Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 4612-4621 D supplementation for osteoporosis in older adults: can we make it help better?

C.-H. DONG 1,2 , Q.-M. GAO 1, Z.-M. WANG 2, A.-M. WANG 2, P. ZHEN 1

1The Center of Orthopaedic Surgery of PLA, the General Hospital of Lanzhou Military Command, Gansu, China 2Department 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. , 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- surface 1. 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 D 2 (). Both D 3 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 body 4. The experts often use the lations at increased risk for osteoporosis, includ - term “vitamin D” interchangeably , referring to 2 4,5 ing the elderly . Therefore, pharmaceutical sup - D3 or D 2 . 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 D 3 (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 tissue 5 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 D 3 passes through hy - ing vitamin D 3. The ultraviolet light catalyzes a droxylation 5. This process yields the circulating chemical reaction in the skin that produces vita - vitamin D metabolite called 25-hydroxyvitamin 4 min D from 7-dehydrocholesterol . 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 D 3 is the cur - referred to as vitamin D 3 (or ; 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 (VDR) which up-regulates transcription of a large group of genes, called “vitamin D-responsive genes”.

4613 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 D 3 to maintain suffi - tabolism have been developed around this cient circulating and intracellular levels of 1,25- metabolite. dihydroxyvitamin D 3. This is why it is important First, the circulating levels of 25-hydroxyvita - that the levels of 25-hydroxyvitamin D 3 are suffi - min D 3 are considered stable, with a half-life of ciently high, and this will be addressed in the about two weeks 6 or even longer 7. 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 - 8 25-hydroxyvitamin D 3 . Thereby, our body ap - min D 3 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 D 3 and muscle tissue for 25- First, the serum concentration of 25-hydrox - hydroxyvitamin D 3 storage. It is possible that for yvitamin D 3 is much higher than that of 1,25-di - this reason, our body maintains healthy levels of hydroxyvitamin D 3, which makes it less chal - 25-hydroxyvitamin D 3 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 D 3 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 D 3 is bound to serum albumin or with 1,25-dihydroxyvitamin D 3. 9 is free . In the kidney, 25-hydroxyvitamin D 3 is However, this does not mean that the analyti - further metabolized to produce the biologically cal tests for 25-hydroxyvitamin D 3 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 D 3 to 1,25-di - some assays report total 25-hydroxyvitamin D 5 hydroxyvitamin D 3 , this conversion is also (i.e. the sum of 25-hydroxyvitamin D 3 and 25- 4 thought to occur in other tissues . The latter vita - hydroxyvitamin D 2), 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 D 3 also ex - Another issue is that many laboratories still erts non-transcriptional (also called “non-genom - continue to utilize radioimmunoassays, or ic”) effects 10 . The transcriptional effects of 1,25- ELISA- / HPL-based assays , while newer labs dihydroxyvitamin D 3 seem to be more important have begun to phase out these assays and replace for bone health 11 . them with the mass spectrometry based assays 12 . Transcriptional and non-transcriptional effects The mass spectrometry based assays offer unri - 13 of 1,25-dihydroxyvitamin D 3 are limited by its valed specificity and sensitivity 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 D 3, meaning trometry -based assays may inaccurately estimate 12 that vitamin D up-regulates the enzymes that 25-hydroxyvitamin D 3 . 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 D 3. mechanism is the mechanism explaining short lifespan of 1,25-dihydroxyvitamin D 3. Since cir - Normal and Abnormal Vitamin D Levels culating levels of 25-hydroxyvitamin D 3 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 food 5. 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 ongoing 16 . At the for relative deficiency of this vitamin D 5. 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 D 3 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 recommendations 17 . 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 D 3 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 D 3 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 D 3 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 deficiency 18 . The importance as normal blood levels 15 . of genetic predisposition for osteoporosis has The Institute of Medicine considers that the been demonstrated by other publications as 19 lowest level of 50 nM of 25-hydroxyvitamin D 3 well . 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 D 3 actually lead to greater health bene - levels of 25-hydroxyvitamin D 3, 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 D 3. the next subsection.

Table I. Normal and abnormal levels of circulating 25-hydroxyvitamin D 3.

