Vitamin D insufficiency and disease risk in the elderly.

Vitamin D insufficiency, milder than deficiency, is common, and a risk of various diseases. Since vitamin D exert diverse actions, both skeletal and non-skeletal, its insufficiency is a risk of various diseases including osteoporosis, sarcopenia, cardiovascular disease, cancer, and even mortality. Regarding the association of vitamin D status and disease risk, a marked discrepancy exists between the results from the observational studies and intervention studies, mostly yielding the positive and negative results in the former and latter, respectively. Such inconsistency probably arises from methodological problems, of which the baseline vitamin D status would be the most important. Vitamin D intervention would be effective in the deficient/insufficient subjects, but not in sufficient subjects. Since the elderly subjects, especially the institutionalized people, are mostly vitamin D deficient/insufficient, they are likely to benefit from improvement of vitamin D status. Vitamin insufficiency is a risk of various diseases, and correcting the vitamin status alone would reduce the risk of many diseases, and favorable to avoid the undesirable consequences of polypharmacy in the elderly. Additionally, disease prevention by nutritional improvement is cheap and free from side effects, and suited for the primary prevention of diseases.

Vitamin K intake and health, consideration from the epidemiological studies.

The most fundamental function of vitamin K is to activate the blood coagulation factors in the liver. Despite the recent recognition of its extra-hepatic actions, the current Dietary Reference Intakes for vitamin K is based on the amount necessary for maintaining the normal blood coagulation in many countries. To define the Dietary Reference Intake for vitamin K, appropriate biomarkers well-reflecting the vitamin K status are essential. Unfortunately, however, no markers are currently available with properties enabling us to properly define the vitamin K status; i.g., no interference by other factors and the presence of widely approved cut-off values. Thus, Adequate Intake is determined, which is an index based on the representative dietary intake data from healthy individuals. Recently, epidemiological studies have been reported regarding the relationship between vitamin K and noncommunicable diseases including osteoporotic fracture. Furthermore, studies focusing on the relationship between vitamin K intake and metabolic syndrome, physical function, depression, cognition, and all-cause mortality have become available, although limited in number. This review summarizes the recent findings in favor of the novel functions of vitamin K. More epidemiological studies are needed to define the appropriate vitamin K intake value based on the prevention of various disorders.

Insufficiency of B vitamins with its possible clinical implications.

Vitamin deficiency causes classical deficiency diseases such as beriberi and rickets. Vitamin insufficiency, which is milder than deficiency, is a risk for various chronic diseases, but its significance has not been recognized in Japan. Vitamin D insufficiency is quite common in Japan, and a serious risk for osteoporotic fracture through its unbeneficial effect on bone and muscle. Insufficiency of B vitamins has been little studied. However, hyperhomocysteinemia caused by the insufficiency of vitamin B12 or folate is a risk for cardiovascular disease, osteoporotic fracture, and cognitive impairment. Additionally, we have recently reported that vitamin B1 insufficiency is a risk for heart failure in the elderly. The effect of improvement of nutritional status including vitamins is less marked compared to drug treatment, but it costs far less, and is suited for the primary prevention of diseases. Randomized controlled trial is considered the study with the most robust evidence in the evaluation of drug treatment, but more emphasis should be put on the well-designed cohort studies in evaluating the role of nutrients. Vitamin insufficiency is quite prevalent, and vitamin requirement is much higher for its prevention than for the prevention of deficiency.

A simple questionnaire for the prediction of vitamin D deficiency in Japanese adults (Vitaimn D Deficiency questionnaire for Japanese: VDDQ-J).

