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Calcium and vitamin D supplementation: State of the art for daily practice


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Background Calcium and vitamin D play an essential role in bone metabolism but deficiency and/or inadequate intake are common. Objectives To describe a practical approach based on the literature regarding clinically important aspects of calcium and vitamin D supplementation. Methods A systematic evaluation of relevant literature in Medline was conducted. We included physiological studies, publications on relevant guidelines, meta-analysis, randomized clinical trials, and cohort studies. Results An adequate calcium intake and vitamin D supplementation is recommended in most guidelines xon fracture prevention. Daily supplementation with 800 IU is advocated in most guidelines, appears to be safe, and with this approach it is generally not necessary to determine vitamin D levels. There are no data on additional effects of loading doses of vitamin D on fracture or fall prevention. Calcium supplementation should be tailored to the patient’s need: usually 500 mg per day is required. The intestinal absorption of calcium citrate is approximately 24% better than that of calcium carbonate independent of intake with meals. Data on difference between calcium absorption with calcium carbonate compared to calcium citrate with simultaneous use of proton pump inhibitors are lacking. Concern has arisen about a possible link between calcium supplementation and an increased risk of myocardial infarction. Probably only well-designed prospective randomized controlled trials will be able to allow definite conclusions on this subject. Conclusion Daily supplementation with 800 IU vitamin D is a practical and safe strategy without the need for prior determination of vitamin D levels. Calcium supplementation should be tailored to the patient’s need based on total daily dietary calcium intake. In most patients 500 mg per day is required to achieve a total intake of 1,200 mg, or in some 1,000 mg per day. More calcium is absorbed from calcium citrate compared to calcium carbonate.
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Calcium and vitamin D supplementation: state of the art for
daily practice
Robert Y. van der Velde
*, Jacobus R. B. J. Brouwers
, Piet P. Geusens
Willem F. Lems
and Joop P. W. van den Bergh
Department of Internal Medicine, VieCuri Medical Centre for North Limburg, Venlo, The Netherlands;
of Geriatric Medicine, Exper tise Centre for Pharmacotherapy in the Elderly, Ephor-UMC Utrecht, The Netherlands;
Department of Rheumatology, CAPHRI, Maastricht UMC, Maastricht, The Netherlands;
Biomedical Research
Centre, University of Hasselt, Diepenbeek, Belgium;
Department of Rheumatology, VU Medical Centre, Amsterdam,
The Netherlands
Background: Calcium and vitamin D play an essential role in bone metabolism but deficiency and/or
inadequate intake are common.
Objectives: To describe a practical approach based on the literature regarding clinically important aspects of
calcium and vitamin D supplementation.
Methods: A systematic evaluation of relevant literature in Medline was conducted. We included physiological
studies, publications on relevant guidelines, meta-analysis, randomized clinical trials, and cohort studies.
Results: An adequate calcium intake and vitamin D supplementation is recommended in most guidelines xon
fracture prevention. Daily supplementation with 800 IU is advocated in most guidelines, appears to be safe,
and with this approach it is generally not necessary to determine vitamin D levels. There are no data on
additional effects of loading doses of vitamin D on fracture or fall prevention. Calcium supplementation
should be tailored to the patient’s need: usually 500 mg per day is required. The intestinal absorption of
calcium citrate is approximately 24% better than that of calcium carbonate independent of intake with meals.
Data on difference between calcium absorption with calcium carbonate compared to calcium citrate with
simultaneous use of proton pump inhibitors are lacking. Concern has arisen about a possible link between
calcium supplementation and an increased risk of myocardial infarction. Probably only well-designed
prospective randomized controlled trials will be able to allow definite conclusions on this subject.
Conclusion: Daily supplementation with 800 IU vitamin D is a practical and safe strategy without the need
for prior determination of vitamin D levels. Calcium supplementation should be tailored to the patient’s need
based on total daily dietary calcium intake. In most patients 500 mg per day is required to achieve a total
intake of 1,200 mg, or in some 1,000 mg per day. More calcium is absorbed from calcium citrate compared to
calcium carbonate.
Keywords: calcium absorption;vitamin D supplementation;fracture prevention;fall prevention;cardiovascular risk
Received: 19 June 2014; Revised: 24 June 2014; Accepted: 1 July 2014; Published: 7 August 2014
The essential role of calcium for bone metabolism
has been known since the animal studies (in 1928)
and calcium balance studies (in 1946) performed
by Albright (1). Rickets was first described more than
300 years ago (Glisson, 15991677), but the essential
role of vitamin D with regards to bone metabolism only
became clear following animal experiments with liver oil
supplements by McCollum (2).
Vitamin D supplements reduce the risk of falls and
fractures in vitamin D-deficient subjects. Vitamin D
deficiency is worldwide considered endemic and there-
fore vitamin D supplementation is recommended in most
guidelines on fracture prevention.
Inadequate intake of calcium via the diet is also
common, even more so in patients with a recent fracture,
and adequate calcium intake is recommended in the
guidelines. The absorption of calcium from the intestines
occurs by means of an active, vitamin D-dependent
process and to a lesser extent by passive diffusion and is
determined among other factors by the solubility of
food & nutrition
Food & Nutrition Research 2014. #2014 Rober t Y. van der Velde et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-
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Citation: Food & Nutrition Research 2014, 58: 21796 -
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calcium and the pH in the different parts of the gastro-
intestinal system. Observational research indicates that
excessive calcium intake could increase the risk of cardi-
ovascular events.
homeostasis will depend on the need of vitamin D
and calcium. There are, however, few all-encompassing
studies available about the relationship between the
dosage of vitamin D supplementation and changes in
serum 25(OH)D to answer questions about the need
amongst the elderly, the target values for serum levels,
and the quantity and frequency of vitamin D supple-
ments. For calcium intake, the question that arises is
what the minimum and maximum calcium dosages
should be for recommendation.
This overview aims to provide an answer to these
questions, based on a review of relevant literature.
Calcium and vitamin D recommendations in
Guidelines on Osteoporosis and Fracture Prevention
The 2011 Dutch Guideline on Osteoporosis and Frac-
ture Prevention (CBO Guideline) advises in the case of
patients taking medication to prevent fractures to aim for
a total calcium intake (diet and supplements) of 1,000
1,200 mg calcium per day and an intake of vitamin D
supplements of 800 IU per day (3).
The United Kingdom NICE 2012 guidelines on
fractures and osteoporosis, that are mainly focused on
fracture risk and other related NICE guidelines, have
no special focus on calcium and vitamin D (http://www. (last
assessed on April 24, 2013). A new guideline on vitamin
D will be available in 2014. Canadian guidelines (4)
advise intake of 1,200 mg calcium daily in women
50 years and older and men 70 years and older. The
vitamin D intake in elderly persons should be 1,000
1,200 IU daily. The Australian guideline (http://www.
(last assessed on April 24th 2013) advises for women over
50 years of age a calcium intake of 1,300 mg per day
and a vitamin D intake of 800 IE. In the international
literature, there is no consensus on the daily vitamin D
supplementary intake (5).
