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© 2016 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.
BEYOND THE GUIDELINES:
Should We Screen for Vitamin D Deficiency?
Medicine Grand Rounds
May 26, 2016
Discussants
BIDMC Series Editor
Moderator
Gordon J. Strewler, MD
Howard Libman, MD
Eileen E. Reynolds, MD
Alan Malabanan, MD
The Series Editors have no conflicts of interest to disclose.
Conflict of Interest Disclosure
The speakers have no financial relationships
with a commercial entity producing
healthcare-related products and/or
services.
Howard Libman, MD
Eileen E. Reynolds, MD
Alan Malabanan, MD
Conflict of Interest Disclosure
Gordon J. Strewler discloses financial
relationships with the following commercial
entity producing healthcare-related products
and/or services:
Recipient
Company
Wife
Veterans Admin
Relationship
Full-time
employee
Content Area
Vitamin D use
guidelines
Our Patient
• Ms. X is a healthy 55 y.o. woman presenting for annual visit
• Last menstrual period was 1.5 years ago; complains of mild
hot flashes but is otherwise asymptomatic
• Past Medical History: Colonic polyps and skin cancer
• Family Medical History: Lung cancer in father, and breast and
thyroid cancers in a sister
• Medications: None
• Allergies: None known
Our Patient
• She is married with grown children and worked in the past as
a dietician
• She exercises regularly, and she does not smoke cigarettes or
drink alcohol
• Physical Examination: Normal vital signs and no abnormalities
• She is educated regarding management of post-menopausal
symptoms and asks about the need for a bone density test
and vitamin D screening
Would you screen Ms. X for Vitamin D deficiency?
Context
• Subclinical vitamin D deficiency is common in the United
States, especially in the winter, and has been associated with
an increased risk of falls, osteoporosis, and possibly fractures
• Decreased intake of dairy products in adulthood may also be a
contributing factor in some patients
• However, controversies exist regarding how to measure
vitamin D, the optimal serum level for good health, and
whether to screen for vitamin D deficiency and, if so, in which
population(s); or, alternatively, whether to recommend that
all patients at risk take a daily vitamin D supplement
Review of Vitamin D Metabolism
• Vitamin D2 and D3 can be taken as supplements, and vitamin
D3 can be obtained via conversion of 7-dehydrocholesterol
from UV light action on skin
• Both D2 and D3 are converted to 25-hydroxyvitamin D in the
liver and then to 1,25-dihydroxyvitamin D (calcitriol), which is
the active compound, in the kidney
• 1,25-dihydroxyvitamin D increases intestinal absorption of
calcium, increases bone resorption, and decreases renal
calcium and phosphate excretion
The Guideline
*LeFevre ML, Force USPST. Screening for vitamin D deficiency in adults: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med. 2015;162:133-140.
Meta-analysis Design
Is there evidence that screening for vitamin D deficiency
results in improved health outcomes?
What are the harms
of screening?
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for
vitamin D deficiency: a systematic review for the U.S. Preventive
Services Task Force. Ann Intern Med. 2015;162:109-122.
Does treatment of vitamin D
deficiency lead to improved
health outcomes?
What are adverse effects of
vitamin D deficiency
treatment?
Evidence
Meta-analysis of Effects of Vitamin D Treatment on Mortality
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Evidence
Meta-analysis of Effects of Vitamin D Treatment on Mortality by
Institutional Status
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Evidence
Meta-analysis of Effects of Vitamin D Treatment on Risk for Falls
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Evidence
Meta-analysis of Effects of Vitamin D Treatment on Number of
Falls per Person
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Evidence
Meta-analysis of Effects of Vitamin D Treatment on Risk for Any
Fracture (top) or Hip Fracture (bottom)
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Summary of Findings
• None of the studies examined the effects of vitamin D screening vs.
not screening on clinical outcomes
• Vitamin D treatment was associated with decreased mortality vs.