Vitamin D deficiency (VDD) is associated with an increased risk of various diseases. Serum 25-hydroxyvitamin D [25(OH)D] concentration is the best marker for vitamin D status and its concentration < 20 ng/mL indicates VDD. However, its measurement is not easily applicable for the evaluation of vitamin D status in the general population because of its cost. Therefore, we aimed to develop a simple questionnaire for easily identifying the risk of VDD. From the total sample (649 healthy subjects aged 19-70 years), 434 and 215 subjects were randomly assigned to the derivation and the validation cohort, respectively. Prediction model for VDD was developed by backward logistic regression analysis. The regression ß coefficients of the significant predictors were transformed into integral numbers and used for the individual score. These individual scores were summed to calculate the total risk score (VDD questionnaire for Japanese score: VDDQ-J score). VDD was present in 54.1% of the total subjects. The model for the prediction of VDD consisted of 7 predictors. Areas under the curve were 0.78 and 0.75 in the data set of internal validation and of the external validation, respectively. The cutoff value was determined to be 31 points (range 0-54) with the sensitivity/specificity and positive predictive value/negative predictive value of 61%/79%, and 81%/57%, respectively. Our VDDQ-J score is easy to answer by the wide range of subjects, and well predicts VDD. This risk score would be useful to identify subjects at risk for VDD both in clinical and epidemiological settings.

Possible involvement of thiamine insufficiency in heart failure in the institutionalized elderly.

Heart failure is a major manifestation of thiamine deficiency; beriberi. Even thiamine insufficiency, milder than deficiency, may be associated with increased heart failure risk. In this cross-sectional study, the relationship between thiamine insufficiency and heart failure was investigated in the Japanese institutionalized elderly from April to November 2017. Fifty-five subjects in four care facilities were evaluated for their whole blood thiamine and plasma brain natriuretic peptide concentrations. Mean whole blood thiamine concentration was 88.7 ± 22.3 nmol/L in men and 92.0 ± 16.5 nmol/L in women, and significantly and negatively correlated with plasma brain natriuretic peptide concentrations (r = -0.378, p = 0.007). In the multiple regression analysis adjusted by age, sex, body mass index, and eGFR, whole blood thiamine concentration was a significant negative contributor (standardized coefficient ß = -0.488, p = 0.001) to plasma brain natriuretic peptide. In the logistic regression analysis adjusted by the same variables, whole blood thiamine concentration significantly contributed to plasma brain natriuretic peptide concentration higher than over 40 pg/ml (OR: 0.898, 95%CI: 0.838-0.962). Whole blood thiamine concentration in subjects with diuretics was significantly lower than those without it (p = 0.023). Thiamine insufficiency was related to increased plasma brain natriuretic peptide concentration and may increase the risk of heart failure.

[The role of gastro-intestinal tract in the calcium absorption].

Calcium is associated with various functions of clinical importance. Its unique distribution;low intracellular and high extracellular concentration, is crucial for the neuro-muscular function. Calcium is also indispensable for the vascular contraction and blood coagulation. Thus, circulating calcium concentration must be strictly maintained within a narrow range, for which parathyroid hormone(PTH), vitamin D, and calcitonin contribute. Food-derived protein-bound calcium must be first released in the acidic condition. Thus, gastric acid is essential for the effective calcium absorption. Intestinal calcium absorption occurs via both active transport and passive transport. For the former, such molecules as transient receptor potential vanilloid type 6(TRPV6), calbindin 9k, and Ca²âº-ATPase contribute. In the adult, calcium absorption rate is approximately 30% under the ordinary condition. Lower calcium intake is associated with increased calcium absorption and decreased urinary excretion. In the Dietary Reference Intakes for Japanese, calcium requirement is determined based on factorial method. Recommended Dietary Allowance(RDA)for calcium ranges from 600-800 mg/day for adult. However, the average calcium intake is far lower than Estimated Average Requirement(EAR). Thus, an effort to increase the calcium intake, rather than considering the detailed calcium absorption rate, is most essential in Japan.

[Bone and Nutrition. The association of vitamin K intake and bone health].

The association of vitamin K with bone mineral density has been reported in some previous cohort studies and intervention studies. In cohort studies, higher vitamin K1 intake was associated with lower fracture incidence. Some intervention studies have described that vitamin K1 and vitamin K2 (menaquinone-4 : MK-4) supplementation were modestly efficacious in preventing fracture, but not in preserving bone mass. Although dietary reference intake (adequate intake : AI) for vitamin K was increased from previous value, current AI was determined as the dose sufficient to maintain normal blood coagulation with little mentioning to bone. Vitamin K intake greater than the current AI would be required for the bone health.

Detective value of historical height loss and current height/knee height ratio for prevalent vertebral fracture in Japanese postmenopausal women.

