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Cranney A, Horsley T, O'Donnell S, et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Aug. (Evidence Reports/Technology Assessments, No. 158.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Effectiveness and Safety of Vitamin D in Relation to Bone Health

Effectiveness and Safety of Vitamin D in Relation to Bone Health.

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1Introduction

Overview

Vitamin D plays an essential role in calcium homeostasis and the development and maintenance of the skeleton. The main source of vitamin D is the cutaneous synthesis of previtamin D3 from 7-dehydrocholesterol through exposure to ultraviolet B (UV-B) light, in the wavelength 290–320 nm. When sun exposure is limited (e.g., during winter months), dietary sources, such as oily fish, fortified foods or dietary supplements, and vitamin D stores help maintain serum 25(OH)D concentrations.

Circulating 25 hydroxyvitamin D [25(OH)D] is a commonly used indicator of vitamin D status. Different approaches to increase vitamin D stores and serum 25(OH)D levels (solar UV-B exposure, dietary sources and vitamin D supplements) have variable efficacy and depend on individual characteristics such as body mass index (BMI), age or race as well as environmental factors such as latitude (for UV-B exposure). Although vitamin D is an important determinant of bone health, there is no currently accepted definition of the optimal concentration of serum 25(OH)D for use as an indicator for bone health throughout life. There is conflicting evidence on both the functional consequences of low serum 25(OH)D concentrations on bone health outcomes and the efficacy of vitamin D supplementation to prevent fractures and falls. A systematic review was conducted to address these issues and to identify areas that require further research.

Objectives

The purpose of this report was to systematically review the literature on the effectiveness and safety of vitamin D relevant to bone health and to address the following objectives put forth by the Agency for Healthcare Research and Quality (AHRQ) and the National Institutes of Health Office of Dietary Supplements (NIH-ODS).

1.

To determine if specific concentrations of serum 25(OH)D are associated with bone health outcomes in infants, children, women of reproductive age, postmenopausal women and elderly men.

2.

To determine if dietary intake from fortified foods and/or vitamin D supplements, and sun exposure, affect the concentrations of circulating 25(OH)D.

3.

To assess the effect of supplemental doses of vitamin D (D2 considered separately from D3) on bone mineral density, fractures and fall risk in women of reproductive age, postmenopausal women and elderly men, and to determine if the benefits of supplementation vary with the baseline serum concentration of 25(OH)D.

4.

To determine if there is a level of sunlight exposure (time of year, latitude, body mass index (BMI), amount of skin exposed) that is sufficient to maintain adequate serum 25(OH)D levels, but that does not increase the risk of melanoma or non-melanoma skin cancer.

5.

To determine if the intake of vitamin D above current reference intakes leads to toxicity e.g., hypercalcemia, calcification of soft tissue and major organs and hypercalciuria.

The findings of the report are intended to assist the AHRQ and the NIH-ODS in identifying areas for future research and in the development of practical information for healthcare providers and consumers.

Background

Osteoporosis is a chronic condition characterized by increased skeletal fragility that predisposes an individual to risk of fracture. Fractures range from asymptomatic vertebral collapse to hip fractures that are accompanied by serious morbidity and potential mortality. In the United States, osteoporosisa at the hip affects 10 million women and men over the age of 50, with an additional 30 million individuals having osteopenia, a lesser degree of bone loss.1 There are 1.5 to 2 million incident fractures annually in the U.S., and the direct medical costs of osteoporosis are estimated at $13.7–20.3 billion (in 2005 dollars).2 The burden of fractures is expected to increase over the next two decades due to the increased proportion of the population over the age of 65 years.1, 3

Vitamin D plays an essential role in calcium homeostasis and the development and maintenance of the skeleton, is recommended for the prevention of rickets, optimization of peak bone mass, and prevention of bone loss, and may reduce the risk of osteoporosis-related fractures.4 In addition, vitamin D has potential extraskeletal effects on the neuromuscular and immune systems.58 The increased suggestions about the potential for vitamin D insufficiency in the general population and its potential impact on bone health, and other health outcomes, have highlighted the need to update our current scientific knowledge in the area.

