Faculty Bibliography

Recent understanding has highlighted the importance of extraskeletal role of vitamin D. Despite numerous observational and interventional studies over the last two decades, the apparent divergent clinical findings have intensified the controversy regarding this role of vitamin D in older adults. This article reviews the existing literature and summarizes the current knowledge of vitamin D status and vitamin D supplementation on falls and physical performance, describes the putative mechanisms underlying this association, and reflects on the controversy surrounding vitamin D recommendations in older adults.

OBJECTIVE: This study examined the association of 25-hydroxyvitamin D [25(OH)D] levels and blood pressure above and below 25(OH)D levels of 20 ng/ml in young adults with African ancestry. METHODS: This cross-sectional analysis utilized data from a pooled sample of 2242 adults with African ancestry from five different latitudes (403 in the United States, 474 in South Africa, 479 in Ghana, 448 in Jamaica, and 438 in Seychelles). Piecewise linear regression models with a single knot were fitted to determine above and below a 25(OH)D level of 20 ng/ml the slope of SBP and DBP while adjusting for covariates including calcium intake and site. RESULTS: The mean age was 34.4 (6.1) years, and 46.3% were men. Mean SBP and DBP were 118.1 (15.6) and 73.2 (12.2) mmHg, respectively, and were significantly higher among the United States vs Ghana, Jamaica, and Seychelles groups (P < 0.001 for all comparisons). 25(OH)D levels were significantly lower in the United States vs all other sites (P < 0.001 for all comparisons). When 25(OH)D levels were less than 20 ng/ml, slopes of SBP [-0.33 (95% confidence interval (CI) -0.57, -0.07)] and DBP [-0.21 (95% CI -0.40, -0.02)] were negative and significantly different from zero after adjustment for covariates. In contrast, with 25(OH)D levels above 20 ng/ml, the slopes of SBP [-0.03 (95% CI -0.13, 0.06)] and DBP [-0.04 (-0.11, 0.03)] did not differ significantly from zero. CONCLUSION: The cross-sectional association of 25(OH)D with blood pressure is strongest when 25(OH)D levels are less than 20 ng/ml in young adults with African ancestry.

CONTEXT: The vitamin D metabolite ratio (VMR) (serum 24,25(OH)2 D3 /25(OH)D3 ) has been proposed as a biomarker of vitamin D sufficiency to replace serum 25(OH)D. OBJECTIVE: To examine the relationships of 24,25(OH)2 D3 and VMR to functional biomarkers of bone health following vitamin D supplementation. SETTING: An ambulatory research centre. DESIGN: Serum from a previous research study of dose response of PTH, calcium absorption and bone turnover to vitamin D supplementation was analysed for vitamin D metabolites (25(OH)D, 24,25(OH)2 D3 ). OUTCOME: The relationship of serum 24,25(OH)2 D3 and VMR to calcium absorption, PTH and bone turnover markers was examined. RESULTS: Although there were strong correlations of serum 25(OH)D with 24,25(OH)2 D3 and free 25(OH)D, its correlation with VMR was lower. After vitamin D supplementation, the change in 25(OH)D, 24,25(OH)2 D3 and VMR was associated with the change in calcium absorption, PTH and CTX. The correlation of the change in PTH with the change in metabolites was the lowest for VMR. Moreover, estimated dose response for standardized values of vitamin D metabolites showed a beta-coefficient for VMR that was significantly less in magnitude compared to other metabolites. CONCLUSION: Serum 24,25(OH)2 D3 is closely associated with the dose response of serum 25(OH)D to vitamin D supplementation. However, the VMR does not appear to be equivalent to either of these metabolites in its response to increasing vitamin D intake or its association with PTH. It is unlikely that VMR will replace 25(OH)D as a biomarker for vitamin D sufficiency.

In the United States, there is a significant disparity in vitamin D status among individuals of African versus European descent. Despite having lower total 25-hydroxyvitamin D levels compared with white Americans, African Americans have higher bone mineral density and lower fracture risk. This article reviews classical and nonclassical vitamin D physiology, describes whether total versus free 25-hydroxyvitamin D is a better marker of vitamin D status in African Americans, and summarizes the influence of vitamin D status and vitamin D supplementation on markers of vitamin D bioactivity (intestinal calcium absorption, parathyroid hormone secretion, bone mineral density, fracture) in African Americans.

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels >/=25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

OBJECTIVE: To compare levels of 25-hydroxyvitamin D (25[OH]D) associated with a plateauing of intact parathyroid (iPTH) across latitudes among adults with African ancestry. METHODS: This study included approximately 500 adults of African ancestry ages 25 to 45 years living in 4 sites: Chicago, Illinois (41 degrees N), Jamaica (17 degrees N), Ghana (6 degrees N), and South Africa (34 degrees S). Multivariate linear regression models, a nonlinear logistic growth curve model, and piecewise linear models with a single knot were fitted to estimate the 25[OH]D level associated with a plateauing of iPTH with adjustment for covariates. Goodness of fit was compared using computer intensive permutation tests. RESULTS: Mean age was 34.7 (SD 6.2) years, and 46.5% were male. Within each site, the percentage of participants with an iPTH level >/=65 pg/mL was higher among females versus males and was most frequent among South African females (17.1%) and lowest among Jamaican males (0.6%). Goodness of fit tests supported linear regression as the preferred model for the association between iPTH and 25[OH]D in the 4 sites with no 25[OH]D level associated with iPTH plateauing in any site. The slope of the association between 25[OH]D and iPTH differed by latitude; it was strongest in the U.S. (beta = -0.81; 95% confidence interval [CI] = -1.03, -0.59), and weakest in Jamaica (beta = -0.45; 95% CI -0.71, -0.18) with covariate adjustment, but differences in slopes were small. CONCLUSION: The association between 25[OH]D and iPTH appears linear among adults with African ancestry regardless of latitude within a range of 25[OH]D levels between 10 and 60 ng/mL. ABBREVIATIONS: BMI = body mass index CI = confidence interval eGFR = estimated glomerular filtration rate iPTH = intact parathryoid hormone 25[OH]D = 25-hydroxyvitamin D.