placebo or no treatment (RR, 0.83 [95% CI, 0.70-0.99])
• Benefits were not seen if trials of institutionalized persons were
excluded
• Vitamin D treatment was associated with possible decreased risk for
having at least 1 fall (RR, 0.84 [CI, 0.69-1.02]) and number of falls per
person (incidence rate ratio, 0.66 [CI, 0.50-0.88]) but not fractures
• Vitamin D treatment was not associated with a statistically
significant increased risk for serious adverse events (RR, 1.17 [CI,
0.74-1.84])
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic
review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Other Guidelines
• The American Academy of Family Physicians has also concluded that
current evidence regarding vitamin D deficiency screening is
insufficient to make a recommendation
• The Endocrine Society recommends screening for vitamin D
deficiency in persons at risk
• Other professional organizations recommend testing for vitamin D
deficiency as part of osteoporosis management or falls prevention
strategies
• The Institute of Medicine does not have formal guidelines on
screening for vitamin D deficiency but published a report of the
recommended dietary allowance, which is 600 IU/day for adults
aged 19-70 years and 800 IU/day for adults older than 70 years
QUESTIONS TO DISCUSSANTS
To structure a debate between our two discussants, we
mutually agreed on the following key questions to consider
when applying these guidelines to clinical practice and to Ms. X
in particular:
1. What are the complications associated with vitamin D
deficiency, and what is the evidence that giving a supplement
is clinically beneficial?
2. What are the pros and cons of screening for vitamin D
deficiency versus recommending vitamin D supplementation
without screening?
3. What would you recommend for Ms. X and why?
OUR MODERATOR & DISCUSSANTS
Eileen E. Reynolds, MD (Moderator)
Vice Chair for Education, Department of Medicine, BIDMC
General Medicine and Primary Care, BIDMC
Associate Professor of Medicine, Harvard Medical School
Gordon J. Strewler, MD
Professor of Clinical Medicine, UCSF School of Medicine
Alan Malabanan, MD
Endocrinology, Diabetes and Metabolism, BIDMC
Assistant Professor of Medicine, Harvard Medical School
Dr. Strewler
An Argument for Vitamin D Screening
What are the complications
associated with vitamin D deficiency,
and what is the evidence that giving
a supplement is clinically beneficial?
Complications Putatively Associated with
Vitamin D Deficiency
•
•
•
•
•
•
•
•
•
Fractures
Falls
Cardiovascular disease
Cancer
Cognitive function
Diabetes
Depression
Immunity and Infections
Mortality
Vitamin D & Calcium Necessary for Bone Health
Vitamin D receptor deficiency
*Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D
receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci
USA. 1997;94:9831-9835. Copyright 1997 National Academy of Sciences.
*Reprinted from The Journal of Pediatrics, Vol. 94, Rosen JF,
Fleischman AR, Finberg L, Hamstra A, DeLuca HF. Rickets
with alopecia: an inborn error of vitamin D metabolism, pp.
729-735, Copyright 1979, with permission from Elsevier.
Calcium Mediates All Important
Effects of Vitamin D on Bone
Vitamin D
Calcium
absorption
Bone
health
The guidelines are based on this
syllogism:
There is no
evidence that
vitamin D prevents
fractures
There is no
reason to screen
So, let’s look
at the evidence
Meta-analysis of Vitamin D Effects on
Fracture Incidence
How NOT to do a meta-analysis
• Included studies both of vitamin D alone and vitamin D
plus calcium
• Included only studies in which vitamin D deficiency
was demonstrated (excluding nearly all large studies)
• Excluded studies in which patients were treated for an
indication (e.g., osteopenia)
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a
systematic review for the U.S. Preventive Services Task Force. Ann Intern Med.
2015;162:109-122.
Meta-analysis of Vitamin D Effects on
Fracture Incidence
How NOT to do a meta-analysis
• Left with only five studies, encompassing 1836 treated
participants, who were treated with vitamin D +/- calcium
• Analysis dominated by WHI study (1074 treated participants)
 Participants could take off-protocol vitamin D
 54% of them did so
• Found no effect of vitamin D plus calcium on fracture incidence -RR 0.98 (0.82-1.16)
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a
systematic review for the U.S. Preventive Services Task Force. Ann Intern Med.