The two main sources of vitamin D are dietary intake and skin synthesis in response to exposure to ultraviolet B light (290–320 nm). Food sources of vitamin D include fatty fish, egg yolks, fish liver oils and foods fortified with vitamin D such as milk, margarine, some cereals and yogurts as well as some fruit juices, soy and rice beverages. Since few foods provide a natural source of vitamin D and food fortification is variable, sunlight is thought to constitute the main source of vitamin D worldwide.9 The amount of vitamin D synthesized in the skin varies by factors such as latitude, season, time of day, degree of skin exposure, use of sunscreen, and skin pigmentation or race. Previous estimates suggest that a single minimal erythemal skin dose of simulated sunlight will raise circulating levels of 25(OH)D comparable to ingestion of 10,000 to 25,000 IU of vitamin D3.10

Role of Vitamin D in Bone Health

The principal physiologic role of vitamin D is to maintain calcium homeostasis although it also has potential non-calcemic actions.11 Its principal sites of hormonal action are the intestine, where it increases calcium absorption, and bone. Vitamin D ensures the mineralization of the organic matrix of bone, and also mediates the release of calcium and phosphate from bone to achieve mineral homeostasis.

In the classical endocrine pathway, vitamin D enters the circulation attached to a D-binding protein, is first hydroxylated in the liver to 25(OH)D and then in the kidney to form the active metabolite, 1,25 dihydroxyvitamin D (1,25-(OH)2 D) or calcitriol. The production of calcitriol is stimulated by parathyroid hormone (PTH), and decreased by calcium.12 Calcitriol also downregulates its own production. 1,25-(OH)2D exerts its effects through the vitamin D receptor leading to gene expression and by more immediate effects mediated by second messengers.12 Calcitriol and the vitamin D receptor are essential for active calcium absorption from the gut, longitudinal bone growth and the activity of osteoblasts (cells that form bone) and osteoclasts (cells that resorb bone). In osteoblasts, vitamin D receptor activation induces expression of the ligand RANKL (receptor activator of nuclear factor kappa beta ligand) on their surface membrane. Interaction of RANKL with its receptor, RANK, on preosteoclasts induces differentiation and activation of osteoclasts.13

The enzyme that catalyzes the synthesis of 1,25-(OH)2D in the kidney, 25-hydroxyvitamin D3-1-α-hydroxylase, is also expressed in other tissues and cells such as colon, prostate, mammary gland, macrophages, antigen-presenting cells, osteoblasts and keratinocytes, resulting in extrarenal production of calcitriol.5 Vitamin D receptor (VDR) expression is also widespread, and many genes encoding proteins involved in the regulation of cell proliferation, differentiation and apoptosis (programmed cell death) contain vitamin D responsive elements. In addition to its calcemic actions, calcitriol has potential immunomodulatory and antiproliferative effects through autocrine and paracrine pathways. These actions have implications for its potential use as a preventive or therapeutic agent in cancer and other chronic conditions, as well as a role in innate immunity.57

Vitamin D promotes active transport of calcium predominantly from the small intestine. At higher calcium loads, more calcium is absorbed by passive absorption, and there is less dependency on vitamin D.

In the vitamin D deficiency state, calcium absorption from the gastrointestinal tract is decreased.14 A low serum calcium stimulates the production of PTH which regulates calcium homeostasis by increasing the conversion of vitamin D to its active form. This in turn mobilizes calcium from bone, increases intestinal calcium absorption, and decreases calcium excretion.

The decline in estrogen that occurs after menopause is associated with a negative calcium balance, as a result of decreased calcium absorption and increased urinary calcium loss. Menopause is also associated with increased bone turnover, bone loss and reductions in circulating total 1,25-(OH)2 D concentrations. The effect of menopause on PTH is less clear, with some studies suggesting that estrogen may modulate PTH secretion directly.