In a recent statement, the US Preventive Services
Task Force (USPSTF) recommends against daily supple-
mentation with 400 IU or less of vitamin D and 1,000 mg
or less of calcium for the primary prevention of frac-
tures in non-institutionalized post-menopausal women
(6). The USPSTF concludes that the current evidence
is insufficient to assess the balance of the benefits and
harms of daily supplementation with greater than 400
IU of vitamin D and greater than 1,000 mg of calcium
for the primary prevention of fractures in the same
population (6).
Meta-analyses reveal that calcium supplementation
reduces the risk of non-vertebral fractures, with the effect
being amplified in combination with vitamin D (7, 8),
particularly for hip fracture reduction (9). Supplementa-
tion of 4001,200 IU of vitamin D per day for the elderly
(65 years), in combination with calcium, results in a
relative reduction of the occurrence of non-vertebral
fractures of 1020% (10, 11).
An association between vitamin D deficiency, falls,
and fracture rates in older women and men has been
demonstrated in several studies (1214).
In a 1-year randomized, population-based, controlled
reduced the risk of falling over a year by about one-
third in women with a serum 25 hydroxyvitamin D
(25OHD) B60 nmol/L and a history of falls in the
previous year (15).
In all randomized clinical trials on the effect of
drugs with fracture prevention as primary endpoint,
both the intervention group and the placebo group were
supplemented with vitamin D and calcium (Table 1).
However, there were large differences in the amount of
calcium and vitamin D supplements in the various
fracture studies.
Most of these studies were performed with standard
dosages of 2501,200 IU/ day for vitamin D and 500
1,000 mg per day for calcium or dosages of calcium and
vitamin D supplements adjusted for dietary intake and
serum values of 25(OH)D. In some studies, vitamin D
supplements were given before the start of the study, in
daily doses during several weeks to months, or in bolus
up to 125,000 IU.
Mechanism and functional aspects of intestinal
absorption of the calcium salts
The intestinal calcium absorption has been studied
extensively in balance studies in patients with chronic
renal insufficiency, revealing that a dietary intake of
1,000 mg calcium results in approximately 400 mg being
absorbed in the digestive tract, whilst 200 mg of calcium
is added to the intestinal lumen via excretion. The total
amount of calcium that passes the digestive tract is
therefore 1,200 mg, of which 800 mg is excreted via
the feces. This means that the average fractional calcium
absorption is 400/1,2000.33 (16, 17). The serum
calcium level and the 24-h calcium excretion can be
measured accurately in clinical practice, but the actual
quantity of calcium that is absorbed by the bones is
much more difficult to measure. This requires the use of
‘bio-markers’, absorption of calcium isotopes, or after
extended treatment bone densitometry. The absorption
of calcium occurs primarily in the small intestine via an
active trans-cellular process on the one hand, regulated
by active vitamin D (1.25 (OH)
), and via para-cellular
diffusion on the other hand (18, 19), the latter being
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largely vitamin D independent. The active transport is a
process that can become saturated and is particularly
important in the event of limited calcium intake. This
results in an upregulation of the production of active
vitamin D. As the fractional calcium absorption is
significantly determined by active vitamin D, vitamin
D deficiency will also result in decreased calcium
absorption. Heaney et al. demonstrated that the calcium
absorption increases up to a serum 25(OH)D level of
80 nmol/L and reaches a plateau at 80 nmol/L (Fig. 1)
(20). Assuming the fact that approximately 35% of the
available calcium is absorbed in the gastrointestinal
system, the question is how significant the contributions
of the active and passive transport systems are and in
which parts of the gastrointestinal system this absorption
The course of calcium absorption and, in particular,
the contribution of active and passive absorption of
calcium over the course of the jejunum, ileum, and colon
is presented in Fig. 2 (19, 21).
The solubility of the type of calcium salts is impor-
tant for this absorption process, because calcium can only
be absorbed in dissolved form (24, 25). However, the
solubility of calcium is primarily dependent on pH, so
that the pH of the digestive tract is an important factor in
this absorption process. In addition, factors such as pCO
and the quantity of bicarbonate and phosphate play
an additional role in the calcium absorption process.
It is known that the pH changes over the course of the
digestive tract: very low in the stomach (pH 12),
approximately pH 6 in the duodenum, gradually increas-
ing in the small intestine from 6 or 6.5 in the proximal
jejunum to 7.4 in the middle of the small intestine and to
7.5 in the ileum. The pH then decreases to 6.4 in the
cecum and in the course of the colon gradually increases
again to 6.7 and finally to 7 in the rectum (Fig. 2)
(22, 26). The average pH is 7.3 in the small intestine and
6.6 in the colon (23).
In this context, it is important to realize that calcium is
not absorbed in the stomach, but in the small and large
intestine. The total amount of calcium that is absorbed
Tab le 1. Calcium and vitamin D supplementation in medicinal fracture intervention studies
Study Medicine Calcium, mg/d Vitamin D, IE/d
Black 1996 Alendronate 500 when required 250
Cummings 1996 Alendronate 500 when required 250
Harris 1999 Risedronate 1,000 500 when required
Reginster 2000 Risedronate 1,000 500 when required
McClung 2001 Risedronate 1,000 500 when required
Chestnut 2004 Ibandronate 500 400
Black 2007 Zoledronate 1,0001,500 4001,200
Lyles 2007 Zoledronaat hip 1,0001,500 25(OH)D B37.5 nmol/L or not measured:
Loading dose: 50120,000
Thereafter 8001,200
Ettinger Raloxifen 500 400600
Neer 2001 Teriparatide 1,000 400 1,200
Greenspan 2007 PTH 700 400
Meunier 2004 SR*SOTI 01,000
Reginster 2005 SR*TROPOS 01,000
Cummings Denosumab 1,000 25(OH)D nmol/L:
3050: 800
50: 400
If the vitamin D level was lower than 40 nmol/L.
To achieve a total intake of 1,000 mg per day.
SR*, strontium ranelate.
Fig. 1. Relationship between serum 25(OH)D level and
fractional calcium absorption (20).
Calcium and vitamin D supplementation
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therefore depends on the amount of calcium consumed,
the passage time in the various segments of the small
and large intestine, and the amount of soluble calcium
available for absorption, which is primarily determined
by the pH in each segment of the gastrointestinal tract. In
the duodenum, and to a lesser extent the jejunum, there is
active calcium transport in addition to passive transport;
in the ileum there is primarily passive transport. The
largest quantity, namely 65% of the absorbed calcium,
is absorbed via passive transport in the ileum, because of
the length of this segment compared to the other parts
of the digestive tract (19, 21).
Calcium supplementation usually happens as a calcium
salt in the form of calcium carbonate or calcium citrate.
There are several calcium compounds available. When a
compound containing calcium carbonate is taken, this is
dissolved in the acidic environment of the stomach. When
a compound which contains calcium carbonate and citric
acid is taken then this will form calcium citrate when
dissolved in a glass of water. These various calcium
compounds are also available in various combination
preparations with low 400/440 IU and higher 800/
880 IU dosages of vitamin D.
The solubility of these salts has been tested in water,
showing that calcium citrate dissolved more completely
than calcium carbonate. However, dissolving calcium
citrate results in a pH of 5.6 and calcium carbonate in a
pH of 8.5, neither of which is an accurate reflection of
solubility in the digestive system. After all, the pH varies
per section of the digestive system and therefore the solu-
bility of the calcium salt will also vary per section (2729).
