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Endocrine Reviews, 2024, 45, 625–654
https://doi.org/10.1210/endrev/bnae009
Advance access publication 27 April 2024
Review
ENDOCRINE
SOCIETY
OXFORD
6,7
8
9
10
Consensus Statement on Vitamin D Status Assessment
and Supplementation: Whys, Whens, and Hows
Andrea Giustina,¹® John P. Bilezikian, 2 Robert A. Adler,³ Giuseppe Banfi,4,5 D
Daniel D. Bikle, ℗ Neil C. Binkley, Jens Bollerslev, Roger Bouillon,
Maria Luisa Brandi, ①℗ Felipe F. Casanueva, 12 Luigi di Filippo, Lorenzo M. Donini,
Peter R. Ebeling, 14 Ghada El-Hajj Fuleihan, 15 Angelo Fassio, 16 Stefano Frara, 1 Glenville Jones, 17
Claudio Marcocci, 18 Adrian R. Martineau, 19 Salvatore Minisola, 20℗ Nicola Napoli,
Massimo Procopio, 22 René Rizzoli, 23 Anne L. Schafer, Christopher T. Sempos,2
Fabio Massimo Ulivieri, and Jyrki K. Virtanen 25D
11
6
1
24
21
13
ID
Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Milan 20132, Italy
2Department of Medicine, Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
³Richmond Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA 23284, USA
AIRCCS Galeazzi Sant'Ambrogio Hospital, Milano 20161, Italy
5 San Raffaele Vita-Salute University, Milan 20132, Italy
17
6 Department of Medicine, University of California and San Francisco Veterans Affairs Health Center, San Francisco, CA 94121-1545, USA
7Department of Endocrinology, University of California and San Francisco Veterans Affairs Health Center, San Francisco, CA 94121-1545, USA
8 School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA
9Faculty of Medicine, University of Oslo, Oslo 0313, Norway
10Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven,
Belgium
11 Italian Foundation for the Research on Bone Diseases (F.I.R.M.O.), Florence 50129, Italy
12 Department of Medicine, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario and CIBER de Fisiopatologia de la
Obesidad y Nutricion (CIBERobn), Santiago de Compostela University, Santiago de Compostela 15706, Spain
13 Department of Experimental Medicine, Sapienza University, Rome 00161, Italy
14 Department of Medicine, School of Clinical Sciences, Monash University, Clayton 3168, Australia
15 Calcium Metabolism and Osteoporosis Program, WHO CC for Metabolic Bone Disorders, Division of Endocrinology, American University of
Beirut, Beirut 1107 2020, Lebanon
16 Rheumatology Unit, University of Verona, Verona 37129, Italy
17 Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, ON K7L 3N6, Canada
18 Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
19 Faculty of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK
20 Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome 00161, Italy
21 Unit of Endocrinology and Diabetes Campus Bio-Medico, University of Rome, Rome 00128, Italy
22 Division of Endocrinology, Diabetology and Metabolic Diseases, "Molinette" Hospital, University of Turin, Turin 10126, Italy
23 Geneva University Hospitals and Faculty of Medicine, Geneva 1205, Switzerland
24 Vitamin D Standardization Program (VDSP), Havre de Grace, MD 21078, USA
25 Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio FI-70211, Finland
Correspondence: John P. Bilezikian, MD, Department of Medicine, PH 8E105G, Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY
10032, USA. Email: [email protected].
Downloaded from https://academic.oup.com/edrv/article/45/5/625/7659127 by guest on 02 April 2025
Abstract
The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism,
assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend
only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-
hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical
or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering
rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to
clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are
likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in
Received: 1 September 2023. Editorial Decision: 7 March 2024. Corrected and Typeset: 27 April 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Page 2
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Endocrine Reviews, 2024, Vol. 45, No. 5
reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route.
Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements.
Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily
produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the
efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and
extraskeletal potential effects of vitamin D.
Graphical Abstract
Non-canonical vitamin D
metabolites assessment
MM
25(OH)D assessment
Impaired metabolism and
genetic polymorphisms
Rx
Vitamin D
status
Vitamin D
deficiency
Reduced synthesis
and dietary intake
Use of vitamin D forms/
metabolites alternative to cholecalciferol
Skeletal
effects
Extra-skeletal effects
Reduced intestinal
absorption
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Cholecalciferol:
oral route
Cholecalciferol:
parenteral route
2024 Endocrine Society
Key Words: vitamin D, cholecalciferol, calcitriol, calcifediol, vitamin D assay, Vitamin D Standardization Program (VDSP)
Abbreviations: 1,25(OH)2D, 1,25 dihydroxyvitamin D; 7-DHC, 7-dehydrocholesterol; 25(OH)D, 25-hydroxyvitamin D; BMD, bone mineral density; BMI, body mass
index; CDC, Centers for Disease Control and Prevention; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, vitamin D binding protein; ES,
Endocrine Society; HAT, histone acetyltransferase activity; HDAC, histone deacetylase activity; ICU, intensive care unit; IL, interleukin; IOM, Institute of
Medicine; LC-MS, liquid chromatography-mass spectrometry; miRNA, microRNA; MR, mendelian randomization; OR, odds ratio; PTH, parathyroid hormone;
RCT, randomized controlled trial; SRC, steroid hormone receptor coactivator; T2D, type 2 diabetes; TSS, transcription start site; UVB, sunlight; VDR, vitamin
D receptor; VDSP, Vitamin D Standardization Program; vitamin D2, ergocalciferol; vitamin D3, cholecalciferol; VDT, vitamin D toxicity.
Page 3
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ESSENTIAL POINTS
• Total serum 25-hydroxyvitamin D concentration is
the accepted biomarker of vitamin D status, but assay
methodology and standardization as well as desirable
levels, which may vary according to the underlying
condition, are still major issues
• Advances in knowledge about vitamin D have in-
cluded its metabolism, identification of noncanonical
metabolites, mechanisms of action, and genetic poly-
morphisms. These insights have added to our under-
standing of vitamin D's role in nutrition and in
disease
• Vitamin D deficiency reduces intestinal calcium ab-
sorption leading to secondary hyperparathyroidism,
bone loss, and increased risk of fractures in older
adults. Meta-analyses of clinical trials show that vita-
min D and calcium, together, decrease hip and other
fractures in nursing home residents
• Post hoc analyses of recent mega trials on extraskele-
tal effects of vitamin D suggest a link between vita-
min D status and immune system and development
of type 2 diabetes mellitus. Cardiovascular events
and mortality may be positively affected as well
• Daily vitamin D regimens seem to be the most effi-
cient and beneficial strategy to improve vitamin D
status but dosing schedules with longer intervals up
to 4 weeks have been proposed to overcome low
compliance with daily schedules
• Oral cholecalciferol (vitamin D3) remains the pre-
ferred form of vitamin D for supplementation, while
other vitamin D analogues (eg, calcifediol, calcitriol,
alfacalcidol) and parenteral administration should be
used in specific conditions
The 6th International Conference "Controversies in Vitamin
D" was held in Florence, Italy, September 21 to 24, 2022, as
part of this series that started in 2017 (1-10). The objective
of this conference, featuring international experts, was to re-
view and discuss controversial topics regarding vitamin
D. Before the event, participants reviewed the available litera-
ture on their assigned topic and presented their findings at the
conference. After each presentation, open sessions enabled full
discussion. On the last day of the conference, all participants
completed their discussion and agreed on a menu for addition-
al research. The 2 main topics addressed were recommenda-
tions on assessing vitamin D deficiency and vitamin D
supplementation. This paper summarizes the findings on the
"whys, whens, and hows" of these two topics.
Vitamin D Metabolism and Mechanism of
Action
Metabolism
Vitamin D3 is produced in the skin from 7-dehydrocholesterol
(7-DHC), while both vitamin D2 (ergocalciferol) and vitamin
D3 (cholecalciferol) can be present in the diet. Vitamin D2 and
D3 are hydroxylated first in the liver (and other tissues) to
25-hydroxyvitamin D (25(OH)D) and then in the kidney
Ꭰ
(and other tissues) to 1,25 dihydroxyvitamin
(1,25(OH)2D). Both 25(OH)D and 1,25(OH)2D are subse-
quently metabolized to their 24 (and for D3 23) hydroxy forms
24,25(OH)2D2/3, 23,25(OH)2D3, and 1,24,25(OH)3D2/3
(or 1,23,25(OH)3D3). Like other steroid hormones, vitamin D
is highly lipophilic and bound to protein carriers that
help maintain stable serum levels. The half-life of serum
25(OH)D is 2 to 3 weeks, and that of the more water-soluble
1,25(OH)2D is approximately 5 to 8 hours. The majority of
circulating 25(OH)D, including its metabolites, are bound
tightly by vitamin D binding protein (DBP) and more loosely
bound by albumin (4).
7-Dehydrocholesterol reductase
Although the production of vitamin D from 7-DHC under the
influence of sunlight (UVB) is a nonenzymatic step, the pro-
duction of 7-DHC is not. Its synthesis in the skin is a step in
the Kandutsch-Russell pathway. DHCR7 converts 7-DHC
to cholesterol, so its activity dictates how much 7-DHC is
available for vitamin D production. Inactivating mutations
of DHCR7 result in Smith-Lemli-Opitz syndrome, a develop-
mental disorder (11). These patients suffer primarily from the
consequences of too little cholesterol, steroids, or bile acids,
but they appear to be more sensitive to UVB light and may pre-
sent with higher serum 25(OH)D concentrations than normal
individuals. The regulation of DHCR7 is incompletely
understood. Cholesterol and vitamin D (but not 1,25(OH)2D)
increase proteasomal degradation of DHCR7, leading to
increased vitamin D production. AMPK (adenosine mono-
phosphate-activated protein kinase C), a key sensor and regu-
lator of cellular energy homeostasis and protein kinase A are
potent inhibitors of DHCR7 (12).
25-Hydroxylases
The liver is the major source of 25(OH)D production from
vitamin D. However, numerous enzymes within both mito-
chondria and microsomes have 25-hydroxylase activity.
Initial studies suggested that CYP27A1, a mitochondrial en-
zyme with substantial homology to CYP27B1 and
CYP24A1 (the 1a and 24-hydroxylases, respectively), was
the major 25-hydroxylase. However, patients with inactivat-
ing mutations in this enzyme develop cerebrotendinous xan-
thomatosis with abnormal bile and cholesterol metabolism
but not rickets (13). Current data support CYP2R1 as the ma-
jor 25-hydroxylase, at least in the liver (and testes), where it
resides in the microsomal compartment (13). When deleted
in mice, serum 25(OH)D levels fall by over 50%, but not
more. There is little effect on serum calcium and phosphate
levels, suggesting that other enzymes with 25-hydroxylase ac-
tivity compensate. Five functional mutations in CYP2R1 have
been described so far. Although these mutations result in little
or no 25-hydroxylase activity in vitro, individuals maintain
normal or even high 1,25(OH)2D levels and, in some cases, re-
spond both to vitamin D and 1a(OH)D with further increases
in 1,25(OH)2D. As children, these individuals develop classic-
al nutritional rickets responding to high doses of vitamin D or
small doses of 25(OH)D; as adults, they tend to lose their need
for vitamin D supplementation (14). Such data suggest that, as
in the mouse, CYP2R1 could not be the only enzyme with
25-hydroxylase activity (14).
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628
Previously, it had been thought that the 25-hydroxylation
of vitamin D was primarily substrate dependent. However, re-
cent evidence indicates that this is not the case. Roizen et al
(15) found that the serum concentration of 25(OH)D, but
not vitamin D, was decreased in mice fed a high-fat diet to in-
duce obesity associated with decreased expression of CYP2R1
in the liver. Aatsinki et al (16) found that a high-fat diet that
induced obesity and type 2 diabetes (T2D), as well as
streptozotocin-induced type 1 diabetes, both decreased the
hepatic messenger RNA and protein concentration of
CYP2R1. Thus, the concept that the low levels of 25(OH)D
in obesity and the limited response to vitamin D supplementa-
tion in these individuals are somehow related to increased
storage of vitamin D in fat is still controversial (17) and needs
further investigation.
CYP27B1―the 25-hydroxyvitamin D-1α-hydroxylase
Unlike the 25-hydroxylases, there is only a single 25(OH)
D-1α-hydroxylase, CYP27B1. This enzyme is found in the
mitochondrion along with CYP24A1. The kidney is the
main source of circulating 1,25(OH)2D, but many tissues, in-
cluding the epidermis and other epithelial tissues, bone, pla-
centa, and immune system cells, also express CYP27B1. The
product, 1,25(OH)2D, likely has paracrine or autocrine ac-
tions (18). Regulation of CYP27B1 in these extracellular sites
differs from that in the kidney. In the kidney, CYP27B1 is
regulated primarily by parathyroid hormone (PTH) and
insulin-like growth factor-1, which stimulate it, as well as by
fibroblast growth factor 23 (FGF23) and 1,25(OH)2D itself,
which inhibit it. In nonrenal tissues cells, such as keratinocytes
and macrophages, cytokines, such as, interferon-gamma
(IFN-y), tumor growth factor alpha (TNFα), and transforming
growth factor beta1 (TGFẞ1) are the major inducers of
CYP27B1. In peripheral blood mononuclear cells, interleukin
(IL)-1, IL-2, and IL-15 also stimulate CYP27B1 activity,
whereas IL-4 is suppressive (19-21). Thus, the induction of
CYP27B1 in these extrarenal tissues is by cytokines, and the
failure of CYP27B1 in these tissues to respond to the increased
circulating levels of 1,25(OH)2D and calcium account for the
hypercalcemia often found in granulomatous diseases, such as
sarcoidosis and lymphomas (22). Mutations in CYP27B1
cause a disease known as pseudovitamin D-deficiency rickets
or type 1A vitamin D-dependent rickets (23); both the renal
and extrarenal CYP27B1 have the same sequence, but their
differences in regulation occur because of differences in
tissue-specific multicomponent control modules within the
regulatory regions of the gene.
CYP24A1 and CYP3A-the 25-hydroxyvitamin D-24(23)
hydroxylases
These are the catabolic enzymes of vitamin D metabolism, with
both 25(OH)D and 1,25(OH)2D as their substrates (24-26).
CYP24A1 is the dominant 24-hydroxylase in most tissues,
but CYP3A4 likely plays a role in the liver and intestine, where
it is highly expressed. Both enzymes have 24-hydroxylase and
23-hydroxylase activity, although the relative proportions of
24-hydroxylase and 23-hydroxylase activity for CYP24A1
are species specific. Both enzymes are induced by
1,25(OH)2D and CYP24A1 is induced by 25(OH)D as
well (27) and the induction of CYP3A4 seems to be at least
as great as that for CYP24A1 in the intestine. To label
CYP24A1 as a purely catabolic enzyme in vitamin D
Endocrine Reviews, 2024, Vol. 45, No. 5
metabolism would appear to be a misnomer. 1,24,25(OH)3D
has a substantial affinity for the vitamin D receptor
(VDR), with approximately 10% of 1,25(OH)2D biological
activity. Moreover, a specific G protein-coupled membrane
receptor for 24,25(OH)2D, Fam57B2, has been identified
in bone and other tissues such as the skin, and through
this receptor, 24,25(OH)2D was found to be involved in
fracture repair (28). CYP24A1 is under the control of
1,25(OH)2D and FGF23 (both stimulatory) and calcium
(29). 5a-Dihydrotestosterone, via the progesterone receptor,
has also been reported to stimulate CYP24A1 (30). In humans,
inactivating mutations in CYP24A1 are now recognized as a
major cause of idiopathic infantile hypercalcemia, a syndrome
marked by severe hypercalcemia, hypercalciuria, and nephro-
calcinosis, decreased PTH, low 24,25(OH)2D, and inappro-
priately normal to high 1,25(OH)2D. Although initially
identified in children (31), more recent case reports indicate
that the diagnosis may not be made until adulthood, generally
following a condition of increased 1,25(OH)2D production
like pregnancy (32, 33). Such adults generally present with
early-onset nephrolithiasis and/or nephrocalcinosis.
Importantly, CYP3A4 mutations or drug-induced excess
CYP3A4 activity have recently been linked to vitamin D defi-
ciency and vitamin D-dependent rickets type 3, with affected
individuals demonstrating greatly accelerated inactivation of
vitamin D metabolites. This represents a novel mechanism
for vitamin D deficiency (34).
Mechanism of Action
The VDR is critical for most of the actions of vitamin D, with
1,25(OH)2D as its major ligand. VDR is a transcription factor
found in nearly all cells. Not surprisingly, vitamin D affects
many cellular processes via the VDR, with one of the most im-
portant being the regulation of intestinal calcium absorption
(Fig. 1) (4). In a recent ontology analysis (35), 11 031 putative
VDR target genes were identified, of which 43% were in-
volved with metabolism, 19% with cell and tissue morph-
ology, 10% with cell junction and adhesion, 10% with
differentiation and development, 9% with angiogenesis, and
5% with epithelial to mesenchymal transition. Furthermore,
VDR can regulate various microRNAs (miRNAs) and long
noncoding RNAs involving the expression of numerous pro-
teins directly or indirectly. As a result of the appreciation
that the VDR is so widespread along with the key vitamin D
metabolizing enzymes such as CYP27B1 and CYP24A1, inter-
est in understanding the role of vitamin D and the VDR in
nonclassic as well as classic target tissues regulating calcium
and phosphate homeostasis has been substantial. Although
most of the actions of VDR involve its role as a transcription
factor within the nucleus, the VDR has also been shown to
have nongenomic actions via its location in the plasma mem-
brane and perhaps even in mitochondria (4).
Regulation
The regulation of VDR expression is cell specific. For ex-
ample, 1,25(OH)2D regulates VDR expression in bone cells
but not in the intestine. Many factors in addition to
1,25(OH)2D regulate VDR expression, including growth fac-
tors, insulin, as well as PTH, glucocorticoids, estrogen, and
retinoic acid, in some cases acting via a variety of transcription
factors, such as AP-1, SP1, C/EBP, and CDX2, C/EBPẞ,
Runx2, cyclic adenosine monophosphate response element
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Calcium
channel
Ca2+
Ca2+
Ca2+
Calbindin
Ca2+
VDR
Claudins
Ca2+
Vitamin D
Figure 1. Three-step mechanism of intestinal calcium absorption by
vitamin D. An important function of vitamin D is stimulating intestinal
calcium absorption by increasing the expression of calcium-permeable
claudins, apical membrane calcium channels, and calcium-binding
protein calbindins. The extrusion of calcium is across the basolateral
membrane. This process is especially enhanced when dietary calcium
intake is low.
binding protein (CREBP), retinoic acid receptor (RAR), and
glucocorticoid receptor (GR). Similarly, calcium upregulates
VDR expression in the parathyroid gland, presumably
through its calcium-sensing receptor. On the other hand,
SNAIL 1 and 2 (SLUG) downregulate VDR expression in sev-
eral cancer cell lines. MicroRNAs can regulate VDR levels, as
exemplified by the binding of miR-125b, miR-298, and
miR-27b to the 3'untranslated region to decrease VDR levels
(4,36).
Genomic actions
Carlberg (36) reported that the human genome contains more
than 23 000 VDR binding sites, most of which are cell specific.
Their locations varied with the duration of ligand exposure,
and only some were readily identified with a specific gene.
The VDR binding sites can be thousands of bases away
from the transcription start site (TSS) of the genes they regu-
late, and genes generally have multiple VDR binding sites,
the activity of which may vary in different cells and species.
An informative example of how this might work in different
cells is the regulation of the RANKL gene (Tnfsf11). This
gene is regulated by PTH and 1,25(OH)2D in osteoblasts
and by AP-1 factors, such as c-fos, in activated T cells (13).
The Pike laboratory identified 7 VDR binding sites in
RANKL up to 88 kb upstream of the TSS, of which the
-75-kb site proved most active in the mouse gene (37, 38),
whereas the proximal site was most active in the human
gene (39). However, in activated T cells, 3 additional sites
even further upstream of the TSS have been identified as sites
of RANKL induction by c-fos (13).
A similar example can be found for Cyp27b1. This gene is
negatively regulated by its product in the kidney but not in
other tissues (40). The VDR binding sites are generally situ-
ated in a region with other transcription factors that may
share regulation of that gene, potentially providing cell-
specific gene regulation. For example, the VDR binding region
of the RANKL gene contains several CREB sites responsible
for the PTH regulation of this gene (41).
Coregulators and epigenetic changes regulating vitamin D
receptor function
The sites of active transcription are marked by epigenetic
changes both in the gene itself and the histones that regulate
access of the transcriptional machinery to the gene. In humans
and mice, 1,25(OH)2D regulates these epigenetic changes by
affecting the binding of coregulators to the VDR, whether as
coactivators with histone acetyltransferase activity (HAT) or
as cosuppressors with histone deacetylase activity (HDAC).
