Vitamin D testing Review Report - the Medical Services Advisory

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MBS Reviews
VITAMIN D TESTING
REPORT
February 2014
February 2014
Table of Contents
Section
Page
LIST OF ABBREVIATIONS ............................................................................................................ 4
EXECUTIVE SUMMARY ..................................................................................................................................... 7
PURPOSE OF THE REVIEW ......................................................................................................................................... 7
VITAMIN D TESTING ................................................................................................................................................. 7
CONCERNS ABOUT VITAMIN D TESTING ................................................................................................................... 7
REVIEW METHODOLOGY .......................................................................................................................................... 8
STAKEHOLDER CONSULTATION ................................................................................................................................ 8
SUMMARY OF FINDINGS ........................................................................................................................................... 8
CONCLUSIONS ........................................................................................................................................................ 14
1 BACKGROUND ON VITAMIN D TESTING ......................................................................... 15
1.1
DESCRIPTION OF CURRENT SERVICES ........................................................................................................ 15
1.2
THE CLINICAL FLOWCHARTS ..................................................................................................................... 23
2 REVIEW METHODOLOGY ..................................................................................................... 24
2.1
SECONDARY DATA ANALYSIS .................................................................................................................... 24
2.2
GUIDELINE CONCORDANCE ....................................................................................................................... 24
2.3
SYSTEMATIC LITERATURE REVIEW FOR CLINICAL EVIDENCE..................................................................... 25
2.4
SYSTEMATIC LITERATURE REVIEW FOR ECONOMIC EVIDENCE .................................................................. 28
3 SECONDARY DATA ANALYSIS ............................................................................................. 29
3.1
MBS ITEM NUMBER USAGE AND EXPENDITURE ......................................................................................... 29
3.2
AGE AND GENDER PROFILE OF PATIENTS ................................................................................................... 32
3.3
FREQUENCY OF TESTING BY PATIENT ........................................................................................................ 33
3.4
PROFILE OF PROVIDERS REQUESTING VITAMIN D TESTING SERVICES ........................................................ 34
3.5
FREQUENCY OF REQUESTS FOR TESTING BY PROVIDER .............................................................................. 35
4 REVIEW OF GUIDELINES RELEVANT TO VITAMIN D TESTING............................. 37
4.1
AUSTRALIAN GUIDELINES ......................................................................................................................... 37
4.2
INTERNATIONAL GUIDELINES .................................................................................................................... 45
5 REVIEW OF THE CLINICAL EVIDENCE FOR VITAMIN D TESTING ....................... 51
5.1
EVIDENCE BASE ........................................................................................................................................ 51
5.2
PREVIOUS HEALTH TECHNOLOGY ASSESSMENTS OF VITAMIN D TESTING .................................................. 53
5.3
RELATIONSHIP BETWEEN VITAMIN D AND HEALTH OUTCOMES ................................................................. 54
5.4
RELATIONSHIP BETWEEN TESTING FOR VITAMIN D LEVELS AND HEALTH OUTCOMES ............................... 56
5.5
EVIDENCE OF THE DIFFERENTIAL CLINICAL UTILITY OF VITAMIN D TESTING ............................................ 56
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5.6
HARMS ASSOCIATED WITH VITAMIN D TESTING OR SUPPLEMENTATION .................................................... 56
5.7
EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION IN HEALTHY POPULATIONS ........................................ 57
5.8
EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION IN PATIENTS WITH CHRONIC DISEASE ......................... 58
5.9
OVERALL SUMMARY FROM THE CLINICAL EVIDENCE ................................................................................ 59
6 REVIEW OF THE ECONOMIC EVIDENCE RELATING TO VITAMIN D TESTING 61
6.1
EVIDENCE BASE ........................................................................................................................................ 61
6.2
COST IMPLICATIONS OF VITAMIN D TESTING ............................................................................................. 61
6.3
COST-EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION ......................................................................... 62
7 FINDINGS AND CONCLUSIONS ............................................................................................ 63
7.1
CURRENT USAGE OF VITAMIN D TESTING SERVICES IN AUSTRALIA ........................................................... 63
7.2
CLINICAL GUIDANCE ON VITAMIN D TESTING ........................................................................................... 64
7.3
RELATIONSHIP BETWEEN VITAMIN D AND HEALTH OUTCOMES ................................................................. 67
7.4
RELATIONSHIP BETWEEN TESTING FOR VITAMIN D LEVELS AND HEALTH OUTCOMES ............................... 67
7.5
EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION................................................................................... 68
7.6
HARMS ASSOCIATED WITH VITAMIN D TESTING OR SUPPLEMENTATION .................................................... 69
7.7
COST IMPLICATIONS OF VITAMIN D TESTING ............................................................................................. 69
7.8
CONCLUSIONS ........................................................................................................................................... 69
APPENDIX 1 – REFERENCES............................................................................................................ 71
APPENDIX 2 – REVIEW CONSULTATION COMMITTEE MEMBERS ............................................... 86
APPENDIX 3 – MBS INFORMATION ................................................................................................ 87
APPENDIX 4 – SEARCH TERM STRATEGY ...................................................................................... 88
APPENDIX 5 – TOOLS FOR ASSESSING THE EVIDENCE IN THE SYSTEMATIC REVIEW ................ 92
APPENDIX 6 – QUOROM FLOWCHART........................................................................................ 94
APPENDIX 7 - GRADING OF RECOMMENDATIONS ........................................................................ 95
APPENDIX 8 – SUMMARY OF INCLUDED STUDIES AND SYSTEMATIC REVIEWS........................... 96
APPENDIX 9 – REVIEW OF THE EFFECTIVENESS OF SUPPLEMENTATION IN HEALTHY PATIENT
POPULATIONS................................................................................................................................. 114
A9.1
EFFECT OF VITAMIN D SUPPLEMENTATION ON MUSCULOSKELETAL HEALTH .......................................... 114
APPENDIX 10 – REVIEW OF THE EFFECTIVENESS OF SUPPLEMENTATION IN PATIENTS WITH
CHRONIC DISEASE.......................................................................................................................... 136
A10.1 EFFECT OF VITAMIN D SUPPLEMENTATION ON OBESITY .......................................................................... 136
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LIST OF ABBREVIATIONS
1,25-(OH)2D
1,25 Dihydroxy vitamin D
25-(OH)D
25 Hydroxy vitamin D
µg
Microgram (unit of measurement)
ACHI
Australian Classification of Health Interventions
AHRQ
Agency for Health Research and Quality
AIHW
Australian Institute of Health and Welfare
BMC
Bone mineral content
BMD
Bone mineral density
BMI
Body mass index
BP
Blood pressure
CAD
Coronary artery disease
CHD
Coronary heart disease
CI
Confidence interval
CKD
Chronic kidney disease
CMFM
Comprehensive Management Framework for the MBS
CRC
Consultation Review Committee
CVD
Cardiovascular disease
CWG
Clinical Working Group
DBP
Diastolic blood pressure
DOES
Dubbo Osteoporosis Epidemiology Study
DRG
Diagnosis-related group
EAR
Estimated average requirements
EDSS
Expanded Disability Status Scale
ESC
Evaluation Sub-Committee (of MSAC)
grp
Group
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1,25-(OH)2D
1,25 Dihydroxy vitamin D
HTA
Health technology assessment
IFN
Interferon
IOM
Institute of Medicine
IR
Insulin resistance
ITT
Intention-to-treat
IU
International Unit
LC-MS
Liquid chromatography-mass spectrometry
MA
Meta-analysis
MI
Myocardial infarction
mm Hg
Millimetre of mercury
mos
Months
MS
Multiple sclerosis
MSAC
Medical Services Advisory Committee
MBS
Medicare Benefits Schedule
MESP
MSAC Expert Standing Panel
MRI
Magnetic Resonance Imaging
NHANES
National Health and Nutrition Examination Survey
NHMD
National Hospital Morbidity Database
NICE
National Institute for Health and Clinical Excellence
NIST
National Institute of Standards and Technology
nmol/L
Nanomole per litre (unit of measurement
NR
Not reported
NS
Not (statistically) significant
OHTAC
Ontario Health Technology Advisory Committee
OR
Odds ratio
PASC
Protocol Advisory Sub-Committee (of MSAC)
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1,25-(OH)2D
1,25 Dihydroxy vitamin D
PBS
Pharmaceutical Benefits Scheme
PICO
Population, intervention, comparator, outcome
PTH
Parathyroid Hormone
QUOROM
Quality of Reporting of Meta-analyses
RACGP
Royal Australian College of General Practitioners
RCPA QAP
Royal College of Pathologists of Australasia Quality Assurance Program
RCC
Research Consultation Committee
RCT
Randomised controlled trials
RDA
Recommended dietary allowance
RDI
Recommended daily intake
RR
Relative risk
SBP
Systolic blood pressure
SD
Standard deviation
SMD
Standard mean difference
SR
Systematic review
Subgrp
Subgroup
TGA
Therapeutics Goods Administration
US
United States
USPSTF
U.S. Preventive Services Task Force
UVB
Ultraviolet B
VA
Veterans Administration
VitD
Vitamin D
WHI
Women’s Health Initiative
Wks
Weeks
WMD
Weighted mean difference
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EXECUTIVE SUMMARY
In the 2011-12 Budget, the Australian Government announced a further commitment to the
Comprehensive Management Framework for the Medicare Benefits Schedule [MBS]
(CMFM), to continue the systematic review of MBS items to ensure that they reflect
contemporary evidence, improve health outcomes for patients and represent value for money.
MBS Reviews aim to ensure the clinical and financial sustainability of the MBS. Reviews
assess specific MBS services (i.e. MBS items) and associated policy issues in a focussed, fitfor-purpose, evidence-based process. Findings recognise that the MBS funding should align
with contemporary evidence, reflecting appropriate patient groups and best clinical practice.
The Reviews have a primary focus on improving health outcomes and the financial
sustainability of the MBS through the following criteria:

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assess patient safety risk;
identify services that have limited health benefit and/or are used inappropriately;
be evidence-based and fit-for-purpose;
be conducted in consultation with key stakeholders including, but not limited to, the
medical profession and consumers;
 include opportunities for public submission; and
 use Government resources efficiently.
Purpose of the review
This Review Report outlines the rationale behind conducting the review of the MBS items
relevant to vitamin D testing and the process undertaken to identify and appraise the available
information on the MBS items to ensure that they reflect contemporary evidence, improve
health outcomes for patients and represent value for money.
Vitamin D testing
Vitamin D is a lipid soluble vitamin that acts as a hormone. It is synthesised in the skin
through exposure to ultraviolet B light (UVB) radiation from sunlight and may also be
obtained from dietary sources and supplements. Vitamin D from sunlight exposure, diet or
supplements first undergoes a hydroxylation reaction in the liver, producing 25hydroxyvitamin D (25-(OH)D; also known as calcidiol). This is the major circulating form
and the metabolite routinely used to assess overall vitamin D status. Further hydroxylation
occurs in the kidney (and in other tissues) to form the hormonal and biologically active 1,25dihydroxyvitamin D (1,25-(OH)2D), also known as calcitriol.
There are two different assays for measuring serum levels of 25-(OH)D: liquid
chromatography-tandem mass spectrometry (LC-MS), which is referred to as the ‘gold
standard’ test, and commercial immunoassays either using radioactive markers or chemical
markers.
Concerns about vitamin D testing
There has been a significant increase in the number of claims and benefits paid for MBS item
numbers relating to vitamin D testing (increased by 4,600% over the last 10 years). There are
concerns that some patient groups may be tested for vitamin D levels unnecessarily and/or
more frequently than necessary.
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Review methodology
The review methodology comprised consulting with key stakeholders; developing a review
protocol document, which outlined the detailed review methodology (including specifying the
key clinical/research questions for the systematic review, preparing the clinical flowcharts,
and documenting the economic review strategy); analysing secondary data sources (MBS
data); conducting an evidence-based systematic literature review on vitamin D testing; and
undertaking an assessment and synthesis of all of the evidence to draw conclusions in relation
to the clinical/research questions.
Stakeholder consultation
Stakeholder engagement is a pivotal part of the MBS Reviews process, particularly as
feedback helps inform Review Reports. During the review process, stakeholders were
informed of the progress of the MBS items being considered. This included ensuring that
relevant documents were released for public consultation at the appropriate time and that
comments were incorporated into the review process.
As part of the MBS Review process, the Department established a Review Consultation
Committee (RCC). The RCC is a time-limited committee of nominated representatives,
established to provide advice to the Department. A list of RCC members is found at
Appendix 2.
Summary of findings
Current usage of vitamin D testing services in Australia
The number of MBS claims for vitamin D testing (item 66608 and 66609) has increased each
year over the past ten years, from 117,474 claims in 2003/04 to 4,331,030 claims in 2012/13.
This represents a 3,587% increase in vitamin D testing services. Over the same time period, a
similar increase (3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04
to $151,129,505 in 2012/13.
Over 98% of vitamin D testing services are for MBS item 66608. The proportion of services
bulk billed for this item from 2008/09 to 2012/13 was high (more than 95% of services),
which is consistent with the high proportion of out-of-hospital services for this item (over
98%). MBS item 66609 was listed on the MBS in May 2007. After a peak in services in
2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13). For
item 66609, over 85% of services were bulk billed from 2008/09 to 2012/13.
Between 2008/09 and 2012/13, the majority of all claims for item 66608 were from NSW and
Victoria; the other states and territories together accounted for less than 30% of total claims in
each year. Victoria had the highest rate of claiming per capita (25,267 claims per 100,000
population), followed by the ACT and NSW. The lowest per capita rates of vitamin D testing
services were in the northernmost states and territories (NT and Queensland). Item 66609
showed much more variability over time, and relatively high usage in Queensland as a
proportion of total claims. The highest number of claims per capita in 2012/13 was for
Tasmania and the ACT, while Victoria had the lowest.
Item numbers 66608 and 66609 are claimed by both genders; however, from 2008/09 to
2012/13, 70.2% of claims for MBS item 66608 and 68.9% of claims for item 66609 were for
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females. The number of claims is particularly significant for females aged between 24 and 84
years. Australian guidelines for general practice recommend that targeted vitamin D testing
should be considered for people who are at risk of osteoporosis and who are at high risk of
vitamin D deficiency. Prevalence estimates from Australia indicate that 31%-36% of adults
are deficient in vitamin D (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to
50%-62% in women during winter-spring or in people residing in southern states. The gender
imbalance and peak in testing for vitamin D levels within the 55-64 year age category is
consistent with epidemiological trends for vitamin D deficiency and osteoporosis. However,
the reason for the high rate of testing in the 45-54 year age category is less clear. An
examination of total services for MBS item 66608 in 2012/13 showed no difference in the
proportion of tests claimed in winter-spring (when the prevalence of vitamin D deficiency is
reported to be at its highest) compared with summer-autumn.
An analysis of vitamin D testing frequency per patient was conducted. The proportion of
patients who received only one test per year increased slightly over time for item 66608
(81.8% in 2008/09 and 83.4% in 2012/13), whereas the proportion of patients who received
two tests per year decreased from 14.8% to 13.9%, and the proportion of patients who
received three or more tests per year decreased from 3.4% to 2.8%. For item 66609, the
proportion of patients who received one or two tests per year was relatively stable over time
whereas the proportion of patients who received three or more tests decreased from 3.1% in
2008/09 to 2.1% in 2012/13. Taken together with the age profile of patients being tested,
these data suggest that the majority of vitamin D testing services are being undertaken for the
purposes of screening/testing rather than monitoring.
From 2008/09 to 2012/13, there were no material changes in the pattern of requesting
providers. GPs and other medical practitioners (OMPs) accounted for nearly two-thirds of all
providers requesting vitamin D testing services for item 66608. Internal medicine consultant
physicians accounted for another 15% of all provider counts, followed by a large variety of
other provider types. For item 66609, GPs and OMPs accounted for over 60% of all
providers requesting vitamin D testing services, followed by internal medicine consultant
physicians (approximately 28%).
An analysis of test requests for item 66608 by frequency from any one provider was
conducted. In 2012/13, the proportion of providers requesting ≤ 10 tests, 11-50 tests, and >
50 tests was 38.7%, 24.5%, and 36.8%, respectively. While the proportion of providers
requesting ≤ 10 tests has decreased since 2008/09, the proportion of providers requesting
more than 50 tests per year has increased. Each year, there is a small number of providers
who request over 400 vitamin D tests per year (682 in 2008/09 rising to 1,867 in 2012/13).
For item 66609, the proportion of providers requesting one test in 2012/13 was 64.1% (up
from 54.5% in 2008/09), whereas the proportion of providers requesting two or more tests per
year was 35.9% (down from 45.5% in 2008/09).
Taken together, these data show that there is a large and increasing number of providers,
primarily GPs and OMPs, who are requesting high volumes of vitamin D tests per year,
presumably for the purposes of screening/testing rather than monitoring.
Clinical guidance on vitamin D testing
The MBS data indicate that the majority of requests for vitamin D testing are initiated by GPs
and OMPs. The relevant College providing practice advice is the Royal Australian College of
General Practitioners (RACGP). Their 2012 guidelines for preventative activities in general
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practice advise that routine screening for vitamin D deficiency is not recommended in low
risk populations. However, targeted testing of people who are at risk of osteoporosis and who
are at high risk of vitamin D deficiency should be considered. High-risk groups for vitamin D
deficiency in pregnancy may also benefit from vitamin D screening. The guidelines do not
advise on the frequency of testing.
The RACGP has also produced a 2010 clinical guideline for the prevention and treatment of
osteoporosis in postmenopausal women and older men. Serum 25-(OH)D is one of the
recommended laboratory tests for the diagnostic assessment for osteoporotic fractures, but
only under particular conditions (e.g. if secondary osteoporosis is suspected).
The Royal College of Pathologists of Australasia (RCPA) released a Position Statement in
May 2013 for the use and interpretation of vitamin D testing. The Position Statement
recommended testing for vitamin D status in individuals at risk of vitamin D deficiency and
showing the following indications:

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
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

signs, symptoms and/or planned treatment of osteoporosis or osteomalacia;
increased alkaline phosphatase with otherwise normal liver function tests;
hyperparathyroidism, hypo- or hypercalcaemia or hypophosphataemia;
malabsorption (e.g. cystic fibrosis, short bowel syndrome, inflammatory bowel disease,
untreated coeliac disease, bariatric surgery);
deeply pigmented skin, or chronic or severe lack of sun exposure for cultural, medical,
occupational or residential reasons;
medications known to decrease vitamin D levels (mainly anticonvulsants); and
chronic renal failure and renal transplant patients.
The Position Statement states that routine testing for vitamin D status in the general
population (including healthy adults, pregnant women, and children) is not currently
recommended. However, it recommended that serum vitamin D levels be retested after three
months following the commencement of vitamin D supplementation. No further testing is
required once desirable 25-(OH)D target levels are achieved. The Position Statement
recommended against high dose annual replacement of cholecalciferol. The Statement
recommended that the target level of serum 25-(OH)D should be >50 nmol/L at the end of
winter.
The Working Group of the Australian and New Zealand Bone and Mineral Society
(ANZBMS), Endocrine Society of Australia and Osteoporosis Australia released a position
statement in 2012 that recommended screening for 25-(OH)D levels in high-risk groups,
defined as:

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older or disabled people in low-level and high-level residential care;
dark-skinned people of either sex, particularly migrants and/or if modest dress is worn;
people with a disability of chronic disease (e.g. multiple sclerosis);
fair-skinned people and those at risk of skin cancer who avoid sun exposure;
obese people; and
people working in an enclosed environment.
The position statement advised for retesting of vitamin D levels three months after
commencement of supplementation.
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In 2013, the Working Group of the ANZBMS and Osteoporosis Australia also released a
position statement on vitamin D and health in pregnancy, infants, children and adolescents.
The position statement advised that universal screening for vitamin D status in pregnant
women, infants, children and adolescents is not supported by the evidence. However, 25(OH)D levels should be tested in those with one or more risk factors for low vitamin D,
defined as:




lack of skin exposure to sunlight (due to lifestyle factors, chronic illness or hospitalisation,
covering clothing or southerly latitude);
dark skin;
medical conditions (obesity, end-stage liver disease, renal disease) or medications
affecting vitamin D metabolism and storage; and
in infants, maternal vitamin D deficiency and exclusive breastfeeding combined with at
least one other risk factor.
Infants, children and adolescents with ongoing risk factors require ongoing monitoring of
vitamin D status with annual testing. Pregnant women with risk factors should be tested at
their first antenatal visit and again at 28 weeks’ gestation. For neonates with moderate or
severe deficiency, follow-up testing is recommended at one month after commencement of
vitamin D supplementation; in other groups, follow-up at three months is usually more
practical; and in the long term, annual testing is recommended. Very frequent testing should
be avoided.
In 2012, Kidney Health Australia published CARI (Caring for Australasians with Renal
Impairment) guidelines on vitamin D therapy in early kidney disease. The guidelines
recommend that patients with early chronic kidney disease on vitamin D therapy have their
25-(OH)D levels monitored regularly. Further details on the frequency of testing are not
provided.
The identified Australian guidelines are consistent with international guidelines that
recommend against routine screening for vitamin D status in adults, pregnant women and
children. However, there are guidelines that support screening in high-risk individuals
(although definitions of at-risk were lacking in these guidelines), and testing vitamin D status
in populations with known poor bone health (such as children with skeletal fragility and
adults with osteoporosis). Follow-up testing is also recommended in people being treated
pharmaceutically for osteoporosis (at 3-4 months after commencement of therapy).
Recommendations against routine screening are consistent with the lack of direct evidence
that vitamin D testing improves outcomes, as well as the lack of moderate or high quality
evidence that supplementation improves outcomes in healthy populations. Recommendations
for testing in populations with known poor bone health are weakly supported by evidence of
the effectiveness of supplementation in these populations, but there is no direct evidence
concerning the clinical utility of testing (see below).
Several guidelines mention that measurement of serum 25-(OH)D is the best way of
estimating vitamin D status, due to its relatively long half-life. Immunoassays are often
automated and are therefore cheaper and faster; however, a weakness is the inability to
quantify vitamin D2 and vitamin D3 separately. LC-MS is more sensitive than immunoassay
but is also more labour intensive and requires expensive equipment and skilled staff.
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The performance of radioimmunoassay is generally considered to be acceptable; however, the
bias and imprecision of many automated methods may be problematic at the lower, clinically
and analytically important range (< 50 nmol/L) of the assay. Prior to the recent introduction
of the standard reference material for 25-(OH)D from the National Institute of Standards and
Technology (NIST), there were numerous publications reporting that different immunoassays
may be yielding different results. However, the introduction of the reference standard has
helped to assess the accuracy of the different immunoassays and provide more reliable results.
All Australian and New Zealand laboratories offering 25-(OH)D testing are required to be
enrolled in external proficiency programs.
Relationship between vitamin D and health outcomes
The evidence suggests a harmful association of serum 25-(OH)D with cancer mortality in
men, but a protective association of serum 25-(OH)D with bone health, cardiovascular health,
type 2 diabetes, colorectal cancer, ovarian cancer and all-cause mortality. The link between
serum 25-(OH)D and cancer (other than colorectal or ovarian) is unclear. There is insufficient
evidence regarding an association of serum 25-(OH)D with obesity, gestational diabetes,
multiple sclerosis, depression and mood disorders.
For disease outcomes where a link has been demonstrated, the evidence does not support
definitive cut-off points at which 25-(OH)D serum levels can be expected to predict optimal
overall health. However, the evidence is consistent with approximately 30 nmol/L as the
level below which there is a risk of deficiency and a threshold ≥ 50 nmol/L, and possibly as
high as 70 nmol/L, for optimal health. Optimal thresholds may vary by the outcome of
interest.
There is very sparse evidence for an association between serum levels of 25-(OH)D and
disease-related outcomes in individuals with chronic disease. Vitamin D screening may have
promise for establishing a prognosis in patients with colon cancer, prostate cancer or
melanoma and for assessing the risk of disease-related events and complications in patients
with hypertension and diabetes; however, the evidence is too sparse to support clinical rules
or cut-off points.
Relationship between testing for vitamin D levels and health outcomes
No trials designed to measure the effect of vitamin D screening or testing on health outcomes,
patient behaviour or clinical decisions were identified. Therefore, trials of vitamin D
supplementation were reviewed as an indication of the potential utility of vitamin D
screening/testing. The rationale was that screening or testing would not improve health
outcomes if there were no effective treatment that could be recommended for individuals with
low serum vitamin D.
Due to a lack of studies directly evaluating the effectiveness of testing, differential
effectiveness and safety by type of assay, frequency of monitoring and time of year that tests
are conducted could not be directly evaluated.
Effectiveness of vitamin D supplementation
A good quality Health Technology Assessment (HTA) published in November 2012 for the
Washington State Health Care Authority evaluated the effect of vitamin D supplementation in
healthy populations (without symptoms or findings of the outcome of interest) and
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populations with chronic disease that may be linked with, but does not cause, vitamin D
insufficiency.
The effect of vitamin D supplementation on outcomes in healthy populations was evaluated in
six systematic reviews and 14 randomised controlled trials (RCTs). Participants were not
selected on the basis of vitamin D test results. The evidence base was generally considered to
be of low quality, except for moderate-quality evidence regarding prevention of mood
disorders. Common weaknesses included variable vitamin D doses across studies and varied
protocols with respect to the use of non-study vitamin D. Where the evidence suggested a
benefit, the effects were small.
In summary, the evidence suggests positive effects of supplementation on musculoskeletal
health and general mortality in older adults. Evidence regarding the effectiveness of
increased vitamin D intake through supplementation does not, in general, support vitamin D
screening to improve non-skeletal health outcomes other than mortality.
The effect of supplementation on disease-related outcomes in patients with chronic disease
was evaluated in three systematic reviews and 16 RCTs. Participants were not selected on the
basis of vitamin D test results. The evidence was considered to be of low to moderate quality.
Even in the disease populations where the evidence showed a benefit, the effects were
generally small and the clinical relevance was questionable.
An exception was the effect of active vitamin D supplementation on bone health in older
adults with osteoporosis or a history of fracture. On the basis of a moderate body of evidence
showing benefit of supplementation in this population, the HTA concluded that vitamin D
testing in patients who have evidence of osteoporosis has the potential to improve bonerelated outcomes. Given the evidence showing supplementation to modestly improve diseaserelated outcomes in individuals with cardiovascular disease or abnormal blood glucose,
vitamin D screening to assess the risk of adverse disease outcomes might also be effective in
these populations. The available evidence regarding the effectiveness of increased vitamin D
intake through supplementation does not, in general, support screening in other disease
populations.
On the basis of the available evidence for supplementation and associations between serum
25-(OH)D and health outcomes, knowledge of vitamin D serum levels might have value:
(1) to demonstrate the need for supplementation in postmenopausal women as a means of
reducing disease and mortality risk (based on low quality evidence); and
(2) to inform treatment for individuals with known or highly suspected osteoporosis (based
on moderate quality evidence).
Harms associated with vitamin D testing or supplementation
Testing for vitamin D status is a relatively safe procedure that relies on a blood draw. The
consequences of inaccurate or inappropriately interpreted test results (false negative and false
positive tests) are relatively small considering that vitamin D supplementation provides
relatively modest effects and is a relatively safe therapy (albeit through low or moderate
quality evidence).
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Cost implications of vitamin D testing
As no trials have assessed the effectiveness of vitamin D testing itself, a cost-effectiveness
analysis of vitamin D testing is not possible. One poor-quality cost analysis of vitamin D
testing was identified, which was based on a retrospective chart review of Veterans Medical
Centers in the United States. There was no comparison of costs between individuals who had
no vitamin D testing at all and those who had one or more tests.
Three cost-effectiveness studies of vitamin D supplementation were identified, all relating to
the prevention of fractures and/or falls in older adult populations. The studies were generally
well designed and the evidence was considered to be of moderate quality. However, the
selected studies did not consider vitamin D testing to be one of the costs associated with
supplementation. The studies provide consistent evidence that suggests that routine
supplementation in older populations reduces costs associated with hip fracture. In that case,
there is no need for vitamin D screening to identify subpopulations in whom there is a
potential for such cost savings. For other populations and outcomes, there is no evidence
relating to the cost implications of vitamin D testing or screening.
Conclusions
There has been a substantial increase in the number of claims for vitamin D testing over the
past ten years. Analysis of MBS data indicates that the majority of vitamin D testing services
are requested by GPs and OMPs for the purposes of screening or testing, rather than followup monitoring. Australian and international clinical practice guidelines recommend against
routine screening for vitamin D status in adults, pregnant women and children. However,
screening is supported in individuals at high risk of vitamin D deficiency (particularly
pregnant women and paediatric populations) and testing is supported in populations with
known poor bone health (such as children with skeletal fragility and adults with osteoporosis).
Follow-up testing at 3-4 months is also recommended in people with osteoporosis or chronic
kidney disease being treated pharmaceutically. Recommendations for testing in populations
with known poor bone health are weakly supported by evidence of the effectiveness of
supplementation in these populations, but there is no direct evidence concerning the clinical
utility of testing in any population.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
1
BACKGROUND ON VITAMIN D TESTING
1.1
Description of current services
This section describes vitamin D and vitamin D testing, recommended vitamin D status, and
the population groups and clinical conditions/risk factors in which vitamin D testing is
recommended.
1.1.1
Vitamin D, metabolism and function
Vitamin D is a lipid soluble vitamin that acts as a hormone.(1) It is synthesised in the skin
through exposure to ultraviolet B light (UVB) radiation from sunlight(2) and may also be
obtained from dietary sources and supplements.(3) There are two forms of vitamin D(4):


vitamin D2 (also known as ergocalciferol), which is present in plants (e.g. mushrooms);
and
vitamin D3 (also known as cholecalciferol), which is the main form obtained from animal
sources (such as some fish) and exposure to sunlight.(5) Vitamin D supplements are
composed of the D3 form and are manufactured by the irradiation of 7-dehydrocholesterol
extracted from lanolin found in sheep's wool.(6)
Figure 1.1 shows that cutaneous synthesis of vitamin D is triggered by the skin’s exposure to
UVB (wavelength 290-315 nm), which converts 7-dehydrocholesterol present in the skin into
pre-vitamin D3, which is then converted into vitamin D3.(3) Experimental data indicates that
exposure of around 15% of the body surface (arms and hands or equivalent) near the middle
of the day will result in the production of about 1000 IU (25 μg) of vitamin D. Achieving this
exposure on most days should generally, though not always, be sufficient to maintain vitamin
D levels in the body.(7) Factors such as seasons and latitude can play a role in vitamin D
synthesis, for example less vitamin D is synthesised in winter, particularly at latitudes further
from the equator.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Figure 1.1: Synthesis of vitamin D
Vitamin D3 (oily fish, supplements)
Vitamin D2 (mushrooms)
Source: adapted from http://gardenofeaden.blogspot.com.au/2012/02/what-is-vitamin-d-deficiency.html
Vitamin D from diet, supplements, or sunlight exposure first undergoes a hydroxylation
reaction in the liver (Figure 1.1), producing 25-hydroxyvitamin D (25-(OH)D; also known as
calcidiol or calcifediol). This is the major circulating form and the metabolite routinely used
to assess overall vitamin D status. Further hydroxylation occurs in the kidney to form the
hormonal and biologically active 1,25-dihydroxyvitamin D (1,25-(OH)2D), also known as
calcitriol.(5) This hydroxylation step can also occur in other tissues.(2, 8) The renal synthesis of
1,25-dihydroxyvitamin D is regulated by plasma parathyroid hormone (PTH), serum calcium
and phosphorus levels.(9)
The active compound of vitamin D promotes intestinal calcium and phosphate absorption and
is important in maintaining adequate calcium levels for bone mineralisation, bone growth and
remodelling, and to prevent hypocalcaemic tetany (i.e. this is an uncommon condition caused
by an abnormally low level of calcium in the blood).(1, 3, 10) Serum PTH has an inverse
correlation with absorbed calcium.(11) Vitamin D deficiency reduces the efficiency of calcium
absorption from the intestines and therefore indirectly results in increased serum PTH(11),
which may lead to the mobilisation of calcium from the bone.(12)
1.1.2
Vitamin D dietary sources, fortification and supplements
Vitamin D (D3) is naturally present in small quantities in certain foods such as fatty fish
(salmon, herring, tuna, sardines, etc.), egg yolks, fish liver oil, and certain types of
mushrooms (see Table 1.1).(3, 13) However, most adults are unlikely to obtain more than 5%–
10% of their vitamin D requirement from dietary foods and is therefore insufficient to meet
daily requirements.(14) Thus, most vitamin D is obtained from exposure to sunlight, some
fortified or unfortified foods, and/or vitamin D supplements.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Table 1.1: Dietary sources of vitamin D(3)
Type of food
Salmon (fresh, farmed), 99 grams
Estimated vitamin D content
100-250 IU vitamin D3
600 – 1,000 IU vitamin D3 (wild)
250 IU vitamin D3
Mackerel (canned), 99 grams
Cod liver oil, 1 teaspoon (also 400-1,000 IU vitamin D3
contains vitamin A)
230 IU vitamin D3
Tuna (canned), 100 grams
Shiitake mushrooms (fresh), 100 100 IU vitamin D2 (fresh)
1,600 IU vitamin D2 (sun-dried)
grams
20 IU vitamin D3 or D2
Egg yolk (1 unit)
Food fortification is defined as the process of adding micronutrients, such as vitamins and
minerals, to food as permitted by the Food Standards Code.(15) Regulations regarding the
fortification of foods with vitamin D vary between countries. In Australia, mandatory
fortification regulations require the addition of vitamin D to margarines and spreads.(15) In
Canada, which has similar regulations to the United States, vitamin D fortification of milk
(including evaporated and powdered milk), soy milk and margarine is mandatory.(13) One
serving (250 mL) of milk contains approximately 44% of the 200 IU adequate daily intake of
vitamin D.(13) Vitamin D fortification is also permitted for orange juice, meal replacements,
nutritional supplements and formulated liquid diet.(13, 16) However, a large proportion of the
American and Canadian populations are vitamin D deficient, indicating that limited
fortification has little impact at a population level.(13, 17)
It is acknowledged that the current (2006) guidelines for recommended dietary intakes (i.e.
adequate intakes) of vitamin D in Australia and New Zealand(18) are out of date.(19) The
recently revised recommended daily allowances (RDAs) for vitamin D in the US are 600 IU
(15 micrograms) for people aged 1–70 years and 800 IU (20 micrograms) for those aged ≥ 71
years, with an upper limit (that includes a generous safety factor) of 4000 IU (100
micrograms).(20)
Vitamin D synthesis through the skin can be influenced by several factors, such as number of
sunshine hours, time of day, season, latitude and skin colour (due to the amount of melanin in
skin). All these factors determine the amount of UBV that reaches the skin. The season is an
important predictor of serum 25-(OH)D levels.(21, 22) In an Australian study that looked at
three populations of women in three locations across Australia and covering a broad
latitudinal range (Tasmania, Geelong and Queensland), vitamin D insufficiency was common
in winter and spring regardless of latitude.(22) However, latitude plays a significant role in
serum 25-(OH)D levels, and higher prevalence of vitamin D deficiencies is reported in people
living at increasing distances from the equator.(23)
Vitamin D toxicity is a rare condition that can be caused by excess oral or intramuscular
administration of vitamin D. The current policy of the Institute of Medicine (IOM) has set the
tolerable upper intake level for vitamin D at 100 micrograms (4000 IU)/day, defining this as
“the highest level of daily nutrient intake that is likely to pose no risks of adverse health
effects to almost all individuals in the general population”.(20) Vitamin D toxicity cannot be
caused by prolonged exposure of the skin to sunlight, which produces 25-(OH)D amounts
equivalent to daily oral consumption of 250 micrograms (10,000 IU)/day The main
symptoms with hypervitaminosis D are hypercalciuria (i.e. a condition of elevated calcium in
the urine), hypercalcaemia (i.e. a condition of elevated calcium in the blood), and calcification
MBS Reviews – Vitamin D Testing Review Report
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February 2014
of soft tissues and kidney.(24) Hypercalcaemia is not seen until serum 25-(OH)D
concentrations have consistently been above 375–500 nmol/L.(25, 26)
1.1.3
Rationale for testing, monitoring and screening
There are a number of clinical factors that suggest the potential for vitamin D insufficiency or
deficiency and thus may be indicators for vitamin D testing.(90(27) Relevant conditions include
poor nutrition, malabsorption due to gastrointestinal disease or malabsorptive bariatric
surgery, hepatic dysfunction, and renal dysfunction or age-related renal changes. Laboratory
findings may also indicate possible vitamin D deficiency, for example low urine calcium
excretion, low serum calcium, low serum phosphorous, elevated parathyroid hormone level,
and elevated alkaline phosphatase. Radiographic findings that might raise suspicion of
deficiency include osteopenia, osteoporosis, nontraumatic fracture and skeletal
pseudofracture.(27) Repeat testing (monitoring) may be undertaken in some patients with a
serious chronic condition, such as chronic renal disease, to assess the impact of replacement
therapy.
In the absence of clinical indicators, vitamin D testing is considered to be screening. The
purpose of screening for vitamin D status is to assess the need to improve the patient’s status
as a preventive measure against health problems.(90(27) When screening is undertaken in
populations defined by the presence of disease (e.g. cancer), the purpose is to assess the need
to improve vitamin D status as a means to improve disease-related outcomes. When
screening is undertaken in healthy populations, it could be universal (routine) or based on
demographic or lifestyle factors associated with low serum vitamin D (i.e. high risk
populations). This review seeks to assess evidence for the utility of vitamin D testing and
screening.
1.1.4
The vitamin D test
A vitamin D test measures 25-(OH)D, the major circulating metabolite to assess vitamin D
status. The 25-(OH)D metabolite has an estimated half-life of approximately two to three
weeks,(5, 28, 29) and provides a measure of the vitamin D originating from both cutaneous
production and dietary/supplement sources.(5) Vitamin D stored in other body tissues is,
however, not reflected in the serum 25-(OH)D levels.(5) 1,25-dihydroxyvitamin D has a halflife of 15 hours and therefore serum levels of this metabolite do not accurately indicate an
individual’s vitamin D status. Since it is closely regulated by PTH and the intake of calcium
and phosphate, serum levels of 1,25-dihydroxyvitamin D(5, 13) may be normal in individuals
with vitamin D deficiency(30) and be elevated in vitamin D excess(31).
There are two different assays for measuring serum levels of 25-(OH)D(32-34):


