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Original Investigation | Less Is More

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline A Randomized Clinical Trial

Heike A. Bischoff-Ferrari, MD, DrPH1,2; Bess Dawson-Hughes, MD3; E. John Orav, PhD4; Hannes B. Staehelin, MD5; Otto W. Meyer, MD1,2; Robert Theiler, MD2; Walter Dick, MD6; Walter C. Willett, MD, DrPH7; Andreas Egli, MD1,2
[+] Author Affiliations
1Department of Geriatrics and Aging Research, University Hospital Zurich, Zurich, Switzerland
2Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
3Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
4Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
5Department of Geriatrics, University of Basel, Basel, Switzerland
6Department of Orthopedic Surgery, University of Basel, Basel, Switzerland
7Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
JAMA Intern Med. 2016;176(2):175-183. doi:10.1001/jamainternmed.2015.7148.
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Importance  Vitamin D deficiency has been associated with poor physical performance.

Objective  To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline.

Design, Setting, and Participants  One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall.

Interventions  Three study groups with monthly treatments, including a low-dose control group receiving 24 000 IU of vitamin D3 (24 000 IU group), a group receiving 60 000 IU of vitamin D3 (60 000 IU group), and a group receiving 24 000 IU of vitamin D3 plus 300 μg of calcifediol (24 000 IU plus calcifediol group).

Main Outcomes and Measures  The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index.

Results  The study cohort comprised 200 participants (men and women ≥70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60 000 IU and 24 000 IU plus calcifediol were more likely than 24 000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60 000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24 000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24 000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60 000 IU group (mean, 1.47) and the 24 000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24 000 IU group (mean, 0.94) (P = .09).

Conclusions and Relevance  Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24 000 IU.

Trial Registration  clinicaltrials.gov Identifier: NCT01017354

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Figure 1.
Consolidated Standards of Reporting Trials Diagram and Inclusion and Exclusion Criteria

Inclusion criteria were mobility with or without a walking aid, ability to use public transportation to attend the clinic visits, and a score of at least 27 on the Mini-Mental State Examination. Exclusion criteria were supplemental vitamin D use exceeding 800 IU/d and unwillingness to discontinue additional calcium and vitamin D supplementation during the course of the trial. Other exclusion criteria were the following: current cancer, malabsorption syndrome, heavy alcohol consumption, uncontrolled hypocalcemia, severe visual or hearing impairment, use of medications affecting calcium metabolism, diseases causing hypercalcemia (eg, sarcoidosis), planned travel to sunny locations for longer than 2 months per year, maximum calcium supplement dose of 250 mg/d (with no additional vitamin D), use of medications affecting serum 25-hydroxyvitamin D level (eg, phenobarbital), body mass index (calculated as weight in kilograms divided by height in meters squared) of 40 or higher, diseases predisposing to falls (eg, Parkinson disease, hemiplegia after stroke, and inflammatory arthritis), hypercalcemia (serum calcium level >10.4 mg/dL [to convert calcium level to millimoles per liter, multiply by 0.25]), and kidney disease (estimated creatinine clearance <15 mL/min/1.73 m2 or kidney stone within 10 years [to convert creatinine clearance to mL/s/m2, multiply by 0.0167]).

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Figure 2.
Unadjusted 25(OH)D Levels by Treatment at Baseline, 6 Months, and 12 Months

At the 6-month and 12-month follow-ups, the mean 25(OH)D levels differed significantly by treatment (P < .001). 25(OH)D indicates 25-hydroxyvitamin D; error bars, SD. To convert 25(OH)D level to nanomoles per liter, multiply by 2.496.

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Another bad outcome or another bad trial?
Posted on January 6, 2016
Rodis D Paparodis, MD
Endocrinology in Private Practice, Patras, Greece
Conflict of Interest: None Declared
We face again and again the same story - excellent colleagues choosing a potential supplementation dose for vitamin D, administering it to a large number of patients, and trying to figure out its effects, when compared to placebo. The inherent problem in this kind of trials, is that it focuses on the supplementation dose, when this is not the real issue. We do not need to find an optimal dose of supplementation for any hormone, because a deficient hormone needs replacement - not supplementation.

In all hormonal systems (including vitamin D), the question lies on what is the optimal hormone (25-OH vitamin D) concentration, and if this is the same for the entire population. Let's think about hypothyroidism - should we base our treatment on the choice of a specific levothyroxine replacement dose or should we maybe look at the TSH values? For vitamin D specifically, the hormonal system is tightly regulated in conjunction with the renal function (ie. 1,25-OH-D production), the dietary and supplemental intake of calcium and its intestinal absorption, the resulting parathyroid hormone (PTH) concentration (in the long run), and the serum concentration of calcium.