More than 250 published coregulators interact with nuclear
hormone receptors. The best-studied coactivators with respect
to the VDR are the steroid hormone receptor coactivators
(SRC 1-3) and the Mediator complex. SRCs recruit HATs to
the VDR. The Mediator complex does not contain HAT activ-
ity but binds directly to RNA polymerase II to help form the
preinitiation complex along with basal transcription factors
such as TFIIB and several TAT-binding proteins. These coac-
tivators all bind to the AF2 domain of the VDR. On the other
hand, corepressors, such as SMRT and NCoR complexes,
have HDAC activity and bind to H3 to H5 in the absence of
a ligand. In the presence of 1,25(OH)2D and the conform-
ational change with H12, these corepressors are displaced, en-
abling the coactivators to bind to their sites on H12.
Hairless is a corepressor of VDR expressed primarily in the
brain and skin. It binds to the central region of the ligand-
binding domain of VDR, as does NCOR/SMRT. The role of
hairless is complex in that it represses ligand-dependent
VDR functions with respect to epidermal differentiation
(42) but is required for ligand-independent VDR regulation
of hair follicle cycling (43). In mice, VDR gene ablation elicits
both rickets and hair loss, while point mutations specifically
compromising either 1,25(OH)2D ligand or coactivator con-
tacts in human VDR result in rickets without hair cycle disrup-
tion. On the other hand, loss-of-function mutations in human
VDR results in disrupted VDR-DNA binding or VDR-RXR
heterodimerization; this impaired corepressor activity on
VDR-mediated transactivation, in part due to the attenuated
interaction of hairless with HDACs, can result in clinical con-
ditions, such as the rare autosomal recessive disease atrichia
with papular lesions or alopecia universalis congenita (42-
44). VDR interaction with its heterodimeric partner RXR is
probably pivotal to hair cycling, as the conditional inactiva-
tion of RXRa in mouse skin results in alopecia resembling
that in VDR-null mice. Similar to mutations in the
VDR-encoding gene, mutations in the mammalian hairless
gene result in congenital hair loss both in mice and humans.
Remarkably, the hair loss phenotype caused by the mutated
human VDR gene resembles the generalized atrichia caused
by mutations in the hairless gene (44).
In summary, new insights into the regulation of vitamin D-
related enzymes and the differential mechanism of action of
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Endocrine Reviews, 2024, Vol. 45, No. 5
Conditions in which vitamin D
status should be evaluated
due to reduced synthesis:
•
• Age >50 years
Low sun exposure
• Sunscreen
•
⋅
Air pollution
Phototype (dark skin)
Major source
(=80%)
SUNLIGHT
UVB
Minor source (20%)
DIETARY intake
Ergocaliferol: plants/supplements
Cholecalciferol: fish (cod liver oil),
meat, fortified milk, egg yolk, butter
Conditions in which vitamin D
status should be evaluated
due to reduced intake:
• Not fortified food
• Restrictive diet
• Gastrointestional malabsorption:
Bariatric surgery, celiac disease,
inflammatory bowel diseases
.
Season and latitude
Skin
(Previtamin D)
7-dehydrocholesterol
Liver
Cholecalciferol→→➤
25-hydroxylase
Clinical conditions in which vitamin D
status should be evaluated:
Low bioavailability: overweight and obese patients
• Increased consumption: patients treated with
interfering drugs
Low 25(OH)D synthesis: Liver dysfunction
25-hydroxyvitamin D
Kidney
25(OH)D renal loss or low 1,25(OH)2D synthesis: Parathyroid
kidney and parathyroid diseases
hormone
.
Small
intestine
Most used
biomarker
for Vitamin D
status
Osteometabolic conditions in which
vitamin D status should be evaluated:
• Parathyroid, kidney diseases and
intestinal disorders
Osteoporosis, osteopenia, skeletal
disorders
→ Active form
1,25-dihydroxyvitamin D
- Increases Ca absorption (small intestine)
- Increases urinary Ca and Phos reabsorption
Increases bone mineralization secondary
to the mineral absorptive and resorptive
functions
1-αhydroxylase
Useful biomarker
in kidney and
parathyroid diseases
Figure 2. Overview of vitamin D metabolism. The figure shows metabolism of vitamin D in physiologic and deficient status, with specific reference to
conditions in which vitamin D should be evaluated.
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VDR have demonstrated important links between metabolic
disorders and vitamin D metabolism. A better understanding
of how the VDR interacts with other transcription factors in a
cell-specific fashion will provide a greater understanding of
how the same molecule can have such different actions in
many physiologic processes. In turn, more insights may lead
to more nuanced and/or specific uses of vitamin D and its me-
tabolites in clinical situations, as discussed next.
Assessment of Vitamin D Status
To date, total serum 25(OH)D, the sum of 25(OH)D3 and
25(OH)D2, is the accepted biomarker of vitamin D status
(Fig. 2). Observational studies have indicated the beneficial ef-
fects of an optimal vitamin D status on various outcomes not
directly associated with the classical target tissues for the
hormone the so-called pleiotropic effects (45). Based on
these studies, mostly using traditional radioimmunoassay
measurements, vitamin D guidelines issued by major organi-
zations worldwide recommend optimal 25(OH)D levels to
be in the range of 50 to 75 nmol/L (20-30 ng/mL) (46, 47).
However, optimal levels are still debated for several reasons
(48-50). Lack of assay standardization contributes to the
problem, and initiatives should be implemented to overcome
it (50, 51). In this perspective, the Endocrine Society (ES)
has asked a task force to review its 2011 guidelines.
Differences in the suggested optimal serum 25(OH)D levels
depend on several factors. It is essential to clarify what is
meant by optimal 25(OH)D level, that is, for whom and for
what, as it is essential to consider patients' clinical profiles
and the outcomes of interest. Many studies have been per-
formed with a focus on osteoporosis and bone metabolism.
Recently, several randomized controlled trials (RCTs) as-
sessed potential pleiotropic effects of 25(OH)D, in general,
with negative results (45, 52, 53). Another pivotal factor in de-
ciding optimal 25(OH)D levels is the perspective used. For ex-
ample, although the outcomes used to derive desirable
25(OH)D levels were similar for the Institute of Medicine
(IOM) (47) and the 2011 ES guidelines (46), most studies in-
cluded conclusions that differed. For example, in the case of
osteomalacia, although the same study was used, conclusions
differed. This is because the ES selected a cutoff above which
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Endocrine Reviews, 2024, Vol. 45, No. 5
no individual had osteomalacia (clinical perspective), whereas
IOM chose a cutoff where 97.5% of the cohort did not have
osteomalacia (public health perspective). Finally, when dis-
cussing vitamin D status assessment, it is also important to dif-
ferentiate between screening, that is, a public health approach
undertaken in the general populations, and testing, that is, tar-
geted testing of high-risk individuals in the clinical setting.
Theoretically, obtaining a 25(OH)D level within an optimal
window for the general population will necessarily result in
overscreening and overtreatment of healthy individuals
(48, 49). While general screening for 25(OH)D deficiency/
insufficiency is not recommended, measurements could be
performed in patients with several risk factors for severe defi-
ciency or who are being evaluated for metabolic bone disease
(46, 53-56). This recommendation may help to mitigate the
dramatic increase in the number of 25(OH)D measurements
and the associated economic burden (45, 52, 54, 56).
Supporting this view, initiatives have been undertaken to re-
duce unnecessary 25(OH)D analyses in Australia (57, 58).
The change in recommended testing criteria halved the num-
ber of measurements but paradoxically increased the number
of unnecessary tests and decreased tests of patients at high
risk of deficiency, with only a small improvement in the detec-
tion of deficiency (56).
Screening and Testing for Vitamin D Status
Screening in the general population-public health approach
Levels of 25(OH)D in the general population vary consider-
ably depending on several factors, including the season, lati-
tude, cultural factors leading to reduced UVB light
exposure, skin pigmentation, body mass index (BMI), sex,
age, level of physical exercise, and food fortification with vita-
min D or use of vitamin D supplements, even among otherwise
comparable Western societies; moreover, genetic factors such
as gene polymorphisms may have major effects on serum
25(OH)D according to twin studies and mendelian random-
ization (MR) reports (4, 48).
In considering when to test for vitamin D deficiency, it is
well recognized that serum 25(OH)D levels vary by season.
This is not surprising, given that most vitamin D is generated
in the skin following UVB exposure with little vitamin D avail-
able from the average unfortified diet (59, 60). Given an ob-
served drop in 25(OH)D levels between seasons, a higher
target (~75 nmol/L) may be required at the end of summer
to allow for the anticipated 10 to 25 nmol/L drop during the
winter months (61). For example, in a sunny country, such
as Australia, the prevalence of vitamin D deficiency
(<50 nmol/L) is as high as 36% during winter and as low as
14% in summer (62). In Lebanon, another sunny country,
mean serum 25(OH)D levels were 12 to 15 nmol/L higher in
summer to fall compared to winter (63). In this regard, meas-
urement of serum 25(OH)D levels at the end of winter or in
early spring would increase the detection of low 25(OH)D lev-
els in the general population (61).
Regardless, in populations with a low prevalence of vitamin
D deficiency, screening of the general population is not cost-
effective, and the decision to assess an individual needs to be
made using a risk stratification approach for having vitamin
D deficiency. Prioritized screening for high-risk groups could
be useful, given the potentially adverse effects of vitamin D de-
ficiency on skeletal and overall health, particularly when the
serum 25(OH)D levels are less than 30 nmol/L (<12 ng/mL).
631
Boosted regression tree models have also been developed
from RCT data to predict the serum 25(OH)D concentration
(64). Several predictor variables of a deseasonalized serum
25(OH)D concentration less than 50 nmol/L have been iden-
tified from training and validation data sets in the D-Health
trial. The 2 strongest predictors were ambient UV radiation
and total intake of vitamin D. Other important predictors of
mild vitamin D deficiency were time spent outdoors, alcohol
consumption, BMI, quality of life measures, and physical ac-
tivity. Thus, a lack of ambient UVB radiation and lack of vita-
min D fortification of food or use of vitamin D supplements
will probably result in a poor vitamin D status, particularly
in individuals in whom other risk factors are also present.
In conclusion, screening for optimal vitamin D status in the
general population should be avoided as it is not informative
and has a considerable economic burden. Nevertheless, sev-
eral characteristics and pathological conditions in the general
population could place individuals at risk for severe deficits.
These populations, which should be recognized, are consid-
ered in the next section.
Testing populations at risk of vitamin D deficiency—clinical
approach
Measurement of 25(OH)D has been recommended in patients
at risk for deficiency (46, 47) (Table 1 and Fig. 2). Thus,
25(OH)D is widely measured in many of these high-risk
groups, for example, in older adults with decreased endogen-
ous vitamin D production and prone to develop osteoporosis,
in patients with parathyroid disorders and liver disease, and in
patients with obesity (46, 47, 54-56, 65-71). Patients with
class III obesity (BMI >40) present with low levels of
25(OH)D for various reasons, including nutritional factors,
psychological reasons leading to less sun exposure, decreased
hepatic expression of CYP2R1, and sequestration of the vita-
min in the excess adipose tissue (15, 72). Class III obesity may
be addressed by bariatric surgery, which, by itself, may lead to
malabsorption and, thereby, a further decrease of 25(OH)D
levels, potentially followed by a secondary hyperparathyroid-
ism (73). Other at-risk groups include those who are house-
bound, those working long hours indoors, dark-skinned
individuals, patients with a chronic disease, those taking med-
ications increasing vitamin D catabolism, etc (see Table 1).
Paradoxically, listing situations where it may be reasonable
to measure 25(OH)D accounts for most people. This would
again result in overtesting with high costs for the health care
system. Rather than testing in situations where it would be
reasonable to, it would be better to test only in situations
that actually warrant it. It comes down to the providers' judg-
ment in first recognizing these high-risk individuals and then
deciding to confirm with a measurement of 25(OH)D. There
is, in fact, little evidence for the scientific utility and cost-
effectiveness of testing for 25(OH)D deficiency, even in
some of these selected groups (53). For example, some guide-
lines have recommended against screening pregnant women
for vitamin D deficiency because of uncertainty about the ben-
efits of vitamin D supplementation for maternal and fetal out-
comes (47, 74). However, a case can be made for optimizing
vitamin D status in all pregnant or breastfeeding women
and their offspring, given the reemerging public health con-
cern of rickets in high-risk children (75) and potential benefits
on future peak bone mass (76). Evidence of a relationship be-
tween low 25(OH)D and adverse maternal outcomes together
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632
•
•
Table 1. Populations at risk of vitamin D deficiency according to a
clinical approach
•
Older people
Housebound people
Disabled people
Institutionalized people
People working long hours indoors
•
•
•
•
Office workers
Factory or warehouse workers
Taxi drivers
Night-shift workers
People with dark skin
Low levels of physical activity
People with a debilitating/chronic disease
• Diabetes
Chronic kidney disease
Gastrointestinal malabsorptive syndromes
Parathyroid disorders
•
Liver diseases
Obesity in particular those with highest levels of waist circumference
Patients after bariatric surgery
People taking medications increasing vitamin D catabolism:
•
•
Phenobarbitone
•
Carbamazepine
•
Dexamethasone
•
Rifampicin
•
Nifedipine
.
Spironolactone
• Ritonavir
Cyproterone acetate
Babies of vitamin D-deficient mothers
Sources: (15, 46, 47, 54-56, 65-70, 72).
with evidence that these adverse outcomes (eg, risk of pre-
eclampsia, gestational diabetes, low birthweight, and the
risk of severe postpartum hemorrhage) are reduced after vita-
min D supplementation have also been shown (77, 78). Poor
vitamin D status has also been associated with increased risk
of low birth weight (79-81), increased risk of
preterm birth
(81, 82), and offspring's adverse anthropometric and neuro-
developmental outcomes (81), while supplementation or suf-
ficient vitamin D status was found to be protective against
the risk of low birth weight, preterm birth, and small for ges-
tational age (80), and associated with improved offspring vita-
min D sufficiency status, reduced fetal or neonatal mortality,
and improved fetal and future linear growth (83, 84).
Screening and testing vitamin D status-conclusions
Screening the general population for vitamin D deficiency is
very expensive and does not result in practical clinical benefits.
25(OH)D measurements have primarily been indicated in pa-
tients with musculoskeletal disorders, but the increased
awareness of potential pleiotropic effects has widened the
interest in screening, although without any definitive evidence.
The most important risk factors in the general population,
as identified by recent studies, include low ambient UV radi-
ation, low vitamin D intake, and gene polymorphisms. Their
inclusion as primary risk factors in risk stratification ap-
proaches to assess vitamin D status will help effectively target
25(OH)D assessment in those most in need and at risk.
Finally, further studies-including those with health
Endocrine Reviews, 2024, Vol. 45, No. 5
economic measures—are warranted to best identify all the sit-
uations in which the assessment of vitamin D status is actually
needed or not.
Methods: Assays, Thresholds, and Standardization
Accuracy and precision of vitamin D measurements are crucial
to properly use the values obtained in biological fluids. The la-
boratory methods should be detailed in clinical trials, scientif-
ic papers, and even in the reports released to physicians and
patients. The measurements could be obtained by either
antibody-based methods (chemiluminescent or immunoenzy-
matic) or by liquid chromatography-mass spectrometry
(LC-MS or LC-MS/MS), with the latter giving more consistent
and accurate results; regardless, the reference material should
also be indicated in the report (85). The laboratory should de-
fine the reference values considering the method used for ana-
lyzing the molecule(s). The unit of measure (molar or mass)
should be clearly indicated. The mol/L unit should be pre-
ferred as the SI standard unit; alternatively, both mol/L and
ng/mL should be reported. Moreover, the critical difference
(or least significance change), or reference change values,
that is, the value (percentage) testifying to a real modification
of the molecule(s) concentration between 2 consecutive meas-
urements, assayed with the same method, in the same patient,
and, on the contrary, that the modification is not only depend-
ent from analytical and biological variability (natural oscilla-
tion of values in individuals), should be known and properly
considered (85).
Assay standardization remains a major challenge to inter-
preting data from various studies evaluating vitamin D and
its metabolites and analogues. It should be a priority to enable
rational pooling of data and implementation of meta-analyses
relating specific vitamin D metabolites to various outcomes of
interest (2). Indeed, it has been suggested that reporting stand-
ardized 25(OH)D results is required for funding and subse-
quent publication of vitamin D-related research data (51).
Mean bias between -5% and +5% is one of the two per-
formance thresholds used to define a 25(OH)D assay as being
standardized by the Vitamin D Standardization Program
(VDSP) (2, 86). However, a flaw in that threshold is that an
assay with a mean bias within that range may display enor-
mous variability outside those limits when, in actuality,
what is wanted is an assay with few measurements outside
them (87).
Data from the VDSP's Vitamin D Standardization
Certification Program conducted by the Centers for Disease
Control and Prevention (CDC) in the November 2019
report the last report before COVID-19-show the flaw in
the mean bias threshold in assays certified by the CDC to be
standardized (88). In the CDC's report, 20 immunoassays
and 17 LC-MS/MS assays were certified as being standardized
for serum total 25(OH)D measurement (Table 2).
The mean individual samples pass rate for LC-MS/MS as-
says (61%) was 2 times higher than the rate for immunoassays
(30%) (t=-7.2; P<.01). LC-MS/MS assays provided the
highest mean value (mean = 61%); however, there was con-
siderable overlap. The Fujirebio Lumpulse had the highest
pass rate for an immunoassay: 68%. The Boditech Ichroma
had a 65% pass rate, and 3 immunoassays had a 42% pass
rate, namely the Abbott Architect, IDS CLIA, and Siemens
Maglumi ones. The VDSP's definition of the mean bias thresh-
old should thus be revised. The criteria we suggest for any
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Endocrine Reviews, 2024, Vol. 45, No. 5
Table 2. Mean individual samples pass rate for 40 serum samples by
Centers for Disease Control-certified standardized laboratories by
assay type
Assay type
No., certified Individual samples pass rate, %
Mean, % SD Minimum Maximum
Immunoassay
LC-MS/MS
20
17
30º
12.5 8
68
61ª
14.0 38
88
CDC individual samples pass rate is the percentage of individual samples out of 40
provided that met the certification criteria of ±5% bias. This information was
provided starting in February 2017. Data analyses by Prof Christopher Sempos.
Source: CDC (87).
Abbreviations: CDC, Centers for Disease Control and Prevention; LC-MS/MS,
liquid chromatography-tandem mass spectrometry.
at=-7.2; P=.00001.
revision are (1) consistent with the original guidelines, that is,
not an abrupt change; (2) easily calculated and easily under-
stood; (3) easy to operationalize; (4) easily modified to pro-
mote change over time; and (5) will promote competition
among assay manufacturers.
Importantly, we also suggest that 25(OH)D assays continue
to monitor their regular performance using an external quality
assessment scheme that provides target reference values from
a reference measurement procedure approved by the Joint
Committee for Traceability in Laboratory Medicine provided
by an LC-MS/MS standardized assay (eg, DEQAS, Charing
Cross Hospital, London UK). Such a process emphasizes the
importance of assay accuracy and, given that true concentra-
tion is available in such specimens, allows their use in retro-
spective standardization of 25(OH)D data (2, 89).
Assessment of Other Vitamin D Forms and Main
Metabolites
As discussed earlier, the vitamin D status assessment is based
on the 25(OH)D serum level measurement. However, other
forms of vitamin D such as free 25(OH)D, bioavailable
25(OH)D, DBP, or 1,25(OH)2D levels could be used as bio-
markers of vitamin D repletion, defined by effect on classical
and nonclassic vitamin D outcomes. As for 25(OH)D meas-
urements, these tests would also need to be standardized to en-
sure accuracy and replicability.
For circulating 25(OH)D, it is estimated that approximately
85% to 90% is bound by DBP and 10% to 15% by albumin;
therefore, free 25(OH)D levels are estimated to be less than
1% of the total and can vary according to DBP and albumin
polymorphisms and binding affinity (90-92). The free and
not the total 25(OH)D concentration in cell cultures affects
a biological response. While this is harder to assess in vivo,
some tissues with the megalin/cubilin complex, like the kidney
and parathyroid gland, can take up the vitamin D metabolites
bound to DBP (93). Nonetheless, free 25(OH)D may be highly
relevant to local intracellular (eg, osteoblasts, renal cells,
muscle cells) synthesis of 1,25(OH)2D, which can behave in
a paracrine and autocrine fashion (4). In normal populations,
total and free 25(OH)D, as well as free and calculated 25(OH)
D, are correlated (~60%-70% in healthy individuals), and
there is no clear evidence for a need to measure free metabo-
lites in healthy individuals and many clinical settings (92-
97). However, this may not hold true in conditions affecting
DBP such as pregnancy, cirrhosis, acute illness, conditions
633
that may affect the affinity of DBP or albumin to its ligands,
and even in aging nursing home residents (4, 69, 94), for
whom the free concentration is a better assessment than the
total.
