Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Steroidogenesis in patients with adrenal incidentalomas: Extended steroid profile measured by liquid chromatography-mass spectrometry after ACTH stimulation and dexamethasone suppression.

OBJECTIVE: Describe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects. DESIGN, SETTING AND PARTICIPANTS: A prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital. METHODS: Collect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography-mass spectrometry (LC-MS): pregnenolone, 17-OH pregnenolone, 17-OH progesterone, 11-deoxycorticosterone, 11-deoxyortisol, 21-deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone. RESULTS: Mean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143-665) nmol/L,(p < .0001), unilateral 268 ± 89 3.2 (range 98-507) nmol/L (p < .019) compared to controls 207 ± 100 (range 72-502) nmol/L. ACTH stimulation showed significantly higher levels in bilateral and unilateral cases compared to controls. After dexamethasone, mean serum cortisol levels suppressed in bilaterals 89 ± 69 (range 30-3) nmol/L (p < .0001), 58 ± 52 (range 16-323) nmol/L in unilateral (p < .01) compared to 26 ± 9 (range 7-46) nmol/L in controls. Mean baseline serum corticosterone was higher in bilateral 9.3 ± 4.8 (range 2.4-18.4) nmol/L (p < .005) and unilateral 7.3 ± 5.7 (range 0.1-30.3) nmol/L (p < .01) compared to controls 4.2 ± 2.4 (range 1.1-10.2) nmol/L, after ACTH stimulation significantly increased to higher levels in bilateral (p < .0002) and unilateral cases (p < .044) compared to controls. After dexamethasone, mean levels were 2.5 ± 2.6 (range 0.5-12.5) nmol/L in bilateral (p < .0006), 1.5 ± 1.6 (range 0.3-9.3) nmol/L in unilateral (p < .09) and 0.75 ± 0.46 (range 0.1-2.1) nmol/L in controls. Mean baseline serum 11-deoxycorticosterone (DOC) was higher in bilaterals 0.32 ± 0.23 (range 0.08-1.1) nmol/L (p < .03) compared to controls 0.15 ± 0.21 (range 0.08-1.1) nmol/L. ACTH stimulation increased levels to 3.27 ± 1.72 (range 0.5-7.4) nmol/L in bilateral cases compared to controls 1.369 ± 1.53 (range 0.1-7.1) nmol/L (p < .0001). Dexamethasone decreased levels to baseline (p ns). There were significant differences in serum 21-deoxycortisol (p < .0002) and serum pregnenolone (p < .004) only after ACTH stimulation. CONCLUSIONS: There is increased activity in several steroid biosynthesis pathways and higher steroid levels in bilateral compared to unilateral cases and evidence of hypercortisolism in 30% unilateral and 62% of bilateral incidentalomas.

Correlation Between Size and Function of Unilateral and Bilateral Adrenocortical Nodules: An Observational Study.

OBJECTIVE. Adrenal incidentalomas occur in 5% of adults and can produce autonomous cortisol secretion that increases the risk of metabolic syndrome and cardiovascular disease. The objective of our study was to evaluate the relationship between adrenal nodule size measured on CT and autonomous cortisol secretion. SUBJECTS AND METHODS. In a prospective study of 73 patients 22-87 years old with incidentalomas, unilateral in 52 patients and bilateral in 21 patients, we measured maximum nodule diameter on CT and serum cortisol levels at 8:00 am, 60 minutes after the adrenocorticotropic hormone stimulation test, and after the dexamethasone suppression test. We also studied 34 age-, sex-, and body mass index-matched control subjects. Statistics used were Spearman correlation coefficients, t tests, ANOVA test, and multivariate analysis. RESULTS. The mean maximum diameter of unilateral nodules measured on CT was larger on the right (2.47 ± 0.98 [SD] cm) than on the left (2.04 ± 0.86 cm) (p = 0.01). In the bilateral cases, the mean diameter of the right nodules was 2.69 ± 0.93 cm compared with 2.13 ± 0.89 cm on the left (p = 0.06). Mean baseline serum cortisol level was significantly higher in the patients with incidentalomas (bilateral, 13.1 ± 4.5 mcg/dL [p < 0.001]; unilateral, 9.7 ± 3.2 mcg/dL [p = 0.019]) than in the control subjects (7.5 ± 3.6 mcg/dL). After dexamethasone suppression test, serum cortisol levels were suppressed to less than 1.8 mcg/dL in 100% of control subjects, 33% of patients with bilateral incidentalomas, and 62% of patients with unilateral incidentalomas (p < 0.001). There were significant correlations between maximum nodule diameter on CT and serum cortisol levels after the dexamethasone suppression test (ρ = 0.500; p < 0.001) and at baseline (ρ = 0.373; p = 0.003). CONCLUSION. Increasing size of adrenal nodules is associated with more severe hyper-cortisolism and less dexamethasone suppression; these cases need further evaluation and possibly surgery because of increased risks of metabolic syndrome and cardiovascular mortality.