2015;162:109-122.
A tale of two meta-analyses…
LeBlanc et al. 2014
Avenell et al. 2014
AHRP
Cochrane Collaboration
1838 participants
49,853 participants
RR 0.98 (0.82-1.16)
RR hip Fx 0.84 (0.740.96, p <0.01)
*LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin
D deficiency: a systematic review for the U.S. Preventive Services Task
Force. Ann Intern Med. 2015;162:109-122.
*Avenell A, Mak JCS, O'Connell D. Vitamin D and vitamin D analogues for
preventing fractures in post-menopausal women and older men.
Cochrane Database Syst Rev. 2014:CD000227.
There is a dearth of
randomized trial evidence of
other benefits of vitamin D.
Randomized Trials of Vitamin D Underway
Worldwide (>10,000 participants)
What are the pros and cons of
screening for vitamin D deficiency
versus recommending vitamin D
supplementation without screening?
High-risk Groups
Bone diseases
Rickets/Osteomalacia
Osteoporosis
Osteopenia
Hyperparathyroidism
Chronic kidney disease
Gastrointestinal disorders
Hepatic failure
Malabsorption syndromes
Cystic fibrosis
Inflammatory bowel disease
Bariatric surgery
Medications
Antiseizure medications
Glucocorticoids AIDS medications
Antifungals, e.g. ketoconazole
Cholestyramine
Older adults
History of falls
History of nontraumatic fractures
Obesity (BMI > 30 kg/m2)
Pregnant and lactating women
African-Americans and Hispanics?
*Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation,
treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
J Clin Endocrinol Metab. 2011;96:1911-1930.
Rationale for Targeted Screening of
25(OH)D Levels
• 25(OH)D levels are correlated with fracture risk, and
supplementation prevents fractures
• Vitamin D deficiency is prevalent
• We can identify high-risk patient groups
• Establishing a baseline allows follow-up to confirm
adherence
• Without active encouragement, adherence is poor at best
(40 – 60% in clinical trials)
• Responses to oral vitamin D preparations are highly variable
Effect of Vitamin D Treatment on 25(OH)D Levels
20
10
*Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and Calcium: A Systematic Review of
Health Outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.)
AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality. August, 2009.
Net change in 25(OH)D, ng/ml
30
“Cons”of Screening 25(OH)D Levels
• Vitamin D screening is expensive (Medicare $42)
• Assays are not fully standardized
• There is no consensus on target levels [We prefer
30 ng/ml (75 nmol/L)]
What would you recommend for Ms.
X and why?
Recommendations for Ms. X
• She should continue her good health habits
• She should be screened in the next few years for
osteopenia/osteoporosis
• A screening 25(OH)D level would be appropriate in that
context
• If deficient in vitamin D, she should be treated to a level
of 30 ng/ml (75 nmol/l)
• She should not receive a drug that inhibits bone
resorption until vitamin D sufficiency is demonstrated
Dr. Malabanan
An Argument Against Vitamin D Screening
What are the complications
associated with vitamin D deficiency,
and what is the evidence that giving
a supplement is clinically beneficial?
Vitamin D Deficiency: Bone Complications
• Vitamin D -- an anti-rachitic component of cod liver oil
• 1,25-dihydroxyvitamin D optimizes intestinal calcium and
phosphate absorption; necessary for bone mineralization
• Osteomalacia is uncommon among the elderly (3.7%),
albeit more common in women (10%) and those > 80 y.o.
(12%) 1
• Osteomalacia is present in 25% of hip fracture patients 2
• At a 25(OH)D level of 16 ng/ml (40 nmol/L), the majority
do not have evidence for osteomalacia 3
1.
2.
3.