Measurement of 1,25(OH)2D may contribute to the diag-
nosis of conditions with low calcitriol levels, such as
1α-hydroxylase deficiency, or those associated with high
1,25(OH)2D levels, such as hereditary vitamin D-resistant
rickets, granulomatous conditions (sarcoidosis and tubercu-
losis), and the hypophosphatemic syndromes (4, 69).
Available evidence to date is rather limited to determine
whether free or bioavailable 25(OH)D or 1,25(OH)2D is the
better biomarker of 25(OH)D availability to local tissues
and of its effect on target organs in special situations. The ex-
tremely low serum concentrations of 25(OH)D and 1,25(OH)
2D found in mice and humans with genetic absence of DBP
without implications on calcium homeostasis is the best argu-
ment for the free “vitamin D” hypothesis.
Assessment of Other Metabolites
Improvements in LC-MS/MS have triggered a revolution in
small-molecule clinical chemistry, particularly the analysis
of steroid hormones. The additional sensitivity and selectivity
provided by the recently emerged LC-MS/MS techniques
make it now feasible to measure most of the circulating vita-
min D metabolites of value to clinicians and physiologists in
human and animal studies. A comprehensive analysis can
now assay 8 metabolites simultaneously (cholecalciferol,
25(OH)D, 3-epi-25(OH)D, 24,25(OH)2D, 25,26(OH)2D,
1,25(OH)2D, 1,24,25(OH)3D, and 25(OH)D-26,23-lactone)
by judicious use of liquid-liquid-extraction and immune-
extraction steps. Besides specific clinical situations (98, 99),
a few previous reports have also highlighted a potential role
for vitamin D metabolites, in particular of the 24,25 to
25(OH)D ratio, in better-predicting fracture risk as compared
to only 25(OH)D levels (100, 101).
Infantile hypercalcemia, type 1, caused by defects in
CYP24A1
Despite the name of the disease, infantile hypercalcemia,
type 1 affects individuals throughout life, usually causing
nephrolithiasis. It is especially problematic in pregnant
females due to the placental production of 1,25(OH)2D3,
which cannot be efficiently metabolized. The utility of meas-
uring 24-hydroxylated forms, particularly the 25(OH)D to
24,25(OH)2D ratio, has been established as a useful screening
tool by groups worldwide. Ratios are elevated from 5 to 25 in
normal individuals to more than 80 in infantile hypercalce-
mia-affected individuals (102). It is important to recognize
that this same enzymatic defect can be identified in adults
with unexplained 1,25(OH)2D-dependent hypercalcemia.
These individuals present with hypercalcemia, hypercalciuria,
kidney stones, and suppressed levels of PTH.
Other hypercalcemias
Many causes of hypercalcemia can be distinguished by
their distinctive pattern of vitamin D metabolites. Kaufmann
et al (98) identified several patient groups by studying
the vitamin D metabolome. These include patients with
Williams syndrome exhibiting an elevated level of 25(OH)
D-26,23-lactone, a stable metabolite with high affinity for
DBP; patients with hypervitaminosis D taking toxic doses of
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634
vitamin D exhibiting very high 25(OH)D but suppressed
1,25(OH)2D, and where several other vitamin D metabolites
may contribute.
Chronic kidney disease
Many studies have documented a fall in serum 25(OH)D and
1,25(OH)2D with a decline in renal function. Studies of the
vitamin D metabolome over the 5 stages of chronic kidney dis-
ease (CKD) have revealed that the same phenomenon also ap-
plies to 24,25(OH)2D. Patients and animal models with
experimental kidney disease both show changes in the levels
of 24,25(OH)2D3 and 1,24,25(OH)3D3 with changes in glom-
erular filtration rates (103). The clinical consequences of these
changes remain to be elucidated.
Routine documentation of vitamin D metabolites in
randomized controlled trials
In most recent large RCTs, participants were monitored only
for health effects and serum 25(OH)D levels. One study—the
so-called Calgary study (or JAMA study) (104)—used doses
of up to 10 000 international units (IU) of vitamin D/day,
monitored only 25(OH)D, and reported deleterious effects
of the vitamin D on bone mineral density (BMD) (BMD was
assessed with high-resolution peripheral quantitative com-
puted tomography and not with dual-energy x-ray absorpti-
ometry). Although this JAMA study reported only 25(OH)D
data (105), by reanalyzing the serum from participants in
the study for the full vitamin D metabolome including
1,25(OH)2D3, 24,25(OH)2D3, and 1,24,25(OH)3D3, Burt
and colleagues (105) found that several vitamin D metabo-
lites, including 1,24,25(OH)3D3 but not 1,25(OH)2D3, were
elevated in individuals given the 10,000 IU of vitamin D/day
dose, a fact that could explain the bone loss observed at
high supplementation rates.
In conclusion, the study of a wider array of vitamin D me-
tabolites provides insight into a limited number of diseases.
It can potentially improve understanding of vitamin D status
and its relationship to multiple diseases.
Clinical Outcomes of Vitamin D Deficiency
Skeletal Outcomes
Skeletal outcomes of vitamin D deficiency are summarized in
Fig. 3. Vitamin D deficiency leads to a decrease in intestinal
absorption of calcium and phosphate. Other biochemical ab-
normalities, such as hypocalcemia, hypophosphatemia, and
an increase in alkaline phosphatase, become apparent when
serum 25(OH)D concentrations are lower than 25 nmol/L
(106). In milder forms of vitamin D deficiency, the lower
calcium concentration causes secondary hyperparathyroid-
ism, which increases the conversion of 25(OH)D into
1,25(OH)2D, increasing calcium absorption and correcting
serum calcium (4, 107). Secondary hyperparathyroidism
causes an increase in bone turnover, with relatively higher
bone resorption at cortical sites (107-112). More severe long-
standing vitamin D deficiency causes a decrease in the mineral-
ization of newly formed osteoid tissue. This is visible in bone
biopsies as an increase in osteoid surface and volume and in-
creased thickness of osteoid seams, leading to the clinical pic-
ture of osteomalacia (4, 107). Vitamin D deficiency and
related secondary hyperparathyroidism cause bone loss and
fractures in older adults. The incidence of hip fractures
Endocrine Reviews, 2024, Vol. 45, No. 5
attributable to vitamin D deficiency has been estimated at
5% to 10% (113). Meta-analyses of clinical trials with vita-
min D and calcium have demonstrated a decrease in hip and
other fractures of around 10% in nursing home residents,
whereas vitamin D alone was not effective (113-115). In these
studies, baseline mean serum 25(OH)D after cross-calibration
was found to be very low-namely less than 25 nmol/L—as
was the calcium intake (116). As almost all effective trials
used a calcium supplement in addition to vitamin D, the effect
on BMD of vitamin D supplements alone is difficult to deter-
mine, but it is considered to be less than 1% (113), and high
doses may even be harmful when administered to vitamin
D-replete individuals (104). Recent RCTs such as the VIDA,
VITAL, and D-Health studies do not show skeletal benefits
for mostly vitamin D-replete adults and older individuals;
for example, in the VITAL trial, cholecalciferol supplementa-
tion did not result in a significantly lower risk of fractures (to-
tal, nonvertebral, and hip fractures) than placebo among
generally healthy midlife and older adults not selected for vita-
min D deficiency, low bone mass, or osteoporosis (117, 118).
In the D-Health study, large bolus monthly doses (60 000 IU)
resulted in no increase nor decrease in fracture risk overall.
However, the hazard ratio appeared to decrease with increas-
ing follow-up time (119). Interestingly, in a recent retrospect-
ive longitudinal study (120), the use of cholecalciferol was
associated with reduced incidence of morphometric vertebral
fractures in high skeletal risk, such as acromegaly (121).
In a recent umbrella review of meta-analyses of vitamin D
RCTs, the only consistent significant findings were for calcium
and vitamin D, and not vitamin D alone, in reducing the risk
of hip fractures by 16% to 39%, in 8 of 13 meta-analyses, and
of any fracture, by 5% to 26%, in 8 of 14 meta-analyses.
These findings were driven by events in institutionalized older
and frailer individuals (122).
In children, the lack of calcium and phosphate causes the
expansion of the epiphyseal growth plates due to decreased
apoptosis of the hypertrophic chondrocytes, clinically visible
as thickening near the joints and radiologically as widening
of the growth plates (4). The weaker bone leads to typical
deformities, such as knock knees (genua valga) and bowlegs
(genua vara). The occurrence of rickets is mainly restricted
to the Middle East and some countries in Asia, such
as Mongolia and parts of China and India (123, 124),
while it is also observed in immigrants and refugees in other
countries (125).
Extraskeletal Outcomes
Putative extraskeletal outcomes of vitamin D deficiency are
summarized in Fig. 4. There are many preclinical data on
the extraskeletal effects of the vitamin D endocrine system, in-
cluding gene regulation, cellular function, and in vivo animal
studies. Indeed, about 3% of the mammalian genome is under
some control of vitamin D, and most cells express VDR or
can synthesize the active hormone 1,25(OH)2D locally.
Observational data largely align with these data as poor vita-
min D status is associated with many human diseases (4). To
complete the observational data, many large-scale trials that
evaluated the effects of vitamin D supplementation on several
extraskeletal health outcomes have been carried out recently,
including the large VITAL (USA) (118, 126-129) and
D-Health (Australia) (64, 129, 130) studies, as well as the
ViDA (New Zealand) (131-133), FIND (Finland) (134,
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Endocrine Reviews, 2024, Vol. 45, No. 5
Reduced synthesis
and dietary intake
Vitamin D
deficiency
Skeletal effects
Reduced intestinal
absorption
Clinical impairment on
metabolism and action
Osteopenia &
osteoporosis
(mild vitamin D deficiency)
Fragility
fractures
635
Osteomalacia &
Rickets
(severe vitamin D deficiency)
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Figure 3. Skeletal effects of vitamin D deficiency. A deficient vitamin D status can cause impairments in the skeletal system such as osteopenia, os-
teoporosis, osteomalacia, and rickets, resulting in high risk for fragility fractures. Clear boxes with dashed outlines refer to the risk factors for vitamin D
deficiency; dark boxes refer to the negative skeletal effects of vitamin D deficiency.
135), and the D2d (USA) (136, 137) trials (Table 3). Smaller
scale studies, such as the Calgary and the DO-Health
(Switzerland), provide additional data. Moreover, there are
now good genetic data on the prediction of serum 25(OH)
D, which resulted in about 100 MR studies (117).
Cancer
No effects of vitamin D supplementation on cancer risk were
observed in the large VITAL and ViDA trials, nor the FIND
trial using daily dosing in older participants, nor on cancer
mortality in the D-Health study, which used monthly dosing
―in line with prior trials and MR results (117, 130, 134).
Based on several MR studies, small changes in vitamin D sta-
tus are unlikely to affect cancer incidence (117). However, a
subanalysis of the VITAL trial (although not corrected for
multiple end point analysis) showed that vitamin D supple-
mentation could have some minor benefits in individuals
with normal BMI (128). In addition, several independent tri-
als have suggested, in post hoc analysis, the potential benefits
of vitamin D supplementation on cancer mortality, especially
when the follow-up is longer than 4 years (139). A meta-
analysis of RCTs suggested that vitamin D supplementation
decreased cancer mortality (140); an updated version of this
study specifically designed to examine whether results varied
by daily vs infrequent large-bolus dosing and by whether the
trial participants had obesity or not found that overall
benefit of vitamin D supplementation is lost when all the
studies are considered. However, when considering daily
regimens, vitamin D supplementation reduced total cancer
mortality and incidence in normal-weight individuals (141).
Therefore, a link between vitamin D status and cancer inci-
dence or mortality can be hypothesized, and supplementation
might be effective only with daily dosages, especially in people
with BMI within a normal range (117, 141).
Cardiovascular risk
Convergent evidence from MR studies and RCTs suggests that
vitamin D supplementation does not decrease the risk of car-
diovascular disease (CVD), especially in vitamin D-replete
adults. This conclusion may also apply to those with vitamin
D deficiency based on subgroup analyses of the ViDA and
VITAL trials. However, both studies recruited very few partic-
ipants with severe vitamin D deficiency (117), rendering these
conclusions uncertain. These null findings were corroborated
by a meta-analysis of 21 RCTs (142). Nonetheless, more recent
findings might suggest some small benefits. A detailed analysis
of the VIDA trial found some modest benefits on central (but
not peripheral) blood pressure, but the implications of this
Page 12
636
Autoimmune &
infectious diseases
Reduced synthesis
and dietary intake
Cardio-respiratory
diseases
(heart failure, hypertension,
pneumonia)
Vitamin D
deficiency
Impaired muscle
function & strength
(increased fall risk)
Reduced intestinal
absorption
Obesity & diabetes
Clinical impairment on
metabolism and action
Cancer incidence
& mortality
Endocrine Reviews, 2024, Vol. 45, No. 5
↑
Quality of life
Mortality
Acute COVID-19 severity
& Long COVID risk
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Figure 4. Putative extraskeletal effects of vitamin D deficiency and their implication in human health. A deficient vitamin D status is associated with
several extraskeletal effects. These include increased risk of diabetes and autoimmune, infectious, cardiovascular, and respiratory diseases, as well as
increase in cancer incidence and mortality. Such impairments result in lower quality of life and higher mortality, and can even increase acute COVID-19
severity and long COVID risk. Clear boxes with dashed outlines refer to the risk factors for vitamin D deficiency; dark boxes refer to the negative extra-
skeletal effects of vitamin D deficiency.
observation are limited because of the small scale of this VIDA
substudy (133). The FIND trial failed to note a reduction in the
number of major CV events, which was one of the two primary
end points (134); however, subsequent exploratory analyses
revealed that high-dose vitamin D supplementation might re-
sult in benefits in atrial fibrillation prevention in older individ-
uals, even in case of relatively high baseline 25(OH)D
concentrations (135). In the D-Health trial, the overall rate
of major CV and especially the rate of myocardial infarction
and coronary revascularization-was lower in the interven-
tion
group compared to the placebo group, although the abso-
lute risk difference was small, and the CI was consistent with a
null finding (hazard ratio 0.91; 95% CI, 0.81-1.01); moreover,
the protective benefits could be higher in those taking CV drugs
at baseline (138).
Respiratory effects
Vitamin D is known to influence the immune system. Most
immune cells express the VDR and vitamin D metabolism-
related enzymes; 1,25(OH)2D, in particular, induces innate
antimicrobial effector mechanisms such as the antimicrobial
peptides cathelicidin LL-37 and human beta-defensin 2 (4).
Indeed, clinical data regarding the effects of adequate vitamin
D status and supplementation on respiratory infections con-
firm, at least in part, its potential beneficial outcomes. Serum
25(OH)D levels of less than 25 nmol/L are associated (obser-
vationally and genetically) with an increased risk of bacterial
pneumonia (143). Individual participant data from a meta-
analysis of 25 trials showed a small but significant decrease
in the incidence of acute respiratory infections in the vitamin
D group compared with the control group when baseline vita-
min D status was poor (<25 nmol/L) (144). A more recent, up-
dated meta-analysis from the same group, including almost 50
RCTs, shows a protective but very small effect against respira-
tory infections following vitamin D supplementation with dai-
ly doses of 400 to 1000 IU; in contrast to their first
meta-analysis, baseline vitamin D status did not modify the re-
sults in this more recent one (145).
As respiratory tract infections are common in children,
some promising data are available also in this setting.
Children with poor vitamin D status were reported to be
more prone to developing respiratory infections, although a
conclusive association between the severity of respiratory
Page 13
Follow-up, Primary outcome(s)
Conclusions and comments
Table 3. Characteristics and results of the most recent and largest randomized controlled trials on vitamin D supplementation
Study
Participants
(n)
Age (mean
± SD), y
Sex (% of
women)
Mean
BMI
Ethnicity"
(% White
ethnicity)
Serum 25(OH)D, ng/mL
Baseline Final
Dose used
y
VITAL (117,
125-128)
25 871
67 ± 7
51
28
71
30.8 ±
10
42 ± 10
2000 IU/d +
omega-3
1 g/d
5.3
D-Health (64,
129, 130)
21 315
69.3
46
28
28
ViDA
(131, 132,
138)
5110
66 ± 8
58
58
96.5%
31 ± 10d 46 ± 12
60 000 IU/mo 5.7
All-cause mortality
Endocrine Reviews, 2024, Vol. 45, No. 5
Invasive cancers and major
CV events
Incidence of metastatic or
fatal cancer
Two or more falls and falls
resulting in a doctor or
hospital visit
All incident autoimmune
diseases
Incident total, nonvertebral,
and hip fractures
Risk of falling
Major CV events
Fractures and falls
Cancer incidence and
mortality
Incident major CVD and
invasive cancer
Atrial fibrillation risk
End point not met, but
reduction in total cancer
mortality when excluding
first 1-2 y of follow-up
VD reduced metastatic or fatal
cancers by 17%; strongest
reduction in normal BMI
End point not met
VD reduced autoimmune
diseases by 22%
End point not met; enrolled
individuals were generally
healthy and not selected for
VD deficiency, low bone
mass, or osteoporosis
End point not met; VD
increased cancer risk when
first 2 y of follow-up were
excluded
End point not met; VD
increased risk when BMI
<25, but not when BMI ≥25
End point not met; VD might
reduce CV events (small
absolute risk difference and
CI consistent with null
finding); VD reduced
myocardial infarction by 19%
End point not met (121); in one
substudy, VD lowered central
blood
pressure in deficient
participants
End point not met
End point not met; daily or
weekly dosing for longer
period may require further
study
End point not met; study failure
possibly due to sufficient VD
status in most participants at
baseline
VD reduced atrial fibrillation
risk by 27%-32%
29 ± 5.1
83
27 ± 9€
54 ± 16
200 000 IU + 3.3
Incident CVD and death
100 000 IU/
mo
FIND
(133, 134)
2495
685
43
43
27 ± 4
100
30 ± 7
40±9 (1600 IU/d
arm) 48 ± 9
(3200 IU/d arm)
1600 or
4.3
3200 IU/d
9/9/9////// w po
(continued)
637
33
Page 14
638
Conclusions and comments
Partly drafted with data from Bouillon et al (117).
T2D in adults with
Development of T2D
according to intratrial
serum 25(OH)D level
prediabetes
End point not met
VD resulting in 25(OH)D level
≥100 nmol/L reduces risk of
T2D
study included Asian people and a small number of indigenous Māori individuals.
"The VITAL and D2d studies included different American racial and/or ethnic groups including Black people and Hispanic people. The ViDA
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; IU, international units; N.A., not available; T2D, type 2diabetes; VD, vitamin D.
"Final serum 25(OH)D concentration vitamin D-treated groups only.
Primary outcome(s) refers both to main trial and subsequent analyses.
"Evaluated in placebo group during follow-up.
Deseasonalized mean values.
Table 3. Continued
Study
(u)
± SD), y
Participants Age (mean
Sex (% of
women)
Mean
Ethnicity"
BMI
(% White
ethnicity)
Serum 25(OH)D, ng/mL
Baseline Final'
Dose used
Follow-up, Primary outcome(s)
y
D2d (135, 136)
2423
60 ± 10
45
32 ± 5
67
28 ± 10
54 ± 15
4000 IU/d
2.5
Endocrine Reviews, 2024, Vol. 45, No. 5
infections and low vitamin D levels was not clearly estab-
lished (146). RCTs show that vitamin D supplementation
can benefit infants, toddlers, and preschool children aged
0 to 5 years with a quicker recovery and fewer respiratory
symptoms (147). Unfortunately, study heterogeneity in
terms of design, vitamin D supplementation doses, and dur-
ation, along with participant characteristics, make it prob-
lematic to pool data and, thus, difficult to draw definitive
conclusions (79, 147).
There is also consistent evidence for an association between
low 25(OH)D levels and poor COVID-19 outcomes, al-
though the evidence supporting a beneficial effect of vitamin
D supplementation in decreasing the risk of COVID-19 com-
plications is conflicting (8, 148-151). An MR study found no
evidence that vitamin D is protective against SARS-CoV-2 in-
fection or COVID-19 severity (152). However, a meta-
analysis of several observational studies comprising almost
2 million adults suggests that inadequate vitamin D status in-
creases susceptibility to COVID-19 and severe COVID-19,
while the association with mortality was less robust. Of
note, the included studies were at high risk of bias and hetero-
geneity, and the heterogeneity in RCTs precluded their meta-
analysis (151). Furthermore, low 25(OH)D levels were also
recently associated with an increased risk for long COVID oc-
currence (150). However, a phase 3 RCT found no effect of
vitamin D supplementation on the risk of developing long
COVID after an episode of COVID-19 (142). Also, deficient
vitamin D status was recently reported to be associated with a
reduced long-term immune response to the anti-COVID-19
vaccination (153).
Vitamin D supplementation also seems effective in safely
and substantially reducing the rate of moderate/severe acute
exacerbations of chronic obstructive pulmonary disease in pa-
tients with baseline 25(OH)D levels less than 25 nmol/L—but
not in those with higher levels (154). A meta-analysis, con-
versely, found no role for vitamin D supplementation in im-
proving expiratory lung function (155).
