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Vitamin D


Foreword: Vitamin D Hormone: Where Do We Stand, Where Are We Heading? xiii

Anat Ben-Shlomo and Maria Fleseriu

Preface: Vitamin D: Mechanisms of Action and Clinical Applications xvii

J. Christopher Gallagher and Daniel D. Bikle

Biology and Mechanisms of Action of the Vitamin D Hormone 815

J. Wesley Pike and Sylvia Christakos
The central role of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is to
regulate calcium and phosphorus homeostasis via actions in intestine, kid-
ney, and bone. These and other actions in many cell types not involved in
mineral metabolism are mediated by the vitamin D receptor. Recent
studies using genome-wide scale techniques have extended fundamental
ideas regarding vitamin Dmediated control of gene expression while
simultaneously revealing a series of new concepts. This article summa-
rizes the current view of the biological actions of the vitamin D hormone
and focuses on new concepts that drive the understanding of the mecha-
nisms through which vitamin D operates.

Global Overview of Vitamin D Status 845

Natasja van Schoor and Paul Lips
Vitamin D deficiency occurs all over the world, mainly in the Middle East,
China, Mongolia, and India. This article focuses on the vitamin D status
in adults. Risk groups include older persons, pregnant women, and
non-Western immigrants. Adequate vitamin D status, defined as serum
25-hydroxyvitamin D greater than 50 nmol/L, is present in less than
50% of the world population, at least in winter. Preventative strategies,
such as increasing fish consumption, fortification of foods, use of vitamin
D supplements, and advice for moderate sunlight exposure, are

Dietary Vitamin D Intake for the Elderly Population: Update on the

Recommended Dietary Allowance for Vitamin D 871
Lynette M. Smith and J. Christopher Gallagher
Vitamin D insufficiency and deficiency can be diagnosed with measure-
ments 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.
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Toward Clarity in Clinical Vitamin D Status Assessment: 25(OH)D Assay

Standardization 885
Neil Binkley and Graham D. Carter
Widespread variation in 25-hydroxyvitamin D (25(OH)D) assays continues
to compromise efforts to develop clinical and public health guidelines
regarding vitamin D status. The Vitamin D Standardization Program helps
alleviate this problem. Reference measurement procedures and standard
reference materials have been developed to allow current, prospective,
and retrospective standardization of 25(OH)D results. Despite advances
in 25(OH)D measurement, substantial variability in clinical laboratory
25(OH)D measurement persists. Existing guidelines have not used stan-
dardized data and, as a result, it seems unlikely that consensus regarding
definitions of vitamin D deficiency, inadequacy, sufficiency, and excess
will soon be reached. Until evidence-based consensus is reached, a
reasonable clinical approach is advocated.

Current Controversies: Are Free Vitamin Metabolite Levels a More Accurate

Assessment of Vitamin D Status than Total Levels? 901
Daniel D. Bikle, Sofie Malmstroem, and Janice Schwartz
The free hormone hypothesis postulates that only the nonbound fraction
(the free fraction) of hormones that otherwise circulate in blood bound to
their carrier proteins is able to enter cells and exert their biologic effects.
For the vitamin D metabolites less than 1% (0.4% for 1,25(OH) 2D
and 0.03% for 25(OH)D) is free, with more than 99% bound to the vitamin
Dbinding protein (DBP) and albumin (approximately 85% and 15%,
respectively). Assays to measure the free vitamin D metabolite levels
have been developed, and initial studies indicated their value in subjects
with altered DBP levels.

Effect of Vitamin D on Falls and Physical Performance 919

Ruban Dhaliwal and John F. Aloia
Recent understanding has highlighted the importance of extraskeletal role
of vitamin D. Despite numerous observational and interventional studies
over the last two decades, the apparent divergent clinical findings have
intensified the controversy regarding this role of vitamin D in older adults.
This article reviews the existing literature and summarizes the current
knowledge of vitamin D status and vitamin D supplementation on falls
and physical performance, describes the putative mechanisms underlying
this association, and reflects on the controversy surrounding vitamin D
recommendations in older adults.

Vitamin D Effect on Bone Mineral Density and Fractures 935

Ian R. Reid
One hundred years ago, vitamin D was identified as the cause and cure of
osteomalacia. This role remains firmly established. Vitamin D influences
skeletal mineralization principally through the regulation of intestinal cal-
cium absorption. It has been proposed that vitamin D has direct beneficial
effects on bone (besides the prevention of osteomalacia), but these have
been difficult to establish in clinical trials. Meta-analyses of vitamin D trials
Contents ix

show no effects on bone density or fracture risk when the baseline 25-hy-
droxyvitamin D is greater than 40 nmol/L. A daily dose of 400 to 800 IU
vitamin D3 is usually adequate to correct such deficiency.

Vitamin D Metabolism in Bariatric Surgery 947

Marlene Chakhtoura, Maya Rahme, and Ghada El-Hajj Fuleihan
Hypovitaminosis D is common in obese patients and persists after Roux-
en-Y gastric bypass and sleeve gastrectomy. Several societies recom-
mend screening for vitamin D deficiency before bariatric surgery and
replacement doses of 3000 IU/d and up to 50,000 IU 1 to 3 times per
week, in case of deficiency, with periodic monitoring. These regimens
are mostly based on expert opinion. Large trials are needed to assess
the vitamin D dose response, by type of bariatric surgery, and evaluate
the effect on surrogate markers of skeletal outcomes. Such data are
essential to derive desirable vitamin D levels in this population.

