results of the present study suggest that pregnant women who smoke cigarettes have a higher folic acid requirement than pregnant nonsmokers.

Yusuf KK, et al. Comparing folic acid dosage strengths to prevent reduction in fetal size among pregnant women who smoked cigarettes: a randomized clinical trial. JAMA Pediatr. 2019;173:493-494.

Is a Gluten-Free Diet Beneficial for Autoimmune Thyroiditis?

Thirty-four women (aged 20-45 years) with autoimmune thyroiditis and an incidental finding of positive IgA anti-tissue transglutaminase antibodies (which is strongly suggestive of celiac disease) were assigned, based on patient preference, to follow a gluten-free diet (n = 16) for six months or to serve as controls (n = 18). At the end of the study, 10 of 16 patients in the diet group and none of those in the control group tested negative for anti-tissue transglutaminase antibodies. (According to Mayo Clinic Laboratories, these antibodies should begin to decrease within 6-12 months after starting a gluten-free diet). The mean titer of thyroid peroxidase (TPO) antibodies decreased by 24% in the diet group and increased by 3% in the control group (p < 0.05 for the difference in the change between groups). Similar results were seen for thyroglobulin antibodies.

Comment: In this study, consumption of a gluten-free diet for six months resulted in a moderate decrease in thyroid antibody titers in women with autoimmune thyroiditis and probable celiac disease. Presumably, the antibodies produced in response to gluten ingestion were cross-reacting with thyroid tissue. It is not known whether a gluten-free diet would also decrease thyroid antibodies in patients with non-celiac gluten sensitivity, although there are anecdotal reports of such.

Krysiak R, et al. The effect of gluten-free diet on thyroid autoimmunity in drug-naïve women with Hashimoto’s thyroiditis: a pilot study. Exp Clin Endocrinol Diabetes. 2019;127:417-422.

Iron Fortification of Infant Formula: How Much Is Too Much?

Four hundred five infants from low- to middle-income neighborhoods in Santiago, Chile, who had normal iron status were randomly assigned at six months of age to consume iron-fortified (12 mg/L) or low-iron (2.3 mg/L) formula for six months. The children subsequently underwent tests of cognitive function at an average age of 16.2 years. Compared with the low-iron group, the iron-fortified group had lower mean scores on eight of nine tests of cognitive function, three of which were statistically significant (visual memory, arithmetic achievement, and reading comprehension achievement).

Comment: The American Academy of Pediatrics Committee on Nutrition recommends that formula-fed infants aged 6-12 months receive iron-fortified infant formula that contains 10-12 mg/L of iron. In contrast, the Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition has no specific recommendation for infants in that age group, and the Committee concluded that it is unclear whether fortification at a level of 10-14 mg/L has any advantages.⁴

In the present study, teenagers who had previously received infant formula containing iron at a concentration recommended by the American Academy of Pediatrics had worse cognitive function, compared with teenagers who had received a low-iron infant formula. It is important to maintain adequate iron status during early childhood because iron plays a key role in brain development. However, excessive iron intake appears to have adverse effects. Further research is needed to determine the optimal level of iron intake for infants.

Gahagan S, et al. Randomized controlled trial of iron-fortified versus low-iron infant formula: developmental outcomes at 16 years. J Pediatr. 2019;212:124-130.e1.

Vitamin B6 Neurotoxicity: Some People Can Tolerate Large Doses

A 30-year-old woman with homocystinuria who had been taking 1,250-1,750 mg per day of pyridoxine for 20 years developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing revealed abnormal sensory nerve potentials, and the patient was diagnosed with sensory ganglionopathy. The pyridoxine dosage was reduced to 500 mg per day, which resulted in the disappearance of sensory symptoms and ataxia, and normalization of sensory nerve potentials.

Comment: There have been a number of case reports of severe peripheral sensory neuropathy developing in people taking large doses of vitamin B6. Most of these patients improved within two months after discontinuing pyridoxine, although subtle neurological dysfunction persisted in some cases for years. The neurotoxicity of vitamin B6 is dose-related. The lowest dose that has clearly been shown to be neurotoxic in humans is 500 mg per day. In some patients with schizophrenia, homozygous homocystinuria, or primary hyperoxaluria, dosages greater than 500 mg per day appear to be needed to achieve optimal clinical results. Many patients tolerate these large doses and do not develop neurotoxicity.

In the present case report, pyridoxine neurotoxicity developed after long-term use of 1,250-1,750 mg per day, but the condition resolved when the dosage was decreased to 500 mg per day. Patients taking large doses of vitamin B6 should be advised to watch for early warning signs of neurotoxicity (such as hypoesthesia or unsteadiness), and they should be given periodic neurological examinations.