When the calcium salts are ingested and enter the
acidic environment of the stomach, dissolved calcium
ions become available (30).
(insoluble) 2 HCl 0Ca2þþ2ClþH2OþCO2
Calcium carbonate Hydrochloric
0Soluble calcium ion
Carbon dioxide
Ca3ðC6H5O7Þ2:4H2O6 HCl 0
Calcium citrate Hydrochloric
0Citric acid
Soluble calcium ion
An increasing pH in the duodenum and jejunum
(due to bicarbonate production) will result in decreased
solubility of calcium because calcium salts are formed
once more:
CaCl2þ2NAHCO3!CaCO3þ2NaCl þCO2þH2O
In vitro study of the pH-dependent solubility of cal-
cium carbonate compared to calcium citrate taking
into consideration the CO
tension that affects the
solubility in the digestive tract shows that the solu-
bility of carbonate is higher at a pHB6.5 and the
solubility of the citrate form is higher at pH6.5
(Fig. 3). At a pH of 7.5, the solubility of citrate is around
two times higher than that of carbonate. However, the
solubility of both calcium salts decreases with increasing
pH (2729).
If we translate this to the practical setting, there
are two clinical questions that need to be asked: Is the
calcium absorption with use of a calcium-containing
supplement the same for calcium carbonate and calcium
citrate? and Does the absorption of calcium carbonate
and calcium citrate differ in the event of a (relative) high
stomach pH, as is the case with the use of antacids or
hypochlorhydria or achlorhydria?
Fig. 2. Calcium absorption, solubility of calcium, contribution of active and passive absorption of calcium and pH in the
various segments of the small and large intestine (19, 22, 23).
Robert Y. van der Velde et al.
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Based on these in vitro models, the stomach pH
does have an effect on the solubility of the various
calcium salts, but because absorption occurs primarily
in the small and large intestine particularly the ileum
at a pH of around 7.5 (Fig. 2: 965% of the total calcium
absorption) it could well be that the pH of the stomach
is far less relevant and that the solubility of the calcium
salt in the pH range of 6.5 to 7.5 is of particular
importance. Of course, the fact that the in vitro models
do not correct for other factors, such as buffering by
amino acids, bile, and food components, should be taken
into consideration (2729).
The difference in calcium absorption with supplemen-
tation of calcium carbonate compared to calcium citrate
has been studied extensively. A meta-analysis was pub-
lished by Sakhaee et al. in 1999, which concluded that
calcium absorption was (statistically significant) 24%
higher in cases of supplementation with calcium citrate
compared with calcium carbonate, both when taken on
an empty stomach and when ingested during a meal
(Table 2, upper portion) (31). A number of studies have
been published since 1999 about this subject, using various
techniques to determine calcium absorption, usually in
healthy study subjects or post-menopausal women and
applying various calcium dosages. The data of these
studies are presented in Table 2, lower portion.
The influence of achlorhydria and proton pump
inhibitors on calcium absorption
Literature about the presence of achlorhydria in the elderly
is limited. A systematic review by Hurwitz et al. (40)
Fig. 3. Concentration of dissolved elemental calcium
(Y-axis, log scale) depending on pH for calcium citrate (blue
line) and calcium carbonate (red line), corrected for CO
tension in the digestive tract. Modified from Goss et al. (29).
Tab le 2. Clinical studies into the effect of intestinal calcium absorption with the use of calcium citrate versus calcium carbonate: the upper
portion lists the studies in the meta-analysis by Sakhaee et al. (31) and the lower portion lists the studies published thereafter
Author Year NGender Population Method Calcium dosage (mg) Meal Effect citrate vs. carbonate (%)
Bo-Linn 1984 6 Normal Lavage 1,000 21.6
Nicar 1985 14 11 f, 3 m Normal Urine Ca excretion 1,000 70.5
Recker 1985 7 Normal Dual isotope 250 8.0
Reid 1986 10 Normal Urine Ca excretion 1,000 64.8
Smith 1987 10 f Normal Dual isotope 250 26.0
Harvey 1988 9 Normal Faecal recovery 100 or 200 28.0
Miller 1988 12 Children Dual isotope 250 36.9
Sheikh 1989 10 Normal Lavage 1,000 4.8
Harvey 1990 20 f Dual isotope 500 25.8
Harvey 1998 21 17 f, 4 m Urine Ca excretion 1,000 55.7
Heaney 1999 17 f Pre-men Serum radioactivity 300 10.8
Sakhaee 1999 Meta-analysis 24% pooled effect
Effect citrate vs. carbonate
Micheletti (32) 1996 14 Dual isotope 11,000 vs. 2500 CaCi
Heller (33) 1999 18 f Post-men Serum Ca, AUC Ca 500 CiCa
Heller (34) 2000 25 f Post-men 61 Serum Ca, AUC Ca, PTH,
urine Ca
500 4694
Heaney (35) 2001 24 f Post-men 58 AUC serum Ca, PTH, urine
Ca excretion
200 n.s.
Kenny (36) 2004 34 f PTH, BSAP, urine Ca excretion,
1,000 mg 12 week co CiCa (CTX, NTX)
Hanzlik (37) 2005 14 f 1933 AUC Ca, PTH 1,200 Ci Ca
Thomas (38) 2008 25 f Post-men PTH, CTX 500 Ci and 1,000 Ca CiCa
Karp (39) 12 f 2230 BSAP, serum Ca, PTH 1,000 
Ffemale, m male, pre-men pre-menopausal, post-men post-menopausal, n.s.not significant, AUCarea under the curve, BSAPbone-specific
alkaline phosphatase.
Calcium and vitamin D supplementation
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shows that only 11% of people older than 65 had a
consistent stomach pH of 3.5 at two consecutive
measurements and 67% had a consistently low pH.
A varying stomach pH (one time 3.5 and one time
B3.5) was found in 22% (40). The effect of achlorhydria
on the absorption of calcium with the use of various
supplements has not been studied in any detail.
The effect of proton pump inhibitors on calcium
absorption was studied in a review in 2008 (41). This
reveals that varying and small groups of patients were
studied, using different methods to evaluate calcium ab-
sorption and that a reliable answer cannot currently be
provided on the question whether the use of antacids
has a detrimental effect on calcium absorption (41). The
most recent article on this issue was a randomized trial
published in 2010 by the same author and revealed no
difference in intestinal calcium absorption between 20 mg
esomeprazole per day and placebo (42). There has been
no research to determine whether there is a difference in
calcium absorption between the various calcium salts
with use of proton pump inhibitors. Furthermore, the
conclusion in the CBO Guideline is that evidence based on
observational research suggesting that protonpump in-
hibitor (PPIs) are fracture-inducing medicines is very
weak, particularly as this association can also be linked
to the diseases for which the PPIs are prescribed (3, 43).