Vertebral fracture (VFx) is associated with various co-morbidities and increased mortality. In this paper, we have studied the detective value of height loss for VFx using two indices; historical height loss (HHL) which is the difference between the maximal height, and the current height (CH), and CH/knee height (KH) ratio. One-hundred and fifty-one postmenopausal women visiting the outpatient clinic of orthopaedics were studied for their CH, self-reported maximal height, KH, and radiographically diagnosed VFx number(s). VFx was present in 41.1 % of the subjects. Multiple regression analyses revealed that the number of prevalent fractures was a significant predictor of HHL and CH/KH ratio. Receiver operator characteristic curve analysis has shown that for HHL, the area under the curve (AUC) with their 95 %CI in the parentheses was 0.84 (0.77, 0.90), 0.88 (0.83, 0.94), and 0.91 (0.86, 0.96) for ≥ 1, ≥ 2, and ≥ 3 fractures, respectively. For the presence of ≥ 1 VFx, the cut-off value was 4.0 cm (specificity 79 %; sensitivity 79 %). Regarding the CH/KH ratio, AUC was 0.73 (0.65, 0.82), 0.85 (0.78, 0.93), and 0.91 (0.86, 0.96) for ≥ 1, ≥ 2, and ≥ 3 fractures, respectively. For the presence of ≥ 1 VFx, the cut-off value was 3.3 (specificity 47 %; sensitivity 91 %). Both cut-off values for HHL and CH/KH ratio had high negative predictivity across the wide range of theoretical VFx prevalence. Thus, HHL and CH/KH were both good detectors of VFx. Our data would be the basis to determine the cut-off value for the screening or case finding of subjects with VFx.

The Association between Atherosclerotic Disease Risk Factors and Serum 25-Hydroxyvitamin D Concentration in Japanese Subjects.

Recent studies have described that vitamin D deficiency/insufficiency is associated with hypertension, insulin resistance, and dyslipidemia, which are major components of metabolic syndrome causing atherosclerosis. Therefore, we investigated the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentration and atherosclerotic disease risk factors in healthy Japanese adults. In the present cross-sectional study, 1,177 subjects (348 males and 829 females) aged 20-72 y living in Japan (34.7-35.0ºN) were evaluated for vitamin D status by measuring serum 25(OH)D concentration. Atherosclerotic disease risk factors were defined as the presence of two or more of the following three risk factors: high blood pressure, dyslipidemia, and hyperglycemia. The percentages of vitamin D deficient and insufficient subjects were 33% and 46% in males and 59% and 32% in females, respectively. Subjects with atherosclerotic disease risk factors were significantly older and had higher BMI than those without it in both sexes. Male subjects with atherosclerotic disease risk factors had significantly lower physical activity and serum 25(OH)D concentration than those without it. In a logistic regression analysis adjusted for confounding factors, serum 25(OH)D concentration showed a significant inverse association with risk factors of atherosclerotic disease in males (OR=0.951, 95%CI: 0.906-0.998), but not in females. A covariance structure analysis also suggested that serum 25(OH)D level has a direct association with risk factors of atherosclerotic disease. In conclusion, we have demonstrated that low serum 25(OH)D level is a significant factor for increased atherosclerotic disease risk factors in males.

Usefulness of Vitamin D Deficiency Questionnaire for Japanese (VDDQ-J) for Screening of Vitamin D Deficiency and Low Muscle Mass in Relatively Healthy Japanese Anti-Aging Health Checkup Examinees.

The Vitamin D Deficiency Questionnaire for Japanese (VDDQ-J) has been developed as an alternative indicator of the vitamin D nutritional status when serum 25(OH)D measurement is unavailable. In the present study, we compared the usefulness of the VDDQ-J with that of serum 25(OH)D concentration and examined the relationship among vitamin D, DXA-based body composition, and muscle strength in 163 anti-aging health check examinees. The median age, 25(OH)D concentration and VDDQ-J score were 62.0 y, 20.1 ng/mL and 22.0 points, respectively. In total, 47.9% of the subjects had serum 25(OH)D concentrations of <20 ng/mL. The VDDQ-J score was significantly negatively correlated with the serum 25(OH)D concentration, and the positive predictive value for vitamin D deficiency was 86.3%. The prevalence of sarcopenia was 6.1%. Low 25(OH)D levels and high VDDQ-J scores were significantly associated with low muscle mass in both univariate analysis and multiple linear regression analysis. The serum 25(OH)D level showed a significant negative correlation with body fat mass. The VDDQ-J score was selected as a significant determinant of low skeletal muscle mass index (<7.0 kg/m2 for men and <5.4 kg/m2 for women) by a multiple logistic regression analysis. In conclusion, the present study showed that a low vitamin D nutritional status as indicated by both low 25(OH)D levels, and high VDDQ-J scores was associated with low muscle mass and the VDDQ-J is considered useful not only for the detection of vitamin D deficiency but also in the screening of individuals with low muscle mass and a high risk of sarcopenia.