Echaniz-Laguna A, et al. Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria. BMJ Case Rep. 2018;2018:bcr-2018-225059.

Questionable-Research Department

Eighty-six Iranian women with polycystic ovary syndrome (PCOS) were randomly assigned to receive, in double-blind fashion, 200 mg per day of coenzyme Q10 (CoQ10), 400 IU per day of vitamin E, both treatments, or placebo for eight weeks. All 86 women were taking 500 mg of metformin three times a day at baseline. Compared with placebo, CoQ10 (with or without vitamin E) significantly improved insulin resistance, as determined by homeostasis model assessment. Compared with placebo, all three active treatments significantly decreased the mean total testosterone level (p < 0.001). One might conclude from this study that CoQ10 improves insulin resistance and that CoQ10 and vitamin E each improve testosterone levels in women with PCOS.

Comment: In an editorial in the July 2019 issue of the Townsend Letter, I expressed concern that a large and growing number of papers from Iran and some other countries have left me wondering whether the research was fabricated. Several aspects of the present study raised my eyebrows. First, there are no clear biochemical mechanisms by which CoQ10 or vitamin E would be expected to improve insulin resistance or testosterone levels in women with PCOS. Second, it is unusual for researchers to invest money in an expensive double-blind trial before there is preliminary evidence of efficacy (such as case reports or uncontrolled trials). The only previously published research that examined these effects of CoQ10 and vitamin E in women with PCOS came from another Iranian researcher whose work was the main focus of my July 2019 editorial. The present study appears to have been rather expensive, since it included 172 measurements each of serum insulin, sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol.

Third, although the use of metformin was not one of the inclusion criteria, all 86 women in the study were taking 500 mg of metformin three times a day. Metformin has a high incidence of gastrointestinal side effects, and as many as one-third of women taking a similar dose of metformin discontinue it because of these side effects.⁵ Therefore, it is difficult to believe that none of the women had discontinued metformin treatment and none had been advised to try a lower dose (side effects often improve when the dosage is lowered).

Fourth, the CoQ10 and vitamin E supplements used in the study were manufactured by a US company, whereas the placebos were manufactured by an Iranian company. It is unusual for a company to attempt to manufacture an identical placebo for a product produced by another company.

Izadi A, et al. Hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104:319-327.

Vitamin C Deficiency Is Common in Hospitalized Patients

Of 149 patients hospitalized in Australia, 77% had a low serum vitamin C level. The median age was significantly higher in patients with vitamin C deficiency than in those with normal vitamin C levels (73 vs. 65 years; p = 0.04). As compared with patients with normal vitamin C levels, those with low levels had higher C-reactive protein concentrations and their median length of hospital stay was two days longer (p = 0.02).

Comment: This study is consistent with previous research demonstrating that low vitamin C status is common in hospitalized patients. Vitamin C plays a key role in a number of physiological processes (such as immune function and wound healing) that are important for patients recovering from surgery or illness. In addition, a randomized controlled trial found that vitamin C supplementation (500 mg twice a day) significantly improved mood in hospitalized patients. In that study, 66% of the patients had a low plasma vitamin C level prior to treatment. Since vitamin C is safe and inexpensive, supplementation should be considered for most hospitalized patients.

Sharma Y, et al. Vitamin C deficiency in Australian hospitalised patients: an observational study. Intern Med J. 2019;49:189-196.

Fiber Supplement Improves Gastroesophageal Reflux Disease

Thirty-six patients (mean age, 35 years) with non-erosive gastroesophageal reflux disease (GERD) whose diet was low in fiber (less than 20 g per day) were advised to continue their usual diet and to take 5 g of psyllium three times a day. Each psyllium dose was consumed as a suspension in 150 ml of water and was followed by an additional one cup of liquid. The proportion of patients who experienced heartburn decreased from 93% at baseline to 40% at the end of the study (p < 0.001), and the mean score on the GERD symptom questionnaire improved by 45% (p < 0.001). The total number of reflux episodes decreased by 38%. The mean value for the minimal lower esophageal sphincter pressure increased significantly, from 5.41 mm Hg at baseline to 11.3 mm Hg at the end of the study (p < 0.03).

Comment: Low dietary fiber intake is associated with decreased gastric motility and delayed gastric emptying, each of which may contribute to gastroesophageal reflux. In the present study, increasing fiber intake by supplementing with psyllium was associated with an increase in lower esophageal sphincter pressure, a decrease in heartburn, and a reduction in the number of reflux episodes in patients with GERD whose diet was low in fiber. Controlled trials are needed to confirm these findings.

Morozov S, et al. Fiber-enriched diet helps to control symptoms and improves esophageal motility in patients with non-erosive gastroesophageal reflux disease. World J Gastroenterol. 2018;24:2291-2299.