In conclusion, the in vitro data and models are complex
and do not entirely explain the calcium absorption
process in vivo. Clinical studies point consistently to
better absorption of calcium with use of citrate than with
carbonate. This difference appears to be explained by a
higher passive transport of calcium, because in the ileum
where 65% of calcium is absorbed by means of passive
transport calcium citrate dissolves better than calcium
carbonate at a pH ]7.5. Studies on the effect of proton
pump inhibitors on the absorption of calcium are not
unanimous in conclusion and have poor methodology,
any differences between calcium citrate and calcium
carbonate in this regard were not studied.
How much calcium and vitamin D should be
The average calcium intake in Great Britain for post-
menopausal women is 645705 mg calcium per day
(44). This figure is 720820 mg calcium per day in
Germany (45) and in France (46). The calcium intake
was also studied in the Netherlands: one-third of the
women in a study performed in Amsterdam consumed
less than 950 mg calcium per day (47); 18% of the women
of approximately the same age in a more rural area
(Ede, the Netherlands) consumed less than 800 mg per
day (48). In a population with an average age of 80 years,
living independently or in care homes, 25% consumed
less than 938 mg per day (49). This shows that there is
a large variation in the average calcium intake between
the different countries. In addition, there is a large
variation between individuals. It is particularly important
to know what the calcium intake is of those individuals
who are most in need of supplementation, for example,
the patients with a recent fracture. This was demonstrated
recently in a study in 502 patients over the age of 50 years
with a recent fracture: only 11% had a calcium intake
1,000 mg per day in combination with serum 25(OH)D
levels 50 nmol/L (Fig. 4) (50). An excessively low serum
vitamin D level in combination with inadequate calcium
intake occurred in 43% (50).
As demonstrated in Fig. 5, this shortage applies to
both men and women, in all examined age categories
50 years and with all types of fractures. It is note-
worthy that the inadequate calcium intake occurred in
equal measures with a normal BMD, osteopenia, and
osteoporosis. Therefore, inadequate calcium intake is an
endemic problem in patients presenting with a fracture
(50). Based on these data, one can conclude that one
should check the calcium intake and vitamin D level in all
fracture patients, even in those with a normal BMD.
Required calcium supplementation
Recently, the required calcium supplementation was
studied in patients with a recent fracture (50, 51). In
order to guarantee calcium intake of 1,000 per day, 12%
of patients required supplementation of 1,000 mg per day
and 57% required 500 mg. If one were to prescribe
500 mg calcium supplementation per day to all patients
for pragmatic reasons, this would only be inadequate
for achieving the required total intake of 1,000 mg per
day in 12% of the patients, whilst only a very small group
of patients achieves an unnecessary daily calcium intake
1,500 mg. If one were to prescribe a standard 1,000 mg
calcium supplementation per day, nearly 90% would
exceed the limit of 1,500 mg per day. Except for a small
group requiring 1,000 mg per day because they consume
virtually no dairy products, 1,000 mg supplementation is
too high a level of substitution, particularly in the light
of indications about the potentially negative cardiovas-
cular effects of high-dose calcium supplementation.
With the use of corticosteroids, there are many factors
that play a role in increasing the risk of osteoporosis and
fractures. One of these is the reduced intestinal absorption
of calcium. A higher level of calcium intake is therefore
required. All studies in patients treated with corticoster-
oids gave supplementation of 1,0001,500 mg calcium per
day, which is more than the recommended supplementa-
tion dose for post-menopausal women and age-related
Required vitamin D supplementation
Dawson-Hughes et al. reported an estimated average
essential vitamin D intake of 8001,000 IU per day (20
25 mg per day) in order to achieve a 25(OH)D 75 nmol/L
Robert Y. van der Velde et al.
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in the elderly. Significantly higher dosages are required
to ensure that virtually all elderly people achieve this level
of vitamin D (52). However, there are no arguments for
dosages higher than 800 IU per day (20 mg per day),
because there are not enough studies to support this.
Cranney et al. performed a meta-analysis in 2007 on the
relationship between serum 25(OH)D and the intake of
vitamin D form the diet. The conclusion of this study was
Fig. 4. Calcium intake and serum 25(OH)D in 50patients with a recent fracture.
Fig. 5. Calcium intake and serum 25(OH)D in 50patients with a recent fracture, according to gender, age, fracture location
and BMD.
Calcium and vitamin D supplementation
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that vitamin D in the diet increased the serum 25(OH)D
concentration, but it was not clear to which extent. The
large discrepancies between the various studies (differ-
ences in initial vitamin D levels, different populations,
different assays for vitamin D, etc.) made it impossible to
indicate how much vitamin D is required for whom (53).
Studies by Heaney (54) show that every 100 IU added
vitamin D causes the serum 25(OH)D level to increase by
2.5 nmol/L (range 1.752.75 nmol/L). Therefore, a dosage
of 800 IU will cause an increase in serum 25(OH)D of
approximately 20 nmol/L.
Based on the 25(OH)D levels in a study of 626 patients
with a recent fracture, one could theoretically going out
from the starting point that every 100 IU of added vitamin
D causes a 2.5 nmol/L increase in the serum 25(OH)D
level tailor the vitamin D supplementation in order to
achieve a level ]50 nmol/L in everyone (55) (Fig. 6).
In order to achieve a level ]75 nmol/L in every patient,
one would theoretically have to give a dosage 800 IU
per day to at least 80% of the patients, even up to 2,400 IU
per day (Fig. 6).
If one assumes a standard supplementation of 800 IU
vitamin D
, this will achieve a 25(OH)D ]50 nmol/L in
75% of the patients (Fig. 7).
A standard supplementation of 2,000 IU vitamin D
would theoretically result in a 25(OH)D ]50 nmol/L in
100% of the patients and a 25(OH)D ]75 nmol/L in 90%
of the patients (Fig. 7).
In addition, there are as yet unidentified sub-groups
that require higher dosages of vitamin D
, such as patients
with a severe vitamin D deficiency with secondary
hyperparathyroidism. The first placebo-controlled study
on the effect of various daily dosages of vitamin D
in healthy post-menopausal women with vitamin D
deficiency (25(OH)D B50 nmol/L) was published very
recently. The authors concluded that a dosage of 800 IU
per day resulted in an increase of the serum 25(OH)D
level to above 50 nmol/L in 97.5% of the women, without
further increase after 12 months. These results show that
a daily dosage of 800 IU is sufficient for the majority of
post-menopausal women with vitamin D deficiency to
exceed the threshold of 50 nmol/L, which most guidelines
consider the desired threshold value of 25(OH)D (56).
Calcium intake and cardiovascular disease
Concern has arisen amongst doctors and patients follow-
ing the epidemiological study by Bolland et al. from 2008
(57). This study found a link between calcium supple-
mentation and an increased risk of myocardial infarction.
This study evaluated healthy elderly women who in
addition to an average calcium intake of 860 mg per day
received either a calcium supplement of 1,000 mg per day
or a placebo for five years in this randomized controlled
trial. A significant problem is therefore the general-
izability of the results of this study. Who would prescribe
such a high level of calcium to healthy women for such
a lengthy period?
Fig. 6. Required dose of vitamin D to achieve a 25(OH)D
level: ]50 (top panel) and ]75 nmol/L (bottom panel).
Fig. 7. 25(OH)D level achieved with use of a set dosage of
vitamin D supplementation (800 IU and 2,000 IU per day).