The active metabolite of vitamin D is important for the transport of calcium across the placenta in order to provide the fetus with mineral, especially during the last trimester. During pregnancy, fractional calcium absorption increases from 35 (non-pregnant state) to 60 percent during the third trimester. Serum 1,25-(OH)2D concentrations increase to facilitate the increased calcium absorption although the underlying mechanism is not fully understood, and increased serum PTH concentrations have not been demonstrated.15

During lactation, neither 1,25-(OH)2D serum concentrations nor calcium absorption are increased. The usual daily loss of calcium ranges from 280–400 mg and in order to meet these demands, skeletal calcium is released by temporary bone demineralization. Bone demineralization is reversible following weaning.16, 17 The extent to which the adaptive processes in calcium homeostasis that occur during pregnancy and lactation depend on maternal vitamin D status, and how this impacts on the mother's bone health, has not been well studied.

Consequences of Vitamin D Deficiency on Bone Health

Vitamin D deficiency is associated with increased bone remodeling which contributes to structural damage, including increased cortical porosity. During skeletal development and growth, severe vitamin D deficiency results in rickets, a mineralization defect of the growth plate.18 The manifestations of rickets include growth failure, muscle weakness, fractures and skeletal deformities. Severe degrees of vitamin D deficiency in the adult result in impaired mineralization of new bone (osteoid) and osteomalacia.

Less severe degrees of vitamin D deficiency lead to secondary hyperparathyroidism. PTH secretion is stimulated to maintain serum calcium levels and results in increased bone turnover and bone loss, and may lead to osteoporosis.

There is a growing recognition that milder or subclinical degrees of vitamin D deficiency, termed insufficiency, may also be associated with suboptimal health outcomes. Various definitions for both vitamin D deficiency and insufficiency have been proposed that may depend on the particular 25(OH)D assay used as well as the functional outcome measured. There is no clear consensus on the optimal definitions of either vitamin D deficiency or insufficiency. Recent relatively high prevalence estimates of vitamin D insufficiency in the general population19, 20may be attributed to the use of higher 25(OH)D thresholds to define low vitamin D status, compared to previously used thresholds.

Populations at Risk of Vitamin D Deficiency

Overt vitamin D deficiency in the general population is low.21, 22 Although vitamin D deficient or nutritional rickets was thought to have been eliminated, contemporary cases have been reported in the literature. It has not been possible to confirm whether the reported cases represent an actual increase in prevalence of rickets over time or reflect an increased awareness of the disease.23, 24 Vitamin D-deficiency rickets has been noted more often in dark skinned infants who are breast-fed by mothers who are not vitamin D replete. Infants who are exclusively breast-fed and those whose primary milk source is human milk are at risk.2527 However, a preliminary study suggests that infants who are breast-fed by vitamin D replete mothers taking high doses of supplemental vitamin D3 achieve similar circulating vitamin 25(OH)D levels as those infants receiving oral vitamin D3.28

Older adults manifest vitamin D insufficiency or deficiency for a variety of reasons, including less efficient skin synthesis of vitamin D3 and a lack of sunlight exposure.10, 2932 The prevalence of vitamin D deficiency in cohorts of hip fracture patients has been reported at 50% (serum 25(OH)D ≤ 30 nmol/L)29 and 69% (serum 25(OH)D < 50 nmol/L).29, 33, 34 A high prevalence of vitamin D deficiency has also been noted in medical inpatients and shut-in individuals.35, 36 Vitamin D deficiency is also more common in adults who cover their skin for cultural reasons and dark skinned individuals.10, 29, 33, 34, 3639

At latitudes above 42 degrees N, ultraviolet energy is inadequate in winter months for the photoconversion of 7-dehydrocholesterol to previtamin D3. As a result, even in the general population, the prevalence of vitamin D insufficiency and deficiency increases during the winter months.19 Large seasonal fluctuations of circulating 25(OH)D concentrations can occur, and summer sun exposure may not sustain adequate vitamin D levels over the winter months in northern latitudes for most individuals.40

Definitions of Optimal Vitamin D Status for Bone Health

Serum 25(OH)D, the most abundant circulating precursor of active vitamin D, is the most widely accepted indicator of vitamin D status and reflects combined contributions from cutaneous synthesis, and dietary intake including fortified foods and supplemental sources of vitamin D. Serum 25(OH)D has a half-life of approximately two to three weeks, and varies over a wide range. In contrast, the active form of vitamin D, 1,25-(OH)2D, has a short circulating half-life and is tightly regulated over a narrow range by parathyroid hormone, calcium and phosphate. Serum 1,25-(OH)2D is not a good measure of vitamin D status since a decrease may not occur until vitamin D deficiency is severe.

