by Alan R. Gaby, MD
D-Mannose Prevents Urinary Tract Infections
A meta-analysis was conducted on three studies that examined whether D-mannose reduces recurrences of urinary tract infections (UTIs) in adult women with recurrent UTIs. One study was a randomized controlled trial, one was a randomized cross-over trial, and one was a prospective cohort study. The pooled relative risk of UTI recurrence comparing D-mannose with placebo was 0.23 (95% confidence interval [CI], 0.14-0.37), indicating a significant 77% reduction in risk. The pooled relative risk comparing D-mannose with prophylactic antibiotics was 0.39 (95% CI, 0.12-1.25), indicating a statistically nonsignificant 61% decrease in risk compared with antibiotics. D-Mannose was generally well tolerated, although a few participants experienced diarrhea.
Comment: About 25 years ago, Dr. Jonathan Wright began using D-mannose (a sugar structurally similar to glucose) to prevent and treat urinary tract infections. The use of D-mannose was based on in vitro evidence that it prevents uropathogenic Escherichia coli from adhering to the epithelial cells of the genitourinary tract. In Wright’s experience, this treatment has an efficacy rate of 85-90%. In addition to being an effective treatment for UTIs, he found that D-mannose can prevent post-intercourse UTIs and is also effective for prophylaxis in women who are prone to recurrent UTIs. Because of the writings and teachings of Dr. Wright, D-mannose is now widely used by practitioners of integrative medicine.
Many people reading this column already know about the benefits of D-mannose, although there has been less interest in the mainstream medical community. The main reason I am reviewing this meta-analysis is to point out that it was published in the American Journal of Obstetrics and Gynecology, a high-impact journal that is read by many conventional practitioners. The publication of this article raises the hope that D-mannose, which is a safe, effective, and inexpensive treatment, will eventually become the standard of care for preventing and treating UTIs caused by E. coli.
Lenger SM, et al. D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;223:265.e1-265.e13.
Can DHEA Help Prevent Osteoporosis?
A meta-analysis was conducted on four randomized double-blind trials (including a total of 295 women and 290 men over age 55 years) that examined the effect of dehydroepiandrosterone (DHEA) supplementation for one year on bone mineral density (BMD). In women, compared with placebo, DHEA significantly increased mean serum concentrations of testosterone and estradiol. Compared with placebo, DHEA significantly increased mean BMD of the lumbar spine, total hip, and trochanter, and nonsignificantly increased BMD of the femoral neck. In men, compared with placebo, DHEA significantly increased the mean estradiol concentration, but had no significant effect on testosterone levels. In men, DHEA had no significant effect on BMD at any site, and there was no clear trend for or against DHEA.
Comment: DHEA levels decline with age, and it has been suggested that this decline contributes to various age-related health conditions. The results of this study demonstrate that DHEA can help prevent bone loss in postmenopausal women but not in middle-aged and elderly men. In addition, DHEA supplementation increased the concentration of estradiol (one of the 3 main forms of estrogen produced in the body) in both men and women. In contrast, DHEA increased testosterone levels only in women. DHEA is apparently converted in part to estrogen and testosterone in both men and women, so it is not clear why DHEA supplementation did not increase testosterone levels in men.
In many clinical trials, the dosage of DHEA was 50 mg per day, which appears to be a supraphysiological dose. Long-term administration of excessive amounts of DHEA has the theoretical potential to promote the development of hormone-dependent cancers, such as breast, ovarian, and endometrial cancer. Circumstantial evidence suggests that a physiological dose for DHEA-replacement therapy is in the range of 5-10 mg per day in women and 10-20 mg per day in men. It has been my practice to consider DHEA supplementation for patients whose serum DHEA level (measured as DHEA-sulfate) is below or near the bottom of the normal range for young adults of the same sex. Using that approach, I have seen physiological doses of DHEA improve BMD, as well as various problems such fatigue, depression, menopausal symptoms, and age-related decline in memory and muscle mass.
