European Review for Medical and Pharmacological Sciences 2016; 20: 4612-4621

Vitamin D supplementation for osteoporosis in

older adults: can we make it help better?
C.-H. DONG1,2, Q.-M. GAO1, Z.-M. WANG2, A.-M. WANG2, P. ZHEN1
1
The Center of Orthopaedic Surgery of PLA, the General Hospital of Lanzhou Military Command,
Gansu, China
2
Department of Orthopedics, Institute of Surgery Research, Daping Hospital, Third Military Medical
University, Chongqing, China

Abstract. – With the increase of the average such diseases is osteoporosis. The true incidence
age of our population, the incidence of diseases of osteoporosis, the disease of weakened bones
specific for older adults has been increasing.
One of such diseases is osteoporosis. The true that causes heightened risk of bone fractures, is
incidence of osteoporosis is unknown. But the unknown. But the estimates indicate that this dis-
estimates indicate that this disease affects wide ease affects wide proportions of the population,
proportions of the population, ranging in mil- ranging in millions or even ten millions in large
lions or even ten millions in large countries like countries like the United States. As this poses a
the United States. As this poses a significant
burden on the health care system, interventions
significant burden on the health care system, in-
that could prevent or treat this condition are in terventions that could prevent or treat this condi-
the focus of clinical research. Vitamin D, the de- tion are in the focus of clinical research. Vitamin
terminant of bone health, has been tested in clin- D, the determinant of bone health, has been test-
ical studies as the agent to treat osteoporosis. ed in clinical studies as the agent to treat osteo-
Despite the progress, there is still some contro- porosis. Despite the progress, there is still some
versy about the targeted blood levels of vitamin
D, most efficient way to supplement this vitamin, controversy about the targeted blood levels of vi-
and clinical efficacy of this supplementation in tamin D, most efficient way to supplement this
the elderly. vitamin, and clinical efficacy of this supplemen-
In the present review, we will highlight the me- tation in the elderly. In the present review, we
tabolism of vitamin D and the aforementioned will highlight the metabolism of vitamin D and
unresolved issues, as well as review the recent the aforementioned unresolved issues, as well as
interventional studies on vitamin D supplemen-
tation. review the recent interventional studies on vita-
min D supplementation.
Key Words:
Elderly, Osteoporosis, Vitamin D, Supplementation, The Metabolism of Vitamin D
Guidelines, Analysis, Biochemistry, Metabolism, Clini- Vitamin D is classified as a fat-soluble vita-
cal efficacy. min, although the chemical structure of its bio-
logically active metabolite is actually close to
steroid hormones. Another similarity between the
Introduction biologically active metabolite and steroid hor-
mones is that both these compounds bind to spe-
With industrialization and urbanization of in- cialized receptors to exert their biological effects.
creasing number of countries in the world, life We will address this metabolite in a few para-
expectancy increases, and so does the relative graphs below.
proportion of older adults. The definition of “old- Humans maintain the circulating levels of vita-
er adults”, or the “elderly”, differs depending on min D mainly through exposure of our skin to the
the country (http://www.who.int/healthinfo/sur- ultraviolet light during sunny days. At higher lati-
vey/ageingdefnolder/en/), and most industrialized tudes, vitamin D production occurs mostly dur-
countries consider the population at the age of 65 ing warm seasons, probably due to the quantity
years or older as “older adults”. Our longer life and quality of sun’s ultraviolet light reaching the
expectancy has also brought about several age- surface1. Minor contributors to circulating levels
related diseases and conditions that had been rel- of vitamin D are dietary sources (such as cod liv-
atively rare in pre-industrialized ages. One of er oil, fish, and milk supplemented with vitamin

4612 Corresponding Author: Ping Zhen, MD; e-mail: [email protected]

 Vitamin D supplementation for osteoporosis in older adults: can we make it help better?