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)

4615 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 plementation 14 . Their expert panel considers the vitamin D, up-regulates expression of proteins healthy levels of 25-hydroxyvitamin D 3 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 20 creased absorption of calcium in the gut . This D (regardless of whether D 3 or D 2) 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 D 3 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 D 3. bone cells )21 , and that these effects depend on the For older adults, the recommendation is to systemic availability of calcium 21 . 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 D 22,23 . 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- 24 14 vitamin D status . Given these data, it is clear hydroxyvitamin D 3 . 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 2 D3 are deficient, how can we replete them? Luck - care facilities 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 D 3. 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 D 3 (< 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 old 14 . words “elderly [Text word]” OR “Aged” [Mesh]

25-hydroxyvitamin D 3 can be used to replete OR old* [Text word] AND “last 10 years” [PDat] our endogenous levels of 25-hydroxyvitamin D 3, AND “Humans” [Mesh] AND “English” [lang] and this approach appears to be more efficacious AND “Clinical Trial” [PType]. These searches 25 and rapid than the use of dietary vitamin D 2/D 3 . have revealed 28 documents. Some publications Direct supplementation of 1,25-dihydroxyvita - have been found by checking reference lists of min D 3, 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. 27 1,25-dihydroxyvitamin D 3 analogs with wider As some publications had tested metabolites therapeutic window and lower calcemic effects of vitamin D in combination with other therapies. (e.g. ) 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 D 3, is teoporosis chronic diseases (such as Crohn’s dis - also short-lived. However, this is in contrast to ease 28 ). Cross-sectional studies exploring the use supplementation with dietary vitamin D 2/D3 or of vitamin D supplements without an active inter - 29 25-hydroxyvitamin D 3 that have a considerably vention arm or without bone density data have longer half-life in blood , and are stored in fat or been excluded from the analysis . muscle tissue. Therefore, vitamin D 2/D 3 or 25- The persistence of circulating levels of 25-hy - hydroxyvitamin D 3 supplements can be taken as droxyvitamin D 3 may be longer than 2 weeks, as bolus supplementation. In contrast to 1,25-dihy - indicated by Mocanu and Vieth 7. In comparison, droxyvitamin D 3, hypercalcemia is only observed the half-life of the biologically active metabolite, at very high doses of 25-hydroxyvitamin D 3 or 1,25-dihydroxyvitamin D 3, and its analogs is not seen at all 25 . 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 D 3 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 D 3 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 D 3, 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 outcomes 32 . 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 studies 33,34 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 D 3 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 D 3 concentrations to target in on bone resorption markers 30,31 . Positive effects clinical studies and existing lab-to-lab analytical had also been observed concerning the muscle differences. All these should be considered in strength 32 . prospective studies. The following studies had tested the effects of Still, despite the existing ambiguity, the pub - either vitamin D 2 or D 3 supplementation on bone lished reports seem to support the beneficial role resorption markers or related outcomes 35-48 . 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 - sis 49,50 . The latter two studies have not been includ - crease in muscle power. These extraskeletal ef - ed in the analysis. Of the included studies, some 48 fects can also be beneficial to limit osteoporosis. 43 had tested oral vitamin or injectable D 2 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 D 2 or D 3 supplementa - porosis management involves other approaches , tion 35-38,40,45,47 . 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 D 53,54 . 48 droxyvitamin D 3 , 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 effects 39,41 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 - comes 42 . 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 doses 14 for preven - ported heterogeneity of responses 37 . 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/D 3 or analogs of 1,25-dihydroxyvitamin D 3, 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 - sions 51,52 . 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 plementation. In the studies in which patients take the supplement on a regular basis, this 1) WEBB AR, K LINE L, H OLICK MF . Influence of season should have a negligible effect because of the and latitude on the cutaneous synthesis of vita - min D3: exposure to winter sunlight in Boston and longer life span of 25-hydroxyvitamin D 3. But Edmonton will not promote vitamin D3 synthesis studies with bolus administration may certainly in human skin. J Clin Endocrinol Metab 1988; 67: suffer from insufficient patients’ compliance. 373-378.

4618 Vitamin D supplementation for osteoporosis in older adults: can we make it help better?

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