Regarding asthma, there are insufficient RCTs to evaluate
the potential benefit of vitamin D or its hydroxylated metab-
olites in improving its control or reducing the risk of exacerba-
tions. However, as individuals with baseline 25(OH)D levels
less than 25 nmol/L and those with severe asthma were poorly
represented, and since one study investigating the effects of
calcidiol yielded positive results, further studies are warranted
in these populations and settings (156).
Autoimmune diseases
Conversely, from the innate immune system, the adaptive im-
mune system is downregulated by 1,25(OH) 2D in animal
models. Thus, vitamin D deficiency might predispose to auto-
immune diseases. Observational studies have suggested this
effect might apply to humans (4).
The VITAL RCT showed that vitamin D supplementation
decreased the risk of autoimmune diseases, especially rheuma-
toid arthritis and polymyalgia rheumatica, and at least 8 large
MR studies all agree that genetically predicted lower 25(OH)
D levels increased the risk of developing multiple sclerosis ei-
ther during adolescence or adulthood (117, 129). In any
case, the low number of intervention studies so far conducted
does not allow clarification of the relationship between vita-
min D and autoimmune diseases. However, these studies to
date seem promising.
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Endocrine Reviews, 2024, Vol. 45, No. 5
Diabetes
Despite observational studies consistently confirming lower
serum 25(OH)D concentrations in patients with T2D or meta-
bolic syndrome (4), most MR studies have not supported these
conclusions (117). In a small subgroup of individuals with obesity
and prediabetes, supplementation provided some modest benefit,
albeit lower than lifestyle modifications or metformin (157).
Of note, daily vitamin D supplementation (4000 IU) in the large
D2d trial did not retard the progression of prediabetes into
T2D. A post hoc and meta-analysis, however, suggested a pos-
sible beneficial effect in individuals with vitamin D deficiency
(<30 nmol/L) at baseline or in participants who were able to
achieve consistently high (≥100 nmol/L) serum 25(OH)D levels
(152). Furthermore, analysis of the combined results of the
D2d (US), Tromsø (Norway), and DPVD (Japan) RCTs―which
were specifically designed and conducted to test whether vitamin
Dreduces the risk of diabetes in adults with prediabetes-showed
that vitamin D supplementation reduced the risk of developing
T2D in people with prediabetes not selected for vitamin D defi-
ciency (158). In all 3 trials, the risk for diabetes was reduced in
the group assigned to vitamin D compared to the placebo group,
which did so in a remarkably similar way. The observed differen-
ces missed statistical significance in any trial because the reported
risk reductions were smaller than each trial was powered to
detect. An updated individual participant data meta-analysis of
the same trials (159) showed that vitamin D reduced the risk of
progression from prediabetes to diabetes by 15%. Also, vitamin
D increased the likelihood of regression to normal glucose regu-
lation by 30%, with no evidence of risk. In additional analyses,
participants in the vitamin D group who maintained intratrial
blood 25(OH)D of 50 ng/mL or greater (≥125 nmol/L)
had a 76% risk reduction in new-onset diabetes compared
to those who maintained blood 25(OH)D of 20 to 29 ng/mL
(50-75 nmol/L). All participants received and were encouraged
to follow the current lifestyle-based advice for diabetes preven-
tion. Based on the results of this meta-analysis, the benefit-to-risk
ratio of vitamin D to lower the risk of developing T2D in adults
with prediabetes is favorable. These results should not be extrapo-
lated to the general population at low or average risk for diabetes,
as the benefit-to-risk ratio of high doses for diabetes prevention
may not be favorable. Despite these promising results, some
questions remain, that is, the optimal vitamin D dose or for-
mulation and the specific blood 25(OH)D level to maximize
benefit with little or no risk of any side effects (159).
Thus, the evidence from large-scale MR studies and RCTs is
convergent and does not support vitamin D supplementation
to prevent T2D in the general population. However, vitamin
D supplementation benefits those with prediabetes and a pre-
disposition to T2D, especially those with vitamin D deficiency.
Additional studies or more in-depth analyses of the existing
studies are needed to validate these findings (117, 159).
Mortality
Observational data have repeatedly linked poor vitamin D sta-
tus with increased mortality. Large, older meta-analyses deal-
ing mostly with women older than 70 years (160, 161) showed
a 6% to 11% reduction in mortality. However, adding the
newest megatrials eliminated this effect, possibly because
they recruited a younger population. In these megatrials, over-
all mortality was much lower than shown in the previous meta-
analyses (160, 161), and no effect of vitamin D supplementa-
tion on overall mortality was observed (128).
639
A Cochrane meta-analysis of 56 randomized trials including
almost 100 000 participants, of whom were women older than
70 years, revealed that vitamin D, administered over 4 years,
decreased mortality; this effect was seen in 38 trials of vitamin
D3, but not with other forms of vitamin D (161). A newer meta-
analysis of 52 RCTs, including more than 75 000 individuals,
concluded that vitamin D (either vitamin D3 or D2) supplemen-
tation did not change mortality compared with no supplemen-
tation (162). Again, subanalyses found that vitamin D3
(instead of D2) supplementation tended to reduce mortality.
Some MR studies found a link between lower predicted serum
25(OH)D and mortality, especially in individuals with rather
poor vitamin D status (<16 ng/mL) (163-165). An individual
participant data meta-analysis of almost 27 000 study partici-
pants with 25(OH)D levels standardized per VDSP protocols
showed an association between low 25(OH)D and increased
risk of all-cause mortality (166). The positive but small effect
of vitamin D on mortality was confirmed by a recent umbrella re-
view of observational, randomized, and MR studies (167). In
conclusion, if vitamin D supplementation benefits extraskeletal
health outcomes and major diseases, it is likely to have some ef-
fects on mortality, especially in older adults with
poor vitamin
D status, but not in younger, replete individuals (117).
Summary of Vitamin D Deficiency-associated
Clinical Outcomes
The long-known skeletal benefits of vitamin D and calcium re-
lated to rickets or osteoporosis remain valid. Most reported
extraskeletal benefits of vitamin D were not confirmed by re-
cent, large RCTs (see Table 3). The gradual increase in vitamin
D levels in Western populations may explain these null find-
ings, and older trials and meta-analyses may be more likely
to show benefits because individuals were more likely to be
vitamin D deficient than they are nowadays. RCTs and meta-
nalyses published to date do not have adequate power to
evaluate important subgroups, such as individuals with low
25(OH)D levels, men, the very old, ethnic groups other than
White individuals, and those from low-income countries.
Moreover, most of the studies use adverse events data to identify
fractures and were performed in adults who were vitamin D re-
plete at baseline in whom benefit would be unlikely and toxicity
possible. Such studies confound the identification of possible
beneficial effects in vitamin D-deficient individuals who might
benefit from supplementation. Thus, when it comes to vitamin
D, it is advisable to "giveth to those who needeth” (168). In
fact, the benefit-to-risk ratio for vitamin D depends on the target
population and medical condition. It would be incorrect to ex-
trapolate vitamin D guidelines that apply to the general popula-
tion (such as those from the US National Academic of Medicine)
to avoid vitamin D deficiency (ie, rickets, osteomalacia) and pro-
mote bone health to special populations for whom the
benefit-to-risk ratio of vitamin D would be different.
Nonetheless, RCTs, MR studies, and metanalyses suggest a
link between vitamin D status with the immune system and
diabetes, as well as fleeting effects on some CV events and
some benefits on mortality risk when vitamin D3 is used.
Vitamin D Supplementation
Dosing Regimens
The term "dose" in relation to vitamin D is typically used to
signify the measured quantity of vitamin D (usually
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640
cholecalciferol, but other formulations such as ergocalciferol,
eldecalcitol, calcifediol, etc are also available) in a pill. It is ex-
pressed as μg or IU (where 10 µg is 400 IU). The dose of chole-
calciferol is considered an important measure as it correlates
with the change in blood 25(OH)D level, which is commonly
used to define vitamin D status and correlates with important
clinical outcomes. Doses can be considered as "loading" or
"maintenance." The most common use of a loading dose is
to rapidly improve a low blood 25(OH)D; however, the clin-
ical wisdom of this approach is questionable, especially given
studies that demonstrate adverse effects with very high doses
given infrequently, as discussed next. Intermittent administra-
tion of large doses is also used to optimize adherence. Daily
doses are generally preferred when vitamin D replacement is
considered necessary. The effect of a given dose on changing
blood 25(OH)D varies considerably from person to person
due to many factors, such as body weight, absorption, diet, de-
gree of adiposity, CYP2R1 activity, DBP. The recommended
dietary allowance for vitamin D by the National Academy
of Medicine is set at 400 to 800 IU per day, and the tolerable
upper intake level at 4000 IU per day; however, the "optimal"
dose of vitamin D varies by the desired outcome, and other au-
thors suggest that the upper limit of safety may be lower than
4000 IU per day (169-171). For example, 400 to 800 IU of
vitamin D per day may be adequate to avoid clinical
vitamin D deficiency and maintain calcium homeostasis in
healthy individuals. Doses of vitamin D higher than the rec-
ommended upper limit may be associated with toxicity; none-
theless, daily doses up to 10 000 IU have been used without
safety concerns (172). Careful and judicious use of vitamin
D will permit the realization of potential benefits and achiev-
ing optimal outcomes.
Generally, there is a lack of consensus about the recom-
mended vitamin D supplementation regimen (doses, adminis-
tration schedule, treatment duration, etc) (173). Such
heterogeneity can be explained, at least partly, by the scarcity
of comparative pharmacokinetics studies for different dosing
schedules (174-176). Moreover, different underlying condi-
tions (eg, obesity) might reduce the effect of vitamin D supple-
mentation (177, 178). Growing evidence suggests that the
treatment schedule itself (ie, bolus vs frequent administration)
may differently affect the effectiveness of the treatment (27,
179) and also clinical outcomes, with recent studies and a
few meta-analyses showing more promising results with fre-
quent administration schedules on skeletal and extraskeletal
outcomes (4, 141, 144, 180, 181).
In this perspective, vitamin D supplementation guidelines
should be specific for age group, body weight, ethnicity
(skin type), and latitude of residence. For example, differences
in serum 25(OH)D by BMI and absolute body weight have
been reported (182-185). Vitamin D dose per kilogram of
body weight per day could explain a 34.5% variation in circu-
lating 25(OH)D in multivariable regression analyses of data
pooled from several studies (184), leading to pronounced dif-
ferences across BMI categories. Obese and overweight indi-
viduals tend to have serum 25(OH)D levels that are, on
average, around 20 nmol/L lower and 8 nmol/L lower than
those of normal-weight individuals, requiring 2.6 and 1.47
times higher supplementation, respectively (185). This is
somewhat consistent with ES guidelines suggesting that the
vitamin D dosage for obese people is "three times" greater
than the recommended dose for individuals with normal
body weight (46).
course,
Endocrine Reviews, 2024, Vol. 45, No. 5
Another example of targeted, specific vitamin D dosing, of
, is in the pediatric setting. Infants and children have dif-
ferent upper tolerance limits compared to adults. To maintain
a desirable 25(OH)D concentration, the 2010 IOM guidelines
recommend 600 IU/d (15 µg) for children, adolescents, and
adults, and 400 IU/d (10 µg) for infants (47). ES guidelines
recommend 400 to 1000 IU/day (10-25 µg) for infants aged
up to 1 year and 600 to 1000 IU/day (15-25 µg) for children
older than 1 year to treat and prevent vitamin D deficiency
(46). These values are consistent with several guidelines issued
by other societies in the past several years. Of course, they can
be increased if a laboratory-confirmed vitamin D deficiency is
being treated (186).
Many studies investigated dosing regimens in pediatric pa-
tients. One trial comparing 4 different daily dosages (400,
800, 1200, 1600 IU) found that all dosages established
25(OH)D concentrations of 50 nmol/L or greater in 97% to
98% of infants at age 3 and 12 months, but only a dosage
of 1600 IU/d 25(OH)D levels to 75 nmol/L or greater in
97.5% of infants at age 3 months; nonetheless, this study
was discontinued prematurely because of elevated plasma
25(OH)D concentrations that have been associated with
hypercalcemia (187). Another study also found that 1600
IU/day given for 10 weeks to infants from 2 weeks to 3 months
of age maintained a 25(OH)D concentration above 80 nmol/L,
but without causing hypercalcemia or hypercalciuria (188).
Daily supplementation
From a physiological perspective, daily administration of
cholecalciferol seems to be most natural. Indeed, it appears
that a daily approach results in higher efficacy in terms of
25(OH)D exposure and extraskeletal benefits.
In a recent RCT comparing 3 different dosing regimens in
vitamin D-deficient participants with similar total
end-of-study cumulative doses (D3 daily 10 000 IU 8 weeks,
then 1000 IU for 4 weeks; 50 000 IU weekly for 12 weeks;
and 100 000 IU every 2 weeks for 12 weeks), the group receiv-
ing the daily supplementation was the quickest to reach suffi-
ciency (<2 weeks, although receiving a higher cumulative dose
in the first 8 weeks when compared to the other 2 arms) and
reached the highest serum 25(OH)D levels (172).
Importantly, daily administration was associated with higher
systemic exposure to 25(OH)D (greater area under the curve,
+23% and +27% compared to weekly and biweekly adminis-
tration, respectively), even when corrected for the cumulative
dose (172). The greater 25(OH)D exposure of daily regimens
could be due to lower activation of the 24-hydroxylase en-
zyme (CYP24A1). In an RCT of lactating women comparing
the effect of bolus (150 000 IU) vs daily vitamin D3 dosing
(5000 IU) on vitamin D3 catabolism, a single high-bolus
dose of vitamin D led to greater production of
24,25(OH)2D3, relative to the 25(OH)D3 value than did daily
vitamin D supplementation, with this effect persisting for at
least 28 days after supplementation (27). The greater thera-
peutic potential of daily regimens compared to other regimens
might be less relevant at lower doses (<2000 IU). Two studies
comparing 2000 IU/day vs 50 000 IU/month (189) and
800 IU/day vs 5600 IU/month (190) found no statistically sig-
nificant differences in the 2 areas under the curves.
Greater 25(OH)D exposure and lesser 24-hydroxylase ac-
tivity might be the rationale behind the potential extraskeletal
benefits of cholecalciferol supplementation. The already cited
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Endocrine Reviews, 2024, Vol. 45, No. 5
metanalysis of 12 RCTs by Keum et al (141) found that the re-
duction in cancer mortality after vitamin D supplementation
was largely attributable to interventions with daily dosing
(as opposed to infrequent bolus dosing). Secondary analyses
of the VITAL trial giving 2000 IU/day of cholecalciferol found
a significant reduction in advanced cancers (metastatic or
fatal), especially among those with normal BMI (126).
However, the opposite was seen with monthly dosing in the
D-Health trial, where the risk of death from cancer was in-
creased (130). In the AMATERASU trial on patients with
digestive-tract cancers, 2000 IU/day of cholecalciferol pro-
vided a cumulative hazard ratio of relapse or death of 0.66,
significantly lower than the placebo group when adjusted by
age quartile (191). Regarding the prevention of autoimmune
diseases, supplementation with 2000 IU/day of cholecalciferol
for 5 years reduced autoimmune diseases by 22% in the
VITAL trial (129). Finally, a meta-analysis on the prevention
of acute respiratory infections after vitamin D supplementa-
tion found that vitamin D given daily had an odds ratio
(OR) of 0.78, compared to an OR of 0.97 to 0.98 if weekly
or bolus regimens (145). Protection was mainly associated
with administering daily doses of 400 to 1000 IU for up to
12 months and an age of 1.00 to 15.99 years at enrollment.
This result is particularly interesting as recommended preven-
tion strategies such as inactivated influenza vaccines in health
adults probably reduce acute respiratory infections from
21.5% to 18.1% with a relative risk of 0.84 (192).
In conclusion, daily cholecalciferol administration might be
the most efficient and beneficial strategy to increase serum
25(OH)D, at least from the biomedical (but not necessarily
bio-psycho-social) perspective. Indeed, most RCT data sug-
gesting extraskeletal benefits of cholecalciferol supplementa-
tion come from studies with daily dosing. Future studies
should investigate this observation in pathologic conditions
(ie, obesity).
Nondaily supplementation
Intermittent vitamin D dosing usually uses a greater amount to
reach equivalent doses with fewer administrations. The ration-
ale of this approach is to enhance adherence and ease manage-
ment of specific patient groups, such as children and
community-dwelling older people (193). Indeed, low adher-
ence to vitamin D prescription has often been reported, al-
though the topic is controversial. For example, Albrecht et al
(194) recently investigated adherence to bone health-promot-
ing lifestyle recommendations concerning osteoporosis status
in a cross-sectional database of community-dwelling older
adults (aged 65-75 years). In high-risk osteoporosis patients,
adherence to vitamin D intake, defined as regular consumption
of vitamin D-rich foods and/or vitamin D supplements, was
high, ranging from 85% (women) to 93% (men). In contrast,
in a cross-sectional study of pediatric outpatients affected by
various diseases, Arshad et al (195) found that adherence to
vitamin D prescription was quite low, particularly in those
with diseases where vitamin D deficiency presents as a high-
risk condition.
For these reasons, recurrent and protracted intervals of vita-
min D supplementation appear to be an effective and conveni-
ent way to achieve and maintain sufficient vitamin D status
and to increase patients' adherence, but there is no agreement
that treatment simplification with intermittent dosing signifi-
cantly improves compliance (196) and there is consistent
evidence to discourage the use of “megadoses” due to the
sible side effects (197).
Weekly and monthly regimens
641
pos-
With equivalent doses and large formulations, daily, weekly,
and monthly supplementation may lead to similar increases
and levels of 25(OH)D in middle-aged (198) and obese indi-
viduals (199), in older individuals with hip fractures (200),
and children with CKD (201). However, one study concluded
that a daily regimen was more efficient in circulating 25(OH)
D than weekly or monthly administration, but with different
formulations (179). As compared with a daily regimen, a bo-
lus dose is associated with a higher 24,25(OH)2D level and a
higher 24,25(OH)2D to 25(OH)D ratio (27). In a monocen-
tric, open-label randomized study in postmenopausal women,
weekly vitamin D was more efficient than monthly in improv-
ing muscular function (measured through the Sit-to-Stand and
Timed-Up-and-Go tests) (202). Monthly regimens have been
tested in several large trials with multiple outcomes.
Compared to a placebo, 100 000 IU monthly did not influence
the risk of CVD, falls, fracture, or cancer, and lung or arterial
functions in vitamin D-replete individuals (203). In those par-
ticipants with baseline 25(OH)D lower than 50 nmol/L, the
100 000 IU vitamin D regimen increased lumbar spine BMD
by 2.6% and improved lung and arterial functions (203). In
the D-Health trial including more than 21 000 individuals,
with 24% of them having a 25(OH)D level less than
50 nmol/L, 60 000 IU monthly did not influence all-cause
mortality (126) but was associated with a higher risk of falls
in those with a BMI of less than 25 (64). This observation
was in agreement with another trial in which a higher percent-
age of fallers was detected with 60 000 IU/month compared to
24 000 IU/month over 1 year (204). In small trials, few epi-
sodes of hypercalcemia were reported with weekly doses be-
tween 20 000 and 100 000 IU in various target populations
(205). Overall, trials with weekly or monthly vitamin D sup-
plementation regimens did not show significant effects on clin-
ical variables. This could be due to the recruited population
(vitamin D-replete or obese individuals) or too large
vitamin D doses leading to a U-shape dose-response relation-
ship. Currently, there is no evidence of a superiority in the
benefit/risk ratio of weekly or monthly vitamin D regimens
over daily supplementation.
Longer intervals
Although one study using high doses with prolonged intervals
(100 000 IU every 4 months) administered to community-
dwelling adults older than 50 years found a reduction in
fractures (206), other similar studies (500 000 IU every year
(193)/150 000 IU every 3 months (207)) did not show a reduc-
tion in hip/vertebral/nonvertebral/total fracture incidence.
This was also evidenced by the systematic review and meta-
analysis of Zhao et al (208). In studies on the efficacy of
vitamin D administration, the basal values of 25(OH)D are
often either not measured (206) or are at normal/high levels
(206), making it difficult to understand the real effect of sup-
plementation on 25(OH)D values. In a subgroup analysis of
Zhao's study, no differences in fracture incidence were found
between intermittent high doses given once every year and
other interval regimens (208). In Zhao's meta-analysis, refer-
ence is made to the study by Witham and colleagues (209) in
which no negative effects of longer intervals of high-dose
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642
vitamin D administration on blood pressure in older patients
with isolated systolic hypertension were reported.
Regarding the relation between long-term intervals of vita-
min D administration and CVD risk, falls, and fracture out-
comes in older and community-dwelling people, in a
systematic review with meta-analysis, Barbarawi et al (142)
did not find significant results favoring vitamin D intervention
(100 000 IU every 4 months (189)/500000 IU yearly (197)) in
preventing falls, fractures, or CVDs. Even in works cited in
this meta-analysis, the basal 25(OH)D values were either
not reported or sufficient.
