RESEARCH - Vitamin D prevents fractures, but only if sufficient doses are used

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Vitamin D prevents fractures, but only if sufficient doses are used

Rheumawire

May 11, 2005

Zosia Chustecka

Boston, MA - Vitamin-D supplementation does prevent fractures in older

people, but only when sufficient doses are usedbetween 700 and 800 IU per

day. At this dose, it significantly reduces the risk of both hip fracture

(by 26%) and any nonvertebral fracture (by 23%) compared with calcium or

placebo. However, the lower dose of vitamin D 400 IU per day has no

appreciable effect, a new meta-analysis concludes.[1]

At present, the recommended intake of vitamin D for middle-aged and older

adults is between 400 and 600 IU/day. " Our results support increasing the

dose, " say the authors.

Writing in the May 11, 2005 issue of the Journal of the American Medical

Association, the researchers comment that the pooled risk difference in the

meta-analysis indicates that 45 people would need to be treated with vitamin

D at 700 to 800 IU/day to prevent 1 person from sustaining a hip fracture,

and 27 people would need to be treated to prevent 1 person from sustaining a

nonvertebral fracture. Given these numbers needed to treat (NNTs) and " the

high morbidity, mortality, and cost of fractures, our results are compelling

for general vitamin-D supplementation in the range of 700 to 800 IU/day in

elderly persons, " they comment.

The role of additional calcium supplementation could not be clearly defined

by the meta-analysis, the authors comment, and a question that should be

addressed in future research is whether calcium adds value (and at what

dose) to the antifracture efficacy of vitamin D.

Lead author Dr Heike Bischoff-Ferrari (Harvard School of Public Health,

Boston, MA) tells rheumawire: " My recommendation for individuals aged 65 or

older is general vitamin-D supplementation with at least 800-IU vitamin D

(cholecalciferol) per day plus calcium at 700 to 1000 mg/day, depending on

the patient's diet. If the person has already had a fracture or has low

levels of 25-hydroxyvitamin D (below 40 nmol/L, according to our studies),

it may be warranted to consider a higher dose of vitamin D. " She adds that

US authorities have defined the safe upper limit as 2000 IU/day.

When asked about the results of 2 recent studies that cast doubt on the use

of vitamin D and calcium supplementation in fracture prevention, reported by

rheumawire a few weeks ago, Bischoff-Ferrari said that both studies had

issues that would have prevented them from being included in the

meta-analysis they conducted (one because it looked at secondary prevention

of fractures, the other because it was an unblinded pragmatic study and not

a randomized controlled clinical trialsee sidebar for further details).

Higher dose reduces fracture risk, lower dose doesn't

For the primary analysis, the researchers included 7 trials, with a total

number of 9820 patients with an approximate mean age of 79 years, of whom

68% were women. All of the participants were in stable health states, the

researchers note: they were living in the community, in apartments or

housing for elderly people, or in nursing homes. In 2 of these trials, the

vitamin-D dose was 400 IU/day and there was no additional calcium

supplementation; in the other 5 trials, vitamin D was taken at 700 to 800

IU/day, and in 4 of these 5 trials, there was also additional calcium

supplementation (500-1200 mg/day). Only 1 trial provided calcium in the

control group. All of trials that were included in the primary analysis used

cholecalciferol as the vitamin-D supplement, and the authors note that

ergocalciferol may have one third the potency at the same dose.

When the researchers analyzed all of the trials together, the variation

between studies was more than expected, indicating heterogeneity, but this

disappeared once they stratified the trials according to higher and lower

doses of vitamin D.

For hip-fracture prevention, there were 3 trials (involving 5572

individuals) in which vitamin D was taken at the higher dose of 700 to 800

IU/day. The pooled RR was 0.74 (95% CI 0.61-0.88), suggesting that it

reduces the risk of hip fracture by 26%. The pooled risk difference was 2%

(95% CI 1%-4%, p<0.001), so the NNT was 45 (95% CI 28-114) for a duration of

treatment of 2 to 5 years.

