Accepted Manuscript Questions about Vitamin D for Primary Care Practice: Input from an NIH Conference Christine L. Taylor, PhD, Paul R. Thomas, EdD, RDN, John F. Aloia, MD, Peter S. Millard, MD, PhD, Clifford J. Rosen, MD PII:
S0002-9343(15)00509-4
DOI:
10.1016/j.amjmed.2015.05.025
Reference:
AJM 13023
To appear in:
The American Journal of Medicine
Received Date: 25 March 2015 Revised Date:
20 May 2015
Accepted Date: 20 May 2015
Please cite this article as: Taylor CL, Thomas PR, Aloia JF, Millard PS, Rosen CJ, Questions about Vitamin D for Primary Care Practice: Input from an NIH Conference, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
1
1
Questions about Vitamin D for Primary Care Practice:
2
Input from an NIH Conference
3
Authors: Christine L. Taylor, PhD1, Paul R. Thomas, EdD, RDN1, John F. Aloia, MD2,
5
Peter S. Millard, MD, PhD3, Clifford J. Rosen, MD4
6
Affiliations:
7
1
8
Room 3B01, MSC 7517, Bethesda, MD 20892-7517, USA, [email protected];
9
[email protected]
RI PT
4
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SC
Office of Dietary Supplements, National Institutes of Health, 6100 Executive Boulevard,
10
2
11
Suite 510, Mineola, NY 11501, USA, [email protected]
12
3
13
[email protected]
14
4
15
81 Research Drive, Scarborough ME 04074, USA, [email protected]
16
Corresponding Author: Christine L. Taylor, Tel: 301-496-0169
17
Word count: 1959
18
Article type: Review
19
Funding sources: This review was prepared from a conference held at the National
20
Institutes of Health (NIH) on December 2-3, 2014 titled "Vitamin D: Moving Toward
21
Evidence-based Decision Making in Primary Care." At the NIH, the primary sponsor was
22
the Office of Dietary Supplements, with co-sponsorship by the National Center for
23
Complementary and Alternative Medicine (now the National Center for Complementary
Bone Mineral Research Center, Winthrop University Hospital, 222 Station Plaza North,
TE D
Seaport Community Health Center, 41 Wight Street, Belfast, ME 04915, USA,
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EP
Center for Clinical & Translational Research, Maine Medical Center Research Institute,
1
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
2
and Integrative Health; NCCIH), National Institute of Arthritis and Musculoskeletal and
25
Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney
26
Diseases (NIDDK), and the National Institute on Aging (NIA). Additional co-sponsorship
27
was provided by the Agency for Healthcare Research and Quality (AHRQ), National
28
Institute of Standards and Technology (NIST), Office of Disease Prevention and Health
29
Promotion (ODPHP) at the Department of Health and Human Services, and the U.S.
30
Food and Drug Administration.
31
Conflicts of Interest by Any of the Authors: None.
32
Verification: Each author participated in the writing of the manuscript and saw and
33
approved the submitted version. Further, each author was involved in the conception
34
and design of this review.
SC
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35
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24
Abstract
37
There is considerable consumer and physician interest in vitamin D as a possible
38
therapeutic agent for a range of clinical conditions, and despite mixed evidence the
39
interest does not appear to lessen. Some clinicians believe that consumption of vitamin
40
D is inadequate and, in turn, advocate vitamin D supplementation to increase serum
41
levels of the nutrient. However, evidence concerning the role of vitamin D in health and
42
disease is conflicting, and primary care physicians have little time to sort through the
43
data and may find it difficult to advise their patients. To better understand the challenges
44
that primary care physicians face regarding vitamin D, and to help inform those who
45
provide guidance for clinical decision-making, the Office of Dietary Supplements at the
46
National Institutes of Health, with co-sponsorship from other federal health agencies,
AC C
EP
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36
2
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
3
held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in
48
Primary Care in December 2014.1 More than 20 invited presenters and panelists
49
considered laboratory methods for measuring vitamin D status, discussed how clinical
50
studies of vitamin D should be evaluated and used in developing recommendations,
51
noted the role of values and preferences in clinical decision making, debated the current
52
science related to at-risk groups, and described emerging data about health risks of
53
excessive intakes of vitamin D. Eight questions about vitamin D stem from the
54
Conference presentations as well as other expert sources.