D). Recommendations have been introduced that is called vitamin D2 (ergocalciferol). Both D3 and
vitamin D supplements should also be recog- D2 forms of vitamin D can be equally well me-
nized as one of the sources, especially for popu- tabolized in our body4. The experts often use the
lations at increased risk for osteoporosis, includ- term “vitamin D” interchangeably, referring to
ing the elderly2. Therefore, pharmaceutical sup- D3 or D24,5. Oral supplementation can be done
plements have become another determinant of with either plant-based or animal metabolites of
the circulating vitamin D levels. vitamin D.
When our skin is exposed to the sun, some of After it is produced in the skin, vitamin D3 (or
the ultraviolet light is absorbed by melanin, the D2) is further metabolized in the liver, or can be
skin pigment. Therefore, people with darker skin stored in the fat tissue5 to be released into the
need longer exposure to the sun than people with blood stream when needed, thereby repleting the
fair skin to achieve similar levels of the circulat- levels. In the liver, vitamin D3 passes through hy-
ing vitamin D3. The ultraviolet light catalyzes a droxylation5. This process yields the circulating
chemical reaction in the skin that produces vita- vitamin D metabolite called 25-hydroxyvitamin
min D from 7-dehydrocholesterol4. The form of D3 (Figure 1). It will be highlighted in the subse-
vitamin D produced in our skin or in animals is quent text that 25-hydroxyvitamin D3 is the cur-
referred to as vitamin D3 (or cholecalciferol; Fig- rent indicator of our body’s vitamin D status
ure 1), whereas its counterpart produced in plants quantified in hospital labs. Notably, clinical rec-

Figure 1. Metabolism of vitamin D. The skin produces the preform of vitamin D (cholecalciferol) from 7-dehydrocholesterol.
After it is produced in the skin, cholecalciferol is hydroxylated in the liver to yield 25-hydroxyvitamin D3. 25-hydroxyvitamin
D3 is the most abundant circulating form of vitamin D in the human body. 25-hydroxyvitamin D3 circulates in blood mostly
bound to the transporting protein (vitamin D binding protein). A very small fraction of 25-hydroxyvitamin D3 is bound to
serum albumin or is free. In kidney and other organs, 25-hydroxyvitamin D3 is further hydroxylated to produce the biological-
ly active 1,25-dihydroxyvitamin D3. The latter vitamin D metabolite in the target organs activates the vitamin D receptor
(VDR) which up-regulates transcription of a large group of genes, called “vitamin D-responsive genes”.

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 C.-H. Dong, Q.-M. Gao, Z.-M. Wang, A.-M. Wang, P. Zhen

