Erin S. LeBlanc, MD, MPH; Bernadette Zakher, MBBS; Monica Daeges, BA; Miranda Pappas, MA; Roger Chou, MD
Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Andrew Hamilton, MLS, MS, for conducting literature searches; Rongwei Fu, PhD, for statistical assistance; and Spencer Dandy, BS, for assistance with drafting this manuscript at the Oregon Health & Science University. The authors also thank Kevin Lutz, MFA, at the Center for Health Research for editorial assistance; AHRQ Medical Officers Robert McNellis, MPH, PA, Tina Fan, MD, MPH, and Tess Miller, DrPH; and U.S. Preventive Services Task Force Leads Linda Baumann, PhD, RN, Doug Owens, MD, MS, and Albert Siu, MD, MSPH.
Grant Support: By the Agency for Healthcare Research and Quality (contract HSSA 290-2007-10057-I).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1659.
Requests for Single Reprints: Erin S. LeBlanc, MD, MPH, Center for Health Research, Kaiser Permanente, 3800 North Interstate Avenue, Portland, OR 97227; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. LeBlanc: Center for Health Research, Kaiser Permanente, 3800 North Interstate Avenue, Portland, OR 97227.
Ms. Zakher, Ms. Daeges, Ms. Pappas, and Dr. Chou: Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Mail code: BICC, Portland, OR 97239.
Author Contributions: Conception and design: E.S. LeBlanc, B. Zakher, M. Pappas, R. Chou.
Analysis and interpretation of the data: E.S. LeBlanc, B. Zakher, M. Pappas, R. Chou.
Drafting of the article: E.S. LeBlanc, M. Pappas, R. Chou.
Critical revision of the article for important intellectual content: E.S. LeBlanc, M. Pappas, R. Chou.
Final approval of the article: E.S. LeBlanc, M. Pappas, R. Chou.
Provision of study materials or patients: M. Daeges.
Statistical expertise: R. Chou.
Obtaining of funding: R. Chou.
Administrative, technical, or logistic support: M. Daeges, M. Pappas.
Collection and assembly of data: B. Zakher, M. Daeges, M. Pappas, R. Chou.
LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122. doi: 10.7326/M14-1659
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Published: Ann Intern Med. 2015;162(2):109-122.
Vitamin D deficiency has been associated with adverse health outcomes.
To systematically review benefits and harms of vitamin D screening in asymptomatic adults.
Ovid MEDLINE (through the third week of August 2014), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews.
Randomized trials of screening for and treatment of vitamin D deficiency and case–control studies nested within the Women's Health Initiative.
One investigator abstracted data, a second reviewed data for accuracy, and 2 investigators independently assessed study quality using predefined criteria.
No study examined the effects of vitamin D screening versus no screening on clinical outcomes. Vitamin D treatment was associated with decreased mortality versus placebo or no treatment (11 studies; risk ratio [RR], 0.83 [95% CI, 0.70 to 0.99]), although benefits were no longer seen after trials of institutionalized persons were excluded (8 studies; RR, 0.93 [CI, 0.73 to 1.18]). Vitamin D treatment was associated with possible decreased risk for having at least 1 fall (5 studies; RR, 0.84 [CI, 0.69 to 1.02]) and falls per person (5 studies; incidence rate ratio, 0.66 [CI, 0.50 to 0.88]) but not fractures (5 studies; RR, 0.98 [CI, 0.82 to 1.16]). Vitamin D treatment was not associated with a statistically significant increased risk for serious adverse events (RR, 1.17 [CI, 0.74 to 1.84]).
Variability across studies in 25-hydroxyvitamin D assays and baseline levels, treatment doses, use of calcium, and duration of follow-up.
Treatment of vitamin D deficiency in asymptomatic persons might reduce mortality risk in institutionalized elderly persons and risk for falls but not fractures.
Agency for Healthcare Research and Quality.
Table 1. Summary of Current Opinions About Appropriate 25-(OH)D Level Cutoffs for Defining Vitamin D Deficiency and Associations Between These Cutoffs and Health Outcomes*
Numbers on figures indicate key questions. For a list of key questions, see the Methods section or Table 2.
Summary of evidence search and selection.
25-(OH)D = 25-hydroxyvitamin D.
* Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Identified from reference lists or by hand-searching or suggested by experts.
‡ Studies that provided data and contributed to the body of evidence were considered included. Studies may have provided data for more than 1 key question or published article; 27 unique studies were included, and a total of 35 articles were included.
Meta-analysis of effects of vitamin D treatment on mortality.