Jankowski CM, et al. Sex-specific effects of DHEA on bone mineral density and body composition: A pooled analysis of four clinical trials. Clin Endocrinol (Oxf). 2019;90:293-300.
Vegan Diet During Pregnancy
A retrospective study was conducted on 1,419 Israeli women to examine the association between consumption of a vegan or vegetarian diet and pregnancy outcomes. A vegetarian diet was defined as consuming meat, poultry, or fish once a month or less and eggs and dairy products once a month or more. A vegan diet was defined as consuming meat, poultry, fish, dairy, or eggs once a month or less. One thousand fifty-two women consumed an omnivorous diet, 133 consumed a vegetarian diet, and 234 consumed a vegan diet. Compared with the infants of omnivores, the infants of vegans had a lower mean birth weight percentile (42.6 vs. 52.5; p < 0.001), and a higher risk of being small for gestational age (adjusted odds ratio = 1.74; p = 0.03). Similar trends were seen when comparing omnivorous and vegetarian diets, but the differences were less pronounced and were not statistically significant. Vegan and vegetarian diets were each significantly associated with a lower risk of excessive maternal weight gain during pregnancy.
Comment: The results of this study suggest that consuming a vegan diet during pregnancy may increase the risk of having a small-for-gestational age baby. Vegan diets often contain virtually no vitamin B12, and they may also be low in protein, iron, vitamin D, zinc, iodine, riboflavin, calcium, and selenium. However, consumption of a vegetarian or vegan diet may reduce the incidence of a number of chronic diseases, including cardiovascular disease, hypertension, gallbladder disease, kidney stones, diabetes, obesity, constipation, and some cancers. A vegan diet, properly planned with the help of a dietitian or nutritionist, and supplementing with vitamin B12 and other appropriate micronutrients might reduce or eliminate the increased risk of having a small-for-gestational age baby.
Kesary Y, et al. Maternal plant-based diet during gestation and pregnancy outcomes. Arch Gynecol Obstet. 2020;302:887-898.
Niacin for Mitochondrial Myopathy
Median concentrations of nicotinamide adenine dinucleotide (NAD) were significantly lower in muscle and blood in five patients with adult-onset mitochondrial myopathy than in age- and sex-matched controls. Muscle concentrations of niacinamide were also significantly lower in patients than in controls. The patients were treated with 250 mg per day of niacin, which was increased progressively, as tolerated, to a maximum of 750-1,000 mg per day, for a total treatment period of 10 months. Niacin treatment increased the median muscle concentration of NAD by 1.3-fold after four months and by 2.3-fold after 10 months. Blood levels of NAD+ also increased. At 10 months, the NAD concentrations had reached those of healthy controls. Niacin supplementation was associated with increased muscle mass after four months and with increased muscle strength after 10 months.
Comment: NAD is a cofactor in the electron-transport chain, which plays a role in the mitochondrial energy production. In this study, patients with adult-onset mitochondrial myopathy were found to have low concentrations of NAD. Supplementation with niacin increased NAD levels, as well as increasing muscle mass and muscle strength. Niacinamide would also likely be effective since it can also increase NAD levels.
Pirinen E, et al. Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metab. 2020;31:1078-1090.e5.
N-Acetylcysteine and Helicobacter pylori
Six hundred eighty Taiwanese patients in with Helicobacter pylori infection were randomly assigned to receive, in open-label fashion, triple therapy (dexlansoprazole, amoxicillin, and clarithromycin) for 14 days, with or without 600 mg of N-acetylcysteine (NAC) twice a day for 14 days. H. pylori eradication was defined as a negative urea breath test at least six weeks after completion of treatment. Among the 95% of patients who adhered to the treatment, the eradication rate was 85.7% with NAC and 88.0% without NAC (p = 0.40).