[SF-36 and EQ-5D in the evaluation of QOL in the osteoporotic patients as the generic questionnaires].

Health-related quality of life (HRQOL) , abbreviated as QOL, can be evaluated by various questionnaires, which are classified as generic and disease-targeted ones. Generic questionnaires are further subdivided into profile-type and preference-based ones. SF-36 and EQ-5D are the best known examples for the former and the latter, respectively. In SF-36 and its shortened one SF-8, the subjects' QOL is expressed by several profiles or subscales. Their advantages include well-conducted validation and availability of national norms. In EQ-5D, a single value representing the subjects' QOL status (utility) is obtained through 5 questions. These generic questionnaires are applicable to patients with various diseases or even to healthy citizens. In contrast, disease-targeted questionnaires lack such features, but can include items that are specifically related to the disease but devoid of general applicability. Thus, generic and disease-targeted questionnaires have their own pros and cons. Selection of the questionnaires depends on the object of the study.

Vitamin D Status in Japanese Young Women in 2016-2017 and 2020: Seasonal Variation and the Effect of Lifestyle Including Changes Caused by the COVID-19 Pandemic.

Avoidance of sunlight and self-restraint due to the COVID-19 pandemic may contribute to reduced vitamin D status. This study provides comparable data on vitamin D status in Japanese young women and assesses the effect of lifestyle, including changes caused by the COVID-19 pandemic, on vitamin D status. In study 1, 39 young healthy Japanese women aged 21-25 y were recruited from May 2016-June 2017. Serum 25-hydroxyvitamin D (25OHD) concentration and diet and lifestyle information were obtained from participants each month (n=124). In study 2, using the same parameters as study 1, young women aged 21-23 y (n=10) were recruited in September 2020. In the results of study 1, we found the frequencies of vitamin D deficiency (25OHD<20 ng/mL) in spring, summer, fall, and winter were 90.5%, 62.5%, 81.5%, and 91.3%, respectively. The substantial difference of serum 25OHD concentration was obtained in spring (Δ3.6 ng/mL) and summer (Δ5.1 ng/mL) depending on the frequency of sunscreen use (0-2 d/wk, 3-7 d/wk). In study 2, serum 25OHD concentration in September 2020 was extremely lower than in September 2016 (13.2 ng/mL vs. 21.7 ng/mL). The number of days spent outside in 2020 decreased drastically compared with 2019. In conclusion, vitamin D deficiency was highly common in Japanese women in their early 20s, and frequent sunscreen use contributed to low vitamin D status. Moreover, because the decrease in days outside due to the COVID-19 pandemic obviously resulted in a decline in vitamin D status, both appropriate sunbathing and increased dietary vitamin D intake are recommended to young women.

Development of a predictive model for vitamin D deficiency based on the vitamin D status in young Japanese women: A study protocol.