There is considerable debate on how best to define adequate vitamin D status for bone health. Various cutpoints of serum 25(OH)D concentrations have been proposed ranging from 40 to 120 nmol/L. This confusion has arisen from two main sources: differences in the functional endpoint (e.g., fractures, serum PTH) and differences in the analytical methods to measure serum 25(OH)D.41

Endpoints to help define adequate vitamin D status for bone health range from biochemical markers (PTH) and other surrogate markers (e.g., BMD) to clinical endpoints such as fractures. For example, serum 25(OH)D concentrations below 20 to 25 nmol/L have been associated with an increased risk of clinical, radiological and histological changes of osteomalacia and rickets. Concentrations above which bone loss is minimized and fracture risk decreased are other endpoints that have been used. Bischoff found the association between serum 25(OH)D concentrations and BMD had a steep positive slope in the reference range, reaching a plateau at a concentration of 90 to 100 nmol/L in an older Caucasian population.42

As serum 25(OH)D levels increase, serum PTH falls and then levels off. The threshold concentration of 25(OH)D above which there is no further suppression of PTH has also been used to distinguish adequate vitamin D status from vitamin D insufficiency.41, 43, 44

Another outcome that might exhibit threshold behavior is intestinal calcium absorption. Heaney reported that postmenopausal women (mean age 64 years and BMI 28.8 kg/m2) with serum 25(OH)D concentrations at the low end of the reference range may not be maximizing their calcium absorption.39 However, another study did not find evidence for a threshold of 25(OH)D in association with calcium absorption.45

Measurement of Serum 25(OH)D Concentrations

There are a variety of assays that measure 25(OH)D. Technical challenges in determining an individual's true circulating 25(OH)D level include the protein's hydrophobic and hydrophilic properties and the strength of its binding to vitamin D binding protein. The available assays vary in complexity of sample preparation, the technical expertise required to run the assays, degree of automation and ability for high throughput, and accuracy of detection of total 25(OH)D and individual isoforms as well as other vitamin D metabolites. Assays include competitive protein binding assays (CPBA), radioimmunoassays (RIA), enzyme-linked immunoassays (ELISA), chemiluminescence assays, high performance liquid chromatography (HPLC) with UV detection, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and gas chromatography coupled with mass spectrometry (GC-MS).4648

The first competitive protein-binding assays (CPBA) required an extraction step, chromatographic clean up for co-extracted contaminants, and radioligand detection. The most recent generation of CPBA includes a chemiluminescent assay that utilizes a specific antibody as a competitive binder and does not require sample extraction. With the availability of commercial assays (e.g., immunoassays), large numbers of samples can be processed rapidly. Chromatographic techniques (HPLC, LC-MS/MS, GC-MS) have the advantage of measuring 25(OH)D2 and 25(OH)D3 separately. The highest attainable analytical accuracy may be through the principle of isotope dilution with stable isotope-labeled internal standard compounds and mass spectrometry.48, 49

It is apparent that results differ between methods, and that different methods may not recognize 25(OH)D2 and 25(OH)D3 equally. Data from the international Vitamin D External Quality Assessment Scheme (DEQAS) provide an indication of the relative performance of participating laboratories.50, 51 DEQAS and other comparative studies have shown that results can differ between laboratories even using the same method.50, 5258 Some studies have reported discordant results in terms of the variability observed, and some have not included an accurate reference method (e.g., LC-MS/MS or HPLC). Even within a particular technique such as RIA, different sources of antibodies may vary in specificity and the ability to detect each isoform, and extraction or purification procedures may also differ.54 Some RIA assays underestimate 25(OH)D2. There are no commercially available standard reference preparations or calibrating materials to help reduce the variability of results between methods and/or laboratories, or to alert the laboratory of any deviation from the true value. Until we can reliably measure serum 25(OH)D concentrations, this important issue must be considered when defining a cut-off point for adequate vitamin D status. It is also possible that assay-specific decision limits may be required in order to define appropriate thresholds, providing further challenges in implementation of recommendations.59