ommendations for healthy and diseased bone me- els of 25-hydroxyvitamin D3 to maintain suffi-
tabolism have been developed around this cient circulating and intracellular levels of 1,25-
metabolite. dihydroxyvitamin D3. This is why it is important
First, the circulating levels of 25-hydroxyvita- that the levels of 25-hydroxyvitamin D3 are suffi-
min D3 are considered stable, with a half-life of ciently high, and this will be addressed in the
about two weeks6 or even longer7. Thus, these subsequent text.
levels are not the subject to diurnal or between-
days variations, and newest reports suggest that Analytical Issues
muscle tissue can be the body’s storage site for There are several reasons why 25-hydroxyvita-
25-hydroxyvitamin D38. Thereby, our body ap- min D3 is still considered the indicator of the
pears to have at least two storage tissues: fat tis- body’s vitamin D status.
sue to store vitamin D3 and muscle tissue for 25- First, the serum concentration of 25-hydrox-
hydroxyvitamin D3 storage. It is possible that for yvitamin D3 is much higher than that of 1,25-di-
this reason, our body maintains healthy levels of hydroxyvitamin D3, which makes it less chal-
25-hydroxyvitamin D3 long after begin of the lenging to develop an analytical assay. The sec-
cold season. ond reason is the much shorter lifespan 1,25-di-
25-hydroxyvitamin D 3 circulates in blood hydroxyvitamin D3 and fluctuation of its levels.
mostly bound to the transporting protein (vitamin Obviously, an indicator should be stable under
D binding protein). A very small fraction of 25- similar bodily conditions, and this is not the case
hydroxyvitamin D3 is bound to serum albumin or with 1,25-dihydroxyvitamin D3.
is free9. In the kidney, 25-hydroxyvitamin D3 is However, this does not mean that the analyti-
further metabolized to produce the biologically cal tests for 25-hydroxyvitamin D3 are problem-
active 1,25-dihydroxyvitamin D 3 (Figure 1). free. There is a discrepancy between analytical
While the kidney is considered the major conver- assays from different suppliers. Furthermore,
sion site from 25-hydroxyvitamin D3 to 1,25-di- some assays report total 25-hydroxyvitamin D
hydroxyvitamin D 3 5 , this conversion is also (i.e. the sum of 25-hydroxyvitamin D3 and 25-
thought to occur in other tissues4. The latter vita- hydroxyvitamin D2), whereas other assays pro-
min D metabolite activates the vitamin D recep- vide information on these two metabolites sepa-
tor (Figure 1) which modulates transcription of a rately. For consistency reasons, the guidelines
large group of genes, called “vitamin D-respon- recommend reporting total 25-hydroxyvitamin D
sive genes” (or “vitamin D-sensitive genes”) levels, as this will be applicable to the patients
(Figure 1). In addition to this transcriptional taking plant-derived supplements.
mechanism, 1,25-dihydroxyvitamin D3 also ex- Another issue is that many laboratories still
erts non-transcriptional (also called “non-genom- continue to utilize radioimmunoassays, or
ic”) effects10. The transcriptional effects of 1,25- ELISA- / HPL-based assays, while newer labs
dihydroxyvitamin D3 seem to be more important have begun to phase out these assays and replace
for bone health11. them with the mass spectrometry based assays12.
Transcriptional and non-transcriptional effects The mass spectrometry based assays offer unri-
of 1,25-dihydroxyvitamin D3 are limited by its valed specificity and sensitivity13 and are, thus,
catabolism. Moreover, the aforementioned vita- becoming the gold standard in the diagnostics of
min D-responsive genes include the enzymes that the vitamin D status. Conversely, non-mass spec-
catabolize 1,25-dihydroxyvitamin D3, meaning trometry-based assays may inaccurately estimate
that vitamin D up-regulates the enzymes that 25-hydroxyvitamin D312.
curb its biological activity. This represents an im- Apart from analytical issues, there is no con-
portant mechanism to prevent excessive accumu- sistent recommendation on what should be con-
lation of 1,25-dihydroxyvitamin D 3. Further- sidered as healthy circulating levels of 25-hy-
more, the existence of this negative feedback droxyvitamin D3.
mechanism is the mechanism explaining short
lifespan of 1,25-dihydroxyvitamin D3. Since cir- Normal and Abnormal Vitamin D Levels
culating levels of 25-hydroxyvitamin D3 exceed In the past, absolute vitamin D deficiency has
the circulating levels of 1,25-dihydroxyvitamin existed and caused clinical disease (rickets, os-
D3 by the factor of 1000, the levels of the latter teomalacia). These are now very rare in Western
metabolite are likely to be repleted very easily. countries because of consumption of vitamin D
Nonetheless, this requires healthy circulating lev- enriched food5. Still, despite the infrequency of

