John F. Aloia

The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

Prevention of Involutional Bone Loss by Exercise

To ascertain whether exercise could prevent involutional bone loss, we studied 18 postmenopausal women, half of whom exercised for 1 h three times a week. Total and regional bone mass were measured before and after 1 year of exercise by the techniques of total-body neutron activation analysis (total body calcium) and photon absorptiometry (bone mineral content) of the distal radius. Total body potassium was measured by whole body counting. Bone mineral content and total body potassium did not change significantly in either group. Total body calcium increased in the exercise group from 781 +/- 95 g of 801 +/- 118 g (SD). In contrast, total body calcium decreased in each subject in the sedentary group. The daily calcium balance derived from the difference in total body calcium measurements was significantly different in the two groups of women (P less than 0.001). These data support the hypothesis that exercise can modify involutional bone loss.

IOM Committee Members Respond to Endocrine Society Vitamin D Guideline

In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.

Risk factors for postmenopausal osteoporosis.

Fifty-eight women with postmenopausal osteoporosis (crush fracture of the spine) were compared with 58 age-matched normal women. The osteoporotic women had lower total-body calcium levels and bone mineral content of the radius, had undergone an earlier menopause, smoked cigarettes more, and had breast-fed less often. They also had lower levels of estrone, estradiol, and testosterone and reduced levels of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D. These findings suggest the presence of changeable risk factors for the development of osteoporosis. Smoking should be discouraged. An adequate intake of calcium and vitamin D should be ensured. It is the opinion of the authors that those women who have had an early menopause or who have a low bone mass at the time of menopause should be given the choice of medically supervised replacement therapy with estrogen and progesterone.

Calcium Supplementation with and without Hormone Replacement Therapy To Prevent Postmenopausal Bone Loss

Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures. Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [1-4]. However, only about 10% of American women elect to receive replacement therapy because of attitudes of physicians and patients, the undesirability of menstrual bleeding, and unresolved questions about the relation of the use of estrogen to breast cancer [5]. Moreover, the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued, yet the incidence of some adverse effects increases with the duration of estrogen use. Safer alternatives to estrogen use have been sought. Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss, and prospective studies have yielded conflicting results [6-17]. Moreover, some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [18]. We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo. The study had a three-arm, randomized, parallel design. The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians, whereas the placebo and calcium groups were double blinded. Methods Healthy, white women between 6 months and 6 years after a natural menopause were recruited to participate in the study. The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory; written informed consent was obtained from each participant. Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign. All participants had a history and physical examination. Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use, gastrointestinal disease, or any chronic illness. Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements. Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm (breast or uterus), undiagnosed vaginal bleeding, thrombophlebitis or thromboembolism, and acute liver disease. Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded: gallbladder disease, history of liver disease, first-degree relatives with breast cancer, and hypertension. Calcium urolithiasis was also an exclusion factor. Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study. One hundred eighteen women entered the study. The women were randomly assigned to three groups: 1) hormonal replacement [estrogen-progesterone-calcium carbonate], 2) calcium carbonate, or 3) placebo. Assignment to the groups was based on computer-generated random numbers provided by the statistician, with stratification for years postmenopause. The women in the hormonal replacement group took conjugated equine estrogens (Premarin, Wyeth-Ayerst Laboratories, Inc.; Philadelphia, Pennsylvania), 0.625 mg daily for 25 days of the month along with medroxyprogesterone (Provera, Upjohn; Kalamazoo, Michigan), 10 mg from days 16 to 25. All women received 400 IU of vitamin D daily in the form of a multivitamin, and calcium supplementation (as Caltrate, Lederle; Clifton, New Jersey) was provided to the two treatment groups. The duration of the study was 2.9 1.1 years (mean SD). A 7-day dietary history was reviewed with a nutritionist every 2 months; calcium was provided as calcium carbonate, 600 mg (Caltrate), and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium (the mean + 2 SD found by Heaney and colleagues [7] to result in zero calcium balance in estrogen-deprived women). The calcium supplements were taken with meals in divided doses. The placebo appeared identical to the calcium carbonate tablets. No patients took antacids or histamine-2 blockers. All women had a baseline mammogram. Measurements Routine laboratory studies included a complete blood count, urinalysis, and serum fasting calcium, phosphorus, urea nitrogen, creatinine, alkaline phosphatase, cholesterol, and aminotransferase measurements [19, 20]. In addition, follicle-stimulating hormone, estradiol, parathyroid hormone, osteocalcin, free thyroxine, and bone alkaline phosphatase were measured, and a urine specimen was collected after an overnight fast for hydroxyproline, calcium, and creatinine determinations, following a 3-day low-hydroxyproline diet [21-23]. Total body calcium was measured annually in the participants, using the delayed neutron activation method at Brookhaven National Laboratory [24, 25]. This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 (natural abundance of 0.187%) in the body. The Brookhaven National Laboratory whole-body counter was upgraded in 1987 to use 32 NaI (T1) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [25]. The activated isotope, Calcium-49, decays with a half-life of 8.72 minutes, emitting a 3.08 MeV characteristic line. More than 99.5% of the body calcium is contained in the bone [26]. The method provides total body calcium with a coefficient of variation of about 1.5% when no substantial change in the body weight occurs during the period of repeated studies. The measurements were made annually. The bone mineral density of the distal radius site was measured using a Lunar Radiation (Madison, Wisconsin) single-photon absorptiometer (SP2). Bone mineral density of the spine (L2-L4) and femur (neck, trochanter, and Ward triangle) was measured using a Lunar Radiation DP4 dual-photon absorptiometer. The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1. All scans were analyzed using the same software version, which corrects for source decay. Instruments were calibrated daily, and the radioactive source was changed annually. Each measurement was done every 6 months. The coefficient of variation of these measurements was 2%, except for the Ward triangle (2.5%). Activity was measured using activity monitors (large-scale integrated monitors), which were worn about the waist [27]. The average of 2 weekdays and 1 weekend day was used as an activity score. Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise. Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons: It measures mass rather than density per unit area; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique; it is more precise than the other measurements; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton. The rate of change in bone mineral was calculated for each woman at each of the sites used in the study. Standard linear regression procedures were used to estimate the rate of bone mineral change for each woman, and the regression intercept was used as the best estimate of the baseline value. Because some women terminated their participation in the study before others, the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [28]. Analyses of covariance were done using body mass index, activity scores, cigarette smoking, calcium intake, age, and years postmenopause as covariates. The data reported in this article are based on all women who provided at least three observations for a particular skeletal site. We considered other criteria, such as using data only from women who had participated in the study for at least 2 years, and all data analyses were done for this subgroup as well. The results of these analyses were invariably similar to those reported here and therefore are not presented separately. The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages; separate analyses were carried out for each. The two indices were similar. Evidence from recent research is substantial that estrogen replacement therapy is effective, whereas the efficacy of calcium supplements is questionable. Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy, and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown. A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions. We used two a priori contrasts: the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo. All P values reported are two-tailed. Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1. Analysis of variance showed no significant differences in the baseline variables. The initial and final activity scores did not differ significantly. Table 1. Baseline Values for Patient Characteristics, Bone Mineral Measurements, and Chemical Variables The range of initial daily calcium intake in the overall study group was 150 to 1263 mg; in the calcium augmentation group, it was 222 to 806

A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects

Transilial bone biopsies following in vivo fluorochrome labeling were obtained from 90 women with postmenopausal osteoporosis and 34 healthy post-menopausal women. Standard histomorphometric data were collected from undecalcified sections. The distribution of values for both structural and remodelling indices was the same for each group. Bone volume was 35% lower (P less than 0.001), wall thickness was 12% lower (P less than 0.001), and trabecular thickness was 11% lower (P less than 0.02) in osteoporotics. Trabecular separation was 34% greater (P less than 0.001) and trabecular number was 36% lower (P less than 0.001) in osteoporotics. Biopsy core width was 11% less (P less than 0.02) and cortical width was 35-50% less (P less than 0.001) in osteoporotics. Static indices of remodelling, mineralizing surfaces, and mineral apposition rate were similar in the two groups. The absolute values for bone histomorphometric variables for both groups are similar to most published data. Osteoporotics had poorer bone structure, marked by decreased trabecular connectivity and thin cortices. There were no major differences in dynamic indices of remodelling. Since the histomorphometric data were distributed the same in both groups, special subsets of osteoporotic subjects not in the normal population did not exist.