There is considerable consumer and physician interest in vitamin D as a possible therapeutic agent for a range of clinical conditions and, despite mixed evidence, the interest does not appear to lessen. Some clinicians believe that consumption of vitamin D is inadequate and, in turn, advocate vitamin D supplementation to increase serum levels of the nutrient. However, evidence concerning the role of vitamin D in health and disease is conflicting, and primary care physicians have little time to sort through the data and may find it difficult to advise their patients. To better understand the challenges that primary care physicians face regarding vitamin D, and to help inform those who provide guidance for clinical decision-making, the Office of Dietary Supplements at the National Institutes of Health, with co-sponsorship from other federal health agencies, held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in Primary Care in December 2014. More than 20 invited presenters and panelists considered laboratory methods for measuring vitamin D status, discussed how clinical studies of vitamin D should be evaluated and used in developing recommendations, noted the role of values and preferences in clinical decision-making, debated the current science related to at-risk groups, and described emerging data about health risks of excessive intakes of vitamin D. Eight questions about vitamin D stem from the Conference presentations as well as other expert sources.

CONTEXT: It has been proposed that serum free 25-hydroxyvitamin D [25(OH)D] may better reflect vitamin D action than total 25(OH)D. An ELISA for serum free 25(OH)D has recently become available, permitting direct assay. OBJECTIVE: To determine whether serum free 25(OH)D provides additional information in relation to calcium absorption and other biomarkers of vitamin D action compared to total serum 25(OH)D. SETTING: Ambulatory research setting in a teaching hospital. OUTCOME: Serum free 25(OH)D measured in a previously performed study of varied doses of vitamin D3 (placebo and 800, 2000, and 4000 IU) on calcium absorption, PTH, procollagen type 1 N-terminal propeptide, and C-terminal telopeptides of type I collagen. Free 25(OH)D was measured by ELISA. Calcium absorption was measured at baseline and at 10 weeks using stable dual calcium isotopes. RESULTS: Seventy-one subjects completed this randomized, placebo-controlled trial. Baseline group mean free and total 25(OH)D varied from 4.7 +/- 1.8 to 5.4 +/- 1.5 pg/mL, and from 23.7 +/- 5.9 to 25.9 +/- 6.1 ng/mL, respectively. Participants assigned to the 4000-IU dose arm achieved free 25(OH)D levels of 10.4 pg/mL and total 25(OH)D levels of 40.4 ng/mL. Total and free 25(OH)D were highly correlated at baseline and after increasing vitamin D dosing (r = 0.80 and 0.85, respectively). Free 25(OH)D closely reflected changes in total 25(OH)D. PTH was similarly correlated at baseline and follow-up with total and free 25(OH)D. Serum C-terminal telopeptides of type I collagen had a moderate positive correlation with total and free 25(OH)D at follow-up. The serum 1,25-dihydroxyvitamin D change increased significantly with the change in 25(OH)D but not with the change in free 25(OH)D. CONCLUSION: There was no advantage from measuring free over total 25(OH)D in assessing the response of calcium absorption, PTH, and markers of bone turnover to vitamin D. Free 25(OH)D responded to increasing doses of vitamin D in a similar fashion to total 25(OH)D.

CONTEXT: African Americans have a lower total serum 25-hydroxyvitamin D [25(OH)D] but superior bone health. This has been referred to as a paradox. A recent publication found that free serum 25(OH)D is the same in black and white individuals. However, the study was criticized because an indirect method was used to measure free 25(OH)D. A direct method has recently been developed. OBJECTIVE: We hypothesized that although total serum 25(OH)D is lower in African Americans, free serum 25(OH)D measured directly would not differ between races. DESIGN: White and black healthy postmenopausal women were matched for age and body mass index. Serum total 25(OH)D, PTH, 1,25-dihydroxyvitamin D, vitamin D binding protein (VDBP), and bone density were measured. Measurement of free 25(OH)D was carried out using an ELISA. SETTING: The study was conducted at an ambulatory research unit in a teaching hospital. OUTCOME: A cross-racial comparison of serum free 25(OH)D was performed. RESULTS: A propensity match resulted in the selection of a total of 164 women. Total 25(OH)D was lower in black women (19.5 +/- 4.7 vs 26.9 +/- 6.4 ng/mL), but a direct measurement of free 25(OH)D revealed almost identical values (5.25 +/- 1.2 vs 5.25 +/- 1.3 ng/mL) between races. VDBP was significantly lower in blacks when using a monoclonal-based ELISA but higher with a polyclonal-based ELISA. Serum PTH, 1,25-dihydroxyvitamin D, and bone density were higher in African Americans. CONCLUSIONS: Free serum 25(OH)D is the same across races despite the lower total serum 25(OH)D in black women. Results comparing VDBP between races using a monoclonal vs a polyclonal assay were discordant.