Robert Y. van der Velde et al.
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There was a slightly increased risk of myocardial
infarction in the treated group.
The study by Lewis et al. (58) contradicts this. In this
study, 1,460 women aged 70 years or older were given a
calcium supplement of 1,200 mg or a placebo. In addition,
these women consumed about 950 mg calcium via the
diet. In this study, the investigators found no evidence
that calcium supplementation causes an increased risk of
cardiovascular conditions during an average follow-up
of 4.5 years.
Several large observational studies performed more
than 10 years ago even show a favorable effect of calcium
supplementation such as the IOWA Health Study (59) and
the Nurses’ Health Study (60). The observed protective
effect of higher calcium intake in these studies is probably
due to the phenomenon of confounding by indication:
healthy women who consume more calcium, will in general
have a healthier lifestyle: more exercise, healthier diet,
and less smoking.
In a reanalysis of The Women’s Health Initiative
Study there was a slight increase in cardiovascular events
in the intervention group, most noticeable in myocardial
infarction (61).
In a recently published prospective (Swedish mammo-
gram) cohort study the use of calcium supplementa-
tion was not associated with cardiovascular mortality or
ischemic heart disease (62). In women who had a dietary
intake of 1,400 mg calcium per day, the use of calcium
supplements was associated with a higher all-cause
mortality rate (62).
In another recently published prospective observation
study an association of calcium supplementation with an
increased risk of cardiovascular mortality was found in
men but not in women (63).
To summarize, probably because of heterogeneity and
limitations in study design, the result of the different
studies are contradictory. Some show a cardio protective
effect of calcium supplementation. Other studies find an
increased risk of myocardial infarction, cardiac mor-
tality, and/or total mortality (but only with a total calcium
intake greatly exceeding the usual recommendations).
Yet other studies find no significant relation between cal-
cium supplementation and cardiac events. Probably
only (well-designed and sufficiently powered) prospec-
tive randomized controlled trials with cardiac events as
a prespecified primary end point will be able to allow
definite conclusions on this subject. After an extensive
literature search we have come to the conclusion that as up
to now no such studies have been published.
Calcium intake and drug interactions and adverse
It is important to note that oral use of calcium salts
can reduce the absorption of bisphosphonates, tetracy-
clines (doxycycline, minocycline, and demeclocycline),
fluoroquinolones (ciprofloxacin, levofloxacin, norfloxa-
cin, ofloxacin, and moxifloxacin), levothyroxine, fiber-
rich food, and levodopa. For these medicines, it is
generally recommended to take these at least 2 h before
ingestion of calcium salts; for the fluoroquinolones an
interval of 4 h is preferable.
As the gastric emptying speed decreases with age and
emptying takes longer in certain patients with specific
conditions (for example in diabetes patients with gastro-
paresis due to autonomic neuropathy), it is probably better
for all these medicines to maintain a period of 4 h between
intake of these medicines and ingestion of calcium salts
(longer if indicated, as in the case of gastroparesis).
Calcium could cause constipation, which can form a
reason to add a laxative, for example, a magnesium salt or
Patient preference
Assuming that therapy compliance is an important
subject in the treatment of osteoporosis, any preference
by the patient for a certain medication is probably
also important. There are very few direct comparative
studies on patient preference, also for calcium tablets.
Which form of administration of calcium supplementa-
tion (tablet or effervescent tablet in solution) does the
patient prefer? Do patient-friendly packages combin-
ing calcium and vitamin D and bisphosphonate pro-
mote therapy compliance? Research performed in the
Netherlands used a randomized, open, cross-over trial in
102 patients to compare Calci-Chew D
chewable tablets
to CaD
sachets (64). It was determined before the start
that patient preference would be the most important
primary measure of outcome: 67% preferred the chewable
tablet, 19% the sachet, and 15% had no preference (64).
The question that arises is how to interpret this: there was
no difference in clinical relevant factors such as tolerance,
compliance, and adverse effects. Also the actual medica-
tion taken was not significantly different: of the 14 days,
the chewable tablet was taken an average of 12.8 days and
the sachet 13.5 days. One point of criticism on this study
is the extent to which these results over a period of
14 days can be extrapolated to the long term, for example
a period of 5 years. The tolerability was similar for the
two formulations. The authors concluded that patient
preference is very important for medication that should
be used chronically but also that the design of studies and
the interpretation of the data are complicated.
Practical advice for calcium and vitamin D
Based on guidelines, optimization of total calcium intake
towards a total of 1,0001,200 mg calcium per day is
considered necessary and sufficient in the context of
osteoporosis and fracture prevention strategies with drug
Calcium and vitamin D supplementation
Citation: Food & Nutrition Research 2014, 58: 21796 - 9
(page number not for citation purpose)
treatment. Calcium supplementation can be achieved by
diet, mainly milk products (milk, yogurt, or cheese) or
calcium-containing tablets. Dietary calcium intake is pre-
ferred and 34 portions of milk products per day should
be advised. If this cannot be achieved, supplementation of
calcium should be considered. If a patient consumes 12
portions of milk products per day, then the advice is to
add 12 portions of milk products per day or 500 mg of
calcium supplementation. If a patient does not take any
milk products, supplementation of 1,000 mg calcium is
needed. No adjustment is required if the patient consumes
34 portions of milk products per day. In the context of
the concern about cardiovascular conditions, calcium
supplementation should be individualized.
When considering the choice of calcium supplements
one should take into account that fractional calcium
absorption is 24% higher for calcium citrate compared to
calcium carbonate, probably because of higher dissolu-
tion in the ileum, where 65% of the total calcium is
absorbed. The effect of proton pump inhibitors on calcium
absorption are inconclusive as is the case with the effect
of age-related changes in gastric physiology (65). The
practical advice concerning vitamin D supplementation as
part of osteoporosis treatment is to prescribe a minimum
dose of 800 IU per day of vitamin D
. This also applies
to people in nursing homes and care homes and patients
with a recent fracture, irrespective of BMD. Higher
dosages could be considered in case of severe vitamin D
deficiency with secondary hyperparathyroidism.
Conflict of interest and funding
The authors have not received any funding or benefits
from industry or elsewhere to conduct this study.
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*Robert Y. van der Velde
Department of Internal Medicine
VieCuri Medical Centre for North Limburg
Venloseweg 210
5912 BL, Venlo, The Netherlands
Robert Y. van der Velde et al.
(page number not for citation purpose) Citation: Food & Nutrition Research 2014, 58: 21796 -
... The US NIH (National Institute of Health) recommends a dietary intake for most adults of 600 IU of vitamin D a day [59]. Care should be taken with the co-administration of vitamin D and calcium supplements [60]. Vitamin D supplements are well tolerated, but the co-administration of calcium can lead to excessive intestinal calcium absorption and hypercalcemia [59]. ...
... Hypercalcemia, in turn, can lead to gastrointestinal disorders, excessive thirst and dehydration, polyuria, and kidney stones [59]. Calcium supplementation of 500 mg per day has been found to be adequate for most patients with a recent fracture [60][61][62]. ...