The 2011 Dietary Reference Intakes for Calcium and Vitamin D: What Dietetics Practitioners Need to Know

The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively reviewed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for ages older than 1 year. For nonskeletal outcomes, including cancer, cardiovascular disease, diabetes, infections, and autoimmune disorders, randomized clinical trials were sparse, and evidence was inconsistent, inconclusive as to causality, and insufficient for Dietary Reference Intake (DRI) development. The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily, respectively, for ages 1 year and older. For vitamin D (assuming minimal sun exposure), the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older, corresponding to serum 25-hydroxyvitamin D (25OHD) levels of 16 ng/mL (40 nmol/L) for EARs and 20 ng/mL (50 nmol/L) or more for RDAs. Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA. Higher serum 25OHD levels were not consistently associated with greater benefit, and for some outcomes U-shaped associations with risks at both low and high levels were observed. The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily, based on calcium excretion or kidney stone formation, and from 1,000 to 4,000 IU daily for vitamin D, based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships. Urgently needed are evidence-based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention.

A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.

Vitamin D has been shown to be an important immune system regulator. Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections (URIs). To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms, 162 adults were randomized to receive 50 microg vitamin D3 (2000 IU) daily or matching placebo for 12 weeks. A bi-weekly questionnaire was used to record the incidence and severity of URI symptoms. There was no difference in the incidence of URIs between the vitamin D and placebo groups (48 URIs vs. 50 URIs, respectively, P=0.57). There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [5.4+/-4.8 days vs. 5.3+/-3.1 days, respectively, P=0.86 (95% CI for the difference in duration -1.8 to 2.1)]. The mean 25-hydroxyvitamin D level at baseline was similar in both groups (64.3+/-25.4 nmol/l in the vitamin D group; 63.0+/-25.8 nmol/l in the placebo group; n.s.). After 12 weeks, 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group, whereas there was no change in vitamin D levels in the placebo group. There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter. Further studies are needed to determine the role of vitamin D in infection.

Differential effect of treadmill exercise on three cancellous bone sites in the young growing rat

The aim of the present study was to examine cancellous bone changes induced by exercise on three different skeletal sites, the lumbar vertebra, the proximal, and the distal tibia, in the young growing rat. Forty 4-week-old female Sprague-Dawley rats were randomized into 4 groups of 10 animals each; 8 weeks exercise (8EX), 8 weeks sedentary control (8CON), 12 weeks exercise (12EX), and 12 weeks sedentary control (12CON). The exercise regimen consisted of treadmill running at 24 m/min 1 hr per day 5 days a week. After each period of exercise, the proximal and distal tibial metaphyses (PTM and DTM, respectively) and the fifth lumbar (L5) vertebral body were processed for histomorphometry of the cancellous bone (secondary spongiosa) and cortical periosteum. Eight and twelve weeks of exercise significantly increased the mineral apposition rate and bone formation rate in the PTM and DTM, and 12 weeks of exercise significantly increased the labeled perimeter in the DTM, compared with the age-matched controls. Eight and twelve weeks of exercise significantly increased cancellous bone volume in the PTM (mean +/- standard deviation, 8EX; 19.1 +/- 2.9% vs 8CON; 14.3 +/- 3.1%, P < 0.05 and 12EX; 18.8 +/- 3.5% vs 12CON; 15.2 +/- 3.3%, P < 0.05), and 12 weeks exercise significantly increased cancellous bone volume in the DTM, compared with age-matched control (12EX; 32.5 +/- 7.7%, 12CON; 22.2 +/- 4.8%, P < 0.05). The increase in cancellous bone volume by 12 weeks exercise was higher in the DTM than that in the PTM (43.4% and 24.0%, respectively). On the other hand, the exercise did not significantly affect cancellous bone volume and bone formation in the L5 vertebral body, although the cortical periosteal bone formation rate and the L5 vertebral bone mass were increased. These findings suggest that cancellous bone adaptation to treadmill exercise is site specific, and the effect may be influenced by factors such as mechanical loading and metaphyseal bone architecture in the young growing rat.

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

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.