The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic

Kidney Disease 983
Ladan Zand and Rajiv Kumar
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are
associated with abnormalities in bone and mineral metabolism, known
as CKD-bone mineral disorder. CKD and ESRD cause skeletal abnormal-
ities characterized by hyperparathyroidism, mixed uremic osteodystrophy,
osteomalacia, adynamic bone disease, and frequently enhanced vascular
and ectopic calcification. Hyperparathyroidism and mixed uremic osteo-
dystrophy are the most common manifestations due to phosphate reten-
tion, reduced concentrations of 1,25-dihydroxyvitamin D, intestinal
calcium absorption, and negative calcium balance. Treatment with 1-hy-
droxylated vitamin D analogues is useful.

Vitamin D Receptor Signaling and Cancer 1009

Moray J. Campbell and Donald L. Trump
The vitamin D receptor (VDR) binds the secosteroid hormone 1,25(OH) 2D3
with high affinity and regulates gene programs that control serum calcium
levels, as well as cell proliferation and differentiation. A significant focus
has been to exploit the VDR in cancer settings. Although preclinical studies
have been strongly encouraging, to date clinical trials have delivered
equivocal findings that have paused the clinical translation of these com-
pounds. However, it is entirely possible that mining of genomic data will
help define precisely what the key anticancer actions of vitamin D com-
pounds are and where these can be used most effectively.

Role of Vitamin D in Cardiovascular Diseases 1039

Vikrant Rai and Devendra K. Agrawal
Vitamin D is critical in mineral homeostasis and skeletal health and plays a
regulatory role in nonskeletal tissues. Vitamin D deficiency is associated
with chronic inflammatory diseases, including diabetes and obesity, both
strong risk factors for cardiovascular diseases (CVDs). CVDs, including
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coronary artery disease, myocardial infarction, hypertrophy, cardiomyop-

athy, cardiac fibrosis, heart failure, aneurysm, peripheral arterial disease,
hypertension, and atherosclerosis, are major causes of morbidity and mor-
tality. The association of these diseases with vitamin D deficiency and
improvement with vitamin D supplementation suggest its therapeutic
benefit. The authors review the findings on the association of vitamin D
deficiency and CVDs.

Regulation of Immune Function by Vitamin D and Its Use in Diseases of

Immunity 1061
An-Sofie Vanherwegen, Conny Gysemans, and Chantal Mathieu
Evidence exists for a role for vitamin D and its active metabolites in modu-
lating immune functions. In animal models, vitamin D deficiency is associ-
ated with a higher risk for autoimmunity in genetically predisposed
subjects and increases in susceptibility to infections. In addition, high-
dose vitamin D can improve immune health, prevent autoimmunity, and
improve defense against infections. In humans, evidence exists on associ-
ations between vitamin D deficiency and impaired immune function, lead-
ing to autoimmunity in genetically predisposed people and increased risk
for infections; data on therapeutic immune effects of vitamin D supplemen-
tation when vitamin D levels are already sufficient are lacking.

Genetic Diseases of Vitamin D Metabolizing Enzymes 1095

Glenville Jones, Marie Laure Kottler, and Karl Peter Schlingmann
Vitamin D metabolism involves 3 highly specific cytochrome P450 (CYP)
enzymes (25-hydroxylase, 1a-hydroxylase, and 24-hydroxylase) in the
activation of vitamin D3 to the hormonal form, 1,25-(OH)2D3, and the inac-
tivation of 1,25-(OH)2D3 to biliary excretory products. Mutations of the acti-
vating enzymes CYP2R1 and CYP27B1 cause lack of normal 1,25-(OH)2D3
synthesis and result in rickets, whereas mutations of the inactivating
enzyme CYP24A1 cause buildup of excess 1,25-(OH) 2D3 and result in hy-
percalcemia, nephrolithiasis, and nephrocalcinosis. This article reviews
the literature for 3 clinical conditions. Symptoms, diagnosis, treatment,
and management of vitamin Ddependent rickets and idiopathic infantile
hypercalcemia are discussed.

Genetic and Racial Differences in the Vitamin D Endocrine System 1119

Roger Bouillon
Twin studies indicate that genetic factors may explain about 50% of the
variation of serum 25-hydroxyvitamin D (25OHD). Polymorphisms of 3
genes, delta-7-sterol-reductase, CYP2R1, and DBP/GC (and maybe
CYP24A1) combined, can explain about 5% to 10% of the variation in
serum 25OHD. These polymorphisms are found in nearly all populations.
The variation in serum 25OHD found in different areas and populations
in the world is mainly due to environmental and lifestyle factors, not truly
dependent on racial differences. One genetic variant of DBP (GC2) is asso-
ciated with a modest (w10%) decrease in serum DBP and 25OHD con-
centrations for unexplained reasons.