4614
 Vitamin D supplementation for osteoporosis in older adults: can we make it help better?

absolute vitamin D deficiency, we remain at risk Therefore, the debate is still ongoing16. At the
for relative deficiency of this vitamin D5. With moment, it can be safely stated that even by the
industrialization and urbanization of developing most conservative estimates, the lowest circulat-
countries, including China, the population is no ing levels of 25-hydroxyvitamin D3 should be 50
longer exposed to the sunlight as frequently as nM, and that the levels lower that this should be
before. Since our skin’s exposure to the sun’s ul- considered deficient. Thereby, the lowest level of
traviolet light is the principal source of vitamin D healthy vitamin D status has been increased from
in our body (Figure 1), modern humans easily the previous recommendations17.
develop suboptimal vitamin D levels, and this The decision of what to consider the normal,
can be defined as insufficiency or relative vita- insufficient and high level of 25-hydroxyvitamin
min D deficiency (Table I). Since vitamin D is D3 is affected by many factors, hence the exis-
essential for bone health (highlighted in the next tence of two major opinions on this matter. As
subsection), its suboptimal levels predispose to 25-hydroxyvitamin D3 is the major determinant
osteoporosis and fall-related fractures. of bone health, it is obvious that bone-related
There are two expert opinions on what to con- outcomes have been considered when the respec-
sider the optimal range of circulating vitamin D tive expert panels have worked out the recom-
levels. The first opinion is advocated by the Insti- mendations. The factors considered included
tute of Medicine. As per this expert opinion, the parathyroid hormone, decreased risk to develop
optimal 25-hydroxyvitamin D3 levels in blood fractures, and some other outcomes.
range between 50 and 100 nM 14. The reader What causes vitamin D relative or absolute de-
should be aware that in the USA, non-SI mea- ficiency? Multiple factors can be involved, in-
surement units are utilized to describe vitamin D cluding decreased synthesis due to diminished
levels. Thus, for 25-hydroxyvitamin D3 levels, exposure to the sun, diminished dietary intake,
US literature uses ng/ml, with the conversion fac- and increased catabolism in the body. Further-
tor being approximately 2.5 times lower than the more, there appears to be a non-linear relation-
SI-based system. Therefore, their recommenda- ship between altered levels of vitamin D and os-
tion in the original publication is expressed as teoporosis. For example, a very recent review has
“20-40 ng/ml”. This review will use SI units addressed genetic and non-genetic factors deter-
throughout. The second expert panel considers mining propensity to develop osteoporosis fol-
the levels between 75 and 125 nM (30-50 ng/ml) lowing vitamin D deficiency18. The importance
as normal blood levels15. of genetic predisposition for osteoporosis has
The Institute of Medicine considers that the been demonstrated by other publications as
lowest level of 50 nM of 25-hydroxyvitamin D3 well19. Furthermore, women develop osteoporo-
is adequate for 97% of people. As the main ratio- sis more frequently than men, which underscores
nale for settling on the highest recommended the gender-associated character of this disease.
range, the Institute of Medicine describes insuffi- Still, there is a consensus in the literature that vit-
cient evidence that higher levels of 25-hydrox- amin D status in the body, reflected by circulated
yvitamin D3 actually lead to greater health bene- levels of 25-hydroxyvitamin D3, is the major de-
fits. Moreover, their experts, using the literature terminant of osteoporosis development. The ef-
data argue, that adverse effects are very likely to fects of vitamin D on bones are highlighted in
occur at high levels of 25-hydroxyvitamin D3. the next subsection.

Table I. Normal and abnormal levels of circulating 25-hydroxyvitamin D3.

Insufficient Normal (or High (or

Absolute (or also called also called also called
deficiency, “Inadequate”), “Adequate”), “Toxic”),
(ng/ml) nM (ng/ml) nM (ng/ml) nM (ng/ml)

The Institute of Medicine < 30 (< 12) 30-< 50 (12-< 20) ≥ 50 (≥ 20)-125 (20) > 125 (> 20)
recommendations (ref. 25)
The Endocrine Society <5 0 (< 20) 50-75 (20-< 30) 75-250
recommendations (ref. 15)

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 C.-H. Dong, Q.-M. Gao, Z.-M. Wang, A.-M. Wang, P. Zhen

