Re: Vitamin D and fractures: quo vadis?

[Guest guest]

What conclusions can be drawn from these trials?

What is MY take on this? Why do a trial if you're not going to do it

right? How can they do a trial for Vitamin D and only test 1% of the

study participants? What a waste of time and money.

a

On Apr 29, 2005, at 2:00 PM, wrote:

> 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.

>

>

>

>

> Not an MD

>

> I'll tell you where to go!

>

> Mayo Clinic in Rochester

> http://www.mayoclinic.org/rochester

>

> s Hopkins Medicine

> http://www.hopkinsmedicine.org

>

>

>

>

[Guest guest]

What conclusions can be drawn from these trials?

What is MY take on this? Why do a trial if you're not going to do it

right? How can they do a trial for Vitamin D and only test 1% of the

study participants? What a waste of time and money.

a

On Apr 29, 2005, at 2:00 PM, wrote:

> 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.

>

>

>

>

> Not an MD

>

> I'll tell you where to go!

>

> Mayo Clinic in Rochester

> http://www.mayoclinic.org/rochester

>

> s Hopkins Medicine

> http://www.hopkinsmedicine.org

>

>

>

>