Comment: In previous studies, NAC increased the eradication rate in patients receiving standard H. pylori eradication therapy. NAC was thought to work by degrading the biofilm produced by H. pylori, thereby allowing for greater penetration of the antibiotics. NAC did not increase the eradication rate in the present study. However, the rate was very high in both groups, so there was little room for NAC treatment to demonstrate a benefit. NAC may be most successful in patients in whom previous attempts at eradication had been unsuccessful. In a previous study, 40 patients who had had at least four unsuccessful attempts to eradicate H. pylori were randomly assigned to receive 600 mg of NAC once a day or no NAC (controls) for one week, followed by a culture-guided eradication regimen that included two antibiotics and a proton pump inhibitor. The eradication rate was significantly higher in the NAC group than in the control group (65% vs. 20%; p < 0.01). Biofilm disappeared in all patients in whom eradication was successful but persisted in patients in whom eradication was unsuccessful.1
Chen CC, et al. Comparison of the effect of clarithromycin triple therapy with or without N-acetylcysteine in the eradication of Helicobacter pylori: a randomized controlled trial. Therap Adv Gastroenterol. 2020;13:1756284820927306.
Riboflavin for Crohn’s Disease
Seventy patients (mean age, 42 years) with Crohn’s disease received 100 mg of riboflavin once a day for three weeks. At baseline, 70% of the patients were in remission, 18.6% had mild disease, and 11.5% had moderate disease. Thirty patients (71.4%) were receiving medications (mostly tumor necrosis factor inhibitors and/or thiopurines). Riboflavin supplementation was associated with a significant improvement in median disease activity (as determined by the Harvey-Bradshaw Index; p < 0.001). The median concentration of interleukin-2 (a biomarker of inflammation) decreased significantly.
Comment: Riboflavin has demonstrated an anti-inflammatory effect in animal models of Crohn’s disease. The results of the present study suggest that riboflavin may also be beneficial in the treatment of humans with Crohn’s disease. Controlled trials are needed to confirm the efficacy of this safe, low-cost therapy.
von Martels JZ, et al. Riboflavin supplementation in patients with Crohn’s disease [the RISE-UP study]. J Crohns Colitis. 2020;14:595-607.
Vitamin D and Bone Health
The VITamin D and OmegA-3 TriaL (VITAL) was a double-blind, placebo-controlled trial of vitamin D (2,000 IU per day) and/or omega-3 fatty acids (1 g per day) in 25,871 US adult men and women. The present study included a subcohort of 771 participants (mean age, 63.8 years) from the original trial. The mean serum 25-hydroxyvitamin D (25[OH]D) level at baseline was 27.6 ng/ml. After two years of treatment, compared with placebo, vitamin D resulted in a nonsignificant trend toward a more favorable change in bone mineral density (BMD) of the spine (0.33% vs. 0.17%; p = 0.55) femoral neck (-0.27% vs. -0.68%; p = 0.16), and total hip (-0.76% vs. -0.95%; p = 0.23), but the opposite trend for whole body (-0.22% vs. -0.15%; p = 0.60). These changes did not vary according to baseline 25(OH)D levels. Among participants with a baseline free-25(OH)D level below the median, vitamin D supplementation resulted in a significant increase in BMD of the spine (0.75% vs. 0%; p = 0.043) and attenuation of loss of BMD of the total hip (-0.42% vs. -0.98%; p < 0.05).
Comment: This study found that vitamin D at a dose of 2,000 IU per day had little effect on BMD in middle-aged and elderly men and women whose mean baseline 25(OH)D level was 27.6 ng/ml. Vitamin D may be beneficial, however, for individuals with lower vitamin D status at baseline. Interestingly, a low baseline 25(OH)D level did not predict a positive response to vitamin D supplementation, whereas a low baseline free-25(OH)D level did predict a positive response to vitamin D. Since free-25(OH)D levels are not commonly measured, standard laboratory testing for vitamin D status may not be useful for predicting who in the general population is likely to benefit from vitamin D supplementation.