Vitamin D Supplementation

Vitamin D3 (cholecalciferol) is a naturally occurring form of vitamin D. Vitamin D2 (ergocalciferol) is found in some plants, dietary supplements, and multivitamins. Both forms of vitamin D are biologically inert and must undergo hydroxylation in the liver and kidneys (or in extra-renal sites) to produce the active metabolite. The average increment in serum 25(OH)D concentrations has been estimated at 1–2 nmol/L for every 40 IU (1 microgram) of vitamin D3 given as an oral dose, depending on baseline 25(OH)D concentrations. Heaney demonstrated that in young men (mean age 38.7 years and BMI 26.2 (2.4) kg/m2), 40 IU of vitamin D3 (1 microgram) resulted in an increment of 0.7 nmol/L or less when given to individuals with higher baseline levels of 70 nmol/L.60 Some studies have reported that vitamin D2 supplements is less effective than vitamin D3 (cholecalciferol) in terms of the effect on serum 25(OH)D concentrations, suggesting that vitamin D2 and D3 may be utilized differently by humans.61 The two isoforms may be metabolized differently, and vitamin D2 has diminished binding to vitamin D binding proteins in plasma.62

Current Dietary Reference Intakes for Vitamin D

The 1997 Institute of Medicine (IOM) Committee was unable to establish estimated average requirements (EAR) on which to base recommended daily allowances (RDA) for vitamin D. The various sources that contribute to circulating 25(OH)D concentrations make this a challenge, and insufficient studies were available to define an RDA. Adequate intakes (AI) were provided instead. Adequate intakes are the amount needed to maintain a defined nutritional state or criterion of adequacy e.g., prevention of rickets or osteomalacia, in all members of a specific healthy population.4 Current dietary reference values are based on vitamin D intakes associated with total circulating 25(OH)D levels. The Institute of Medicine's adequate reference intakes for vitamin D are: 200 IU (5 μg/day) for children from infancy to 19 years; 200 IU (5 μg/day) for individuals aged 19 to 50 years; 400 IU/day (10μg/day) for adults 51 to 70 years of age; and 600 IU/day for adults over the age of 70.4, 63 The AIs for children up to 19 years and adults aged 19 to 50 years represent decreases from prior reference intakes of 400 IU.4, 63 The AI for infants is based primarily on data from the United States, Norway and China that showed a vitamin D intake ≥ 200 IU will prevent physical signs of vitamin D deficiency and maintain serum 25(OH)D above 27.5 nmol/L.63 Vitamin D intakes required for optimal bone health are less well-defined for children and adult populations, especially for those living at northern latitudes.

The more recently published 2005 Dietary Guidelines for Americans (for individuals two years of age or older) recommend higher daily dietary vitamin D intakes (1,000 IU) for individuals who are exposed to insufficient UV-B light, older adults, and people with dark skin.64 Concerns about toxicity include the potential for high vitamin D intakes to cause hypercalcemia, hypercalciuria, renal stones and soft tissue calcification. The current tolerable upper limit of vitamin D intake for infants is 1,000 IU and for children and adults, including pregnant and lactating women, is 2,000 IU.4

Summary

Research has helped clarify the role of vitamin D in bone health but a number of evidence gaps exist. The optimal level of circulating 25(OH)D required for bone health may vary depending on the functional outcome. There are considerable technical problems related to the measurement of 25(OH)D concentrations, including variability in assays and a lack of standardization, that contribute to heterogeneous results and limit pooling of data. The uncertainty surrounding biochemical evidence of vitamin D insufficiency or deficiency and its relation to clinical endpoints requires clarification. In addition, the evidence for efficacy of vitamin D supplementation for the prevention of fractures and falls is conflicting and requires a systematic review, given recent large randomized trials. The safety of UV exposure, food fortification and supplementation in different age groups also requires a systematic assessment.

Footnotes

a

Using the definition of osteoporosis that reports an individual's bone mineral density relative to a standard reference population of young adults (at peak bone mass) and defines osteoporosis as a BMD ≥ 2.5 standard deviations below the mean of the reference population, and osteopenia as 1 to < 2.5 SD below the mean of the reference population.

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