Bone Health and Vitamin D ily, there is a large choice of vitamin D metabo-
We have mentioned previously that vitamin D- lites and their analogs to choose from.
associated effects on bone health are determined The first objective of vitamin D supplementa-
by transcriptional up-regulation of vitamin D-re- tion is to maintain the healthy circulating levels.
sponsive genes, that is, by transcriptional mecha- The aforementioned recommendation Institute of
nisms. The vitamin D-responsive genes relevant Medicine provides detailed guidelines on the ten-
to bone health are present both in the gut and in tative lower and upper ranges of vitamin D sup-
the bone. For example, the gut tissue, exposed to plementation14. Their expert panel considers the
vitamin D, up-regulates expression of proteins healthy levels of 25-hydroxyvitamin D3 to be be-
increasing absorption of calcium, the mineral vi- tween 50 and 100 nM. To achieve these circulat-
tal for bone health. This is a clinically important ing levels, healthy adults are estimated to require
mechanism as older age is associated with de- approximately 400 to 800 IU of dietary vitamin
creased absorption of calcium in the gut20. This D (regardless of whether D3 or D2) per day. It is
causes osteomalacia, or inadequate mineraliza- thought that each 100 IU of dietary vitamin D
tion of the bone tissue. In addition, vitamin D will be converted in the body to yield between
suppresses the parathyroid hormone that removes 1.75 and 2.5 nM. A large glass of fortified milk
calcium from the bones. in North America contains about 100 IU of vita-
In the bone, expression of the receptor activa- min D. Dietary supplementation comes on top of
tor of nuclear factor B ligand (RANKL) is up- endogenous 25-hydroxyvitamin D3 levels and re-
regulated. RANKL promotes maturation of bone pletion happens much more efficient if endoge-
cells and their functional activity. Also, studies in nous levels are low. Therefore, the experts be-
mice have demonstrated that vitamin D exerts in- lieve that the recommended intake is sufficient to
direct effects on the bone (i.e., not involving maintain healthy levels of 25-hydroxyvitamin D3.
bone cells)21, and that these effects depend on the For older adults, the recommendation is to
systemic availability of calcium21. take slightly higher levels of vitamin D supple-
An important contributor to bone health is the ment (between 51 and 70 years old: a minimum
liver. For example, under certain conditions or in of 600 IU per day; > 70 years old: at least 800
certain diseases, the liver defines the functional IU/day; Table II). The recommendation is further
efficacy of vitamin D22,23. Another contributor is extended to individuals with diseases and condi-
the kidney, and kidney diseases affect the body’s tions that may affect the circulating levels of 25-
vitamin D status24. Given these data, it is clear hydroxyvitamin D314. Importantly, the expert rec-
that the mechanism and the end effect of vitamin ommendation on vitamin D intake is done in par-
D effects on bone health is very complex, involv- allel with the recommendation on calcium intake.
ing several organs (gut, liver, kidney and bone) This is because calcium deficiency modifies the
and several cell types. effects of vitamin D supplementation.
For certain, high-risk populations, alternative
Supplementation With Vitamin D recommendations exist. For example, Canadian
If the circulating levels of 25-hydroxyvitamin guidelines for preventing fractures in long-term
D3 are deficient, how can we replete them? Luck- care facilities2 recommend taking between 800

Table II. Recommended daily intake guidelines on calcium and vitamin D pertinent to older patients (> 65 years).

19-70 years > 70 years

Calcium, Vitamin D, Calcium, Vitamin D,

Gender mg/day IU/day mg/day IU/day

The Institute of Medicine recommendations Men 1000 600 (4000 max)* 1200 800 (4000 max)*
(ref. 25) Women 1200 600 (4000 max) 1200 800
The Endocrine Society recommendations Not stratified 1500-2000 1500-2000
(ref. 15) by gender (10,000 max) (10,000 max)

Footnote: Canadian Osteoporosis Society (ref. 2) recommends taking between 800 and 2000 IU/day for preventing fractures in
long-term care facilities.