Liquid chromatography-tandem mass spectrometry (LC-MS): this is a sensitive and
reasonably specific method (with some cross reactivity with the epimer 3-epi 25(OH)D3)(35) for the detection of 25-(OH)D (in its two analyte forms D2 and D3) based on
their respective chemical properties. This method has been referred to as a ‘gold standard’
test, but it is slow and requires expensive equipment and skilled staff.
Commercial immunoassays either using radioactive markers or chemical markers:
these are automated immunoassays (e.g. the Abbott Architect, Diasorin Liaison and the
Siemens Centaur) to measure total vitamin D levels. These assays may be cheaper and
quicker to conduct (about half the cost of liquid chromatography). Most are less sensitive
as they do not distinguish between the two metabolites of vitamin D.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
It is not clear from the literature if the detection of both D2 and D3 metabolites has any clinical
relevance. A systematic review and meta-analysis comparing vitamin D2 and D3
supplementation in raising serum 25-(OH)D status indicated that vitamin D3 is more
efficacious at raising serum 25-(OH)D concentrations than is vitamin D2.(36) Moreover, some
current automated immunoassays have a limited capacity to detect 25-(OH)D2.(37) It is
currently accepted in Australia that total 25-(OH)D measurement is appropriate to judge a
patient’s vitamin D status.(38)
1.1.5
Concerns about the accuracy and precision of vitamin D tests
Different immunoassays are readily available for measurement of 25-(OH)D3. Prior to the
recent introduction of the standard reference material for 25-(OH)D, called SRM 972,
introduced from the National Institute of Standards and Technology (NIST)(39), there were
numerous publications reporting that different immunoassays may be yielding different
results, with inter-assay variation reaching up to 25% at low serum 25-(OH)D levels (15
nmol/L).(28, 38) However, the introduction of the reference standard helps to assess the
accuracy of the different immunoassays for the measurement of 25-(OH)D in serum and can
serve as an adjunct to quality assurance programs for vitamin D measurements.(40)
The performance of radioimmunoassay and enzyme-linked assays is acceptable; however, the
bias and imprecision of many automated methods may be problematic at the lower, clinically
and analytically important range (< 50 nmol/L) of the assay. (19) The new reference standard is
available at four different concentrations (called Level 1 – Level 4 by the manufacturer).(39)
The first SRM 972 concentration (Level 1) is prepared from “normal” human serum and is the
only standard that has not been altered through dilutions or enrichments (59.6 nmol/L). The
second concentration (called Level 2) was prepared by diluting Level 1 with horse serum to
achieve a lower 25-(OH)D concentration, whereas Level 3 and Level 4 had 25-(OH)D3 added
to them.(39) The development of this reference standard for vitamin D in blood serum has
assisted laboratories to validate the accuracy of their test methods, as well as to validate new
analytical methods as they are developed.(40)
In addition, all Australian and New Zealand laboratories (including those offering 25-(OH)D
testing) are required to be enrolled in external proficiency programs (such as the Royal
College of Pathologists of Australasia Quality Assurance Program (RCPAQAP), which allow
each laboratory to monitor its performance compared with its peers.(19) These standardisation
efforts are essential to the reliable diagnosis, evaluation and treatment of vitamin D deficiency
in a population and help clinicians to more accurately interpret the results from vitamin D
testing.(41)
1.1.6
Serum vitamin D target values
Some evidence suggests that optimal mineral metabolism, bone density and muscle function
is achieved at serum 25-(OH)D concentrations of greater than 50-60 nmol/L(42-45). However,
an optimal serum concentration of vitamin D has not been established and this value may vary
across different stages of life.(5) Some authors believe that target serum levels should be
above 50 nmol/L(1, 3, 10, 28, 29), while others believe that it should be above 75 nmol/L.(2, 3, 5, 29,
46)
. One study indicated that 25-(OH)D concentrations <75 nmol/L showed increased
unmineralised bone matrix, making this value an appropriate cut-off for optimal bone
health.(47) This, however, may require vitamin D supplementation.(10)
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February 2014
Vitamin D deficiency is defined as serum 25-(OH)D levels below 25 nmol/L(3, 4, 28), based
primarily on the risk of rickets in infants and osteomalacia in adults.(48) Mild vitamin D
deficiency is defined as a serum level below 50 nmol/L.(19) Severe deficiency has been
defined as a serum level below 12.5 nmol/L.(1, 2, 10) Table 1.2 summarises serum vitamin D
concentrations and health.
Table 1.2: Serum 25-(OH)D concentrations reflective of vitamin status(19, 45)
Vitamin D status
Optimal
Sufficient
Mild deficiency (49)
Moderate deficiency (50)
Severe deficiency
Serum vitamin D concentrations nmol/L*
>75
50 – 75
25 – 49
12.5 – 24
< 12.5
*1 nmol/L = 0.4 ng/mL
1.1.7
Prevalence of vitamin D deficiency in Australia
Two publications have attempted to measure the prevalence of vitamin D deficiency in the
Australian population. The first study was conducted by the Baker IDI Heart and Diabetes
Institute.(51) The population included 11,218 adults aged 25-95 years. The study reported that
4% of the Australian population had severely deficient vitamin D levels (defined as serum 25(OH)D levels < 25 nmol/L) and an estimated 31% of adults in Australia have inadequate
vitamin D status (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to 50% in
women during winter-spring and in people residing in southern states. Individuals at greatest
risk for deficiency were identified to be women, the elderly, the obese, people doing less than
2.5 hours of physical activity a week, and people of non-European background.
The second study assessed 24,819 ambulant and inpatient samples taken from a large
reference laboratory in NSW between 1st July 2008 and 30th July 2010.(52) This crosssectional study reported that 36% of subjects overall were deficient in vitamin D (defined as
serum 25-(OH)D levels < 50 nmol/L), and this increased to 58% in spring. The highest
prevalence of deficiency occurred in female inpatients (42% in summer and 62% in spring).
Factors associated with lower 25-(OH)D included being tested in spring, an inpatient, female,
aged 20–39 years or over 79 years, socioeconomically disadvantaged, and from a major city.
1.1.8
Conditions that may cause vitamin D deficiency
There are several factors reported in the literature that can cause vitamin D deficiency in a
diverse group of individuals. Table 1.3 summarises the risk factors for vitamin D deficiency.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Table 1.3: Risk factors for vitamin D deficiency(5)





Reduced sun
exposure
Elderly(53)
Darker skin
pigmentation(54)
Winter
season(55)
Indoor
workers(19)
People who
habitually wear
long sleeves,
protective
clothing, or
stay in the
shade(56)
1.1.9
Dietary intake

Exclusive
breastfeeding
(risk for the
infant)(57)
Age and disease conditions







Obesity(58)
Older age worsened by immobility and aging
kidneys(59)
Chronic kidney disease(60, 61)
Malabsorption syndromes/other conditions :
Crohn’s disease, cystic fibrosis, severe liver
disease(62)
Drug interactions: anticonvulsants, cimetidine,
thiazides, corticosteroids(63, 64)
Drugs that decrease absorption: mineral oil,
laxatives orlistat, cholestiramine, etc(65)
Genetics: Indo-Asians(66), individuals with generic
variants influencing vitamin D status (67)
Incidence and prevalence of diseases relevant to the vitamin D testing review
Table 1.4 presents the incidence and prevalence of clinical conditions relevant to vitamin D
testing.
Table 1.4: Incidence and prevalence of conditions relevant to vitamin D testing
Condition
Osteoporosis
Description
The condition where bone is lost at a higher rate than its
replacement, causing loss of bone mineral density(68)
Osteomalacia Softening of bones, inadequate mineralisation of bone
matrix caused by vitamin D deficiency(5, 70)
Vitamin D deficiency in children resulting in
Rickets
inadequate bone mineralisation and softening of the
growth plate, leading to soft bones, skeletal
deformities and growth retardation(71)
Chronic
kidney
disease
Crohn’s
Refers to all conditions of the kidney, lasting at least three
months, where a person has had evidence of kidney
damage and/or reduced kidney function, regardless of the
specific diagnosis of disease or condition causing the
disease. There are five stages depending on the level of
damage(73)
A form of inflammatory bowel disease, usually affecting
MBS Reviews – Vitamin D Testing Review Report
Prevalence/incidence
692,000 cases (3.4% of
the total population);
occurs mainly in people
aged 55 years and over
(84.0%), with women
accounting for the
majority of all cases
(81.9%)(69)
Data on prevalence is
not available
Australian
Paediatric
Surveillance Unit
(APSU) study
suggests that the
overall incidence in
children ≤ 15 years
of age in Australia
is 4.9/100
000/year(72)
Stages 1-2: 5.6%(73)
Stages 3-5: 7.8%(73)
29.3/100,000 (incidence
Page 21
February 2014
Condition
disease
Coeliac
disease
Cystic
fibrosis
Description
the intestines, but may occur anywhere from the mouth to
the end of the rectum(74)
An autoimmune disease affecting the intestines and
resulting in chronic inflammation of the gastrointestinal
tract(74)
A genetic disease affecting the secretory organs, causing
thick, sticky mucus to build up in the lungs, digestive
tract, and other areas of the body. It is one of the most
common chronic lung diseases in children and young
adults(77)
Prevalence/incidence
rate)(75)
1% prevalence(76)
3,200 cases
(prevalence)(78)
There is an increasing number of medical conditions associated with low vitamin D status.
Prolonged vitamin D deficiency causes rickets in children(48) and osteomalacia in adults.(5)
Other symptoms associated with vitamin D deficiency include bone pain and muscle
weakness, although the mechanisms are not clear.(79)
Vitamin D deficiency is classified as one of the risk factors for osteoporosis.(69) Even though
osteoporosis does not cause death, osteoporotic fractures can, however, lead to premature
death among the elderly. In 2007, osteoporosis was listed as the underlying cause of 240
deaths in Australia. Fractures of hip and pelvis (40.5%) and wrist and forearm (17.1%) were
the most common sites of minimal trauma fractures in 2007–08. The total direct health
expenditure for osteoporosis in 2004-05 was $304 million (Table 2.5). Over 70% of this was
spent to cover the cost of pharmaceutical medicines ($215 million). Surgical and non-surgical
procedures to treat fractures in hospitals constitute another large component of this outlay
($35 million, 11.5%).
Table 1.5: Direct health expenditure for osteoporosis, 2000-01 and 2004-05(69)
Health service area
Admitted patient services
Out-of-hospital medical services
Prescription pharmaceuticals
Research
Total
2000-01
$31.8 m
$29.4 m
$75.5 m
$2.6 m
$139.3 m
2004-05
$35.0 m
$47.3 m
$215.0 m
$7.0 m
$304.3 m
Percent growth
10.1
60.8
184.8
169.2
118.5
Source: AIHW 2009. AIHW Disease Expenditure Database
Data collected in the world’s longest running epidemiological study of osteoporotic fractures
in men and women, the Dubbo Osteoporosis Epidemiology Study (DOES), and which
included more than 2,500 men and women aged 60 years or more from the Australian
regional city of Dubbo, showed that osteoporotic fracture affects 44% of women and 25% of
men in Australia.(80) In addition, re-fractures contributed substantially to overall mortality
associated with fracture. The majority of mortality and re-fractures occurred in the first five
years following the initial fracture. The study reported that 24% of women and 20% of men
with incident fracture had a re-fracture within five years. Of those who had an incident
fracture, 26% of women and 37% of men died without re-fracture. Of those who re-fractured,
a further 50% of women and 75% of men died. Therefore, the total five-year mortality was
39% in women and 51% in men.(80)
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1.1.10 Service providers claiming MBS benefits for vitamin D testing
Most pathology in Australia is provided in comprehensive laboratories that provide a wide
range of testing services at a single location. Only approved pathology practitioners are
eligible to claim MBS items for vitamin D testing.
1.2
The clinical flowcharts
The clinical decision pathway that determines whether vitamin D testing should be
undertaken is provided in Figure 1.1.
Figure 1.1: Clinical flow chart for vitamin D testing
Patient presents to General Practitioner
Does the patient have any of the following risk factors associated with
vitamin D deficiency?
Does the patient have any of the following clinical symptoms of
vitamin D deficiency?
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Widespread bone pain or tenderness
Nonspecific myalgia
Myalgia on strain
Proximal muscle weakness
Non-stress fracture
Stress fracture e.g. femoral neck, scapula, ribs or vertebrae
Rickets
Low serum calcium or high Alkaline Phosphatase
Low serum phosphate
Low bone density on DEXA or osteopenia on x ray
Yes
Measure serum Vitamin D
Claim MBS item numbers
66608 or 66609
No Yes
No
Is Vitamin D testing medically
necessary?
Yes
Housebound or in residential aged care facility
Patients >65
Indoor worker
Long sleeve clothing, staying in the shade
Dark skinned
Vegetarians
Diabetes
Renal/liver disease
Pregnancy or breast feeding
Gastrointestinal disorders e.g. Crohn’s, Coeliac, gastrectomy
Obesity
Is Vitamin D testing medically
necessary?
No
No MBS claim for vitamin
D testing
No
No MBS claim for vitamin
D testing
MBS Reviews – Vitamin D Testing Review Report
Is Vitamin D testing medically
necessary?
Yes
Measure serum Vitamin D
Claim MBS item numbers
66608 or 66609
No
No MBS claim for vitamin
D testing
Page 23
February 2014
2
REVIEW METHODOLOGY
The review methodology comprises an analysis of secondary data (e.g. MBS claims), a
guideline concordance analysis, and a systematic literature review for clinical and economic
evidence. This Chapter presents clinical research questions and the methodology used for
each of these review components.
2.1
Secondary data analysis
Data from Medicare Australia were analysed to determine whether the existing MBS item
numbers for vitamin D testing (66608 and 66609) are appropriate.
2.1.1
The research questions for the MBS analysis
The MBS data were examined to determine:
(1) Whether the existing MBS items for service (66608 and 66609), including the associated
explanatory notes, are appropriate
a. How frequent are the MBS item number under review claimed?
b. Are there any age, sex, temporal or geographic trends associated with usage of these
item numbers?
c. What are the characteristics of patients undergoing vitamin D testing?
d. Are the Medicare claims data consistent with trends in the incidence/prevalence of the
conditions/diseases being addressed by the services?
e. What is the frequency of vitamin D testing by service provider?
2.1.2
Methods for analysis of MBS data
MBS data relates to private medical services (provided in- or out-of-hospital), where the
services are provided to patients regardless of whether or not they have private health cover.
MBS in-hospital services are mainly provided in private hospitals and day surgery clinics, but
patients can elect to be treated as a private patient in a public hospital.
MBS data were analysed by patient gender, age group, patterns of use and discipline of
provider claiming the benefit.
Results of the analysis of the MBS data is presented in Chapter 3.
2.2
2.2.1
Guideline concordance
The research questions for the guideline concordance analysis
The research question addressed as part of the Review using guideline concordance analysis
is:
(1) Is the existing MBS item for service (66608 and 66609) appropriate?
a. Is the descriptor for the MBS item number/service under review consistent with
evidence-based (or in the absence of evidence, consensus-based) recommendations
provided in relevant clinical practice guidelines?
(2) What are the appropriate clinical indications for vitamin D testing?
(3) How frequently should vitamin D levels be tested?
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February 2014
2.2.2
Methods for guideline concordance analysis
Searches of guidelines databases1 and relevant discipline websites were undertaken to locate
any existing guidelines relevant to vitamin D testing. Analysis of MBS item numbers 66608
and 66609 was undertaken relative to ‘best practice’, as recommended in relevant Australian
clinical practice guidelines. Where Australian clinical practice guidelines do not exist, other
guidelines in operation in comparable health systems overseas were included. Where
guidelines existed, they were assessed for quality using the AGREE II instrument(81).
Differences in the purpose and intended audience of any such guidelines were considered,
documented and acknowledged.
See Chapter 4 for results of the concordance analysis for vitamin D testing.
2.3
Systematic literature review for clinical evidence
2.3.1
The clinical/research questions for the systematic literature review
The clinical/research questions that were the focus of the literature review are:
(1) What are the appropriate clinical indications for medically necessary vitamin D testing?
(2) What is the effectiveness of vitamin D testing in improving outcomes in each target
population?
(3) What are the safety and quality implications (including morbidity, mortality and patient
satisfaction) associated with vitamin D testing in each target population?
(4) How do safety and quality outcomes of vitamin D testing vary according to:
a. the difference in testing methodologies?
b. frequency of testing?
2.3.2
Search strategy
A comprehensive search of peer-reviewed scientific literature was conducted to identify
relevant studies addressing the key questions. Electronic databases were searched for original
research papers, including systematic reviews as shown in Table 2.1. Searches were restricted
to studies published in the English language between January 2002 and December 2012.
Databases maintained by Health Technology Assessment (HTA) agencies were searched to
identify existing assessments of vitamin D testing.
1
The search included: Guidelines International Network (G-I-N) at http://www.g-i-n.net/library/internationalguidelines-library/; National Guidelines Clearinghouse at www.guidelines.gov; National Health and Medical
Research Council (NHMRC) at http://www.nhmrc.gov.au/guidelines-publications
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Table 2.1: Databases searched
Database
MEDLINE
PubMed
The Cochrane Library (includes Cochrane Database of Systematic
Reviews, Database of Abstracts of Reviews of Effects, Cochrane
Central Register of Controlled Trials, NHS Economic Evaluation
Database, Health Technology Assessment, Cochrane Methodology
Register)
Relevant HTA websites and databases2
Search period
Jan 2002 – Dec 2012
Jan 2002 – Dec 2012
2002 – May 2013
Up to May 2013
Reference lists of systematic, semi-systematic and selected narrative reviews were also
reviewed. In addition, during the consultation process clinicians were asked if they were
aware of any relevant clinical guidelines, unpublished studies or reviews relevant to this
review of vitamin D testing.
2.3.3
Eligibility criteria for studies
The PICO (Population, Intervention, Comparator, Outcomes) criteria(82) was used to develop
well-defined questions for the search of published literature. This involved focusing the
question on four elements:




the target population for the intervention;
the intervention being considered;
the comparator for the existing MBS service (where relevant); and
the clinical outcomes that are most relevant to assess safety and effectiveness.
The PICO criteria were determined on the basis of information provided in the literature, as
well as clinical advice. The PICO criteria for the review of vitamin D testing is shown in
Table 2.2.
2
The following HTA websites were searched: Agency for Healthcare Research and Quality (AHRQ) at
www.ahrq.gov; Canadian Agency for Drugs and Technologies in Health (CADTH) at http://www.cadth.ca/en;
National Institute for Health and Care Excellence (NICE) at www.nice.org.uk; Australasian College of Surgeons
(ASERNIP-S) at http://www.surgeons.org/for-health-professionals/audits-and-surgical-research/asernip-s/
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Table 2.2: PICO criteria for the vitamin D testing items under review
Population
Patients at risk of vitamin D
deficiency, including (but not
limited to):
(1) Postmenopausal women and
elderly men with bone
disease (e.g. osteoporosis,
osteomalacia)
(2) Patients with chronic
disease (cancer, CVD,
kidney disease, diabetes)
(3) Patients with multiple
sclerosis
(4) General population
(includes pregnant women,
overweight or obese
individuals, dark-skinned
people etc)
(5) Children with rickets
Intervention
Serum
vitamin D
testing
Comparator
No testing
Outcomes
Effectiveness
 Physical health outcomes (e.g.
improved physical
performance or bone health,
reduction in falls or fractures,
osteomalacia, reduction in allcause mortality, CVD,
diabetes, multiple sclerosis,
depression).
Safety
 Complications associated with
vitamin D testing (e.g.
infection, needle injuries)
The detailed search strategy and terms used are presented in Appendix 4. Separate searches
were undertaken for each of the PICO populations. A search was also undertaken without the
population terms in the search string.
Studies were excluded on the basis of citation information and/or abstract, where it was
obvious that they did not meet the inclusion criteria. Where there was any doubt about any
reference based on the title and/or abstract, the full paper was retrieved and evaluated. Table
2.3 lists the pre-specified inclusion and exclusion criteria.
Table 2.3: Inclusion/exclusion criteria for identification of relevant studies
Characteristic
Search period
Publication
type
Intervention
Comparator
Outcome
Criteria
2000 – Dec 2012
Should there be limited data available during this period, the search will be extended
back in five year increments until sufficient data are sourced.
Clinical studies included. Non-systematic reviews, letters, editorials, animal, in
vitro and laboratory studies were excluded.
Systematic reviews
Systematic reviews that have been superseded were excluded
Primary studies
Primary studies published during the search period of included systematic reviews
were excluded
Effectiveness studies included if:
 prospective, comparative trial
 >20 patients
Safety studies included if:
 >50 patients.
Vitamin D testing
No vitamin D testing
Studies must report on at least one of the following outcomes:
 Change in patient management
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February 2014
Characteristic
Language
2.3.4
Criteria
 Patient outcomes: morbidity, mortality, quality of life
 Safety: adverse physical health outcomes or complications associated with testing
or subsequent patient management
Non-English language articles excluded
Process for classifying the evidence
All eligible studies were assessed according to the National Health and Medical Research
Council (NHMRC) Dimensions of Evidence (refer to Appendix 5). There are three main
domains: strength of the evidence, size of the effect, and relevance of the evidence. One
aspect of the ‘strength of the evidence’ domain is the level of evidence, which is assigned
using the NHMRC Levels of Evidence (Appendix 5). For any eligible publications, study
quality was evaluated and reported using the NHMRC Quality Criteria (Appendix 5) for
randomised controlled trials (RCTs), cohort studies, case-control studies and systematic
reviews.
The results of the review of clinical evidence for vitamin D testing are presented in Chapter 5.
2.4
Systematic literature review for economic evidence
The research question for the review of economic literature is:
(1) What is the evidence regarding the cost implications associated with vitamin D testing
services in each target population
Consistent with the terms of reference, a formal modelled economic evaluation of vitamin D
testing was not in-scope. The review relied on published costing studies and economic
analyses identified through a systematic literature search of the databases shown in Table 2.1.
The detailed search strategy and terms used are presented in Appendix 4. Citations were
reviewed to identify acceptable evidence including: trial-based costing studies, cost analyses
and economic modelling studies. Acceptable outcomes were limited to: cost, incremental
cost-effectiveness ratio (e.g. cost per event avoided, cost per life year gained, cost per quality
adjusted life year or disability adjusted life year).
The results of the search for economic evaluations of vitamin D testing are presented in
Chapter 6.
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February 2014
3
SECONDARY DATA ANALYSIS
This Chapter presents an analysis of the available secondary data (including MBS data) that
describes the use of vitamin D testing in Australia.
3.1
MBS item number usage and expenditure
Figure 3.1 shows that the number of MBS claims for vitamin D testing has increased each year
over the past ten years (2003/04 to 2012/13), from 117,474 claims in 2003/04 to 4,331,030
claims in 2012/13. Over 98% of vitamin D testing services are for MBS item 66608.
Figure 3.1: Claims for MBS items 66608 and 66609, 2003/04 to 2012/13
5,000,000
4,500,000
Number of claims
4,000,000
3,500,000
3,000,000
2,500,000
2,000,000
1,500,000
1,000,000
500,000
0
2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013
66608
66609
Source: Department of Human Services – Medicare Australia
As shown in Table 3.1, there has been a 3,587% increase in vitamin D testing services (item
66608 and 66609) from 2003/04 to 2012/13. Over the same time period, a similar increase
(3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04 to $151,129,505 in
2012/13.
Table 3.1: Claims and benefits paid for MBS items 66608 and 66609, 2003/04 to 2012/13
Source: Department of Human Services – Medicare Australia
MBS item 66609 was listed on the MBS in May 2007. After a peak in services for item 66609
in 2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13)
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February 2014
(Table 3.1). Over the past five years (2008/09 to 2012/13), the number of claims for item
66609 decreased by 26%, while the number of claims for item 66608 increased by 190%.
Table 3.2 shows that the average fee per service for MBS item 66608 has decreased by 5%
from $37.16 in 2008/09 to $35.19 in 2012/13. There has also been a decrease of similar
magnitude in the average benefits paid per service. For item 66608, the proportion of services
bulk billed was high (more than 95% of services) from 2008/09 to 2012/13, which is consistent
with the high proportion of out-of-hospital services for item 66608 (over 98%). For item
66609, over 85% of services were bulk billed from 2008/09 to 2012/13.
Table 3.2: Fees charged and benefits paid for MBS items 66608 and 66609, 2008/09 to 2012/13
Source: Department of Human Services – Medicare Australia
*Average out-of-pocket cost is equal to ‘fees charged for patient-billed out-of-hospital services’ minus ‘benefits paid for patient-billed out-ofhospital services’ divided by ‘number of patient-billed out-of-hospital services’
The claiming pattern for vitamin D services over the past five years is further analysed by state
and territory (Figure 3.2). Between 2008/09 and 2012/13, 36%-38% of all claims for item
66608 were from New South Wales (NSW), while 34%-41% were from Victoria (VIC). The
other states and territories together accounted for less than 30% of total claims in each year.
Item 66609 showed much more variability over time, and relatively high usage in Queensland
(QLD) as a proportion of total claims.
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February 2014
Figure 3.2: Relative proportion of total claims for MBS items 66608 and 66609 by state and
territory, 2008/09 to 2012/13
Item 66608
Proportion of total claims
100%
80%
60%
40%
20%
0%
2008/2009
2009/2010
NSW
VIC
QLD
2010/2011
SA
WA
2011/2012
TAS
ACT
2012/2013
NT
Proportion of total claims
Item 66609
100%
80%
60%
40%
20%
0%
2008/2009
2009/2010
NSW
VIC
QLD
2010/2011
SA
WA
2011/2012
TAS
ACT
2012/2013
NT
Source: Department of Human Services – Medicare Australia
Table 3.3 shows vitamin D testing services per capita (i.e. per 100,000 population), according
to the address at the time of claiming by the patient to whom the service was rendered. In
2012/13, there were 18,629 claims for item 66608 per 100,000 people enrolled in Medicare
across Australia. VIC had the highest rate of claiming of item 66608 per capita (25,267 claims
per 100,000 population), followed by the Australian Capital Territory (ACT) and NSW. The
lowest per capita rates of vitamin D testing services were in the northernmost states and
territories (Northern Territory and QLD). For item 66609, the highest number of claims per
capita in 2012/13 was for Tasmania (TAS) and the ACT, while VIC had the lowest.
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February 2014
Table 3.3: Claims for MBS items 66608 and 66609 per capita (100,000 population)*, 2008/09 to
2012/13
Source: Department of Human Services – Medicare Australia
* Services per capita (i.e. per 100,000 population) is calculated by dividing the number of services processed in a month by the number of
people enrolled in Medicare at the end of that month.
An epidemiological study from Australia reported that the proportion of adults with vitamin D
deficiency (defined as serum 25-(OH)D levels < 25 nmol/L) was approximately 50% in women
during winter-spring and in people residing in southern states.(51) An examination of total
services in 2012/13 for MBS item 66608 showed no difference in the proportion of tests
claimed in winter-spring compared with summer-autumn (48% versus 52%, respectively).
3.2
Age and gender profile of patients
The patterns of usage of items 66608 and 66609 were examined by age and gender for the fiveyear time period from July 2008 to June 2013. There were no material changes in the age and
gender profile over time, except for a slight shift towards higher usage in the in female 25-34
year age category relative to the 35-44 year age category. As shown in Figure 3.3, vitamin D
testing claimed under MBS item numbers 66608 and 66609 is performed for both genders;
however, the number of claims is particularly significant for females aged between 24 and 84
years. Over the five-year period from 2008/09 to 2012/13, 70.2% of claims for MBS item
66608 were for females and 68.9% of claims for item 66609 were for females.
Australian guidelines for general practice recommend that targeted vitamin D testing should be
considered for people who are at risk of osteoporosis and who are at high risk of vitamin D
deficiency (see Chapter 4). As discussed in Chapter 1.1.7, an epidemiological study from
Australia has reported that vitamin D deficiency (defined as serum 25-(OH)D levels < 50
nmol/L) is more prevalent in females, particularly those aged 20–39 years or over 79 years.(52)
According to the AIHW, there were 692,000 reported cases of osteoporosis in 2007/08, with
84.0% of cases in people aged 55 years and over, and women accounting for 81.9% of all cases
(Chapter 1.1.9). The gender imbalance and peak in testing for vitamin D levels within the 5564 year age category is therefore consistent with epidemiological trends for vitamin D
deficiency and osteoporosis. However, the reason for the high rate of testing in the 45-54 year
age category is less clear.
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February 2014
Figure 3.3: Usage of MBS items 66608 and 66609 by age category and gender, July 2008 to June
2013
Total number of MBS claims
Item 66608
2,000,000
1,800,000
1,600,000
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
0-4
5-14
15-24
25-34
35-44
female
45-54
55-64
65-74
75-84
85+
75-84
85+
male
Total number of MBS claims
Item 66609
8000
7000
6000
5000
4000
3000
2000
1000
0
0-4
5-14
15-24
25-34
35-44
female
45-54
55-64
65-74
male
Source: Department of Human Services – Medicare Australia
3.3
Frequency of testing by patient
An analysis of vitamin D testing frequency per patient was conducted. For item 66608, there
was an increase over the period 2008/09 to 2012/133 in the overall number of patients tested for
vitamin D, from 1,248,566 in 2008/09 to 3,193,278 in 2012/13. As shown in Figure 3.4, the
proportion of patients who received only one test per year increased slightly over time (81.8%
in 2008/09 and 83.4% in 2012/13). The proportion of patients who received two tests per year
decreased from 14.8% in 2008/09 to 13.9% in 2012/13, while the proportion of patients who
received three or more tests per year decreased from 3.4% in 2008/09 to 2.8% in 2012/13. In
patients receiving three or more tests, the average number of services was 4.6 in 2008/09 and
3.7 in 2012/13.
For item 66609, there was a decrease over the period 2008/09 to 2012/13 in the overall number
of patients tested for vitamin D, from 7,413 in 2008/09 to 4,716 in 2012/13. The proportion of
patients who received only one test per year was relatively stable over time (89.7% in 2008/09
3
Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
and 90.6% in 2012/13). Similarly, the proportion of patients who received two tests per year
did not change significantly over time (7.2% of patients received two vitamin D testing services
in 2008/09 and 2012/13). The proportion of patients who received three or more tests
decreased from 3.1% in 2008/09 to 2.1% in 2012/13.
Taken together with the age profile of patients being tested, these data suggest that the majority
of vitamin D testing services are being undertaken for the purposes of screening/testing rather
than monitoring.
Figure 3.4: Frequency of claiming MBS items 66608 and 66609 per year by patient, 2008/09 to
2012/13*
Percentage of patients
Item 66608
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
2008/09
2009/10
1 test
2010/11
2 tests
2011/12
2012/13
2011/12
2012/13
3+ tests
Item 66609
Percentage of patients
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
2008/09
2009/10
1 test
2010/11
2 tests
3+ tests
Source: Department of Human Services – Medicare Australia
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
3.4
Profile of providers requesting vitamin D testing services
The profile of providers requesting vitamin D services was examined over time from 2008/09
to 2012/13 (Table 3.4). Over the five-year time period, there were no material changes in the
pattern of requesting providers. General practitioners (GPs) and other medical practitioners
(OMPs) accounted for nearly two-thirds of all providers requesting vitamin D testing services
for item 66608. Internal medicine consultant physicians accounted for nearly 15% of all
provider counts over the five-year time period, followed by general surgeons (specialist –
subspecialties) (3.5%), interns (3.3%), psychiatrists (2.6%), obstetricians/gynaecologists
(2.1%), general surgeons (specialist) (1.9%), other temporary resident doctors (1.4%), and nonspecialist surgeons (1.0%). There was a large variety of other providers requesting services,
but they each accounted for less than 1% of provider counts. For item 66609, GPs and OMPs
MBS Reviews – Vitamin D Testing Review Report
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February 2014
accounted for over 60% of all providers requesting vitamin D testing services, followed by
internal medicine consultant physicians (approximately 28%).
Chapter 4 summarises recent clinical practice guidelines relating to vitamin D testing. None of
the guidelines recommend screening in low risk populations. However, as mentioned in
Section 3.2, Australian guidelines for general practice recommend that targeted vitamin D
testing should be considered in people who are at risk of osteoporosis and who are at high risk
of vitamin D deficiency.
Table 3.4: Number of providers requesting MBS items 66608 and 66609, 2008/09 to 2012/13
Source: Department of Human Services – Medicare Australia
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
#
Other includes the following peer groups, which each accounted for <1% of the provider count: IVF, Anaesthetics (specialist and nonspecialist), Diagnostic Imagist (specialist and non-specialist), Dermatologist, Therapeutic Radiologist/Therapeutic Nuclear MedicineSpecialist, Pathologist, Specialist physician - internal medicine, Acupuncture, Dentist/Orthodontist, Unclassified miscellaneous (specialist and
non-specialist), Other Medical Specialist, Other Allied Health, Abortion/fertility control
€
List of other providers not available
3.5
Frequency of requests for testing by provider
An analysis of vitamin D test requests by frequency from any one provider was conducted. For
item 66608, there was an increase over the period 2008/09 to 2012/13 in the overall number of
providers requesting vitamin D testing. As shown in Figure 3.5, the proportion of providers
requesting ten or fewer tests per year decreased from 53.6% in 2008/09 to 38.7% in 2012/13,
whereas the proportion of providers requesting 11-50 tests per year remained relatively stable
(from 25.4% to 24.5% over the five-year period). In contrast, the proportion of providers
requesting more than 50 tests per year has increased from 21.0% in 2008/09 to 36.8% in
2012/13. Each year, there is a small number of providers who request over 400 vitamin D tests
per year. In 2008/09, there were 682 of these providers (representing 2.1% of providers); in
2012/13 there were 1,867 providers requesting more than 400 tests per year (4% of providers
for item 66608).
For item 66609, the proportion of providers requesting one test per year increased from 54.5%
in 2007/08 to 64.1% in 2012/13 (Figure 3.5). In contrast, the proportion of providers
requesting two or more tests decreased from 44.5% in 2008/09 to 35.9% in 2012/13.
MBS Reviews – Vitamin D Testing Review Report
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February 2014
Taken together, these data show that there is a large and increasing number of providers,
primarily GPs and OMPs, who are requesting high volumes of vitamin D tests per year,
presumably for the purposes of screening/testing rather than monitoring.
Figure 3.5: Frequency of MBS items 66608 and 66609 requested per year by any provider,
2008/09 to 2012/13*
Item 66608
Percentage of requests
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
2008/09
0-10
2009/10
11-50
2010/11
51-100
101-200
2011/12
201-300
2012/13
301-400
401 +
Item 66609
Percentage of requests
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
2008/09
1
2
2009/10
3
4
2010/11
5
6
7
2011/12
8
9
2012/13
10
11 +
Source: Department of Human Services – Medicare Australia
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
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February 2014
4
REVIEW OF GUIDELINES RELEVANT TO VITAMIN D TESTING
This Chapter presents the results of the literature search for clinical practice guidelines
relating to vitamin D testing.
4.1
Australian guidelines
The literature search identified several recent Australian clinical practice guidelines and
position statements that provide guidance regarding vitamin D testing in general healthy
populations and specific clinical conditions (Table 4.1). Clinical practice guidelines that
recommend vitamin D supplementation, but do not mention vitamin D testing or screening,
have not been included.
Table 4.1: Australian clinical practice guidelines relevant to vitamin D testing
Publishing body
Adults
The Royal College of
Pathologists of
Australasia
(RCPA)(83)
Royal Australian
College of General
Practitioners
(RACGP)(84)
Release
date
May
2013
2012
Working Group of the June
Australian and New
2012
Zealand Bone and
Mineral Society,
Endocrine Society of
Australia and
Osteoporosis
Australia(19)
Disease- or risk-factor specific
The Royal College of
May
Pathologists of
2013
Australasia
(RCPA)(83)
Title of
guideline
Use and
interpretation of
vitamin D
testing; a
Position
Statement
Guidelines for
preventative
activities in
general practice,
8th edition.
Vitamin D and
health in adults
in Australia and
New Zealand: a
Position
Statement
Use and
interpretation of
vitamin D
testing; a
Position
Statement
MBS Reviews – Vitamin D Testing Review Report
Guidance regarding vitamin D
testing
 Routine screening for vitamin D
deficiency is not recommended
in adults
Frequency of
testing
Retesting three
months after
commencement
of
supplementation
 Routine screening for vitamin D
deficiency is not recommended
in low-risk populations
 Targeted testing of people who
are at risk of osteoporosis and
who are at high risk of vitamin
D deficiency should be
considered
 High-risk groups for vitamin D
deficiency in pregnancy may
benefit from vitamin D
screening
 Screening for 25-(OH)D levels
is recommended in high-risk
groups#
 Screening should be performed
by a reputable laboratory
participating in a the Vitamin D
External Quality Assessment
Scheme proficiency program
Not reported
 Measurement of 25(OH)-D in
individuals at risk of vitamin D
deficiency is an appropriate
case-finding strategy
Retesting three
months after
commencement
of
supplementation
Retesting three
months after
commencement
of
supplementation
Page 37
February 2014
The Royal College of
Pathologists of
Australasia
(RCPA)(83)
May
2013
Royal Australian
College of General
Practitioners
(RACGP)(85)
Feb 2010
Kidney Health
July 2012
Australia CARI
guidelines (Caring for
Australasians with
Renal Impairment)(86)
Pregnant women and children
The Royal College of
May
Pathologists of
2013
Australasia
(RCPA)(83)
Working Group of the
Australian and New
Zealand Bone and
Mineral Society and
Osteoporosis
Australia(45)
Feb 2013
Use and
interpretation of
vitamin D
testing; a
Position
Statement
Clinical
guideline for the
prevention and
treatment of
osteoporosis in
postmenopausal
women and
older men.
Vitamin D
therapy
(supplementatio
n) in early
kidney disease.
 Measurement of 25(OH)-D in
individuals at risk of vitamin D
deficiency is an appropriate
case-finding strategy
Retesting three
months after
commencement
of
supplementation
 Serum 25-(OH)D is one of the
recommended laboratory tests
used for the diagnostic
assessment for osteoporotic
fractures, but only under
particular conditions*
Not reported
 Early chronic kidney disease
patients on vitamin D therapy
have their 25-(OH)D levels
monitored regularly
“Regular”
monitoring not
defined
Use and
interpretation of
vitamin D
testing; a
Position
Statement
Vitamin D and
health in
pregnancy,
infants, children
and adolescents
in Australia and
New Zealand: a
Position
Statement
 Routine screening for vitamin D
deficiency is not recommended
in pregnant women, healthy
infants and children
Retesting three
months after
commencement
of
supplementation
 Population-wide screening for
vitamin D status in infants,
children and adolescents is not
supported by the evidence
 25-(OH)D levels should be
tested in those with one or more
risk factors for low vitamin D€
 Infants, children and adolescents
with ongoing risk factors require
ongoing monitoring of vitamin
D status with annual testing
 Recently arrived migrant
children at risk of low vitamin D
should have testing repeated at
the end of their first winter in
Australia.
 Vitamin D testing could be
considered in exclusively
breastfed infants or mixed fed
infants with at least one other
risk factor
 Universal screening of pregnant
women is not supported by the
evidence
 Pregnant women with one or
more risk factors should be
tested at their first antenatal visit
and again at 28 weeks’ gestation
Annual testing
of people with
risk factors for
low vitamin D.
Follow-up
testing should be
performed in
patients on
vitamin D
supplementation
MBS Reviews – Vitamin D Testing Review Report
For neonates
with moderate or
severe
deficiency,
follow-up at one
month is
recommended;
in other groups,
follow-up at
three months is
usually more
practical; and in
the long term,
annual testing is
recommended.
Very frequent
testing should be
avoided.
Page 38
February 2014
The Royal College of
Pathologists of
Australasia
(RCPA)(83)
May
2013
Munns et al, Medical
Journal of Australia.
[Working group
included members of
the Australasian
Paediatric Endocrine
Group and Paediatric
Bone Australasia](87)
2006
Use and
interpretation of
vitamin D
testing; a
Position
Statement
Prevention and
treatment of
infant and
childhood
vitamin D
deficiency in
Australia and
New Zealand: a
consensus
statement
 Routine screening for vitamin D
deficiency is not recommended
in pregnant women, healthy
infants and children
Retesting three
months after
commencement
of
supplementation
 All pregnant women, especially
those who are veiled or darkskinned, should have their serum
25-(OH)D concentration
evaluated during the first
trimester of pregnancy
Not mentioned,
but implied that
testing should
continue until
supplements
have restored
vitamin D levels
to normal.
* if fractures after minimal trauma were the reason for the diagnostic assessment; the medical history and/or clinical examination reveals or
is compatible with secondary osteoporosis; the Z-score is less than -2.0 measured by Dual-energy X-ray Absorptiometry.
#
defined as: older or disabled people in low-level and high-level residential care, particularly housebound community-dwelling geriatric
patients admitted to hospital; dark-skinned people of either sex, particularly migrants and/or if modest dress is worn; people with a disability
of chronic disease (e.g. multiple sclerosis); fair-skinned people and those at risk of skin cancer who avoid sun exposure; obese people; and
people working in an enclosed environment, such as office workers, factory or warehouse workers, taxi drivers, night-shift workers.
€
defined as lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors, chronic illness or hospitalisation, complex
disability, covering clothing for religious or cultural reasons or southerly latitude); dark skin; medical conditions or medications affecting
vitamin D metabolism and storage (obesity, end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as
rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease and inflammatory bowel disease]); in infants,
maternal vitamin D deficiency and exclusive breastfeeding combined with at least one other risk factor.
In 2013 the Royal College of Pathologists of Australasia (RCPA) published a Position
Statement for the use and interpretation of vitamin D testing. The purpose of the Statement is
to clarify the role of vitamin D testing in the context of diagnosing and monitoring vitamin D
deficiency states and their treatment. The recommendations in the Position Statement are
consistent with recent guidelines on the diagnosis and management of vitamin D deficiency in
adults, pregnant women, infants, children and adolescents in Australia and New Zealand.(19, 45)
The Position Statement does not recommend routine screening for vitamin D deficiency in
adults, including pregnant women, healthy infants and children. Measurement of 25-(OH)D
is considered to be an appropriate, case-finding strategy in individuals at risk of vitamin D
deficiency.
Initial testing for vitamin D status is recommended for adult patients (as well as paediatric
patients when relevant) with the following indications:







signs, symptoms and/or planned treatment of osteoporosis or osteomalacia;
increased alkaline phosphatase with otherwise normal liver function tests;
hyperparathyroidism, hypo- or hypercalcaemia or hypophosphataemia;
malabsorption (e.g. cystic fibrosis, short bowel syndrome, inflammatory bowel disease,
untreated coeliac disease, bariatric surgery);
deeply pigmented skin, or chronic or severe lack of sun exposure for cultural, medical,
occupational or residential reasons;
medications known to decrease vitamin D levels (mainly anticonvulsants); and
chronic renal failure and renal transplant patients.
The Position Statement does not explicitly recommend routine testing for vitamin D status in
the general population. However, it recommends that serum vitamin D levels should be
retested after three months following the commencement of vitamin D supplementation. No
further testing is required once desirable 25-(OH)D target levels are achieved. The position
Statement recommends against high dose annual replacement of cholecalciferol as this has
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February 2014
been associated with increased falls and fractures in elderly men and women. The Statement
recommends that the target level of serum 25-(OH)D should be >50 nmol/L at the end of
winter.
The Position Statement also includes sections on measurement of vitamin D and interpretation
of results. Serum 25-(OH)D, reported in nmol/L units, is considered to be the best marker for
clinical assessment of an individual’s vitamin D status. The Statement acknowledges the
imprecision of the current immunoassay method used for 25-(OH)D testing, and warns
clinicians to be aware of the variation in the current vitamin D assay methods. The Statement
advises monitoring of serum 25-(OH)D levels following treatment in the same laboratory. The
Statement recommends that a vitamin D assay that measures only one of the two vitamin D
isoforms (the 25-(OH)-D3 isoform) is adequate for use in Australia.
In 2012 the Royal Australian College of General Practitioners (RACGP) published
guidelines for preventative activities in general practice. The ‘red book’ has been published
since 1989 and is accepted as the main guide to preventative care in Australian general
practice. The intention is to provide a comprehensive and concise set of recommendations for
patients in general practice. The recommendations in the guidelines are based on current,
evidence-based guidelines for preventative activities relevant to Australian general practice.
Where Australian guidelines are not available or recent, other sources have been used, such as
Canadian or United States preventative guidelines or the results of systematic reviews.
In the section on prevention of chronic disease, a sub-section on nutrition states that vitamin
supplementation is not of established value in asymptomatic individuals (with the exception
of folate and iodine in pregnancy). Routine screening for vitamin D deficiency is not
recommended in low-risk populations. Patients with vitamin D deficiency (defined as <60
nmol) are identified as having increased risk of osteoporosis. However, the guidelines state
that screening for vitamin D is not indicated just for risk assessment. In terms of preventative
actions for osteoporosis, the guidelines state that population screening for vitamin D
deficiency is not recommended, but targeted testing of people who are at risk of osteoporosis
and who are at high risk of vitamin D deficiency should be considered. Vitamin D
supplements could be considered in deficient individuals if increasing sun exposure is
contraindicated or not feasible, or if deficiency is more than mild (i.e. <25 nmol/L) and so is
less likely to be corrected by safe sun exposure (Practice Point).
In terms of preventative interventions for falls, the guidelines state to consider prescribing
vitamin D for people with vitamin D levels <50 nmol/L for older people living in the
community (III,C) and consider routinely prescribing vitamin D (unless contraindicated) for
all older people living in residential aged care (I,B), as routine sun exposure in residential
aged care may not be feasible. Testing for vitamin D levels in these populations is not
specifically mentioned.
The guidelines include a section on screening tests of unproven benefit in low-risk general
practice populations. Due to the high prevalence of vitamin D deficiency, variability in
assessment and lack of rigorous evidence of benefit of screening, screening for vitamin D
deficiency is not recommended for chronic disease prevention. Vitamin D screening is
considered to be of indeterminate value in pregnancy. The reason cited is the moderate
prevalence and associated morbidity, but no RCT evidence of benefit. However, the
guidelines state that high-risk groups for vitamin D deficiency in pregnancy may benefit from
vitamin D screening and supplementation.
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In 2010 the Royal Australian College of General Practitioners (RACGP) published a
clinical guideline for the prevention and treatment of osteoporosis in postmenopausal women
and older men, which presents a comprehensive review of pharmacological management of
osteoporosis within the Australian health care context, based on the best available evidence to
2009.(85) The guideline contains the following recommendations of relevance to vitamin D:
 Recommendation 7 – Lifestyle (Grade D consensus)
General practitioners should recommend adequate but safe exposure to sunlight as a source
of vitamin D for all postmenopausal women and older men.
 Recommendation 11 – Calcium and vitamin D supplementation (Grade C)
There is mixed evidence on the effectiveness of calcium and vitamin D supplementation
for prevention of bone loss and osteoporotic fractures in postmenopausal women and
older men. There may be some benefit for those who have inadequate levels, particularly
institutionalised patients.
 Recommendation 18 – Calcium and vitamin D supplementation (Grade C)
There is good evidence for high prevalence of vitamin D insufficiency in institutionalised
and home bound individuals and vitamin D supplementation is considered to be standard
care in these populations. There may be some benefit for dietary change or calcium
supplementation in postmenopausal women and older men with osteoporosis who have
low dietary calcium intake.
The 2010 RACGP guideline described three systematic reviews with a focus on vitamin D in
conjunction with calcium supplementation and their effectiveness in the reduction of fractures
and bone loss.(85) A systematic review by Tang et al. (2007)(88) found that calcium
supplementation alone was associated with a 13% reduction in risk of fractures, and with 10%
reduction in risk of fractures in trials using calcium supplements in combination with vitamin
D. The guideline also described the Cochrane review of 38 RCTs by Avenell et al. (2009)(89)
which showed a significant reduction in incidence of new hip fracture and non-vertebral
fractures for vitamin D combined with calcium. However, the guideline cautioned that the
results for institutionalised older adults included in the systematic review may have
influenced the overall analysis as no significant effect was found for community dwelling
individuals. There was also no evidence for effectiveness of vitamin D alone for prevention
of fractures. The guideline also describes the systematic review by Boonen et al. (2007)(90)
which showed that vitamin D alone was not associated with a reduction in risk of hip fracture
or a reduction in risk of non-vertebral fractures when compared to placebo. Similar to the
Avenell review, significant reduction in the risk of hip fracture and non-vertebral fracture was
observed in patients receiving vitamin D in conjunction with calcium supplements when
compared to placebo or no treatment.(85)
Furthermore, the guideline listed serum 25-(OH)D as one of the recommended laboratory
tests used for the diagnostic assessment for osteoporotic fractures, with cut-off value less than
50 nmol/L defined as “vitamin D deficiency or insufficiency”. According to the evidence
statement, for some patients at risk, laboratory findings can reveal unsuspected secondary
osteoporosis or may influence some aspects of diagnostics and therapy. Laboratory tests are
used to exclude the most important forms of secondary osteoporosis and other potential bone
diseases. The evidence statement directs that laboratory tests (including serum 25-(OH)D)
should follow medical history, clinical examination and bone densitometry if(85):


fractures after minimal trauma were the reason for the diagnostic assessment;
the medical history and/or clinical examination reveals or is compatible with secondary
osteoporosis;
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February 2014

the Z-score is less than -2.0 measured by Dual-energy X-ray Absorptiometry (DXA).
The guideline does not explicitly recommend routine screening for vitamin D status in the
elderly population or in individuals who are at general high risk of bone disease.(85) The
guideline recommends the intake of vitamin D (and calcium) supplementation and
maintaining “high vitamin D status” as a preventive therapy against osteoporosis, but it is not
clearly stated whether serum vitamin D levels should be monitored via testing in this
population group.
The 2010 guideline identifies Asians, people with darker skin and veiled women to be at
greater risk of vitamin D insufficiency and relatively low calcium intakes, and both should be
corrected before initiating anti-osteoporotic therapy (vitamin D and calcium
supplementation). Correction of vitamin D insufficiency can be achieved by greater daily
sunlight exposure. The guideline refers to the current recommended amount of sunlight
required to produce optimum levels of vitamin D, defined as exposure of approximately 15%
of the body (i.e. hands, face and arms) for 6–8 minutes, 4–6 times per week, and before 10
am or after 2 pm (standard time) for moderately fair skinned people.(85)
In June 2012 the Working Group of the Australian and New Zealand Bone and Mineral
Society (ANZBMS), Endocrine Society of Australia, and Osteoporosis Australia
published a Position Statement on vitamin D and health in adults in Australia and New
Zealand. The authors claim that the statement is evidence-based, but it is not clear whether it
was underpinned by a systematic literature review. On the basis of the evidence, the position
statement recommends that a serum 25-(OH)D level of ≥50 nmol/L at the end of winter (1020 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal
musculoskeletal health. Vitamin D deficiency is defined as: mild 30-49 nmol./L, moderate
12.5-29 nmol/L, severe <12.5 nmol/L.
The statement acknowledges that higher serum 25-(OH)D levels are likely to play a role in the
prevention of some disease states, but there is insufficient evidence from RCTs to recommend
higher targets. It identifies the groups at greatest risk of vitamin D deficiency as:






older or disabled people in low-level and high-level residential care, particularly
housebound community-dwelling geriatric patients admitted to hospital;
dark-skinned people of either sex, particularly migrants and/or if modest dress is worn;
people with a disability of chronic disease (e.g. multiple sclerosis);
fair-skinned people and those at risk of skin cancer who avoid sun exposure;
obese people; and
people working in an enclosed environment, such as office workers, factory or warehouse
workers, taxi drivers, night-shift workers.
The statement notes the imprecision of current 25-(OH)D testing, and warns to exercise
caution when interpreting results in clinical practice. Although the performance of
radioimmunoassay and enzyme-linked assays is acceptable, the bias and imprecision of many
automated methods may be problematic at the lower, clinically and analytically important
range (< 50 nmol/L) of the assay. Adoption and alignment of assays to the National Institute
of Standards and Technology reference material should reduce bias (see Section 1.1.5);
however, imprecision will remain problematic. Consequently, some laboratories are using
more exacting methods of analysis, such as liquid chromatography–tandem mass
spectrometry. All Australian laboratories offering 25-(OH)D testing are required to be
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February 2014
enrolled in external proficiency programs (see Section 1.1.4), which allow each laboratory to
monitor its performance compared with its peers.
The position statement includes recommendations for assessment and management of vitamin
D deficiency states. In high-risk groups, screening blood test for 25-(OH)D level is
recommended, followed by appropriate vitamin supplementation. The statement advises that
25-(OH)D levels should be checked after three months, as there is such an individual variation
of response to vitamin D supplementation. Retesting should not take place before three
months, as it may take up to 2-5 months for serum levels of 25-(OH)D to plateau. The
position statement recommends that supplementation without initial screening may be
appropriate for adults in disadvantaged communities at high risk of vitamin D deficiency (e.g.
dark-skinned migrants from low socioeconomic backgrounds, people in residential care
establishments).
In February 2013 the Working Group of the Australian and New Zealand Bone and
Mineral Society (ANZBMS) and Osteoporosis Australia published a position statement on
vitamin D and health in pregnancy, infants, children and adolescents in Australia and New
Zealand. The position statement is based on articles on vitamin D dosing in paediatric age
groups and during pregnancy and lactation, which were identified by a systematic search of
the Medline database (1946 to July 2011). According to the statement, there is inadequate
evidence to recommend population-wide screening for vitamin D status in infants, children
and adolescents in Australia. Those with one or more risk factors for low vitamin D should
have their serum 25-(OH)D, calcium, phosphate and alkaline phosphatase levels measured;
parathyroid hormone levels should also be measured in those with symptoms or signs of
deficiency, multiple risk factors or inadequate calcium intake. Infants, children or adolescents
with low serum calcium or phosphate and those who have clinical signs of rickets require
urgent specialist assessment and further investigations.
The position statement identified the following risk factors for low vitamin D:




lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors,
chronic illness or hospitalisation, complex disability, covering clothing for religious or
cultural reasons or southerly latitude);
dark skin;
medical conditions or medications affecting vitamin D metabolism and storage (obesity,
end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as
rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease
and inflammatory bowel disease]);
in infants, maternal vitamin D deficiency and exclusive breastfeeding combined with at
least one other risk factor.
The position statement advises that infants, children and adolescents with low 25-(OH)D
levels should be treated to restore their 25-(OH)D levels to the normal range. Infants,
children and adolescents with ongoing risk factors for low vitamin D require ongoing
monitoring of vitamin D status with annual testing, as well as a long-term plan to maintain
normal 25-(OH)D levels and calcium status through behavioural change, where possible,
and/or supplementation if behavioural change is inadequate. It is acknowledged that it may
not be possible for people with risk factors (especially multiple risk factors) to maintain their
25-(OH)D levels during winter in the southern parts of Australia. Recently arrived migrant
children at risk of low vitamin D may have normal 25-(OH)D levels on initial health
screening, so testing should be repeated at the end of their first winter in Australia. Some
children with significant ongoing risk factors (e.g. dark skin and covering clothing) may
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February 2014
require high-dose vitamin D supplementation more than once a year. The position statement
suggests that levels at the start and end of winter can be useful to guide dosing frequency.
The position statement advises that exclusively breastfed infants with at least one other risk
factor for low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the
first year of life and adherence should be monitored, particularly after the first months of
supplementation. Checking 25-(OH)D levels or adding daily vitamin D supplements should
be considered in infants with other risk factors for low vitamin D who are fed a mixture of
breast milk and formula, or who have appropriately reduced their formula intake after the
introduction of solids.
For pregnant women with one or more risk factors for low vitamin D, the position statement
advises that serum 25-(OH)D levels should be measured at their first antenatal visit. The
position statement acknowledges that a recommendation for universal screening of pregnant
women is not supported, due to the geographic variation in the prevalence of vitamin D
deficiency and insufficient evidence on the impact on maternal and child health of vitamin D
supplementation during pregnancy. The authors argue that while the cost of measuring 25(OH)D levels is significant, pregnant women undergo screening for conditions of much lower
prevalence, and there are no data or cost-effectiveness studies on alternative management
strategies (such as supplementation without testing during winter).
Pregnant women with 25-(OH)D levels < 50 nmol/L should be started on daily vitamin D3
supplementation. The position statement advises that testing should be repeated at 28 weeks’
gestation. In women whose 25-(OH)D levels have corrected to > 50 nmol/L, supplementation
(at a lower dose) should be given throughout the remainder of pregnancy.
Based on a review of 98 clinical trials of vitamin D supplementation, the position statement
provides recommended oral doses of vitamin D3 for the management of mild and moderate or
severe vitamin D deficiency in infants, children and adolescents. In terms of monitoring, the
position statement advises that adherence with daily dosing should be monitored and followup blood tests should be performed. For neonates with moderate or severe deficiency, followup at one month is recommended; in other groups, follow-up at three months is usually more
practical; and in the long term, annual testing is recommended. Very frequent testing should
be avoided. Follow-up blood tests should include tests for serum 25-(OH)D, calcium,
phosphate and alkaline phosphatase. Repeat high-dose therapy may be required if 25-(OH)D
levels are low at follow-up.
A 2006 consensus statement on the prevention and treatment of infant and childhood vitamin
D deficiency in Australia and New Zealand was also identified. The consensus statement was
developed by a working group which included members of the Australasian Paediatric
Endocrine Group, Paediatric Bone Australasia, migrant health paediatricians,
obstetricians, public health specialists and a member of the working group responsible for the
adult guidelines on vitamin D and bone health. Treatment guidelines were arrived at through
a combination of published best practice and local experience. The statement advises that
serum 25-(OH)D concentration provides the best indicator of vitamin D status, and should be
used when testing for deficiency states (normal concentration is defined as > 50 nmol/L). The
concentration of 1,25-(OH)2D must not be used, as it may be elevated even in severe vitamin
D deficiency. Different 25-(OH)D assays give different results, with some not determining
D2 as well as they do D3. The statement warns that this may result in spuriously reduced 25OHD results in children supplemented with ergocalciferol. The position statement advises
that routine vitamin D supplementation of all pregnant women cannot be recommended.
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February 2014
However, all pregnant women, especially those who are veiled or dark-skinned, should have
their serum 25-(OH)D concentration evaluated during the first trimester of pregnancy. If they
are moderately to severely vitamin D deficient, pregnant women should receive vitamin D
supplementation until the serum 25-(OH)D concentration is over 50 nmol/L.
The Caring for Australasians with Renal Impairment (CARI) guidelines are published by
Kidney Health Australia (KHA) in association with the Council of the Australian and New
Zealand Society of Nephrology (ANZSN). These guidelines include a section on vitamin D
therapy in early chronic kidney disease (CKD). The aim of the CARI guidelines is to improve
the health care and outcomes of paediatric and adult patients with kidney disease, by helping
clinicians and health care workers to adhere to evidence-based medical practice as often as
possible.
The CARI guidelines on vitamin D supplementation in early CKD indicate that there is
insufficient evidence to determine the effect of vitamin D compounds on mortality and
cardiovascular outcomes in the CKD stages 1-3 population.(86) The guidelines described one
RCT with CKD stages 1-3 patients which indicated that supplementation of calcium (1200
mg) and vitamin D3 (800 IU (20 μg)) to suboptimal diets significantly increased 25-(OH)D
and decreased Intact Parathyroid Hormone (iPTH) levels in patients (level I evidence).(91)
The guidelines noted that, currently, the optimal levels of serum vitamin D and dosage of
supplementation required are not clearly defined. There is also evidence that vitamin D
therapy in early CKD may be associated with potential harm, including hypercalcaemia,
elevated troponin T levels and accelerated progression of CKD.(92) . In addition, the
guidelines indicate that currently there are no studies evaluating the cost-effectiveness of
prophylactic therapy in patients with CKD and its effects on patient-level outcomes.(86)
The CARI guidelines define vitamin D insufficiency and deficiency as serum 25-(OH)D
levels of 37.5-75 nmol/L and <37.5 nmol/L, respectively. The guidelines recommend that
early chronic kidney disease patients on vitamin D therapy have their calcium, phosphate,
PTH, alkaline phosphatase and 25-(OH)D levels monitored regularly (grade 1C
recommendation, according to GRADE approach). No further details are provided regarding
the frequency of regular monitoring.
4.2
International guidelines
Eleven guidelines related to vitamin D testing were identified and are summarised in Table
4.2. The summary does not include guidelines that referred to supplementation without
mentioning testing for vitamin D status.
Table 4.2: International clinical practice guidelines relevant to vitamin D testing
Publishing body
Release
date
Title of guideline
Adults
American Medical
Directors
Association
(AMDA)(93)
2009
Osteoporosis and
fracture
prevention in the
long-term care
setting.
The Endocrine
Society(94)
2011
Clinical practice
guideline for
evaluation,
MBS Reviews – Vitamin D Testing Review Report
Guidance regarding vitamin D testing
 Routine administration of vitamin D3 in
long-term care residents
 May be advisable to measure 25-(OH)D
levels in patients who are at risk of
osteoporosis and for those with a
diagnosis of osteoporosis to help
determine aetiology
 Screening only in individuals who are at
risk of vitamin D deficiency; population
screening of individuals not at risk is not
Quality*
Fair
quality
Good
quality
Page 45
February 2014
Publishing body
Osteoporosis
Canada(95)
Release
date
2010
Pregnant and lactating women
American Congress
2011
of Obstetricians and
Gynecologists
(ACOG)(96)
Children
American Academy
of Paediatrics
(AAP)(97)
American Academy
of Paediatrics
(AAP)(98)
Title of guideline
Guidance regarding vitamin D testing
treatment, and
prevention of
vitamin deficiency
recommended
 Measurement of serum circulating 25(OH)D by a reliable assay is the
recommended method to screen
individuals at risk of vitamin D
deficiency
 In healthy adults at low risk for vitamin D
deficiency, serum 25-(OH)D should not
be measured
 For individuals receiving pharmacologic
therapy for osteoporosis, measurement of
serum 25-(OH)D should follow 3-4
months of adequate supplementation and
should not be repeated if the optimal level
is achieved
 Measurement of serum 25-(OH)D is
recommended for individuals with
recurrent fractures, bone loss despite
osteoporosis treatment or comorbid
conditions that affect vitamin D
absorption or action
 Doses ≤ 50 µg (2000 IU) are safe and do
not require monitoring. Patients taking
daily doses above Health Canada’s
‘tolerable upper intake level’ should
undergo monitoring of serum 25-(OH)D
Vitamin D in adult
health and disease
Quality*
Good
quality
Vitamin D –
screening and
supplementation
during pregnancy
 Routine screening of pregnant women is
not recommended.
 Screening may be considered in pregnant
women considered to be at an increased
risk of deficiency.
Very
poor
quality
2008
Prevention of
rickets and
vitamin D
deficiency in
infants, children
and adolescents
Good
quality
2011
Bone
densitometry in
children and
adolescents
 In children who receive supplementation
due to increased risk of vitamin D
deficiency, such as those with
malabsorption disorders or use of certain
medications, serum 25-(OH)D levels
should be checked at 3 month intervals
until normal levels (defined as ≥50
nmol/L) have been achieved.
 Serum 25-(OH)D concentrations should
be measured in children with skeletal
fragility to ensure that adequate stores are
present
MBS Reviews – Vitamin D Testing Review Report
Good
quality
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February 2014
Disease- and risk-factor specific
National
Osteoporosis
Society(99)
April
2013
Vitamin D and
bone health: A
practical clinical
guideline for
patient
management
National Institute for
Health and Care
Excellence
(NICE)(100)
2012
Institute for Clinical
Systems
Improvement
(ICSI)(101)
Kidney Disease:
Improving Global
Outcomes
(KDIGO)(102)
2011
The diagnosis and
management of
the epilepsies in
adults and
children in
primary and
secondary care
Diagnosis and
treatment of
osteoporosis
National Institute for
Health and Care
Excellence
(NICE)(103)
2008
2009
Clinical practice
guideline for the
diagnosis,
evaluation,
prevention, and
treatment of
chronic kidney
disease–mineral
and bone disorder
Early
identification and
management of
chronic kidney
disease in adults
in primary and
secondary care
MBS Reviews – Vitamin D Testing Review Report
 Measurement of serum 25-(OH)D is
the best way of estimating vitamin D
status
 Universal screening of asymptomatic
healthy populations, including those
with risk factors for low vitamin D, is
not recommended
 Serum 25-(OH)D measurement is
recommended for patients with: bone
diseases that may be improved with
vitamin D treatment; bone diseases,
prior to specific treatment where
correcting vitamin D deficiency is
appropriate; musculoskeletal
symptoms that could be attributed to
vitamin D deficiency
 Routine vitamin D testing may be
unnecessary in patients with
osteoporosis or fragility fracture, who
may be co-prescribed vitamin D
supplementation with an oral
antiresorptive treatment
 Routine monitoring of serum 25(OH)D is generally unnecessary but
may be appropriate in patients with
symptomatic vitamin D deficiency or
malabsorption and where poor
compliance with medication is
suspected
 Assessment of 25-(OH)D status on
replacement therapy should be
undertaken after 3 or 6 months
 Monitoring vitamin D levels is
recommended every 2 to 5 years for
individuals who are receiving enzymeinducing drugs as part of their epilepsy
treatment regimen
Fair
quality
 Serum 25-(OH)D testing in all patients
with osteoporosis (optimum level 75
nmol/L)
Good
quality
 In patients with chronic kidney disease
Stages 3-5D, 25-(OH)D levels might be
measured, and repeated testing
determined by baseline values and
therapeutic intervention
Good
quality
 Routine measurement of vitamin D levels
in individuals with Stage 1, 2, 3A or 3B
chronic kidney disease is not
recommended
Good
quality
Good
quality
Page 47
February 2014
* Assessed according to the Appraisal of Guidelines Research and Evaluation (AGREE) Instrument.
International guidelines are consistent with Australian guidance in terms of recommending
against routine screening for vitamin D status in adults, pregnant women and children.
However, there are several guidelines that support screening in high-risk individuals
(although definitions of at-risk were lacking in these guidelines), and testing vitamin D status
in populations with known poor bone health (such as children with skeletal fragility and
adults with osteoporosis). Follow-up testing is also recommended in people being treated
pharmaceutically for osteoporosis (at 3-4 months after commencement of therapy).
Guidelines relating to adults
The American Medical Directors Association (AMDA) released guidelines in 2009 on
osteoporosis and fracture prevention in the long-term care setting. The AMDA is a national
organisation in the United States comprised of medical directors, attending physicians, and
other practitioners who care for patients in the long-term care setting. Its clinical practice
guidelines are produced by interdisciplinary workgroups using both medical evidence and
medical consensus. In terms of vitamin D testing, AMDA considers serum 25-(OH)D testing
to be an appropriate companion test with serum calcium, creatinine, and alkaline phosphatase
testing in patients who have a history of fracture. AMDA stated that it may be advisable to
measure 25-(OH)D levels in patients who are at risk for osteoporosis and for those with a
diagnosis of osteoporosis to help to determine the etiology of the condition.
In 2011, The Endocrine Society in the United States released a clinical practice guideline on
the evaluation, treatment and prevention of vitamin D deficiency. The guideline was created
via a consensus process involving a Task Force, which commissioned two systematic reviews
of the literature to obtain information regarding vitamin D deficiency, as well as committees,
sponsors, and members of The Endocrine Society. On the basis of high quality evidence, the
guideline recommends that individuals who are at risk of vitamin D deficiency should be
screened, but population screening of individuals who are not at risk of deficiency is not
recommended. Risk is not defined in the recommendation; however, inadequate sun
exposure, skin pigmentation, high body mass index, renal disease, and vitamin D-depleting
medication are discussed in the background section. The guideline also recommends that
measurement of serum circulating 25-(OH)D by a reliable assay is the recommended method
to screen individuals at risk of vitamin D deficiency. The serum 1,24-dihydroxyvitamin D
assay is not recommended for this purpose. Both of these recommendations were based on
high-quality evidence and were designated as strong recommendations.
Osteoporosis Canada released a review and guideline statement on vitamin D in adult health
and disease in 2010. The guidelines were underpinned by a systematic review of the literature
(through June 2008) and a consensus process. Recommendations are graded according to the
type of supporting evidence that is available (Grade A=highest, D=lowest). The guidelines
recommend that laboratories performing 25-(OH)D testing should take part in external
proficiency surveys and should demonstrate that values reported for shared samples
approximate the consensus of values reported by others (level 4 evidence, grade D
recommendation). In healthy adults at low risk for vitamin D deficiency (defined as below
age 50 years, without osteoporosis or conditions affecting vitamin D absorption or action),
routine vitamin D supplementation is recommended. However, serum 25-(OH)D should not
be measured (grade D recommendation). The guideline advises that serum 25-(OH)D should
be measured only if deficiency is suspected or would affect the person’s response to therapy
(e.g. in cases of impaired intestinal absorption, such as celiac disease, or osteoporosis
requiring pharmacologic therapy. For individuals receiving pharmacologic therapy for
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February 2014
osteoporosis, measurement of serum 25-(OH)D should follow 3 to 4 months of adequate
supplementation and should not be repeated if the optimal level is achieved (grade D
recommendation). Measurement of serum 25-(OH)D is recommended for individuals with
recurrent fractures, bone loss despite osteoporosis treatment, or comorbid conditions that
affect vitamin D absorption or action (grade D recommendation). In these cases, serum 25(OH)D should be measured as part of the initial assessment, and supplementation with
vitamin D should be based on the measured value. Dose requirements above Health Canada’s
current tolerable upper intake level (50 μg [2000 IU]) may be needed, in which case
monitoring of serum 25-(OH)D levels is required (grade D recommendation).
Guidelines relating to pregnant and lactating women
The American Congress of Obstetricians and Gynecologists (ACOG) released an opinion
statement by the Committee on Obstetric Practice regarding vitamin D screening and
supplementation during pregnancy. There is no indication that the statement is evidencebased or was underpinned by a systematic review. The opinion statement advises that current
evidence is insufficient to support a recommendation to screen all pregnant women for
vitamin D deficiency. However, the statement advises that serum 25-(OH)D levels might be
tested in pregnant women considered to be at an increased risk of deficiency. Increased risk is
undefined in the recommendation statement, but vegetarian diet, inadequate sun exposure, and
dark skin are listed as risk factors in the background section.
Guidelines relating to children
The American Academy of Pediatrics (AAP) released a policy in 2008 on the prevention of
rickets and vitamin D deficiency in infants, children, and adolescents. The AAP recommends
that healthy infants, children, and adolescents receive vitamin D at 400 international units per
day (IU/day).
No recommendations regarding screening were made.
Specific
recommendations regarding supplementation were made for breastfed and partially breastfed
infants, non-breastfed infants, children and adolescents. The policy advised that children who
are at an increased risk of vitamin D deficiency, such as those with malabsorption disorders or
use of certain medications, may need higher doses of vitamin D supplementation. It was
recommended that serum 25-(OH)D levels should be checked at 3-month intervals until
normal levels (defined as ≥ 50 nmol/L in infants and children)have been achieved.
The American Academy of Pediatrics (AAP) also published a clinical report in 2011 on
bone densitometry in children and adolescents, which was derived from consensus statements
generated at a Paediatric Position Development Conference of the International Society of
Clinical Densitometry in 2007. The AAP recommends that serum 25-(OH)D concentrations
be measured in children with skeletal fragility to ensure that adequate stores are present.
Disease- or risk-factor specific guidelines
In 2013, the National Osteoporosis Society in the United Kingdom released a practical
clinical guideline for patient management relating to vitamin D and bone health. The
guideline focuses on the management of vitamin D deficiency in adults with, or at risk of
developing, bone disease. The developers used evidence from the Institute of Medicine
(IOM) report in 2010(20), supplemented by literature reviews, to identify subsequent published
papers. Where clear-cut evidence was unavailable to inform the guideline, the authoring
group offered pragmatic advice based on a consensus of their own views and experience. The
guideline recommends that measurement of serum 25-(OH)D is the best way of estimating
vitamin D status. The commentary around this recommendation states that the assay should
have the ability to recognise all forms of 25-(OH)D (D2 or D3) equally. In practice, this
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means that it should use either high performance liquid chromatography or, more likely,
tandem mass spectrometry. None of the immunoassays offer the ability to recognise all forms
of 25-(OH)D. The guideline recommends 25-(OH)D measurement for patients with bone
diseases that may be improved with vitamin D treatment, patients with bone diseases prior to
specific treatment where correcting vitamin D deficiency is appropriate, and patients with
musculoskeletal symptoms that could be attributed to vitamin D deficiency. Routine vitamin
D testing may be unnecessary in patients with osteoporosis or fragility fracture, who may be
co-prescribed vitamin D supplementation with an oral antiresorptive treatment. The guideline
states that routine monitoring of serum 25-(OH)D is generally unnecessary but may be
appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where
poor compliance with medication is suspected. The limited evidence for when to monitor
response to therapy is acknowledged. The guideline states that it is a waste of resources to
measure vitamin D levels too soon after therapy has started. A minimum of three months’
treatment must be given and it may be more prudent to wait until six months have passed.
The Institute for Clinical Systems Improvement (ICSI) released a guideline in 2011 on the
diagnosis and treatment of osteoporosis. The ICSI recommends that serum 25-(OH)D levels
be determined for all patients with osteoporosis, with the optimum defined as ≥ 75 nmol/L to
maximally suppress parathyroid hormone secretion.
The Australian CARI guidelines refer to 2009 clinical practice guidelines from the Chronic
Kidney Disease – Mineral and Bone Disorder (CKD–MDB) Work Group of Kidney Disease:
Improving Global Outcomes (KDIGO). These guidelines for the diagnosis, evaluation,
prevention and treatment of CKD–MDB4, suggest that in patients with CKD Stages 3-5D, 25(OH)D levels might be measured, and repeated testing determined by baseline values and
therapeutic intervention [grade 2C recommendation]. The guidelines suggest that vitamin D
deficiency and insufficiency is corrected using treatment strategies recommended for the
general population [grade 2C recommendation].
The National Institute for Health and Care Excellence (NICE) and the National
Collaborating Centre for Chronic Diseases developed guidance in 2008 on the early
identification and management of chronic kidney disease in adults in primary and secondary
care. NICE developed evidence-based guidance using its public health program process.
Although individuals with chronic kidney disease may develop osteoporosis and bone
metabolism complications, NICE does not recommend routine measurement of vitamin D
levels in individuals with stage I, 2, 3A, or 3B chronic kidney disease.
In 2012, NICE also prepared guidelines for the diagnosis and management of the epilepsies in
adults and children in primary and secondary care. NICE recommends monitoring vitamin D
levels, among other tests of bone metabolism, every 2 to 5 years for individuals who are
receiving enzyme-inducing drugs as part of their epilepsy treatment regimen.
4
Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice
guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone
disorder (CKD–MBD). Kidney International. 2009; 76 (Suppl 113): S1-S130.
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5
REVIEW OF THE CLINICAL EVIDENCE FOR VITAMIN D TESTING
This Chapter presents the results of the systematic literature review on vitamin D testing in
relation to the clinical research questions.
5.1
5.1.1
Evidence base
Search results
The search strategy retrieved a total of 4,873 citations. Appendix 6 provides a Quality of
Reporting Meta-analyses (QUOROM) flowchart describing the sequence of steps undertaken
to select relevant studies for the review of vitamin D testing. In total, 61 studies met the
inclusion criteria described in Table 2.3 (Chapter 2).
Data were extracted from 61 studies and reviews, and meta-analysis was performed on
eligible studies.
5.1.2
Existing health technology assessments and systematic reviews
The search for existing systematic reviews and HTAs on vitamin D testing identified 12
systematic reviews and two HTAs. Table 5.1 presents the characteristics and quality
assessment of these reviews. Data were extracted from all studies presented in Table 5.1 and
are summarised in Chapter 8.
Table 5.1: Characteristics and quality assessment of existing systematic reviews
Author and
Objectives
Patient population
Year
Vitamin D supplementation for promotion of musculoskeletal health
Chung
To systematically review, with a
All included RCTs
meta-analysis, to assess the
recruited adults >50
(2011)(104)
benefits and harms of vitamin D
years old.
update to
supplementation with or without
Chung et al.
calcium on outcomes of cancer
(2009)(9)
(AHRQ report) and fractures in adults.
Murad et al.
To assess systematically, with a
All RCTs included
meta-analysis, the effectiveness
adult.
(2011)(105)
vitamin D supplementation in
preventing falls.
Michael et al.
(2010)(106)
(AHRQ report)
Avenell et al.
(2009)(107)
To evaluate systematically the
benefits and harms of
interventions (including vitamin
D or vitamin D +calcium) to
prevent falls among community
dwelling older adults.
To systematically review, with
meta-analysis, the effects of
vitamin D or related compounds,
with or without calcium, for
preventing fractures in older
people.
MBS Reviews – Vitamin D Testing Review Report
Included
studies
Search period
16
Up to July 2011
26
Up to August
2010
All included RCTs
recruited adults >50
years old.
9
Up to Feb 2010
All included RCTs
recruited men >65
years old and postmenopausal women.
45 RCTs
Up to Oct 2007
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Chung
(2011)(104)
update to
Chung et al.
(2009)(9)
(AHRQ report)
Chung et al.
(2009)(9, 104)
(AHRQ report)
Cranney et al.
(2007)(108)
(AHRQ report)
To systematically review, with a
meta-analysis, to assess the
benefits and harms of vitamin D
supplementation with or without
calcium on outcomes of cancer
and fractures in adults.
To systematically summarise the
evidence on the relationship
between vitamin D, calcium, and
a combination of both with a
wide range of health outcomes
identified by IOM, including
BMC/BMD, physical
performance and falls.
To assess systematically for
evidence-based EAR and RDA
values to be determined by the
IOM, with an emphasis on
musculoskeletal outcomes such
as BMC/BMD, physical
performance, and falls.
All included RCTs
recruited adults >50
years old.
16
Up to July 2011
All included RCTs
recruited adults >50
years old.
9 RCTs
1 SR
Up to Dec 2008
Studies included
children and adults.
17 RCTs
Up to June 2006
42
prospective
studies
(cohort or
nested case
control)
Up to June 2010
Vitamin D supplementation in individuals with cancer
Touvier et al.
(2011)(109)
To evaluate systematically, with
meta-analysis, the evidence of an
inverse relationship between
vitamin D intake and 25-(OH)D
levels and risk of colorectal
cancer.
All included
prospective studies
recruited adults >50
years old.
Vitamin D supplementation in individuals with cardiovascular disease
Witham et al.
(2009)(110)
To evaluate systematically the
ability of vitamin D
supplementation or ultraviolet
radiation to reduce BP.
All included RCTs
recruited adults >50
years old.
7 RCTs
From 1996 to
June 2006
All included RCTs
recruited adults >50
years old.
15 RCTs
Up to March
2011
All included RCTs
and observational
cohort studies
recruited adults >50
years old.
32 studies
(17 RCTs,
15
observational
cohort
studies)
Up to Nov 2009
All included RCTs
recruited pregnant
women.
6 RCTs
Up to Oct 2011
1 RCT
Up to May 2010
Vitamin D supplementation in individuals with diabetes
George et al.
(2012)(111)
Pittas et al.
(2010)(112)
(AHRQ report)
To systematically review, with
meta-analysis, the evidence for
the effect of vitamin D
supplementation on glycaemia,
insulin resistance, progression to
diabetes and complications of
diabetes.
To evaluate systematically the
evidence on the association of
vitamin D levels and the effects
of vitamin D supplementation on
type 2 diabetes, hypertension or
cardiovascular disease.
Vitamin D supplementation during pregnancy
De-Regil et al.
(2012)(113)
To systematically assess the
effects and safety of vitamin D
supplementation on maternal and
newborn outcomes.
Vitamin D supplementation in patients with MS
Jagannath et al.
(2010)(114)
To systematically evaluate the
safety and effectiveness of
vitamin D in the management of
multiple sclerosis.
The included RCT
recruited patients
with MS.
Vitamin D health technology assessments
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Hayes, Inc
(2012)(27)
Ontario Health
Technology
Assessment
(2010)(115)
5.2
Health technology assessment of
the evidence for vitamin D
supplementation in patients with
osteoporosis.
Health technology assessment
which evaluated the clinical
utility of vitamin D testing in
average risk Canadians and in
those with kidney disease. This
report also includes a systematic
literature review of the
prevalence of vitamin D
deficiency in these two
subgroups.
SRs and RCTs of
healthy populations
or patients with
chronic disease.
Studies included
children and adults.
18 RCTs
From 2002 to
July 2012
14
Between
January 1998
and July 2009
Previous health technology assessments of vitamin D testing
As shown in Table 5.1, two HTAs were identified in the literature. One HTA from 2010 was
performed by the Ontario Health Technology Advisory Committee (OHTAC) for the Medical
Advisory Secretariat (MAS) of the Ministry of Health and Long-Term Care, Ontario.(115) This
fair quality HTA reviewed the clinical utility of vitamin D testing. The assessment was
initiated due to the increased volume of Canadian laboratory vitamin D tests from 2004 to
2009. The purpose of the assessment was to evaluate vitamin D testing, with specific
reference to the prevalence rates of vitamin D deficiency in both the general population and in
patients with kidney disease. The assessment focused primarily on bone health and relied
heavily on two reports by the Agency for Healthcare Research and Quality (AHRQ).(9, 108) It
was noted that the use of vitamin D, with or without calcium, has been reported to reduce the
risk of fractures and falls in elderly men and postmenopausal women.
The OHTAC concluded that vitamin D testing was not warranted for the average-risk
population. Average risk was not defined, but the rationale for this conclusion included the
lack of precise target serum levels and the lack of clear supplementation guidelines from
Health Canada. The report also concluded that individuals with renal or liver disease,
osteoporosis, malabsorption syndromes, or conditions requiring medications that can affect
vitamin D absorption or metabolism should follow physician guidance regarding testing as
well as supplementation. With respect to non-bone related health, the report concluded that as
of August 2009, there were insufficient data to support a link between vitamin D and different
non-bone health outcomes such as cancer, all-cause mortality and some cardiovascular
outcomes.
The most recent HTA, undertaken by Hayes, Inc. for the Washington State Health Care
Authority in November 2012, assessed serum vitamin D testing in:
 healthy populations – defined as generally healthy adults, including pregnant women, and
children without symptoms or findings of the outcome of interest; and
 populations with chronic disease that may be linked with, but does not cause, vitamin D
insufficiency, defined as adults and children with chronic diseases such as poor bone
health, obesity, cardiovascular disease, cancer, diabetes, multiple sclerosis, or
depression.(27)
The HTA was of good quality and included the following five key clinical questions, several
of which are relevant to the current MBS review:
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Q1: Has a relationship between serum vitamin D and health outcomes been demonstrated
and have clinically valid cutoff points for serum measurement been defined (clinical
validity)?
o in healthy populations
o in populations with chronic disease
Q2: Is there evidence that testing for serum vitamin D levels improves health outcomes
(clinical utility)?
o as a routine screening test in healthy patients
o in patients who already have chronic disease thought to be associated with low
serum vitamin D
Q3: Are there harms associated with vitamin D testing or with subsequent
supplementation?
Q4: What is the evidence of the differential clinical utility of vitamin D testing,
considering the risk of low serum concentrations and clinical impact of
supplementation doses in (i) healthy populations, and
(ii) patients who already have chronic disease, according to factors such as patient
characteristics and testing parameters?
Q5: What are the cost implications of vitamin D testing, including the cost-effectiveness
of testing compared with not testing?
The findings of the HTA in relation to each of these clinical questions are presented in the
following sections.
5.3
Relationship between vitamin D and health outcomes
Healthy populations
Four reports from the AHRQ provided evidence for the relationship between serum vitamin D
and health outcomes in healthy populations: Cranney et al. 2007 (bone health)(108), Chung et
al. 2009 (bone and other health outcomes)(9), Pittas et al. 2010 (cardiometabolic outcomes)(112)
and Chung et al. 2011 (cancer and fractures)(104). The data reported by the AHRQ reports
came from prospective cohort studies and nested case-control studies, which represent study
designs least subject to bias in assessing epidemiological associations. Individual studies
generally controlled for confounders but the studies varied as to which confounders were
considered.
On the basis of recent systematic reviews, narrative reviews, and clinical trials, the authors of
the HTA provided a summary of the link between serum levels of vitamin D and the risk of
disease (shown in Table 5.2).
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Table 5.2: Link between serum levels of vitamin D and the risk of disease
Disease/condition
Cancer mortality in men
Bone health
Cardiovascular health
Type 2 diabetes
Colorectal cancer
Ovarian cancer
All-cause mortality
Cancer other than colorectal or ovarian cancer
Obesity
Gestational diabetes
Multiple sclerosis
Depression and mood disorders
Association with serum 25-(OH)D
Harmful
Protective
Unclear (inconsistent)
Insufficient*
Source: HTA undertaken by Hayes, Inc. for the Washington State Health Care Authority in November 2012 (27)
* Evidence was missing, sparse, or based on lower quality study designs that are subject to bias (non-nested case-control studies or crosssectional studies).
The HTA cited fair quality (according to the key AHRQ systematic reviews) evidence
showing a link between serum 25-(OH)D and bone mineral density in some populations, but
noted that the evidence did not show a link with outcomes such as fracture or falls, and no
studies have investigated a link with any measure of bone health in younger adults. Analyses
by vitamin D assay type were missing in the reviewed literature.
In terms of cut-off values, the HTA concluded that for disease outcomes where a link has
been demonstrated, the evidence does not support definitive cut-off points at which 25-(OH)D
serum levels can be expected to predict optimal overall health. Although some studies have
conducted analyses according to different strata of serum levels, there was variation across
studies as to how those strata were defined. Other studies did not specify a cut-off point but
analysed associations treating serum level as a continuous variable. The HTA acknowledged
that optimal thresholds may vary by the outcome of interest, but stated that the evidence to
date is consistent with approximately 30 nmol/L as the level below which there is a risk of
deficiency and a threshold ≥ 50 nmol/L, and possibly as high as 70 nmol/L, for optimal
health. The authors concluded that “the lack of definitive cut-off points diminishes the validity
of serum measurements and thereby sheds doubt on the utility of vitamin D screening, and
findings of a possible harmful association between serum 25-(OH)D and cancer mortality in
men complicates interpretation of serum measurements”.
Populations with chronic disease
The authors noted very sparse evidence concerning an association between serum levels of
25-(OH)D and disease-related outcomes in individuals with chronic disease. They identified
a small number of studies in adults suggesting that higher levels of serum 25-(OH)D may be
associated with better prognosis for some types of cancer (colon, prostate and melanoma),
fewer cardiovascular events in individuals with hypertension, fewer complications in
individuals with diabetes, fewer relapses in individuals with MS, and less severe symptoms in
individuals with depression.
The authors concluded that vitamin D screening may have promise for establishing a
prognosis, or for assessing the risks of disease-related events and complications in some
patients; however, the evidence is too sparse to support clinical rules or cut-off points.
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5.4
Relationship between testing for vitamin D levels and health
outcomes
No trials designed to measure the effect of vitamin D screening or testing on health outcomes,
patient behaviour, or clinical decisions were identified. The authors of the 2012 HTA also
noted that this type of evidence was not discussed in recent systematic reviews, narrative
review articles, or practice guidelines. Thus, trials of vitamin D supplementation were
reviewed as an indication of the potential utility of vitamin D screening/testing. The rationale
for this approach was that screening or testing would not improve health outcomes if there
were no effective treatment that could be recommended for individuals with low serum
vitamin D. The evidence for the effectiveness of supplementation was then used by the
authors to identify populations in which screening or testing might be effective. Due to the
large volume of literature available on vitamin D supplementation, only systematic reviews
and RCTs were included.
In total, the HTA identified six systematic reviews and 14 RCTs (23 publications) that
evaluated the effect of vitamin D supplementation on the health outcomes of interest in
healthy populations. In patients with chronic disease, three systematic reviews and 16 RCTs
(18 publications) were identified that evaluated the effect of vitamin D supplementation on
disease-related outcomes. However, in all studies, participants were not selected on the basis
of vitamin D test results. An assessment of the effectiveness of vitamin D supplementation on
healthy populations is presented in Section 5.7. An assessment of the effectiveness of vitamin
D supplementation on patients with chronic disease is presented in Section 5.8.
5.5
Evidence of the differential clinical utility of vitamin D testing
In terms of testing parameters, no studies directly evaluated the effectiveness of testing.
Therefore, differential effectiveness and safety by type of assay, frequency of monitoring, and
time of year that tests are conducted could not be directly evaluated. The trials that assessed
the relationship between baseline serum 25-(OH)D and a treatment effect from vitamin D
supplementation used assays that are often considered reference standards (such as
competitive protein binding assays, chromatographic assays, radioimmunoassay). Most
supplementation trials spanned all seasons of the year, but none analysed effects by season.
5.6
Harms associated with vitamin D testing or supplementation
In terms of harms, vitamin D testing relies on a blood draw, which is a safe procedure. The
authors of the 2012 HTA consider that the consequences of inaccurate or inappropriately
interpreted test results are relatively small. The rationale is that the review of the
effectiveness of vitamin D supplementation showed relatively modest effects at best;
therefore, safety issues associated with false-negative test results would be minimal (see
Sections 5.7 and 5.8 for the assessment of the effectiveness of vitamin D supplementation in
healthy populations, and patients with chronic disease, respectively). Furthermore, since
vitamin D supplementation was found to be a relatively safe therapy (albeit through low or
moderate quality evidence), the authors concluded that the consequences of false-positive test
results would not be serious.
The individual trials reviewed in the 2012 HTA did not discuss adverse events, indicated that
none were reported, or found no important difference between supplementation and placebo
groups. The most comprehensive data relating to adverse effects was from the WHI trial,
which randomised 36,282 women to 400 IU/day of vitamin D plus calcium or placebo and
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followed them for 7 years. The trial showed a statistically significant increased risk of kidney
stones (HR: 1.17, 95% CI: 1.02 to 1.4; P=0.02).(116) However, there was no difference
between groups in self-reported symptoms such as moderate to severe abdominal symptoms.
A Cochrane review of vitamin D supplementation showed an increased risk of
hypercalcaemia with vitamin D supplementation.(117) For inactive forms of vitamin D (12
trials; 11,091 participants), HR: 1.26 (95% CI: 0.78 to 2.05), and for active forms of vitamin
D (3 trials; 410 participants), HR: 3.18 (95% CI: 1.17 to 8.68).
5.7
Effectiveness
populations
of
vitamin
D
supplementation
in
healthy
The literature does not provide direct evidence of the effectiveness of vitamin D testing on
health outcomes. However, as mentioned in Section 5.4, trials of vitamin D supplementation
provide an indication of the potential utility of vitamin D screening/testing. Six systematic
reviews and 14 RCTs (23 publications) evaluated the effect of vitamin D supplementation on
the following health outcomes:










musculoskeletal health, including bone mineral density (BMD), falls and fractures;
obesity;
cancer;
cardiovascular disease;
type 2 diabetes;
multiple sclerosis (MS);
mood disorders;
all-cause mortality;
outcomes related to pregnancy; and
children and adolescents.
A review of the evidence relating to the effectiveness of supplementation on the health
outcomes listed above is presented in Appendix 9.
Table 5.3 summarises the findings relating to vitamin D supplementation from the 2012
Hayes, Inc. HTA for the Washington State Health Care Authority.(27) The evidence for the
benefits of supplementation was generally considered to be of low quality, except for
moderate quality evidence regarding prevention of mood disorders. Common weaknesses
included variable vitamin D doses across studies (with studies using low doses more likely to
report negative or non-significant results) and varied protocols with respect to the use of nonstudy vitamin D. Where the evidence suggested a benefit, the effects were small.
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Table 5.3: Summary of the effectiveness of vitamin D supplementation in healthy populations
Source: HTA undertaken by Hayes Inc. for the Washington State Health Care Authority in November 2012 (27)
* Predominantly postmenopausal women
#
Vitamin D plus calcium
Given the evidence suggesting positive effects of supplementation on musculoskeletal health
and general mortality in older adults, screening for low vitamin D status might be effective for
these two particular outcomes.(27) Evidence regarding the effectiveness of increased vitamin
D intake through supplementation does not, in general, support vitamin D screening to
improve non-skeletal health outcomes other than mortality.
5.8
Effectiveness of vitamin D supplementation in patients with
chronic disease
Three systematic reviews and 16 RCTs (18 publications) evaluated the effect of vitamin D
supplementation on disease-related outcomes in patients with chronic disease:








obesity
poor musculoskeletal health;
cancer;
cardiovascular disease;
type 2 diabetes;
multiple sclerosis;
depression and other mood disorders; and
all-cause mortality.
A review of the evidence relating to the effectiveness of supplementation on the health
outcomes listed above is presented in Appendix 10.
Table 5.4 summarises the findings from the 2012 Hayes Inc. HTA for the Washington State
Health Care Authority(27) relating to vitamin D supplementation in patients with chronic
disease. The HTA considered the evidence regarding supplementation in patients with
chronic disease to be of low to moderate quality, depending on the disease population.
However, even in the disease populations where the evidence showed a benefit, the effects
were generally small and the clinical relevance was questionable. An exception was the
effects of active vitamin D supplementation on bone health in older adults with osteoporosis
or a history of fracture.
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Table 5.4: Summary of the effectiveness of vitamin D supplementation in patients with chronic
disease
Source: HTA undertaken by Hayes Inc. for the Washington State Health Care Authority in November 2012 (27)
On the basis of the evidence of the effectiveness of supplementation with active forms of
vitamin D, vitamin D testing in patients who have evidence of osteoporosis has the potential
to improve bone-related outcomes.(27)
Furthermore, given the evidence showing
supplementation to modestly improve disease-related outcomes in individuals with
cardiovascular disease or abnormal blood glucose, vitamin D screening to assess the risk of
adverse disease outcomes might be effective in these populations. The available evidence
regarding the effectiveness of increased vitamin D intake through supplementation does not,
in general, support screening in other disease populations.
5.9
Overall summary from the clinical evidence
Vitamin D supplementation and vitamin D screening/testing are reasonably safe
interventions.(27) No trials have directly assessed the impact of screening or testing on health
outcomes, patient behaviour, or clinical decision making therefore no definitive conclusions
can be drawn about the effectiveness of vitamin D screening or testing. However, there is
evidence for an association between serum levels and/or a positive effect of supplementation
on some health outcomes in some populations. Vitamin D screening/testing therefore has
potential utility for identifying individuals who could benefit from the preventative or diseasemodifying effects of supplementation.
On the basis of the available evidence for supplementation and associations between serum
25-(OH)D and health outcomes, the 2012 Hayes Inc. HTA for the Washington State Health
Care Authority(27) concluded that knowledge of vitamin D serum levels might have value:
(1) to demonstrate the need for supplementation in postmenopausal women as a means of
reducing disease and mortality risk (based on low quality evidence); and
(2) to inform treatment for individuals with known or highly suspected osteoporosis (based
on moderate quality evidence).
An additional indication for vitamin D screening may be to assess the need for
supplementation to promote musculoskeletal health in adult populations selected only because
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of older age. However, evidence that routine supplementation of postmenopausal or
institutionalised women without screening is cost-effective as a preventative treatment for
fracture suggests that screening is unnecessary in this population.
For other populations and outcomes, the available evidence suggests no benefit from vitamin
D screening or was insufficient to draw conclusions.
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6
REVIEW OF THE ECONOMIC EVIDENCE RELATING TO VITAMIN D
TESTING
This Chapter presents a preliminary economic evaluation of vitamin D testing, which is
limited to a summary of the findings from the available studies identified through the
systematic literature review. A formal modelled economic evaluation of vitamin D testing
was not within the scope of this review.
6.1
Evidence base
The 2012 HTA prepared for the Washington State Health Care Authority aimed to assess the
cost implications of vitamin D testing and the cost-effectiveness of testing compared with not
testing.(27) The relevant clinical question posed in the 2012 HTA was: What are the cost
implications of vitamin D testing, including the cost-effectiveness of testing compared with not
testing?
The HTA did not identify any systematic reviews undertaken to evaluate the costeffectiveness of vitamin D testing. The HTA identified one poor-quality cost analysis of
vitamin D testing.(118) However, no cost-effectiveness studies of vitamin D screening or
testing were identified. In the absence of evidence for the cost-effectiveness of testing, the
authors sought evidence for the cost-effectiveness of vitamin D supplementation and
identified seven potentially relevant studies, of which four were excluded because of serious
limitations in the assumption about prevalence or the basis of the effectiveness estimate. The
three included studies evaluated vitamin D supplementation for the prevention of fractures
and/or falls in older adult populations.(119-121) Importantly, none of studies considered vitamin
D testing to be one of the costs associated with supplementation. Thus, these studies are only
briefly discussed below.
6.2
Cost implications of vitamin D testing
The poor-quality cost analysis identified by the 2012 HTA was based on a retrospective chart
review of Veterans Medical Centers in the southeastern United States.(118) The cost analysis
suggested that, assuming at least one routine vitamin D test, subsequent monitoring of serum
vitamin D levels could reduce medical costs from the perspective of Veterans Administration
(VA) Medical Centres.(118) Data for 15,340 patients seen at six VA centres were collected.
Total outpatient and total inpatient costs were analysed according to the number of follow-up
tests after an initial vitamin D test, vitamin D sufficiency at the time of initial test, the latitude
and season of initial blood draw, and site.
Both inpatient and outpatient costs over a one-year time frame following blood draw were
lower in individuals who had sufficient serum vitamin D levels at initial testing (and thus no
need for monitoring) compared with individuals who tested as vitamin D deficient. However,
inpatient and outpatient costs were lower in patients who had ≥ 2 follow-up tests, compared
with no follow-up or one follow-up test. All factors were statistically significant explanations
of cost variation. However, the lack of data on initial test results, the distribution of vitamin
D-replete and vitamin D-deficient individuals who had no follow-up test, disease prevalence
and severity, and prescribed supplementation regimens makes these findings difficult to
interpret. Furthermore, there was no comparison of costs between individuals who had no
vitamin D testing at all and those who had ≥ 1 test.(27)
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6.3
Cost-effectiveness of vitamin D supplementation
The three included cost-effectiveness studies identified by the 2012 Hayes Inc HTA evaluated
vitamin D supplementation in different older adult populations, generally from a payer
perspective(119-121). All three studies assumed that individuals would receive 800 IU/day of
vitamin D3 combined with calcium. The summary of findings for each study is found in
Appendix 8 (Table A8.3).
The economic analysis by Gajic-Veljanoski et al. (2012)(119) demonstrated that vitamin D plus
calcium supplementation in a population of 50-year-old postmenopausal women in Canada
could reduce the direct medical costs associated with fracture. Lifetime cost savings were
estimated to be $US4,196 to $US4,283 per woman in 2009, taking into account long-term
care. As noted in Appendix 8 (Table A8.3), there are some concerns that suggest the
effectiveness estimate may be somewhat biased in favour of the cost-savings finding.
The economic analysis by Lilliu et al. (2003)(120) found supplementation to be cost-saving for
prevention of hip fracture in institutionalised women. The analysis used data from seven
European countries to estimate costs associated with treating a hip fracture. Effectiveness
estimates were derived from a placebo-controlled RCT of vitamin D supplementation to
prevent hip fractures in elderly women.(122) The results suggested total savings of $US87,137
to $US784,233 per 1,000 women, depending on how costs were reported and the follow-up
interval (≤ 1 year postfracture). The cost savings reported by Lilliu and colleagues are
imprecise because of the variable manner in which costs were reported by different
countries.(27)
The study by Singh et al. (2004)(121) considered vitamin D and calcium supplementation to be
standard care and conducted a study of the cost utility of hip protectors for elderly nursing
home residents in Canada. The perspective of the analysis was described as societal, but only
direct medical costs were considered. The cost of hip protectors and supplements were
obtained from local retail suppliers. The cost of fracture treatment included only immediate
hospitalisation in the base case and was estimated by the finance department of a local
hospital associated with the nursing home. Effectiveness estimates were obtained from a
Cochrane Review of hip protectors and a 1992 placebo-controlled RCT of vitamin D
supplementation in elderly women(122). The economic analysis concluded that hip protectors
were cost-saving in comparison with supplementation for women and men.
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7
FINDINGS AND CONCLUSIONS
This Chapter sets out the findings and conclusions of the review of vitamin D testing – as
represented by MBS item numbers 66608 and 66609 – based on the analysis of the available
MBS data; evidence obtained through systematic literature review; and the information
derived from the stakeholder consultations.
7.1
Current usage of vitamin D testing services in Australia
The number of MBS claims for vitamin D testing (item 66608 and 66609) has increased each
year over the past ten years, from 117,474 claims in 2003/04 to 4,331,030 claims in 2012/13.
This represents a 3,587% increase in vitamin D testing services. Over the same time period, a
similar increase (3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04
to $151,129,505 in 2012/13.
Over 98% of vitamin D testing services are for MBS item 66608. The proportion of services
bulk billed for this item from 2008/09 to 2012/13 was high (more than 95% of services),
which is consistent with the high proportion of out-of-hospital services for this item (over
98%). MBS item 66609 was listed on the MBS in May 2007. After a peak in services in
2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13). For
item 66609, over 85% of services were bulk billed from 2008/09 to 2012/13.
Between 2008/09 and 2012/13, the majority of all claims for item 66608 were from NSW and
Victoria; the other states and territories together accounted for less than 30% of total claims in
each year. Victoria had the highest rate of claiming per capita (25,267 claims per 100,000
population), followed by the ACT and NSW. The lowest per capita rates of vitamin D testing
services were in the northernmost states and territories (NT and Queensland). Item 66609
showed much more variability over time, and relatively high usage in Queensland as a
proportion of total claims. The highest number of claims per capita in 2012/13 was for
Tasmania and the ACT, while Victoria had the lowest.
Item numbers 66608 and 66609 are claimed by both genders; however, from 2008/09 to
2012/13, 70.2% of claims for MBS item 66608 and 68.9% of claims for item 66609 were for
females. The number of claims is particularly significant for females aged between 24 and 84
years. Australian guidelines for general practice recommend that targeted vitamin D testing
should be considered for people who are at risk of osteoporosis and who are at high risk of
vitamin D deficiency. Prevalence estimates from Australia indicate that 31%-36% of adults
are deficient in vitamin D (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to
50%-62% in women during winter-spring or in people residing in southern states. The gender
imbalance and peak in testing for vitamin D levels within the 55-64 year age category is
consistent with epidemiological trends for vitamin D deficiency and osteoporosis. However,
the reason for the high rate of testing in the 45-54 year age category is less clear. An
examination of total services for MBS item 66608 in 2012/13 showed no difference in the
proportion of tests claimed in winter-spring (when the prevalence of vitamin D deficiency is
reported to be at its highest) compared with summer-autumn.
An analysis of vitamin D testing frequency per patient was conducted. The proportion of
patients who received only one test per year increased slightly over time for item 66608
(81.8% in 2008/09 and 83.4% in 2012/13), whereas the proportion of patients who received
two tests per year decreased from 14.8% to 13.9%, and the proportion of patients who
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received three or more tests per year decreased from 3.4% to 2.8%. For item 66609, the
proportion of patients who received one or two tests per year was relatively stable over time
whereas the proportion of patients who received three or more tests decreased from 3.1% in
2008/09 to 2.1% in 2012/13. Taken together with the age profile of patients being tested,
these data suggest that the majority of vitamin D testing services are being undertaken for the
purposes of screening/testing rather than monitoring.
From 2008/09 to 2012/13, there were no material changes in the pattern of requesting
providers. GPs and OMPs accounted for nearly two-thirds of all providers requesting vitamin
D testing services for item 66608. Internal medicine consultant physicians accounted for
another 15% of all provider counts, followed by specialist general surgeons, non-specialist
surgeons, interns, psychiatrists, obstetricians/gynaecologists, and other temporary resident
doctors. There were a large variety of other provider types requesting services, but they each
accounted for less than 1% of provider counts. For item 66609, GPs and OMPs accounted for
over 60% of all providers requesting vitamin D testing services, followed by internal
medicine consultant physicians (approximately 28%).
An analysis of vitamin D test requests by frequency from any one provider was conducted.
For item 66608, there was an increase over the period 2008/09 to 2012/13 in the overall
number of providers requesting vitamin D testing. The proportion of providers requesting ten
or fewer tests per year decreased from 53.6% in 2008/09 to 38.7% in 2012/13, whereas the
proportion of providers requesting 11-50 tests per year remained relatively stable (from 25.4%
to 24.5%). In contrast, the proportion of providers requesting more than 50 tests per year has
increased from 21.0% in 2008/09 to 36.8% in 2012/13. Each year, there is a small number of
providers who request over 400 vitamin D tests per year (682 in 2008/09 rising to 1,867 in
2012/13). For item 66609, the proportion of providers requesting one test per year increased
from 54.5% in 2007/08 to 64.1% in 2012/13. In contrast, the proportion of providers
requesting two or more tests decreased from 44.5% in 2008/09 to 35.9% in 2012/13.
Taken together, these data show that there is a large and increasing number of providers,
primarily GPs and OMPs, who are requesting high volumes of vitamin D tests per year,
presumably for the purposes of screening/testing rather than monitoring.
7.2
Clinical guidance on vitamin D testing
The MBS data indicate that the majority of requests for vitamin D testing are initiated by GPs
and OMPs. The relevant College proving practice advice is the Royal Australian College of
General Practitioners (RACGP). The 2012 RACGP guidelines for preventative activities in
general practice advise that routine screening for vitamin D deficiency is not recommended in
low risk populations. However, targeted testing of people who are at risk of osteoporosis and
who are at high risk of vitamin D deficiency should be considered. High-risk groups for
vitamin D deficiency in pregnancy may also benefit from vitamin D screening. The
guidelines do not advise on the frequency of testing.
The RACGP has also produced a 2010 clinical guideline for the prevention and treatment of
osteoporosis in postmenopausal women and older men. Serum 25-(OH)D is one of the
recommended laboratory tests for the diagnostic assessment for osteoporotic fractures, but
only under particular conditions (e.g. if secondary osteoporosis is suspected). The guideline
does not mention vitamin D testing for the management of osteoporosis.
The Royal College of Pathologists of Australasia (RCPA) released a Position Statement in
May 2013 for the use and interpretation of vitamin D testing. The Position Statement
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recommended testing for vitamin D status in individuals at risk of vitamin D deficiency and
showing the following indications:







signs, symptoms and/or planned treatment of osteoporosis or osteomalacia;
increased alkaline phosphatase with otherwise normal liver function tests;
hyperparathyroidism, hypo- or hypercalcaemia or hypophosphataemia;
malabsorption (e.g. cystic fibrosis, short bowel syndrome, inflammatory bowel disease,
untreated coeliac disease, bariatric surgery);
deeply pigmented skin, or chronic or severe lack of sun exposure for cultural, medical,
occupational or residential reasons;
medications known to decrease vitamin D levels (mainly anticonvulsants); and
chronic renal failure and renal transplant patients.
The Position Statement did not explicitly recommend routine testing for vitamin D status in
the general population (including healthy adults, pregnant women, and children). However, it
recommended that serum vitamin D levels be retested after three months following the
commencement of vitamin D supplementation. No further testing is required once desirable
25-(OH)D target levels are achieved. The position Statement recommended against high dose
annual replacement of cholecalciferol as this was associated with increased falls and fractures
in elderly men and women. The Statement recommended that the target level of serum 25(OH)D should be >50 nmol/L at the end of winter.
The Working Group of the Australian and New Zealand Bone and Mineral Society
(ANZBMS), Endocrine Society of Australia and Osteoporosis Australia released a position
statement in 2012 for vitamin D and health in adults in Australia and New Zealand. The
position statement recommended screening for 25-(OH)D levels in high-risk groups. The
following high-risk groups were identified:






older or disabled people in low-level and high-level residential care, particularly
housebound community-dwelling geriatric patients admitted to hospital;
dark-skinned people of either sex, particularly migrants and/or if modest dress is worn;
people with a disability of chronic disease (e.g. multiple sclerosis);
fair-skinned people and those at risk of skin cancer who avoid sun exposure;
obese people; and
people working in an enclosed environment, such as office workers, factory or warehouse
workers, taxi drivers, nigh-shift workers.
The position statement advised for retesting of vitamin D levels three months after
commencement of supplementation.
In 2013, the Working Group of the ANZBMS and Osteoporosis Australia also released a
position statement on vitamin D and health in pregnancy, infants, children and adolescents.
The position statement advised that universal screening for vitamin D status in pregnant
women, infants, children and adolescents is not supported by the evidence. However, 25(OH)D levels should be tested in those with one or more risk factors for low vitamin D. Risk
factors for low vitamin D in pregnancy, infants, children and adolescents include:


lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors,
chronic illness or hospitalisation, complex disability, covering clothing for religious or
cultural reasons or southerly latitude);
dark skin;
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

medical conditions or medications affecting vitamin D metabolism and storage (obesity,
end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as
rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease
and inflammatory bowel disease]); and
in infants, maternal vitamin D deficiency and exclusive breastfeeding combined with at
least one other risk factor.
Infants, children and adolescents with ongoing risk factors require ongoing monitoring of
vitamin D status with annual testing. Recently arrived migrant children at risk of low vitamin
D should have testing repeated at the end of their first winter in Australia. Pregnant women
should be tested at their first antenatal visit and again at 28 weeks’ gestation. Vitamin D
testing should also be considered in exclusively breastfed infants or mixed fed infants with at
least one other risk factor. The position statement advises that follow-up testing should be
performed in patients on vitamin D supplementation. For neonates with moderate or severe
deficiency, follow-up at one month is recommended; in other groups, follow-up at three
months is usually more practical; and in the long term, annual testing is recommended. Very
frequent testing should be avoided.
In 2012, Kidney Health Australia published CARI (Caring for Australasians with Renal
Impairment) guidelines on vitamin D therapy (supplementation) in early kidney disease. The
guidelines recommend that patients with early chronic kidney disease on vitamin D therapy
have their 25-(OH)D levels monitored regularly. Further details on the frequency of testing
are not provided.
The Australian guidelines are consistent with international guidelines that recommend against
routine screening for vitamin D status in adults, pregnant women and children. However,
there are guidelines that support screening in high-risk individuals (although definitions of atrisk were lacking in these guidelines), and testing vitamin D status in populations with known
poor bone health (such as children with skeletal fragility and adults with osteoporosis).
Follow-up testing is also recommended in people being treated pharmaceutically for
osteoporosis (at 3-4 months after commencement of therapy).
Recommendations against routine screening are consistent with the lack of direct evidence
that vitamin D testing improves outcomes, as well as the lack of moderate or high quality
evidence that supplementation improves outcomes in healthy populations. Recommendations
for testing in populations with known poor bone health are weakly supported by evidence of
the effectiveness of supplementation in these populations, but there is no direct evidence
concerning the clinical utility of testing (see below).
Several guidelines mention that measurement of serum 25-(OH)D is the best way of
estimating vitamin D status. 25-(OH)D has a relatively long half-life and is therefore a better
indicator of vitamin D stores, whether obtained from sunlight or dietary sources. The main
methods available to estimate 25-(OH)D levels are immunoassay or LC-MS (see Section
1.1.4). Immunoassays are often automated and are therefore cheaper and faster to run a large
number of samples. Apart from issues of calibration and standardisation, a weakness is the
inability to quantify vitamin D2 and vitamin D3 separately, which means they give an
estimation of total 25-(OH)D. LC-MS is considered to be the ‘gold’ standard’ and is able to
simultaneously estimate 25-(OH)D in its two analyte forms, D2 and D3. The technique is
more sensitive than immunoassay but is more labour intensive and requires expensive
equipment and skilled staff.
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The performance of radioimmunoassay is generally considered to be acceptable; however, the
bias and imprecision of many automated methods may be problematic at the lower, clinically
and analytically important range (< 50 nmol/L) of the assay. Prior to the recent introduction
of the standard reference material for 25-(OH)D from the National Institute of Standards and
Technology (NIST), there were numerous publications reporting that different immunoassays
may be yielding different results. However, the introduction of the reference standard has
helped to assess the accuracy of the different immunoassays for the measurement of serum
25-(OH)D and can serve as an adjunct to quality assurance programs for vitamin D
measurements. As discussed in Section 1.1.5, all Australian and New Zealand laboratories
offering 25-(OH)D testing are required to be enrolled in external proficiency programs, which
allow each laboratory to monitor its performance compared with its peers. These
standardisation efforts are essential to the reliable diagnosis, evaluation, and treatment of
vitamin D deficiency and help clinicians to more accurately interpret the results from vitamin
D testing.
7.3
Relationship between vitamin D and health outcomes
On the basis of a review of recent systematic reviews, narrative reviews and clinical trials in
healthy populations, the evidence suggests a harmful association of serum 25-(OH)D with
cancer mortality in men, but a protective association of serum 25-(OH)D with bone health,
cardiovascular health, type 2 diabetes, colorectal cancer, ovarian cancer and all-cause
mortality. There was an ‘unclear’ link between serum 25-(OH)D and cancer (other than
colorectal or ovarian) and insufficient evidence regarding an association of serum 25-(OH)D
with obesity, gestational diabetes, multiple sclerosis, depression and mood disorders.
For disease outcomes where a link has been demonstrated, the evidence does not support
definitive cut-off points at which 25-(OH)D serum levels can be expected to predict optimal
overall health. However, the evidence is consistent with approximately 30 nmol/L as the
level below which there is a risk of deficiency and a threshold ≥ 50 nmol/L, and possibly as
high as 70 nmol/L, for optimal health. Optimal thresholds may vary by the outcome of
interest.
There was very sparse evidence concerning an association between serum levels of 25-(OH)D
and disease-related outcomes in individuals with chronic disease. Vitamin D screening may
have promise for establishing a prognosis in patients with colon cancer, prostate cancer or
melanoma and for assessing the risk of disease-related events and complications in patients
with hypertension and diabetes; however, the evidence is too sparse to support clinical rules
or cut-off points.
7.4
Relationship between testing for vitamin D levels and health
outcomes
No trials designed to measure the effect of vitamin D screening or testing on health outcomes,
patient behaviour or clinical decisions were identified. Therefore trials of vitamin D
supplementation were reviewed as an indication of the potential utility of vitamin D
screening/testing. The rationale was that screening or testing would not improve health
outcomes if there were no effective treatment that could be recommended for individuals with
low serum vitamin D.
Due to a lack of studies directly evaluating the effectiveness of testing, differential
effectiveness and safety by type of assay, frequency of monitoring and time of year that tests
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are conducted could not be directly evaluated. Most supplementation trials spanned all
seasons of the year, but none analysed effects by season.
7.5
Effectiveness of vitamin D supplementation
A 2010 HTA from the Ontario Health Technology Advisory Committee (OHTAC) reviewed
the clinical utility of vitamin D testing. The HTA noted that the use of vitamin D, with or
without calcium, has been shown to reduce the risk of fractures and falls in elderly men and
postmenopausal women. There were insufficient data to support a link between vitamin D
and non-bone health outcomes such as cancer, all-cause mortality and some cardiovascular
outcomes. The OHTAC recommended that routine testing of vitamin D levels should not be
endorsed for the general population, but only conducted for patients with certain bone-related
conditions, renal disease or malabsorption syndromes.
A good quality HTA published in November 2012 for the Washington State Health Care
Authority evaluated the effect of vitamin D supplementation in:
 healthy populations – defined as generally healthy adults, including pregnant women, and
children without symptoms or findings of the outcome of interest; and
 populations with chronic disease that may be linked with, but does not cause, vitamin D
insufficiency, defined as adults and children with chronic diseases such as poor bone
health, obesity, cardiovascular disease, cancer, diabetes, multiple sclerosis, or depression.
The effect of vitamin D supplementation on outcomes in healthy populations was evaluated in
six systematic reviews and 14 RCTs (23 publications). Participants were not selected on the
basis of vitamin D test results. The evidence base was generally considered to be of low
quality, except for moderate-quality evidence regarding prevention of mood disorders.
Common weaknesses included variable vitamin D doses across studies and varied protocols
with respect to the use of non-study vitamin D. Where the evidence suggested a benefit, the
effects were small.
In summary, the evidence suggests positive effects of supplementation on musculoskeletal
health and general mortality in older adults. Evidence regarding the effectiveness of
increased vitamin D intake through supplementation does not, in general, support vitamin D
screening to improve non-skeletal health outcomes other than mortality.
The effect of vitamin D supplementation on disease-related outcomes in patients with chronic
disease was evaluated in three systematic reviews and 16 RCTs (18 publications).
Participants were not selected on the basis of vitamin D test results. The evidence was
considered to be of low to moderate quality, depending on the disease population. However,
even in the disease populations where the evidence showed a benefit, the effects were
generally small and the clinical relevance was questionable.
An exception was the effect of active vitamin D supplementation on bone health in older
adults with osteoporosis or a history of fracture. On the basis of a moderate body of evidence
showing benefit of supplementation in this population, the HTA concluded that vitamin D
testing in patients who have evidence of osteoporosis has the potential to improve bonerelated outcomes. Given the evidence showing supplementation to modestly improve diseaserelated outcomes in individuals with cardiovascular disease or abnormal blood glucose,
vitamin D screening to assess the risk of adverse disease outcomes might also be effective in
these populations. The available evidence regarding the effectiveness of increased vitamin D
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intake through supplementation does not, in general, support screening in other disease
populations.
On the basis of the available evidence for supplementation and associations between serum
25-(OH)D and health outcomes, the 2012 HTA concluded that knowledge of vitamin D serum
levels might have value:
(1) to demonstrate the need for supplementation in postmenopausal women as a means of
reducing disease and mortality risk (based on low quality evidence); and
(2) to inform treatment for individuals with known or highly suspected osteoporosis (based
on moderate quality evidence).
7.6
Harms associated with vitamin D testing or supplementation
Testing for vitamin D status is a relatively safe procedure that relies on a blood draw. The
consequences of inaccurate or inappropriately interpreted test results (false negative and false
positive tests) are relatively small considering that vitamin D supplementation provides
relatively modest effects and is a relatively safe therapy.
Supplementation with inactive vitamin D is associated with a moderate increase in the risk of
both hypercalcaemia and kidney stones (which are related conditions). The evidence base is
of moderate quality. Based on low quality (and quantity) evidence, treatment with active
(pharmaceutical) vitamin D is associated with an approximately threefold increase in the risk
of hypercalcaemia. Vitamin D therapy may be associated with musculoskeletal and
gastrointestinal symptoms, but a causal relationship has not been proven. No serious adverse
events have been reported in trials of vitamin D supplementation.
7.7
Cost implications of vitamin D testing
As no trials have assessed the effectiveness of vitamin D testing itself, a cost-effectiveness
analysis of vitamin D testing is not possible. The 2012 HTA for the Washington State Health
Care Authority identified one poor-quality cost analysis of vitamin D testing, which was
based on a retrospective chart review of Veterans Medical Centers in the United States. There
was no comparison of costs between individuals who had no vitamin D testing at all and those
who had one or more tests.
Three cost-effectiveness studies of vitamin D supplementation were identified, all relating to
the prevention of fractures and/or falls in older adult populations. The studies were generally
well designed and the evidence was considered to be of moderate quality. However, the
selected studies did not consider vitamin D testing to be one of the costs associated with
supplementation.
The authors of the 2012 HTA concluded that there is consistent evidence that suggests that
routine supplementation in older populations reduces costs associated with hip fracture.
Therefore, there is no need for vitamin D screening to identify subpopulations in whom there
is a potential for such cost savings. For other populations and outcomes, there is no evidence
relating to the cost implications of vitamin D testing or screening.
7.8
Conclusions
There has been a substantial increase in the number of claims for vitamin D testing over the
past ten years. Analysis of MBS data indicates that the majority of vitamin D testing services
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are requested by GPs and OMPs for the purposes of screening or testing, rather than followup monitoring. Australian and international clinical practice guidelines recommend against
routine screening for vitamin D status in adults, pregnant women and children. However,
screening is supported in individuals at high risk of vitamin D deficiency (particularly
pregnant women and paediatric populations) and testing is supported in populations with
known poor bone health (such as children with skeletal fragility and adults with osteoporosis).
Follow-up testing at 3-4 months is also recommended in people with osteoporosis or chronic
kidney disease being treated pharmaceutically. Recommendations for testing in populations
with known poor bone health are weakly supported by evidence of the effectiveness of
supplementation in these populations, but there is no direct evidence concerning the clinical
utility of testing in any population.
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Peacock M, Liu G, Carey M, McClintock R, Ambrosius W, Hui S, et al. Effect of calcium or
25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the
age of 60. J Clin Endocrinol Metab 2000 Sep;85(9):3011-9.
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and cancer mortality in the United States. J Natl Cancer Inst 2007 Nov 7;99(21):1594-602.
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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 Aug 11;168(15):1629-37.
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Forman MR, Levin B. Calcium plus vitamin D3 supplementation and colorectal cancer in
women. N Engl J Med 2006 Feb 16;354(7):752-4.
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Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, et al. Serum vitamin D
concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 2008
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Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and
prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000
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cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol
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Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic
levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control 1995
May;6(3):235-9.
175.
Jacobs ET, Giuliano AR, Martinez ME, Hollis BW, Reid ME, Marshall JR. Plasma levels of
25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid
Biochem Mol Biol 2004 May;89-90(1-5):533-7.
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Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of
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Med 2007 Mar;4(3):e103.
177.
Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Vitamin D
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Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, et al. Serum
vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii,
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179.
Park SY, Cooney RV, Wilkens LR, Murphy SP, Henderson BE, Kolonel LN. Plasma 25hydroxyvitamin D and prostate cancer risk: the multiethnic cohort. Eur J Cancer 2010
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180.
Travis RC, Crowe FL, Allen NE, Appleby PN, Roddam AW, Tjonneland A, et al. Serum
vitamin D and risk of prostate cancer in a case-control analysis nested within the European
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Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol 2009 May
15;169(10):1223-32.
181.
Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, et al. Both high and
low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal,
nested case-control study in the Nordic countries. Int J Cancer 2004 Jan 1;108(1):104-8.
182.
Nilas L, Christiansen C. Treatment with vitamin D or its analogues does not change body
weight or blood glucose level in postmenopausal women. Int J Obes 1984;8(5):407-11.
183.
Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other
metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr
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184.
Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, et al. Circulating 25hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European
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prospective studies. Diabetologia 2012 Aug;55(8):2173-82.
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vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research
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187.
Ortega RM, Lopez-Sobaler AM, Aparicio A, Bermejo LM, Rodriguez-Rodriguez E, Perea JM,
et al. Vitamin D status modification by two slightly hypocaloric diets in young
overweight/obese women. Int J Vitam Nutr Res 2009 Mar;79(2):71-8.
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Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, et al. Vitamin D
supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J
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190.
Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during
pregnancy: effect on neonatal calcium homeostasis. J Pediatr 1986 Aug;109(2):328-34.
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in pregnancy: a controlled trial of two methods. Obstet Gynecol 1986 Sep;68(3):300-4.
192.
Marya RK, Rathee S, Dua V, Sangwan K. Effect of vitamin D supplementation during
pregnancy on foetal growth. Indian J Med Res 1988 Dec;88:488-92.
193.
Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D supplementation on
toxaemia of pregnancy. Gynecol Obstet Invest 1987;24(1):38-42.
194.
Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation
during pregnancy. Clin Endocrinol (Oxf) 2009 May;70(5):685-90.
195.
Roth DE, Al Mahmud A, Raqib R, Akhtar E, Black RE, Baqui AH. Pharmacokinetics of highdose weekly oral vitamin D3 supplementation during the third trimester of pregnancy in
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196.
Roth DE, Al Mahmud A, Raqib R, Akhtar E, Perumal N, Pezzack B, et al. Randomized
placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in
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197.
Soheilykhah S, Mojibian M, Moghadam MJ, Shojaoddiny-Ardekani A. The effect of different
doses of vitamin D supplementation on insulin resistance during pregnancy. Gynecol
Endocrinol 2013 Apr;29(4):396-9.
198.
Poel YH, Hummel P, Lips P, Stam F, van der Ploeg T, Simsek S. Vitamin D and gestational
diabetes: a systematic review and meta-analysis. Eur J Intern Med 2012 Jul;23(5):465-9.
199.
Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, et al. Effect of weekly
vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in
India up to age 6 months: randomised controlled trial. Bmj 2011;342:d2975.
200.
Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D
supplementation on symptoms of depression in overweight and obese subjects: randomized
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201.
Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors
in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern
Med 2010 May;267(5):462-72.
202.
Major GC, Alarie F, Dore J, Phouttama S, Tremblay A. Supplementation with calcium +
vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein
concentrations. Am J Clin Nutr 2007 Jan;85(1):54-9.
203.
Rosenblum JL, Castro VM, Moore CE, Kaplan LM. Calcium and vitamin D supplementation
is associated with decreased abdominal visceral adipose tissue in overweight and obese adults.
Am J Clin Nutr 2012 Jan;95(1):101-8.
204.
Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in
weight reduction in overweight and obese subjects. Eur J Endocrinol 2008 Dec;159(6):675-84.
205.
Zittermann A, Frisch S, Berthold HK, Gotting C, Kuhn J, Kleesiek K, et al. Vitamin D
supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk
markers. Am J Clin Nutr 2009 May;89(5):1321-7.
206.
Major GC, Alarie FP, Dore J, Tremblay A. Calcium plus vitamin D supplementation and fat
mass loss in female very low-calcium consumers: potential link with a calcium-specific
appetite control. Br J Nutr 2009 Mar;101(5):659-63.
207.
Steffensen LH, Jorgensen L, Straume B, Mellgren SI, Kampman MT. Can vitamin D
supplementation prevent bone loss in persons with MS? A placebo-controlled trial. J Neurol
2011 Sep;258(9):1624-31.
208.
Kampman MT, Steffensen LH, Mellgren SI, Jorgensen L. Effect of vitamin D3
supplementation on relapses, disease progression, and measures of function in persons with
multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial.
Mult Scler 2012 Aug;18(8):1144-51.
209.
Gloth FM, 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the
treatment of seasonal affective disorder. J Nutr Health Aging 1999;3(1):5-7.
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210.
Khajehei M, Abdali K, Parsanezhad ME, Tabatabaee HR. Effect of treatment with
dydrogesterone or calcium plus vitamin D on the severity of premenstrual syndrome. Int J
Gynaecol Obstet 2009 May;105(2):158-61.
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APPENDIX 2 – Review Consultation Committee members
As part of the MBS Review process, the Department established a Review Consultation
Committee (RCC). The RCC is a time-limited committee of nominated representatives to
provide advice to the Department to inform the review process, such as the development of
review reports, i.e. scope and protocol documents, clinical practice and policy issues.
Name
A/Prof Ken Sikaris
A/Prof Hans Schneider
Dr Zhong Lu
Dr Paul Glendenning
Dr Richard Whiting
Dr Andrew Boyden
Prof Rebecca Mason
Dr Shelley Evans
Dr Gail Morgan
Prof Markus Seibel
Dr Ie-Wen Sim
Dr Peter Harman
Dr Dan McLaughlin
Dr Walid Jammal
Chair and Secretariat
Representing
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Australian Medical Association
NPS Medicinewise
Osteoporosis Australia
Osteoporosis Australia (to September 2013)
Osteoporosis Australia (from September 2013)
Australian and New Zealand Bone and Mineral Society
Endocrine Society of Australia
IVD Australia
Australian and New Zealand Association of Neurologists
General Practitioner
MSAC Evaluation Sub-Committee (ESC) member
Department of Health
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APPENDIX 3 – MBS information
The MBS item numbers for vitamin D testing in scope of this review include 66608 and
66609 (see Table A3.1)
Table A3.1: Vitamin D testing services listed on the MBS
Item number
66608
MBS item number descriptor
Vitamin D or D fractions - 1 or more tests
Fee: $39.05
Benefit: 75% = $29.30
85% = $33.20
66609
A test described in item 66608 if rendered by a receiving APP - 1 or more tests
(Item is subject to rule 18)
Fee: $39.05
Benefit: 75% = $29.30
85% = $33.20
Description of Rule 18: The term “Episode Cone” describes an arrangement under which Medicare
benefits payable in a patient episode for a set of pathology services, containing more than three items,
ordered by a general practitioner for a non-hospitalised patient, will be equivalent to the sum of the
benefits for the three items with the highest Schedule fees.
Item 66609 is not included in the count of the items performed when applying the episode cone.
Source: Department of Human Services – Medicare Australia, accessed September 2013
Note: APP is an approved pathology practitioner
Table A3.2 shows when the MBS item numbers for vitamin D testing were included on the
MBS.
Table A3.2: Item number, descriptor and schedule fee start dates for MBS item numbers
Source: Department of Human Services – Medicare Australia, accessed September 2013
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APPENDIX 4 – Search term strategy
The literature search strategies focused on the clinical evidence for vitamin D testing (Table
A4.1) and the cost implications associated with vitamin D testing (Table A4.2).
Table A4.1: Search strategy for clinical evidence
Population
Healthy
population
Patients
diagnosed
with
osteoporosis
and
osteomalacia
Search Terms
Embase and Medline
Population – (‘preeclampsia ’/exp OR ‘preeclampsia’ OR ‘pregnancy’/exp OR ‘pregnancy’ OR
‘infant’/exp OR ‘infant’ OR ‘human milk’/exp OR ‘human milk’ OR ‘lactation’/exp OR
‘lactation’ OR ‘dark skin’/exp OR ‘dark skin’ OR ‘obesity’/exp OR ‘obesity’ OR ‘elderly’/exp
OR ‘elderly’ OR ‘aged’/exp OR ‘aged’ OR ‘indoor workers’)
AND
Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR 25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin
D’ OR ‘25-hydroxycholecalciferol’/exp OR
‘25-hydroxycholecalciferol’ OR ‘25hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’
OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)
AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane
Population – ((MeSH descriptor Preeclampsia explode all trees) OR (MeSH descriptor
Pregnancy explode all trees) OR (MeSH descriptor Infant explode all trees) OR (MeSH
descriptor Human Milk explode all trees) OR (MeSH descriptor Lactation explode all trees) OR
(MeSH descriptor Obesity explode all trees) OR (MeSH descriptor Aged explore all trees) OR
((preeclampsia) OR (preeclampsia):ti,ab,kw) OR ((pregnancy) OR (pregnancy):ti,ab,kw) OR
((infant) OR (infant):ti,ab,kw) OR ((human milk) OR (human milk):ti,ab,kw) OR ((lactation)
OR (lactation):ti,ab,kw) OR ((dark skin) OR (dark skin):ti,ab,kw) OR ((obesity) OR
(obesity):ti,ab,kw) OR ((indoor worker) OR (indoor worker):ti,ab,kw))
AND
Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR
(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor
25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode
all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw
OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin
D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all
trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)
OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR
(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR
(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR
(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR
(Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – (‘osteoporosis’/exp OR ‘osteoporosis’ OR ‘osteomalacia’/exp OR ‘osteomalacia’
OR ‘bone density’/exp OR ‘bone density’ OR ‘bone’/exp OR ‘bone’ OR ‘fractures’/exp OR
‘fractures’ OR ‘falls’/exp OR ‘falls’ OR osteoporo* OR osteomalac*)
AND
Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR 25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin
D’ OR ‘25-hydroxycholecalciferol’/exp OR
‘25-hydroxycholecalciferol’ OR ‘25hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’
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Population
Children
diagnosed
with rickets
Search Terms
OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)
AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane
Population – ((MeSH descriptor Osteoporosis explode all trees) OR (MeSH descriptor
Osteomalacia explode all trees) OR (MeSH descriptor Bone density explode all trees) OR
(MeSH descriptor Bone explode all trees) OR (MeSH descriptor Fractures explode all trees) OR
(MeSH descriptor Falls explode all trees) OR ((osteoporosis) OR (osteoporosis):ti,ab,kw) OR
((osteomalacia) OR (osteomalacia):ti,ab,kw) OR ((bone density) OR (bone density):ti,ab,kw)
OR ((bone) OR (bone):ti,ab,kw) OR ((fractures) OR (fractures):ti,ab,kw) OR ((falls) OR
(falls):ti,ab,kw) OR osteoporo* OR osteomalac*)
AND
Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR
(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor
25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode
all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw
OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin
D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all
trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)
OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR
(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR
(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR
(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR
(Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – ((‘rickets’/exp OR ‘rickets’) OR (‘rachitis’/exp OR ‘rachitis’) OR (‘bone
development’/exp OR ‘bone development’))
AND
Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR 25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin
D’ OR ‘25-hydroxycholecalciferol’/exp OR
‘25-hydroxycholecalciferol’ OR ‘25hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’
OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)
AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane
Population – ((MeSH descriptor Rickets explode all trees) OR (MeSH descriptor rachitis
explode all trees) OR (MeSH descriptor Bone Development explode all trees) OR((rickets) OR
(rickets):ti,ab,kw) OR ((rachitis) OR (rachitis):ti,ab,kw) OR ((bone development) OR (bone
development):ti,ab,kw))
AND
Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR
(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor
25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode
all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw
OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin
D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all
trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)
OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR
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Population
Patients with
chronic
disease
Search Terms
(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR
(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR
(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR
(Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – ((‘cardiovascular disease’/exp OR ‘cardiovascular disease’) OR (‘heart
disease’/exp OR ‘heart disease’) OR (‘ coronary disease’/exp OR ‘coronary disease’) OR
‘myocardial infarct*’ OR (‘stroke’/exp OR ‘stroke’) OR (‘ischemia’/exp OR ‘ischemia’) OR
‘pulmonary embol*’ OR ‘embol*’ OR (‘heart failure’/exp OR ‘heart failure’) OR (‘peripheral
vascular disease’/exp OR ‘peripheral vascular disease’) OR (‘kidney disease’/exp OR ‘kidney
disease’) OR (‘diabetes mellitus’/exp OR ‘diabetes mellitus’) OR (‘rheumatoid arthritis’/exp OR
‘rheumatoid arthritis’) OR (‘multiple sclerosis’/exp OR ‘multiple sclerosis’) OR (‘breast
cancer’/exp OR ‘breast cancer’) OR (‘prostate cancer’/exp OR ‘prostate cancer’) OR
(‘inflammatory bowel disease’/exp OR ‘inflammatory bowel disease’) OR (‘Crohn’s
disease’/exp OR ‘Crohn’s disease’) OR (‘ulcerative colitis’/exp OR ‘ulcerative colitis’))
AND
Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR 25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin
D’ OR ‘25-hydroxycholecalciferol’/exp OR
‘25-hydroxycholecalciferol’ OR ‘25hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’
OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)
AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane
Population – ((MeSH descriptor Cardiovascular Disease explode all trees) OR (MeSH descriptor
Heart Disease explode all trees) OR (MeSH descriptor Coronary Disease explode all trees) OR
(MeSH descriptor Myocardial Infarction explode all trees) OR (MeSH descriptor Stoke explode
all trees) OR (MeSH descriptor Ischemia explode all trees) OR (MeSH descriptor Pulmonary
Embolism explode all trees) OR (MeSH descriptor Heart Failure explode all trees) OR (MeSH
descriptor Peripheral Vascular Disease explode all trees) OR (MeSH descriptor Kidney Disease
explode all trees) OR (MeSH descriptor Diabetes Mellitus explode all trees) OR (MeSH
descriptor Rheumatoid Arthritis explode all trees) OR (MeSH descriptor Multiple Sclerosis
explode all trees) OR (MeSH descriptor Breast Cancer explode all trees) OR (MeSH descriptor
Prostate Cancer explode all trees) OR (MeSH descriptor Inflammatory Bowel Disease explode
all trees) OR (MeSH descriptor Crohn’s Disease explode all trees) OR (MeSH descriptor
ulcerative colitis explode all trees) OR (Cardiovascular disease) OR (cardiovascular
disease):ti,ab,kw OR (heart disease) OR (heart disease):ti,ab,kw OR (coronary disease) OR
(coronary disease):ti,ab,kw OR (myocardial infarction) OR (myocardial infarction):ti,ab,kw OR
(stroke) OR (stroke):ti,ab,kw OR (ischemia) OR (ischemia):ti,ab,kw OR (heart failure) OR
(heart failure):ti,ab,kw OR (peripheral vascular disease) OR (peripheral vascular
disease):ti,ab,kw OR (kidney disease) OR (kidney disease):ti,ab,kw OR (diabetes mellitus) OR
(diabetes mellitus):ti,ab,kw OR (rheumatoid arthritis) OR (rheumatoid arthritis):ti,ab,kw OR
(multiple sclerosis) OR (multiple sclerosis):ti,ab,kw OR (breast cancer) OR (breast
cancer):ti,ab,kw OR (prostate cancer) OR (prostate cancer):ti,ab,kw OR (inflammatory bowel
disease) OR (inflammatory bowel disease):ti,ab,kw OR (Crohn’s disease) OR (Crohn’s
disease):ti,ab,kw OR (ulcerative colitis) OR (ulcerative colitis):ti,ab,kw)
AND
Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR
(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor
25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode
all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw
OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin
D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all
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Population
Search Terms
trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)
OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR
(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR
(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR
(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR
(Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Table A4.2: Search strategy for economic evidence
Population
Patients
undertaking
vitamin D
testing
Search Terms
Embase and Medline
Intervention – (Vit*D OR ‘vitamin D’/exp OR ’vitamin D’ OR 25-OHD OR 25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin
D’ OR ‘25-hydroxycholecalciferol’/exp OR
‘25-hydroxycholecalciferol’ OR ‘25hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’
OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)
AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)
AND
Economic Terms – (‘economic aspect’/exp OR ‘cost benefit analysis’ OR cost* OR ‘cost
effectiveness’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane
Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR
(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor
25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode
all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw
OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin
D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all
trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)
OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR
(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR
(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR
(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR
(Haematologic test*):ti,ab,kw)
AND
Economic Terms – (((economic aspect) OR (economic aspect):kw) OR ((cost benefit) OR (cost
benefit):kw)) OR ((cost effectiveness) OR (cost effectiveness):kw) OR (MeSH descriptor CostBenefit Analysis explode all trees) OR (MeSH descriptor Costs and Cost Analysis explode all
trees))
AND
Limits [humans]/lim AND [english]/lim
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February 2014
APPENDIX 5 – Tools for assessing the evidence in the systematic
review
Table A5.1: NHMRC Dimensions of Evidence(123)
Type of evidence
Strength of the evidence
 Level