Campbell GA, Kemm JR, Hosking DJ, Boyd RV. How common is osteomalacia in the elderly? Lancet. 1984;2:386-388.
Sokoloff L . Occult osteomalacia in American (U.S.A.) patients with fracture of the hip. Am J Surg Pathol. 1978;2:21-30.
Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, et al. Bone mineralization defects and vitamin D deficiency:
histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res.
2010;25:305-312.
*Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, et al. Bone mineralization defects and
vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010;25:305-312.
Vitamin D Deficiency: Definition
• The Institute of Medicine suggested a 25(OH)D level of 20
ng/ml as sufficiency and suggested deficiency as < 12 ng/ml 1
• Vitamin D deficiency may produce bone problems before
osteomalacia due to secondary hyperparathyroidism and
accelerated bone loss.
• Chapuy et al 2 showed that 1200 mg calcium and 800 IU
vitamin D  hip fracture risk 43% and  NVF risk 32%
• USPSTF meta-analysis showed no fracture risk benefit of
vitamin D 3
1.
2.
3.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 Dietary Reference Intakes for
Calcium and Vitamin D: what dietetics practitioners need to know. J Am Diet Assoc. 2011;111:524-527.
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip
fractures in the elderly women. N Engl J Med. 1992;327:1637-1642.
LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic review for
the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
*Reprinted from The Lancet Diabetes & Endocrinology, Vol. 2, Bolland MJ, Grey A, Gamble GD,
Reid IR, The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a
trial sequential meta-analysis, pp. 307-320, Copyright 2014, with permission from Elsevier.
Vitamin D Deficiency: Other Complications
• Non-skeletal sequela have included mortality, falling,
cancer, diabetes mellitus, cardiovascular disease,
infectious disease, and autoimmune disease 1
• Potential biologic mechanisms are present 1
• 25(OH)D is an acute phase reactant,  40% 24-48 h after
elective surgery, remaining low 3 months post-op 2
• USPSTF meta-analysis: Mortality; Fall Risk; Cancer ;
T2DM  3
1.
2.
3.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
Reid D, Toole BJ, Knox S, Talwar D, Harten J, O'Reilly DS, et al. The relation between acute
changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D
concentrations after elective knee arthroplasty. Am J Clin Nutr. 2011;93:1006-1011.
LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a
systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109122.
*Reproduced from Journal of Clinical Pathology, Vitamin D: a negative acute phase reactant, Waldron JL,
Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, Chugh S, Deshpande S, Ford C, Gama R, Vol. 66, pp.
620-622, (C) 2013, with permission from BMJ Publishing Group Ltd.
What are the pros and cons of
screening for vitamin D deficiency
versus recommending vitamin D
supplementation without screening?
Screening: Ideal Situation
• Correct identification of those who would benefit from
supplements
• Correct identification of those who would be harmed by
supplements
• Presumes:
– A suitable and acceptable test
– A recognized latent or early symptomatic stage
– An accepted and effective treatment
– Cost of screening and treatment should be less than
cost of unnecessary treatment
Screening: Problem List
• Problems with testing
– Variable assays and lack of standardization 1
– Role of vitamin D binding protein 2
– Controversy about vitamin D adequacy which affects
the prevalence (18.2% vs. 52.0% for 25(OH)D 20 vs. 30
ng/l) 3
– Acute phase reactant 4
1.
2.
3.
4.
Binkley N, Krueger D, Gemar D, Drezner MK. Correlation among 25-hydroxy-vitamin D
assays. J Clin Endocrinol Metab. 2008;93:1804-1808.
Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D-binding
protein and vitamin D status of black Americans and white Americans. N Engl J Med.
2013;369:1991-2000.
Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, et al. Prevalence of Vitamin D
inadequacy among postmenopausal North American women receiving osteoporosis
therapy. J Clin Endocrinol Metab. 2005;90:3215-3424.
Waldron JL, Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, et al. Vitamin D: a
negative acute phase reactant. J Clin Pathol. 2013;66:620-622.
