J. Christopher Gallagher, MD; Adarsh Sai, MBBS; Thomas Templin, MD; Lynette Smith, MS
Acknowledgment: The authors thank all study participants and the Bone Metabolism Unit research staff for their hard work and contribution to the study; Jane Meza, PhD, University of Nebraska Medical Center, for important statistical advice; Vinod Yalamanchili, MBBS, for review of the article; the members of the data safety and monitoring board (Meir Stampfer, MD, DrPH; Doug Kiel, MD; Bruce Hollis, PhD; Bess Dawson-Hughes, MD; Munro Peacock, MD; Judy Hannah, PhD; and Becky Costello, PhD) for their scientific guidance; and the institutional review board at Creighton University School of Medicine.
Grant Support: By the National Institute on Aging (RO1-AG28168) and Office for Dietary Supplements.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1566.
Reproducible Research Statement:Study protocol: Available from Dr. Gallagher (e-mail, email@example.com). Statistical code and data set: Not available.
Requests for Single Reprints: J. Christopher Gallagher, MD, Bone Metabolism Unit, Creighton University School of Medicine, 601 North 30th Street, Suite 6718, Omaha, NE 68131; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Gallagher: Bone Metabolism Unit, Creighton University School of Medicine, 601 North 30th Street, Suite 6718, Omaha, NE 68131.
Dr. Sai: Department of Medicine, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA 92354.
Dr. Templin: Department of Surgery, Creighton University School of Medicine, 601 North 30th Street, Suite 6718, Omaha, NE 68131.
Ms. Smith: College of Public Health, Nebraska Medical Center, Omaha, NE 68198-4375.
Author Contributions: Conception and design: J.C. Gallagher, L.M. Smith.
Analysis and interpretation of the data: J.C. Gallagher, A.J. Sai, L.M. Smith.
Drafting of the article: J.C. Gallagher, A.J. Sai, L.M. Smith.
Critical revision of the article for important intellectual content: J.C. Gallagher, A.J. Sai, T.J. Templin, L.M. Smith.
Final approval of the article: J.C. Gallagher, A.J. Sai, L.M. Smith.
Provision of study materials or patients: J.C. Gallagher, A.J. Sai.
Statistical expertise: A.J. Sai, L.M. Smith.
Obtaining of funding: J.C. Gallagher.
Administrative, technical, or logistic support: J.C. Gallagher, A.J. Sai, T.J. Templin.
Collection and assembly of data: J.C. Gallagher, A.J. Sai, T.J. Templin.
Gallagher JC, Sai A, Templin T, Smith L. Dose Response to Vitamin D Supplementation in Postmenopausal Women: A Randomized Trial. Ann Intern Med. 2012;156:425-437. doi: 10.7326/0003-4819-156-6-201203200-00005
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Published: Ann Intern Med. 2012;156(6):425-437.
This article has been corrected. The original version (PDF) is appended to this article as a supplement.
Serum 25-hydroxyvitamin D (25-[OH]D) is considered the best biomarker of clinical vitamin D status.
To determine the effect of increasing oral doses of vitamin D3 on serum 25-(OH)D and serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency (defined as a 25-[OH]D level ≤50 nmol/L) in the presence of adequate calcium intake. These results can be used as a guide to estimate the Recommended Dietary Allowance (RDA) (defined as meeting the needs of 97.5% of the population) for vitamin D3.
Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00472823)
Creighton University Medical Center, Omaha, Nebraska.
163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year.
Participants were randomly assigned to receive placebo or vitamin D3, 400, 800, 1600, 2400, 3200, 4000, or 4800 IU once daily. Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg.
The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months.
The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D3. The RDA of vitamin D3 to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed-effects model predicted that 600 IU of vitamin D3 daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m2), obese women (≥30 kg/m2) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D3 (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose.
Findings may not be generalizable to other age groups or persons with substantial comorbid conditions.