To convert ng/mL to nmol/L, divide by 0.40. 25-(OH)D = serum 25-hydroxyvitamin D.
* ≥90% of study participants had 25-(OH)D levels <20 ng/mL.
† ≥90% of study participants had 25-(OH)D levels ≤30 ng/mL, and ≥10% had 25-(OH)D levels ≥20 ng/mL.
‡ Included an institutionalized population.
§ This is a nested case–control study from the Women's Health Initiative calcium-vitamin D trial (64).
Meta-analysis of effects of vitamin D treatment on mortality, by institutionalized status.
* This is a nested case–control study from the Women's Health Initiative calcium-vitamin D trial (64).
Meta-analysis of effects of vitamin D treatment on risk for any fracture (top) or hip fracture (bottom).
To convert ng/mL to nmol/L, divide by 0.40. 25-(OH)D = 25-hydroxyvitamin D.
† Population institutionalized.
‡ ≥90% of study participants had 25-(OH)D levels ≤30 ng/mL, with ≥10% with 25-(OH)D levels ≥20 ng/mL.
Meta-analysis of effects of vitamin D treatment on risk for falls.
‡ ≥90% of study participants had 25-(OH)D levels ≤30 ng/mL, and ≥10% had 25-(OH)D levels ≥20 ng/mL.
§ The calculated risk ratio is different from the one reported by the study.
Meta-analysis of effects of vitamin D treatment on the number of falls per person.
To convert ng/mL to nmol/L, divide by 0.40. 25-(OH)D = 25-hydroxyvitamin D; PY = person-year.
Appendix Table. Studies of Effectiveness and Harms of Vitamin D Treatment
Table 2. Summary of Evidence for Screening for Vitamin D Deficiency in Asymptomatic Adults
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Author Insight Video - Erin S. LeBlanc, MD, MPH
Dr Kirti Kain
Senior Clinical Lecturer, University of Leeds
December 10, 2014
Total versus bioavailable active Vitamin D
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults . Current evidence is from studies whereby supplementation (variable doses of either vitamin-D2 or D3 with or without calcium) has been monitored mainly by the measurement of total concentrations of 25OHD. Future research studies should focus on assessing bioavailable vitamin D instead of total concentrations of 25OHD . It is known that concentrations of total status 25OHD as well as 1,25-dihydroxyvitamin-D measured routinely are different from bioavailable vitamin-D . Free and bioavailable vitamin-D is dependent on the vitamin-D binding protein and ethnicity  . In addition we need evidence of techniques of increasing bioavailable vitamin-D. One such technique could be increased outdoor physical activity which might possibly increase biosynthesis and bioavailable vitamin D3 circumventing hypervitaminosis D  .It is possible that harmful effects of hypervitaminosis D are solely due to excess biosynthesized sequestrated vitamin D as a result of inappropriate oral supplementations and not being converted to active bioavailable vitamin D . Excess Vitamin D is arteriotoxic and it causes elastocalcinosis which induces destruction of elastic fibers, which leads to arterial stiffness  and induces arterial calcification through up regulation of 1,25(OH)2D3 receptor and increased calcium uptake in smooth muscle cells of the arteries [7;8]. Research resources are finite in these times of austerity hence they ought to be allocated appropriately. Robust and pertinent evidence is needed to formulate educational and interventional policies that can be implemented to prevent the global public health problem of decreased bioavailable vitamin-D associated cardio-metabolic diseases, autoimmune and neoplastic conditions. References 1 LeFevre ML: Screening for Vitamin D Deficiency in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2014. 2 Wong MS, Leisegang MS, Kruse C, Vogel J, Schurmann C, Dehne N, Weigert A, Herrmann E, Brune B, Shah AM, Steinhilber D, Offermanns S, Carmeliet G, Badenhoop K, Schroder K, Brandes RP: Vitamin D Promotes Vascular Regeneration. Circulation 2014. 3 Holick MF: Bioavailability of vitamin D and its metabolites in black and white adults. N Engl J Med 2013;369:2047-2048. 4 Kain K: Circulation. In press. 5 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF: Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690-693. 6 Jegger D, da SR, Jeanrenaud X, Nasratullah M, Tevaearai H, von Segesser LK, Segers P, Gaillard V, Atkinson J, Lartaud I, Stergiopulo N: Ventricular-arterial coupling in a rat model of reduced arterial compliance provoked by hypervitaminosis D and nicotine. Am J Physiol Heart Circ Physiol 2006;291:H1942-H1951. 7 Rajasree S, Umashankar PR, Lal AV, Sarma PS, Kartha CC: 1,25-dihydroxyvitamin D3 receptor is upregulated in aortic smooth muscle cells during hypervitaminosis D. Life Sci 2002;70:1777-1788. 8 Rajasree S, Rajpal K, Kartha CC, Sarma PS, Kutty VR, Iyer CS, Girija G: Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. Eur J Epidemiol 2001;17:567-571.