SC
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47
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55 56
Keywords: Vitamin D; supplementation; vitamin D status; 25-hydroxyvitamin D;
57
25(OH)D; screening; laboratory testing
58
60
What is the evidence for vitamin D health benefits? •
TE D
59
There is widespread agreement that vitamin D promotes bone health and, together with calcium, helps to protect older adults from bone loss. Also, there
62
appears to be benefit from vitamin D supplementation to prevent falls in the frail
63
elderly who are at risk for vitamin D deficiency. Whether vitamin D supplementation offers the same benefit in healthy, well-nourished older
64
individuals is unclear.
65 66
AC C
EP
61
•
Beyond bone health and possibly fall prevention, research during the last 15
67
years has provided tantalizing and well-publicized suggestions that adequate
68
vitamin D status might provide other benefits including reduced risk for
69
cardiovascular disease, cancer, diabetes, autoimmune diseases, and infectious 3
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
4
respiratory diseases.
70
o Most of the research linking vitamin D to non-bone health outcomes stems
71
from observational studies, which identify associations, rather than
73
randomized controlled trials. Observational studies are poor guides for
74
therapeutic interventions because of uncontrolled confounding.
RI PT
72
o Several large trials are in progress to investigate the effects of vitamin D
75
supplementation on outcomes such as cancer and cardiovascular
77
disease. Results from these studies will not be available for several years,
78
but they will help to clarify whether or not vitamin D is beneficial in ways
79
other than bone health.2 •
M AN U
80
SC
76
Some contend that promoting vitamin D even in the absence of data from clinical trials is a public-health good consistent with clinical judgment, while others
82
believe that clinicians acting ahead of the science risk losing the confidence of
83
patients should future research dispute the conclusions about vitamin D from
84
observational data. Prior enthusiasm for high-dose nutritional therapies based on
85
observational studies of vitamin E, beta-carotene, and selenium waned when
86
clinical trials demonstrated not only lack of benefit but potential harms.
AC C
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TE D
81
87
88
89
What do serum measures tell us about vitamin D status? •
Serum concentration of 25-hydroxyvitamin D (25(OH)D)—the major and most
90
stable circulating form of the vitamin—is the best available indicator of vitamin D
91
status.
4
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
o Serum 25(OH)D reflects the total supply of vitamin D to the body from all
92
sources: food, dietary supplements, and sun exposure.
93 94
5
•
There is disagreement about 25(OH)D concentrations associated with health, or whether 25(OH)D can serve as a surrogate for health outcomes of interest.
RI PT
95
o Different vitamin D experts suggest concentrations that range from 16-20
97
ng/mL (40-50 nmol/L) 3 to 30 ng/mL (75 nmol/L),4 and a search of internet
98
sites finds recommendations of 50 ng/mL (125 nmol/L) or more.
99
SC
96
The Institute of Medicine concluded that 20 ng/mL serum 25(OH)D is the top end of the requirement for a serum vitamin D level in
101
almost all (97.5%) of the general population, and that many
102
persons have requirements that are satisfied at levels less than 20
103
ng/mL.3 The Endocrine Society agreed with the Institute of
104
Medicine conclusions for the general population, but not for those
105
“at risk” such as older adults, pregnant women and dark-skinned
106
persons for whom they recommended 30 ng/mL.4
not need more than 600-800 IU vitamin D per day. The Endocrine
108
Society indicated that in order to ensure its suggested serum
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109
concentrations of 30 ng/mL or higher, vitamin D intakes should be
110
1,000-2,000 IU per day.
111
o The majority of Americans have serum 25(OH)D concentrations above 20
112
ng/mL but not above 30 ng/mL.3
113 114
The Institute of Medicine has suggested that most individuals do
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•
Furthermore, newer understandings about genetic differences in population
5
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
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115
groups may affect our assessment about the vitamin D status of these groups
116
when 25(OH)D is the measure of status. o For example, total serum 25(OH)D levels are systematically lower in
117
African Americans, yet they experience notably better bone health. Recent
119
studies have found that African Americans, despite having lower total
120
25(OH)D levels, have levels of free 25(OH)D (i.e., 25(OH)D is not bound
121
to the circulating protein and is “bioavailable”) similar to Caucasians. Since
122
the free form of the substance is likely the form used by cells, African
123
Americans may not be at greater risk of deficiency, as had been assumed
124
in the past. Others are concerned about the laboratory assay used to
125
measure both free 25(OH)D and the vitamin D binding protein. These
126
issues must be resolved before conclusions can be drawn about the
127
relative vitamin D status of African Americans.