Biological agents in management of osteoporosis.

Osteoporosis is a skeletal disease associated with an imbalance between formation and resorption, leading to net loss of bone mass, loss of bone microarchitecture, and development of fractures. Bone resorption is primarily due to an activation of osteoclastogenesis and an increase in receptor activator of nuclear factor kappa-B ligand (RANKL) expression, a cytokine involved in the final pathway of the osteoclast cycle.Recent studies of genetic diseases led to the discovery of the wingless-type (Wnt) signaling pathway that plays a major role in bone formation. Further work showed that sclerostin produced by osteocytes and the Dickkopf (DKK1) protein secreted in bone were negative regulators of the Wnt signaling bone formation pathway that act directly by binding to the co-receptors LRP5 and LRP6 of WnT and thereby inhibiting the anabolic Wnt pathway. This understanding of the bone remodeling led to the discovery of new biological drugs that target these pathways and have been evaluated in clinical trials.The current article discusses the role of these newer "biological" agents in management of osteoporosis. Denosumab, a human monoclonal antibody that specifically binds RANKL, blocks the binding of RANK to its ligand markedly reducing bone resorption, increases bone density, and reduces fractures and is approved for osteoporosis. Parathyroid hormone PTH 1-34 (teriparatide) stimulates bone formation through inhibition of sclerostin, DKK1, and frizzled protein; increases BMD; improves microarchitecture; and decreases fractures and is approved for osteoporosis. The anti-sclerostin antibodies (romosozumab, blosozumab) increase bone mass by neutralizing the negative effects of sclerostin on the Wnt signaling pathway. These biologics are being evaluated now in a clinical trial and early data looks promising. Cathepsin K is a proteolytic enzyme that degrades bone matrix and inhibitors such as odanacatib show increasing bone density and perhaps decreased fractures. The potential power of combining these newer antiresorptives with the newer anabolic agents could theoretically increase bone mass rapidly to normal within 1 year and reduce fractures. These newer treatments are revolutionizing the management of osteoporosis.

Controversies in osteoporosis management: antiresorptive therapy for preventing bone loss: when to use one or two antiresorptive agents?

Women who have significant bone loss or a new fracture on monotherapy are considered for combination therapy. Combination therapies increase bone density more than monotherapy by targeting different parts of the osteoclast pathway.In early postmenopausal women who are symptomatic, the use of combination antiresorptives should include hormone therapy with a bisphosphonate or with bazodoxifene. In women who initially receive a weaker antiresorptive such as the SERM raloxifene, a combination with bisphosphonates and calcium supplementation is necessary to prevent bone loss. In older women over 65 years of age who often have impaired calcium absorption, the combination of calcitriol with bisphosphonates has been shown to increase bone density more than monotherapy.

Dose response to vitamin D supplementation in postmenopausal women: a randomized trial.