A vitamin D3 dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women; however, a model predicted the same response with a vitamin D3 dosage of 600 IU/d. These results can be used as a guide for the RDA of vitamin D3, but prospective trials are needed to confirm the clinical significance of these results.
National Institute on Aging.
Vitamin D supplementation is widely recommended to patients, but the optimal dose is debated.
Postmenopausal white women with vitamin D insufficiency received either placebo or increasing doses of vitamin D3, as well as calcium supplements. A dosage of vitamin D3, 800 IU/d, achieved a serum 25-hydroxyvitamin D level greater than 50 nmol/L, which is the Recommended Dietary Allowance for vitamin D3 recently recommended by the Institute of Medicine.
This study did not assess clinical outcomes. A dosage of 600 IU/d of vitamin D3 was not studied but might have been comparable to 800 IU/d.
Relatively modest doses of vitamin D3 can achieve the current Recommended Dietary Allowance for vitamin D.
Table 1. Terms Used to Quantify Requirements for Nutrient Intake
Study flow diagram.
25-(OH)D = 25-hydroxyvitamin D; BMD = bone mineral density; BMI = body mass index; PCP = primary care physician.
* Participants who discontinued the study who came in for the final visit.
† Participants who were ineligible because of age criteria were included in the intention-to-treat analysis; there were no crossovers from assigned groups.
Table 2. Exclusion Criteria
Table 3. Baseline Characteristics
Vitamin D dose–response curve.
Baseline, 6-mo, and final serum 25-(OH)D levels are presented according to dosage of vitamin D or placebo. A quadratic curve was the best fit for data. Levels of 25-(OH)D at 6 and 12 mo were significantly lower in the placebo group compared with all vitamin D dose groups individually (P < 0.05). 25-(OH)D = 25-hydroxyvitamin D.
Appendix Table 1. Dose–Response Mixed-Effects Model, by Estimating the Dose Response of Serum 25-(OH)D and PTH Levels at Each Time Point
Serum 25-(OH)D levels according to vitamin D dosage.
Levels are shown with a fitted line by using the mixed-effects model, with 95% bootstrapped limits at 12 mo. 25-(OH)D = 25-hydroxyvitamin D.
Appendix Table 2. Multivariate Mixed-Effects Models of Serum 25-(OH)D and PTH Levels
Appendix Table 3. Mixed-Effects Model of BMI, Dose, and Time on Serum 25-(OH)D
Effect of BMI and vitamin D dose on levels of serum 25-(OH)D at 12 months.
BMI <25 kg/m2, n = 31; BMI 25.0–29.9 kg/m2, n = 56; and BMI ≥30.0 kg/m2, n = 76. 25-(OH)D = hydroxyvitamin D; BMI = body mass index.
Serum PTH levels, according to vitamin D dosage at 12 months.
PTH = parathyroid hormone.
Table 4. Adverse Events
Table 5. Occurrence of Hypercalcemia and Hypercalciuria
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In this video, J. Christopher Gallagher, MD, offers additional insight into his original research article, "Dose Response to Vitamin D Supplementation in Postmenopausal Women. A Randomized Tria
Subhash CArya, MIcrobiologist, Nirmala Aagarwal
Sant Parmanand Hospital
March 22, 2012
Vitamin D supplementation in elderly people
Apart from any daily supplementation with vitamin D3 an annual injection of 600, 000 IU is also commonly practised. However, such daily supplementation alone may fail to bring the levels to a minimum of 75 nmol/l in 20-30 per cent of cases1. A once-yearly intramuscular cholecalciferol injection containing 600,000 IU is a more effective therapy for vitamin D deficiency, which is safe and remarkably cost- effective and its simple dosing allows convenient outpatient management2. Rapid, point-of-care assay formats to measure 25-(OH)-D deficiency in health care centers, if available, will be useful to measure it and also the post-supplementation response Annual rather than daily vitamin D3 supplementations would also be advantageous in elderly persons as they are known to be at an increased risk of medication-prescribing and administration errors. The incidence of administration errors is likely to be high in long-term, home-based care. Even a barcode medication administration system has been planned to apprehend such errors in nursing and residential homes for the elderly3. However, barcode administration would not be suitable for elderly men and women living at places other than homes for the elderly. Any plans to address vitamin D deficiency in a community or in elderly populations, apart from vitamin D3 supplementation, should include surveillance of post -supplementation levels.
