Interview: Dr. Bischoff-Ferrari addresses Vitamin D intake

Vitamin D is known to be essential in bone health, but the science is still out on whether it is a key factor in protecting fast-twitch muscles or in preventing falls.  A study in the Jan. 4 issue of JAMA Internal Medicine shows that higher monthly doses of vitamin D effectively reached a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, but it did not improve lower extremity function and in fact, the data in a trial of 200 participants, showed that it was associated with an increased risk of falls at very high doses beyond 24,000 IU. "Our trial supports 24,000 IU vitamin D dose per month as an effective and safe treatment for both vitamin D deficiency and fall prevention, while higher monthly doses of vitamin D or a combination with calcifediol may not be warranted in seniors age 70+ with a prior fall event due to a potentially deleterious effect on falls,'' said Heike A. Bischoff-Ferrari, M.D., Dr.PH., corresponding author of the Jan. 4 study in JAMA Internal Medicine and chair of the Department of Geratrics and Aging Research at the University Hospital of Zurich.

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In an accompanying editorial, Steven R. Cummings, M.D., of the California Center Research Institute in San Francisco, and colleagues, suggests getting recommended dosages of vitamin D and other vitamins from a balanced diet, not vitamin supplementation.

“The strategy of supplementation with vitamin D to achieve serum levels of at least 30 ng/mL has not been established by research clinical trials to reduce the risk of falls and fractures. It may increase the risk of falling. Until that approach is supported by randomized trials with updated meta-analyses, it would be prudent to follow recommendations from the Institute of Medicine that people 70 years or older have a total daily intake of 800 IU of vitamin D without routine measurement of serum 25 (OH) D levels,“ he wrote.

In this Q&A, Dr. Bischoff-Ferrari, discusses the significance of the study, recommendations for rheumatologists and other physicians, and she responds to issues raised in the editorial.

Vitamin D supplementation has been proposed as a possible preventive strategy to delay functional decline. How did this strategy come about?

We and others contributed to that literature. Several trials among seniors at risk for vitamin D deficiency, demonstrated a benefit of vitamin D supplementation on lower extremity function and this benefit translated in a reduction in falls in the same trials1-3. Extending to trials among individuals with a lower risk of vitamin D deficiency, a recent meta-analysis of 17 RCTs suggested that a benefit of vitamin D on lower extremity strength could not be excluded (p = 0.07) among individuals with 25(OH)D starting levels of > 25 nmol/l, while a significant benefit was reported only among those with 25(OH)D starting levels < 25 nmol/l4.

Further, several epidemiological studies suggest a dose-response relationship between lower extremity function and serum 25(OH)D levels among adults age 65 and older ^(5-7). From these studies a threshold between 20 to 30 ng/ml has been suggested for optimal lower extremity function, while for the largest of the 3 epidemiologic studies⁽⁶⁾ a threshold beyond which lower extremity function would not further improve was not identified.

Finally, based on our small pilot trial among young postmenopausal women⁽⁸⁾, we expected a greater gain in lower extremity function with the higher dose groups.

How can vitamin D reduce one’s chances of falling?

Mechanistically, several lines of evidence link vitamin D to muscle strength and falling⁽⁹⁾. Proximal muscle weakness is a feature of clinical vitamin D deficiency⁽¹⁰⁾.  Also, the vitamin D receptor (VDR) is expressed in human muscle tissue^(11,12), and its activation promotes de novo protein synthesis preferentially in type II fast twitch muscle fibers relevant for fall prevention^(13-15).

How does this study add to the literature?

Each year, one out of three older persons age 65 and older experience at least one fall. 9% of these falls require an emergency room visit, and about 6% result in a fracture⁽³⁾. Thus fall prevention is a key public health target thriving with the rapid rise of the older segment of the population.

Current evidence from double-blind clinical trials among seniors age 65 and older support the correction of vitamin D deficiency with the current recommendation of 800 IU vitamin D per day (equivalent to our monthly dose of 24,000 IU) for fall⁽¹⁶⁾ and fracture⁽¹⁷⁾ prevention. However, if and to what extend higher doses of vitamin D are beneficial has not been studied conclusively.

In our recent trial, all 200 participants had fallen in the prior year. During the 12 month follow-up under treatment, 61% (121 of 200) fell, 48% in the 24,000 IU vitamin D group, 67% in the 60,000 IU group, and 66% in the 24,000 IU plus calcifediol group.