BACKGROUND: Serum 25-hydroxyvitamin D (25-[OH]D) is considered the best biomarker of clinical vitamin D status. OBJECTIVE: To determine the effect of increasing oral doses of vitamin D(3) on serum 25-(OH)D and serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency (defined as a 25-[OH]D level ≤50 nmol/L) in the presence of adequate calcium intake. These results can be used as a guide to estimate the Recommended Dietary Allowance (RDA) (defined as meeting the needs of 97.5% of the population) for vitamin D(3). DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00472823) SETTING: Creighton University Medical Center, Omaha, Nebraska. PARTICIPANTS: 163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year. INTERVENTION: Participants were randomly assigned to receive placebo or vitamin D(3), 400, 800, 1600, 2400, 3200, 4000, or 4800 IU once daily. Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg. MEASUREMENTS: The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months. RESULTS: The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D(3). The RDA of vitamin D(3) to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed-effects model predicted that 600 IU of vitamin D(3) daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m(2)), obese women (≥30 kg/m(2)) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D(3) (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose. LIMITATION: Findings may not be generalizable to other age groups or persons with substantial comorbid conditions. CONCLUSION: A vitamin D(3) dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women; however, a model predicted the same response with a vitamin D(3) dosage of 600 IU/d. These results can be used as a guide for the RDA of vitamin D(3), but prospective trials are needed to confirm the clinical significance of these results. PRIMARY FUNDING SOURCE: National Institute on Aging.

Vitamin D: 100 years of discoveries, yet controversy continues.

Over the past 100 years, many major breakthroughs and discoveries have occurred in relation to vitamin D research. These developments include the cure of rickets in 1919, the discovery of vitamin D compounds, advances in vitamin D molecular biology, and improvements in our understanding of endocrine control of vitamin D metabolism. Furthermore, recommended daily allowances for vitamin D have been established and large clinical trials of vitamin D, aimed at clarifying the effect of Vitamin D in the prevention of multiple diseases, have been completed. However, disappointingly, these clinical trials have not fulfilled the expectations many had 10 years ago. In almost every trial, various doses and routes of administration did not show efficacy of vitamin D in preventing fractures, falls, cancer, cardiovascular diseases, type 2 diabetes, asthma, and respiratory infections. Although concerns about side-effects of long-term high-dose treatments, such as hypercalcaemia and nephrocalcinosis, have been around for four decades, some trials from the past 5 years have had new and unexpected adverse events. These adverse events include increased fractures, falls, and hospitalisations in older people (aged >65 years). Several of these clinical trials were powered appropriately for a primary outcome but did not include dose response studies and were underpowered for secondary analyses. Furthermore, more attention should be paid to the safety of high doses of vitamin D supplementation, particularly in older people. In addition, despite universal recommendations by osteoporosis societies for combining calcium supplements with vitamin D there remains insufficient data about their efficacy and effect on fracture risk in the highest risk groups. More trials are needed for people with severe vitamin D deficiency (ie, serum 25-hydroxyvitamin D <25nmol/L [10ng/mL]). In this Personal View, we summarise and discuss some of the major discoveries and controversies in the field of vitamin D.

The 2011 IOM report on vitamin D and calcium requirements for north america: clinical implications for providers treating patients with low bone mineral density.

Vitamin D is an essential nutrient for skeletal mineralization and maintenance of bone mass. Most healthy individuals can meet their vitamin D requirements through dietary means, modest supplementation and solar exposure for short periods of time. The serum level of 25OHD that determines adequacy is 20 ng/ml, which corresponds with consumption of 6-800 IU of vitamin D per day, according to the Institute of Medicine review. There is still debate about whether higher doses of vitamin D are required for treating patients with osteoporosis.

Does tibolone reduce the risk of fracture in older postmenopausal women with osteoporosis?

This Practice Point commentary discusses a double-blind, placebo-controlled trial by Cummings et al. that investigated the effects of tibolone 1.25 mg per day in 4,534 postmenopausal women (mean age 68 years) with osteoporosis. Tibolone is a synthetic steroid with estrogenic, progestational and androgenic effects. It has been used as an alternative to estrogen to treat menopausal symptoms for 30 years. Cummings et al. found that tibolone reduced the incidence of vertebral fractures by 45%, nonvertebral fractures by 26%, breast cancer by 68% and colon cancer by 69%. The trial was discontinued 2 months before a median treatment time of 3 years because the major end point (reduction of fractures) was reached. In addition, tibolone increased the risk of stroke, although the absolute risk was small. Similarly to other compounds with estrogenic activity that increase the risk of stroke, such as estrogen and selective estrogen-receptor modulators, clinicians must weigh the risks and benefits of therapy for individual patients. This risk might be lower in women aged 50-60 years than in those aged >60 years.

Advances in osteoporosis from 1970 to 2018.

