Faculty Bibliography

CONTEXT: Bone health is influenced by the intake of both calcium and vitamin D. OBJECTIVE: Our objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration. INTERVENTIONS: Subjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 mug) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months. MAIN OUTCOME MEASURES: Serum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured. RESULTS: Before study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium. CONCLUSIONS: Fasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 mug vitamin D3/d does not.

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.

The recent publication of the Endocrine Society clinical practice guideline, "Evaluation, Treatment, and Prevention of Vitamin D Deficiency,[has generated considerable controversy. Although there are some agreements in this new guideline with the Institute of Medicine (IOM) Committee's 2011 "Report on Dietary Reference Intakes for Calcium and Vitamin D,[there are substantial differences between these 2 guidelines. These disagreements on several important issues generate confusion for clinicians, researchers, and the public. In this commentary, members of the IOM committee address a number of conclusions in the Endocrine Society guideline that are not supported by adequate evidence and are in need of reconsideration. Disagreements of the Committee with The Endocrine Society guideline relate to whether targeted serum 25OHD levels are different for the general and at-risk populations, on how vitamin D deficiency should be defined, and on who constitutes a population at risk versus the general population. Targeted serum 25OHD levels: The guideline does not provide adequate evidence for the assertion that serum levels of 25OHD at 30 ng/mL or higher would be beneficial for at-risk populations (patients with specific underlying conditions such as osteoporosis, kidney or liver dysfunction, malabsorption syndromes, obesity, and pregnancy) compared with the general population. The guideline conclusion with respect to serum 25OHD levels and calcium absorption was based in large part on a single small study published in 2003 evaluating 34 subjects who did not undergo formal calcium absorption tests. The guideline did not include more appropriate data from trials evaluating more than 1000 subjects who underwent formal calcium absorption tests. The overall data from these larger studies contradict the 2003 study and show that calcium absorption reaches near maximum between serum 25OHD levels of 8 to 20 ng/mL. Definition of vitamin D deficiency: The guideline mistakenly concludes that vitamin D is beneficial for a large segment of our population only when serum levels are at 30 ng/mL 25OHD and more and that individuals with serum 25OHD levels less than 20 ng/mL are deficient in vitamin D. The assertion that vitamin D deficiency is present for serum levels of 25OHD in the general population that are less than 20 ng/mL is inconsistent with data showing that a serum level of 16 ng/mL is adequate in 50% of the general population. In addressing the question of insufficient levels of vitamin D, the guideline includes a selected subgroup of available data with no explanation for inclusion of these studies and the exclusion of others. Who constitutes a population at risk versus the general population? The intent of the guideline was to target those with disease and high-risk populations not covered by the IOM report, but in doing so, it inappropriately includes some conditions that are considered to be part of the general population. The IOM committee believes that a systematic evidence-based approach assessing the evidence for both benefits and risks of supplementation for individuals with underlying health conditions is needed. The current Endocrine Society guideline does not reflect an evidence-based approach and needs to be reexamined.

Growth hormone (GH) deficiency causes decreased bone mineral density and osteoporosis, predisposing to fractures. We investigated the mechanism of action of GH on bone modeling and remodeling in hypophysectomized (HX) female rats. Thirty female Sprague-Dawley rats at age 2 months were divided into three groups with 10 rats each: control (CON) group, HX group, and HX + GH (3 mg/kg daily s.c.) group, for a 4-week study. Hypophysectomy resulted in cessation of bone growth and decrease in cancellous bone mass. Periosteal bone formation decreased and bone turnover rate of endocortical and trabecular surfaces increased as compared to the CON group. GH administration for 4 weeks restored weight gain and bone growth and mitigated decrease in bone density after hypophysectomy. However, trabecular bone mass in the proximal tibial metaphysis remained lower in group HX + GH than in group CON. Dynamic histomorphometric analysis showed that bone modeling of periosteal bone formation and growth plate elongation was significantly higher in group HX + GH than in group HX. New bone formed beneath the growth plate was predominately woven bone in group CON and group HX + GH. Bone remodeling and modeling-remodeling mixed modes in the endocortical and PTM sites were enhanced by GH administration; both bone formation and resorption activities were significantly higher than in group HX. In conclusion, GH administration to HX rats reactivated modeling activities in modeling predominant sites and increased new bone formation. GH administration also increases remodeling activities in remodeling predominant sites, giving limited net gain in the bone mass.

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.

This report summarizes the findings of the 2011 Institute of Medicine Committee on dietary intake requirements for calcium and vitamin D in North America, and provides updated data from the previous Institute of Medicine report of 1997. The Committee extensively reviewed existing published evidence on dietary and supplemental intake requirements for calcium and vitamin D with respect to both skeletal health and extraskeletal chronic disease outcomes. Calcium and vitamin D intake requirements were examined for several risk indictors of bone and skeletal health as well as extraskeletal outcomes (including cancer, cardiovascular disease, diabetes, and autoimmune disorders, infectious diseases, neuropsychological function, and disorders of pregnancy). Recommended Dietary Allowance (RDA) was defined as the level of intake of calcium or serum 25-hydroxyvitamin D that would meet the requirements of at least 97.5% of the population. The available scientific data supported an important role for calcium and vitamin D in bone and skeletal health outcomes that was consistent with a cause-and-effect relationship. However, data from randomized clinical trials for extraskeletal health outcomes were limited and inconclusive regarding a possible relationship with calcium and vitamin D intake requirements, and no evidence was found for dose-response or other established criteria for cause-and-effect. For bone health outcome, RDAs of calcium ranged from 700 to 1300 mg/d for life-stage groups at >= 1 year of age, and RDAs of vitamin D were 600 IU/d for ages 1 to 70 years and 800 IU/d for ages >= 71 (corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/mL [50 nmol/L]). There was an assumption of minimal or no sun exposure for estimation of RDA levels because of the wide variation in vitamin D synthesis from ultraviolet light and concern over risk of skin cancer. No consistent evidence was found that dietary or supplemental intake of vitamin D levels above the RDA provides additional benefit for bone health or extraskeletal outcomes; several investigators have found an U-shaped curve for several outcomes related to vitamin D intake, with increased risks at both low and high levels. The findings of this report suggest that prevalence of vitamin D deficiency in North America has been overestimated. The data show that almost all individuals in this population meet their RDA for vitamin D.

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.

Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation. 2-Methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D(3) (2MD) is a vitamin D analogue that potently stimulates bone formation activity in vitro and in the ovariectomized rat model. In this randomized, double-blind, placebo-controlled study of osteopenic women, the effect of daily oral treatment with 2MD on bone mineral density (BMD), serum markers of bone turnover, and safety were assessed over 1 year. Volunteers were randomly assigned to three treatment groups: placebo (n = 50), 220 ng of 2MD (n = 54), and 440 ng of 2MD (n = 53). In general, 2MD was well tolerated. Although 2MD caused a marked increase in markers of bone formation, it did not significantly increase BMD. Since 2MD also shows marked activity on bone resorption (as revealed by dose-dependent increases in serum C-telopeptide cross-links of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone remodeling.