The two monthly high doses, 60,000 IU and 24,000 IU plus calcifediol, had no benefit on lower extremity function and had higher percentages of participants who fell. Participants in the 24,000 IU vitamin D group (equivalent to 800 IU/day) experienced the most improved lower extremity function and also had the fewest number of falls.

Our trial supports 24,000 IU vitamin D dose per month as an effective and safe treatment for both vitamin D deficiency and fall prevention, while higher monthly doses of vitamin D or a combination with calcifediol may not be warranted in seniors age 70+ with a prior fall event due to a potentially deleterious effect on falls.

Did the findings meet your expectations?

Based on our small pilot trial among young postmenopausal women⁽⁸⁾, we expected a greater gain in lower extremity function with the higher dose groups and also expected a greater reduction in falls among these groups. However, contrary to our expectations, we found that participants in the standard dose of vitamin D (24,000 IU per month) had the best improvement in lower extremity function, the lowest odds of falling and the fewest number of falls compared with the two high dose groups.

One explantion may be that there is a therapeutic range for vitamin D with respect to fall prevention among seniors who had a prior fall. In fact, our study points to the range between 21 to 30 ng/ml as optimal because both 25-Hydroxyvitamin D blood levels below 21 ng/ml (vitamin D deficiency) and above 45 ng/ml were associated with increased risk of falling.

This is consistent with our earlier meta-analysis among 2,426 participants from 8 double-blind RCTs where fall prevention started at levels above 20 ng/ml. However, at the time trials that achieved 25-hydroxyvitamin D levels greater than 38 ng/ml were missing⁽¹⁸⁾.

An alternative explanation may be that monthly doses of vitamin D is not advantageous at the higher dose used in this study. In two prior studies testing 500,000 IU vitamin D annually⁽¹⁹⁾ or 100,000 IU every 4 months⁽²⁰⁾, fall risk increased significantly by 15% or declined by non-significantly by 7%. Notably, the physiology behind a possible detrimental effect of a high dose of vitamin D monthly or less frequently on muscle function and falls remains unclear and needs further investigation.

Finally, there is the possibility that high dose monthly vitamin D may increase physical activity in seniors at risk of falling too rapidly and thereby provide the opportunity to fall more often. We explored this hypothesis in our analyses but could not confirm it based on the physical activity measures assessed in our trial. 

What is your response to the editorial?

We think that the editorial conclusion about not giving vitamin D at all is over stated, but may be right track about higher monthly doses.

Entering the trial, all 200 participants had fallen in the prior year. During the 12 month follow-up under treatment, 61% (121 of 200) fell, 48% in the 24,000 IU vitamin D group, 67% in the 60,000 IU group, and 66% in the 24,000 IU plus calcifediol group. Thus, a benefit of the standard vitamin D dose is likely even in the absence of a true placebo group as a comparator. The fall reduction benefit in the 24,000 IU group is further supported by our finding that lower extremity function improved significantly over time in this group.

Further, the editors seem to suggest that vitamin D supplementation may only be beneficial in vitamin D deficient institutionalized individuals. Notably, in our trial fall risk reduction was most pronouced at achieved 25-hydroxy vitamin D levels between 21 and 30 ng/ml, and 58% of our community-dwelling population had levels below 21 ng/ml at baseline. This finding is also consistent with national survey data in the U.S. showing that about half of adults and the large majority of people with darker skin have blood levels below 21 ng/ml21.  Also, even among those participants who started in our trial with 25-hydroxyvitamin D levels in the normal range (> 20 ng/ml) the monthly dose of 24'000 IU was safe and did not push any of the particpants to the blood level range of 45 ng/ml and higher where fall risk was increased.

It is likely that many community dwelling seniors have 25-hydroxyvitamin D levels close to the ideal range of 21 to 30 ng/ml and do not need further supplementation. However about 50% of the world population are expected to be below this range⁽²²⁾ and will likely benefit from supplementation. In the latest U.S. National Health and Nutrition Examination Survey 2005 to 2006 data vitamin D deficiency (25-hydroxyvitamin D concentrations ≤20 ng/ml), the overall adult prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%)21. Given the demonstrated safety of 24,000 IU vitamin D per month among those who start below or above 20 ng/ml, current recommendations of general supplementation without prior measurement of 25-Hydroxyvitamin D hold.