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o Obese individuals tend to have lower serum 25(OH)D levels compared to
128
those of normal weight. The reason(s) for this difference (e.g., increased
130
clearance from circulation, volume dispersion, or greater sequestration
131
into adipose tissue) have not been elucidated nor are its health
132
consequences, if any, understood.
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133
134
Why do so many laboratory reports indicate a deficiency?
135
•
136
With no agreed-upon serum 25(OH)D level linked to vitamin D benefits, medical laboratories often establish cut-points based on their interpretation of the current
6
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
7
literature.
137 138
o These cut-points can vary greatly or change over time.
139
o Clearly, the higher the cut-points selected by the laboratory, the more people
RI PT
are classified as deficient.
140
o An apparent increase in the prevalence of vitamin D deficiency is explained
141
by the use of high cut-points.
142
o Some laboratories use a reference range from “low” to “high,” and bracket the
144
low end of the range by using a reference value established by the Institute of
145
Medicine as the highest need (97.5%), and using as the top end of the range
146
the reference value that demarcates the point at which the risk for harm from
147
excess levels begins to increase (Upper Level). Clinicians can be misled by
148
this reporting method because by definition the low end of the range is
149
adequate for virtually all individuals.
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143
Despite the debates and related measurement issues, serum 25(OH)D concentrations below 12 ng/mL are universally associated with deficiencies and
152
should trigger treatment. Likely candidates for low serum 25(OH)D concentrations
153
are the frail institutionalized elderly, because their diets may be poor and they often
154
lack exposure to the sun.
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155
156
Are laboratory tests for vitamin D status reliable?
157
•
158
Primary care physicians may not be aware of issues surrounding the measurement of serum 25(OH)D. Medical laboratories use any of several test methods, including
7
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
8
159
competitive protein binding, immunoassay, high performance liquid chromatography,
160
and combined high-performance liquid chromatography and mass spectrometry.5
161
o The sensitivity and specificity of these methods varies, both among the methods of measurement and between laboratories using the same testing
163
method. Moreover, there is no internationally recognized reference standard.
164
Discrepancies between methods and laboratories likely range from 10% to
165
20%.
SC
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162
o Also, 25(OH)D levels may decrease in response to inflammation and acute
166
illness (and possibly as a result of changes in the related binding protein and
168
other carriers), potentially explaining why vitamin D status appears low when
169
patients are sick.
o It is unclear whether common laboratory reference ranges are appropriate for
170
•
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all ethnic groups.
171 172
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167
The bottom line is that laboratory testing of vitamin D status may misclassify individuals as vitamin D insufficient or adequate due to the variability of the assay
174
and laboratory used, especially when the individual’s value is close to the cut-point
175
selected.
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173
o This suggests the need for caution and the consideration of other factors
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176
when individuals present with measurements very close to whatever cut-point
177
is used.
178 179
180
Are there recommendations about screening for vitamin D status?
181
•
Most organizations do not recommend universal screening for vitamin D. 8
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
9
o The U.S. Preventive Services Task Force concluded that the benefits as well
182 183
as any potential harms from vitamin D screening and early interventions
184
cannot be determined.5
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o Further, groups such as the Endocrine Society,4 the American Geriatrics
185
Society,6 the American Academy of Pediatrics,7 and the American College of
187
Obstetricians and Gynecologists8 have concluded that routine screening is
188
not necessary.
SC
186
o Nevertheless, routine laboratory blood work on patients may include
189
screening for 25(OH)D levels. Some clinicians may be concerned about
191
potential legal liability if they fail to screen their patients for vitamin D status,
192
particularly if it is part of a clinical pathways or standard order sheet, but
193
vitamin D screening is not considered a mandatory healthcare practice. •
Widespread screening in the face of these recommendations can incur unnecessary health care costs.
195
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194
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o The marked increase in routine vitamin D screening in the last several years
196
has undoubtedly incurred substantial costs for the health care system.