BACKGROUND: Vitamin D deficiency (VDD) is associated with an increased risk for lifestyle-related diseases. In Japan, VDD is quite prevalent in all age groups, with its high risk in young women. Furthermore, its association during pregnancy with gestational hypertension and low birth weight has also been reported. VDD can be diagnosed by serum 25-hydroxyvitamin D [25(OH)D] levels, which, however, is not suited for screening. Therefore, we will create a predictive model for serum 25(OH)D concentration and prevalence of VDD based on such data as region, sun exposure habit, and vitamin D intake in young women. METHODS: From 2020 to 2022, we conduct a cross-sectional study of 600 young women in four regions of Japan, identify the indices associated with serum 25(OH)D concentrations such as sun exposure habits, habitual vitamin D intake, ultraviolet-B irradiation, seasons (summer and winter) and latitude, and construct prediction models for serum 25(OH)D concentrations and VDD risk. This study has been registered with UMIN-CTR (ID: UMIN000041527). RESULTS: One hundred and fifteen subjects have been collected from 6 institutions in winter as of May 2021. When data from more than 200 subjects have become available, we will conduct the interim analysis, summarize the data by region and facility, review the inclusion criteria for analysis, and check for missing values and outliers. Prediction models for serum 25(OH)D concentration and VDD will be determined in the final analysis when all cases have been collected. CONCLUSIONS: A screening tool for VDD risk to be developed in our study based on the predictive model would help the public and medical professionals prevent lifestyle-related diseases through improving VDD. Additionally, the results may serve as the scientific basis for determining the appropriate vitamin D intake and sun exposure standards.

Association of blood pressure and dietary intake of Sunomono, Japanese vinegared side dishes, in community-dwelling Japanese: A cross-sectional study.

Objective: Vinegar has been reported to have a hypotensive effect. We aimed to investigate the relationship between the consumption of vinegar-based side dishes and blood pressure. Research methods & procedures: This cross-sectional study included 746 individuals (257 men and 489 women) aged ≥40 years from Tarumizu, Kagoshima, Japan. Nutrient intake was estimated based on the brief-type self-administered diet history questionnaire. The intake frequency of vinegar-based side dishes (Sunomono and pickles) was determined using a self-administered diet history questionnaire. Participants who did not consume vinegar-based side dishes for a month were defined as having no Sunomono or pickle eating habit. Blood pressure was categorized into four groups according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension. The association between the intake of vinegar-based side dishes and blood pressure categories was analyzed using ordinal logistic regression analysis adjusted for age, body mass index, smoking history, excessive alcohol intake, living situation, energy intake, protein intake, sodium intake, potassium intake, and seaweed intake. Results: Approximately 13.6% men and 6.1% women had no Sunomono eating habits. In men, eating Sunomono, but not pickles, was significantly related to blood pressure categories (estimate, -0.702; 95% CI, -1.122 to -0.310), whereas more frequent consumption of Sunomono did not show an improvement in the blood pressure category. The relationship between eating Sunomono and blood pressure categories was not recognized in women. Conclusion: This was the first study assessing the association between consumption of vinegar-based side dishes and blood pressure categories. We highlighted the effect of Sunomono consumption on blood pressure categories in men. Consumption of Sunomono may improve blood pressure in men.

Comparison of Vitamin D and 25-Hydroxyvitamin D Concentrations in Human Breast Milk between 1989 and 2016-2017.

BACKGROUND: Breast milk is considered the optimal source of nutrition during infancy. Although the vitamin D concentration in human breast milk is generally considered poor for infants, vitamin D in breast milk is an important source for exclusively breastfed infants. Increases in vitamin D insufficiency and deficiency in lactating mothers may reduce vitamin D concentrations in breast milk. This study aimed to compare vitamin D and 25-hydroxyvitamin D (25OHD) concentrations in breast milk collected in 1989 and 2016-2017 and simultaneously analyze them with liquid chromatography-tandem mass spectrometry (LC-MS/MS); the association between the lifestyle of recent lactating mothers (2016-2017) and vitamin D status in human breast milk was also evaluated. METHOD: Lactating mothers were recruited from three regions of Japan in 1989 (n = 72) and 2016-2017 (n = 90), and milk from 3-4 months was collected in summer and winter. The samples were strictly sealed and stored at -80℃ until measurement. Breast milk vitamin D and 25OHD concentrations were analyzed by LC-MS/MS. Vitamin D intake, sun exposure, and sunscreen use of the lactating mothers in 2016-2017 were assessed. RESULTS: Both vitamin D and 25OHD concentrations in breast milk were higher in the summer regardless of the survey year. Significantly lower vitamin D and 25OHD concentrations were observed in 2016-2017 compared with 1989 in summer, but no survey year difference was observed in winter. The stepwise multiple regression analyses identified season, daily outdoor activity, and suntan in the last 12 months as independent factors associated with vitamin D3 concentrations. CONCLUSION: The results suggest that low vitamin D status in recent lactating mothers may have decreased vitamin D and 25OHD concentrations in breast milk compared with the 1980s. These results are helpful for developing public health strategies to improve vitamin D status in lactating mothers and infants.