In a systematic review with meta-analysis, Yang et al (210)
cited 2 works that investigated the effect of intermittent high
doses of vitamin D as adjuvant treatment in pneumonia in
children (100 000 IU every 3 months (211) and 300 000 IU
quarterly for 1 year (212)) on the incidence rate of repeated
episodes of pneumonia, rate of intensive care unit (ICU) hos-
pital admission, and complications rate. In both cases, no sig-
nificant definitively positive effects were found. Regarding the
safety of longer-interval vitamin D supplementation, in a re-
cent systematic review with meta-analysis on children,
Brustad et al (213) did not find any association with severe
side effects. This was also seen in other studies with protracted
intervals of vitamin D administration (211, 212, 214, 215).
Summary of Vitamin D Dosing Regimens
In conclusion, one of the major justifications for longer inter-
vals with high doses in vitamin D administration, namely, to
address low compliance with more frequent regimens, is con-
troversial. The rationale gains support in children and adoles-
cents rather than in older individuals. However, it has to be
taken into account that the cited meta-analyses underscored
the point that there is no evidence of efficacy in intermittent
high-dose and longer intervals of vitamin D administration
in reducing fracture rate, falls, CV events, or infectious dis-
eases. An increase in falls in older individuals has been ob-
served with large, intermittent dosing (197, 216) (the
literature regarding falls is somewhat controversial in part be-
cause there are no reliable methods to capture falls, as both
diaries and self-reports are flawed). These conclusions should
be tempered by inherent flaws in many reports in which the
baseline vitamin D dosage or pretreatment 25(OH)D levels
are not provided.
Routes of Administration
Oral supplementation of cholecalciferol is the most commonly
used approach. It is effective, simple, and generally safe.
Therefore, it is the preferred way to supplement vitamin
D. However, sometimes, the parenteral route may be a better
method for improving vitamin D status than oral administra-
tion of vitamin D, particularly in situations like intestinal mal-
absorption. Interestingly, a new transdermal route of vitamin
D administration is being proposed (217) but will not be dis-
cussed here due to the paucity of data.
Oral administration
Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D₂)
are fat-soluble vitamins that are absorbed in the small intes-
tine. Because they are lipophilic compounds, their absorption
is similar to the absorption of lipids. Vitamin D is incorporated
into micelles with biliary salts on the micelle surface. On aver-
about 80% of vitamin D is absorbed, but the variation in
age,
Endocrine Reviews, 2024, Vol. 45, No. 5
absorption can be large (55%-99%) (218-220). Taking vita-
min D supplements with a fat-containing meal may improve
vitamin D absorption (218, 220). Cholecalciferol and ergocal-
ciferol are both rapidly absorbed, and the plasma levels peak
after about 24 hours of ingestion. Absorption into the entero-
cytes of the intestinal wall was thought to be a passive process,
but there is some evidence that vitamin D, especially in dietary
doses, is also actively transported through the enterocyte mem-
branes via cholesterol transporter proteins. However, passive
transport seems to occur with pharmacological doses of vita-
min D. From the enterocytes, vitamin D is exported in chylomi-
crons by the lymphatic route (218-220).
Bariatric surgery and intestinal malabsorption syndromes
that reduce fat absorption, such as inflammatory bowel dis-
eases, cystic fibrosis, and severe cholestasis, can also reduce
vitamin D absorption (10, 221). However, intestinal malab-
sorption does not seem to affect the absorption of calcidiol
as much, most likely because calcidiol is more water soluble,
thus not requiring bile salts for absorption, and because calci-
diol is absorbed by the portal route instead of the lymphatic
route (219).
As cholesterol transporters are involved in vitamin D ab-
sorption, factors that interfere with cholesterol absorption
could also affect vitamin D absorption. However, ezetimibe,
an inhibitor of cholesterol transport, does not seem to
affect vitamin D absorption despite the reduction in choles-
terol absorption. There is also no strong evidence that
phytosterols, plant sterols used to inhibit cholesterol absorp-
tion, impair vitamin D absorption. In contrast, there is some
evidence that drugs used to reduce intestinal fat absorption,
such as orlistat and olestra, may also reduce vitamin D
absorption (219).
Vitamin D supplements are available in different vehicles,
such as oil-containing gel capsules, oily drops, and hard pow-
der tablets. Although it could be hypothesized that vitamin D
would be better absorbed from oil-based vehicles, no convin-
cing evidence supports this premise. In fact, there is some evi-
dence that vitamin D may be better absorbed from a
powder-based vehicle than from an oil-based vehicle in cases
of intestinal fat malabsorption, such as in cystic fibrosis (222).
Parenteral administration
The optimal treatment of hypovitaminosis D in the general
population and disease states is still debated (7). Parenteral
administration of intermittent vitamin D boluses may be indi-
cated in patients with hypovitaminosis D who are not suitable
for oral intake or with intestinal malabsorptive diseases, in-
cluding inflammatory bowel disease, celiac disease, pancreatic
insufficiency, short-bowel syndrome, and post bariatric sur-
gery (10, 221). Based on advantageous pharmacokinetic prop-
erties and evidence-based clinical data, intramuscular
cholecalciferol may be the preferred form of vitamin D to be
used in these clinical settings. In fact, it has been shown that
cholecalciferol was able to reach higher serum 25(OH)D lev-
els more rapidly than ergocalciferol when both vitamin D
forms were administered as a single large intramuscular
dose (300 000 UI) in adult or older patients with hypovitami-
nosis D (223-225). Moreover, in the study by Romagnoli
et al (224), 2 months after administration of this large, intra-
muscular cholecalciferol dose, serum 25(OH)D levels were
higher than those obtained after the same oral dose.
Therefore, intermittent intramuscular cholecalciferol could
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Endocrine Reviews, 2024, Vol. 45, No. 5
Table 4. Characteristics of different forms/metabolites of vitamin D and when to use them
Vitamin D form
Holl...
H
643
Circulating
half-life
Around 1 day
(longer functional
half-life
in correlation
with its
slow release
from the
adipose tissue)
Features
Native form of human- and animal-produced vitamin D
Lipophilic, stored in fat and released on need
• Useful in clinical practice as it renders possible
intermittent administration regimes
• Wide safety range thanks to the predicted mechanisms
regulating its hydroxylation
When to use it
Most clinical situations where a vitamin D
deficiency must be addressed (see
below for exceptions)
Cholecalciferol
(vitamin D3)
Around 2 days
HO""
Ergocalciferol
(vitamin D2)
H
OH
HO"
Calcifediol
(25(OH)D)
OH
OH
H
Calcitriol
(1,25(OH)2D)
2-3 weeks
5-8 hours
Inferior to cholecalciferol in increasing 25(OH)D
serum levels
•Risk of over- or under-estimation of total 25(OH)D in
the presence of substantial amounts of 25(OH)D2
with subsequent risk of vitamin D toxicity in case of
dose increments
• Widely prescribed in the USA in high doses (50,000 IU)
•High doses alter vitamin D metabolism, increasing 24
hydroxylase activity
Hydrophilic, thus higher solubility in organic solvents,
less sequestration in adipose tissue, smaller
distribution volume and shorter half-life compared
to cholecalciferol
•⚫ Fast increase in 25(OH)D serum levels along with PTH
suppression
• Easier to manage than cholecalciferol in case of toxicity
• More efficient internalization in cells expressing the
megalin-cubilin system
•Promotes active intestinal calcium absorption and
suppresses PTH secretion
• Increases the activity of the CYP24A1, which stimulates
the degradation of 25(OH)D
•Risk of hypercalcemia and hypercalciuria
• To be administered daily or in lower doses distributed
over a 24-hour period
Only in cases of patients' ethical concern
(e.g., vegetarianism, veganism, others).
However, vegan D3 supplements (made
from lichen) are available and should
be considered instead of D2
supplements
Malabsorption syndromes, obesity,
CYP2R1 dysfunction, or in situations
in which a quick attainment of vitamin
D sufficiency is desirable
As a hormone replacement for patients
with limited/absent renal tubular
1-α-hydroxylase activity; vitamin D
resistant rickets type 1, X-linked
hypophosphataemic rickets, chronic
hypoparathyroidism, as an alternative
to the use of the native missing
hormone PTH, and moderate-to-severe
kidney failure
Consider replacing it with analogs with
less calcemic activity (maxacalcitol;
falecalcitriol; paricalcitol; doxercalciferol)
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be useful in clinical conditions when rapid correction of hypo-
vitaminosis D is unnecessary and for long-term maintenance
of adequate serum vitamin D levels, as in some older patients,
to improve their adherence to vitamin D supplementation.
However, safety concerns limit the clinical use of intermittent,
excessive vitamin D doses. In fact, large intramuscular boluses
(300 000 IU) induce unwanted effects such as an increase in
falls and fracture events or enhance bone turnover (226, 227).
There is a consensus to administer vitamin D boluses not
higher than 100 000 IU (228). In conclusion, the therapeutic
regimen to recover from vitamin D deficiency should be tail-
ored to patients' characteristics, such as age, BMI, severity
of vitamin D deficiency, concurrent comorbidity, and use of
other drugs.
Different Forms of Vitamin D Supplementation
The main supplemental oral forms of vitamin D are cholecal-
ciferol (vitamin D3) and ergocalciferol (vitamin D2). Both are
readily available without a prescription. Cholecalciferol is the
most used form of supplemental vitamin D. Calcidiol (calcife-
diol, 25(OH)D), the inactive vitamin D metabolite produced
in the liver, and other vitamin D analogues, such as calcitriol
(1,25(OH)2D, the physiologically active form of vitamin D)
and alfacalcidol (1-hydroxyvitamin D), are used as prescrip-
tion medicines in some conditions (Table 4).
Ergocalciferol
Ergocalciferol does exist in nature (mainly in plants and fungi),
and low circulating levels of 25(OH)D2 are present in free-
ranging nonhuman primates and human population studies
(229, 230). The 2 forms of vitamin D, cholecalciferol (D3) and
ergocalciferol (D2), are often used interchangeably as supple-
mentation or treatment of vitamin D deficiency as, historically,
vitamins D2 and D3 were considered equally effective in treating
rickets (231). Similarly, previous recommendations consider vi-
tamins D2 and D3 interchangeable (46). Subsequently, however,
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644
multiple studies and meta-analyses comparing the effect of D2
and D3 on circulating 25(OH)D concentration have found
cholecalciferol to be superior (223-225, 232).
Challenges to 25(OH)D measurement are widely recog-
nized. The presence of 2 circulating 25(OH)D forms,
25(OH)D3 and 25(OH)D2, adds additional challenges, not-
ably for automated immunoassays. Importantly, it is possible
that the antibodies used in immunoassays may not detect
25(OH)D2 and 25(OH)D3 equally, and the proprietary ap-
proach to releasing 25(OH)D from DBP may not liberate the
2 forms equally (233). As such, it is perhaps unsurprising
that multiple reports find overestimation or underestimation
of total 25(OH)D in the presence of substantial amounts of
25(OH)D2 (233-236). This problem was corroborated by a re-
cent interlaboratory comparison performed at the behest of
the VDSP (87). Assay underestimation of total 25(OH)D in
the presence of substantial amounts of 25(OH)D2 can have
clinical consequences. A recent small report of patients receiv-
ing 50 000 IU of ergocalciferol every 2 weeks found 40%
(6/15) to have total 25(OH)D levels less than 30 ng/mL
when measured by immunoassay whereas all had values above
42 ng/mL when measured by LC-MS/MS (237). It is easy to im-
agine that such patients with “low” 25(OH)D values would
have their dose increased, with at least potential toxicity, or
undergo additional evaluation, such as for malabsorption.
Thus, these assay issues are not clinically inconsequential.
Issues surrounding ergocalciferol use are of note for the
United States, where 50 000 IU of vitamin D2 was the only
high-dose preparation available by physician prescription
and, therefore, ergocalciferol was widely prescribed. Now, in-
stead, 50 000 IU of vitamin D3 is available by prescription. In
addition to assay issues, widespread use of intermittent high-
dose ergocalciferol ("bolus" therapy) appears to alter vitamin
D metabolism, with increased 24-hydroxylase activity (27).
Other adverse consequences of high-dose vitamin D therapy,
notably increased fall risk (197), are reported and have led
to calls to critically assess daily vs bolus vitamin D therapy
(238).
To summarize, vitamins D2 and D3 are not equivalent in
raising circulating 25(OH)D, and bolus dosing may have ad-
verse effects on vitamin D metabolism and clinical outcomes.
As such, it is to be expected that calls for the use of only
cholecalciferol and avoidance of ergocalciferol have been
and continue to be published (233, 239, 240) with recent
osteoporosis-treatment guidance advising cholecalciferol
over ergocalciferol (241) (see Table 4). Despite these recom-
mendations, high-dose ergocalciferol remains widely pre-
scribed in the United States.
Calcifediol
Calcifediol is the intermediate metabolite between cholecalcif-
erol and calcitriol. Several pharmacokinetic studies performed
in the last 4 decades have demonstrated its hydrophilic prop-
erties, leading to higher solubility in organic solvents, less se-
questration in adipose tissue, smaller distribution volume, and
shorter half-life when compared to cholecalciferol (242-244).
By virtue of its hydrophilic properties, calcifediol is readily ab-
sorbed via the venous portal system and thus quickly increases
circulating concentrations of 25(OH)D 3. In contrast to chole-
calciferol, which is mostly stored in fat tissue, 25(OH)D tends
to be more evenly distributed throughout the body (20% in
muscle, 30% in circulation, 35% in fat, and 15% elsewhere)
Endocrine Reviews, 2024, Vol. 45, No. 5
(245). The administered dose will generally lead to predictable
25(OH)D levels and effective PTH suppression. In cases of
toxicity, this form of vitamin D is easier to manage than chole-
calciferol (244). Moreover, the greater affinity of calcifediol
for DBP allows for more efficient internalization in cells ex-
pressing the megalin-cubilin system of endocytic receptors,
such as the parathyroids and the renal tissue (246).
Such properties provide the rationale for using calcifediol in
specific clinical conditions. The clinical situations that make
use of calcifediol attractive are obesity, hepatic failure, pa-
tients with inactivating mutations of genes encoding
CYP2R1 (the principal enzyme that is responsible for vitamin
D 25-hydroxylation), or patients taking drugs that could in-
fluence the activity of cytochrome enzymes (ie, antiretroviral
or antitubercular). Calcifediol was shown to have the same
bioavailability in healthy adults with differing BMI and adults
with intestinal malabsorption compared to controls (247). In
an RCT on vitamin D-deficient, postmenopausal women,
weekly calcifediol was found to be more effective and faster
acting compared to cholecalciferol in increasing 25(OH)D se-
rum levels. This more favorable kinetics led to greater im-
provement in muscle function (202). In another RCT in 35
healthy women aged 50 to 70 years, calcifediol given daily,
weekly, or as a single bolus was about 2 to 3 times more potent
in increasing plasma 25(OH)D3 concentrations than cholecal-
ciferol (190).
New extended-release calcifediol formulations are more ef-
fective than cholecalciferol in raising serum 25(OH)D levels
even in overweight nondialytic CKD patients with secondary
hyperparathyroidism (248); nonetheless, it must be noted that
these data arise from observational, retrospective data and
subgroup post hoc analysis of RCTs.
Recently, retrospective studies have highlighted the role of
calcifediol administration on various end points related to
COVID-19 infection. To demonstrate a causative effect,
Nogues et al (249) investigated 2 cohorts of patients with
COVID-19, 1 of whom was untreated and 1 assigned to the
oral calcifediol group. The treatment regimen consisted of
oral calcifediol (0.532 mg the day of admission), followed
by doses of 0.266 mg on days 3, 7, 15, and 30. Out of 447 pa-
tients treated with calcifediol at admission, 20 (4.5%) re-
quired the ICU, and 21 (4.7%) died; this was significantly
lower compared to the untreated group of 391 patients, of
whom 82 (21%) required the ICU and 62 (15.9%) died
(both P<.01). Adjusted logistic regression of calcifediol treat-
ment on ICU admission indicates that patients treated with
calcifediol had a lower risk of ICU admission (OR 0.02;
95% CI, 0.07-0.23) and mortality (OR 0.21; 95% CI,
0.10-0.43), suggesting an effectiveness of calcifediol treatment
(249).
In summary, calcifediol seems to represent a form of vita-
min D that is useful for replenishing vitamin D status. Most
attractive clinical settings include malabsorption syndromes,
obesity, CYP2R1 dysfunction, or situations in which
quick attainment of vitamin D sufficiency is desirable (see
Table 4).
Calcitriol
Calcitriol is the active hormonal form of vitamin D and the nat-
ural VDR ligand. It promotes active intestinal calcium absorp-
tion and suppresses PTH secretion. Calcitriol has a short
half-life of around 5 to 8 hours; therefore, it should be
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Endocrine Reviews, 2024, Vol. 45, No. 5
administered daily (or with intermittent regimens) and some-
times in lower doses distributed over a 24-hour period (240,
250). As calcitriol is not an organic micronutrient, its use in clin-
ical practice requires careful monitoring. Calcitriol increases the
activity of CYP24A1, which stimulates the degradation of
25(OH)D. This results in serum 25(OH)D not being useful as
a marker of adequate vitamin D supplementation and reduced
potential benefits of physiological extrarenal/local production
of calcitriol due to reduced substrate availability. Moreover,
some studies have reported a more significant incidence of ad-
verse events such as hypercalcemia and hypercalciuria. Thus,
there is a need to monitor serum and urine calcium and phos-
phate (240, 251, 252). Because of these safety and clinical prac-
ticality issues, there is consensus that calcitriol use should be
limited to hormone replacement for patients with limited/absent
renal tubular 1-a-hydroxylase activity, as their capacity to pro-
duce calcitriol is severely limited (240, 251, 252). Indeed, calci-
triol was first used to treat patients with vitamin D-resistant
rickets type 1 (23). Other indications are X-linked hypophospha-
temic rickets, chronic hypoparathyroidism, as an alternative to
the use of the native missing hormone PTH, and moderate-to-
severe kidney failure when calcitriol production is impaired
or to suppress excessive PTH secretion. This use helps to
control secondary hyperparathyroidism and resultant meta-
bolic bone diseases. However, as calcitriol use is associated
with frequent hypercalcemia, its use could be replaced by ana-
logues with less calcemic activity approved for use in patients
with secondary hyperparathyroidism in renal failure, in par-
ticular maxacalcitol (22-oxa-1,25(OH)2D3) and falecalcitriol
(1,25(OH)2-26,27-F6-D3), which are currently available in
Japan, and paricalcitol (19-nor-1,25(OH)2D2) and doxercalci-
ferol (1a(OH)D2), available in the United States (253, 254).
Calcitriol has also been proposed for the treatment of osteopor-
osis, but it is not approved in this setting (240, 251, 252).
In conclusion, calcitriol is not suitable for supplementation
or nutritional fortification, and none of many excellent
reviews, guidelines, and policy papers consider the use
of calcitriol in the nutritional context (supplementation
and fortification). However, guidelines suggest that vitamin
D supplementation is advised in patients with chronic
hypoparathyroidism, chronic kidney failure, and low
vitamin D status in addition to receiving therapeutic doses
of calcitriol (see Table 4). Such a recommendation is moti-
vated by the activity of extrarenal 1-a-hydroxylase, which is
compromised by reduced renal function (ie, not regulated
by PTH) and is not regulated by feedback mechanisms (240,
251, 252).
Vitamin D Safety and Monitoring
Vitamin D supplementation is generally a safe treatment with
minimal adverse events and no need for strict monitoring.
However, side effects of vitamin D treatment exist and can re-
sult in vitamin D toxicity (VDT).
Vitamin D toxicity
VDT is a clinical condition characterized by excess vitamin D
(hypervitaminosis D), resulting in severe hypercalcemia that
may persist for a prolonged period of time, leading to serious
health consequences. Signs and symptoms of VDT are related
primarily to hypercalcemia, with complications encompassing
adverse events in the CV, renal, gastrointestinal, neurological,
and musculoskeletal systems (255, 256). VDT prevalence is
645
unknown, but it is rare due to the wide therapeutic index of
vitamin D (255, 256). Evidence from systematic studies of
VDT in humans is missing for ethical reasons, and data mostly
stem from studies of VDT in animals and anecdotal reports.
The condition of infantile hypercalcemia was first described
in the United Kingdom and Switzerland, showing symptoms
such as failure to thrive, osteosclerosis, developmental delay,
and even death, but was not immediately associated with vita-
min D intake. Suggestions were made that excess vitamin D in-
take may be a causative factor (children received up to
35 000 IU daily). Eventually, the British Ministry of Health
suggested a substantial reduction in vitamin D allowance, re-
sulting in a marked decrease in infantile hypercalcemia cases
(257-260). As the prescriptions of vitamin D products are in-
creasing worldwide, so is the number of VDT reports, with
more than 75% published since 2010. Many of these cases re-
sult from inappropriate prescribing; moreover, the prescrip-
tion of high-dose unlicensed and poorly manufactured
treatments can be greater than 60%, as they are cheaper
(261, 262).