In previous studies, 800 IU per day of vitamin D slowed the rate of bone loss, whereas 400 IU per day was ineffective. In a 2019 study that I reviewed in the February/March 2020 issue of the Townsend Letter, bone loss was significantly greater in participants who received 4,000 IU per day of vitamin D than in those who received 400 IU per day.2 When considered together, these findings suggest that there is a “therapeutic window” with respect to vitamin D and bone health, such that vitamin D is less effective when the dose is either too low or too high. Based on the available evidence, I have suggested that the optimal vitamin D dosage range for preventing bone loss may be 800-1,200 IU per day. If that is true, the unimpressive results seen in the present study might be explained by the use of an excessive dose of vitamin D.
LeBoff MS, et al. Effects of supplemental vitamin D on bone health outcomes in women and men in the VITamin D and OmegA-3 TriaL (VITAL). J Bone Miner Res. 2020;35:883-893.
Update on Suspected Iranian Research Fraud
I have written several times in the Townsend Letter over the past few years about the large number of nutrition studies coming from Iran and other countries that appear to be fraudulent. Of particular concern has been the work of Zatollah Asemi, an Iranian researcher who has published more than 170 randomized controlled trials over a period of about six years. As I reviewed Asemi’s papers, I became increasingly skeptical about how outrageously prolific he was, and about the large number of highly implausible aspects of his research. In March 2018, I contacted a researcher in New Zealand who had a history of exposing fraudulent research. I informed him about Asemi, and he agreed that Asemi’s papers had many of the hallmarks of fabricated research. The New Zealand research team was able to obtain a grant to investigate Asemi’s studies. With a small amount of my input, a 115-page report was created in July 2019, which outlined hundreds of major problems in Asemi’s body of 172 randomized controlled trials.
This report was sent to the editors of all 65 journals in which Asemi’s papers had been published, as well as to the companies that published the journals (such as Elsevier and Wiley). These efforts had very little effect for more than a year, but in October 2020 a few journals began to notify their readers of an “expression of concern” regarding some of Asemi’s papers. An expression of concern is typically an interim step before further investigation leads to a retraction of the paper by the journal editors. As of November 12, 2020, an expression of concern had been posted for eight papers. Around the same time, Retraction Watch, a website that keeps a record of retracted studies, reported that more than three dozen of Asemi’s papers had been flagged because of concerns about the integrity of the data.3
Over the past few years, I have spent several hundred hours analyzing apparently fraudulent research and trying to blow the whistle on the perpetrators. Sometimes I get annoyed that I have to waste so much time trying to protect the medical literature from people who appear to be “challenged” in the conscience department. But I have to admit: it can also be a lot of fun pretending to be Sherlock Holmes.
References
1. Cammarota G, et al. Biofilm demolition and antibiotic treatment to eradicate resistant Helicobacter pylori: a clinical trial. Clin Gastroenterol Hepatol. 2010;8:817-820.e3.
2. 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.
3. No author listed. Journals flag concerns in three dozen papers by nutrition researchers. Retraction Watch: https://retractionwatch.com/2020/11/10/journals-flag-concerns-in-three-dozen-papers-by-nutrition-researchers. Accessed November 11, 2020.
This column was originally published in Townsend Letter, February 2021.
About the Author
Alan R. Gaby, MD, received his undergraduate degree from Yale University, his M.S. in biochemistry from Emory University, and his M.D. from the University of Maryland. He was in private practice for 19 years, specializing in nutritional medicine. Over the past 36 years, Dr. Gaby has developed a computerized database of more than 28,000 individually chosen medical journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, Washington, from 1995 to 2002.
He is past president of the American Holistic Medical Association who has given expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), The Doctor’s Guide to Vitamin B6 (Rodale Press, 1984), the co-author of The Patient’s Book of Natural Healing (Prima, 1999).
He is Chief Science Editor for Aisle 7 (formerly Healthnotes, Inc.) and has appeared on the CBS Evening News and the Donahue Show. In 2010, Dr. Gaby completed a 30-year project: the textbook Nutritional Medicine. Over the past six years, he has worked on completing the updated second edition of Nutritional Medicine.