Introduction Several pharmacological drugs have shown proof of concept for longevity in animal models. I aimed to identify and review those longevity drug candidates that are undergoing clinical trials. Areas covered Recent (post-2017) longevity clinical trials were found in US and EU clinical trial registries. Longevity drug candidates are the antidiabetic drugs metformin and acarbose, and the immunosuppressant rapamycin. These medicinal drugs are tested on biochemical and clinical markers of aging. In addition, vitamin D supplementation is being investigated in two mega-trials (sample size> 5000) for its efficacy in reducing all-cause mortality. Expert opinion Anti-aging effects of longevity drug candidates suggest, but do not demonstrate that they prolong life. The two megatrials with vitamin D supplementation make it possible to detect differences in life expectancy between vitamin D and placebo. Therefore, a protocol similar to that for vitamin D could be used to demonstrate pro-longevity effects of metformin, acarbose, and rapamycin.
... Most of the Ca (approximately 65%) is absorbed where the pH is 6.5-7.5. It is important to note that Ca is not absorbed in the stomach (van der Velde, Brouwers, Geusens, Lems, & van den Bergh, 2014). To be able to cross the intestinal barrier, Ca must be in a soluble form, generally ionized (Ca 2+ ) or bound to a soluble organic molecule. ...
... The solubility of Ca ingredients is directly affected by the pH level. Also, Ca absorption involves other nutrients including protein, vitamin D, and phosphorus (van der Velde et al., 2014). Moreover, the chemical structure of the Ca salt influences its final availability since different solubility and dissociation constants are related to the chemical structure. ...
The bioaccessibility and bioavailability of a functionalized Calcium (Ca) salt as food ingredient, based on modified Ca carbonate and hydroxyapatite (FCC), was determined and compared with frequently used Ca sources (Ca citrate tetrahydrate (CCT), tri-Ca phosphate (triCP) and Ca carbonate (CC). Results showed a similar Ca bioaccessibility for CCT (76.44 ± 9.73 %), CC (73.7 ± 8.18 %) and FCC (74.4 ± 1.87 %) and a lower value for tri-CP (46.07 ± 8.68 %). FCC showed the highest bioavailability, 5.68 ± 0.26 %, compared to CC, CCT and tri-CP (3.93 ± 0.99 %, 3.41 ± 0.33 %, 1.85 ± 0.34 %, respectively). The innovative chemical composition and structure of FCC based on amorphous hydroxyapatite combined with Ca carbonate, a greater porosity, lower agglomerates and particle size, improve the Ca solubility in the intestinal media, explaining the similar bioaccessibility but higher bioavailability of FCC compared to CCT, tri-CP and CC.
... Apart from those advantages, calcium carbonate is a very cheap material, recovery of which can be hard to argue from an economic standpoint. However, calcium salt supplements [18] have become very popular in recent years, with "biogenic" or "natural" calcium sources marketed as superior alternatives to mined (rock) lime or limestone. Precipitation from acetate solution or washing with different acid (e.g. ...
... Acetic acid has many advantages for calcium carbonate removal: it forms soluble salts with calcium, is a fairly weak acid, non-toxic, and its excess can be easily removed by evaporation. However, following the determination of high incrust content we decided to repeat the full procedure using citric acid -as it retains most of the aforementioned advantages (save for volatility), but calcium citrate is an already well-established nutritional supplement [18]. Despite the fact that the majority of citric acid/calcium citrate was indeed removed in the first step, the damage to bioactive compounds in the material even with brief washing was evident (Fig. 2c). ...
Full-text available
During our studies concerning the isolation of sulfated polysaccharides (SPs) from freshwater algae species widespread in Poland, an improved overall extraction methodology has been developed. This new, multi-step procedure allows for obtainment of several fractions that could find use in cosmetic and food industries, with the final one containing the valuable SPs, important both from economic and scientific perspective. Moreover, the process allows for easy use of typical chelating agents to remove harmful heavy metal ions without important losses in natural compounds of interest. Furthermore, a material balance has been established for said process, allowing for its easier implementation on bigger scales, and highlighting the areas which could still be improved to positively affect the final time-cost ratio of the methodology. Combined with previously published information concerning the detailed composition of obtained fractions, we aim to provide a robust and informative outlook on the potential of native freshwater algae species as cheap, raw and easily purifiable resource, usable in a number of important industries. According to the mass balance, nearly 5 % of dry mass of Cladophora glomerata is extractable with ethanol and this fraction consists mostly of fatty acids, phenolics and pigments. Another 5 % of mass can be isolated as pure SPs from aqueous fraction. Additionally, calcium from natural incrustations on the surface of C. glomerata amounts to 17 % of dry material weight and can be reclaimed from acidic wash by simple precipitation; such calcium salts have garnered significant interest as nutritional supplements.
... The absorption of Ca 2+ in the intestine mainly depends on the staying time in the intestine and the solubility of Ca 2+ . However, the duodenum is the site with the greatest solubility of Ca 2+ (52). The rate of Ca 2+ absorption in the intestine is as follows: duodenum > jejunum > ileum (53). ...
Full-text available
This study intended to explore the effect and mechanism of different doses of dietary quercetin on calcium and phosphorus metabolism to provide an experimental basis for preventing leg disease in broilers. A total of 480 1-day-old healthy Arbor Acre broilers were randomly allotted into four groups (0, 0.02, 0.04, 0.06%) for 42 days. Compared with control, 0.06% quercetin significantly increased the unit weight and the relative weight of tibia in broilers ( P < 0.05). Meanwhile, phosphorus content and bone mineral density (BMD) were significantly increased by 0.06% dietary quercetin supplementation in tibia ( P < 0.05). Ash of tibia was significantly increased by 0.04 and 0.06% quercetin in broilers ( P < 0.05). In addition, 0.06% quercetin significantly increased the content of serum calcium-binding protein (CB), estradiol (E 2 ), osteocalcin (OC), alkaline phosphatase (ALP), and calcitonin (CT) ( P < 0.05); 0.04% quercetin significantly increased 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( P < 0.05) content in serum of broilers. The content of serum parathyroid (PTH) was significantly decreased by 0.02 and 0.06% quercetin ( P < 0.05) in broilers. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the Wnt signaling pathway was a key signaling pathway of calcium and phosphorus metabolism in broilers which was significantly regulated by quercetin. The differentially expressed genes (DEGs) from transcriptome sequencing were validated with real-time quantitative PCR (RT-qPCR). In conclusion, 0.06% dietary quercetin supplementation improved calcium and phosphorus metabolism by regulating the Wnt signaling pathway in broilers.
... Але спектр біологічно активних добавок, що впливають на репаративний остеогенез, а тому мають системний уплив на остеоінтеграцію, більш широкий. Ефект біологічно активних добавок, що застосовують для інтенсифікації репаративного остеогенезу, в основному, спрямований на забезпечення організму кальцієм (кальцій і вітамін D), а також на забезпечення процесу синтезу колагену (остеотропні мікроелементи) (Clark et al., 2008;Plawecki & Chapman-Novakofski, 2010;Van der Velde et al., 2014). ...