In healthy individuals, hypervitaminosis D is usually de-
fined as "exogenous" as it develops after uncontrolled use of
megadoses of vitamin D or its metabolites or analogues, as
in case of high dose of calcifediol leading to a faster increase
in 25(OH)D serum levels compared with cholecalciferol but
easier to manage than cholecalciferol in case of toxicity for
its hydrophilicity and lesser sequestration in adipose tissue.
On the other hand, excessive production of calcitriol in
granulomatous disorders, lymphomas, primary hyperpara-
thyroidism, and idiopathic infantile hypercalcemia results in
"endogenous" hypervitaminosis D (255, 256).
VDT is defined by a biochemical phenotype with
markedly elevated calcifediol concentrations (>150 ng/mL
or >375 nmol/L), along with dihydroxylated metabolites
(24,25(OH)2D3; 25,26(OH)2D3, 25(OH)D3-26,23-lactone),
unless the causal agents are vitamin D analogues, such as par-
icalcitol. Calcitriol levels may be in the normal reference range
or even reduced in exogenous VDT while elevated in endogen-
ous VDT. PTH levels can be very low or undetectable (263).
VDT thus results in severe hypercalcemia, hypercalciuria,
and hyperphosphatemia. Pathogenetically, hypercalcemia is
a consequence of high calcifediol levels in exogenous VDT
(with calcifediol at pharmacological concentrations overcom-
ing VDR affinity disadvantages and/or displacing 1,25(OH)
D2 from DBP (264)), while high calcitriol levels cause en-
dogenous VDT. Exogenous factors that interact with VDT
risk include dosage, calcium in the diet or as a supplement,
vitamin D intake with the diet, social status (ie, neglected pa-
tients), artificial UV light treatment sessions, quantity of sup-
plement use, and time of exposure. Endogenous risk factors
comprise age, sex, vitamin D status, hypersensitivity syn-
dromes, and the pharmacogenetics of the vitamin D response
and metabolism (253, 254, 263). This is why there is no clear
cutoff above which VDT occurs and below which it does not.
In conclusion, VDT is a rare but life-threatening event most-
ly caused by unintentional overdosing due to pharmaceutical
products. The prescriber and dispenser should avoid un-
licensed vitamin D products. VDT should always be consid-
ered a differential diagnosis when evaluating patients with
hypercalcemia. Future studies should encompass the evalu-
ation of concurrent conditions that increase the risk of VDT
and include the evaluation of classic and nonclassic adverse
events for VDT.
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Monitoring vitamin D status during treatment
Monitoring treatments is important to assess their efficacy
and safety. Regarding vitamin D supplementations, there is
limited evidence for when to monitor response to therapy or
toxicity.
When it comes to achieving sufficiency in deficient patients, it
seems there is no need to monitor differently according to differ-
ent dosage regimens (dose and/or frequency) or baseline 25(OH)
D serum values. The increase in serum 25(OH)D concentration
after supplementation follows a curvilinear response with the in-
crease of the cumulative doses (265, 266). The delta increase
over 100 IU depends on baseline levels, and there is less increase
100 IU with high doses than low doses (267). Van Groningen
per
et al (268) calculated that the cholecalciferol loading dose re-
quired to reach the serum 25(OH)D target level of 75 nmol/L
can be calculated as dose (IU) = 40 × [75 - serum 25(OH)
D] body weight. Mean 25(OH)D levels over a 2-month period
are similar to daily, weekly, or monthly administrations (al-
though monthly dosing is associated with more variability),
and sufficiency can be reached independently from the baseline
25(OH)D values (200). In the study by Fassio et al (172), all par-
ticipants normalized 25(OH)D safely, regardless of dosing regi-
mens and including patients receiving 10 000 IU/day for the first
8 weeks; moreover, no cases of hypercalcemia were recorded.
With regard to recent megatrials results, no effects were found
on serum calcium or calciuria unless very high doses were
used, such as 4000 to 10 000 IU per day in the Calgary study
(104). Furthermore, these studies did not confirm the modestly
increased risk of kidney stones observed in the WHI trial
(400 IU per day) (117). However, there might be a need for mon-
itoring in case of other vitamin D metabolite use. As discussed
earlier, calcifediol acts much more rapidly than cholecalciferol
in increasing serum 25(OH)D levels, resulting in greater fluctu-
ation of 25(OH)D levels. For example, supplementation with
20 µg (800 IU) of cholecalciferol (vitamin D3) increases
25(OH)D concentrations toward 70 nmol/L (28 ng/mL) within
16 weeks, while supplementation with 10 or 15 µg calcifediol
(25(OH)D) increases 25(OH)D levels more than 75 nmol/L
(>30 ng/mL) in 8 and 4 weeks, respectively (269).
To summarize, cholecalciferol can maintain physiological
25(OH)D serum levels above 30 ng/mL (75 nmol/L) but be-
low 50 ng/mL (125 nmol/L) for a long time, regardless of
whether the dosage given is daily or intermittent (weekly, fort-
nightly, or monthly), due to its slow pharmacokinetic elimin-
ation caused by prolonged storage and release on demand
according to physiological needs (270). Routine monitoring
of 25(OH)D levels is generally unnecessary for patients on
long-term maintenance vitamin D doses of up to at least
2000 IU/day. Retesting after 8 to 12 weeks from the start of
supplementation may be appropriate when poor compliance
is suspected, in case of symptoms suggestive of vitamin D de-
ficiency, and for patients at risk of persistent 25(OH)D level
below 30 ng/mL (75 nmol/L). These comprise institutional-
ized or hospitalized individuals, people in whom vitamin D
therapy uncovers subclinical primary hyperparathyroidism,
obese individuals, individuals undergoing bariatric surgery,
individuals who use of certain concomitant medications (eg,
anticonvulsant medications, glucocorticoids), and patients
with malabsorption, including inflammatory bowel disease
and celiac disease. For patients on potent antiresorptive agents
(eg, denosumab or zoledronic acid), vitamin D levels should
be checked annually per protocol (71).
Conclusions
The metabolism, mechanisms of action, and pathophysiology
of vitamin D and its multifaceted implications in human
health have been extensively investigated for more than a cen-
tury. However, the role of vitamin D status assessment and the
detailed outcomes of vitamin D deficiency and its supplemen-
tation are still not completely understood. Thus, we extensive-
ly reviewed the literature on controversial vitamin D topics
to better clarify and summarize the "whys, whens, and
hows" of vitamin D assessment and supplementation in gener-
ally healthy populations and clinical conditions.
genes.
Vitamin D metabolism involves a different extensive panel of
enzymes, resulting in various hormonal metabolites. Moreover,
the VDR has been demonstrated to act as a key role transcrip-
tion factor in most cells and can regulate a plethora of
New insights into the regulation of vitamin D-related enzymes
and the differential mechanism of action of VDR have demon-
strated potential links between several metabolic disorders and
vitamin D effects. In this perspective, assessing a distinctive pat-
tern of noncanonical vitamin D metabolites may allow us to bet-
ter characterize different pathological conditions related to
vitamin D metabolism that do not depend only on reduced solar
exposure or vitamin D diet intake.
Besides the potential utility of the evaluation of noncanonical
vitamin D metabolites, 25(OH)D is nowadays the most widely
accepted biomarker to evaluate vitamin D status; however, its
optimal levels are still debated. Recommendations on optimal
25(OH)D levels deriving from international societies and guide-
lines can differ due to the different approaches used, including
clinical perspectives (level of cutoff at which no individual has
an undesirable outcome) or public health perspectives (level of
cutoff at which 97.5% of individuals do not have an undesirable
outcome). Another critical issue is the lack of an accepted labora-
tory test assay standardization, and this prevents a proper inter-
pretation of data reported by different studies, resulting in
enabling rational data pooling and implementation of meta-
analyses focused on vitamin D influence in various clinical out-
comes of interest. Thus, 25(OH)D laboratory assays should be
monitored in their performance through external quality assess-
ment plans providing target reference values from standardized
measurement procedures.
Vitamin D deficiency has been extensively related to the oc-
currence of skeletal disorders, such as rickets and osteomal-
acia. It can also be negatively implicated in osteopenia and
osteoporosis, which must be mandatory and managed with
vitamin D supplements. More recently, the interest in the
putative extraskeletal effects of vitamin D have resulted in
several clinical trials addressing vitamin D's influence on
cancer and CV risk, respiratory effects, autoimmune diseases,
diabetes, and mortality. The null results of some of these
RCTs especially the megatrials-hampered the enthusiasm
around these topics. However, these trials were progressively
revised, and their null results were mainly related to the enroll-
ment of vitamin D-replete adults in whom benefit would be
unlikely and the inhomogeneous methodologies in vitamin
D supplementation with different forms, metabolites, and
doses. Indeed, subsequent secondary analyses have progres-
sively shown that vitamin D might be useful in reducing cancer
incidence and mortality in the long term, in reducing auto-
immune diseases and CV events (in particular central arterial
hypertension, myocardial infarction, and atrial fibrillation)
occurrence, and the development of diabetes from prediabetes
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Endocrine Reviews, 2024, Vol. 45, No. 5
forms. Nonetheless, these RCTs and the following meta-
analyses were not powerful enough to evaluate these crucial
subgroups, and further studies with better methodological
conductions are warranted.
Regarding the different forms and metabolites used for vita-
min D supplementation, oral administration is the preferred
route, and parenteral administration should be reserved for spe-
cial clinical situations, such as in patients with severe gastrointes-
tinal malabsorption syndromes or after bariatric surgery.
Cholecalciferol remains the preferred choice, and it is generally
safe, requiring less strict monitoring. Ergocalciferol has been
demonstrated to be less effective in raising 25(OH)D serum lev-
els and, thus, should be reserved for specific clinical conditions.
Calcifediol could be recommended in patients with obesity, mal-
absorption syndromes, CYP2R1 dysfunction, or in situations in
which a quick, rapid achievement of vitamin D sufficiency is de-
sirable. Calcitriol use should be limited for patients with limited/
absent renal tubular 1-α-hydroxylase activity and in vitamin D—
resistant rickets type 1, X-linked hypophosphatemic rickets, and
chronic hypoparathyroidism.
Growing preclinical and clinical observations associating
vitamin D with many health clinical conditions have been pro-
gressively reported in recent years. However, the lack of rigor-
ous methodologies on patient enrollment, vitamin D
supplements, and standardized laboratory assays have limited
the ability to draw definitive conclusions about these data that
still need to be more clearly understood.
Thus, a "whys, whens, and hows" of vitamin D assessment
and supplementation derived from an international expert
panel discussion about controversial topics regarding vitamin
D metabolism, assessment, actions, and supplementation is
needed to help the scientific community in evaluating and con-
ducting future further studies with more rigorous methodolo-
gies, to better explore any clinical setting potentially