198
o Sales of vitamin D dietary supplements have increased dramatically, from
EP
197
approximately $108 million in 2007 to $713 million in 2013.9
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199 200
201
Does vitamin D treat depression or improve mood?
202
•
203 204
Patients who present with fatigue and depression are sometimes tested for vitamin D deficiency or treated empirically. o Virtually no evidence links vitamin D status to depression or these related 9
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
10
conditions.
205
o While vitamin D therapy may be used at the discretion of the clinician, it is
207
important to note that vitamin D supplementation is not necessarily benign
208
and should be used cautiously and judiciously.
209
Are there concerns about over-supplementing with vitamin D?
210
•
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206
SC
There is a common misconception that vitamin D supplementation is safe at any reasonable level, or that if some is good, more may be better.
211
o It is clear that vitamin D intakes and serum 25(OH)D must be very high –
M AN U
212 213
perhaps 200-400 ng/mL – to cause the classic toxicity of marked
214
hypercalcemia and kidney and liver damage.
o However, emerging observational data suggest that adverse outcomes may
215
occur at much lower levels, such as in the 50-75 ng/mL range. These
217
suspected adverse outcomes appear to include increases in all-cause
218
mortality and increases in the rate of heart disease and some cancers.
219
Limited evidence suggests that African Americans may be more susceptible
220
to these adverse effects.
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•
Nevertheless, there is little concern about vitamin D excess at doses between 400-
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221
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216
222
1,000 IU per day. Concerns have been raised about supplementation in the range of
223
10,000-50,000 IU per day, which may be excessive.
224
225
Is vitamin D a topic for shared decision making?
226
•
Testing for vitamin D status and potentially deciding on the use of supplements 10
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
11
227
might be the subject of a conversation between the clinician and patient that
228
includes taking into account values and preferences of the patient. o While the many uncertainties surrounding vitamin D may make it a good
229
candidate for shared decision making in the minds of some, others argue that
231
there are too many uncertainties to allow a meaningful conversation. As
232
suggested by those in the latter group, clinicians have limited time to spend
233
with their patients and there are likely other health matters more pressing
234
than vitamin D, so the best course of action would be not to bring up the issue
235
of vitamin D unless the patient asks or there is a clinical reason to do so.
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230
236
Acknowledgements: The authors thank Drs. Patsy Brannon, Andrew Hoofnagle,
238
Susan Mayne, and J. Sanford Schwartz for their help in the initial development of this
239
article and its contents. They also thank Joyce Merkel for her help in preparing this
240
manuscript for publication.
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References
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1. Vitamin D. Moving Toward Evidence-based Decision Making in Primary Care.
244
December 2-3, 2014. Bethesda, MD. Conference Web site:
245
http://ods.od.nih.gov/Research/VitaminDConference2014.aspx. Accessed: March,
246
2015.
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2. Manson JE, Bassuk SS. Vitamin D research and clinical practice: at a crossroads.
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242
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JAMA. 2015 Feb 19. [Epub ahead of print] doi: 10.1001/jama.2015.1353.
249
3. Food and Nutrition Board, Institute of Medicine. DRI (Dietary Reference Intakes):
250
Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds.
251
Washington, DC: The National Academies Press; 2011.
252
4. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and
253
prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J
254
Clin Endocrinol Metab. 2011;96(7):1911-1930. doi: 10.1210/jc.2011-0385.
255
5. LeFevre ML, US Preventive Services Task Force. Summaries for patients. Screening
256
for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation
257
statement. Ann Intern Med. 2015;162(2):133-140. doi: 10.7326/M14-2450.
258
6. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older
259
Adults. Recommendations abstracted from the American Geriatrics Society Consensus
260
Statement on vitamin D for prevention of falls and their consequences. J Am Geriatr
261
Soc. 2014;62(1):147-152. doi: 10.1111/jgs.
262
7. Golden NH, Abrams SA; Committee on Nutrition. Optimizing bone health in children
263
and adolescents. Pediatrics. 2014;134(4):e1229-43. doi: 10.1542/peds.2014-2173.
264
8. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 495: Vitamin
265
D: screening and supplementation during pregnancy. Obstet Gynecol. 2011;118(1):197-
266
198. doi: 10.1097/AOG.0b013e318227f06b.
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9. Nutrition Business Journal. NBJ's Supplement Business Report 2014. New York, NY:
268
Penton Media, Inc. 2014.