1. Schwalfenberg GK. A step in the right direction. CMAJ 2010;182:1763
2. Diamond TH, Ho KW, Rohl PG, Meerkin M. Annual intramuscular injection of a megadose of cholocalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Australia 2005;183:10-12.
3. Szczepura, A., Wild, D., Nelson, S. Medication administration errors for older people in long-term residential care. BMC Geriatrics 2011; p. 82. Article in Press
Arthur B.Chausmer, MD, PhD, FACP, FACE, FACN, CNS
Endocrinology, Diabetes and Metabolism, Laurel, MD
April 2, 2012
Critical Appraisal Warranted
In the March 20, 2012 issue of the Annals there was an article about the adequacy of dosing of vitamin D. While it correctly stated that there was a relationship between the 25 hydroxycalciferol (25 OHD) intermediate metabolite and the oral dose, there are some other important points to consider. It is important to note that, contrary to popular opinion, the level of circulating 25 OHD should not be considered an appropriate indicator of true vitamin D sufficiency or insufficiency.
Since the total body load of any of the D metabolites has yet to be quantitatively assessed, there is no way of knowing if there is a deficiency state or not; what relationship, if any, exists between blood levels and the total body stores; or what the relationship between the active and inactive metabolites might be. These are key points. The popular, and probably wrong, interpretation of low serum 25 hydroxycholecalciferol (25 OHD) is that this reflects a vitamin D deficiency state. Since no one has any idea what the actual total body stores of 25 OHD or 1,25 dihydroxycholecalciferol (1,25 OHD) are, this is only an assumption. 25 OHD is inactive for all practical purposes, and measurements of this metabolite are of questionable physiologic significance. The extrapolations of indirect data on which some of the basic assumptions have been made are, at best, supposition and cannot be considered proof on which clinical decisions should be made. In hyperphosphatemic tumoral calcinosis, for example, the 25 OHD levels are very low, the 1,25 levels are very high, and there is markedly enhanced calcium absorption.
25 OHD is an intermediate which is the result of 25 hydroxylation of calciferol in the liver. It is no more an index of whole body D status, or even 25 OHD status, than a low serum Na reflects total body Na stores in edema or low serum K reflects intracellular K stores until there is profound depletion. The total body stores of D can be high, as it is a fat soluble vitamin, and the serum level low if the 25 hydroxylase is relatively inactive. The stores can be low and the circulating 250HD high if the 25 hydroxylase has been stimulated. This is but one set of examples. There are, of course, several other scenarios, such at the previously mentioned tumoral calcinosis, in which there is a less than acceptable correlation.
While there may be some suggestive evidence of non calcium activity for 25 OHD, it must still be considered physiologically inactive for all practical purposes. There has been no evidence other than suggestive correlations for these, and even those studies are arguable. A key point to be remembered is that no matter how strong a statistical correlation may be, it in no way infers causality. These points suggest a critical, and even skeptical, approach to the study presented before any clinical actions are taken based on these data. These views are my own and not necessarily of any organization with which I am affiliated.