4616
 Vitamin D supplementation for osteoporosis in older adults: can we make it help better?

and 2000 IU per day of vitamin D3. Still, this rec- A secondary search with a broader choice of
ommendation does not exceed the upper level of keywords has been conducted in the Medline to
daily supplementation with vitamin D3 (< 4000 ascertain that all relevant publications have been
IU/day) given by the Institute of Medicine for found. The search strategy has included the key-
people above 51 years old14. words “elderly [Text word]” OR “Aged” [Mesh]
25-hydroxyvitamin D3 can be used to replete OR old* [Text word] AND “last 10 years” [PDat]
our endogenous levels of 25-hydroxyvitamin D3, AND “Humans” [Mesh] AND “English” [lang]
and this approach appears to be more efficacious AND “Clinical Trial” [PType]. These searches
and rapid than the use of dietary vitamin D2/D325. have revealed 28 documents. Some publications
Direct supplementation of 1,25-dihydroxyvita- have been found by checking reference lists of
min D3, the biologically active metabolite, can al- the previously found publications, and some pub-
so be done, but is severely limited by the narrow lications have been excluded manually after read-
therapeutic window and adverse effects, includ- ing the abstracts. Altogether, the searches have
ing hypercalcemia. There thus exist synthetic revealed 88 publications.
1,25-dihydroxyvitamin D3 analogs with wider As some publications27 had tested metabolites
therapeutic window and lower calcemic effects of vitamin D in combination with other therapies.
(e.g. paricalcitol) 26. Paricalcitol has been ap- These publications have been included in the final
proved in the USA for secondary hyperparathy- analysis if the study design allowed to clearly dis-
roidism during kidney disease. The biological ef- cern the effects of vitamin D supplementation on
fects of paricalcitol are rapid, and this compound osteoporosis (such by testing the markers of bone
is rapidly eliminated from blood (http://www.ac- turnover). A similar approach has been applied if a
cessdata.fda.gov/drugsatfda_docs/label/2011/020 publication had stated conducting the study in el-
819s025lbl.pdf). This is to be expected, since its derly patients with osteoporosis and other, non-os-
parent compound, 1,25-dihydroxyvitamin D3, is teoporosis chronic diseases (such as Crohn’s dis-
also short-lived. However, this is in contrast to ease28). Cross-sectional studies exploring the use
supplementation with dietary vitamin D2/D3 or of vitamin D supplements without an active inter-
25-hydroxyvitamin D3 that have a considerably vention arm or without bone density data29 have
longer half-life in blood, and are stored in fat or been excluded from the analysis.
muscle tissue. Therefore, vitamin D2/D3 or 25- The persistence of circulating levels of 25-hy-
hydroxyvitamin D3 supplements can be taken as droxyvitamin D3 may be longer than 2 weeks, as
bolus supplementation. In contrast to 1,25-dihy- indicated by Mocanu and Vieth7. In comparison,
droxyvitamin D3, hypercalcemia is only observed the half-life of the biologically active metabolite,
at very high doses of 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D 3, and its analogs is
not seen at all25. considerably shorter (several hours). Given dif-
fering half-lives and transcriptional activities of
Efficacy of vitamin D Supplementation to these two forms of vitamin D (25-hydroxyvita-
Alleviate Osteoporosis in the Elderly min D3 needs to be converted to 1,25-dihydrox-
We have conducted Medline and Google yvitamin D3 for biological effects, whereas 1,25-
Scholar searches to identify clinical studies that dihydroxyvitamin D3 is transcriptionally active),
had addressed clinical usefulness of vitamin D we have analyzed the published studies separate-
supplementation for osteoporosis in the elderly. ly for either metabolite.
The searches have been done using the keywords Out of 5 studies that had dealt with the analogs
“osteoporosis”, “vitamin D”, “clinical study”, of 1,25-dihydroxyvitamin D3, two studies had
“clinical trial”, and “human”, and have been lim- made a direct comparison of the effects on bone
ited to English language publications and to the resorption markers between the analogs and
past 10 years because of newest recommenda- placebo 30 31, and the third study has evaluated
tions 14,15. After the searches have not yielded muscle-based outcomes32. We have included the
many publications, we have expanded the search- first two studies in the analysis, as well as the
es by adding the “post-menopausal” keyword. third study because of the relevance of muscle
These searches yielded 39 documents in the strength to fractures in the elderly. The remaining
Medline and 25 documents in Google Scholar. two studies33,34 have been excluded. These stud-
The latter documents have included the 4 docu- ies had compared different analogs of 1,25-dihy-
ments dated before 2006, which have been ex- droxyvitamin D3 and have thus been considered
cluded from the analysis. irrelevant for our objective.