In order to interpret in a significant way the effects of vitamin D replacement, on any aspect of human life, we need first to achieve a specific concentration of vitamin D, independent of the dose required to get us there (not interpret the results of supplementation with a specific dose independent of the concentrations achieved). Afterwards we need to observe our research subjects for a pre-specified period of time regarding the outcomes that we want to look at, while vitamin D concentration remains stable. This should happen in a pre-specified calcium/1,25-D/PTH environment, so that there is no major confounding in the effects evaluated.

Until this type of clinical trials is published, I fear that we cannot base any decision for the clinical management of our patients with vitamin D deficiency/insufficiency on the present data.


The sun will not set on the benefits of vitamin D for the prevention of falls
Posted on February 12, 2016
Shirwan Mirza, MD, FACP, FACE
Private Practice: Endocrinology, Metabolism, and Nutrition-Auburn, New York
Conflict of Interest: None Declared
The benefits of vitamin D for bone and muscle strength and its multiple other extra skeletal advantages are one of the major medical breakthroughs of the past decade. yet, we continue to see new trials, such as this study under discussion, trying to cast doubts on this important nutrient that works as a hormone on all the systems of the body. The study by Heike A. Bischoff-Ferrari, MD and et al starts without any working hypothesis and ends with the statement that \"the physiology behind a possible detrimental effect of a high monthly bolus dose of vitamin D on muscle function and falls remains unclear and needs further investigation\".
Reviewing the full study protocol in the attached supplements, the weak foundation and the design flaws of this study are on full display. The authors have mentioned some good exclusion criteria while missing major other diseases and drugs that are very commonly encountered in the population of this study. Neurological and calcium metabolism disorders are justifiably excluded along with steroid and anti-epilepsy drugs. The following disorders and drugs must have been exclusion criteria but they are missing in the study design. Hypertension, hyperlipidemia and diseases of autonomic nervous system (or drugs affecting this system) are not excluded. Statins are commonly used in geriatric population with major detrimental effect on the proximal muscles of the lower extremities predisposing such patients to falls. Diuretics, vasodilators, including alpha blockers, nitrates, drugs for benign prostate hypertrophy, drugs used in erectile dysfunction, widely used anti-cholinergic medications, and anti-histamines (including anti-depressants and drugs for overactive bladder) are all missing as exclusion criteria. It is possible that the group with the high-dose vitamin D included more users of such drugs. Diabetes was also not included as exclusion criteria. Most patients with advanced type 1 or type 2 diabetes do have a certain degree of autonomic dysfunction, which includes orthostatic hypotension, a major risk factor for falls. Uncontrolled diabetes causes volume depletion and osthostasis and increases the risk of falls. The new-generation of anti-diabetes drugs such as canagliflozin, causes volume depletion and increases risk of falls. Furthermore, a placebo group is missing in this trial. The reference range 25-hydroxy vitamin D is relatively wide: 32-100 ng/ml. From our experience with the use of high dose vitamin D3 in our large practice of 6500 patients since 1998, with an average dose of vitamin D3 of 5000 IU once a day between Novemeber- May and 2500 IU a day between May-Novemeber, we have not encountered any increase in the risk of falls in our patients. . As long as the metabolic parameters stay within normal limits, namely, calcium, parathyroid hormone and 25-hydroxy vitamin D, there is no plausible biological reason to justify the conclusion of this study. Unless the authors address the above-mentioned flaws in the design of their trial, I will declare their conclusion flawed as well.
Loading or maintenance
Posted on March 14, 2016
Fatih Tufan, Gulistan Bahat, Mehmet Akfi Karan
Istanbul University, Istanbul Faculty of Medicine, Department of Geriatrics
Conflict of Interest: None Declared
One potential problem with this study is the method of supplementation of vitamin D. Although vitamin D has a long half-life and a wide therapeutic index, we do not know exactly if it is safe to give the monthly cumulative dose at once. Previous studies also showed increased risk of falls in subjects who received 300 000 U of vitamin D as loading at once. We know the potential toxic effects regarding calcium metabolism but we do not know its toxic effects on other systems. In addition, it is clear that the lower extremity functions of the subjects who received higher vitamin D doses did not become worse compared with lower doses. We suggest that loading of high doses of vitamin D might have had some detrimental effects on balance or cardiovascular system. It may be rational to design a similar study with daily doses of vitamin D. Nonetheless, several studies indicate that a 25-OH vitamin D level of 20 ng/ml may be optimal for bone health and subjects with seemingly low 25-OH vitamin D along with normal calcium and parathyroid hormone levels may not benefit from replacement or supplementation of vitamin D.
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