Literature Review and Commentary

by Alan R. Gaby, MD

Folic Acid, Vitamin B12, and Osteoporosis

In the B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study, 2919 individuals aged 65 years or older (mean age, 74 years) living in the Netherlands who had an elevated homocysteine level (12–50 µmol/L) were randomly assigned to receive daily, in double-blind fashion, 400 µg of folic acid and 500 µg of vitamin B12 or placebo for 2 years. Both groups received 600 IU per day of vitamin D. The incidence of osteoporotic fractures was 4.2% in the vitamin group and 5.1% in the placebo group. Compared with placebo, B vitamins decreased osteoporotic fracture risk nonsignificantly by 16% in intent-to-treat analysis and by 19% among those who completed the trial. In pre-specified subgroup analysis of individuals over age 80 who completed the trial, active treatment significantly decreased osteoporotic fracture risk by 70% (p < 0.02).

Comment

: Individuals with the rare genetic disease, homocystinuria, have markedly elevated plasma homocysteine levels and develop osteoporosis at an early age. Homocysteine has been shown to interfere with collagen cross-linking, which is important for the stability and strength of connective tissue. Hyperhomocysteinemia might therefore decrease the integrity of the protein matrix of bone, thereby causing bones to become fragile. In a recent editorial in the Townsend Letter, I mentioned a study in which folic acid and vitamin B12 supplementation decreased the incidence of hip fractures by 78% in patients with a history of a stroke and high homocysteine levels. However, recently expressed concerns about possible scientific misconduct have cast doubt on the reliability of that study (Bauchner H, Fontanarosa PB. Expression of Concern: Sato et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA. 2005;293:1082—1088. JAMA. 2015;313:1914.). In a 2013 double-blind trial, patients with a recent stroke and a high prevalence of hyperhomocysteinemia received daily B vitamins (2 mg of folic acid, 25 mg of vitamin B6, and 500 µg of vitamin B12) or placebo. After a median of 2.8 years of treatment and 3.4 years of follow-up, the incidence of any osteoporotic fracture was nonsignificantly lower by 14% and the incidence of hip fracture was nonsignificantly lower by 6% in the vitamin group than in the placebo group. The results of the new study described above are similar to the findings from the 2013 study, and suggest that the effect of homocysteine-lowering on fracture risk is modest at best. However, the new study did identify a subset of participants (those over 80 who adhered to the program) that may benefit substantially from this treatment. The reduction of fracture risk in these elderly individuals appeared to be due to an improvement in bone quality, rather than an effect on bone mineral density.

Van Wijngaarden JP et al. Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Am J Clin Nutr. 2014;100:1578–1586.

Ubiquinol and Parkinson’s Disease

Thirty-one patients with Parkinson’s disease who were experiencing the “on-off” phenomenon while receiving levodopa (Group 1), and 33 other patients with Parkinson’s disease who were not being treated with levodopa (Group 2) were randomly assigned to receive, in double-blind fashion, 300 mg per day of ubiquinol (the reduced form of coenzyme Q10) or placebo for 48 weeks (Group 1) or 96 weeks (Group 2). Among the patients in Group 1, treatment with ubiquinol resulted in an improvement in mean symptom severity, as determined by the Unified Parkinson’s Disease Rating Scale (p < 0.05 compared with the change in the placebo group). Among the patients in Group 2, symptoms worsened in both groups, with no significant difference between groups.

Comment

: With prolonged use of levodopa, disabling side effects such as random daily motor fluctuations (known as the “on-off” phenomenon) and random drug-resistant “off” periods occur in a large proportion of patients with Parkinson’s disease. These abnormalities are thought to be due to erratic delivery of levodopa to the brain, which may result from the fact that large neutral amino acids (phenylalanine, tyrosine, methionine, leucine, isoleucine, valine, and tryptophan) compete with levodopa for intestinal absorption and for transport across the blood-brain barrier. One group of investigators found that, if protein intake at breakfast and lunch was severely restricted (i.e., a total of no more than 7 g of protein until the evening meal), then daytime plasma concentrations of large neutral amino acids remained relatively low, and the “on-off” phenomenon was eliminated in many patients. Although symptoms typically returned after the high-protein evening meal, many patients were able to function almost normally during the day.

