Vitamin D and fractures: quo vadis?

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The Lancet

DOI:10.1016/S0140-6736(05)66385-4

Vitamin D and fractures: quo vadis?

Philip Sambrook

" I had come to an entirely erroneous conclusion, which shows my dear ,

how dangerous it always is to reason from insufficient data. " 1

Vitamin D deficiency is generally considered to be a major contributor to

falls and fractures in older people. Since the landmark study by Chapuy et

al,2 it has been assumed that treatment with calcium and/or vitamin D

reduces the risk of osteoporotic fractures in older people. In this issue of

The Lancet, the RECORD study, a large randomised trial of participants with

a recent low-trauma fracture, failed to show any benefit of calcium or

vitamin D on fracture. Have we come to an erroneous conclusion about vitamin

D? If so, in what aspects are the Chapuy data insufficient?

The primary prevention trial of Chapuy et al found that calcium plus vitamin

D significantly reduced the risk of hip and non-vertebral fracture compared

with calcium alone in elderly women.2 However, the vitamin D status of the

population was assessed in only 4·3% of 3270 patients. It was assumed that

all participants were largely deficient in vitamin D because in this

subgroup (n=142), serum 25 hydroxyvitamin D levels were low at baseline (33

nmol/L in the placebo group). A subsequent smaller study by Dawson- et

al3 of 389 people living in the community, whose baseline 25 hydroxyvitamin

D levels were much higher at 82·5 nmol/L, also reported benefit from calcium

plus vitamin D on bone loss and fracture, although the study was not powered

for the latter. It was unclear from these studies whether vitamin D needed

to be combined with calcium, and what effect vitamin D had in secondary

prevention.

The factorial design of the RECORD trial attempted to determine the relative

contributions of calcium versus vitamin D on fractures. In this secondary

prevention trial, 5292 ambulatory patients were randomised to receive

calcium alone (1000 mg daily), vitamin D3 (800 IU daily), a combination of

the two, or placebo. After follow-up of at least 24 months, there were no

significant differences in fracture rates between the four groups.

Interpretation of the study is limited by two main factors. First,

compliance with medication was only moderate. It declined to 63% after 2

years and might have been as low as 45% when non-responders to the

questionnaire about compliance were included. On this basis it is difficult

to see how the authors can be sure there was " no evidence that true

differences may have been obscured by poor compliance " . Although the

analysis was appropriate by intention-to-treat, it is possible to correct

for the effect of non-compliance, which will dilute any physiologically

achievable treatment effect in inverse proportion to the degree of

compliance and so widen the confidence intervals.4 Second, the study

perpetuates the limitations of most previous studies by measuring

25-hydroxyvitamin D in only a small sample (n=60-ie, just 1·1% of the study

population). Thus the vitamin D status of the trial population at baseline

remains largely unknown, although, because the patients were younger than in

other studies, ambulatory, and living in the community, they were less

likely to have vitamin D deficiency. There have been two subsequent studies

of vitamin D in patients living at home. Trivedi et al5 reported a

significant reduction in fractures after treatment with 100000 IU

cholecalciferol every 4 months compared with placebo in a randomised trial

of 2686 patients over 5 years. Serum 25-hydroxyvitamin D was not assessed at

baseline but was measured after 4 years of the trial in a subgroup (n=253)

and was 53·3 nmol/L in the placebo group. However, a study of 9440

community-dwelling patients aged 75-100 years, randomised to either an

annual injection of 300000 IU cholecalciferol or placebo, found no

protective effect on fractures.6 Again, vitamin D status was assessed in

only a small sub-sample.

What conclusions can be drawn from these trials? Overall, the data are still

consistent with a therapeutic benefit of vitamin D on fractures in people

deficient in vitamin D. But the effect of vitamin D supplementation in

vitamin-D-replete individuals living in the community is less clear. Indeed,

given uncertainties about the efficacy of vitamin D alone or in combination

with calcium on falls,7 more studies in older people with suboptimum vitamin

D levels are appropriate to establish benefit on both falls and fracture

endpoints. Compliance and adherence are now recognised as a problem in

osteoporosis prevention and the RECORD trial also raises questions about the

generalisability of any treatment benefit when there is poor compliance. And

if the data are not to remain insufficient, future clinical trials need to

clearly establish the vitamin D status of the study population.

I declare that I have no conflict of interest

References

1. Conan Doyle A. The speckled band. French 1912; London

2. Chapuy M, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent

hip fractures in the elderly women. N Engl J Med 1992; 327: 1637-1642.

MEDLINE

3. Dawson- B, SS, Krall EA, Dallal GE. Effect of calcium and

vitamin D supplementation on bone density in men and women 65 years of age

or older. N Engl J Med 1997; 337: 670-676. MEDLINE | CrossRef

4. Newcombe RG. Explanatory and pragmatic estimates of the treatment effect

when deviations from allocated treatment occur. Stat Med 1988; 7: 1179-1186.

MEDLINE

5. 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: 469-475. CrossRef

6. FH, HE, Raphael HM, Crozier SR, C. Effect of annual

intramuscular vitamin D supplementation on fracture risk in 9440 community

living older people: the Wessex Fracture Prevention Trial. J Bone Miner Res

2004; 19: 1220abstr

7. Latham N, CS, Reid IR. Effects of vitamin D supplementation on

strength, physical performance and falls in older persons: a systematic

review. J Am Geriatr Soc 2003; 51: 1219-1226.

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