For the prevention of any nonvertebral fracture, there were 5 trials

(n=6098) with the higher dose of vitamin D, giving a pooled RR of 0.77 (95%

CI 0.68-0.87), suggesting a 23% reduction in risk. The pooled risk

difference was 4% (95% CI 2%-5%, p=0.02), so the NNT was 27 (95% CI 19-49)

for a treatment duration of 2 to 5 years.

For 2 trials (n=3722) in which vitamin D was used at the lower dose of 400

IU/day, the pooled RR for hip fracture was 1.15 (95% CI 0.88-1.50) and for

any nonvertebral fracture was 1.03 (95% CI 0.86-1.24), suggesting that this

lower dose does not reduce fracture risk.

The researchers also examined data on serum levels of 25-hydroxyvitamin D

and found that higher levels were associated with a greater reduction in the

risk of both hip and nonvertebral fractures. Optimum fracture prevention

appeared to occur at mean levels of approximately 100 nmol/L.

Ties in with previous findings

These results are consistent with two previous findings, Bischoff-Ferrari et

al comment. The same group previously found, in a national US survey among

adults aged >50 years, that bone-mineral density (BMD) increased

monotonically with higher serum levels of 25-hydroxyvitamin D levels, up to

at least 80 nmol/L. And in a previous meta-analysis of falls, they found

that vitamin-D supplementation at 800 IU/day reduced the risk of falls by

35% but found no such reduction with the lower dose of vitamin D 400 IU/day.

The researchers suggest 2 physiological explanations for the beneficial

effects of vitamin D on fracture risks in older people. In addition to the

well-described bone loss in older people, vitamin D also appears to have a

beneficial effect on muscle strength and balance, mediated through highly

specific receptors in muscle tissue, and has been associated with a

significant reduction in the risk of falling in older individuals. These

benefits of strength and falls have been observed within 2 to 3 months in

previous studies, they comment.

Critique of 2 recent studies

In recent weeks, 2 studies casting doubt on the use of vitamin D

and calcium supplements in the prevention of fractures have been published

[2,3] and were reported at the time rheumawire. When asked how those results

fit in alongside the findings of this current meta-analysis,

Birschoff-Ferrari offered a critique of both studies and said that neither

would have met her group's inclusion criteria.

The study published in the BMJ from Porthouse et al was an

unblinded pragmatic trial and did not report 25-hydroxyvatamin D levels at

baseline or follow-up, she notes. " Their effect size for hip fracture is

similar to our pooled results; however, it is surrounded by a large

confidence interval (0.75; 95% CI 0.31-1.78). One source of bias toward a

null result may have been that the authors gave out written information to

the control group on adequate vitamin-D intake and fall prevention. This may

explain to some degree why they did not find a difference between treatment

and control. "

The RECORD trial in the Lancet was a secondary-prevention trial,

Birschoff-Ferrari notes, pointing out that her group's meta-analysis focused

only on first fractures. However, she comments that this was a " high-quality

trial . . . [and] one wonders why the authors did not see an effect of

vitamin D on fractures or falls. " One explanation may be that 800-IU vitamin

D with or without calcium is not enough for this patient population, who

have already had 1 osteoporotic fracture. Another explanation may be that

these patients did not achieve high enough serum levels of 25-hydroxyvitamin

D. The authors report mean serum levels of only 62 nmol/L (24.8 ng/mL),

whereas, according to her group's results, levels need to reach 80 to 100

nmol/L to achieve fracture efficacy, she comments.

Sources

a. Bischoff-Ferrari H, Willet WC, Wong JB, et al Fracture

prevention with vitamin D supplementationa meta-analysis of randomized

controlled trials JAMA 2005; 293:2257-2264.

b. Porthouse J, Cockayne S, King C, et al. Randomised

controlled trial of supplementation with calcium and cholecalciferol

(vitamin D3) for prevention of fractures in primary care. BMJ 2005;

330:1003-1006.

c. Grant AM, FH, Avenell A, et al. On behalf of the

RECORD trial group. Oral vitamin D3 and calcium for secondary prevention of

low-trauma fractures in elderly peoplerandomised evaluation of calcium or

vitamin D (RECORD): a randomised placebo-controlled trial. Lancet 2005;DOI:

10.1016/S0140-6736(05)63013-9. Available at: http://www.lancet.com.

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