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ACCEPTED MANUSCRIPT
Clinical Significance
• Despite physician and patient interest in vitamin D, its role in health and disease beyond bone is conflicting, and guidance for clinical decision-making is needed.
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• Serum 25-hydroxyvitamin D is the best indicator of vitamin D status, but disagreement exists about concentrations associated with health and whether 25(OH)D is a surrogate for health outcomes of interest.
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• This review provides information focused on 8 questions a physician may ask about vitamin D.
S0002-9343(15)00509-4
DOI:
10.1016/j.amjmed.2015.05.025
Reference:
AJM 13023
To appear in:
The American Journal of Medicine
Received Date: 25 March 2015 Revised Date:
20 May 2015
Accepted Date: 20 May 2015
Please cite this article as: Taylor CL, Thomas PR, Aloia JF, Millard PS, Rosen CJ, Questions about Vitamin D for Primary Care Practice: Input from an NIH Conference, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
1
1
Questions about Vitamin D for Primary Care Practice:
2
Input from an NIH Conference
3
Authors: Christine L. Taylor, PhD1, Paul R. Thomas, EdD, RDN1, John F. Aloia, MD2,
5
Peter S. Millard, MD, PhD3, Clifford J. Rosen, MD4
6
Affiliations:
7
1
8
Room 3B01, MSC 7517, Bethesda, MD 20892-7517, USA, [email protected];
9
[email protected]
RI PT
4
M AN U
SC
Office of Dietary Supplements, National Institutes of Health, 6100 Executive Boulevard,
10
2
11
Suite 510, Mineola, NY 11501, USA, [email protected]
12
3
13
[email protected]
14
4
15
81 Research Drive, Scarborough ME 04074, USA, [email protected]
16
Corresponding Author: Christine L. Taylor, Tel: 301-496-0169
17
Word count: 1959
18
Article type: Review
19
Funding sources: This review was prepared from a conference held at the National
20
Institutes of Health (NIH) on December 2-3, 2014 titled "Vitamin D: Moving Toward
21
Evidence-based Decision Making in Primary Care." At the NIH, the primary sponsor was
22
the Office of Dietary Supplements, with co-sponsorship by the National Center for
23
Complementary and Alternative Medicine (now the National Center for Complementary
Bone Mineral Research Center, Winthrop University Hospital, 222 Station Plaza North,
TE D
Seaport Community Health Center, 41 Wight Street, Belfast, ME 04915, USA,
AC C
EP
Center for Clinical & Translational Research, Maine Medical Center Research Institute,
1
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
2
and Integrative Health; NCCIH), National Institute of Arthritis and Musculoskeletal and
25
Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney
26
Diseases (NIDDK), and the National Institute on Aging (NIA). Additional co-sponsorship
27
was provided by the Agency for Healthcare Research and Quality (AHRQ), National
28
Institute of Standards and Technology (NIST), Office of Disease Prevention and Health
29
Promotion (ODPHP) at the Department of Health and Human Services, and the U.S.
30
Food and Drug Administration.
31
Conflicts of Interest by Any of the Authors: None.
32
Verification: Each author participated in the writing of the manuscript and saw and
33
approved the submitted version. Further, each author was involved in the conception
34
and design of this review.
SC
M AN U
35
RI PT
24
Abstract
37
There is considerable consumer and physician interest in vitamin D as a possible
38
therapeutic agent for a range of clinical conditions, and despite mixed evidence the
39
interest does not appear to lessen. Some clinicians believe that consumption of vitamin
40
D is inadequate and, in turn, advocate vitamin D supplementation to increase serum
41
levels of the nutrient. However, evidence concerning the role of vitamin D in health and
42
disease is conflicting, and primary care physicians have little time to sort through the
43
data and may find it difficult to advise their patients. To better understand the challenges
44
that primary care physicians face regarding vitamin D, and to help inform those who
45
provide guidance for clinical decision-making, the Office of Dietary Supplements at the
46
National Institutes of Health, with co-sponsorship from other federal health agencies,
AC C
EP
TE D
36
2
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
3
held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in
48
Primary Care in December 2014.1 More than 20 invited presenters and panelists
49
considered laboratory methods for measuring vitamin D status, discussed how clinical
50
studies of vitamin D should be evaluated and used in developing recommendations,
51
noted the role of values and preferences in clinical decision making, debated the current
52
science related to at-risk groups, and described emerging data about health risks of
53
excessive intakes of vitamin D. Eight questions about vitamin D stem from the
54
Conference presentations as well as other expert sources.
