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 MBS Reviews Vitamin D Testing Review Report Page 2 February 2014 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 MBS Reviews Vitamin D Testing Review Report Page 3 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 4 February 2014 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) MBS Reviews – Vitamin D Testing Review Report Page 5 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 6 February 2014 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: 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. MBS Reviews – Vitamin D Testing Review Report Page 7 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 8 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 9 February 2014 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: 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: 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. MBS Reviews – Vitamin D Testing Review Report Page 10 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 11 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 12 February 2014 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). MBS Reviews – Vitamin D Testing Review Report Page 13 February 2014 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 Page 14 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 Page 15 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 Page 16 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 Page 17 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 Page 18 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) MBS Reviews – Vitamin D Testing Review Report Page 19 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 Page 20 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) MBS Reviews – Vitamin D Testing Review Report Page 22 February 2014 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? MBS Reviews – Vitamin D Testing Review Report Page 24 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 Page 25 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 Page 26 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 MBS Reviews – Vitamin D Testing Review Report Page 27 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. MBS Reviews – Vitamin D Testing Review Report Page 28 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) MBS Reviews – Vitamin D Testing Review Report Page 29 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. MBS Reviews – Vitamin D Testing Review Report Page 30 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. MBS Reviews – Vitamin D Testing Review Report Page 31 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. MBS Reviews – Vitamin D Testing Review Report Page 32 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 Page 33 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 Page 34 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 Page 35 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. MBS Reviews – Vitamin D Testing Review Report Page 36 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 MBS Reviews – Vitamin D Testing Review Report Page 39 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. MBS Reviews – Vitamin D Testing Review Report Page 40 February 2014 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; MBS Reviews – Vitamin D Testing Review Report Page 41 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 MBS Reviews – Vitamin D Testing Review Report Page 42 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 MBS Reviews – Vitamin D Testing Review Report Page 43 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. MBS Reviews – Vitamin D Testing Review Report Page 44 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 Page 46 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 MBS Reviews – Vitamin D Testing Review Report Page 48 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 MBS Reviews – Vitamin D Testing Review Report Page 49 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 50 February 2014 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 Page 51 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 52 February 2014 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: MBS Reviews – Vitamin D Testing Review Report Page 53 February 2014 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). MBS Reviews – Vitamin D Testing Review Report Page 54 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 55 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 56 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 57 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 58 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 59 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 60 February 2014 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) MBS Reviews – Vitamin D Testing Review Report Page 61 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 62 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 63 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 64 February 2014 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; MBS Reviews – Vitamin D Testing Review Report Page 65 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 66 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 67 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 68 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 69 February 2014 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 Page 70 February 2014 APPENDIX 1 – References 1. Pedersen JI. Vitamin D requirement and setting recommendation levels - current Nordic view. Nutr Rev 2008 Oct;66(10 Suppl 2):S165-9. 2. Mosekilde L. Vitamin D requirement and setting recommendation levels: long-term perspectives. Nutr Rev 2008 Oct;66(10 Suppl 2):S170-7. 3. Holick MF. Vitamin D deficiency. N Engl J Med 2007 Jul 19;357(3):266-81. 4. Johnson MA, Kimlin MG. Vitamin D, aging, and the 2005 Dietary Guidelines for Americans. Nutr Rev 2006 Sep;64(9):410-21. 5. Office of Dietary Supplements. Dietary supplement fact sheet. Vitamin D. 2009; Available from: http://ods.od.nih.gov/factsheets/VitaminD_pf.asp. 6. AGD Nutrition LLC. Vitamin D3 http://www.agdnutrition.com/d3-story.html. 7. Rhodes LE, Webb AR, Fraser HI, Kift R, Durkin MT, Allan D, et al. Recommended summer sunlight exposure levels can produce sufficient (> or =20 ng ml(-1)) but not the proposed optimal (> or =32 ng ml(-1)) 25(OH)D levels at UK latitudes. J Invest Dermatol 2010 May;130(5):1411-8. 8. Johal M, Levin A. 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Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial. Hypertension 2008 Nov;52(5):847-55. 146. Caan B, Neuhouser M, Aragaki A, Lewis CB, Jackson R, LeBoff MS, et al. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Arch Intern Med 2007 May 14;167(9):893-902. 147. Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007 Feb 20;115(7):846-54. 148. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007 Jun;85(6):1586-91. 149. Dumville JC, Miles JN, Porthouse J, Cockayne S, Saxon L, King C. Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. J Nutr Health Aging 2006 Mar-Apr;10(2):151-3. 150. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. Bmj 2003 Mar 1;326(7387):469. 151. Winzenberg T, Powell S, Shaw KA, Jones G. Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis. Bmj 2011;342:c7254. 152. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001-2006. NCHS Data Brief 2011 Mar(59):1-8. 153. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing 2006 Sep;35(5):482-6. MBS Reviews – Vitamin D Testing Review Report Page 80 February 2014 154. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002 Apr;17(4):709-15. 155. Inkovaara J, Gothoni G, Halttula R, Heikinheimo R, Tokola O. Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. Age Ageing 1983 May;12(2):124-30. 156. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebocontrolled trial. Lancet 2005 May 7-13;365(9471):1621-8. 157. Harwood RH, Sahota O, Gaynor K, Masud T, Hosking DJ. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Age Ageing 2004 Jan;33(1):45-51. 158. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 1996 Feb 15;124(4):400-6. 159. Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, et al. Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int 2007 Jun;18(6):811-8. 160. 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. 161. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 2007 Dec;46(12):1852-7. 162. Avenell A, Grant AM, McGee M, McPherson G, Campbell MK, McGee MA. The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design. Clin Trials 2004;1(6):490-8. 163. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 2002 Mar;13(3):257-64. 164. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997 Sep 4;337(10):670-6. 165. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. Bmj 2005 Apr 30;330(7498):1003. MBS Reviews – Vitamin D Testing Review Report Page 81 February 2014 166. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006 Feb 16;354(7):66983. 167. Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, et al. Twoyear randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res 2007 Apr;22(4):509-19. 168. Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007 Nov 7;99(21):1594-602. 169. 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. 170. 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. 171. 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 Jun 4;100(11):796-804. 172. 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 Oct;11(9):847-52. 173. Baron JA, Beach M, Wallace K, Grau MV, Sandler RS, Mandel JS, et al. Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 2005 Mar;14(3):586-9. 174. 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. 176. Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007 Mar;4(3):e103. 177. Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Prostate 2007 Jun 15;67(9):911-23. 178. 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, United States). Cancer Causes Control 1998 Aug;9(4):425-32. 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 Mar;46(5):932-6. 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 MBS Reviews – Vitamin D Testing Review Report Page 82 February 2014 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 Soc 2013 Feb;72(1):89-97. 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 Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia 2012 Aug;55(8):2173-82. 185. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes 2008 Oct;57(10):2619-25. 186. Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr 2011 Sep;65(9):1005-15. 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. 188. Harris S, Dawson-Hughes B. Seasonal mood changes in 250 normal women. Psychiatry Res 1993 Oct;49(1):77-87. 189. 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 1980 Mar 15;280(6216):751-4. 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. 191. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation 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 Dhaka, Bangladesh. Nutrients 2013 Mar;5(3):788-810. MBS Reviews – Vitamin D Testing Review Report Page 83 February 2014 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 Bangladesh: the AViDD trial. Nutr J 2013 Apr 12;12(1):47. 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 double blind trial. J Intern Med 2008 Dec;264(6):599-609. 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. MBS Reviews – Vitamin D Testing Review Report Page 84 February 2014 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. MBS Reviews – Vitamin D Testing Review Report Page 85 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 86 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 87 February 2014 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’ MBS Reviews – Vitamin D Testing Review Report Page 88 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 89 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 90 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 91 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? MBS Reviews – Vitamin D Testing Review Report Page 92 February 2014 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). MBS Reviews – Vitamin D Testing Review Report Page 93 February 2014 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) MBS Reviews – Vitamin D Testing Review Report Page 94 February 2014 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 MBS Reviews – Vitamin D Testing Review Report Page 95 February 2014 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 Page 96 February 2014 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. Page 97 February 2014 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 Page 111 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) Page 112 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). MBS Reviews – Vitamin D Testing Review Report 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. MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report 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 MBS Reviews – Vitamin D Testing Review Report 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) MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report 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. MBS Reviews – Vitamin D Testing Review Report 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 < MBS Reviews – Vitamin D Testing Review Report 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 MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report February 2014 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. MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report February 2014 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. MBS Reviews – Vitamin D Testing Review Report February 2014 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 MBS Reviews – Vitamin D Testing Review Report February 2014 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. MBS Reviews – Vitamin D Testing Review Report February 2014 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. MBS Reviews – Vitamin D Testing Review Report