Yours truly, Arthur B. Chausmer, MD, PhD Endocrinology, Diabetes and Metabolism FACP, FACE, FACN, CNS
John C.Gallagher, Director Bone Metabolism Unit, Adarsh Sai
Creighton University Medical Center
April 28, 2012
Re:Critical Appraisal Warranted
In a letter following our article on the effect of vitamin D on serum 25OHD (1) it was suggested that measurement of serum 25- hydroxyvitamin D (25OHD) had no value. We disagree; serum 25OHD is a valid indicator of total body vitamin D status- because there is no other biomarker of nutritional status and because it is the substrate for 1,25(OH)2D, the main regulatory hormone in calcium and vitamin D metabolism. Whether 25OHD has an independent physiologic action on the vitamin D receptor is unknown because 1,25(OH)2D is always present but since 25OHD circulates at a concentration 1000 times higher than 1,25(OH)2D in blood it could play a role in non-physiologic situations e.g. renal failure. Usually serum 1,25(OH)2D levels do not decrease unless there is renal failure or a decrease in its substrate serum 25OHD to below 10ng/ml (2) however serum 1,25(OH)2D levels would probably decrease at a higher serum 25OHD between 20-30ng/ml were it not for the development of secondary hyperparathyroidism (3). When serum 25OHD is < 20ng/ml there is an increase in bone resorption markers and increase in hip fractures (3). These are just some of the reasons that the Institute of Medicine (IOM) selected a serum 25OHD of < 20ng/ml as a definition of insufficiency and why it is important clinically to measure serum 25OHD (4). In addition our data applies to a worldwide population where serum 25OHD levels are often less than 10 ng /ml increasing the incidence of osteomalacia (5).
In the letter the author describes a special disease Hyperphosphatemic tumoral calcinosis that leads to abnormal vitamin D metabolism and is irrelevant to a discussion of vitamin D insufficiency. Mutations in Fibroblast Growth Factor (FGF 23) and other genes decrease renal phosphate excretion, stimulate 24-hydroxylase that converts 25OHD and 1,25(OH)2D into inactive metabolites causing secondary hyperparathyroidism, stimulating 1,25(OH)2D and calcium absorption. Sunlight is responsible for producing 80 percent of the nutritional supply of vitamin D in the body that maximizes serum 25OHD in summer and autumn. During winter there is a 50 percent decrease in serum 25OHD levels, secondary hyperparathyroidism and minimal change in serum 1,25(OH)2D. Storage of vitamin D in fat must be minimal otherwise one would have expected these stores to buffer the lack of vitamin D input from sunlight in the autumn and winter (3). As our data shows in fig 3, the difference in serum 25OHD in those with obesity: BMI >30 compared to normal < 25 kg/m2 or 130-220lbs for average height is only 7ng/ml suggesting that fat is not a significant storage site for vitamin D and the difference of 7ng/ml in obese versus thin people could be related to extracellular volume dilution. We suggest that measuring and maintaining a serum 25OHD level >20ng/ml in the population is highly advisable because numerous studies show poor clinical health outcomes and increased mortality below 20ng/ml (4); whether it is a marker of disease or causation is still uncertain. In our discussion we point out that in defining an RDA for vitamin D sufficiency i.e. serum 25OHD ? 20ng/ml there should be a clinical outcome. All the evidence suggests that serum 25OHD demonstrates biological significance and there is no other substitute for nutritional assessment of vitamin D.
1. Gallagher JC, Sai A, Templin T 2nd, Smith L.Dose response to vitamin D supplementation in postmenopausal women: a randomized trial.Ann Intern Med. 2012 Mar 20;156(6):425-37
2. Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BC 2008 Vitamin D metabolites and calcium absorption in severe vitamin D deficiency Journal of Bone and Mineral Research 23(11):1859-186
3. Sai AJ, Walters RW, Fang X, Gallagher JC. 2011 Relationship between Vitamin D, Parathyroid Hormone, and Bone Health. J Clin Endocrinol. Metab. 96, (3) E436-446.
4. Institute of Medicine 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press.
5.Priemel, M., von Domarus, C., Klatte, T. O., Kessler, S., Schlie, J., Meier, S., Proksch, N, Pastor, F., Netter, C., Streichert, T., P?schel, K. and Amling, M. (2010), Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675?patients. J Bone Miner Res, 25: 305 -312.
Gallagher JC Sai A
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