SC
RI PT
47
M AN U
55 56
Keywords: Vitamin D; supplementation; vitamin D status; 25-hydroxyvitamin D;
57
25(OH)D; screening; laboratory testing
58
60
What is the evidence for vitamin D health benefits? •
TE D
59
There is widespread agreement that vitamin D promotes bone health and, together with calcium, helps to protect older adults from bone loss. Also, there
62
appears to be benefit from vitamin D supplementation to prevent falls in the frail
63
elderly who are at risk for vitamin D deficiency. Whether vitamin D supplementation offers the same benefit in healthy, well-nourished older
64
individuals is unclear.
65 66
AC C
EP
61
•
Beyond bone health and possibly fall prevention, research during the last 15
67
years has provided tantalizing and well-publicized suggestions that adequate
68
vitamin D status might provide other benefits including reduced risk for
69
cardiovascular disease, cancer, diabetes, autoimmune diseases, and infectious 3
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
4
respiratory diseases.
70
o Most of the research linking vitamin D to non-bone health outcomes stems
71
from observational studies, which identify associations, rather than
73
randomized controlled trials. Observational studies are poor guides for
74
therapeutic interventions because of uncontrolled confounding.
RI PT
72
o Several large trials are in progress to investigate the effects of vitamin D
75
supplementation on outcomes such as cancer and cardiovascular
77
disease. Results from these studies will not be available for several years,
78
but they will help to clarify whether or not vitamin D is beneficial in ways
79
other than bone health.2 •
M AN U
80
SC
76
Some contend that promoting vitamin D even in the absence of data from clinical trials is a public-health good consistent with clinical judgment, while others
82
believe that clinicians acting ahead of the science risk losing the confidence of
83
patients should future research dispute the conclusions about vitamin D from
84
observational data. Prior enthusiasm for high-dose nutritional therapies based on
85
observational studies of vitamin E, beta-carotene, and selenium waned when
86
clinical trials demonstrated not only lack of benefit but potential harms.
AC C
EP
TE D
81
87
88
89
What do serum measures tell us about vitamin D status? •
Serum concentration of 25-hydroxyvitamin D (25(OH)D)—the major and most
90
stable circulating form of the vitamin—is the best available indicator of vitamin D
91
status.
4
ACCEPTED MANUSCRIPT Vitamin D for Primary Care Practice
o Serum 25(OH)D reflects the total supply of vitamin D to the body from all
92
sources: food, dietary supplements, and sun exposure.
93 94
5
•
There is disagreement about 25(OH)D concentrations associated with health, or whether 25(OH)D can serve as a surrogate for health outcomes of interest.
RI PT
95
o Different vitamin D experts suggest concentrations that range from 16-20
97
ng/mL (40-50 nmol/L) 3 to 30 ng/mL (75 nmol/L),4 and a search of internet
98
sites finds recommendations of 50 ng/mL (125 nmol/L) or more.
99
SC
96
The Institute of Medicine concluded that 20 ng/mL serum 25(OH)D is the top end of the requirement for a serum vitamin D level in
101
almost all (97.5%) of the general population, and that many
102
persons have requirements that are satisfied at levels less than 20
103
ng/mL.3 The Endocrine Society agreed with the Institute of
104
Medicine conclusions for the general population, but not for those
105
“at risk” such as older adults, pregnant women and dark-skinned
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persons for whom they recommended 30 ng/mL.4
not need more than 600-800 IU vitamin D per day. The Endocrine
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Society indicated that in order to ensure its suggested serum
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concentrations of 30 ng/mL or higher, vitamin D intakes should be
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1,000-2,000 IU per day.
