Response to Letter to the Editor from Dalan: "Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D?"

We thank Rinkoo Dalan for the comments on our paper (1, 2). We agree that although the reduction in diabetes risk with vitamin D supplementation among people at high risk for diabetes appears to be moderate (~ 12% relative risk reduction compared to placebo) (3), certain individuals may derive a higher (or lower) benefit based on certain characteristics. For example, in the simplest demonstration of such heterogeneity, vitamin D supplementation reduced diabetes risk by 62% among participants in the Vitamin D and Type 2 Diabetes (D2d) study who had a baseline serum 25-hydroxyvitamin D (25[OH]D) level of less than 12 ng/mL (30 mmol/L) (2). Consistent with the focus of the scientific community on precision nutrition, we agree that we need to better understand responsiveness to vitamin D supplementation for specific outcomes of interest. The vitamin D response index is an interesting concept that reflects activation of the vitamin D receptor, and it is determined on the basis of measuring vitamin D–triggered changes in the expression of 24 target genes in peripheral blood mononuclear cells and 12 clinical and biochemical parameters (4). There are at least 2 limitations: 1) Although such an index may reflect vitamin D–induced changes in specific response parameters, these changes may not necessarily translate to clinically meaningful outcomes, such as lowering diabetes risk. 2) Low-, mid-, and high-responders are determined with statistical means within a specific cohort but that can be calculated only retrospectively; specific cutoffs to define degree of response need to be established for use in real time in research or in the clinical setting. The author also suggests that daily, steady exposure to vitamin D is preferred over intermittent exposure for optimal benefit, and we agree. In a secondary analysis from the D2d study, we reported that participants who received the active intervention (100 mcg [4000 units] of vitamin D3 daily) and maintained high 25(OH)D levels that were stable throughout the trial period had the lowest risk of diabetes, whereas participants in the placebo group who maintained similar overall 25(OH)D levels that fluctuated during follow-up did not derive significant benefit (5)

Plasma 25-Hydroxyvitamin D and Progression to Diabetes in Patients at Risk for Diabetes

OBJECTIVE To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes. RESEARCH DESIGN AND METHODS Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying “lagged” covariates, as the mean of the previous and current visits at which diabetes status was assessed. RESULTS After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56–0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52–0.94) versus lifestyle arm (0.80; 0.54–1.17). CONCLUSIONS Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies

Interstate Variation in the Burden of Fragility Fractures

Demographic differences may produce interstate variation in the burden of osteoporosis. We estimated the burden of fragility fractures by race/ethnicity, age, sex, and service site across five diverse and populous states. State inpatient databases for 2000 were used to describe hospital fracture admissions, and a Markov decision model was used to estimate annual fracture incidence and cost for populations ≥50 yr of age for 2005–2025 in Arizona (AZ), California (CA), Florida (FL), Massachusetts (MA), and New York (NY). In 2000, mean hospital charges for incident fractures varied 1.7-fold across states. For hip fracture, mean charges ranged from $16,700 (MA) to$29,500 (CA), length of stay from 5.3 (AZ) to 8.9 days (NY), and discharge rate to long-term care from 43% (NY) to 71% (CA). In 2005, projected fracture incidence rates ranged from 199 (CA) to 266 (MA) per 10,000. Total cost ranged from $270 million (AZ) to$1,434 million (CA). Men accounted for 26–30% of costs. Across states, hip fractures constituted on average 77% of costs; “other” fractures (e.g., leg, arm), 10%; pelvic, 6%; vertebral, 5%; and wrist, 2%. By 2025, Hispanics are projected to represent 20% of fractures in AZ and CA and Asian/Other populations to represent 27% of fractures in NY. In conclusion, state initiatives to prevent fractures should include nonwhite populations and men, as well as white women, and should address fractures at all skeletal sites. Interstate variation in service utilization merits further evaluation to determine efficient and effective disease management strategies

Effect of body composition methodology on heritability estimation of body fatness