Preliminary research suggested that coenzyme Q10 can improve symptoms in patients with Parkinson’s disease, but several large follow-up studies concluded that coenzyme Q10 was of little or no value. The new study suggests that ubiquinol (and, presumably, coenzyme Q10 as well) can improve symptoms in a subset of patients: those experiencing the difficult-to-treat “on-off” phenomenon. It is possible that treatment with ubiquinol or coenzyme Q10 would also allow these patients to liberalize their very restricted diet.

Yoritaka A et al. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:911–916.

Azelaic Acid for Acne

Fifty-five women (aged 18–45 years) with adult acne were randomly assigned to receive topical 15% azelaic acid gel twice a day or 0.1% adapalene gel once a day for 9 months. Both groups improved significantly. The improvement in lesion counts, acne severity, and Dermatology Life Quality Index score were comparable between groups, whereas dryness and scaling were significantly less (p < 0.05) with azelaic acid than with adapalene.

Comment

: Azelaic acid is a 9-carbon straight-chain dicarboxylic acid that occurs naturally in some foods. It has both antibacterial and anti-inflammatory effects. In clinical trials that included patients with mild-to-moderate acne, topical application of azelaic acid (usually as a 20% cream) was significantly more effective than placebo and of comparable efficacy to other topical treatments (i.e., 0.05% tretinoin, 5% benzoyl peroxide, and 2% erythromycin). In the present study, azelaic acid was at least as effective as adapalene, another commonly used treatment for acne.

Thielitz A et al. A randomized investigator-blind parallel-group study to assess efficacy and safety of azelaic acid 15% gel vs. adapalene 0.1% gel in the treatment and maintenance treatment of female adult acne. J Eur Acad Dermatol Venereol. 2015;29:789–796.

Iron Deficiency in Patients with Coronary Artery Disease

Bone marrow aspirates were obtained from the sternum in 65 patients with stable coronary artery disease during cardiac surgery, and from the iliac crest of 10 healthy controls. Bone marrow iron deficiency was found in 48% of the patients and in none of the controls (p < 0.01). Among the patients, iron deficiency was present in 10 of 16 (63%) with and 21 of 49 (43%) without anemia. Serum soluble transferrin receptor had the strongest association with bone marrow iron deficiency. Using the most accurate cut-off level of 1.32 mg/L or higher, the sensitivity was 67% and the specificity was 97%. For serum ferritin, using the most accurate cut-off level of 112 µg/L or lower, the sensitivity was 52% and the specificity was 79%. For transferrin saturation, using the most accurate cut-off level of 31.6% or lower, the sensitivity was 55% and the specificity was 90%.

Comment

: The results of this study indicate that almost half of patients with stable coronary artery disease are deficient in iron. In addition to being a component of oxygen-carrying hemoglobin, iron is a cofactor for cytochrome oxidase, which is essential for mitochondrial energy production through its role in the electron-transport chain. Thus, iron deficiency might aggravate ischemic heart disease by 2 different mechanisms. Iron deficiency, with or without anemia, is a risk factor for poor outcomes in patients with congestive heart failure. Whether it is also associated with poor outcomes in patients with coronary artery disease has not been well studied. Nevertheless, it would seem like a good idea to test for iron deficiency in these patients, and to supplement with iron when appropriate. The results of the present study suggest that the most reliable noninvasive test for identifying iron deficiency in patients with coronary artery disease is serum soluble transferrin receptor.

Jankowska EA et al. Bone marrow iron depletion is common in patients with coronary artery disease. Int J Cardiol. 2015;182:517–522.

Probiotic for Periodontal Disease

Thirty patients with chronic periodontitis and moderately deep pockets were treated with scaling and root planing and were randomly assigned to receive, in double-blind fashion, probiotic lozenges twice a day (morning and evening after toothbrushing) or placebo lozenges for 3 weeks. The probiotic lozenges (Prodentis; BioGaia, Lund, Sweden) contained at least 10⁸ colony-forming units each of Lactobacillus reuteri strains DSM17938 and ATCC PTA 5289 (this information was not mentioned in the study, but came from a personal communication with one of the authors). Evaluations were performed at baseline and on days 21, 90, 180, and 360. Compared with placebo, probiotic treatment resulted in significant improvements in plaque index, gingival index, bleeding on probing, probing depth, and attachment gain at every time point. Biochemical studies on gingival crevicular fluid revealed a reduction in inflammatory markers in the probiotic group.