*Republished with permission of The Journal of Clinical Endocrinology & Metabolism, from
Correlation among 25-hydroxy-vitamin D assays, Binkley N, Krueger D, Gemar D, Drezner MK,
Vol. 93, 2008; permission conveyed through Copyright Clearance Center, Inc.
Treatment without Testing
•
•
•
•
•
Inexpensive compared to testing, treating, and testing
Unclear benefit
USPSTF meta-analysis: no clear harm 1
Caution from IOM:
– Reverse J-shaped curve,  mortality 25(OH)D > 50 ng/ml2
– 2X risk pancreatic ca with 25(OH)D > 40 ng/ml 3
Confirmed  mortality 25(OH)D > 40 ng/ml 4
1.
2.
3.
4.
LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic review for the U.S.
Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population.
Arch Intern Med. 2008;168:1629-1637.
Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, Qi D, Patel AV, Helzlsouer KJ, et al. Circulating 25-hydroxyvitamin D and risk
of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172:81-83.
Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, Schleicher RL, et al. Is there a reverse J-shaped
association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative
NHANES. J Clin Endocrinol Metab. 2013;98:3001-3009.
CV Mortality and 25(OH)D
*Reprinted from The American Journal of Medicine, Vol. 126, Amer M, Qayyum R. Relationship between 25-hydroxyvitamin D and
all-cause and cardiovascular disease mortality, pp. 509-514, Copyright 2013, with permission from Elsevier.
What would you recommend for Ms.
X and why?
Ms. X Health Risks
• One year post-menopause – at risk for accelerated bone
loss and osteoporosis
• 55 years old – at risk for breast and colorectal cancer
• At Risk for Vitamin D deficiency?
– Supportive: Northern Latitude, 39% NHANES III 1
– Against: Caucasian, Healthy, Normal Weight, Good
Diet, Active with Sun Exposure
– Unknown: Sunscreen, Milk and Fatty Fish Intake
1.
Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D
status: United States, 2001-2006. NCHS Data Brief. 2011;Mar:1-8.
VIDSUN Questionnaire
• Most useful questions:
– Black race: Yes=0, No=1
– BMI ≥ 28.0: Yes=0, No =1
– Suntan within the past year: Yes=1, No=0
– Sun exposure past 3 mo: Never=0, Occ=1, Reg=2
– Sunscreen use: Always=1, Never=0
– Supplemental vit D intake > 400 IU/d: No=0, Yes= 1
• Score of  2.25 ≥ 89% sensitivity  35% specificity
*Nabak AC, Johnson RE, Keuler NS, Hansen KE. Can a questionnaire predict vitamin D status in
postmenopausal women? Public Health Nutr. 2014;17:739-746.
Recommendations for Ms. X
• Do not screen for vitamin D deficiency because she is at
low risk
• Counsel about dietary sources of vitamin D
• Start supplement in the winter and be sure there is
adequate calcium intake
• Counsel about sunscreen use and skin cancer risk
• If future bone density shows low bone mass, then I would
test for vitamin D deficiency
Reverend Bayes Meets the Vitamin D
Questionnaire
• Imagine that an individual has a 20% chance
of being vitamin D insufficient (prior probability 0.20)
• She fills out the questionnaire of Nabak et al.,
which indicates vitamin D insufficiency
• Her post-test probability of being vitamin D deficient
is <26% (because specificity <35%)
*Nabak AC, Johnson RE, Keuler NS, Hansen KE. Can a questionnaire predict vitamin D status in
postmenopausal women? Public Health Nutr. 2014;17:739-746.
Would you screen Ms. X for Vitamin D deficiency?
We would like to thank…
Our Patient, Ms. X
Gordon J. Strewler, MD & Alan Malabanan, MD
Risa Burns, MD, MPH
Deborah Cotton, MD, MPH
Howard Libman, MD
Eileen E. Reynolds, MD
Gerald Smetana, MD
Last Minute Productions
BIDMC Media Services
Lizzie Williamson
© 2016 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.