Humic substances are able to influence mineral metabolism due to their properties to form chelate complexes. Directly, the state of bone tissue is closely related to general processes that ensure the exchange of minerals in the body as a whole. Polylactic acid (PLA) is a biopolymer which, due to its high biocompatibility and osseointegration properties, is increasingly used for the manufacture of implants. Among the methods of improving the osseointegration of implants, gaining popularity, the use of pharmacological drugs and dietary supplements that have a direct effect on bone tissue or act indirectly by affecting the body’s systems and metabolism. For the experiment 32 rabbits were divided into groups of 8 rabbits each In two model groups, 16 rabbits were implanted with PLA implants in the bilateral defect of the parietal bone, one of which was immersed in a 1% humilid solution and the other in a 0.9% NaCl solution before administration. From the operated rabbits, 8 received humilid during treatment, and 8 others were intact. 16 rabbits who did not undergo surgery were divided into two groups, one of which drinked humilid and the other clean water. The aim of our work was to determine the mineral metabolism in rabbits during implantation of PLA implants. The ability of humic substances to influence the redistribution of calcium ionized and copper in the blood serum and femur in rabbits of the model group in comparison with intact animals was proved.. There was also an increase in the content of iron and calcium ionized in the serum, and calcium, iron, copper and a decrease in the content of zinc in the femur of rabbits treated with humilide. It has been proved that the introduction of humilid into the diet caused an increase in newly formed bone tissue in PLA implants of rabbits of the model group. Therefore, an increase in macro- microelements in blood serum and their redistribution in the bone tissue of rabbits receiving humilides suggests the possibility of using humilid to correct mineral metabolism and improve the condition of bone tissue. Leveling reduction macro- microelements in the blood and bone tissue, together with an increase in newly formed bone tissue in PLA implants of a model group of rabbits receiving humilide indicate a systemic effect of humilid on the osseointegration of PLA implants.
... The mechanisms involved may be via modification of calcium through urine extraction, the intestines carry out for the calcium process and bone homeostasis. An adequate calcium intake and vitamin D supplementation is recommended in guidelines on osteoporosis and fracture prevention [3][4][5]. ...
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Background Vitamin D and calcium are essential dietary components for human body, and their deficiency is linked to poor bone health and osteoporosis. Adequate knowledge of health staff regarding vitamin D and calcium is critical for general population awareness. The current work was to evaluate the awareness regarding the importance of vitamin D and calcium among undergraduate health science students in Al Kharj.MethodsA self-distributed validated questionnaire-based cross-sectional study was conducted. Undergraduate health science students in Prince Sattam bin Abdulaziz University from the College of Medicine, College of Pharmacy, College of Dentistry, and College of Applied Medical Science were included in the study. Students between the age of 18 and 25 years have participated in the study.ResultsFour hundred fifty-seven undergraduate health science students participated in the study. The vast majority of students knew about the importance of calcium (96.7%) and vitamin D (95.4%), whereas only 89.4% knew about osteoporosis. The participant students reported in their answers that the sources of knowledge were the Internet (42.8%), physicians (41.5%), textbooks (21.2%), teachers (19.1%), family and relatives (18.3%), and/or other sources (6.1%). The overall attitude was poor in about (54%) of the participants showing gender differences regarding sun-exposure duration and supplementation of calcium and vitamin D.Conclusion The study revealed that both male and female undergraduate health science students in Al Kharj were familiar with the importance of vitamin D and calcium; however they reported improper attitude that warrants further health guidance and educational programs.
... Intestinal Ca 2+ absorption in humans reaches approximately 35% of dietary load [7] . The amount of Ca 2+ absorbed mainly depends on the quantity of Ca 2+ consumed, the transit time in different parts of the gut and the solubility of Ca 2+ , which is inversely related to luminal pH [8] . Even though the absorption is more efficient in the duodenum and jejunum, where pH is lower, the amount of Ca 2+ absorbed is greater in the ileum, since intestinal content remains ten times longer in this portion, which is finally responsible for almost 65% of Ca 2+ absorption [9] . ...
Ca2+ has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine, kidney, bone and parathyroid glands. The intestinal Ca2+ absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23 (FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca2+ movement seems to be vitamin D independent. Intestinal Ca2+ absorption changes according to different physiological conditions. It is promoted under high Ca2+ demands such as growth, pregnancy, lactation, dietary Ca2+ deficiency and high physical activity. In contrast, the intestinal Ca2+ transport decreases with aging. Oxidative stress inhibits the intestinal Ca2+ absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca2+ absorption, some hypercalciurias show Ca2+ hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca2+ absorption.
The aim of the current study was to investigate the effect of an acidity regulator (SPORIX®), lactose, and vitamin D3 as excipient ingredients on digestive solubility and intestinal transport of calcium from four different calcium materials (tricalcium phosphate (TCP), fish bone (FB), nano-fish bone (NFB), and algae calcium (AC)) through an in vitro digestion model system combined with Caco-2 cells. The concentration of ionized calcium (Ca²⁺) in an aqueous fraction after in vitro digestion increased with the addition of SPORIX®, and it was further enhanced by adding SPORIX® + lactose + vitamin D3 into TCP, FB, NFB, and AC, respectively. In particular, FB with SPORIX® + lactose + vitamin D3 enhanced calcium ionization to 33.89 ± 0.69 mg g⁻¹, which was about 11.76 times higher than that of FB only. In the case of intestinal cellular uptake of calcium, there was no significant difference in all the tested calcium materials with SPORIX® + lactose + vitamin D3. However, the absolute amount of intestinal transport of calcium in FB (43.95 ± 3.29 μg) was significantly higher than other calcium materials with the addition of SPORIX® + lactose + vitamin D3 (p < 0.05). This study suggests that the co-consumption of SPORIX®, lactose, and vitamin D3 with FB could enhance the calcium bioavailability by lowering pH as well as improving calcium intestinal transport by modulating the paracellular and transcellular uptake mechanism.
Despite the previously reported health benefits of calcium intake for the attenuation of metabolic disease, few studies have investigated the relationships among calcium intake, gut microbiota, and host metabolism. In this study, we assessed the effects of calcium supplementation on host microbial community composition and metabolic homeostasis. Mice were fed a high-fat diet with different calcium concentrations (4 and 12 g/kg) of 2 calcium supplements, calcium carbonate and calcium citrate. Supplementation with the higher concentration of calcium citrate significantly prevented body weight gain and decreased plasma biomarkers for metabolic disorder compared to calcium carbonate supplementation. Both calcium supplementation led to changes in microbial composition, increased propionate production and increased anorexigenic GLP-1 gene expression. The calcium citrate groups also experienced less metabolic endotoxemia. Our findings suggested that calcium supplementation could ameliorate host metabolic disorder caused by a high-fat diet, due to gut microbiota changes as well as decreased intestinal inflammation.
Vitamin D deficiency and insufficiency has become a pandemic health problem with a consequent increase of requests for determining circulating levels of 25-hydroxyvitamin D [25(OH)D]. However, the analytical performance of these immunoassays, including radioimmunoassay and ELISA, is highly variable, and even mass spectrometric methods, which nowadays serves as the gold standard for the quantitatively determination of 25(OH)D, do not necessarily produce comparable results, creating limitations for the definition of normal vitamin D status ranges. To solve this problem, great efforts have been made to promote standardization of laboratory assays, which is important to achieve comparable results across different methods and manufacturers. In this review, we performed a systematic analysis evaluating critically the advantages and limits of the current assays available for the measure of vitamin D status, i.e., circulating 25(OH)D and its metabolites, making suggestions that could be used in the clinical practice. Moreover, we also suggest the use of alternatives to blood test, including standardized surveys that may be of value in alerting health-care professionals about the vitamin D status of their patients.