Comment

: This study demonstrates that the use of lozenges containing L. reuteri was beneficial as an adjunct to scaling and root planing in patients with chronic periodontitis and moderately deep pockets. The beneficial effect of the probiotic lozenges persisted long after the treatment was discontinued. Although the mechanism of action is not certain, it may be related to an alteration of the oral bacterial flora.

Ince G et al. Clinical and biochemical evaluation of lozenges containing Lactobacillus reuteri as an adjunct to non-surgical periodontal therapy in chronic periodontitis. J Periodontol. 2015;86:746–754.

Curcumin for Ulcerative Colitis

Fifty patients with mild-to-moderate ulcerative colitis that had failed to respond sufficiently to mesalamine were randomly assigned to receive, in double-blind fashion, 3 g per day of curcumin (in 2 divided doses per day before meals) or placebo for 1 month, while continuing mesalamine. In intent-to-treat analysis, the proportion of patients who achieved clinical remission (defined as a score of 2 or lower on the Simple Clinical Colitis Activity Index [SCCAI]) was significantly higher in the curcumin group than in the placebo group (53.8% vs. 0%; p = 0.01). The proportion of patients who had a clinical response (defined as a reduction of at least 3 points in the SCCAI score) was also significantly higher in the curcumin group than in the placebo group (65.3% vs. 12.5%; p < 0.001). Endoscopic remission was seen in 38% of the patients in the curcumin group and 0% of those in the placebo group (p < 0.05). No significant side effects were seen.

Comment

: Curcumin, a compound present in turmeric, has anti-inflammatory activity. In a previous study, administration of curcumin reduced the recurrence rate in patients with ulcerative colitis in remission. The results of the present study indicate that the addition of curcumin to mesalamine therapy was effective for inducing clinical and endoscopic remission in patients with mild-to-moderate active ulcerative colitis that had failed to respond to mesalamine alone.

Lang A et al. Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol. 2015;13:1444–1449.e1.

Sugar-Sweetened Beverages and Fatty Liver

The association between intake of sugar-sweetened beverages or diet soda and fatty liver disease was examined in a cross-sectional study of 2,634 participants in the Framingham Offspring and Third Generation cohorts. After adjustment for age, sex, smoking status, energy intake, body mass index, and other potential confounding variables, the odds ratios for fatty liver disease were 1, 1.16 (95% confidence interval [CI], 0.88–1.54), 1.32 (95% CI, 0.93–1.86), and 1.61 (95% CI, 1.04–2.49) across sugar-sweetened beverage consumption categories (p for trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine aminotransferase levels (p for trend < 0.01). There was no association between consumption of diet soda and fatty liver disease.

Comment

: In this study, increasing consumption of sugar-sweetened beverages was associated with an increased risk of fatty liver disease. Although observational studies cannot prove causation, the results are consistent with intervention studies in both animals and humans, in which high intake of fructose increased the amount of fat in the liver. In the present study, the results were adjusted for total energy intake and body mass index, which suggests that sugar-sweetened drinks cause harm by mechanisms that are at least in part unrelated to their high calorie content.

Ma J et al. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. J Hepatol. 2015;63:462–469.

Bad News About Bisphenol a Substitutes

A review of 32 studies (25 in vitro and 7 in vivo) revealed that bisphenol S and bisphenol F have endocrine-disrupting effects similar to those of bisphenol A.

Comment

: Because of concerns that bisphenol A is an endocrine disrupter, this chemical has been removed from some consumer products. These products, which are often labeled “BPA-free,” may contain other bisphenols, such as bisphenol S and bisphenol F. However, the evidence indicates that these other bisphenols may not be any safer than bisphenol A.

Rochester JR, Bolden AL. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environ Health Perspect. 2015;123:643–650.