We also note that the editorial recommends getting the recommended level of vitamin D of 800 IU daily from natural food sources. However, this is virtually impossible to do without consuming an extreme amount of fish, and almost no one in the U.S. or Europe achieves this intake. Thus, it is reasonable to ensure vitamin D sufficiency with vitamin D supplementation.

What do these results suggest regarding vitamin D supplementation in people who are found to be deficient?

The 24,000 IU vitamin D per month is an effective and safe treatment for both vitamin D deficiency and fall prevention.

Falls are the primary risk factor for fractures among seniors and vitamin D has been shown to have a direct effect on muscle next to its established role in calcium metabolism and related bone health. Our trial was too small to look at fracture endpoints. We did perform a sensitivity analysis for falls that caused injury including fractures. For this endpoint, we saw the same pattern as for all falls.

Any other comments about your findings?

Prevention of falls is only one likely benefit of having adequate vitamin D levels. The evidence is strong that low blood levels increase the risk of fractures and overall mortality, and low levels are consistently associated with elevated risks of colorectal cancer. Our data supports the efficacy and safety of the monthly 24,000 IU supplementation for the correction of vitamin D deficiency in seniors age 70 and older. 

As stated earlier, we also agree with the editorial comment that further research is needed to define the optimal dose and frequency of vitamin D supplementation.

References:

Heike A. Bischoff-Ferrari, MD, DrPH; Bess Dawson-Hughes, MD; et. al.,

"

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline 

A Randomized Clinical Trial,"

JAMA Internal Medicine. Jan. 4, 2016. doi:10.1001/jamainternmed.2015.7148 Steven R. Cummings, MD; Douglas P. Kiel, MD, MPH; et. al. 

"Vitamin D Supplementation and Increased Risk of Falling 

A Cautionary Tale of Vitamin Supplements Retold,"

JAMA Internal Medicine. Jan. 4, 2016. doi:10.1001/jamainternmed.2015.7568. 

ADDITIONAL REFERENCES

 1.         Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 2008;16:16.

2.         Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15:1113-8.

3.         Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 2003;18:343-51.

4.         Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 2011;22:859-71.

5.         Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;6:6.

6.         Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged >=60 y. Am J Clin Nutr 2004;80:752-8.

7.         Houston DK, Tooze JA, Neiberg RH, et al. 25-hydroxyvitamin D status and change in physical performance and strength in older adults: the Health, Aging, and Body Composition Study. Am J Epidemiol 2012;176:1025-34.

8.         Bischoff-Ferrari HA, Dawson-Hughes B, Stocklin E, et al. Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Miner Res 2012;27:160-9.

9.         Bischoff-Ferrari HA. Relevance of vitamin D in muscle health. Rev Endocr Metab Disord 2012;13:71-7.

10.       Al-Shoha A, Qiu S, Palnitkar S, Rao DS. Osteomalacia with bone marrow fibrosis due to severe vitamin D deficiency after a gastrointestinal bypass operation for severe obesity. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2009;15:528-33.

11.       Bischoff-Ferrari HA, Borchers M, Gudat F, Durmuller U, Stahelin HB, Dick W. Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res 2004;19:265-9.

12.       Ceglia L, da Silva Morais M, Park LK, et al. Multi-step immunofluorescent analysis of vitamin D receptor loci and myosin heavy chain isoforms in human skeletal muscle. J Mol Histol 2010;41:137-42.

13.       Sorensen OH, Lund B, Saltin B, et al. Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Colch) 1979;56:157-61.

14.       Freedman LP. Transcriptional targets of the vitamin D3 receptor-mediating cell cycle arrest and differentiation. J Nutr 1999;129:581S-6S.

15.       Ceglia L, Niramitmahapanya S, Morais MD, et al. A randomized study on the effect of vitamin D3 supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab 2013.

16.       Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692.

17.       Bischoff-Ferrari HA, Orav EJ, Willett WC, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. New England Journal of Medicine;  July 5th 2012 2012.

18.       Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:339:b3692.

19.       Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815-22.

20.       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;326:469.

21.       Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutrition research 2011;31:48-54.

22.       van Schoor NM, Lips P. Worldwide vitamin D status. Best Pract Res Clin Endocrinol Metab 2011;25:671-80.