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To investigate the association between long term intake of dietary and supplemental calcium and death from all causes and cardiovascular disease. Prospective longitudinal cohort study. Swedish mammography cohort, a population based cohort established in 1987-90. 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years. Primary outcome measures, identified from registry data, were time to death from all causes (n=11 944) and cause specific cardiovascular disease (n=3862), ischaemic heart disease (n=1932), and stroke (n=1100). Diet was assessed by food frequency questionnaires at baseline and in 1997 for 38 984 women, and intakes of calcium were estimated. Total calcium intake was the sum of dietary and supplemental calcium. The risk patterns with dietary calcium intake were non-linear, with higher rates concentrated around the highest intakes (≥1400 mg/day). Compared with intakes between 600 and 1000 mg/day, intakes above 1400 mg/day were associated with higher death rates from all causes (hazard ratio 1.40, 95% confidence interval 1.17 to 1.67), cardiovascular disease (1 49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09) but not from stroke (0.73, 0.33 to 1.65). After sensitivity analysis including marginal structural models, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average associated with all cause or cause specific mortality but among calcium tablet users with a dietary calcium intake above 1400 mg/day the hazard ratio for all cause mortality was 2.57 (95% confidence interval 1.19 to 5.55). High intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke.
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Importance Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health. Objective To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease (CVD), heart disease, and cerebrovascular diseases. Design and Setting Prospective study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan. Participants A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health–AARP Diet and Health Study. Main Outcome Measures Dietary and supplemental calcium intake was assessed at baseline (1995-1996). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks (RRs) and 95% CIs. Results During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR>1000 vs 0 mg/d, 1.20; 95% CI, 1.05-1.36), more specifically with heart disease death (RR, 1.19; 95% CI, 1.03-1.37) but not significantly with cerebrovascular disease death (RR, 1.14; 95% CI, 0.81-1.61). In women, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96-1.18), heart disease death (1.05; 0.93-1.18), or cerebrovascular disease death (1.08; 0.87-1.33). Dietary calcium intake was unrelated to CVD death in either men or women. Conclusions and Relevance Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health.
To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986, Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.
Osteoporotic bone fractures are becoming an increasing burden worldwide-socially and economically-as the population ages. Supplemental calcium, alone or combined with vitamin D, has been proposed as a relatively inexpensive way of preventing osteoporotic bone loss, but whether it lowers the risk of fracture remains uncertain. Meta-analyses have, up to now, yielded inconsistent results. The present meta-analysis is based on 29 randomized trials totalling 63,897 adults aged 50 years and older. Seventeen trials numbering 52,625 persons reported fracture as an outcome, while 23 trials comprising 41,419 individuals reported bone mineral density (BMD) as an outcome. All trials compared calcium, alone or combined with vitamin D supplementation, with a placebo. In trials reporting fracture as an outcome, supplementation was associated with a 12% reduction in fractures of all types (risk ratio, 0.88; 95% confidence interval, 0.83-0.95; P = 0.0004). In trials reporting BMD as an outcome, treatment correlated with a reduced rate of bone loss averaging 0.54% (0.35%-0.73%; P < 0.0001) at the hip and 1.19% (0.76%-1.61%) at the spine. The reduction in fracture risk was significantly greater (by 24%) in trials with high compliance rates. A more substantial treatment effect was noted with calcium doses of 1200 or more than with lower doses (0.80 versus 0.94; P = 0.006), and with vitamin D doses of at least 800 IU (0.84 versus 0.87; P = 0.03). Neither gender nor a history of fracture influenced observed treatment effects. Adding vitamin D to calcium also did not alter treatment effects. Subjects with relatively low serum vitamin D levels had a greater risk reduction, but the difference was not significant. Lesser risk reductions were noted in persons 50-70 years of age than in those older than 70. These findings demonstrate that supplemental calcium, alone or combined with vitamin D, can prevent osteoporotic bone fractures. Analysis of the estimated number needed to treat shows that 63 patients will have to be treated over 3.5 years to prevent a single fracture. At least 1200 mg of calcium and 800 IU of vitamin D are recommended for combined supplementation.
BACKGROUND: Antifracture efficacy with supplemental vitamin D has been questioned by recent trials. METHODS: We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial. RESULTS: The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation. CONCLUSION: Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.
Context. —Early studies suggested that gastric acidity declines as people age. However, sequelae of achlorhydria are uncommon in older people, making this conventional wisdom unlikely.Objective. —To ascertain the prevalence of basal gastric acidity and atrophic gastritis (indicated by serum pepsinogen ratio) in older adults.Design. —Cross-sectional study in a volunteer sample.Setting. —Retirement communities in suburbs of Kansas City, Mo.Subjects. —A total of 248 white male and female volunteers aged 65 years or older living independently.Main Outcome Measures. —Presence of basal unstimulated gastric acid was evaluated noninvasively by having subjects swallow quininium resin. Gastric acid with a pH lower than 3.5 releases quinine, which is then absorbed and excreted into urine. Atrophic gastritis was defined as a ratio of serum pepsinogen l/pepsinogen II of less than 2.9.Results. —Basal unstimulated gastric content was acidic (pH <3.5) in 208 (84%) of 248 elderly subjects. On retesting 66 subjects (35 normals and 31 hyposecretors), 28 (80%) of 35 had pH less than 3.5 both times, and 22 (71%) of 31 had pH of 3.5 or higher twice; in the remaining 16 subjects, low vs high gastric pH changed between tests. Weighted population prevalence estimates in this sample were 67% for consistent acid secretion, 22% for intermittent secretion, and 11% for consistent gastric pH higher than 3.5. Whereas 14 (67%) of 21 consistent hyposecretors had serum pepsinogen ratios of less than 2.9, indicating atrophic gastritis, only 2 (5%) of 44 consistent or intermittent secretors of acid had ratios in this range (P<.001).Conclusions. —In contrast to what is commonly stated, nearly 90% of elderly people in this study were able to acidify gastric contents, even in the basal, unstimulated state. Of those who were consistent hyposecretors of acid, most had serum markers of atrophic gastritis.
Description: New U.S. Preventive Services Task Force (USPSTF) recommendation statement on vitamin D and calcium supplementation to prevent fractures in adults. Methods: The USPSTF commissioned 2 systematic evidence reviews and a meta-analysis on vitamin D supplementation with or without calcium to assess the effects of supplementation on bone health outcomes in community-dwelling adults, the association of vitamin D and calcium levels with bone health outcomes, and the adverse effects of supplementation. Population: These recommendations apply to noninstitutionalized or community-dwelling asymptomatic adults without a history of fractures. This recommendation does not apply to the treatment of persons with osteoporosis or vitamin D deficiency. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men. (I statement)The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (I statement)The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (D recommendation).