Compressive force induces osteoclast differentiation via prostaglandin E(2) production in MC3T3-E1 cells.

In orthodontic tooth movement, prostaglandin E(2) (PGE(2)) released from osteoblasts can alter the normal process of bone remodeling. We previously showed that compressive force (CF) controls bone formation by stimulating the production of PGE(2) and Ep2 and/or Ep4 receptors in osteoblasts. The present study was undertaken to examine the effect of CF on the production of PGE(2), cyclooxygenase-2 (COX-2), macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) using osteoblastic MC3T3-E1 cells and to examine the indirect effect of CF on osteoclast differentiation using RAW264.7 cells as osteoclast precursors. MC3T3-E1 cells were cultured with or without continuous CF (1.0 or 3.0 g/cm(2)) for 24 hr, and PGE(2) production was determined using ELISA. The expression of COX-2, M-CSF, RANKL, and OPG genes and proteins was determined using real-time PCR and ELISA, respectively. Osteoclast differentiation was estimated using tartrate-resistant acid phosphatase (TRAP) staining of RAW 264.7 cells cultured for 10 days with conditioned medium from CF-treated MC3T3-E1 cells and soluble RANKL. As CF increased, PGE(2) production and the expression of COX-2, M-CSF, and RANKL increased, whereas OPG expression decreased. The number of TRAP-positive cells increased as CF increased. Celecoxib, a specific inhibitor of COX-2, blocked the stimulatory effect of CF on TRAP staining and the production of PGE(2), M-CSF, RANKL, and OPG. These results suggest that CF induces osteoclast differentiation by increasing M-CSF production and decreasing OPG production via PGE(2) in osteoblasts.

[Nutrition and bone health. Dietary sodium intake and bone health].

Dietary sodium (Na) intake has been known to influence urinary calcium (Ca) excretion. High Na intake has been reported to increase urinary Ca excretion and bone resorption markers, and to be associated with bone loss. In these studies, however, the effect of high Na intake is small, and also affected by other nutrients intakes such as Ca or potassium intakes. Therefore, the association of Na intake and bone health could not be studied alone, but should be studied with full consideration of its interaction with other nutrients.

[Nutrition and bone health. Protein intake and bone ; pros and cons].

The association of protein intake and bone health is still controversial. The negative effects have been reported such as the association between high protein intake and increasing urinary calcium excretion. In contrast, high protein intake has beneficial effect on bone mineral density (BMD) and bone mineral content (BMC) . Recent meta-analyses or systematic reviews indicate that protein intake dose not promote net loss of whole body calcium, and hence have a small positive effect on BMD and BMC. However, the effect of high protein intake on hip fracture prevention is not supported by previous cohort studies. Therefore, long-term cohort studies are required to clarify the association between protein intake and fracture.

Vitamin D in the Dietary Reference Intakes for Japanese (DRIs) 2020.

Dietary Reference Intakes for Japanese (DRIs) are revised every five years. In DRIs 2020, major revision has been made on vitamin D (VD). In DRIs, five indices are defined for nutrients; estimated average requirement (EAR), recommended dietary allowance (RDA) and adequate intake (AI) for the prevention of deficiency/insufficiency, tolerable upper intake level (UL) for avoiding excess intake, and tentative dietary goal for preventing life-style related diseases (DG) for the primary prevention of life-style related diseases. For VD, AI has been determined. VD deficiency causes rickets and osteomalacia. VD insufficiency, milder than deficiency, is a risk for various diseases including osteoporotic fracture. Previously, the basis of AI for VD was the prevention of rickets and osteomalacia, but was changed to the median intake of healthy subjects in DRIs 2005. Recent studies have shown, however, that VD deficiency/insufficiency is quite prevalent, and the above basis is considered inadequate. Then in DRIs 2020, AI was defined as the amount necessary for fracture prevention (15 µg/d) minus that possibly produced in Sapporo during winter in the skin by ultraviolet (5 µg/d). UL and AI for infants were revised in DRIs 2015. For the future DRIs, more clinical and epidemiological studies are urgently needed.