influenced by vitamin D, and to provide reliable data required
to update our international recommendations.
Acknowledgments
The authors wish to acknowledge Fabio Perversi (Polistudium
srl, Milan, Italy) for medical writing and Aashni Shah
(Polistudium srl, Milan, Italy) for linguistic and editorial
assistance.
Funding
This work was supported, in part, by the International
Vitamin D Expert Association (IDEA). The conference and
editorial assistance were supported by an unrestricted educa-
tional grant from Abiogen Pharma, Pisa, Italy. The sponsors
had no role in the selection of discussion topics, speakers, or
authors, preparation, or review of this paper. Work partially
supported by Glucocorticoid induced Osteoporosis Skeletal
Endocrinology Group (GIOSEG).
Disclosures
647
A.G. is a consultant for Abiogen and Takeda and received re-
search grant to institution from Takeda. J.P.B. is a consultant
for Abiogen. Travel and accommodation expenses for the
6th International Workshop on Controversies in Vitamin D
for R.B., C.M., and G.H.F. were covered by Abiogen Pharma
S.p.A. P.E. has received research funding from Amgen,
Sanofi, and Alexion, and honoraria from Amgen. A.F. has re-
ceived advisory board honoraria, consultancy fees, and/or
speaker fees from Boehringer Ingelheim, UCB Pharma, and
Abiogen. S.F. has received research grants to institution
from Abiogen Pharma. A.R.M. reports grants from Barts
Charity, The Fischer Family Foundation, DSM Nutritional
Products, The Exilarch's Foundation, The Karl R Pfleger
Foundation, The AIM Foundation, Thornton and Ross,
Warburtons, Hyphens Pharma, and Mr Matthew Isaacs (all
paid to his institution), and from UK National Institute for
Health Research Clinical Research Network and the HDR
UK BREATHE Hub (paid to Edinburgh University); consult-
ancy fees from DSM Nutritional Products; honoraria from
Oregon State University; payment for expert testimony from
Qiagen; and support for attending meetings from Abiogen
Pharma and Pharma Nord. A.R.M. is chair of the Data
Safety Monitoring Board for the VITALITY (vitamin D for
adolescents with HIV to reduce musculoskeletal morbidity
and immunopathology) trial, and a member of the data safety
monitoring board for a trial of vitamin D and zinc supplemen-
tation for improving treatment outcomes among COVID-19
patients in India; a program committee member for a vitamin
D workshop; and has received vitamin D capsules for clinical
trials from Pharma Nord, Synergy Biologics, and Cytoplan.
S.M. has served as speaker for Abiogen Pharma, Bruno
Farmaceutici, Diasorin, Geopharma, Sandoz, and UCB. He
also served on advisory boards for Abiogen, Eli Lilly, Kyowa
Kirin, Novo Nordisk, and UCB. R.R. has been a speaker or
participated on advisory boards for Abiogen, Naturex,
Nestlé, ObsEva, and Theramex. A.L.S. has received a research
grant from Amgen. N.N., M.P., C.T.S., F.M.U., J.V., G.J.,
P.L., R.A.A., G.B., D.D.B., N.C.B., J.B., M.L.B., F.F.C.,
L.d.F., and L.M.D. have nothing to declare.
|
# 补充钙和维生素D 防治骨质疏松症的全球临床指南进展
摘要: 补充钙和维生素D 防治骨质疏松症一直是全球权威学术机构临床指南的基本策略。然而，近来一些研究对过量补充
钙和维生素D 的健康骨骼益处提出不同的观点，从而干扰了国际公认的防治骨质疏松症的基本策略，混淆了临床医师的视
听。因此，笔者综述近几年来中国、 美国、 加拿大、 英国、 波兰、 日本、 韩国等权威学术机构的临床指南的观点，重点介绍骨质疏
松症的发病机制和病理生理学关注的骨重建的主要局部调节剂［受体激活剂核因子kb(ＲANK)及其配体ＲANKL 和诱饵受体
骨保护素(OPG);罗列各国为防治骨质疏松症推荐的钙和维生素D 摄入量;联合补充钙和维生素D 有利于防治骨质疏松症和
骨质疏松性骨折;分析补充钙和维生素D 的健康骨骼争议，一般健康人每天服用钙补充剂不应该超过1000 mg。 特别是基于亚
洲人(中国人、 日本人、 韩国人)的膳食钙摄入量、 血脂水平、 身体体重指数(BMI)和维生素D 营养状况，参考中国、 日本、 韩国
的补充钙和维生素D 防治骨质疏松症的临床指南，提出钙和维生素D 补充的方法:每日一次服用碳酸钙和维生素D3 补充剂
的剂量以元素钙500 ～ 600 mg 和维生素D3 200 IU 为宜，比较适合中国成年人群预防骨质疏松症。如果需要补充更多剂量的
钙和维生素D，必须分成多次服用。这些信息供我国临床医师参考使用。
关键词: 钙;维生素D;临床指南;骨质疏松症;骨质疏松性骨折
The progre ss in global clinical guide line s on the pre ve ntion and tre atme nt of oste oporosis using calcium and vitamin D supple me ntation
Abstract: Calcium and vitamin D supplementation has alw ays been the basic strategy of clinical guidelines for the prevention and
treatment of osteoporosis from global authoritative academic institutions． Ｒecently，how ever，several studies had different view s on
the benefits of excessive calcium and vitamin D supplementation on healthy bones，thus conflicted w ith the internationally recognized
basic strategy for the prevention and treatment of osteoporosis，and confused clinicians． Therefore，w e review ed the clinical
guidelines of authoritative academic institutions in China，USA，Canada，UK，Poland，Japan and Korea，and highlighted that the
receptor activator of nuclear factor-kb (ＲANK)，its ligand ＲANKL，and a decoy receptor，osteoprotegerin (OPG) have emerged
as major local regulators of bone remodeling in the pathogenesis and pathophysiology of osteoporosis． We listed the recommended
calcium and vitamin D intakes for the prevention and treatment of osteoporosis，and summarized that both calcium and vitamin D
supplementation are beneficial in the prevention and treatment of osteoporosis and osteoporotic fractures． The controversy of calcium
and vitamin D supplementation for healthy bones w as analyzed，and in general healthy people taking calcium supplements should not
exceed 1000 mg daily． Based especially on calcium intake，serum lipid levels，BM I and vitamin D nutritional status in Asians
(Chinese，Japanese and Korean )，referencing to Chinese，Japanese and Korean clinical guidelines on calcium and vitamin D
supplementation for the prevention and treatment of osteoporosis，it is suggested calcium and vitamin D supplementation as calcium
carbonate and vitamin D3 supplements (calcium 500 － 600 mg and vitamin D3 200 IU daily ) are suitable for the prevention of
osteoporosis in the Chinese population． If you need to add more calcium and vitamin D supplementation，you must divide them into
multiple doses． These information are provided to Chinese clinicians for reference and clinical application．
Ke y words: Calcium; Vitamin D; Clinical guidelines; Osteoporosis; Osteoporotic fracture
钙和维生素D 是骨骼健康的基本组分，补充钙
和维生素D 是防治骨质疏松症的重要的基本策略。
骨质疏松症的常见严重并发症是骨折， 2016 年美国
国家骨质疏松基金会的荟萃分析结论为中老年人服
用钙和维生素D 补充剂能够作为降低骨折风险的
干预措施［1 ］
。然而，近来对补充钙和维生素D 的健
康骨骼益处发生争议，甚至提出过量钙补充对心血
管健康发生潜在的有害影响，从而混淆了临床医师
的视听，干扰了国际公认的防治骨质疏松症的基本
策略。2016 年10 月25 日美国国家骨质疏松基金
会和美国预防心脏病学会的临床指南［2 ］明确指出:
一般健康成年人无论从食物或补充剂补充钙(不管
是否有/ 或没有维生素D)与其心脑血管疾病风险、
死亡率、 全因死亡率都没有任何关系(有益或有
害)。为此，笔者综述近几年来中国、 美国［2-4 ］
、 加拿
大［5 ］
、 英国［6 ］
、 波兰［7 ］
、 日本［8 ］
、 韩国［9 ］等权威学术
机构的补充钙和维生素D 防治骨质疏松症的临床
指南的观点，引用指南中的学术文献，以期介绍骨质
疏松症的发病机制和病理生理学进展，分析补充钙
和维生素D 的健康骨骼争议，指导正确的钙和维生
素D 补充剂量等等，供我国临床医师参考。
1 骨质疏松症的定义
骨质疏松症(osteoporosis，OP)是一种以骨量低
下，骨微结构损坏，导致骨脆性增加，易发生骨折为
特征的全身性骨病。2001 年美国国立卫生研究院
(NIH)提出骨质疏松症是以骨强度下降、 骨折风险
性增加为特征的骨骼系统疾病，骨强度反映骨骼的
两个主要方面，即骨密度(占70% )和骨质量(占
30% )［8 ］
。
2 骨质疏松症的流行病学
骨质疏松症是一种静悄悄的疾病，直到由于轻
微创伤后发生骨折或在某些情况下没有创伤就发生
骨折才知道患有骨质疏松症。
2016 年张智海等［10 ］通过对万方数据与中国知
网数据库检索，对国内已发表骨质疏松症发病率文
献中10011 例男性和12943 例女性分析骨质疏松发
病率的结果:(1)40 ～ 49 岁年龄段:女性为(7. 75 ±
\6. 38)% ，男性为(4. 00 ± 2. 90)% ;(2)50 ～ 59 岁年
龄段:女性为(28. 00 ± 15. 72)% ，男性为(15. 73 ±
\9. 49)% ;(3)60 ～ 69 岁年龄段: 女性为(52. 67 ±
\10. 76)% ，男性为(30. 55 ± 10. 79)% ;(4)70 ～ 79 岁
年龄段: 女性为(79. 45 ± 9. 53)% ，男性为(43. 46 ±
\7. 30)% ;(5 )80 岁以上年龄段: 女性为(89. 55 ±
\1. 04)% ，男性为(66. 19 ± 17. 56)% 。由此可见，中
国男性在各年龄段发病率均低于同年龄段女性发病
率，并随年龄增长骨质疏松症发病率逐渐增多，男性
与女性的每10 年骨质疏松症增长率分别约为15%
和20% ; 40 岁以上人群骨质疏松症发病率为
\24. 62% (约25% )，约1. 4 亿患病人群。
2013 年Svedbom 等报告，在欧盟每年约有350
万新的脆性骨折发生，仅仅在2010 年这些脆性骨折
就产生了37 亿欧元的花费，造成43000 人死亡［11 ］
。
3 骨质疏松症的发病机制和病理生理
\3. 1 骨质疏松症的发病机制
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］提出，成年人的低骨量和骨骼脆性可能
是由于青少年时期的低峰值骨量、 以后的骨丢失过
多、 或两者都有的结果。人的一生骨骼总是在不断
变化。童年期和青春期是骨骼的成长时期，骨骼的
大小、 形状和成分都在改变。在青春期结束时骨骺
闭合，骨骼形状和大小的变化完成，随后5 ～ 10 年是
骨骼成长的巩固时期(取决于骨骼的部位)，一直到
达到成年人的峰值骨量，这通常发生在青少年或在
20 多岁时期［12-13 ］
。
大约70% ～ 80% 的峰值骨量是由遗传决定
的［14-17 ］
。许多非遗传因素也有助于骨骼成长，这包
括营养(例如钙、 磷酸盐、 蛋白质和维生素D)、 承重
的活动和儿童成长期和青春期相关的激素。
\3. 2 骨质疏松症的病理生理
一旦达到成年人的峰值骨量维持期后，就进入
骨骼的重建阶段，老骨被新骨替换。骨重建取决于
吸收老骨的破骨细胞和产生新骨的成骨细胞相互作
用。这些细胞的数量和活性，以及全身的激素和局
部的细胞因子参与。最近，受体激活剂核因子kb
(ＲANK)及其配体ＲANKL 和诱饵受体骨保护素
(OPG)，已经成为骨重建的主要局部调节剂［18 ］
。
ＲANKL 是由成骨细胞和基质细胞合成并存在于骨
微环境中，结合ＲANK，在骨髓的破骨细胞前体细胞
中表达，并促进破骨细胞生成。OPG 是也由成骨细中国骨质疏松杂志 2017 年3 月第23 卷第3 期 Chin J Osteoporos，March 2017，Vol 23，No． 3
胞和基质细胞合成并作为ＲANKL 的诱饵受体起作
用，防止ＲANKL 结合至ＲANK。破骨细胞活性的调
节至少部分取决于ＲANKL 和OPG 之间的平衡。
ＲANKL 和OPG 的相对含量是受到全身激素(如雌
激素)、 局部因子(如白细胞介素-6 和肿瘤坏死因
子)，也许还有其他因素控制。刺激能导致特异性
部位骨重建的级联活动触发机制尚不知道。然而，
研究表明健康个人骨重建过程至少50 年是平衡的
(也就是说，骨形成速率等于骨吸收速率)。直到50
岁，骨量一般几乎没有净丢失或净增加。Wnt 信号
是影响成骨细胞骨形成的重要途径。这是复杂的，
涉及许多超越骨骼的生理系统。
妇女整个围绝经期和绝经后初期的激素变化
(直接和间接地)刺激ＲANKL 产生，导致骨丢失加
速。大多数数据表明，骨转换率(和骨质丢失)在最
后一次月经前3 ～ 5 年加速和在最后一次月经后
3 ～ 5年又减缓。随着骨转换率的加速，骨平衡受到
干扰，因为每一次骨重建被激活，其骨量净丢失比增
加多。在这一时期平均骨质流失速率大约每年
1% ， 或者说，在绝经期的过渡阶段平均骨质流失速
率大约10% 。与绝经相关的骨丢失相反，男性和女
性在60 岁开始发生与年龄相关的骨丢失，从而使较
慢的骨质流失速率每年增加大约0. 5% 。虽然年龄
相关的骨丢失涉及的骨重建骨量与绝经相关的骨丢
失发生有相同的不平衡，但是起始过程尚不清晰。
结合由于绝经或老龄化的骨量丢失，骨质量也
有变化。骨质量变化包括松质骨的微结构单位(骨
小梁)破坏、 骨皮层变薄、 骨骼矿化程度降低、 以及
可能其他尚未知道的因素［19 ］
。许多因素包括营养、
维生素D、 运动、 吸烟以及患有其他疾病和使用药物
都可以影响骨丢失速率和骨折风险。在老龄化期间
和骨生长期间营养很重要。尤其是维生素D 缺乏，
无论是单独发生还是伴有更广泛的营养不良，几乎
已经在世界各地普遍发生。虽然严重维生素D 缺
乏会损害骨骼的矿化，但是即使轻度至中度维生素
D 缺乏也会减少钙吸收并可导致甲状旁腺激素
(PTH)介导的骨吸收增加。维生素D 缺陷也能够
引起肌肉力量和人体平衡的损害，导致跌倒风险增
加。大多数骨质疏松性骨折就是跌倒的结果，越来
越多的证据表明，低骨量的患者在更广泛的创伤后
骨折风险也增加［20 ］
。
4 补充钙防治骨质疏松症
\4. 1 钙的生物学作用
373
2014 年美国国家骨质疏松症基金会(NOF)的
预防和治疗骨质疏松症临床医生指南［3 ］认为，人体
99% 的钙储量在骨骼中，终身足够的钙摄入量对于
人体获得理想的峰值骨量和随后维持骨骼健康是必
要的。当外源性钙供应不足时，骨组织从骨骼吸收
出钙，释放到血液，以保持血清钙水平的恒定［3 ］
。
因此，足够的钙摄入量对骨骼健康是很重要的［21 ］
。
基于钙的生物学作用，几项流行病学研究已经证实
钙摄入量和骨密度或骨质量之间存在正相关关
系［22-23 ］
。因此，鼓励足够的钙摄入量或服用钙补充
剂已经成为治疗或预防骨质疏松症的基本策
略［6， 9 ］
。
\4. 2 防治骨质疏松症的钙推荐总摄入量
2014 年美国国家骨质疏松症基金会(NOF)的
预防和治疗骨质疏松症临床医生指南［3 ］认为，足够
的钙摄入量是任何骨质疏松症预防或治疗方案的基
本要求和任何年龄健康骨骼的生活方式。美国国家
骨质疏松症基金会(NOF)与美国医学科学院(IOM)
的膳食钙推荐摄入量一致［3， 24 ］
，2014 年的美国NOF
的临床医生指南［3 ］对绝经后妇女和50 岁及以上的
男性的推荐的膳食总钙摄入量:50 ～ 70 岁男性为
1000 mg / d，男性(70 岁以上)和女性(50 岁以上)为
1200 mg / d，如果饮食摄入量不足，就应该服用钙补
充剂。没有证据表明，超过这些钙的摄入量会赋予
额外的骨强度增加。也没有证据表明，超过1200 ～
1500 mg / d 的摄入量可能增加发生肾结石、 心血管
疾病和中风的风险［25-28 ］
。
2010 年加拿大骨质疏松症诊断和治疗的临床
实践指南［5 ］推荐， 50 岁以上中老年人每日摄入总的
元素钙(通过膳食和补充剂)应该为1200 mg。
2015 年韩国骨矿物研究学会的补充钙和维生
素D 指南［9 ］认为:研究明确显示韩国人钙摄入量增
加能够显著降低骨质疏松症的风险［29-30 ］
。钙摄入
量与所有骨骼部位的骨密度(BMD)值呈正相关关
系。 达到饮食膳食钙总摄入量 800 mg / d ～
1200 mg / d的水平，钙摄入量和骨密度之间的关联增
加［31-32 ］
。中国或日本妇女的短期和长期研究都已
经证明补充钙对骨质流失有预防作用［33-34 ］
。2015
年韩国的补充钙和维生素D 指南［9 ］提出:众所周知
韩国人膳食钙摄入量低。绝经后妇女和50 岁以上
男性每日钙摄入量为800 ～ 1000 mg / d。 当膳食钙摄
入不足时，应考虑服用钙补充剂。
2011 年日本骨质疏松学会、 日本骨矿物研究学
会和日本骨质疏松基金会的预防和治疗骨质疏松症473 的指南［8 ］建议补充钙和维生素D 作为防治骨质疏
松症的基本治疗，每天摄入钙700 ～ 800 mg，以优化
药物治疗的效果。
2013 年中国居民膳食每天钙推荐摄入量:18 ～
50 岁为800 mg，50 岁以上为1000 mg。 中晚期孕妇
和乳母为1000 mg［35 ］
。 2011 年中华医学会骨质疏松
和骨矿盐疾病分会的原发性骨质疏松症诊治指南推
荐，平均每日应补充的元素钙量为500 ～ 600 mg，应
注意避免超大剂量补充钙剂潜在增加肾结石和心血
管疾病的风险。2013 年中国居民膳食指南钙每天
可耐受最高摄入量(UL 值)为2000 mg(4 岁以上到
老年人)［35 ］
。
\4. 3 补充钙的安全问题
众所周知，补充钙具有健康骨骼益处。但是近
来全球各国的指南越来越多地关注过量钙补充对人
类健康(特别是与心血管疾病风险相关)的潜在有
害影响［36-38 ］
。最近几个流行病学调查或荟萃分析
研究提出了在奥克兰钙研究报告后较高钙摄入量增
加心血管事件的风险问题［37-38 ］
。在瑞典，61433 名
妇女乳房X 线照相队列研究中，与每天膳食钙摄入
量为600 ～ 1000 mg / d组，钙摄入量大于1400 mg / d
组全因死亡率和心血管死亡率更高。在包括11 项
前瞻性研究的荟萃分析数据中，每日膳食钙摄入量
高于1200 mg 时，心血管死亡率开始增加［39 ］
。来自
美国国立卫生研究院的AAＲP 饮食和健康前瞻性队
列研究的数据显示，388229 名50 岁以上男性和女
性的前瞻性队列研究，总心血管病死亡率与男性的
总钙摄入量呈U 型相关关联，在钙摄入量1500 mg /
d 和更高时能够观察到总心血管病死亡率增加［40 ］
。
一项关注钙补充与肾结石风险的大型研究［41 ］显示，
钙补充可能恶化高钙尿症，但是研究并没有评估参
与者的肾脏钙消耗。此外，肾结石的绝对风险差别
很小(钙补充剂组为2. 5% ，而对照组为2. 1% )。
另外，这些研究对象的平均总钙摄入量(饮食和补
充剂)高于目前的钙推荐摄入量。一般来说，健康
人不应该每天服用超过1000 mg 的钙补充剂。具有
肾结石病史的患者在决定服用钙补充剂前，应评估
肾结石形成的原因和是否患有高钙尿症。
另一方面，一些观察性研究报道了钙摄入量和
心血管病风险或死亡风险之间缺乏相关关联或甚至
负相关关联，研究表明较高水平的钙摄入量可能减
少心血管病发生或降低死亡率。妇女健康倡议的钙
加维生素D 补充(钙剂服用的是碳酸钙，元素钙量
每天1000 mg;维生素D3 为每天400 IU)的随机试
中国骨质疏松杂志 2017 年3 月第23 卷第3 期 Chin J Osteoporos，March 2017，Vol 23，No． 3
验报道，绝经后妇女服用钙和维生素D 补充剂的7
年期间，既不增加也不降低其冠心病或脑血管意外
的风险［42 ］
。在爱荷华州妇女健康研究中，超过
30000 名绝经后妇女，高膳食或补充剂的钙摄入量
与缺血性心脏病死亡率降低相关［43 ］
。
2016 年10 月25 日美国国家骨质疏松症基金
会和美国预防心脏病学会的临床指南［2 ］明确指出，
缺乏证据将一般健康成年人补充钙和维生素D / 单
独补充钙与心血管疾病联系在一起。临床指南认
为，钙是骨骼中存在的主要矿物质和美国膳食中短
缺钙。对于没有从其膳食中摄入足够量钙的人，笔
者已经推荐服用钙补充剂作为预防骨质疏松症和骨
质疏松性骨折的标准策略。临床指南的立场是:有
中等质量医学证据(B 级)显示一般健康成年人从
食物或钙补充剂补充钙和维生素D / 单独补充钙与
心脑血管疾病的发生风险、 和死亡率或者全因死亡
率都没有任何关系(有益的或有害的)。根据迄今
可获得的证据，从心血管观点来看，从食物和补充剂
摄入钙只要钙摄入量不超过可耐受最高摄入量(由
美国国家医学科学院制定为2000 ～ 2500mg / d)应该
被认为是安全的。
2013 年英国国家骨质疏松指南组(NOGG)更新
的骨质疏松症的诊断和治疗指南［6 ］指出，有研究提
示， 钙补充可能潜在与不良心血管结果相关［27， 37 ］
，
但这些研究已受到广泛批评，这种假定的关联需要
进一步澄清［44 ］
。虽然纵向队列研究也提示钙补充
可能心血管事件的风险，但是这个现象并没有在高
膳食钙摄入者中看到［45 ］
