J. Christopher Gallagher

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.

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.

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.

Effects of Denosumab Treatment and Discontinuation on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Women with Low Bone Mass

CONTEXT Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

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

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.

Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women

OBJECTIVE To evaluate the efficacy of the tissue-selective estrogen complex, bazedoxifene/conjugated estrogens (BZA/CE), for postmenopausal osteoporosis prevention. DESIGN Multicenter, randomized, double-blind, placebo- and active-controlled, phase 3 trial (Selective estrogen Menopause And Response to Therapy [SMART]-1). SETTING Outpatient clinical study. PATIENT(S) Women (n = 3,397) more than 5 years and 1-5 years postmenopause were enrolled in the Osteoporosis Prevention I and II Substudies, respectively. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg) each with CE (0.625 or 0.45 mg), raloxifene (60 mg), or a placebo taken daily for 2 years. MAIN OUTCOME MEASURE(S) The primary outcome for both substudies was change in bone mineral density of the lumbar spine; bone mineral density was also measured at the hip. RESULT(S) In both substudies, bone mineral density increased significantly more with all BZA/CE doses compared with placebo at the lumbar spine and total hip, and for most BZA/CE doses compared with raloxifene at the lumbar spine. Osteocalcin and N-telopeptide significantly decreased with all BZA/CE doses vs. placebo and most BZA/CE doses vs. raloxifene. CONCLUSION(S) BZA/CE combinations decreased bone turnover and bone loss in postmenopausal women at increased risk for osteoporosis.

Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen

PURPOSE To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen. SUBJECTS AND METHODS A prospective, randomized clinical trial was performed in 81 postmenopausal women aged 51.7 +/- 4.4 years (mean +/- SD). They were assigned to one of four groups: Provera 20 mg, Premarin 0.6 mg, Premarin 0.3 mg plus Provera 10 mg, and a placebo. In addition, all women received calcium supplementation, if necessary, to a calcium intake of 1,000 mg/day. We used single- and dual-photon absorpiometry, metacarpal radiogrammetry, and computed axial tomography to measure bone mineral density in the total skeleton, spine, radius, and metacarpal. RESULTS Women receiving placebo lost bone at all sites (p less than 0.01). The Provera-treated group showed no change in total body calcium, but there were decreases in radial density (p less than 0.01), metacarpal cortex (p less than 0.01), and spine density (p less than 0.01). The Premarin-treated group had an increase in spine density and total body density (p less than 0.05), but a decrease in radial density (p less than 0.05). The Premarin-plus-Provera group showed no change in spine density, total body calcium, or radial density but had a decrease in metacarpal cortex (p less than 0.01). CONCLUSIONS Compared to placebo, Provera reduced the rate of loss in cortical areas of the skeleton, but not in the spine, which contains more trabecular bone. In contrast, Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton. The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone, suggesting that there may be a synergistic effect of this hormone combination on bone. Serum cholesterol levels decreased with Provera, Premarin, and the combination of both, whereas levels of serum triglycerides increased with Premarin treatment, decreased with the Provera regimen, and were unchanged with the combination therapy. Provera does not adversely affect the lipid profile.

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.

Calciotropic hormones and bone markers in the elderly

There is a lack of substantial data on changes in calciotropic hormones and bone markers in elderly subjects living in North America. Parathyroid hormone (PTH), serum 25‐hydroxyvitamin D (25(OH)D) and bone markers (serum osteocalcin and urine N‐telopeptide), were measured in 735 Caucasian subjects (235 men and 500 women) aged 65–87 years. There was a significant increase in serum osteocalcin and urine N‐telopeptide with age in men, and a significant increase in serum osteocalcin with age in women. Serum PTH and 25(OH)D showed no significant change with age in men or women. After adjusting for age, calcium intake, serum creatinine, season, and weight, mean serum PTH (p = 0.01), serum osteocalcin (p = 0.0001) and 24 h urine N‐telopeptide (p = 0.0001) were higher in women than men, and mean serum 25(OH)D (p = 0.0001) and 24 h urine calcium (p = 0.0001) were higher in men than women. Serum PTH was correlated with serum osteocalcin in men and women, r = 0.24, r = 0.17, p < 0.001, but not with urine N‐telopeptide. Serum PTH was inversely correlated with serum 25(OH)D (r = −0.25, r = −0.34, p < 0.001), and positively correlated with serum creatinine (r = 0.14, r = 0.17, p < 0.01) in men and women. The prevalence of serum 25(OH)D levels below 12 ng/ml was only 3.3% in females and 0.4% in men. Thus vitamin D deficiency was very uncommon in the U.S.A. compared with Europe. Although mean serum PTH was increased in the elderly, only 4–6% had PTH levels above the normal range. In summary, the increase in serum PTH in the elderly can be explained more by changes in vitamin D status than by declining renal function. These data also show significantly higher (p = 0.001) bone remodeling markers in women.

14th Vitamin D Workshop consensus on vitamin D nutritional guidelines.

As background information, the reader should appreciate that at he 13th Vitamin DWorkshop in 2006 it was agreed that about half f elderly North Americans and Western Europeans and probably lso two thirds of the rest of the world are vitamin D deficient as udgedby their inability tomaintain a healthy bonedensity [1–3]. It as also generally agreed that the serum concentration of 25(OH)D n normal subjects is the best indicator for judging the vitamin D tatus in patients with vitamin D-related disease states [4]. The14thWorkshoponVitaminD,held inBrugge, Belgium,Octoer 4–8, 2009wasattendedby419 scientists from35countrieswho ere privileged to listen and participate in a Vitamin D Roundtable hat was held in order to allow presentation and broad discusion of two distinct views of and approaches to worldwide vitamin nutritional status. One Roundtable position is that an absolute inimum 25(OH)D level of 20ng/ml (50nmol/l) is necessary in all ndividuals in order to support and maintain all the classic actions f vitamin D on bone andmineral health and that, according to this riterion, a large proportion of the world’s population is vitamin D eficient. Thosewhohold this position further believe that thehuge ffort needed to ameliorate this deficiency must be undertaken as oon and actively as possible and that the target 25(OH)D levels of 20ng/ml should be obtained in the majority of the target populaion. The second Roundtable position is that newer data showing ssociations between vitamin D status and prevalence of several iseases such as cardiovascular disease, hypertension, colon and reast cancer, multiple sclerosis as well as the involvement of vitain D in muscle strength and immune functions [5], indicates that arget levels of 25(OH)D should be 30–40ng/ml (75–100nmol/l) t the minimum. As a basis for policy decision making, these two ositions are incompatible with one another. However, through onsideration of the aspects of vitamin D nutrition upon which the roponents of the two views agree, as well as acknowledging diferences in opinion, consensus on how to proceed in the near term an emerge. This was the goal of the Vitamin D Roundtable. TheRoundtable, chaired byAnthonyNorman (USA) andChristoher Gallagher (USA), began with 15-min presentations from obert Heaney (USA) and Reinhold Vieth (Canada), both propoents of 25(OH)D>40ng/ml, followed by presentations by Roger ouillon (Belgium) and Paul Lips (Netherlands),who advocateminmum25(OH)D levels of 20ng/ml. A selected group of experts from round theworld, Bess Dawson-Hughes (USA), John Pettifor (South frica), Peter Ebeling (Australia), and Christine Lamberg-Allardt