Mark J Bolland, Andrew Grey, Ian R Reid
University of Auckland
February 4, 2015
Missing studies from vitamin D meta-analyses
The number of meta-analyses of vitamin D supplements for falls and fractures is about twice the number of randomized trials that have been carried out. Differences in conclusions of these meta-analyses are largely due to the methods adopted, including the choice of studies included (1, 2). In their review for the US Preventative Services Task Force (USPSTF), LeBlanc and colleagues assessed the effectiveness of vitamin D supplementation on mortality, falls, and fractures in vitamin D deficiency, including 11, 5 and 5 trials for each outcome respectively (3). In contrast, we included 38, 20 and 23 trials respectively, in meta-analyses of vitamin D supplementation for these conditions (4, 5). The differences in study inclusion are largely due to the requirement of LeBlanc and colleagues that baseline 25 hydroxyvitamin D (25OHD) was measured in all participants. Their aim was to include only studies in which 90% of participants had 25OHD <75 nmol/L, but random sampling of baseline 25OHD is sufficient to assess this criterion. Baseline 25OHD, either in a sample or in all participants, was reported in the majority (34/42) trials in our meta-analyses, with 25/32 (78%) reporting mean baseline 25OHD <50 nmol/L, meaning it is very likely that 90% of participants had 25OHD <75 nmol/L.Inconsistency in study and participant inclusion is an additional consequence of the methodology used by LeBlanc and colleagues. Of two studies carried out by the same investigators in the same population group (6, 7), one was included with 25OHD measured in all participants (7), whereas the other was excluded because 25OHD was only measured in a subset of participants (6), even though mean baseline 25OHD was similar in the two studies. Likewise, a small subset of participants in two studies (8, 9) were included in this meta-analysis because they were selected to have baseline 25OHD measured whereas the majority of participants in both studies were excluded.The upshot is that the meta-analyses by LeBlanc and colleagues contain few events and participants, and do not include the majority of studies with fracture or falls as the primary endpoint. The same issue of non-inclusion of eligible studies (2, 10) has occurred in previous reviews on vitamin D for the USPSTF (11, 12). Consequently, conclusions based on these reviews may not be reliable.References1. Bolland MJ, Grey A, Reid IR. Differences in overlapping meta-analyses of vitamin d supplements and falls. J Clin Endocrinol Metab. 2014;99(11):4265-72.2. Bolland MJ, Grey A. A case study of discordant overlapping meta-analyses: vitamin d supplements and fracture. PLoS One. 2014;9(12):e115934.3. LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin d deficiency: a systematic review for the u.s. Preventive services task force. Ann Intern Med. 2015;162(2):109-22.4. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(4):307-20.5. Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(7):573-80.6. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327(23):1637-42.7. 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;13(3):257-64.8. 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;124(4):400-6.9. Karkkainen MK, Tuppurainen M, Salovaara K, Sandini L, Rikkonen T, Sirola J, et al. Does daily vitamin D 800 IU and calcium 1000 mg supplementation decrease the risk of falling in ambulatory women aged 65-71 years? A 3-year randomized population-based trial (OSTPRE-FPS). Maturitas. 2010;65(4):359-65.10. Bolland MJ, Grey A, Reid IR. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. Ann Intern Med. 2014;160(9):655-6.11. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827-38.12. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(12):824-34.