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o The majority of Americans have serum 25(OH)D concentrations above 20
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ng/mL but not above 30 ng/mL.3
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The Institute of Medicine has suggested that most individuals do
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groups may affect our assessment about the vitamin D status of these groups
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when 25(OH)D is the measure of status. o For example, total serum 25(OH)D levels are systematically lower in
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African Americans, yet they experience notably better bone health. Recent
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studies have found that African Americans, despite having lower total
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25(OH)D levels, have levels of free 25(OH)D (i.e., 25(OH)D is not bound
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to the circulating protein and is “bioavailable”) similar to Caucasians. Since
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the free form of the substance is likely the form used by cells, African
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Americans may not be at greater risk of deficiency, as had been assumed
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in the past. Others are concerned about the laboratory assay used to
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measure both free 25(OH)D and the vitamin D binding protein. These
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issues must be resolved before conclusions can be drawn about the
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relative vitamin D status of African Americans.
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o Obese individuals tend to have lower serum 25(OH)D levels compared to
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those of normal weight. The reason(s) for this difference (e.g., increased
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clearance from circulation, volume dispersion, or greater sequestration
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into adipose tissue) have not been elucidated nor are its health
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consequences, if any, understood.
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Why do so many laboratory reports indicate a deficiency?
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With no agreed-upon serum 25(OH)D level linked to vitamin D benefits, medical laboratories often establish cut-points based on their interpretation of the current
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literature.
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o These cut-points can vary greatly or change over time.
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o Clearly, the higher the cut-points selected by the laboratory, the more people
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are classified as deficient.
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o An apparent increase in the prevalence of vitamin D deficiency is explained
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by the use of high cut-points.
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o Some laboratories use a reference range from “low” to “high,” and bracket the
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low end of the range by using a reference value established by the Institute of
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Medicine as the highest need (97.5%), and using as the top end of the range
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the reference value that demarcates the point at which the risk for harm from
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excess levels begins to increase (Upper Level). Clinicians can be misled by
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this reporting method because by definition the low end of the range is
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adequate for virtually all individuals.
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Despite the debates and related measurement issues, serum 25(OH)D concentrations below 12 ng/mL are universally associated with deficiencies and
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should trigger treatment. Likely candidates for low serum 25(OH)D concentrations
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are the frail institutionalized elderly, because their diets may be poor and they often
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lack exposure to the sun.
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Are laboratory tests for vitamin D status reliable?
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Primary care physicians may not be aware of issues surrounding the measurement of serum 25(OH)D. Medical laboratories use any of several test methods, including
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competitive protein binding, immunoassay, high performance liquid chromatography,
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and combined high-performance liquid chromatography and mass spectrometry.5
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o The sensitivity and specificity of these methods varies, both among the methods of measurement and between laboratories using the same testing
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method. Moreover, there is no internationally recognized reference standard.
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Discrepancies between methods and laboratories likely range from 10% to
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20%.
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o Also, 25(OH)D levels may decrease in response to inflammation and acute
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illness (and possibly as a result of changes in the related binding protein and
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other carriers), potentially explaining why vitamin D status appears low when
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patients are sick.
o It is unclear whether common laboratory reference ranges are appropriate for
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all ethnic groups.
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The bottom line is that laboratory testing of vitamin D status may misclassify individuals as vitamin D insufficient or adequate due to the variability of the assay
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and laboratory used, especially when the individual’s value is close to the cut-point
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selected.
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o This suggests the need for caution and the consideration of other factors
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when individuals present with measurements very close to whatever cut-point
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is used.
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Are there recommendations about screening for vitamin D status?
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Most organizations do not recommend universal screening for vitamin D. 8
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o The U.S. Preventive Services Task Force concluded that the benefits as well
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as any potential harms from vitamin D screening and early interventions
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cannot be determined.5
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o Further, groups such as the Endocrine Society,4 the American Geriatrics
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Society,6 the American Academy of Pediatrics,7 and the American College of
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Obstetricians and Gynecologists8 have concluded that routine screening is
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not necessary.
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o Nevertheless, routine laboratory blood work on patients may include
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screening for 25(OH)D levels. Some clinicians may be concerned about
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potential legal liability if they fail to screen their patients for vitamin D status,
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particularly if it is part of a clinical pathways or standard order sheet, but
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vitamin D screening is not considered a mandatory healthcare practice. •
Widespread screening in the face of these recommendations can incur unnecessary health care costs.
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o The marked increase in routine vitamin D screening in the last several years
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has undoubtedly incurred substantial costs for the health care system.
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o Sales of vitamin D dietary supplements have increased dramatically, from
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approximately $108 million in 2007 to $713 million in 2013.9
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Does vitamin D treat depression or improve mood?