。因此，可能需要谨慎地增
加膳食钙摄入量和单独服用维生素D，应该考虑同
时补充钙和维生素D ［46 ］
。
2011 年日本骨质疏松学会、 日本骨矿物研究学
会和日本骨质疏松基金会的预防和治疗骨质疏松症
的指南［7 ］指出，据报道，钙补充剂可能增加心血管
疾病的风险。但是，相同的膳食钙摄入量尚未显示
增加心血管风险。此外，这些不良结果是从日本外
部报告的，其中钙摄入量、 血清脂质水平和体重指数
(BMI)与日本不同。此时，钙作为药物或补充剂，每
次剂量不应该超过500 mg。
2015 年韩国骨矿物研究学会的补充钙和维生
素D 指南［8 ］指出:膳食钙摄入量低也被认为与心血
管事件或死亡风险增加有关［47 ］
。亚洲人群的膳食
钙摄入量较低， 50 岁以上人群的平均饮食钙摄入量
约为470 mg / d，远低于可比的西方人群［48 ］
。此外，
一些提示较高钙摄入量伴有心血管病发生或死亡率中国骨质疏松杂志 2017 年3 月第23 卷第3 期 Chin J Osteoporos，March 2017，Vol 23，No． 3
增加的研究显示，钙摄入量较低的人群心血管病发
生率或死亡率明显增加或有增加的倾向［36 ］
。
2004 年我国卫生部、 科技部、 国家统计局发布
的中国居民营养与健康现状［49 ］指出:全国城乡居民
膳食钙摄入量仅为391 mg，相当于中国营养学会钙
推荐摄入量(800 ～ 1000 mg)的41% 。因此，中国居
民平均每日补充的元素钙量为500 ～ 600 mg。
5 补充维生素D 防治骨质疏松症
维生素D 在钙吸收、 骨骼健康、 肌肉性能、 人体
平衡和跌倒的风险中起主要作用。维生素D 在骨
骼和矿物质代谢中起着关键作用。维生素D 能增
加肠道吸收钙和磷酸盐，促进骨矿化。维生素D 也
对骨细胞有直接作用［50 ］
。因此，临床上维生素D 不
足会伴有骨质疏松症和骨折，维生素D 缺乏可导致
骨矿化缺陷，造成佝偻病和骨软化症。因此，维持充
足的维生素D 状态是骨骼健康的必要的先决条件。
同时，大量研究证明维生素D 对非骨骼疾病(包括
心血管疾病、 糖尿病、 癌症、 感染和自身免疫性疾
病)具有潜在预防作用［51-57 ］
。
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］认为，儿童和成年人预防骨质疏松症，
重要的是要确保其维生素D 的充足。大多数“ 健
康” 成年人血清25(OH)D 低于所期望的值［58 ］
。大
多数天然食物不含有维生素D。主要含有维生素D
的食物:鱼油(包括鳕鱼肝油)、 强化的牛奶、 谷物和
面包。没有涂防晒剂的皮肤在阳光下能够产生维生
素D，但是在北部或南部的冬天是不能产生维生素
D。美国国家科学院推荐:51 ～ 70 岁正常成年人每
天需要维生素D 400 IU 和70 岁以上的正常成年人
需要600 IU。现在许多专家认为这些推荐摄入量太
低［59 ］
。美国国家骨质疏松症基金会推荐:50 岁或
以上的成年人每天需要维生素D 800 ～ 1000 IU，但
许多专家推荐更多:1000 ～ 2000 IU / d(维生素D 的
“ 安全上限” 是4000 IU / d)。居家行动受限的个人、
肠道吸收不良的患者、 或正在接受长期抗惊厥药或
糖皮质激素治疗的患者，尤其存在维生素D 缺乏的
风险的患者，需要相当多的维生素D 补充才能达到
所需的水平。25(OH)D 水平低于30 ng / mL 的患者
补充维生素D 能改善钙吸收分数，但是25 (OH)D
水平高于30 ng / mL 的患者补充维生素D 不能改善
钙吸收分数。一项绝经后妇女研究的荟萃分析发
现， 每天补充维生素D 剂量700 ～ 800 IU 以上的绝
经后妇女髋骨骨折和非椎骨骨折明显减少［60 ］
。
573
美国国家骨质疏松症基金会(NOF)的膳食维
生素D 推荐摄入量比美国医学科学院(IOM )的
高［3， 24 ］
，IOM 的膳食维生素D 推荐摄入量为600
IU / d(直到70 岁) 和800 IU / d (70 岁以上)［24 ］
。
2014 年的美国NOF 的临床医生指南［3 ］指出，适当
提高维生素D 摄入量:800 ～ 1000 IU / d (50 岁以上
中老年人)，如果需要应该服用维生素D 补充剂。
2010 年加拿大骨质疏松症诊断和治疗的临床
实践指南［5 ］指出，维生素D 缺乏风险低的健康成年
人每日常规补充维生素D3 400 ～ 1000 IU (10 ～ 25
μg);维生素D 缺乏中度风险的50 岁以上成年人每
日补充维生素D3 800 ～ 1000 IU(20 ～ 25 μg)。为了
达到最佳的维生素D 状态，可能需要每日补充维生
素D3 1000 IU(25 μg)以上。每日补充维生素D3 剂
量高达2000 IU(50 μg)是安全的，不需要监测。
2011 年日本骨质疏松学会、 日本骨矿物研究学
会和日本骨质疏松基金会的预防和治疗骨质疏松症
的指南［8 ］推荐，每天维生素D 摄入量为400 ～ 800
IU(10 ～ 20 μg)。
2015 年韩国骨矿物研究学会的补充钙和维生
素D 指南［9 ］提出:众所周知韩国人维生素D 缺乏。
建议维生素D 摄入量每天超过800 IU，这似乎可以
降低骨折的风险。
2011 年中华医学会骨质疏松和骨矿盐疾病分
会的原发性骨质疏松症诊治指南推荐每天维生素D
摄入量:成年人为200 IU(5μg)，老年人为400 ～ 800
IU(10 ～ 20 μg)，维生素D 用于治疗骨质疏松症时
为800 ～ 1000 IU(20 ～ 25 μg)。2013 年中国居民膳
食指南［35 ］维生素D 每天可耐受最高摄入量(UL
值)为2000IU(11 岁以上)。
6 同时补充钙和维生素D 防治骨质疏松症
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］指出，
“ 骨健康” 的生活方式(足够的膳
食钙和维生素D、 运动、 避免烟草等)对每个人都很
重要(婴儿、 儿童、 青少年、 年轻的成人和骨质疏松
症患者)。其目标为:(1)骨骼成熟期优化骨骼发育
和最大化峰值骨量;(2)预防年龄相关性骨质流失
和继发性骨质流失的原因;(3)保持骨架的结构完
整性;(4)预防骨折。
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］认为，老年人钙的需求量增加，因此，老
年人特别容易钙缺乏，其导致钙缺乏的因素包括肠
吸收钙和维生素D 都减少和肾功能不全导致维生673 素D 激活降低。患有胃肠道吸收不良的患者、 正在
服用大剂量糖皮质激素的患者、 胃酸产生减少的患
者(例如，有胃旁路术史、 伴有恶性贫血、 或使用质
子泵抑制剂)、 接受抗癫痫药物的患者，甚至那些无
症状的腹腔疾病患者，都特别容易发生钙和维生素
D 缺乏。那些需要药物治疗的候选患者应考虑实验
室检查来评估钙和维生素D 是否充足。研究已被
证明服用钙补充剂能够轻微增加BMD，但没有科学
证据支持单独服用钙补充剂(而不同时补充维生素
D)能够减少骨折风险。单独服用钙补充剂降低骨
折风险的证据缺乏可能部分归因于研究设计和患者
依从性问题［41， 61 － 63 ］
。
2014 年波兰骨质疏松症的诊断和处理指南［7 ］
指出， 2012 年中欧国家［64 ］
、 2011 年美国［65 ］和2012
年欧洲［66 ］的维生素D 补充的专家共识明确推荐，需
要同时补充钙和维生素D［血清25 (OH)D 水平＞
30ng / ml ］作为预防和药物治疗骨质疏松症必不可少
的标准。
2014 年国家骨质疏松症基金会的临床医生指
南［3 ］认为，所有骨质疏松症患者每日摄入充足的钙
和维生素D 是一种安全和廉价的防治方法，有助于
降低骨折风险。对照的临床试验已经证明，同时补
充钙和维生素D 可以降低骨折的风险［67 ］
。骨质疏
松症常见的并发症骨折，给老年人带来巨大的医疗
负担和个人痛苦，并对国家造成重大的经济损失。
2016 年美国国家骨质疏松基金会［68 ］从PubMed
检索2011 年7 月1 日至2015 年7 月31 日期间的
补充钙和维生素D 与预防骨折的随机对照研究，符
合纳入标准的8 项研究30970 例参与者中，有髋部
骨折195 例和所有骨折2231 例。Meta 分析结果显
示:补充钙和维生素D 能够显著降低总的骨折风险
15% ，其总体相对风险评估［SＲＲE］为0. 85 (95%
CI， 0. 73 ～ 0. 98)和显著降低髋骨骨折风险30% ，其
SＲＲE 为0. 70 (95% CI，0. 56 ～ 0. 87 )。结论:本项
ＲCT 的荟萃分析支持社区和养老院的中老年人服
用钙加维生素D 补充剂作为降低骨折风险的干预
措施。
2014 年Hiligsmann 等［69 ］对老年骨质疏松症患
者(女性和男性)补充钙和维生素D 与未补充治疗
所获得的每个质量调整生命年(QALY)的成本效益
进行比较。结果:补充钙和维生素D 组的成本小于
无补充组治疗骨质疏松性骨折的成本。结论:本研
究提示60 岁以上的骨质疏松症患者(女性和男性)
补充维生素D 和钙成本效益好的。从经济角度来
中国骨质疏松杂志 2017 年3 月第23 卷第3 期 Chin J Osteoporos，March 2017，Vol 23，No． 3
看，年龄超过60 岁的人群(包括正在采取其它骨质
疏松症治疗的患者)都应该服用钙和维生素D 补充
剂。
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］关注的妇女健康倡议(WHI)研究显示，
每天补充钙1000 mg 和维生素D 400IU 组的患者髋
骨BMD 有小但显着的增加(1% )［41 ］
。除了维生素
D 的骨骼效应以外，研究也显示补充维生素D 能改
善肌肉力量、 人体平衡能力和降低跌倒风险［70 － 72 ］
，
还能改善存活率［73 ］
。
2013 年英国国家骨质疏松指南组(NOGG)更新
的骨质疏松症的诊断和治疗指南［6 ］指出， 50 岁以上
的绝经后妇女和男性应该纠正钙和维生素D 缺乏。
目前已经广泛向居家不出或生活在住宅区或养老院
的老年人推荐补充钙和维生素D，因为他们常见维
生素D 缺乏和膳食钙摄入量低。经常提倡补充钙
和维生素D 作为其他治疗骨质疏松症的辅助措施。
有研究提示，钙补充可能潜在与不良心血管结果相
关［37， 74 ］
，绝经后妇女的骨质疏松症患者治疗骨质疏
松症的主要药物是双磷酸盐、 狄诺塞麦、 雷奈酸锶、
雷洛昔芬和甲状旁腺激素肽。所有这些药物治疗已
经显示，当患者服用钙和维生素D 补充剂时，都能
够降低椎骨骨折的风险，有些也能够降低非椎骨骨
折的风险，在某些情况下特别降低髋骨骨折的风险。
2015 年韩国骨矿物研究学会考虑到50 岁以上
的韩国男性和绝经后妇女补充钙和维生素D 防治
骨质疏松症的重要性，研究表明，同时补充维生素D
与钙可以降低骨折和跌倒的风险，但单独补充维生
素D 可能无效［27， 75 ］;荟萃分析结果显示， 50 岁或以
上人群补充1200 mg 钙和800 IU 维生素D 的最小
推荐剂量防治骨质疏松症的效果最佳［76 ］
。
7 补充钙和维生素D 防治继发性骨质疏
松症
继发性骨质疏松症是由于疾病、 药物、 器官移植
等原因所致的骨量减少、 骨微结构破坏、 骨脆性增加
和易于骨折的代谢性骨病。
2013 年英国国家骨质疏松指南组(NOGG)更新
的骨质疏松症的诊断和治疗指南［6 ］指出，继发性骨
质疏松症的原因:类风湿关节炎、 男性和女性未治疗
性腺功能减退、 长时间不动、 器官移植、 I 型糖尿病、
甲状腺功能亢进、 胃肠道疾病、 慢性肝病、 慢性阻塞
性肺疾病。特别是糖皮质激素治疗(任何剂量、 口
服3 个月以上)。中国骨质疏松杂志 2017 年3 月第23 卷第3 期 Chin J Osteoporos，March 2017，Vol 23，No． 3
73
2006 年中华医学会骨质疏松和骨矿盐疾病分
会的继发性骨质疏松症诊疗指南(讨论稿)指出，继
发性骨质疏松症的基础治疗之一是适当补充钙和维
生素D 制剂。大部分继发性骨质疏松症(例如，糖
皮质激素性骨质疏松症、 制动性骨质疏松症、 长期肠
外营养支持性骨质疏松症、 糖尿病性骨质疏松症、 器
官移植后骨质疏松症等)除了原发疾病的治疗以
外，可以参考上述原发性骨质疏松症诊疗指南补充
钙和维生素D 制剂。但是，对于少数特殊疾病需要
特别注意:血液透析性骨质疏松症避免使用含铝透
析液和低磷低钙透析液;如果患者伴有高钙血症
(如肿瘤或甲状旁腺功能亢进症者)应该禁忌使用
钙剂及维生素D 制剂;如患者伴有肾结石及高尿
钙，则应慎用钙剂及维生素D 制剂。
2012 年巴西风湿性疾病学会与巴西医学会和
巴西风湿内科医师学会制定的预防和治疗糖皮质激
素性骨质疏松症指南［77 ］推荐，糖皮质激素性骨质疏
松症患者同时补充钙和维生素D 有益于预防骨量
丢失。绝经前妇女服用碳酸钙制剂(钙500 mg / d)
维持正在糖皮质激素治疗的妇女腰椎BMD。补充
钙和维生素D 被认为是低毒性和低成本治疗GIO
的第一步。补充钙和维生素D 能显著改善33% 正
在糖皮质激素治疗的患者腰椎和桡骨BMD;与安慰
剂组减少骨量比较，类风湿性关节炎患者和长期服
用糖皮质激素的患者组补充碳酸钙(1000 mg / d)和
维生素D(500 IU / d)能够增加骨量。
8 钙和维生素D 补充剂
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］认为，膳食钙摄入量不足的患者应该改
变他们的饮食或服用钙补充剂。许多钙补充剂中碳
酸钙补充剂通常是最便宜，并且需要服用的片剂数
最少。然而，碳酸钙可能引起胃肠道(GI)不适(便
秘和腹胀)，在胃酸分泌缺乏的患者，必须进食后立
即服用才能充分吸收。柠檬酸钙补充剂价格通常比
碳酸钙补充剂贵，并需要服用更多的片剂才能达到
所需的剂量;然而，柠檬酸钙的吸收不依赖胃酸，并
且很少可能引起胃肠道不适。
2010 年美国临床内分泌学家协会的临床实践
医学指南［4 ］指出，每日补充维生素D2 和D3 似乎同
样有效，但是与间歇补充剂量(每周1 次或每月1
次)，维生素D3 似乎比维生素D2 更有效约3 倍［78 ］
。
2014 年英国国家骨质疏松学会(NOS)公布了
2013 年维生素D 和骨健康:实用临床患者管理指
南［79 ］强调，口服维生素D3 是治疗维生素D 缺乏的
首选方法。治疗采用口服维生素D3 而不是口服维
生素D2 是基于补充后达到的血清25 (OH)D 水平
证据的荟萃分析［80 ］
。
综上所述，近几年来中国、 美国［2-4 ］
、 加拿大［5 ］
、
英国［6 ］
、 波兰［7 ］
、 日本［8 ］
、 韩国［9 ］等的补充钙和维生
素D 防治骨质疏松症的临床指南介绍骨质疏松症
的发病机制和病理生理学进展，分析补充钙和维生
素D 的健康骨骼争议，推荐正确选择钙和维生素D
补充剂量和类型。依据中国、 日本［8 ］和韩国［9 ］指南
的相关部分，每日1 次服用钙剂量为500 ～ 600 mg
和维生素D3 剂量为200 IU 的碳酸钙和维生素D3
补充剂比较适合中国成年人群预防骨质疏松症。如
果需要补充更多剂量的钙和维生素D，必须分成多
次服用。 |
{
"text": "{\"text\":\"DOI : 10.3969/j. issn. 1674-2591. 2011. 02. 014\\n\\n《编者按》:由国际著名维生素 D 研究专家 Holick MF 教授牵头的专家组为美国内分泌学会 临床学术期刊 JCEM 撰写的\\\"维生素 D 缺乏的评价、预防及治疗\\\"(指南)一文,于2011年6月6 日首先以电子版发表,本文做了重点节译,供读者参考。这是一篇基于循证医学和流行病学研究 资料基础上所成之文,对内分泌临床及其他有关涉及骨矿盐代谢疾病领域的专业人员都有重要 的实际指导意义。但也应看到,该文所依据的资料大都来自对西方人群的研究,文内提出的对维 生素 D 缺乏诊断依据、标准,以及对预防及治疗时所设定的剂量范围,是否完全适合东方人群, 特别是我国人群,尚需我们自己的工作进一步阐明。又如,作者认为维生素 D2和Dg的实际应用 效果是一样的,但有研究资料显示,在调控人类骨钙代谢效能方面,D。较 D,强2~4倍。对此如 何看待?似值得考虑。\\n\\n# 维生素 D 缺乏的评价、预防及治疗 -- 内分泌学会临床实践指南\\n\\n近年来,维生素D不足或缺乏现象引起了大 家的关注与重视,如何规范地补充维生素 D 制剂, 也引起了学术界的广泛兴趣。2011年 Michael F. Holick 等多名专家联合制定了关于评价、治疗及预 防维生素 D 缺乏的内分泌学会临床实践指南,于 2011年6月6日发表在《临床内分泌代谢杂志》 ( Journal of Clinical Endocrinology and Metabotism , JCEM)。该临床实践指南主要包括了维生素 D 缺 乏的诊断、维生素 D 缺乏高危人群饮食摄入维生 素 D的建议、维生素 D 缺乏的防治策略及维生素 D 调节钙代谢以外的益处。现简要介绍如下:\\n\\n## 维生素 D 缺乏的诊断\\n\\n该指南建议应针对可能存在维生素 D 缺乏风 险的人群进行筛查,推荐采用可靠的分析方法来测 量血清25 羟D(250HD) 浓度,以评价患者是否 存在维生素 D 缺乏。维生素 D 缺乏是指 250HD 浓 度低于20 ng/mL(50 nmol/L)。1,25-双羟维生素 D 浓度检测只用于一定的疾病状态,如获得性及遗 传性维生素 D 代谢异常疾病及磷代谢异常的疾病。\\n\\n维生素 D 缺乏高危人群营养摄入维生素 D 的 建议 (表1)\\n\\n指南建议0~1 岁的婴幼儿应至少补充维生素 D 400 U/d (1 U=25 ng), 1 岁以上儿童,应至少 摄入600 U/d维生素 D,以使骨骼最大程度的获益。 是否此剂量能使婴幼儿与儿童获得足够的骨骼外益 处,尚不清楚。此外,如果要使血清250HD 浓度 持续大于 30 ng/mL (75 nmol/L),可能需要至少 补充1 000 U/d的维生素 D。\\n\\n·泽\\n\\n文 ·\\n\\n指南建议 19 ~ 50 岁的成年人应至少摄人 600 U/d的维生素 D,以使骨骼和肌肉最大程度的 获益。此剂量是否足以获得维生素D 相关的骨骼 外益处,尚不清楚。然而,如果要使得成年人血清 250HD 浓度持续大于30 ng/mL,可能需要至少补 充1500~2000 U/d的维生素 D。\\n\\n对于 50~70 岁及 >70 岁的人群,指南建议至 少分别摄人600U或 800 U/d的维牛素 D,600~ 800 U/d的维生素 D 是否能够获得维生素 D 相关的 骨骼外益处,尚不清楚。然而,要使得成年人血清 250HD 浓度持续大于30 ng/mL,可能需要至少摄 入1 500~2 000 U/d的维生素 D。\\n\\n对于妊娠期及哺乳期的妇女,指南建议至少补 充600 U/d的维生素 D,要使血清 250HD 浓度超 过 30 ng/mL,至少需要补充 1 500~2 000 U/d的 维生素 D。\\n\\n指南建议对于肥胖的儿童及成年人、以及服用 抗癫痫药物、糖皮质激素、酮康唑等抗真菌药物和 治疗艾滋病药物者,至少需要补充2~3 倍剂量的 维生素 D,以满足机体维生素 D 的需要量。\\n\\n指南建议应使维生素 D 水平保持在可接受范 围的上限,在缺乏医疗监督的情况下,维生素 D 剂量不能超过如下范围:6月龄以内的婴儿,最大 饮食补充量为1 000 U/d, 6个月~1 岁的婴儿不超 过1 500 U/d,1~3 岁儿童不超过2 500 U/d,4~ 8 岁儿童不超过3 000 U/d,8 岁以上儿童不超过 4 000 U/d。然而,为了校正维生素 D 缺乏,需要 补充更大剂量的维生素 D,0~1 岁的儿童可以补 充2 000 U/d的维生素 D, 1~18 岁的儿童可以补 充 4 000 U/d的维生素 D, > 19 岁的成人可以补充 10 000 U/d的维生素 D(表2)。\\n\\n## 维生素 D 缺乏的防治策略\\n\\n指南建议采用维生素 D2 或维生素 D2 治疗和预 防维生素 D 缺乏。\\n\\n指南建议对0~1岁婴幼儿维生素D 缺乏者, 采用维生素 D,或维生素 D2 2 000 U/d治疗,或使 用50000U维生素 D2或维生素 D3,每周1次,共 6周,使血250HD 水平达到30 ng/mL以上,之后 用 400 ~ 1 000 U/d维持。\\n\\n指南建议对1~18岁儿童维生素 D 缺乏者, 采用维生素 D,或维生素 D, 2 000 U/d治疗至少 6 周,或采用维生素 D,或维生素 D3 50 000 U,每 周1 次,共6周,使血250HD 水平达到30 ng/mL 以上,之后用600~1000 U/d维持。\\n\\n指南建议所有成人维生素 D 缺乏者,采用维 生素 D,或维生素 D2 50000U,每周1次,共8 周,或采用维生素 D,或维生素 D26000U/d 的等 同剂量,使血250HD水平达到30 ng/mL以上,之 后用1 500~2 000 U/d 维持。\\n\\n指南建议对肥胖、吸收不良综合征和服用影响 维生素 D代谢药物者采用大剂量维生素 D(2~3 倍剂量, 至少 6 000~10 000 U/d) 治疗维生素 D 缺乏,使血250HD 水平达到30 ng/mL以上,之后 用3 000~6 000 U/d 维持。\\n\\n某些患有结节病、结核病等患者,因其体内被 激活的巨噬细胞能以不被调控的方式将 250HD 转变 成1,25(OH)2D,使肠钙吸收和动员骨钙都增加, 产生高钙血症和高尿钙。指南建议对这种肾外异常 产生1,25(OH)2D的患者,在治疗维生素D 缺乏期 间应监测250HD和血清钙水平,预防高钙血症。\\n\\n对于原发性甲状旁腺功能亢进症合并维生素 D 缺乏者,指南建议进行维生素 D 治疗,同时监测 血清钙水平。\\n\\n# 维生素 D 调节钙代谢以外的益处\\n\\n针对维生素 D 的调节骨代谢和钙以外作用, 指南仅推荐使用维生素 D 预防跌倒,并不推荐使 用维生素 D 预防心血管事件、死亡和提高生活质 量。其他骨骼以外的益处尚需进一步评估。\\n\\n| 维生素 D 缺乏的风险人群 | | 生理需要量(U/d)<br>维持最佳骨骼和肌肉功能 | 维牛素 D 补充<br>上限(U/d) | 维持 250HD > 30 ng/mL<br>的补充量 | 纠正维生素 D 缺乏补充<br>上限(U/d) | |\\n|---------------|---------|---------------------------|---------------------|-----------------------------|-------------------------|--|\\n| 0~1 男 | 0~6个月 | 400 | 1 000 | 1 000 | 2 000 | |\\n| | 6~12 个月 | 400 | 1 500 | 1 000 | 2 000 | |\\n| | | 400 | | | | |\\n| 1 ~ 18 岁 | 1~3 岁 | 600 | 2 500 | 1 000 | 4 000 | |\\n| | 4~6岁 | 600 | 3 000 | 1 000 | 4 000 | |\\n| | 9~18 发 | 600 | 4 000 | 1 000 | 4 000 | |\\n| 19 ~ 50 % | | 600 | 4 000 | 1 500~2 000 | 10 000 | |\\n| 51 ~70 岁 | | 600 | 4 000 | 1 500~2 000 | 10 000 | |\\n| >70 岁 | | 800 | 4 000 | 1 500~2 000 | 10 000 | |\\n| 妊娠哺乳妇女 | | 600 | 4 000 | 1 500~2 000 | 10 000 | |\\n\\n营养摄入维生素 D 的建议 表 1\\n\\n(C)1994-2022 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net\\n\\n· 146 ·\\n\\n| 表2 年生素D 缺乏的治疗剤量 | | | | | | |\\n|-----------------------------------|----------------------------|------|--------------------|--|--|--|\\n| 对象 | 治疗阶段<br>使 250HD > 30 ng/mL | | 维持阶段 | | | |\\n| 0~1 岁 | 2 000 U/d | 6 周 | 400 ~ 1 000 U/d | | | |\\n| | 50 000 U/周 | | | | | |\\n| 【~18岁 | 2 000 U/d | 至少6周 | 600 ~ 1000 U/d | | | |\\n| | 50 000 U/周 | | | | | |\\n| 所有成人 | 50 000 U/周 | 8 周 | 1 500~2 000 U/d | | | |\\n| | 6 000 U/d | | | | | |\\n| 肥胖老<br>吸收不良综合征<br>使用影响维生素 D 代谢的药物 | 6 000 ~ 10 000 U/d | | 3 000 ~ 6 000 U/d | | | |\\n| 伴有肾外1,25(OH)。D生成者 | 注意监测 250HD 和血钙水平 | | 防治维生素 D 治疗期间发生高钙血症 | | | |\\n| 原发性甲状旁腺功能亢进症 | 根据需要补充维生素 D | | 监测血钙水平 | | | |\\n\\n# 测定血 25OHD 的适应证(筛查候选)\\n\\n如果在临床上遇到以下情况,需要考虑进行维 生素 D 营养状态的判断:何偿病、骨软化症、骨 质疏松、慢性肾功能不全、肝衰竭、吸收不良综合 征、囊性纤维化、炎性肠病、Crohn 病、比罗式手 术、放射性肠炎、甲状旁腺功能亢进症、药物、抗 抽搐药、糖皮质激素、AIDS 药物、抗真菌药(如 酮康唑)、消胆胺、非裔美洲人、西班牙人、妊娠 期和哺乳期妇女、有跌倒史的老年人、有低创骨折 的老年人、肥胖的儿童和成人\\n\\nBMI 30 kg/m²、肉芽肿性疾病、结节病、结 核、组织胞浆菌病、球孢子菌病、镀中毒和部分淋 巴瘤。\\n\\n总之,维生素D缺乏非常普遍,对具有高风 险的人群可以考虑测定 250HD 水平判断维生素 D 的营养状态。针对维生素 D的补充,必需强调日\\n\\n光照射是机体维生素D合成的主要来源,如果日 照不足最好从食物中补充足够的维生素 D,但是富 含维生素 D 的食物太少。日照时为了避免黑色素 瘤或其他皮肤癌的风险,可以避开正午时分。居住 在纬度33 度以上地区的人群,需要注意补充维生 素 D。就预防你俊病和骨软化症而言,需要使血液 中维生素 D 水平 >20 ng/mL,为了使维生素 D 发 挥更大的调节钙、骨骼和肌肉的作用,需要将血液 维生素 D 水平维持在 > 30 ng/mlL水平。当维生素 D 水平在30 ng/mL以上,才可能发挥降低肿瘤、2 型糖尿病、心血管疾病和感染等疾病的风险。今后 需要加强研究,以评价补充较大量维生素 D(如 2 000~5 000 U/d)对钙和骨骼以外的益处。\\n\\n> (夏维波 李梅 摘译) (收稿日期:2011-06-10)\"}"
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"Page 1\n2025/4/2 13:12\n中国儿童维生素A、维生素D临床应用专家共识(2024版)\n杂(...TRUNCATED) |
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