Toshihiro Sugiyama, Yoon Taek Kim, Hiromi Oda
Saitama Medical University
February 16, 2015
Risk reduction of falls but not fractures by treatment of vitamin D deficiency
A systematic review for the U.S. Preventive Services Task Force by LeBlanc and colleagues (1) concludes that treatment of vitamin D deficiency in asymptomatic adults might reduce risk for falls but not fractures. This requires reasonable explanation, because a fall is one of the strongest risk factors for a fracture. Here we would like to present an evidence-based mechanistic insight.Muscle force is related to bone strength and the risk reduction of falls but not fractures (1) theoretically means that treatment of vitamin D deficiency reduces fall risk by improving balance (rather than muscle force) but does not change fracture risk by impairing bone strength. The former would be consistent with clinical evidence, while the latter could be associated with skeletal adaptation to mechanical environment (2-5). There is a yield force at which a bone begins to deform plastically and normal physical activity causes the pre-yield “elastic” deformation (strain) of bone. A decrease in bone quality associated with mineral induces an increase in the “elastic” deformation, while the skeleton responds to mechanical environment to maintain the resultant strain of bone. Consequently, mineral-related impairment of bone quality can be compensated by mechanical strain-related feedback control and might act to improve bone fragility if compensated efficiently (3). For example, patients with hypophosphatemic rickets/osteomalacia have lower quality and higher quantity of bone (2). Vitamin D deficiency impairs bone quality and children with nutritional rickets would also have bigger long bones (4). Furthermore, a recent study in children with cerebral palsy showed an inverse correlation between serum levels of 25-hydroxyvitamin D [25-(OH)D] and Z-scores for areal bone mineral density (BMD) in the distal femur (4). Notably, the latest meta-analysis in adults found that the effects of daily supplementation with 800 IU or more of vitamin D on areal BMD were lower than that with less than 800 IU of vitamin D in the lumbar spine and potentially in the femoral neck, but not in the forearm (5).Finally, a number of observational studies have shown an association between lower levels of 25-(OH)D and higher incidences of fracture in adults. The present conclusion (1), however, suggests that confounding biases the association. Vitamin D status is strongly influenced by sunlight exposure associated with outdoor activity while mechanical loading from habitual physical activity is the primary determinant of bone strength, implying that higher incidences of fracture could result from lower levels of physical activity rather than 25-(OH)D.References1. LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-22. 2. Sugiyama T, Kim YT, Oda H. Osteoporosis therapy: a novel insight from natural homeostatic system in the skeleton. Osteoporos Int. 2015;26:443-7.3. Sugiyama T, Torio T, Sato T, Matsumoto M, Kim YT, Oda H. Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality. Front Endocrinol. 2015;6:6.4. Sugiyama T, Yoshioka H, Sakaguchi K, Kim YT, Oda H. An evidence-based perspective on vitamin D and the growing skeleton. Osteoporos Int. 2015 doi:10.1007/s00198-014-2975-z5. Sugiyama T, Tanaka S, Miyajima T, Kim YT, Oda H. Vitamin D supplementation and fracture risk in adults: a new insight. Osteoporos Int. 2014;25:2497-8.
Erin S. LeBlanc, MD, MPH (1,2), Roger Chou, MD (2,3), Miranda Pappas, MA (2)
1. Center for Health Research Kaiser Permanente Northwest Portland, OR 2. Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Portland, OR 3. Department o
March 14, 2015
The purpose of our systematic review was to determine if screening for vitamin D deficiency in asymptomatic persons improved health outcomes. Therefore, we determined a priori that we would only include studies of populations who had documented vitamin D deficiency and were not selected based on a history of osteoprorosis, prior fractures, or falls. Thus, we included fewer studies than the meta-analyses by Bolland et al., (1, 2) which also included trials of participants with normal vitamin D levels and with osteoporosis and prior fractures or falls. We did not exclude any study solely because only a random sample of the population had vitamin D deficiency according to our definition (90% of people with levels less than 30 ng/mL). Either the subsample did not meet this deficiency definition, or there was another reason that the study was excluded (e.g., patients with prior fractures or falls). In the specific example mentioned by Bolland, Grey, and Reid (3, 4), the subsample of participants did not meet our criteria for deficiency although when all participants were measured, over 90% were deficient. Although some of our analyses had relatively few events, expanding inclusion to clinically heterogeneous populations that are not of interest in order to increase statistical power would not have been appropriate.We agree with Kain that research on the role of bioavailable vitamin D levels is important to better understand the effects of vitamin D treatment on clinical outcomes. We also agree with Sugiyama, Kim, and Oda that research is needed on mechanisms for how vitamin D might prevent falls but not fracture.In response to an editorial by Heaney and Armas (5), we explicitly defined the scope of the review prior to starting the work. We addressed the factors brought up in the editorial as potentially impacting estimates in sensitivity and stratified analyses. Further stratifying or restricting the analysis, as suggested by Heaney and Armas, would only result in even less evidence to support benefits of vitamin D treatment.Reference List1. Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014 Jul; 2(7):573-580.2. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014 Apr; 2(4):307-320.3. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992 Dec 3; 327(23):1637-1642.4. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, Garnero P, Meunier PJ. 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):257-264.5. Heaney RP, Armas LA. Screening for vitamin d deficiency: is the goal disease prevention or full nutrient repletion? Ann Intern Med 2015 Jan; 162(2):144-145.
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