Heritability estimates of human body fatness vary widely and the contribution of body composition methodology to this variability is unknown. The effect of body composition methodology on estimations of genetic and environmental contributions to body fatness variation was examined in 78 adult male and female monozygotic twin pairs reared apart or together. Body composition was assessed by six methods - body mass index (BMI), dual energy x-ray absorptiometry (DXA), underwater weighing (UWW), total body water (TBW), bioelectric impedance (BIA), and skinfold thickness. Body fatness was expressed as percent body fat, fat mass, and fat mass/height2 to assess the effect of body fatness expression on heritability estimates. Model-fitting multivariate analyses were used to assess the genetic and environmental components of variance. Mean BMI was 24.5 kg/m2 (range of 17.8-43.4 kg/m2). There was a significant effect of body composition methodology (p<0.001) on heritability estimates, with UWW giving the highest estimate (69%) and BIA giving the lowest estimate (47%) for fat mass/height2. Expression of body fatness as percent body fat resulted in significantly higher heritability estimates (on average 10.3% higher) compared to expression as fat mass/height2 (p=0.015). DXA and TBW methods expressing body fatness as fat mass/height2 gave the least biased heritability assessments, based on the small contribution of specific genetic factors to their genetic variance. A model combining DXA and TBW methods resulted in a relatively low FM/ht2 heritability estimate of 60%, and significant contributions of common and unique environmental factors (22% and 18%, respectively). The body fatness heritability estimate of 60% indicates a smaller contribution of genetic variance to total variance than many previous studies using less powerful research designs have indicated. The results also highlight the importance of environmental factors and possibly genotype by environmental interactions in the etiology of weight gain and the obesity epidemic.R01 AR046124 - NIAMS NIH HHS; R01 MH065322 - NIMH NIH HHS; T32 HL069772 - NHLBI NIH HHS; R21 DK078867 - NIDDK NIH HHS; R37 DA018673 - NIDA NIH HHS; R01 DK076092 - NIDDK NIH HHS; R01 DK079003 - NIDDK NIH HHS; F32 DK009747 - NIDDK NIH HHS; R01 DA018673 - NIDA NIH HH

Intervention thresholds and diagnostic thresholds in the management of osteoporosis.

peer reviewe

The need to distinguish intervention thresholds and diagnostic thresholds in the management of osteoporosis.

peer reviewedThis position paper of the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) addresses the rationale for separate diagnostic and intervention thresholds in osteoporosis. We conclude that the current BMD-based diagnostic criteria for osteoporosis be retained whilst clarity is brought to bear on the distinction between diagnostic and intervention thresholds

Combined vitamin D, omega-3 fatty acids, and a simple home exercise program may reduce cancer risk among active adults aged 70 and older : A randomized clinical trial

Objective: The aim of this study was to test the individual and combined benefit of vitamin D, omega-3, and a simple home strength exercise program on the risk of any invasive cancer. Design: The DO-HEALTH trial is a three-year, multicenter, 2 × 2 × 2 factorial design double-blind, randomized-controlled trial to test the individual and combined benefit of three public health interventions. Setting: The trial was conducted between December 2012 and December 2017 in five European countries. Participants: Generally healthy community-dwelling adults ≥70 years were recruited. Interventions: Supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. Main outcome: In this pre-defined exploratory analysis, time-to-development of any verified invasive cancer was the primary outcome in an adjusted, intent-to-treat analysis. Results: In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized. Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs, 95% CI, cases intervention versus control) were 0.76 (0.49–1.18; 36 vs. 45) for vitamin D3, 0.70 (0.44–1.09, 32 vs. 49) for omega-3s, and 0.74 (0.48–1.15, 35 vs. 46) for SHEP. For combinations of two treatments, adjusted HRs were 0.53 (0.28–1.00; 15 vs. 28 cases) for omega-3s plus vitamin D3; 0.56 (0.30–1.04; 11 vs. 21) for vitamin D3 plus SHEP; and 0.52 (0.28–0.97; 12 vs. 26 cases) for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39 (0.18–0.85; 4 vs. 12 cases). Conclusion: Supplementation with daily high-dose vitamin D3 plus omega-3s, combined with SHEP, showed cumulative reduction in the cancer risk in generally healthy and active and largely vitamin D–replete adults ≥70 years. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT01745263

The authors reply: Letter on: 'Pitfalls in the measurement of muscle mass: a need for a reference standard' by Clark et al.

However, semantics aside, we think that DXA can indeed serve as a reference standard for measuring muscle mass. Obviously, CT and MRI are advanced techniques that can and have been used to obtain important information such as muscle size/volume and more recently amount and distribution of intra- and intermuscular adipose tissue. Also individual muscles can be assessed separately. However, with respect to muscle mass, the comparison of DXA with CT/MRI is rather difficult because DXA and QCT/MRI measure different physical parameters

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.