In 1970, there were no drugs under study for osteoporosis. Estrogen was used, but little was known about the correct dose for preventing bone loss. At that time, fractures were not even recognized as a disease, but regarded as part of normal aging. From 1970 to this year (2018), there have been extensive advances in the osteoporosis field ranging from fracture epidemiology to the remarkable invention of bone density measurements. There have been major advances in therapeutic options available for patients for prevention and treatment of osteoporosis. In parallel, the advances in the laboratory helped elucidate the process of bone remodeling, not only at the macroscopic level but also at the cellular level. This led to rapid advances in translational research from cellular biology to new therapies exemplified by the development of monoclonal antibodies for osteoporosis. Further understanding of the signaling pathways in bone cells will lead to new small molecules made for osteoporosis treatment, perhaps causing less adverse events. University-based research throughout the world has been a leader in most of these advances, and Pharma support for phase 1 to 4 studies helped bring these discoveries to patients. In the osteoporosis field alone, one sees the tremendous value of grant support for university research by National funding agencies such as the National Institute of Health in this country and similar agencies in other countries. There are clinical challenges that have to be solved with long-term compliance with osteoporosis medication if we want to reduce fracture incidence in the long term.

Dose ranging effects of vitamin D3 on the geriatric depression score: A clinical trial.

Depression is a common problem affecting millions, usually treated with selective serotonin uptake inhibitors. Interest in vitamin D as a co-therapy was stimulated by some association studies that correlated depression with low serum 25OHD levels. There are few longitudinal studies of vitamin D and depression and most are single doses of vitamin D. In this study we examined the effect of one-year treatment with several doses of vitamin D on the Geriatric depression score (GDS) in older Caucasian and African American women. The clinical trial was a study of seven daily oral doses of vitamin D (400-4800IU/d) in Black and White older women. The trial was a double blind, randomized and placebo controlled lasting 12-months. The main inclusion criterion was serum 25 hydroxyvitamin D (25OHD)≤20ng/mL (50nmol/L). Calcium supplements were given to maintain calcium intake 1000mg/day in young people and 1200-1400mg/day in older women. Data on Geriatric depression (GDS) was collected using the validated long form at baseline and 12-months. The change in serum 25OHD was the primary outcome and GDS was one of the secondary outcomes. Adjustments were made for relevant covariates. Analysis of vitamin D effect was by dose low, medium and high compared to placebo or by quintiles. Serum 25OHD increased as a quadratic curve function to a mean of 46ng/mL (115nmol/L) in white women and 49ng/mL (122.5nmol/L) in black women on the highest dose of 4800 IU. In older women mean GDS scores changed from 3.8 (SD±4.2) at baseline to 3.6 (SD±4.1) at 12 months in whites and from 3.0 (SD±3.7) to 3.02 (SD±4.2) in Blacks. (p=0.790 in whites; p=0.958 in blacks). After 12-months there was no effect of dose on change in GDS score in women treated with different doses of vitamin D (p=0.507 in whites and p=0.340 in blacks). When both Caucasians and African Americans were divided into 3 dose groups, low (400-800 IU), medium (1600-3200 IU) and high (4000-4800 IU) doses, the change in score was 0.8 on low dose, -0.30 on medium dose and -0.31 on high dose compared to 0.11 on placebo (p=0.546). In summary, there was no improvement in GDS scores in Caucasians or African Americans on either increasing doses of vitamin D or quintiles of achieved response in serum 25OHD. The changes were small and not significant perhaps because of the relatively lower numbers of depressed women in the groups. Further studies should recruit larger numbers, 3 dose groups covering a serum25OHD range of 20-60ng/mL and more subjects with clinical depression in order to fully address the question of vitamin D effects on depression.

Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations.

Context: The optimal measure of vitamin D status is unknown. Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design: Cross-sectional analysis. Setting: Seven academic sites. Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79). Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype. Main outcome measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates). Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype. Conclusions: Total 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment.