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Patients who present with fatigue and depression are sometimes tested for vitamin D deficiency or treated empirically. o Virtually no evidence links vitamin D status to depression or these related 9
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conditions.
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o While vitamin D therapy may be used at the discretion of the clinician, it is
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important to note that vitamin D supplementation is not necessarily benign
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and should be used cautiously and judiciously.
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Are there concerns about over-supplementing with vitamin D?
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There is a common misconception that vitamin D supplementation is safe at any reasonable level, or that if some is good, more may be better.
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o It is clear that vitamin D intakes and serum 25(OH)D must be very high –
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perhaps 200-400 ng/mL – to cause the classic toxicity of marked
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hypercalcemia and kidney and liver damage.
o However, emerging observational data suggest that adverse outcomes may
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occur at much lower levels, such as in the 50-75 ng/mL range. These
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suspected adverse outcomes appear to include increases in all-cause
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mortality and increases in the rate of heart disease and some cancers.
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Limited evidence suggests that African Americans may be more susceptible
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to these adverse effects.
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1,000 IU per day. Concerns have been raised about supplementation in the range of
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10,000-50,000 IU per day, which may be excessive.
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Is vitamin D a topic for shared decision making?
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might be the subject of a conversation between the clinician and patient that
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includes taking into account values and preferences of the patient. o While the many uncertainties surrounding vitamin D may make it a good
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candidate for shared decision making in the minds of some, others argue that
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there are too many uncertainties to allow a meaningful conversation. As
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suggested by those in the latter group, clinicians have limited time to spend
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with their patients and there are likely other health matters more pressing
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than vitamin D, so the best course of action would be not to bring up the issue
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of vitamin D unless the patient asks or there is a clinical reason to do so.
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Acknowledgements: The authors thank Drs. Patsy Brannon, Andrew Hoofnagle,
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Susan Mayne, and J. Sanford Schwartz for their help in the initial development of this
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article and its contents. They also thank Joyce Merkel for her help in preparing this
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manuscript for publication.
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References
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1. Vitamin D. Moving Toward Evidence-based Decision Making in Primary Care.
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December 2-3, 2014. Bethesda, MD. Conference Web site:
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http://ods.od.nih.gov/Research/VitaminDConference2014.aspx. Accessed: March,
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2015.
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2. Manson JE, Bassuk SS. Vitamin D research and clinical practice: at a crossroads.
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JAMA. 2015 Feb 19. [Epub ahead of print] doi: 10.1001/jama.2015.1353.
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3. Food and Nutrition Board, Institute of Medicine. DRI (Dietary Reference Intakes):
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Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds.
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Washington, DC: The National Academies Press; 2011.
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4. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and
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prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J
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Clin Endocrinol Metab. 2011;96(7):1911-1930. doi: 10.1210/jc.2011-0385.
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5. LeFevre ML, US Preventive Services Task Force. Summaries for patients. Screening
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for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation
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statement. Ann Intern Med. 2015;162(2):133-140. doi: 10.7326/M14-2450.
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6. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older
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Adults. Recommendations abstracted from the American Geriatrics Society Consensus
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Statement on vitamin D for prevention of falls and their consequences. J Am Geriatr
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Soc. 2014;62(1):147-152. doi: 10.1111/jgs.
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7. Golden NH, Abrams SA; Committee on Nutrition. Optimizing bone health in children
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and adolescents. Pediatrics. 2014;134(4):e1229-43. doi: 10.1542/peds.2014-2173.
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8. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 495: Vitamin
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D: screening and supplementation during pregnancy. Obstet Gynecol. 2011;118(1):197-
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198. doi: 10.1097/AOG.0b013e318227f06b.
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9. Nutrition Business Journal. NBJ's Supplement Business Report 2014. New York, NY:
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Penton Media, Inc. 2014.
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Clinical Significance
• Despite physician and patient interest in vitamin D, its role in health and disease beyond bone is conflicting, and guidance for clinical decision-making is needed.
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• Serum 25-hydroxyvitamin D is the best indicator of vitamin D status, but disagreement exists about concentrations associated with health and whether 25(OH)D is a surrogate for health outcomes of interest.
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• This review provides information focused on 8 questions a physician may ask about vitamin D.