Quality
Statistical precision
Size of effect
Relevance of evidence
Definition
The study design used, as an indicator of the degree to which bias has been
eliminated by design.
The methods used by investigators to minimise bias within a study design.
The p-value or, alternatively, the precision of the estimate of the effect (as
indicated by the confidence interval). It reflects the degree of certainty about the
existence of a true effect.
The distance of the study estimate from the “null” value and the inclusion of only
clinically important effects in the confidence interval.
The usefulness of the evidence in clinical practice, particularly the appropriateness
of the outcome measures used.
Table A5.2: NHMRC designations of levels of evidence for an intervention(123)
Level
I
Intervention
A systematic review of level II studies
II
A randomised controlled trial
III-1
A pseudo randomised controlled trial (i.e. alternate allocation or some other
method)
III-2
A comparative study with concurrent controls:
 Non-randomised, experimental trial
 Cohort study
 Case-control study
 Interrupted time series with a control group
A comparative study without concurrent controls:
 Historical control study
 Two or more single arm study
 Interrupted time series without a parallel control group
Case series with either post-test or pre-test/post-test outcomes
III-3
IV
Source: Hierarchies adapted and modified from: NHMRC 1999; Bandolier 1999; Lijmer et al. 1999; Phillips et al. 2001
Table A5.3: NHMRC quality criteria for RCTs, cohort studies, case-control studies and systemic
reviews(123)
Study type
Randomised controlled
trialsa
Cohort studiesb
Case-control studiesb
Quality criteria
Was the study double blinded?
Was allocation to treatment groups concealed from those responsible for recruiting
the subjects?
Were all randomised participants included in the analysis?
How were subjects selected for the ‘new intervention’?
How were subjects selected for the comparison or control group?
Does the study adequately control for demographic characteristics, clinical features
and other potential confounding variables in the design or analysis?
Was the measurement of outcomes unbiased (i.e. blinded to treatment group and
comparable across groups)?
Was follow-up long enough for outcomes to occur?
Was follow-up complete and were there exclusions from the analysis?
How were cases defined and selected?
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Study type
Systematic reviewsc
Quality criteria
How were controls defined and selected?
Does the study adequately control for demographic characteristics and important
potential confounders in the design or analysis?
Was measurement of exposure to the factor of interest (e.g. the new intervention)
adequate and kept blinded to case/control status?
Were all selected subjects included in the analysis?
Was an adequate search strategy used?
Were the inclusion criteria appropriate and applied in an unbiased way?
Was a quality assessment of included studies undertaken?
Were the characteristics and results of the individual studies appropriately
summarised?
Were the methods for pooling the data appropriate?
Were sources of heterogeneity explored?
Source: National Health and Medical Research Council (NHMRC), 2000. How to review the evidence: systematic identification and review
of the scientific literature, NHMRC, Commonwealth of Australia, Canberra.
a
Based on work of Schulz et al (1995) and Jadad et al (1996)
b
Based on quality assessment instruments developed and being tested in Australia and Canada
c
Based on articles by Greenhalgh (1997) and Hunt and McKibbon (1997).
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APPENDIX 6 – QUOROM flowchart
The QUOROM flowchart below shows the process used to select studies that were eligible for
the clinical review of vitamin D testing.
Figure A6.1: QUOROM flowchart for the review of the clinical evidence
Potentially relevant studies
identified in the literature
searches and screened for
retrieval: (n= 4873)
Studies excluded because they
did not meet the inclusion
criteria: (n=4518)
Studies retrieved for more
detailed evaluation: (n= 355)
Studies excluded because they
did not meet the inclusion
criteria: (n= 294)
Wrong study type (n= 182)
Wrong intervention (n= 49)
Level IV studies (n= 63)
Eligible studies to be included
in the systematic review: (n=
61)
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APPENDIX 7 - Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) quality criteria
Tools used in Washington State HTA include internally developed Quality Checklists for
evaluating the quality (internal validity) of different types of studies, a checklist for judging
the adequacy of systematic reviews used instead of de novo analysis, and Hayes EvidenceGrading Guides for evaluating bodies of evidence for different types of technologies. Hayes
methodology is in alignment with the GRADE (Grading of Recommendations, Assessment,
Development, and Evaluation) system, which was developed by the GRADE Working Group,
an international collaborative body.
Table A7.1: Quality criteria according to GRADE
Step 1
Individual study appraisal
a. Initial rating according to study design
Good: Randomised Controlled Trials
Fair: Nonrandomised Trial (controlled, parallel group, quasi-randomised)
Poor: Observational Analytic Studies (prospective or retrospective trials involving historical
controls, pre-test posttest control trial [patients legitimately serve as their own controls],
casecontrol,
registry/chart/database analysis involving a comparison group)
Very Poor: Descriptive Uncontrolled Studies (case reports, case series, cross-sectional surveys
[individual-level data], correlation studies [group-level data])
b. Consider the methodological rigor of study execution according to items in a proprietary
Quality Checklist
c. Repeat for each study
Step 2
Evaluation of each body of evidence by outcome, key question, or application
a. Initial quality designation according to best study design in a body of evidence
b. Downgrade/upgrade
Downgrade factors: Study weaknesses (Quality Checklists), lack of applicability, inconsistency
of results, small quantity of data, publication bias (if adequate information is available)
Possible upgrade factors: Strong association, dose-response effect, bias favoring no effect
c. Assign final rating: High-Moderate-Low-Very Low
d. Repeat for each outcome/question/application
Step 3
Evaluation of overall evidence
a. Rank outcomes by clinical importance
b. Consider overall quality of the evidence for each critical outcome
c. Assign overall rating based on lowest-quality body: High-Moderate-Low-Very Low
Step 4
Evidence-based conclusion
Overall quality of the evidence + Balance of benefits and harms
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APPENDIX 8 – Summary of included studies and systematic reviews
Table A8.1: Summary of findings from systematic reviews assessing the effectiveness of vitamin D supplementation on musculoskeletal health and
chronic diseases
Author and
Search
Description
No of SRs/ RCTs
year
date
Vitamin D supplementation for promotion of musculoskeletal health
Chung
USPSTF Focused
16 RCTs
Up to

(2011)(104)
update SR-MA
July 2011
(update to
(funded by AHRQ)
Chung et al. to assess the
2009)
benefits and harms
of vitamin D

supplementation
with or without
calcium on
outcomes of cancer
and fractures in
adults

Murad et al.
(2011)(105)
SR-MA to assess
26 RCTs (45,782
the effectiveness of participants)
vitamin D
supplementation in
preventing falls
Up to
August
2010




Michael et al. SR and MA to
(2010)(106)
describe the
9 RCTs (5780
participants);
MBS Reviews – Vitamin D Testing Review Report
Up to Feb 
2010
Key findings and conclusions
Quality of included studies
RR of fracture, vitD with or without calcium vs placebo in elderly men and women:
 Overall: RR=1.03 (CI, 0.84-1.26; moderate heterogeneity) (5 RCTs); RRs in
individual studies ranged from 0.80-1.33)
 Institutionalised: RR=0.99 (CI, 0.72-1.34; low heterogeneity) (2 RCTs) Community
dwelling: RR=1.06 (CI, 0.77- 1.46; high heterogeneity) (3 RCTs)
RR of fracture, vitD+calcium vs placebo in mostly postmenopausal women:
 Overall: RR=0.88 (CI, 0.79-0.99; low heterogeneity) (11 RCTs; RRs in individual
studies ranged from 0.0.46- 1.08)
 Institutionalised: RR=0.71 (CI, 0.57-0.89; no heterogeneity) (3 RCTs)
 Community dwelling: RR=0.89 (CI, 0.76- 1.04; low heterogeneity) (6 RCTs)
 Community dwelling with history of fracture: RR=1.02 (CI, 0.89-1.16; no
heterogeneity) (2 RCTs)
Meta-regression analysis of RR:
 Per 100-IU increase in vitD dose: RR=1.01 (CI, 0.97-1.07) (16 RCTs)
 Per 100 IU increase in BL serum 25-(OH)D: RR=1.02 (CI, 0.86-1.2) (12 RCTs)
 Authors’ conclusions: VitD+calcium supplementation can reduce fracture risk, but
the effects may be smaller among community-dwelling older adults than among
institutionalized elderly persons
Overall OR: OR=0.86 (CI, 0.77-0.96), range 0.10-1.31 in individual trials (I2=66%;
P=0.01)
Vitamin D deficient vs not deficient: OR=0.53 (CI, 0.39-0.72) vs OR=0.90 (CI, 0.810.99) (P=0.00)
Co-administration of calcium: VitD+calcium had greater effect compared with calcium
alone (OR=0.63; CI, 0.50-0.81) than compared with placebo (OR=0.83; CI, 0.72-0.93)
and greater placebo-controlled effect (OR=0.83) than vitD alone (OR=0.97; CI, 0.841.11) (global P=0.01). NOTE: vitamin D alone had NS effect. Other: No sig interaction
of treatment with community vs institution, intramuscular vs oral, documented increase
in serum 25-(OH)D, D2 vs D3, adherence, high dose (>800 IU/day), and study quality.
Authors’ conclusions: VitD combined with calcium reduces the risk of falls in a
population consisting primarily of elderly women.
Overall RR, vitD with or without calcium: RR=0.83 (CI, 0.77-0.89); NS statistical
heterogeneity. RRs in individual studies ranged from 0.60-0.98 and were generally NS
According to Chung et al. 5
RCTs of vitD alone were of
good (1), fair (3), and poor
(1); 11 RCTs of
vitD+calcium were good (2),
fair (5), and poor (4),
May not be applicable to
adults <50 yrs.
According to Murad et al.:
Allocation concealed in 18
trials, double blinding in 18,
mean loss to follow-up 10%
(NR in 9 trials); commercial
funding in 34% of studies.
Moderate statistical
heterogeneity. Results may
not be generalisable to
populations with lower
baseline risk of falls or
adequate vitD status.
According to Michael et al.:
All vitD studies, fair; most
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Chung
(2011)(104)
(update to
Chung et al.
2009)
USPSTF Focused
16 RCTs
update SR-MA
(funded by AHRQ)
to assess the
benefits and harms
of vitamin D
supplementation
with or without
calcium on
outcomes of cancer
and fractures in
adults
Up to

July 2011


Chung et al.
(2009)(9, 104)
benefits and harms
of interventions
(including vitamin
D or vitamin D
+calcium) to
prevent falls among
community
dwelling older
adults
AHRQ report to
support IOM
possible revision of
DRI. SR and MA
to summarise the
evidence on the
relationship
between vitamin D,
calcium, and a
combination of
both with a wide
range of health
outcomes
identified by IOM,
including



1 SR (Cranney
Up to Dec 
2007)/ 9 new
2008
RCTs selected for
assessment of the
effect of

vitD or
vitD+calcium
supplementation
on incidence of
BMD and falls
MBS Reviews – Vitamin D Testing Review Report



RR of fracture, vitD with or without calcium vs placebo in elderly men and women:
 Overall: RR=1.03 (CI, 0.84-1.26; moderate heterogeneity) (5 RCTs); RRs in
individual studies ranged from 0.80-1.33)
 Institutionalised: RR=0.99 (CI, 0.72-1.34; low heterogeneity) (2 RCTs) Community
dwelling: RR=1.06 (CI, 0.77- 1.46; high heterogeneity) (3 RCTs)
RR of fracture, vitD+calcium vs placebo in mostly postmenopausal women:
 Overall: RR=0.88 (CI, 0.79-0.99; low heterogeneity) (11 RCTs; RRs in individual
studies ranged from 0.0.46- 1.08)
 Institutionalised: RR=0.71 (CI, 0.57-0.89; no heterogeneity) (3 RCTs)
 Community dwelling: RR=0.89 (CI, 0.76- 1.04; low heterogeneity) (6 RCTs)
 Community dwelling with history of fracture: RR=1.02 (CI, 0.89-1.16; no
heterogeneity) (2 RCTs)
Meta-regression analysis of RR:
 Per 100-IU increase in vitD dose: RR=1.01 (CI, 0.97-1.07) (16 RCTs)
 Per 100 IU increase in BL serum 25-(OH)D: RR=1.02 (CI, 0.86-1.2) (12 RCTs)
 Authors’ conclusions: VitD+calcium supplementation can reduce fracture risk, but
the effects may be smaller among community-dwelling older adults than among
institutionalized elderly persons
(CIs crossed null).
Reanalysis, including a trial (Sanders 2010) published after the search ended and
showing an increase in falls with a 1-time dose of 500,000 IU, yielded a new estimate of
RR=0.83 (CI, 0.71-0.979). The other included RCT using a megadose (Dhesi 2004 (124))
reported neither a positive or negative effect on risk of falling
Effect of patient characteristics on pooled estimate: None according to age, sex
distribution, history of falls, or risk status (history of falls or vitD deficiency).
Authors’ conclusion: VitD supplementation can reduce falls in community-dwelling
older adults
BMD/BMC: In the newly published RCTs, effects of vitD alone on BMC/BMD
(children/adolescents, 3 poor-fair RCTs) or BMD (adults, 4 generally fair-good RCTs)
were small (difference in % change, –0.3% to 7.0% and, in most studies, NS, but CIs
around differences in % change were large in some studies of postmenopausal women.
Physical performance: Very small between-group differences in change. Significant for
chair stands and walking time; NS for grip strength (1 poor RCT).
Falls: HR=0.95 (CI, 0.79-1.15; NS) (Lyons 2007); RR=0.82 (CI, 0.59-1.16; NS)
(Burleigh 2007); NS difference in fall-free survival curves (Bunout 2006)
Stress fracture: RR=0.8 (CI, 0.64-0.99; P=0.026); OR=0.79 (CI, 0.62-1.01; P=0.059)
(Lappe 2008)
Other fracture: See Chung et al. (2011)
Effect of patient characteristics: Not discussed
Assay kits: Large variation, according to authors, but specifics not discussed.
Authors’ conclusions: the conclusion of Cranney et al. (2007) regarding to
vitD3+calcium in postmenopausal women (vitD supplementation has, at best, small
According to Chung et al. 5
RCTs of vitD alone were of
good (1), fair (3), and poor
(1); 11 RCTs of
vitD+calcium were good (2),
fair (5), and poor (4),
May not be applicable to
adults <50 yrs.
trials underpowered and
most assessed self-reported
falls retrospectively with
recall of 6 wks – 12 mos.
According to Chung et al.:
Potential bias in most
studies, especially in older
adults; generally fair.
Other comments: VitD doses
were usually less than
current IOM
recommendations.
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Chung
(2011)(104)
(update to
Chung et al.
2009)
USPSTF Focused
16 RCTs
update SR-MA
(funded by AHRQ)
to assess the
benefits and harms
of vitamin D
supplementation
with or without
calcium on
outcomes of cancer
and fractures in
adults
Up to

July 2011


BMC/BMD,
physical
performance, and
falls
Cranney et al. AHRQ report to
17 RCTs
Up
to 
(2007)(108)
provide support
June 2006
for evidence-based
EAR and RDA
values to be
determined by the
IOM, with an
emphasis on
musculoskeletal

outcomes such as
BMC/BMD,
physical
performance, and
falls.
Vitamin D supplementation in individuals with osteoporosis
MBS Reviews – Vitamin D Testing Review Report
RR of fracture, vitD with or without calcium vs placebo in elderly men and women:
 Overall: RR=1.03 (CI, 0.84-1.26; moderate heterogeneity) (5 RCTs); RRs in
individual studies ranged from 0.80-1.33)
 Institutionalised: RR=0.99 (CI, 0.72-1.34; low heterogeneity) (2 RCTs) Community
dwelling: RR=1.06 (CI, 0.77- 1.46; high heterogeneity) (3 RCTs)
RR of fracture, vitD+calcium vs placebo in mostly postmenopausal women:
 Overall: RR=0.88 (CI, 0.79-0.99; low heterogeneity) (11 RCTs; RRs in individual
studies ranged from 0.0.46- 1.08)
 Institutionalised: RR=0.71 (CI, 0.57-0.89; no heterogeneity) (3 RCTs)
 Community dwelling: RR=0.89 (CI, 0.76- 1.04; low heterogeneity) (6 RCTs)
 Community dwelling with history of fracture: RR=1.02 (CI, 0.89-1.16; no
heterogeneity) (2 RCTs)
Meta-regression analysis of RR:
 Per 100-IU increase in vitD dose: RR=1.01 (CI, 0.97-1.07) (16 RCTs)
 Per 100 IU increase in BL serum 25-(OH)D: RR=1.02 (CI, 0.86-1.2) (12 RCTs)
 Authors’ conclusions: VitD+calcium supplementation can reduce fracture risk, but
the effects may be smaller among community-dwelling older adults than among
institutionalized elderly persons
positive effects on BMD and physical performance; suggests small effects on BMD in
adolescent girls and on stress fractures in healthy Navy recruits; and identifies new
populations in which vitD supplementation may reduce falls) was cited; no other
conclusions about musculoskeletal health were stated.
BMD, quantitative analysis, adults:
 VitD3+calcium vs placebo: Small effect on lumbar spine, femoral neck, and total
body BMD (WMD range 0.60-1.40, all sig) (7 RCTs). NS for effect on forearm
(1RCT).
 VitD3+calcium vs calcium: NS in 5 RCTs; small effect on BMD in femoral neck
(1 RCT).
 VitD3 vs placebo: Small effect on BMD in femoral neck (1 RCT); NS but wide CI
(WMD=0.06; CI, –3.74 to 3.86), forearm (1 RCT).
BMD/BMC, qualitative findings by population:
 Infants: Inconsistent findings (2 RCTs) (quality fair-high).
 Older children and adolescents: Inconsistent across sites (2 RCTs) (higher
quality).
 Postmenopausal women and older men: No effect in 5 RCTs; positive effect in 1
RCT (quality fair-high).
According to Chung et al. 5
RCTs of vitD alone were of
good (1), fair (3), and poor
(1); 11 RCTs of
vitD+calcium were good (2),
fair (5), and poor (4),
May not be applicable to
adults <50 yrs.
According to Cranney et al.:
13 trials were of higher
quality on Jadad scale but
did not adequately report
allocation concealment.
Page 98
February 2014
Hayes, Inc
(2012)(125)
Health technology 18 RCTs, 3601
assessment of
participants
vitamin D
supplementation for
patients with
osteoporosis
From

2002 to
July 2012



Vitamin D supplementation in individuals with cancer
Buttigliero et SR (including MA 3 RCTs, 1273
al. (2011)(126) of overall survival participants
data) to determine
whether
hypovitaminosis D
is associated with
poor prognosis and
if vitD repletion
improves prognosis
of cancer patients
Up
to 
June 2010



VitD3+calcium: Conflicting results for effect on BMD at different sites; positive effects
were small (2 RCTs involving patients with history of fracture). 1 RCT found a
pronounced increase in lumbar spine BMD in patients ≤70 yrs of age (0.993±0.131) and
a decrease in patients >70 yrs (0.868±0.216; P<0.05).
Dose effects (vitD3): No clear effect (2 RCTs)
Active vitD:
 Significant effect on BMD compared with no vitD (2 RCTs).
 More effective than inactive vitD (BMD, fractures, and falls) (2 RCTs).
 Less effective than bisphosphonate (BMD) (4 RCTs).
 Combination with bisphosphonate more effective than either drug alone (BMD
and/or fractures and falls, 3 RCTs)
 Less effective than HRT (1 RCT)
 Combination with HRT more effective than HRT alone (BMD and/or fractures; 2
RCTs)
Authors’ conclusions: Active vitD combined with bisphosphonate is effective; active
vitD combined with HRT may be effective; insufficient evidence for inactive vitD; no
dose-response effect of inactive vitD has been proven.
Limitations of selected
evidence according to Hayes:
follow-up ≤1 yr in 11 RCTs
(limits assessment of effect
on fractures/falls); lack of
blinding in many studies;
small sample sizes;2 studies
were commercially funded;
individual study quality
ratings NR
Adjusted HR (<1 favours vitD): Beer 2007: 0.67 (CI, 0.45-0.97; P=0.07) Scher 2010:
1.33 (P=0.19)
Median overall survival OS (vitD arm, control) (mos): Scher 2010: 16.8, 19.9
(significance NR) Attia: 17.8, 16.4 (NS)
Median Relapse Free Survival (RFS): No difference in Attia 2008; NR for other 2
studies.
Pooled estimate of RR of death:
 Fixed effects model: 1.07 (CI, 0.93-1.23)
 Random-effects model: 1.00 (CI, 0.71-1.40)
 Test for heterogeneity was significant (P=0.001)
Limitations of selected
evidence according to
Buttigliero et al.: Adequate
sequence generation and
allocation concealment
unclear; potential bias due to
early stopping in 2 trials
(Attia 2008 , Scher 2010),
different chemotherapy
schedules in the 2 arms (Beer
2007), primary endpoint was
biochemical response in 2
studies (Attia 2008, Scher
2010).
Statistical heterogeneity,
perhaps due to heterogeneity
in tx protocols; largest study
(Scher 2010) lacked a true
control grp; no analysis of
differential effectiveness
according to pt factors
MBS Reviews – Vitamin D Testing Review Report
Page 99
February 2014
Vitamin D supplementation in individuals with cardiovascular disease
Witham et al. SR and MA to
7 RCTs, <545
From

Pooled estimate of difference in change (vitD minus control) (7 RCTs):
(2009)(110)
assess the ability of participants
1996 to
 SBP: –3.3 mm Hg (CI, –8.2 to 1.7; NS)
vitD
June 2006
 DBP: –2.3 mm Hg (CI, –4.6 to 0.0; P=0.05)
supplementation or
Significant heterogeneity >50% was present across the 8 studies in hypertension (HTN)
ultraviolet radiation
populations, which included 1 study of ultraviolet radiation.
to reduce BP

Individual study estimates of difference in change (vitD minus control):
 SBP: –13.9 to 5 mm Hg
 DBP: –9.2 to 0.4 mm Hg

Activated vitD vs vitD2/vitD3:
Effect on SBP was significant only in the subgrp of studies using vitD2/vitD3, but CIs
for the 2 subgrp estimates overlapped. No difference in effect on DBP.
 Data from studies reporting other outcomes are captured for this report in other evidence
tables. Witham et al. did not report a pooled estimate for outcomes other than BP.
 Authors’ conclusions: There is weak evidence of a small reduction in BP using vitD
compounds in patients with HTN. Witham et al. cited a study suggestion that a 3 mm Hg
reduction in SBP translates to a 10% reduction in CV deaths at population level.
Vitamin D supplementation in individuals with abnormal blood glucose
George et al. SR and MA
6 RCTs, 622
Up
to 
Pooled SMD (George 2012):
(2012)(111)
participants
March
 Insulin resistance IR: 0.03 (CI, –0.18 to 0.23) (no heterogeneity)
2011
 FPG: –0.25 (CI, –0.48 to –0.03) (no heterogeneity)
 HbA1C: –0.32 (CI, –0.57 to –0.07) (no heterogeneity)

Authors’ conclusions: Current evidence is insufficient to recommend vitD
supplementation for improving glycaemia or insulin resistance in patients with diabetes.
Pittas et al. SR and MA (but
4 RCTs, 243
(2010)(112)
MAs were not
participants
applicable to this
evidence report) to
evaluate the
evidence on the
association of
vitamin D levels
and the effects of
vitamin D
supplementation on
type 2 diabetes,
hypertension or
cardiovascular
disease
MBS Reviews – Vitamin D Testing Review Report
Up
to 
Nov 2009
check
papers
after this
date
Authors’ conclusion: No clinically significant effect of vitD supplementation at the
dosages given.
All studies were RCTs;
generally insufficient detail
to allow assessment of
allocation concealment or
ITT analysis; blinding in
most studies; no suggestion
of publication bias in funnel
plot; statistical heterogeneity;
insufficient reporting and/or
too few studies to allow
assessment of effect
modification by BL 25(OH)D or vitD dose; few
studies reported a rigorous
method for measuring BP.
Unclear or missing ITT
analysis in most studies;
otherwise, criteria were met;
too few studies to allow
meta-regression analysis of
effect modification by BL
25-(OH)D level or BL
glucose
All studies judged to be fair
Page 100
February 2014
Table A8.2: Summary of vitamin D studies included in the review
Author
Protocol
Diabetes or insulin resistance
MozaffariWomen with first time gestational diabetes randomised
Khosravi et al.
to vitD (1 injection of 300,000IU immediately after
(2012)(127)
delivery)or control
Sample size
45
Eftekhari et al.
(2011)(128)
Women with gestational diabetes randomised to vitamin
D (calcitriol 0.5μg/day) or placebo
70
Mitri et al.
(2011)(129)
Patients at high risk of diabetes were randomised to one
of the following groups:

VitD and calcium grp: VitD3 2000 IU and calcium
800 mg daily

VitD grp: VitD3 2000 IU and calcium placebo
daily

Calcium grp: Calcium 800 mg and vitD placebo
daily

Placebo grp: Calcium placebo and vitD placebo
daily
Diabetic patients were randomised to receiving either
plain yogurt drink (placebo grp), yogurt drink with
vitD3 500 IU and calcium 150 mg (vitD/low calcium
grp), or yogurt drink with vitD3 500 IU and calcium 250
mg (vitD/high calcium grp) twice daily for 12 wks; all
participants participated in weight maintenance diabetic
diet
92
Nikooyeh et al.
(2011)(130)
MBS Reviews – Vitamin D Testing Review Report
90
Results
Quality

Fair
Changes in fasting plasma glucose (FPG), (oral glucose tolerance test
(OGTT), and glycated hemoglobin (HbA1C) were similar and change
differences NS.

Insulin sensitivity substantially dropped in control grp but remained
stable in vitD grp (P=0.002).

Insulin resistance stayed high in control grp but declined in vitD gr
(homeostasis model assessment, P=0.004; C-peptide P=0.05

There were no significant differences in the mean FPG, fasting insulin, Good
or HbA1C between grps at any time point of study.

Repeated measurements analyses revealed significant increases in FPG
in placebo grp (P=0.038) but not vitD grp (P=0.712; difference
between grps P<0.05). Fasting insulin and HbA1C significantly
increased in both grps (all analyses P≤0.01).
Adjusted change (P for treatment):
Fair

VitD vs no vitD: HbA1C, 0.08% vs 0.03% (P=0.024) after elimination
of 2 outliers; no effect on FPG or 2-hr plasma glucose

VitD+calcium vs placebo: HbA1C, 0.05% vs 0.18% (P=0.036)

VitD vs placebo: FPG. 24 mmol/L vs 8.4 mmol/L (P-0.051)



Differences in change in FPG, fasting serum insulin, insulin resistance,
HbA1C, weightt, BMI, waist circumference, and waist-to-hip ratio
were small but statistically significant and favored vitD or
vitD+calcium.
Change in BP did not differ between grps
There was a significant inverse relationship between changes in 25(OH)D and changes in wt (r=– 0.331, P=0.001), FPG (r=–0.208,
P=0.049), serum insulin (r=–0.308, P=0.003), and HbA1C (r=–0.215,
P=0.042).
Poor
Page 101
February 2014
Multiple sclerosis
Soilu-Hanninen Patients with multiple Sclerosis (MS) randomized to
et al. (2012)(131) vitD3 (Weekly vitD3 (20,000 IU);or placebo
66


Mosayebi et al.
(2011)(132)
Burton et al.
(2010) Kimball
etl. al. (2011)(133,
134)
Mahon et al.
(2003)(135)
Participants were randomised to either receiving
intramuscular injection of vitD3 300,000 IU or placebo
every mo for 6 mos; all participants received interferon
B- 1a
Participants were either randomised to either receiving
vitD (vitD and calcium 1200 mg/day calcium was
initiated 2 wks before initiation of vitD; vitD dose
increased stepwise from 4000 IU/day to a maximum of
40,000 IU/day then decreased to 0 for final 4 wks of
study (average 14,000 IU/day); calcium supplementation
ceased in final 4 wks of study.) or control
62

49

Patients with MS were randomised to either vitD (1000
IU/day) + calcium (n=17) or calcium+placebo (n=22)
39






Increase in T2 burden of disease was greater in placebo grp (287 mm3)
than in vitD grp (83 mm3) (NS). Fewer gadolinium enhancing lesions
on T1 MRI at 12 mos in vitD grp (P=0.004). Most other differences in
MRI changes were NS
Improvement in Expanded Disability Status Scale (EDSS) score and
walking test times favored vitD grp but were NS. No difference in
relapse rates at 12 mos
NS changes in Expanded Disability Status Scale (EDSS) and # lesions
within or between grps (all analyses P>0.05).
Good
Fair
Clinical responses: Annual relapse rate was lower in vitD grp (0.26; CI, Fair
–0.06 to 0.53) than control grp (0.45; CI, 0.19-0.72), but the difference
between grps was NS (P=0.09).
Proportion of participants completing trial with increased EDSS was
0.08 for vitD grp and 0.375 for control grp (P=0.019)
Peripheral blood mononuclear cell proliferative responses: Reduction in
response to 7 of 17 antigens was significantly greater in vitD+calcium
grp than in control grp (P≤0.001). Differences with respect to the other
10 antigens were NS. Between-grp differences were significant overall
and for 3 of 5 subsets of antigens
At 6 mos, TGFB1 levels were substantially higher in vitD+calcium grp Fair
and unchanged in placebo grp.
IL-2 levels diminished to a greater extent in vitD+calcium grp than in
placebo grp, but significance of between-grp differences was NR.
Changes and between-grp differences in inflammatory cytokines were
contradictory and NS.
Mean 25-(OH)D level at 6 mos in the vitD grp was 70 nmol/L.
Cardiovascular disease
Witham et al.
(2010)(136)
Participants randomized to vitD (vitD2 100,000 IU) or
placebo at baseline and at 10 wks
105



Schleithoff et al. Patients were assigned to 2000 IU/day
(2006)(137)
vitD3+calcium or placebo+calcium
93


MBS Reviews – Vitamin D Testing Review Report
There were no significant changes in the Functional Limitations Profile Good
within or between grps (all analyses P≥0.13).
No difference in improvement in 6-min walk time.
VitD grp had a greater increase in the Minnesota Living With Heart
Failure questionnaire score at 20 wks compared with placebo
(difference between grps = 5.3; CI, 0.5-10.2; P=0.03); BL scores were
23.6 and 24.7.
Differences in change at 9 mos from BL were NS and generally slight Poor
for cardiovascular biochemical and hemodynamic variables.
15-mo survival was very similar.
Page 102
February 2014
Witham et al.
(2010)(136)
Participants randomized to vitD (vitD2 100,000 IU) or
placebo at baseline and at 10 wks
105




Healthy individuals
Brunner et al.
Postmenopausal women randomised to vitD (400 IU and
(2011)(138)
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670






Grimnes et al.
(2011)(139)
Participants were randomised to vitD (20,000IU vitD
twice/wk) or placebo
Follow up: 6 months
Sanders et al.
(2011)(140)
Community-dwelling older women randomised to vitD
(single oral dose of vitD 500,000 IU/year in autumn or
winter) or placebo
Follow up: 3-5 years
104

2,258



MBS Reviews – Vitamin D Testing Review Report
There were no significant changes in the Functional Limitations Profile Good
within or between grps (all analyses P≥0.13).
No difference in improvement in 6-min walk time.
VitD grp had a greater increase in the Minnesota Living With Heart
Failure questionnaire score at 20 wks compared with placebo
(difference between grps = 5.3; CI, 0.5-10.2; P=0.03); BL scores were
23.6 and 24.7.
25-(OH)D levels at 9 mos exceeded 50 nmol/L in vitD grp and almost
reached that level in placebo grp. Dietary intake of vitD and calcium
and medication use did not change significantly in either grp during
study period.
Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
Fair
Serum HbA1C (vitD; placebo) (% patients):
 BL: 5.5%; 5.44%
 6 mos: 5.64%; 5.64%
(differences between grps NS)
Good
10.2% of vitD grp and 9.8% of placebo grp withdrew from study.
Overall SF-12 scores (vitD; placebo):
 Physical score: 41.4; 41.2
 Mental score: 52.5; 52.6
(all analyses NS)
Overall GHQ score ≥3 (vitD; placebo) (% patients):
 BL: 14%; 15%
Page 103
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670






Daly and
Nowson
(2009)(141)
Men were randomised to vitD (milk fortified with vitD
400 IU and calcium) or placebo
167


LaCroix et al.
(2009)(142)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
36,282



MBS Reviews – Vitamin D Testing Review Report
Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
 12 mos: 13.8%; 13.7%
 15 mos: 17.7%; 16.9%
(all analyses NS)
Fair
Weight change (kg) (vitD; control):
 6 mos: 0; –0.3
 12 mos: 0.5; 0.1
 18 mos: 0; –0.7
 24 mos: 0.6; 0.1
There was no significant effect of supplementation in subgrp who had
BL 25-OHD levels <75 nmol/L.
Good
There were 744 mortalities in vitD grp and 807 in placebo grp
(HR=0.91; CI, 0.83-1.01). HRs close to unity for specific causes of
mortality, including stroke, cancer, CAD, and other causes
HRs for total mortality, CVD death, CAD death, cerebrovascular death,
cancer death, and other/I death were similar in subgrps defined by age
(<70 vs ≥70 yrs).Interaction by ethnicity, calcium use, total calcium
intake, total vitD intake latitude, BL blood pressure, smoking status,
physical activity, CVD risk, BMI, history of CVD, number of chronic
conditions, and self-reported health status with treatment was NS for
effect on total mortality.
Nested case-control analysis (n=323) suggested a protective effect
(OR=0.79; NS) in the subgrp with BL 25-(OH)D <35.4 nmol/L and a
harmful effect (NS) in the higher tertiles of BL 25-(OH)D. NS
interaction.
Page 104
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670







Chlebowski et
al. (2008)(143)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
36,282



de Boer et al.
(2008)(144)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
MBS Reviews – Vitamin D Testing Review Report
33,951

Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
Subgrp analysis suggested greater reduction in total mortality for
adherent women within <70 yrs age grp
Good
Breast cancer in 668 participants (0.52%) in vitD grp and 693
participants (0.54%) in placebo grp (HR=0.96; CI, 0.85-1.09). Tumor
size was 1.54 cm in vitD grp and 1.71 cm in placebo grp (P=0.05).
There were 23 cancer-related mortalities in each grp. Cancer stage and
histology were similar between grps.
Effect of BL vitD intake: Participants in highest quartile had more
breast cancer in vitD than placebo grp (HR=1.34; CI, 1.01- 1.78) and
those in lowest quartile had fewer breast cancers in vitD than placebo
grp (HR=0.79; CI, 0.65-0.97) (P=0.003 for interaction). However, there
were no significant interactions in the nested case-control analyses
between BL characteristics, including serum 25-(OH)D, and treatment
assignment, after adjustment for other factors.
Logistic regression analysis of nested case-control subgrp adjusted for
age, race, latitude, breast cancer family history, prior breast biopsies,
hormone treatment, and participation in hormone treatment or diabetes
mellitus trials revealed that higher BL 25-(OH)D levels were associated
with lower breast cancer risk (P=0.04). This association was lost when
analyses further adjusted for BMI and physical activity (P trend=0.2)
Good
Main effect
 Unadjusted: HR=0.97 (CI, 0.86- 1.09)
 Adjusted for non-study use of calcium or vitD: HR=1.01 (CI, 0.94
to 1.10) (overlapping CIs indicate NS difference in the 2 HR
Page 105
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670







Margolis et al.
(2008)(145)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
36,282



Caan et al.
(2007)(146)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
MBS Reviews – Vitamin D Testing Review Report
36,282

Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
estimates)
Effect according to patient factors: NS interaction with age,
race/ethnicity, education, family history of diabetes, calcium intake at
BL (trend toward significance), vitD intake at BL, multivitamin use,
alcohol intake, smoking, sun exposure, physical activity, BMI, waist
circumference, hormone treatment at BL, FPG, metabolic syndrome,
25-(OH)D level (<32.2/32.2-43.6/43.7-60.1/≥60.2 nmol/L; no clear
pattern in variation of HRs)
Good
By end of study, systolic BP declined by 1 mm Hg and diastolic by 4
mm Hg; however, differences between grps was NS. No subgrps,
including demographic characteristics, hypertension risk factors,
calcium and vitD intake, and 25-(OH)D levels, had a significant change
in BP associated with vitD treatment.
Hypertension developed in 3377 participants (19.6%) in vitD grp and
3315 participants (18.3) in placebo grp (HR=1.01; CI, 0.96- 1.06).
Treatment effect by BL 25-(OH)D:
 <34.4 nmol/L, HR=1.52 (CI, 0.89-2.59);
 34.4-47.6 nmol/L, HR=1.48 (CI, 0.89-2.46);
 47.7-64.6 nmol/L, HR=1.15 (CI, 0.69-1.92);
 ≥64.7 nmol/L, HR=0.79 (CI, 0.51-1.22)
(P=0.01 for interaction)
Participants in vitD grp had smaller annual weight gains than those in
placebo grp (mean difference – 0.13 kg, range –0.21 to –0.05;
Good
Page 106
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670






Follow up: 7 years




Hsia et al.
(2007)(147)
Postmenopausal women randomised to vitD (total dose
of 400IU vitD and 1000mg calcium/day) or placebo
Follow up: 7 years
MBS Reviews – Vitamin D Testing Review Report
36,282

Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
P=0.001).
Mean difference in weight change according to BL BMI (kg/m2) (kg)
(range):
 <25: –0.08 (–0.23 to 0.06)
 25 to <30: –0.09 (–0.22 to 0.04)
 30 to <35: –0.23 (–0.4 to –0.06)
 ≥35: –0.17 (–0.38 to 0.04)
Participants who were heavier (i.e., higher BMI) had a greater
treatment effect (P=0.04 for interaction).
Treatment effects did not vary for other BL characteristics, including
ethnicity, age, education level, waist circumference, total calcium and
vitD intake, energy intake, smoking, physical activity, and fruit and
vegetable intake.
Odds of weight gain after 3 yrs in study (1-3 kg gain; >3 kg gain):
 Effect of calcium+vitD: OR=0.95 (CI, 0.90-1.01); OR=0.94 (CI,
0.90- 0.99) (P=0.05 for interaction)
 Calcium <1200 mg: OR=0.89 (CI, 0.83-0.96); OR=0.89 (CI, 0.840.95)
 Calcium >1200 mg: OR=1.05 (CI, 0.96-1.15); OR=1.01 (CI, 0.931.10) (total calcium intake P=0.008 for interaction)
Good
Main effects
 MI or CAD death: HR=1.04 (CI, 0.92-1.18)
 Stroke: HR=0.95 (CI, 0.82-1.10)
 Risk of coronary revascularization, hospitalized heart failure,
Page 107
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670












Lappe et al.
(2007)(148)
Community-dwelling women randomised to calcium
(1400mg calcium citrate or 1500 mg calcium carbonate),
MBS Reviews – Vitamin D Testing Review Report
1179

Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
confirmed angina, TIA, and composite outcomes were similar
between grps.
Effect on MI or CAD death by BMI subgrp:
 <25 kg/m2: HR=1.16; ≈CI, 0.8-1.5
 25-<30 kg/m2: HR=1.18; ≈CI, 0.9-1.5
 ≥30 kg/m2: HR=0.91; ≈CI, 0.7-1.2
(P=0.04 for interaction)
Effect on MI or CAD death by other subgrps: NS test for interaction for
age, waist circumference, medication use, CVD risk factors or CVD at
BL, and calcium/vitD intake at BL.
Effect on stroke by use of anticholesterol medication:
 Yes, HR=0.69 (≈CI, 0.5-1.0);
 no, HR=1.04 (≈CI, 0.8-1.5) (P=0.04 for interaction)
Effect on stroke by CAD risk factors:
 None, HR=1.14 (≈CI, 0.7- 1.6);
 1-2, HR=0.9 (≈CI, 0.7-1.1);
 ≥3, HR=0.76 (≈CI, 0.3-2.2) (P=0.02 for interaction)
Effect on stroke by use of statin at BL:
 Yes, HR=0.54 (≈CI, 0.2-0.9);
 no, HR=1.0 (≈CI, 0.8-1.2) (P=0.04 for interaction)
Effect on CAD or stroke by calcium or vitD intake at BL: No
interaction
Good
Cancer incidence (vitD; calcium; placebo) (# patients):
Lack of vitD only
 Yrs 1-4: 13; 17; 20
Page 108
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670






vitD 1000 IU+calcium, or placebo
Follow up: 4 years


Dumville et al.
(2006)(149)
Healthy participants randomised to vit D combined with
calcium (800 IU oral cholecalciferol for 6 months) or
placebo
2117



WactawskiWende et al.
(2006)(116)
Postmenopausal women randomized to vitD (total dose
of 400IU vitD and 1000mg calcium/day) or placebo
followup: 7 years
MBS Reviews – Vitamin D Testing Review Report
36,282

Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
 Yrs 2-4: 8; 15; 18
VitD and calcium grps had lower incidence of cancer compared with
placebo grp (P<0.03). Cancer risk in vitD and calcium grps, RR=0.402
(CI, 0.20-0.82; P=0.013) and RR=0.532 (CI, 0.27-1.03; P=0.006),
respectively. Cancer risk after yr 1, RR=0.232 (CI, 0.09-0.60; P<0.005)
in vitD grp and unchanged in calcium grp.
Logistic regression revealed that treatment assignment was an
independent predictor of cancer incidence after adjustment for 12-mo
25-(OH)D (P<0.03) independent determinant of cancer risk. Cancer
risk per unit concentration of serum 25-(OH)D at BL, RR=0.983 (CI,
0.968-0.997; P<0.01) after adjustment for tx; 35% reduced risk of
cancer for every 25 nmol/L increase in serum 25-(OH)D. No subgrp
analysis or test for interaction between treatment and BL 25-(OH)D
level.
74.6% of vitD grp and 78.1% of control grp had valid score at both
assessment times.
Differences between grps mean MCS (100-point scale) at BL (–0.59;
CI, –1.51 to –0.33) and 6 mos (1.76; CI, –0.81 to –1.16) were NS.
Differences were NS after controlling for BL score and age (– 0.49; CI,
–1.34 to –0.81).
Invasive colorectal cancer (CRC): HR=1.08 (CI, 0.86- 1.4; NS).
Similar HRs after exclusion for poor adherence or history of CRC. NS
differences in HRs across subgrps defined by age at screening,
race/ethnicity, education, 1st-degree relative with CRC, history of
Good
group
Fair
Good (fair for CRC
outcome)
Page 109
February 2014
Brunner et al.
(2011)(138)
Postmenopausal women randomised to vitD (400 IU and
calcium 1000 mg/day) or placebo
Follow up: 7 years
34,670








MBS Reviews – Vitamin D Testing Review Report
Good
Invasive cancer in 1306 participants (7%) in vitD grp and 1333
participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).
There were no differences between grps for the incidence of specific
invasive cancers. Similar HR after omission of nonadherent participants
from analysis.
Cancer mortality in 315 participants (1.7%) in vitD grp and 347
participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).
Greater protective treatment effect in participants with first-degree
relative with cancer and in past smokers (significant interaction).
Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at
BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels
of BL intake (P<0.04 for treatment-intake interaction).
There was a greater incidence of invasive cancers in vitD grp for
participants in highest quartile of total vitD intake (HR=1.22; CI, 1.021.45; P<0.04).
Age, ethnicity, education, BMI, physical activity, caloric intake,
calcium intake, latitude, solar irradiation, alcohol intake, and current
smoking status were not associated with the rate of invasive cancer.
polyp removal, BMI, physical activity, total energy intake, energy from
saturated fat, total calcium intake, total vitD intake, regional solar
exposure, multivitamin use, smoking status, NSAID use, and hormonetreatment use.
Other outcomes:
 Cancer: HR=0.98 (CI, 0.91-1.05; NS)
 CRC-related mortality: HR=0.82 (CI, 0.52-1.29; NS)
 Cancer-related mortalilty: HR=0.89 (CI, 0.77-1.03; NS)
 All-cause mortality: HR=0.91 (CI, 0.8-1.01; NS)
Analysis of nested case-control subgrp (306 pairs) revealed a
significant interaction between treatment grp and BL 25-OHD (P=0.02
for trend). . ORs decreased from 1.15 at ≥58.4 nmol/L to 0.7 at <31.0
nmol/L, but all were NS.
Page 110
February 2014
Trivedi et al.
(2003)(150)
Healthy participants randomised to vit D (100,00 IU oral
cholecalciferol every four months for 5 years) or
placebo
2686

Mortality (vitD; placebo) (age adjusted RR) (%):
 All-cause: 16.7; 18.4 (RR=0.88; CI, 0.74-1.06)
 CVD: 7.5; 8.7 (RR=0.84; CI, 0.65- 1.10)
 Cancer: 4.7; 5.4 (RR=0.86; CI, 0.61- 1.2)
(All analyses NS)

Incidence (vitD; placebo) (age adjusted RR) (%):
 CVD: 35.5; 37.5 (RR=0.90; CI, 0.77- 1.06)
 Cancer: 14.0; 12.9 (RR=1.09; CI, 0.86-1.36)

Subgroup analysis according to sex:
 All RRs remained NS within men and women subgrps. Compared
with RRs for men, RRs for women were higher for CVD, and
exceeded 1.00 for cerebrovascular disease; RRs for women were
dramatically lower for cancer. However, men women differences
were NS (overlapping CIs).
Good
Table A8.3: Cost-effectiveness studies and cost analyses as reported by in the 2012 Hayes Inc. HTA(27)
Author/year
(2012)(118)
Bailey et al.
6 VA Medical Centres
Cross-sectional analysis of
costs vs vitamin D status and
monitoring (retrospective
chart review)
Perspective: VA
Medical Centres
Population/Intervention/
Comparators/Outcomes
15,340 patients(mean age
67
yrs; mean BMI 29; 93%
men; 88% white) seen at
6 VA Medical Centres
F/u vitamin D testing vs no
f/u




<20 ng/mL was considered vitamin D
insufficient.
% patients with ≥ f/u test ranged from approx
48% to 69%.
Discounting: N/A
Base year/inflation rate: NR

University of Toronto,
Toronto, Canada



postmenopausal
women without
osteoporosis
VitD3 (800 IU/day) +
calcium (1200
mg/day);
VitD3+calcium+vitK2
; VitD3+calcium+Vit
K1; VitK2alone
No supplementation
Hip, clinical vertebral,
MBS Reviews – Vitamin D Testing Review Report
Findings and conclusions




Total input and output
costs
Gajic-Veljanoski et al.
(2012)(119)
Cost-effectiveness study of
vitD+calcium and
vitD+calcium+vitK
(probabilistic decision
analytic
Data sources/methods




Assumptions: Duration of QOL and cost
impact varied by fracture. Woman would take
alendronate for 5 years after first clinical
fracture.
Fracture risk: Swedish Malmö registry (ageand site specific) and published MA (for
successive fractures).
Mortality risk: Canadian life tables; increased
for 1 year after hip fracture.
Effectiveness:
 VitD: Authors’ MA of 3 RCTs† (hip,





Total output costs (no f/u test, 1 f/u test; ≥2 f/u tests, vitamin D
deficient, non-deficient): Approx $76,000; $83,000; $10,200;
$10,000, $8000
Total input costs (no f/u test, 1 f/u test; ≥2 f/u tests, vitamin D
deficient, non-deficient): Approx $11,500; $7500; $6250; $11,000,
$7000
Latitude, season of vitamin D draw, and vitamin D status, and
monitoring were statistically significant explanations of cost
variation, but considerable residual variation was attributed to site.
Authors’ conclusions: Testing serum vitamin D once or twice yearly
until stable and appropriate levels are documented is appropriate
VitD+calcium: Cost-saving (–$4196 to – $4283 per woman) over a
lifetime. Because of dominance over no supplementation,
vitD+calcium became relevant comparison for vitK treatments.
VitD+calcium+vitK: $9557-$12,896/QALY
VitK2 alone: More expensive and less effective than
vitD+calcium+vitK
ICERs were the result of computer simulation with repeated
sampling; thus, estimates varied slightly for different sets of
calculations for different vitK interventions.
Sensitivity analyses: Varied all input parameters and several base
case assumptions. Most sensitive to assumptions regarding
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February 2014
Author/year
model)
Perspective: Payer
Population/Intervention/
Comparators/Outcomes
morphometric
vertebral, or wrist
fracture
Time horizon: Lifetime or
age 100 yrs


Funding source: No external
funding
Lilliu et al. (2003)(120)
Institutionalized women
Cost data from 7
European countries
Supplementation
with
vitD3 (800 IU/day) +
calcium (1200 mg/day)
No supplementation
Cost-effectiveness and cost
analysis
Data sources/methods





Hip fracture
Perspective: Mixed

Time horizon: ≤1 yr postfracture (costs)


Singh et al. (2004)(121)
Elderly NH residents

Canada
Cost-effectiveness and Costutility analysis (decision
Hip protectors vs
standard care

MBS Reviews – Vitamin D Testing Review Report
RR=0.68; vertebral, RR=0.87; wrist,
RR=0.69)
 VitK2: Published MA and single study in
Japanese patients
 VitK1: Single RCT in postmenopausal
Canadian women
Utility weights: Published literature
Costs: All direct medical costs for treated
fracture, including LTC. Cost of alendronate,
vitD3+calcium (CAD 89.90/yr [USD 85.69];
no dispensing costs), and vitK.
Discounting: 3% for costs and life-years
Base year, inflation adjustment: 2009 USD, NR
Fracture risk: Prevalence in the study grp of the
effectiveness estimate source (Chapuy et al.,
1992)(122).
Effectiveness: RCT with placebo control and
ITT analysis (Chapuy et al., 1992 (122)); 25%
fewer cases (RR 0.75)*
Costs: Published data for each country. (1)
Supplements (€0.29/day-€0.54/day); (2)
treatment of hip fracture.
Cost components varied by country (medical
only vs societal, incremental vs total, 6 mos to
1 yr, initial costs only vs midterm rehab also,
derived from previously non-institutionalised
population in 1 country). Estimates
corresponded to 880 IU/day vitD and/or 1000
mg/day calcium in some countries. Cost of
delivering supplements considered negligible.
Long-term institutionalization not included as a
cost consequence.
Discounting: N/A
Base year, inflation adjustment: NR (2003
assumed), N/A
BL incidence: 43/1000 persons/yr, based on
chart review of a local NH facility.
Effectiveness estimate: Obtained from a
Cochrane Review of hip protectors (RR=0.37)
and from Chapuy et al. (1992)(122) for
Findings and conclusions









effectiveness and costs of vitK.
Authors’ conclusions: No overall conclusion concerning vitD
supplementation since vit K supplementation was the focus.
Cost-saving for all countries: €79,000- €711,000 (USD 87,137-USD
784,233)/1000 women.
Greatest cost savings for the country (UK) for which cost estimates
derived from non-institutionalised population.
Sensitivity analyses: For worst case scenario (20% increase in #
fractures), results suggested that supplementation either remained
cost-saving (€123,000- €174,000/1000 women [USD 135,669- USD
191,922/1000 women]) or was reasonably cost-effective (€64,000€134,000/1000 women [USD 70,592-USD 147,802/1000 women]) in
additional costs.
Highly cost-saving for all countries under best-case scenario (20%
fewer fractures). Daily supplementation price for equal costs in
supplementation and placebo grps, €0.64-€1.45 (USD 0.64-USD
1.60).
Currency conversions based on rates as of April 25, 2003.
Authors’ conclusions: Analysis probably underestimates costeffectiveness since supplementation has been shown to also prevent
non-vertebral fractures other than hip.
Cost savings/hip fracture averted: Hip protector vs no treatment:
CAD 10,713 (USD 7820) Hip protector vs supplementation: CAD –
10,198 (USD –7445)
Cost savings/QALY gained (women; men): Hip protector vs no
treatment: CAD 16,204 (USD 11,829); CAD 18,272 (USD 13,339)
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February 2014
Author/year
analytic modeling using
hypothetical cohort)
Perspective: Described as
“societal” but only direct
medical costs were
considered; equivalent to
payer perspective
Population/Intervention/
Comparators/Outcomes
No treatment or
vitD3+calcium
supplementation (800
IU/day vitD, 1200 mg/day
calcium)
Data sources/methods

Hip fractures averted,
QALYs gained
Time horizon: 1 yr
postfracture (costs), lifetime
(QALYs gained)



MBS Reviews – Vitamin D Testing Review Report
supplementation (RR=0.73).
Utility values (for QALY estimates): Published
study of EuroQol scores for patients aged 7584 yrs with and without hip fracture for 1st and
2nd yrs postfracture; subsequent yrs assumed
to be equivalent to 2nd yr. Probability of death
for 1st yr, 10%; for subsequent yrs, based on
Canadian Life Table data for NH home
residents without fracture. 0.63, no fracture;
0.43, 1 yr postfracture; 0.53, 2nd or subsequent
yr postfracture
Costs (1 year): Cost of fracture treatment
included only immediate hospitalisation in the
base case and was estimated by finance
department of local hospital associated with
NH. Cost of hip protector (CAD 150, USD
110) and supplements (CAD 56, USD 41)
obtained from local retail suppliers; cost of side
effects excluded (evidence suggests they are
negligible).
Discounting: N/A for costs; 3% for QALYs.
Base year/inflation rate: 2001, N/A
Findings and conclusions



Hip protector vs supplementation: CAD 15,426 (USD 11,261); CAD
17,394 (USD 12,698)
2-way and 1-way sensitivity analysis, hip protector vs
supplementation: Limits of 95% CI of effectiveness estimate for hip
protectors, 33% increase and decrease in costs, and addition of
nursing aide for putting on protector. Analyses yielded C/E ratios of
$299-$18,727/fracture averted and $403-$28,326/QALY, when cost
of nursing aid was considered and/or upper limit of effectiveness was
assumed; otherwise, cost savings were maintained.
Probabilistic sensitivity analysis (computer simulation), hip protector
vs supplementation: 95% probability that cost/fracture averted is
<CAD 20,000 (USD 14,600); 96% probability of cost savings if no
nursing aide time is required and cost of hip protector is <CAD 150
(USD 110). Similar findings for QALYs gained as the outcome.
Authors’ conclusion: Hip protectors appear to be a cost-effective
treatment option.
Page 113
February 2014
APPENDIX 9 – Review of the effectiveness of supplementation in
healthy patient populations
The 2012 Hayes Inc. HTA for the Washington State Health Care Authority(27) identified six
systematic reviews and 14 RCTs (23 publications) that evaluated the effect of vitamin D
supplementation on the following health outcomes:










musculoskeletal health, including bone mineral density (BMD), falls and fractures;
cancer;
cardiovascular disease;
type 2 diabetes;
obesity;
multiple sclerosis;
mood disorders;
all-cause mortality;
outcomes related to pregnancy; and
children and adolescents.
A9.1
Effect of vitamin D supplementation on musculoskeletal health
Evidence relating to musculoskeletal health was obtained from six systematic reviews of
RCTs.(9, 104-106, 108, 151) One of the selected RCTs was the Women’s Health Initiative (WHI), a
seven-year U.S. study following 36,282 postmenopausal women, all of whom were aged 50
years or older. Women were randomised to 400 IU/day of vitamin D plus calcium, or to
placebo, and were allowed continued use of personal supplements. Baseline serum 25-(OH)D
levels were not reported for the overall study group; however, in a nested case-control
analysis derived from this study, 72% of women had baseline serum levels < 52.4 nmol/L. (142)
When compared with the overall American population, the WHI trial population had a much
greater prevalence of vitamin D insufficiency (72% vs 28% the prevalence of vitamin D
insufficiency in American Women aged ≥ 50 years)(152). Nine different publications provided
data from this trial.
Based on an analysis of more than seven RCTs (including meta-analyses where possible), the
AHRQ report by Cranney et al. (2007)(108) concluded that vitamin D3 (≤ 800 IU/day) plus
calcium resulted in small increases in BMD of the spine, total body, femoral neck and total
hip in populations consisting predominantly of women in late menopause. This conclusion is
consistent with the AHRQ review by Chung et al. (2009)(9), which included three additional
RCTs in older women. However, five RCTs included in the two AHRQ reports showed
inconsistent findings for an effect on physical performance measures.
Another systematic review with meta-analysis by Michael et al. (2010)(106), also from the
AHRQ, found that vitamin D at median doses of 800 IU/day, with or without calcium,
reduced the incidence of falls by 14% (risk ratio [RR]: 0.82; 95% confidence interval [CI]:
0.77 to 0.89) in community-dwelling older adults (nine RCTs; 5,780 participants).(106)
A more recent systematic review and meta-analysis by Murad et al. (2011)(105), commissioned
by the Endocrine Society, reported results very similar to those reported by Michael et al.
(2010), although no restriction on participant dwelling was made (results from community
and institutionalised participants were pooled): the odds ratio (OR) was 0.86 (95% CI: 0.77 to
MBS Reviews – Vitamin D Testing Review Report
February 2014
0.96) for vitamin D with or without calcium, based on 26 RCTs and a total of 45,782
participants with a mean age of 76 years.(105) In the studies reviewed by Murad et al. (2010),
patients generally received vitamin D at doses of 400 to 1000 IU/day. The population
represented by the studies included in the review by Murad et al. (2010) was at a substantial
risk of falls (median risk 50%; range 15% to 69% across studies). Statistical tests for
interaction suggested that the treatment effect did not differ by community versus institutional
dwelling.
Combined data from 18 studies (N=13,628) was used to evaluate the effect of vitamin D
supplementation (with or without calcium) on the risk of falls (Figure A9.1). Meta-analysis
shows that supplementation with vitamin D significantly reduces the risk of falls in the elderly
population (OR: 0.73; 95% CI: 0.60 to 0.89).
Figure A9.1: Meta-analysis of the effects of vitamin D alone or with calcium, compared with
placebo, on the risk of falls
Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people
who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the
overall meta-analysis.
The data were analysed to determine the effect of vitamin D plus calcium on the risk of falls
in the elderly population. Nine studies (N=6,033) were included in the meta-analysis (Figure
A9.2). The results show that supplementation with vitamin D in combination with calcium
significantly reduces the risk of falls (OR: 0.73; 95% CI: 0.58 to 0.92).
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.2: Meta-analysis of the effects of vitamin D plus calcium, compared with placebo, on
the risk of falls
Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people
who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the
overall meta-analysis.
A meta-analysis was also conducted to examine the effect of vitamin D alone on the risk of
falls. Data from nine studies (N=7,594) were included in the meta-analysis (Figure A9.3).
The results show that supplementation with vitamin D alone significantly reduces the risk of
falls in the elderly population (OR: 0.73; 95% CI: 0.54 to 0.98).
Figure A9.3: Meta-analysis of the effects of vitamin D alone, compared with placebo, on the risk
of falls
Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people
who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the
overall meta-analysis.
A9.2
Effect of vitamin D supplementation on fractures
There was a single Cochrane systematic review of RCTs performed by Avenell and
colleagues (2009)(89) which assessed the efficacy of supplementation with vitamin D or a
vitamin D-related compound in the reduction of hip, non-vertebral, vertebral or any new
fracture. It included 42 RCTs, one cluster randomised trial(153), and two quasi-randomised
trials(154, 155). The included RCTs compared vitamin D2, vitamin D3, or 25-(OH)D, with or
without co-administration of calcium, against placebo, no treatment or calcium alone.(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Ten of the 42 RCTs evaluated the effects of vitamin D supplementation alone versus placebo
or no treatment on fracture reduction.(107, 150, 153, 154, 156-161) Nine trials (24,749 participants)
compared vitamin D alone with placebo on the risk of hip fracture. Meta-analysis of these
trials showed no statistically significant reduction in hip fracture due to vitamin D
supplementation (RR: 1.15, 95% CI: 0.99 to 1.33, Figure A9.4).(89)
Figure A9.4: Meta-analysis of the effects of vitamin D supplementation alone compared with
placebo on new hip fracture
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review)(89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip
fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.
One trial of 3,440 participants showed no statistically significant effect of vitamin D alone
compared with placebo on non-vertebral fracture (RR: 0.96, 95% CI: 0.80 to 1.15). Figure
A9.5 presents a meta-analysis comparing the effects of vitamin D alone on the risk of
vertebral fractures. Based on five trials with 9,138 participants, there was no statistically
significant effect of vitamin D alone versus placebo on vertebral fracture or deformity (RR:
0.90, 95% CI: 0.42 to 1.92, Figure A9.5).(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.5: Meta-analysis of the effects of vitamin D supplementation alone compared with
placebo on new vertebral fracture or deformity
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review)(89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of
vertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall metaanalysis.
Figure A9.6 presents a meta-analysis of the effects of vitamin D alone on the risk of new
fracture. Based on ten trials with a total of 25,016 participants, there was no statistically
significant effect of vitamin D alone compared with placebo (RR: 1.01, 95% CI: 0.93 to 1.09,
Figure A9.6).(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.6: Meta-analysis of the effects of vitamin D supplementation alone compared with
placebo on any new fracture
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review)(89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of any
fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.
Eight of the 42 RCTs evaluated the effect of vitamin D in combination with calcium
supplementation on the risk of hip, vertebral and any fracture.(122, 156, 157, 162-166) Pooled data
from eight trials (46,658 participants) showed a statistically significant reduction in the risk of
hip fracture in the population receiving vitamin D plus calcium compared with placebo or no
treatment (RR: 0.84, 95% CI: 0.73 to 0.96, Figure A9.7).(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.7: Meta-analysis of the effects of vitamin D plus calcium supplementation compared
with placebo on new hip fracture: sub-group analysis by history of previous
fracture
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review) (89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip
fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis
In the subgroup analyses shown in Figure A9.7 by history of prior fracture, there was no
evidence of a statistically significant reduction in effect of calcium plus vitamin D (four trials
with 6,134 participants, RR: 1.02, 95% CI: 0.71 to 1.47), but the pooled data from studies
where a previous osteoporotic fracture was not a selection criterion did show a statistically
significant reduction (four trials with 40,524 participants, RR: 0.81, 95% CI: 0.71 to 0.93,
Figure A9.7). The difference between subgroups did not reach statistical significance (P =
0.24).(89)
In the subgroup analysis by residential status (institution versus community, Figure A9.8),
there was a statistically significant reduction in hip fracture incidence in the institutionalised
residents subgroup (two trials with 3,853 participants, RR: 0.75, 95% CI: 0.62 to 0.92), but
not in the community dwelling group (six trials with 42,805 participants, RR: 0.91, 95% CI:
0.76 to 1.08). However, there was no statistically significant difference between subgroups (P
= 0.17).(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.8: Meta-analysis of the effects of vitamin D plus calcium supplementation compared
with placebo on new hip fracture: subgroup analysis by residential status
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review) (89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip
fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis
Nine of the 42 RCTs assessed the effects of vitamin D plus calcium supplementation in the
reduction of non-vertebral fractures.(122, 156, 157, 162-167) Overall, supplementation with vitamin
D plus calcium was not associated with a statistically significant reduction in the incidence of
new non-vertebral fracture compared with placebo (nine trials with 46,781 participants, RR:
0.95, 95% CI: 0.90 to 1.01, Figure A9.9).
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February 2014
Figure A9.9: Meta-analysis of the effects of vitamin D plus calcium supplementation compared
with placebo on non-vertebral fracture: sub-group analysis by history of previous
fracture
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review) (89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of nonvertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall metaanalysis.
In the subgroup analyses shown in Figure A9.9 by history of prior fracture, there was no
statistically significant reduction in non-vertebral fracture in participants selected on the basis
of prior fracture (four trials with 6,134 participants, RR: 0.93, 95% CI: 0.79 to 1.10, Figure
A9.9), or in participants not selected on the basis of prior fracture (five trials with 40,647
participants, RR: 0.95, 95% CI: 0.90 to 1.01, Figure A9.9). There was no statistically
significant difference between subgroups (P = 0.81).(89)
In the subgroup analysis by residential status (institution versus community: Figure A9.10),
there was a statistically significant reduction in new non-vertebral fracture incidence in the
institutional residents subgroup (two trials with 3,853 participants, RR: 0.85, 95% CI: 0.74 to
0.98), but not in the community dwelling group (seven trials with 42,928 participants, RR:
0.97, 95% CI = 0.91 to 1.02). There was no statistically significant difference between
subgroups (P = 0.09).(89)
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.10: Meta-analysis of the effects of vitamin D and calcium supplementation as
compared with placebo on non-vertebral fracture: subgroup analysis by
residential status
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review) (89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of nonvertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall metaanalysis.
Three of the 42 trials assessed the effects of vitamin D plus calcium supplementation
compared with placebo or no treatment on the reduction of vertebral fractures.(156, 162, 166)
There was no evidence of a statistically significant preventive effect on clinical vertebral
fractures from the administration of vitamin D plus calcium (three trials with 38,990
participants, RR: 0.91, 95% CI: 0.75 to 1.11, Figure A9.11).
MBS Reviews – Vitamin D Testing Review Report
February 2014
Figure A9.11: Meta-analysis of the effects of vitamin D and calcium supplementation compared
with placebo on new vertebral fracture: sub-group analysis by previous fracture
Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis
(Review) (89)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of
vertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall metaanalysis.
Overall, the meta-analyses did not show a statistically significant effect of vitamin D alone on
hip, vertebral, non-vertebral or any fracture. However, there was a statistically significant
reduction in the risk of new hip fracture in the population receiving vitamin D plus calcium
compared with placebo or no treatment. This effect was statistically significant in
institutionalised patients but not in community dwelling patients.
An attempt was made in one of the systematic reviews to evaluate the effect of vitamin D in
the prevention of osteoporosis in younger women (19-49 years old), but no RCTs conducted
among this age group were identified.(108) In addition, there are currently no identified studies
that have investigated the link between serum 25-(OH)D levels with any outcome measure of
bone health (such as BMD, falls or fractures) in younger adults.
A9.3
Effect of vitamin D supplementation on cancer
Overall cancer risk
The AHRQ systematic review by Chung et al. (2009) included four RCTs(116, 143, 148, 150) and
two cohort studies(168, 169) that evaluated the effects of vitamin D on overall cancer risk.(9)
These studies are summarised in Table A9.1. The RCTs evaluated the effects of vitamin D
with or without calcium supplementation on cancer incidence or cancer mortality risk, with a
mean follow-up of four to seven years. In two RCTs(116, 150), colorectal cancer was evaluated
as a secondary outcome, the studies being originally designed to evaluate the effects of
vitamin D on fracture risk.
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Table A9.1: Summary of RCTs from the AHRQ systematic review by Chung et al. (2009)(9)
Sample
size
1,180
Study
Population
Outcome
Lappe et al.
(2007)(148)
Postmenopausal
women taking
either VitD3 1,000
IU +Ca 1,400-1,500
mg/day (n=446) or
Ca 1,400-1,500
mg/day (n=445) or
placebo (n=288)
 Incidence of
any cancer
(secondary
endpoint)
 Self-reported
(confirmed
in medical
record)
Chlebowski
et al.
(2007)(143)
Postmenopausal
women receiving
either VitD 400 IU
+ Ca 1g vs. placebo
 Medical
records
(blinded
investigators)
36,282
 Incidence of
any cancer
 Secondary
endpoint
 Self-reported
(confirmed
in medical
record)
36,282
 Any cancer HR: 0.98
(0.91, 1.05) VitD vs.
placebo
 Compliance: ~ 60%
 Incidence of
any cancer
 Cancer
mortality
 Self-reported
2,686
 Any cancer RR 1.09
(95% CI: 0.86, 1.36)
 Overall cancer
mortality RR 0.86
(98% CI: 0.61, 1.20)
 Completed the
study: 76.5%
 Compliance rate:
76%
Participants were
allowed to use up to
600 IU (1,000 IU
later) and 1,000 mg
Ca/day in addition
to study drugs)
WactwaskiWende et al.
(2006)(116)
Trivedi et
al.
(2003)(150)
Postmenopausal
women receiving
either VitD 400 IU
+ Ca 1 g vs.
placebo
Participants were
allowed to use up to
600 IU (1,000 IU
later) and 1,000 mg
Ca/day in addition
to study drugs
Elderly men and
women taking
either vitamin D3
100,000 IU every
four months
equivalent to ~ 800
IU/day) or placebo
Findings
Summary of conclusions
 VitD+ Ca vs.
placebo RR: 0.402
(95% CI 0.2, 82)
 Ca vs. placebo RR:
0.532 (0.27,1.03)
Excluding cancers
developed in yr 1
VitD+ Ca RR: 0.232
(0.09 , 0.6)
 Completed the
study: 86.8%
 Compliance: 85.7%
 Breast cancer HR:
0.96 (0.86 , 1.07)
 Several subgroups
evaluated
 Age 70-79 yrs HR:
1.08 (0.82 , 1.43)
 Baseline VD ≥
600IU 1.34 (1.01 ,
1.78
 Compliance 60-63%
 Association between
use of vitD and Ca and
reduced risk of cancer.
 Logistic regression
does not take into
account censoring and
may affect the validity
of the results
 Authors mention
association between
higher calcium and
lower risk.
 No association
between lower breast
cancer risk and higher
serum vitamin D levels
after adjusting for
body mass index
(BMI) and physical
activity in addition to
other variables (nested
case control).
 No association
between VitD + Ca
and cancer vs. placebo.
 Use of VitD and/or Ca
in addition to study
drugs may have biased
the results towards the
null.
 No association
between VitD + Ca
and cancer vs. placebo
Lappe et al. (2007) conducted a four-year RCT designed to compare the effects of vitamin D3
(1,000 IU/day) plus calcium (1,400-1,500 mg/day) to a placebo and the same dose of calcium
alone, on the risk of fractures. Treatment effects on the risk of any type of cancer was a
secondary endpoint.(148) The study included 1,179 healthy postmenopausal women (> 55
years old) without any known cancer, chronic kidney disease, or metabolic bone disease. All
women were white with a mean age of 66.7 ± 7.3 years and a mean baseline 25-(OH)D level
of 71.8 ± 20.3 nmol/L.(148) Baseline characteristics by study group were not provided and the
authors did not mention if they were comparable, especially with regards to cancer risk
factors. An intention-to-treat (ITT) analysis with logistic regression was used. Cox
proportional hazards analysis was not used as, according to the authors, the assumption of a
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February 2014
constant hazard ratio was not satisfied by their data. The authors did not, however, provide
additional information on how the violation occurred.(148)
A total of 1,024 of 1,180 (86.8%) subjects completed the study with treatment adherence
being 85.7% in the vitamin D and calcium group and 74.4% in the calcium group. Cancer
was diagnosed in 20 of 288 (6.9%) patients in the placebo group, 17 of 445 (3.8%) in the
calcium group, and 13 of 446 (2.9%) in the vitamin D and calcium group over four years of
follow-up. There was a 60% decrease in cancer risk with vitamin D and calcium compared to
placebo (unadjusted RR: 0.402, 95% CI: 0.20, 0.82) and a trend to risk reduction with calcium
compared with placebo (RR: 0.532, 95% CI: 0.27, 1.03). Excluding the cancer cases
diagnosed during the first year, the RR for vitamin D and calcium was 0.232 (95% CI: 0.09,
0.60) and 0.587 (95% CI: 0.29, 1.21) for calcium alone.(148)
The study by Lappe et al. (2007) had some limitations which included the use of logistic
regression to analyse time-to-event data, which may have led to bias since losses-to-follow-up
and censoring was not taken into account. In addition, demographic characteristics by study
group were not provided and the authors did not provide comment on whether the two groups
were comparable.
The RCT by Wactawski-Wende et al. (2006) was part of the Women’s Health Initiative
(WHI) study, which compared the effects of vitamin D (400 IU/day) and calcium (1,000
mg/day) to placebo on the risk of hip fractures (primary outcome), colorectal cancer
(secondary outcome), and other types of cancer.(116) Women in both study groups were
allowed to take up to 600 IU/day of vitamin D (later increased to 1,000 IU) and up to 1,000
mg of calcium/day in addition to the study drug. The women included in the vitamin D and
calcium study had been participating for a year in a component of the WHI trial in which
women were randomised to either:




dietary interventions through a low-fat diet high in fruits and vegetables;
postmenopausal hormone therapy;
a combination of the two; or
placebo and usual diet.(170)
The effect of vitamin D plus calcium on overall cancer and colorectal cancer was evaluated
based on an ITT time-to-event analysis using a Cox proportional hazards model. A total of
36,282 postmenopausal women, 50 to 79 years old, without a history of hypocalcaemia or
renal calculi, not using corticosteroids or > 600 IU/day of vitamin D, were included (18,176 in
the vitamin D plus calcium group and 18,106 in the placebo group). The results were
stratified by age, colorectal cancer history, and hormone therapy/dietary modification study
group assignment. The mean follow-up was 7 ± 1.4 years. Treatment compliance was low in
both groups, at approximately 60%. This study reported that there was no statistically
significant difference in the overall risk of cancer with vitamin D plus calcium compared to
placebo (HR: 0.98, 95% CI: 0.91, 1.05). There were 1,634 cases (1.28% per year) in the
combination group and 1,655 (1.30%/ per year) in the placebo group. Despite being a large
study, the fact that vitamin D plus calcium intake in addition to the study drug was allowed, as
well as a relatively low compliance rate, may have contributed to the lack of a statistically
significant difference between the study groups.
The RCT by Trivedi et al. (2003) (150) evaluated the effect of vitamin D3 (100,000 IU every
four months) compared to placebo on the risk of fracture and overall mortality in 2,686 men
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February 2014
and women, 65 to 85 years old, selected from the Doctors Study Register in the UK.(150)
Cancer incidence was a secondary outcome. The two groups were comparable with regards to
demographic characteristics with a mean participant age of 74 ± 4.6 years. The mean calcium
intake of 742 mg/day at four years did not differ between the study groups. The compliance
rate was approximately 76% and did not differ between the study groups. There were 188
(14%) cancer cases reported in the treatment group and 173 (13%) in the control group. After
a follow-up of five years, there were no statistically significant differences between the study
groups with regards to both incidence of cancer (RR: 1.09, 95% CI: 0.86, 1.36) and overall
cancer mortality (RR: 0.86, 98% CI: 0.61, 1.20).
In addition to the three RCTs, there were two cohort studies identified in the AHRQ
systematic review by Chung et al. (2009)(9). Both studies used participants of the Third
National Health and Nutrition Examination Survey (NHANES III), which included a national
sample of non-institutionalised subjects in the US.(168, 169) Both evaluated the association
between baseline serum 25-(OH)D and rate of cancer mortality over a mean follow-up of
eight years. Therefore, the effect of vitamin D intake on cancer mortality was not directly
evaluated. Moreover, there was limited adjustment for potential confounders that may have
affected serum vitamin D levels in the analysis (e.g. adjustment for calcium intake was not
done in these studies).
The first study by Freedman et al. (2007)(168) included 16,818 men and women over the age of
17. A cox proportional hazards analysis adjustment for age, ethnicity and smoking was used.
Baseline serum 25-(OH)D was divided into quintiles and the rate of cancer mortality over
eight years of follow-up was compared among the quintiles. The mean age varied between 40
and 45 years depending on the baseline 25-(OH)D. In total, there were 536 deaths due to
cancer but no association between baseline 25-(OH)D and cancer mortality over the eight
years of follow-up.(168)
The second study by Melamed et al. (2008)(169) evaluated the association between baseline 25(OH)D and overall mortality. Cancer mortality was a secondary endpoint, along with
mortality due to cardiovascular disease, infectious disease, or external causes. Participants
included men and women over the age of 20 who were given both a baseline 25-(OH)D
measurement and a physical examination. The baseline serum 25-(OH)D was divided into
quartiles and the rate of cancer mortality over eight years of follow-up was compared among
quartiles. A total of 13,331 participants were included with a mean age of 42 to 46 years,
depending on the baseline 25-(OH)D quartile. In total, 424 deaths due to cancer occurred but
no association was found between baseline 25-(OH)D levels and cancer mortality over the
eight-years of follow-up.(169)
Colorectal cancer
Only two RCTs (116, 150) were identified that evaluated the effects of vitamin D with or without
calcium supplementation on risk of colorectal cancer and colorectal adenocarcinoma in men
and women aged 50 years and older (Table A9.1). In both RCTs, colorectal cancer was
evaluated as a secondary outcome, the studies being originally designed to evaluate the effects
of vitamin D on fracture risk. The two RCTs reported no association between vitamin D with
or without calcium and the incidence of colorectal cancer or colorectal adenocarcinoma, with
a mean follow-up of five to seven years.(116, 150) However, despite not finding an association
between vitamin D use and the risk of colorectal cancer, the WHI RCT found that subjects
with higher baseline serum 25-(OH)D had a lower risk of colorectal cancer (P for trend:
0.02).(116)
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Despite the inconsistent findings of the two RCTs, authors of the 2011 AHRQ report
calculated pooled ORs for risk of cancer per 10 nmol/L increase in serum 25-(OH)D, with
adjustment for as many potential confounders as possible. An inverse (and thus protective)
association was found between high vitamin D levels and reduced risk of colorectal cancer.
Similarly, a more recent meta-analysis performed by Touvier et al. (2012)(109) observed a
significant inverse association between increases of 100 international units per litre (IU/L) in
serum 25-(OH)D and reduced risk of colorectal cancer.(109)
Therefore, despite the evidence from prospective cohort studies supporting the protective
effect of high serum vitamin D levels in reducing the risk of colorectal cancer, RCTs
establishing the same association are still lacking.
Breast cancer
The review by Chung et al. (2009)(9) identified two RCTs(143, 150) that assessed the effects of
vitamin D, with or without calcium, on the risk of breast cancer. Similar to the trials
evaluating the efficacy of vitamin D in colorectal cancer, the RCTs were originally designed
to evaluate bone health outcomes. Neither of the RCTs (mean follow-up of five and seven
years) showed an association between vitamin D and breast cancer risk. In the study by
Chlebowski et al. (2008)(143), a higher baseline vitamin D level was not associated with a
decrease in breast cancer risk after adjusting for BMI and physical activity, in addition to
other variables (nested case-control analysis).
Prostate cancer
No RCTs evaluating the effects of vitamin D supplementation, with or without calcium, on
prostate cancer risk were identified. However, the AHRQ systematic review by Chung et al.
(2009)(9) identified 11 nested case-control studies that evaluated the association between
baseline serum vitamin D levels and prostate cancer risk.(171-181) Prostate cancer risk was a
secondary outcome in most of these studies. Sample sizes ranged from 61 to 749 subjects
with mean ages between 44 and 68 years. Follow-up periods ranged from two to 16 years.
The results obtained in the observational studies were inconsistent. One study found an
increased risk of prostate cancer (OR: 1.7; 95% CI: 1.1, 2.4) in subjects with higher serum
vitamin D levels (25-(OH)D 80 nmol/L) vs. lower levels (40-49 nmol/L).(171) Another study
found a protective effect of vitamin D but only in men younger than 52 years (OR 3.5; 95%
CI: 1.7, 7.0; ≤ 40 nmol/L vs. > 40 nmol/L)(172). A third study reported that the lowest risk of
prostate cancer is associated with the normal average serum concentration of 25-(OH)D (40–
60 nmol/l).(181) The remaining eight observational studies did not find a significant
association between serum vitamin D and prostate cancer risk.(9)
A9.4
Effect of vitamin D supplementation on cardiovascular disease
Four publications related to two RCTs(142, 145, 147, 150) evaluated the effects of vitamin D, with
or without calcium, on the development of cardiovascular disease. However, both RCTs were
originally designed to evaluate the effect of vitamin D on fractures (compared to placebo).
No statistically significant association between vitamin D, with or without calcium
supplementation, and cardiovascular outcomes were found in the two RCTs. The first RCT
by Trivedi et al. (2003)(150) evaluated the effect of vitamin D3 (100,000 IU every four months)
compared to placebo on fractures and overall mortality in 2,686 men and women, aged 65 to
85 years old, selected from the Doctors Study Register in the UK.(150) The mean calcium
intake at four years of 742 mg/day did not differ between the study groups. The authors
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February 2014
reported non-significant estimates favourable to vitamin D alone: an RR of 0.90 (95% CI:
0.77 to 1.06) for incidence of CVD and an RR of 0.84 (95% CI: 0.65 to 1.10) for CVD
mortality. Therefore, after a follow-up of five years, there was no statistically significant
difference between the study groups with regards to several cardiovascular outcomes and
cardiovascular death (Table A9.2).(150)
Three studies were analyses derived from the WHI trial, which randomised 36,282
postmenopausal women to daily supplementation with 400 IU vitamin D plus calcium or
placebo.(142, 145, 147) The cardiovascular outcomes evaluated were secondary endpoints. One
of the WHI study analyses evaluated the effect of vitamin D supplementation on the
development of hypertension and detected no effect.(145) In the study by Hsia et al. (2007)(147),
vitamin D plus calcium had no overall effect on a composite measure of coronary artery
disease mortality or myocardial infarction, or on the incidence of stroke, coronary
revascularisation, heart failure, angina, or transient ischemic attack. Therefore, no statistically
significant association between vitamin D, with or without calcium, and cardiovascular
outcomes was observed. The authors concluded that there was no evidence of increased or
decreased risk in cardiovascular outcomes with vitamin D and calcium.(142, 147)
Table A9.2: Summary of RCTs evaluating the effect of vitamin D, with or without calcium, on
cardiovascular disease
Study
Population
LaCroix et
al.
(2009)(142)
Margolis
et al.
(2008)(145)
Hsia et al.
(2007)(147)
Postmenopausal
women receiving
either VitD 400
IU + Ca 1 g vs.
placebo
Trivedi et
al.
(2003)(150)
Elderly men and
women taking
either VitD3
100,000 IU every
four months
equivalent to ~
800 IU/day) or
placebo
Outcome
 Cardiovascular
outcomes and
mortality
 Self-reported and
confirmed in
medical records
Sample
size
36,282
Participants were
allowed to use up
to 600 IU (1,000
IU later) and
1,000 mg Ca/day
in addition to
study drugs
 Cardiovascular
outcomes
(secondary
endpoint)
 From death
certificate or selfreported in
questionnaire
 Multiple outcomes
evaluated
MBS Reviews – Vitamin D Testing Review Report
2,686
Findings
 MI: 1.05 (0.91, 1.20)
 Coronary artery bypass graft or PCI:
1.08 (0.98, 1.22)
 Hospitalised for heart failure: 0.95
(0.83, 1.10)
 Angina: 1.08 (0.94, 1.24)
 Stroke: 0.95 (0.82, 1.10)
 TIA: 1.16 (0.95, 1.42)
 Composite (stroke, TIA):1.02 (0.91,
1.15)
 Cardiac composite (MI, CHD, death,
CABG, or PCI): 1.08 (0.99, 1.19)
 Cardiac composite (MI or CHD
death): 1.04 (0.92, 1.18)
 Cardiovascular death: 0.92 (0.77,
1.07)
 Coronary heart disease death: 1.01
(0.79, 1.29)
 Cerebrovascular death: 0.89 (0.62,
1.29)
 Cardiovascular disease (CVD) HR
0.90 (95% CI: 0.77, 1.06)
 Ischemic heart disease (IHD) HR 0.94
(95% CI: 0.77, 1.15)
 Cerebrovascular disease: HR 1.02
(95% CI: 0.77, 1.36)
 CVD death: HR 0.84 (95% CI: 0.65,
1.10)
 IHD death: HR 0.84 (95% CI 0.56,
1.27)
 Cerebrovascular disease death: HR
1.04 (95% CI: 0.61, 1.77)
February 2014
A9.5
Effect of vitamin D supplementation on type 2 diabetes
The 2012 HTA identified three RCTs that evaluated the effect of vitamin D supplementation
on diabetes outcome measures in healthy adults(139, 144, 182). An analysis of data derived from
the WHI study showed that supplementation (400 IU/day plus calcium) had no effect on the
incidence of diabetes over a seven-year follow-up.(144) Another study that enrolled 104 adults
(mean age 52 to 53 years) found that vitamin D supplementation (equivalent of 2,857 IU/day
without calcium) for six months had no effect on serum levels of glycated haemoglobin.(139)
A third study using the same dose of vitamin D observed no effect on blood glucose at one or
two years.(182) Overall, the results suggest that supplementation with vitamin D has no effect
on the incidence of diabetes or diabetes markers in adults. However, the overall quality of the
evidence is low due to the small number of studies and intermediate outcome measures in the
two smaller studies.
Although not directly evaluating the effects of vitamin D supplementation, a recent systematic
review and meta-analysis evaluating the effect of vitamin D levels on type 2 diabetes was
performed up to August 2012 by Khan et al. (2013)(183). It included 18 prospective studies,
comprising 210,107 participants, reporting association of circulating or dietary vitamin D with
incident type 2 diabetes, metabolic syndrome and insulin resistance (IR) outcomes. The
included studies collected a total of 15,899 metabolic events during a median follow up of 10
years (range 3-22 years). The RR for individuals in top versus bottom thirds of baseline
vitamin D were 0.81 (95% CI 0.71, 0.92); 0.86 (95% CI 0.80, 0.92); and 0.84 (95% CI 0.64,
1.12) for type 2 diabetes, metabolic syndrome and IR outcomes, respectively. Findings were
generally consistent across various study-level characteristics.
Another systematic review and meta-analysis conducted by Forouhi et al. (2012)(184) included
new data from two previously unpublished studies, the European Prospective Investigation
into Cancer (EPIC)-Norfolk study(184), which is a nested case-cohort study, and the Ely
prospective study(185). The systematic review included 11 prospective studies (3,612 cases
and 55,713 non-cases) on the association between serum 25-(OH)D concentration and
incident type 2 diabetes published until January 2012. The authors performed a meta-analysis
combining available evidence with results from the EPIC-Norfolk and Ely studies. In the
EPIC-Norfolk, baseline 25-(OH)D was lower among incident type 2 diabetes cases (mean
[SD] 61.6 [22.4] nmol/L; N=621) vs non-case sub-cohort participants (mean 65.3 [23.9]
nmol/L; N=826). There was an inverse association between baseline 25-(OH)D and incident
type 2 diabetes in multivariable-adjusted analyses: HR 0.66 (95% CI: 0.45, 0.97), 0.53 (95%
CI: 0.34, 0.82), 0.50 (96% CI: 0.32, 0.76), comparing consecutive increasing 25-(OH)D
quartiles with the lowest. In the Ely study (185), 37 incident type 2 diabetes cases were
identified among 777 participants. In meta-analysis shown in Figure A9.12, the combined RR
of type 2 diabetes comparing the highest with lowest quartile of 25-(OH)D was 0.59 (95% CI:
0.52, 0.67). Therefore, these findings demonstrate an inverse association between circulating
25-(OH)D and incident type 2 diabetes.
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February 2014
Figure A9.12: Meta-analysis of the effects of serum 25-(OH)D on incident type 2 diabetes
Source: Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the EPIC-Norfolk cohort and updated
meta-analysis of prospective studies(184)
The sizes of the boxes for individual studies are inversely proportional to the variances of log RRs, and horizontal lines represent 95% CI.
All analyses were performed using Stata/SE10.1 (Stata, College Station, TX, USA)
The systematic review by Mitri et al. (2011)(186) examined the association between serum
vitamin D status and incident type 2 diabetes, and the effect of vitamin D supplementation on
glycaemic outcomes. It included eight longitudinal cohort studies and 11 RCTs published
until February 2011. In the meta-analyses of four observational studies shown in Figure
A9.13, vitamin D intake >500 IU/day decreased the risk of type 2 diabetes by 13% (RR: 0.87,
95% CI: 0.76-0.99) compared with vitamin D intake<200 IU/day.
Figure A9.13: Meta-analysis of the effects of higher vitamin D intake as compared to lower
vitamin D intake on incident type 2 diabetes
Source: Vitamin D and type 2 diabetes: a systematic review(186)
Horizontal lines represent 95% CI. All analyses were performed using Comprehensive Meta-Analysis version 2.2.050 (Biostat, Englewood,
NJ, USA)
Figure A9.14 shows the combined data from seven longitudinal studies that found that a
serum 25-(OH)D concentration > 25 ng/mL (62.5 nmol/L), compared with a concentration <
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February 2014
14 ng/mL (35 nmol/L), was associated with a statistically significant reduction in the
incidence of type 2 diabetes at 1.3 to 22 years (43%, 95% CI: 24%, 57%).
Figure A9.14: Meta-analysis of the effects of higher blood 25-(OH)D as compared with lower
blood 25-(OH)D on incident type 2 diabetes
Source: Vitamin D and type 2 diabetes: a systematic review(186)
Horizontal lines represent 95% CI. All analyses were performed using Comprehensive Meta-Analysis version 2.2.050 (Biostat, Englewood,
NJ, USA)
In post hoc analyses from eight trials among participants with normal glucose tolerance at
baseline and in three small underpowered (n=32 to 62) trials of patients with established type
2 diabetes, there was no effect of vitamin D supplementation on glycaemic outcomes. In two
trials among patients with baseline glucose intolerance, vitamin D supplementation improved
insulin resistance. The authors of the review did not perform meta-analysis on any of the 11
included RCTs because the trials were too heterogeneous. The authors concluded that
vitamin D may play a role in type 2 diabetes; however, to better define the role of vitamin D
in the development and progression of type 2 diabetes, high-quality observational studies and
RCTs that measure serum 25-(OH)D concentration and clinically relevant glycaemic
outcomes are needed.(186)
In summary, vitamin D status at baseline in apparently healthy adults is inversely associated
with future risks of type 2 diabetes and metabolic syndrome. However, reliable evidence
from adequately dosed randomised trials of vitamin D supplementation is needed to confirm
the observational findings.
A9.6
Effect of vitamin D supplementation on the risk of obesity
The 2012 HTA published by Washington State Health Care Authority(27) reported that there
were no observational studies which assessed the association between vitamin D status and
the presence or risk of obesity; however, two RCTs were identified that evaluated the effect of
vitamin D supplementation on body weight or development of obesity(141, 146). The study by
Caan et al. (2007)(146) was derived from the WHI trial and enrolled only postmenopausal
women. It included 22,827 participants who were not obese at baseline. The authors reported
that over a seven-year follow-up, slightly less weight gain was observed among the non-obese
participants who were randomised to vitamin D, although the prescribed dose of vitamin D
was relatively low (400 IU/day): –0.08 kg (95% CI: –0.23 to 0.06) for normal-weight
individuals and –0.09 kg (95% CI: –0.22 to 0.04) for overweight individuals. The RCT by
Daly and Nowson (2009)(141) enrolled Caucasian men (N=167). Participants were, on average,
middle-aged (mean age 61 years) and mildly overweight (BMI 26.2). Men were randomised
to the treatment group of 400 IU/day of vitamin D3 added to milk. No effect on weight
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change over a two-year period was observed, and, in fact, neither group exhibited meaningful
weight changes. Therefore, these two fair-quality studies did not demonstrate an effect in
middle-aged to older non-obese adults.(27)
There was one RCT that compared the effects of two hypocaloric diets in overweight or obese
women which found that the diet associated with greater weight loss also led to greater
vitamin D intake and a greater mean increase in serum 25-(OH)D levels.(187) However, no
conclusions about causality can be drawn from this study.
A9.7
Effect of vitamin D supplementation on multiple sclerosis
The 2012 HTA did not identify any RCTs that examined the effect of vitamin D
supplementation on the incidence of MS.
A9.8
Effect of vitamin D supplementation on mood disorders
The 2012 HTA published by Washington State Health Care Authority(27) identified three
RCTs (4,625 participants) that evaluated the effect of vitamin D on mental health in
unselected populations (all postmenopausal women or elderly adults).(140, 149, 188) The three
RCTs were rated as fair- to good-quality; the overall body of evidence was considered to be
of moderate quality. Baseline serum 25-(OH)D was not reported for the overall study group
in any of these trials. A wide range of supplementation regimens were used across the trials,
from 400 IU/day vitamin D plus calcium to 1,370 IU/day vitamin D alone. Follow-up ranged
from 6 months to 5 years. Overall, supplementation had no effect on the mental component
score of the SF-12 Health Survey questionnaire(140, 149), the Profile of Mood States
questionnaire(188), or the General Health Questionnaire(140). The World Health Organization
Well-Being Index and the Patient Global Impression Improvement Scale was also assessed in
a subgroup of 118 participants and no treatment effect of vitamin D was apparent.(140)
A9.9
Effect of vitamin D supplementation on all-cause mortality
Two good quality studies provided evidence for all-cause mortality. Trivedi et al. (2003)(150)
evaluated the effect of vitamin D3 100,000 IU every four months (approximately 833 IU/day)
for five years in 2,686 men and women, aged 65 to 85 years old. Approximately 28% of
participants had CVD at baseline. The RR of all-cause mortality favoured supplementation
but was not statistically significant (RR: 0.88, 95% CI: 0.74 to 1.06). A second report
analysed data from the WHI study, which randomised 36,282 postmenopausal women to daily
supplementation with 400 IU vitamin D plus calcium or placebo for seven years.(142) The HR
for all-cause mortality was 0.91 (95% CI: 0.88 to 1.01).
Evidence was also available from a Cochrane Review with pooled data from 50 RCTs (94,148
participants) to assess the effect of vitamin D supplementation on mortality in adults.(117) The
studies were not analysed according to population or indication. Overall, the review found
that vitamin D decreased mortality (RR: 0.97, 95% CI: 0.94 to 1.00).
A9.10 Effect of vitamin D supplementation on maternal and neonatal outcomes
The Cochrane review by De-Regil et al. (2012)(113) examined whether vitamin D alone or in
combination with other micronutrients given during pregnancy improved maternal and
neonatal outcomes. It included six RCTs (total of 1,023 women), five of which were
published in the 1980s(189-193) and one in 2009(194). Five RCTs compared the effects of
vitamin D alone versus no supplementation/placebo(189-192, 194) and one trial compared the
effects of vitamin D and calcium versus no supplementation(193). The outcomes measured in
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these studies were pre-eclampsia, gestational diabetes, serum vitamin D levels, baby birth
weight and adverse events.
The study by Marya et al. (1987)(193) reported that: women who received 1,200 IU of vitamin
D along with 375 mg of elemental calcium per day were as likely to develop pre-eclampsia as
women who received no supplementation (RR: 0.67; 95% CI: 0.33 to 1.35).
Data from four trials involving 414 women consistently showed that women who received
vitamin D supplements had higher concentrations of vitamin D in serum at term than those
women who received no intervention or a placebo; however, the magnitude of the response
was highly heterogeneous.(189-191, 194)
Data from three trials involving 463 women suggested that women who receive vitamin D
supplements during pregnancy less frequently had a baby with a birth weight below 2,500
grams than those women receiving no treatment or placebo; statistical significance was
borderline (RR: 0.48; 95% CI: 0.23 to 1.01).(189, 191, 192)
Only the study by Yu et al. (2009) assessed the safety of vitamin D supplementation during
pregnancy. There were no significant differences in adverse side effects, including nephritic
syndrome, stillbirths or neonatal deaths, between women who received vitamin D
supplements in comparison with women who received no treatment or placebo.(194)
In addition to the six included trials, three publications based on two RCTs(195-197) are
published post the Cochrane review by De-Regil et al. (2012). The AViDD trial by Baqui and
colleagues (2013)(196) evaluated the effect of high-dose vitamin D3 supplementation (35,000
IU/week till delivery) administered prenatally during the 3 rd trimester on maternal and
neonates (assessed by measuring cord blood 25-(OH)D concentration). It included 160
pregnant women from Bangladesh randomised to either a placebo group (N=80) or
intervention group (N=80). Mean maternal 25-(OH)D concentration was significantly higher
in the intervention group at term when compared to placebo (134 vs. 38 nmol/L; P < 0.001).
Similarly, neonates serum 25-(OH)D concentration was also significantly higher in the
mothers who received vitamin D supplementation compared with the placebo group (cord
blood: 103 vs. 39 nmol/L; P < 0.001). More importantly, there were no reported adverse
events (e.g. hypercalcemia) due to the administration of the relatively high dose of vitamin D
supplementation in pregnant women.
The same research team performed a preceding pilot trial in Dhaka, Bangladesh (N=28
pregnant women) and found that 3rd trimester regimens of 14,000 IU/week (≈2000 IU/day)
and 35,000 IU/week (≈5000 IU/day) led to mean 25-(OH)D concentrations of 76 nmol/L (rise
of 36 nmol/L) and 98 nmol/L (rise of 57 nmol/L), respectively, following 10 weeks of
supplementation (until delivery).(195)
The recent study by Soheilykhah et al. (2013)(197) evaluated the effects of three different doses
of vitamin D on insulin resistance (IR) during pregnancy. This was an un-blinded RCT (thus
potential high risk of bias) done on 120 women (during the first trimester of pregnancy until
delivery). The pregnant women were randomised to three groups receiving three different
doses of vitamin D (200 IU/day, 50,000 IU/month and 50,000 IU/2 weeks). The increase in
the mean serum 25-(OH)D concentration was greatest in the 50,000 IU/2 weeks group (from
7.3 to 34.1 ng/ml) when compared to the 50,000 IU/month group (increased from 7.3 to 27.23
ng/ml) and the 200 IU/day group (increased from 8.3 to 17.7 ng/ml) (P < 0.001). The mean
differences of insulin and IR before and after intervention in the 200 IU/day and the 50,000
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IU/2 weeks were significant (P = 0.01, P = 0.02). This study shows that supplementation of
pregnant women with 50,000 IU vitamin D every two weeks improved IR significantly.
There are no systematic reviews of RCTs evaluating the effects of vitamin D supplementation
(or serum levels of vitamin D concentration) on the risk of gestational diabetes. The
systematic review and meta-analysis performed by Poel et al. (2012)(198) was based on the
analyses of results from seven cross-sectional or case control studies and included no RCTs.
The authors of this review found that serum 25-(OH)D < 50 nmol/L was significantly
associated with gestational diabetes.(198)
In summary, vitamin D supplementation up to 5000 IU/day (35,000 IU/week) in the third
trimester of pregnancy is considered to be safe and increases serum vitamin D concentrations
≥ 80 nmol/L in virtually all mothers and newborns. However, the role and clinical
significance of vitamin D supplementation, as well as the significance of optimal serum 25(OH)D concentration (levels exceeding 80 nmol/L), in pregnancy remains unclear. There are
currently six RCTs in progress that are further evaluating the clinical significance of vitamin
D during pregnancy.
A9.11 Effect of vitamin D supplementation on children and adolescents
One large RCT by Kumar et al. (2011)(199) evaluated the effect of supplementation in young
children. The RCT demonstrated that a high dose of vitamin D (1400 IU/day) over a sixmonth period improved most anthropometric measures in low-birthweight infants in India, but
health outcomes were not affected. Loss to follow-up was high. No relevant studies
evaluating the non-skeletal effects of vitamin D supplementation on growth-related outcome
measures in older children and adolescents were identified.
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APPENDIX 10 – Review of the effectiveness of supplementation in
patients with chronic disease
The 2012 Hayes, Inc. HTA for the Washington State Health Care Authority(27) identified three
systematic reviews and 16 RCTs (18 publications) that evaluated the effect of vitamin D
supplementation on disease-related outcomes in patients with chronic disease:








obesity
poor musculoskeletal health;
cancer;
cardiovascular disease;
type 2 diabetes;
multiple sclerosis;
depression and other mood disorders; and
all-cause mortality.
A10.1
Effect of vitamin D supplementation on obesity
The 2012 HTA included eight RCTs involving 32,111 randomised participants with a BMI >
25 kg/m2 (146, 200-206). Study quality was generally good in the analyses involving > 400
participants but was fair in smaller studies (which had dropout rates exceeding 20% and no
ITT analysis). Participants were generally in early middle age and more women than men
were included. Vitamin D dosage varied from 300 IU/day to 5714 IU/day, with most
participants also receiving calcium supplementation. Overall, there was no effect on weightrelated outcomes or cardiometabolic outcomes, including weight or other measures of obesity,
blood pressure, or glycemia measures. No studies analysed the effect on blood pressure
according to baseline values. However, additional large trials using doses in the higher range
could change these results, especially with the analysis of baseline measures of blood pressure
and glycemia. Evidence relating to mortality or cardiovascular events in obese individuals is
lacking.
A10.2 Effect of vitamin D supplementation on poor musculoskeletal health
A recent review evaluated vitamin D supplementation for patients with osteoporosis.(125) The
report included 17 RCTs with patients selected on the basis of a diagnosis of osteoporosis or
indirect evidence of poor musculoskeletal health (such as a history of vertebral fracture).
Study participants (N=2,547 in total across the 17 RCTs) were generally vitamin D deficient.
The evidence suggests that inactive vitamin D at doses of 800 to 1400 IU/day is not effective
for improving bone health in patients who have a history of fracture. Two RCTs evaluated
vitamin D3 plus calcium in patients with a history of fracture consistent with osteoporosis.
The effect on BMD at different sites varied widely; where positive effects were observed,
they were very small. In contrast, three RCTs comparing active vitamin D (calcitriol or
synthetic analogs) with control found it to be effective in maintaining or improving BMD.
Two RCTs found that active vitamin D was more effective than inactive vitamin D for
maintaining or improving BMD and/or reducing fractures and falls. Four RCTs found that
active vitamin D was less effective than bisphosphonates and one RCT found that active
vitamin D was less effective than hormone replacement therapy. However, five RCTs
showed that active vitamin D as an add-on to either bisphosphonate or hormone replacement
therapy was more effective than bisphosphonates or HRT alone, suggesting that active forms
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of vitamin D may improve the effectiveness of some pharmaceutical treatment for poor bone
health.
A10.3 Effect of vitamin D supplementation on cancer
One systematic review evaluated vitamin D in cancer patients.(126) The review identified three
RCTs (total N=1273), all of which involved patients with advanced prostate cancer. The
RCTs were considered to be of fair quality, although two were subject to bias because of early
stopping based on interim analysis. The results relating to overall survival were conflicting
and pooled estimates were imprecise.
A10.4 Effect of vitamin D supplementation on cardiovascular disease
The 2012 HTA report by WA Health Care Authority identified a systematic review by
Witham et al. (2009)(110) that evaluated the effect of vitamin D supplementation on blood
pressure (BP). It included 11 RCTs involving participants (< 545 participants in total) with
hypertension, defined as systolic blood pressure (SBP) > 140 mmHg and diastolic blood
pressure (DBP) > 90 mmHg.(27, 110) Inactive vitamin D (D2 or D3) doses fell within the range
of 800 to 2,000 IU/day. The authors performed a meta-analysis of the difference in blood
pressure change and found a small beneficial effect: –3.6 mmHg (95% CI: –8.0 to 0.7; Figure
A10.1) for SBP and –3.1 mm Hg (95% CI: –5.5 to 0.6; Figure A10.2) for DBP. The authors
cited evidence suggesting that a reduction in SBP of 3 mmHg would correspond to 10%
reduction in cardiovascular deaths on a population level.(27)
Figure A10.1: Meta-analysis showing the effects of vitamin D on systolic blood pressure
Source: Effect of vitamin D on blood pressure: a systematic review and meta-analysis (110)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate mean difference in
systolic blood pressure and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall
meta-analysis.CI, confidence interval, SD, standard deviation, WMD, weighted mean difference.
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Figure A10.2: Meta-analysis showing the effects of vitamin D on diastolic blood pressure
Source: Effect of vitamin D on blood pressure: a systematic review and meta-analysis (110)
Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate mean difference in
diastolic blood pressure and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall
meta-analysis.CI, confidence interval, SD, standard deviation, WMD, weighted mean difference.
Subgroup analysis suggested a greater effect on SBP in trials using inactivated vitamin D (D2
or D3) than in trials using activated vitamin D (calcitriol or synthetic analogues) (-6.18
mmHg, 95% CI: -12.32 to -0.04 vs +0.71 mmHg, 95% CI: -4.81 to 6.23; Figure A10.1).
However, the difference in the effect between the two trial subgroups was not significant. (27,
110)
Therefore, the meta-analysis performed by Witham et al. (2009)(110) suggested a small but
potentially clinically meaningful reduction in SBP associated with vitamin D
supplementation, and an uncertain effect on DBP, in patients with hypertension.
Two RCTs evaluated vitamin D in patients with congestive heart failure. An RCT (N=93
evaluable patients) comparing vitamin D3 (2000 IU/day) plus calcium with calcium plus
placebo found no difference in physiological measures at 9 months and no difference in
cumulative survival at 15 months.(137) However, this study was considered to be of poor
quality and there was a substantial withdrawal of sicker patients. Another RCT (N=105)
randomised patients with chronic heart failure to two administrations of 100,000 IU of
vitamin D2 at baseline and 10 weeks, or placebo, in order to assess the effect on function and
quality of life.(136) At 20 weeks, there was no difference in measures of function (according to
the Functional Limitations Profile or six-minute walk time) but a significant difference
favouring vitamin D2 in quality of life (assessed using the Minnesota Living with Heart
Failure Questionnaire).
A10.5 Effect of vitamin D supplementation on type 2 diabetes
The 2012 HTA identified a total of 12 RCTs involving individuals with abnormal blood
glucose (frank diabetes, impaired glucose control, or insulin resistance). Eight of the RCTs
(with a total of 707 patients) were identified from two systematic reviews(111, 112), one of
which conducted a meta-analysis. An additional four RCTs (297 randomised participants)
were selected involving patients with frank type 2 diabetes, abnormal blood glucose and high
risk of type 2 diabetes or gestational diabetes.(127-130) Trial quality was considered to be fair.
Active vitamin D or very high doses of inactive vitamin D were used in these trials, most of
which did not combine calcium with vitamin D. No studies showed harmful effects.
Among 11 trials that reported measures of glycemia (fasting plasma glucose or HbA1C) or
insulin resistance, the estimates of differences in change between vitamin D and control
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groups consistently favoured vitamin D but ranged from negligible in magnitude and
statistically non-significant, to uncertain because of very wide confidence intervals, to
statistically significant but small in magnitude. Evidence from 6 RCTs evaluating an effect
on insulin resistance was inconsistent. Three trials were consistent in showing no effect on
blood pressure. A single trial found no effect on albuminuria. Evidence relating to other
outcomes, such as weight control or renal function, was insufficient.
A10.6 Effect of vitamin D supplementation on multiple sclerosis
The Cochrane review by Jagannath et al. (2010)(114) evaluated the effect of vitamin D on MS
and included a single RCT by Burton et al. (2010)(134). The trial included 49 patients with MS
and was conducted over 52 weeks. Patients were treated with escalating doses of vitamin D
plus calcium (N=25) compared with control (N=24). All of the patients were permitted to
continue personal use of supplements. The trial provided some evidence of the potential
benefit of high vitamin D doses on the reduction of annualised relapse rate, Expanded
Disability Status Scale (EDSS) scores, and suppression of T-cell proliferation. There were no
adverse events reported over the study period. However, the authors of the review judged the
included RCT to be a low powered trial with a potential high risk of bias (due to the lack of
allocation concealment and blinding), thus limiting the evidence on the use of vitamin D in
MS.
Three publications based on two RCTs(131, 207, 208) were published after the 2010 Cochrane
review. The small study by Soilu-Hanninen et al. (2012)(131) evaluated the effectiveness and
safety of vitamin D3 in conjunction with interferon β-1b (IFNB) in patients with MS. This
was a double-blind placebo-controlled trial that recruited 66 MS patients randomised to either
vitamin D supplementation or placebo. The authors reported a median change in the primary
outcome measure of T2 Burden of Disease (BOD) on MRI scan5 of 287 mm3 in the placebo
group and 83 mm3 in the vitamin D group (P=0.105). In addition, serum levels of 25-(OH)D
increased two-fold from a mean of 54 (range 19-82) nmol/L to 110 (range 67-163) nmol/L in
the vitamin D group (with 84% of patients reaching a serum 25-(OH)D level >85 nmol/L in
the vitamin D group vs 3% in the placebo group (P<0.0001)). Patients in the vitamin D group
showed fewer new T2 lesions (P=0.286) and a significantly lower number of T1 enhancing
lesions (P=0.004), as well as a tendency to reduced disability accumulation (P=0.071) and to
improved timed tandem walk (P=0.076). There were no significant between-group
differences in adverse events or in the annual relapse rate. The authors of the study concluded
that vitamin D3 in conjunction with IFNB reduces MRI disease activity in MS.(131) The
authors of this study did not evaluate the effect of vitamin D supplementation alone on the
same primary outcomes.
The two publications by Kampman and colleagues (based on one RCT)(207, 208) evaluated the
effects of high dose of vitamin D supplementation (20,000 IU/week) on the prevention of
bone loss and on reducing the risk of relapses and disease progression in patients with MS.
Participants were randomised to either vitamin D (20,000 IU/week) plus calcium (500
mg/day) or placebo. Median serum 25-(OH)D concentration increased from 55 nmol/L at
baseline to 121 nmol/L following 96 weeks of vitamin D supplementation.(207, 208) There was
no significant difference between groups in annualised relapse rate, EDSS, MS functional
composite components, grip strength or fatigue.(208) This trial also evaluated the effect of
5
T2-weighted magnetic resonance imaging (MRI) scan shows the total number of lesions (lesion load) and
BOD. These are hyperintense lesions, meaning that they appear as bright spots on the MRI image.
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vitamin D supplementation on percentage change in BMD at the hip, the spine, and the
ultradistal radius over the 96-week period. There was no significant percentage change in
BMD between groups at any site. BMD decreased at the hip by 0.7% in the treatment group
(95% CI: -1.6 to 0.2) and 1.4% in the placebo group (95% CI: -2.3 to -0.4).(207) Therefore, in
this small RCT, supplementation with 20,000 IU vitamin D3 weekly did not result in
beneficial effects on the measured MS-related outcomes and did not prevent bone loss.
However, this study was not powered to address clinical outcomes as none of the results were
suggestive of an effect in this sample population of MS patients.
Due to the conflicting results and small quantity of data, the overall body of evidence is
considered to be of low quality and firm conclusions cannot be drawn.
A10.7 Effect of vitamin D supplementation on mood disorders
Two RCTs of vitamin D supplementation were identified in individuals with mood disorders.
(209, 210)
However, both studies did not meet the inclusion criteria due to small sample size
(<20 patients), short follow-up interval (< 3 months), and/or lack of calcium only or placebo
control group. One study of 15 individuals with seasonal affective disorder showed that
vitamin D plus calcium improved symptoms after one month, whereas phototherapy did
not.(209) The other study of 180 women with premenstrual syndrome reported that calcium
plus vitamin D was comparable to hormone therapy, but neither treatment had more than a
very small effect on symptoms, compared with placebo, after two months.(210)
A10.8 Effect of vitamin D supplementation on all-cause mortality
The literature search did not identify any relevant data on all-cause mortality in patients with
chronic disease.
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