4617
 C.-H. Dong, Q.-M. Gao, Z.-M. Wang, A.-M. Wang, P. Zhen

Two out of the three included studies had pre- Other unresolved questions are the range of 25-
sented evidence of positive effects of the analogs hydroxyvitamin D3 concentrations to target in
on bone resorption markers30,31. Positive effects clinical studies and existing lab-to-lab analytical
had also been observed concerning the muscle differences. All these should be considered in
strength32. prospective studies.
The following studies had tested the effects of Still, despite the existing ambiguity, the pub-
either vitamin D2 or D3 supplementation on bone lished reports seem to support the beneficial role
resorption markers or related outcomes35-48. Anoth- of this vitamin to improve unwanted bone resorp-
er two studies have been identified, but they had tion. In addition, vitamin D supplementation
addressed secondary post-corticosteroid osteoporo- shows some extraskeletal effects, such as an in-
sis49,50. The latter two studies have not been includ- crease in muscle power. These extraskeletal ef-
ed in the analysis. Of the included studies, some48 fects can also be beneficial to limit osteoporosis.
had tested oral vitamin or injectable D243 supple- In addition to vitamin D supplementation, as
mentation. The majority of the studies had reported recommended by international guidelines, osteo-
beneficial effects of vitamin D2 or D3 supplementa- porosis management involves other approaches,
tion35-38,40,45,47. Interestingly, the described effects such as changes in the lifestyle and diet, and the
had sometimes been limited to elevation of 25-hy- use of medications other than vitamin D53,54.
droxyvitamin D348, but this we have still considered We also would like to underscore that the stud-
beneficial. The remaining studies had reported ei- ies analyzed in this subsection represent interven-
ther no beneficial effects39,41 44 or even negative im- tion studies with relatively short-term designs,
pact of the supplementation on the studied out- and some of them had used quite high supple-
comes42. Interestingly, one of the studies showing mentation doses. Large long-term studies using
positive effects of the supplementation had also re- the recommended daily intake doses14 for preven-
ported heterogeneity of responses37. tion of osteoporosis are also urgently needed.
Based on this literature search, we have con- This will help to assess better whether the current
cluded that the publications generally show posi- recommendations are adequate in preventing os-
tive effects of supplementation with vitamin teoporosis in elderly patients.
D2/D3 or analogs of 1,25-dihydroxyvitamin D3,
but there is a considerable heterogeneity of the
outcomes. This heterogeneity is demonstrated by Conclusions
not all studies yielding positive results. More-
over, patients’ response to supplementation Vitamin D is an important determinant of bone
demonstrates heterogeneity as well. health, especially in older people. The majority of
Therefore, it can be summarized that there still studies demonstrate its beneficial role as a thera-
exists some controversy about beneficial effects peutic agent to maintain bone density in older pa-
of vitamin D supplementation, as some studies tients with osteoporosis. The progress has been
had reported ambivalent results. The meta-analy- somewhat hampered by the lack of uniform analyt-
sis studies on this topic also confirm our conclu- ical assay and expert consensus on targeted circu-
sions51,52. lating levels of this vitamin. Future studies should
This controversy could be because of patients’ adjust the study designs to reflect all these issues,
heterogeneity, but could also be caused or aggra- as well as potential patient heterogeneity.
vated by the wide variation of study designs. In-
deed, the studies had utilized different metabo- –––––––––––––––––-––––
lites as supplements, at different doses, and even Conflict of Interest
administered through different routes. The dis- The Authors declare that there are no conflicts of interest.
crepancies could have contributed to negative re-
sults observed in some studies. Another impor-
tant factor is patients’ compliance with the sup- References
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4618
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