CONTEXT: Decreased calcitriol production due to impaired renal function may be a significant risk factor for falls in normal aging population. OBJECTIVE: The objective of the study was to examine the association between creatinine clearance (CrCl) and the incidence of falls and fallers in groups treated with placebo, calcitriol, estrogen therapy (ET)/estrogen + progestin therapy (HT), and calcitriol + ET/HT. DESIGN: This was a 3-yr, double-blind, placebo-controlled study designed to test the efficacy of calcitriol and ET/HT on bone loss and falls with analysis by intention to treat and post hoc. SETTING: The study was conducted at an academic outpatient center. PARTICIPANTS: Four hundred eighty-nine normal elderly women aged 65-77 yr; 415 women completed the study. INTERVENTION: Subjects were randomized to placebo, calcitriol 0.25 mug twice a day, ET daily (conjugated equine estrogens 0.625 mg), HT (conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg) and calcitriol + ET/HT. MAIN OUTCOME MEASURES: Cumulative number of falls and fallers were compared between groups with 24-h urine CrCl less than 60 and 60 ml/min or greater. RESULTS: Calcitriol treatment decreased the number of fallers and falls. Low CrCl less than 60 ml/min was a predictor of the number of falls per person but not fallers in the placebo group (P = 0.007). In the low CrCl group (<60 ml/min), the rate of falls decreased on calcitriol by 53% [95% confidence interval (CI) -71% to -22%; P = 0.003], calcitriol + ET/HT by 61% (95% CI -76% to -37%; P = 0.001), and ET/HT by 25% (95% CI: -55% to +24%; not significant). Calcitriol reduced the rate of falls by 30% (95% CI -49% to -4%; P = 0.027) in the CrCl 60 ml/min or greater group. CONCLUSION: Calcitriol treatment decreases falls in all subjects but especially in elderly women with decreased renal function (<60 ml/min) and frequent fallers.

Effect of early menopause on bone mineral density and fractures.

OBJECTIVE: To review the data on the effect of early menopause on bone. Do women undergoing early menopause develop lower bone mineral density at an earlier age and do they have a higher incidence of osteoporotic fractures? Is there a difference on bone between women who undergo early natural menopause compared to women who have early menopause after oophorectomy? RESULTS: The earlier in life that menopause occurs, the lower the bone density will be later in life. Low bone density is associated with a higher fracture rate, and several studies show a relationship between early menopause, oophorectomy, and an increase in osteoporotic fractures. CONCLUSIONS: Early menopause is a risk factor for osteoporosis. Women with an early menopause should have bone density testing performed within 10 years of menopause so that osteopenia or osteoporosis will be diagnosed early and appropriate anti-resorptive therapy initiated.

Smoking is a risk factor for decreased physical performance in elderly women.

BACKGROUND: In 487 elderly women aged 65-77 years, we examined the association of smoking with physical performance measures of muscle function and whether the effect of smoking on physical performance measures is mediated through its effect on vitamin D or estrogen metabolism. METHODS: Timed rise, timed walk at normal and fast speed, grip strength, and serum biochemical measurements were compared between smokers, past smokers, and nonsmokers. Analysis of covariance was used to compare physical performance variables while adjusting for confounding variables. RESULTS: Compared to nonsmokers and past smokers, current smokers were significantly (p <.05) slower on timed rise and timed walk tests and had decreased grip strength. From multivariate analysis, smoking, age, total body fat, and serum 1,25(OH)(2)D examined as quartiles were predictors of physical performance measures. The effect of current smoking on physical performance was equivalent to a normal age-related decline in physical performance tests of 7-11 years depending on the test. CONCLUSIONS: The results of this study suggest that current smoking is a risk factor for decreased muscle strength leading to decreased physical performance in elderly women. The effect of smoking on physical performance is in part mediated by its effect on 1,25(OH)(2)D metabolism. Smoking may also have an independent effect on physical performance possibly by a direct effect on muscle or through an effect on vascular function.

Dietary Vitamin D Intake for the Elderly Population: Update on the Recommended Dietary Allowance for Vitamin D.

Vitamin D insufficiency and deficiency can be diagnosed with measurements of serum 25-hydroxyvitamin D (25OHD). Most vitamin D is derived from sunlight (80%), so serum 25OHD levels are lowest in late winter and early spring. Dietary vitamin D in North America is small, about 100 to 200 IU daily. A recent review of the literature shows many association studies relating vitamin D deficiency and insufficiency to several diseases. Large randomized trials of vitamin D are underway and soon there may be answers as to whether vitamin D is clinically effective and what level of serum 25OHD is necessary.

Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: A randomized clinical trial.

Falls are a serious health problem in the aging population. Because low levels of vitamin D have been associated with increased fall rates, many trials have been performed with vitamin D; two meta-analyses showed either a small effect or no effect of vitamin D on falls. We conducted a study of the effect of vitamin D on serum 25 hydroxyvitamin D (25OHD) and data on falls was collected as a secondary outcome. In a 12-month double blind randomized placebo trial, elderly women, mean age 66 years, were randomized to one of seven daily oral doses of vitamin D or placebo. The main inclusion criterion for study was a baseline serum 25OHD<20ng/ml (50nmol/L). A history of falls was collected at baseline and fall events were collected every 3 months. Results showed that the effect of vitamin D on falls followed a U-shaped curve whether analyzed by dose or serum 25OHD levels. There was no decrease in falls on low vitamin D doses 400, 800 IU, a significant decrease on medium doses 1600, 2400,3200 IU (p=0.020) and no decrease on high doses 4000, 4800 IU compared to placebo (p=0.55). When compared to 12-month serum 25OHD quintiles, the faller rate was 60% in the lowest quintile <25ng/ml (<50nmol/L), 21% in the low middle quintile 32-38ng/ml (80-95nmo/L), 72% in the high middle quintile 38-46ng/ml (95-115nmo/L) and 45% in the highest quintile 46-66ng/ml (115-165nmol/L). In the subgroup with a fall history, fall rates were 68% on low dose, 27% on medium doses and 100% on higher doses. Fall rates on high doses were increased compared to medium doses (Odds Ratio 5.6.95% CI: 2.1-14.8). In summary, the maximum decrease in falls corresponds to a 12- month serum 25OHD of 32-38ng/ml (80-95nmol/L) and faller rates increase as serum 25OHD exceed 40-45ng/ml (100-112.5nmol/L). The Tolerable upper limit (TUL) recently increased in 2010 from 2000 to 4000 IU/day may need to be reduced in elderly women especially in those with a fall history.

Improved Screening Test for Idiopathic Infantile Hypercalcemia Confirms Residual Levels of Serum 24,25-(OH)2 D3 in Affected Patients.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D3 :24,25-(OH)2 D3 ratio (R) can identify IIH patients on the basis of reduced C24-hydroxylation of 25-OH-D3 by CYP24A1 in vivo. Although values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25-(OH)2 D3 remains detectable. The current study explores possible explanations for this including: residual CYP24A1 enzyme activity in individuals with certain CYP24A1 genotypes, expression of alternative C24-hydroxylases, and the possibility of isobaric contamination of the 24,25-(OH)2 D3 peak on LC-MS/MS. We employed an extended 20-min run time on LC-MS/MS to study serum vitamin D metabolites in patients with IIH due to mutations of CYP24A1 or SLC34A1; in unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; as well as in normal subjects exhibiting a broad range of 25-OH-D levels. We identified 25,26-(OH)2 D3 as a contaminant of the 24,25-(OH)2 D3 peak. In normals, the concentration of 24,25-(OH)2 D3 greatly exceeds 25,26-(OH)2 D3 ; however, 25,26-(OH)2 D3 becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25-(OH)2 D3 levels are low when CYP24A1 function is compromised. Mean R in 30 IIH-CYP24A1 patients was 700 (range, 166 to 2168; cutoff = 140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25-(OH)2 D3 levels and lower R (mean R = 268; n = 8) than patients with other mutations. We conclude that a chromatographic approach which resolves 24,25-(OH)2 D3 from 25,26-(OH)2 D3 produces a more accurate R that can be used to differentiate pathological states where CYP24A1 activity is altered. The origin of the residual serum 24,25-(OH)2 D3 in IIH patients appears to be multifactorial. © 2017 American Society for Bone and Mineral Research.

Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis.

UNLABELLED: Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12-24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo. INTRODUCTION: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. MATERIALS AND METHODS: We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 microg or placebo for 12-24 months (median, 19.8 months) in the Fracture Prevention Trial. RESULTS: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. CONCLUSIONS: Direct evidence is presented that 12-24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.