Randomised controlled trial of calcium and supplementation with cholec
http://www.100md.com
《英国医生杂志》
1 York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, 2 Bone Clinic, Freeman Hospital, Newcastle upon Tyne, 3 Hertfordshire Primary Care Network, Ware, Herts
Correspondence to: D J Torgerson djt6@york.ac.uk
Objective To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
Design Pragmatic open randomised controlled trial.
Setting Practice nurse led clinics in primary care.
Participants 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
Intervention Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
Main outcome measures Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
Results 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
Conclusion We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture.
Registration ISRCTN26118436, controlled trials registry.
Low trauma fractures represent a major burden of illness and cost to society.1-3 This burden is likely to increase with ageing populations and because the age specific incidence of hip fracture seems to be increasing.4 Effective strategies are needed in a community setting to prevent the continuing rise in hip and other fractures and to reduce the associated excess morbidity and cost.
One relatively inexpensive method of reducing fracture rates might be supplementation with calcium and vitamin D. A randomised trial among female residents of French nursing homes showed significant reductions in both hip and non-hip fractures among those assigned supplementation with calcium and cholecaliferol (vitamin D3),5 and a study among community dwelling American men and women also noted a reduction in non-vertebral fractures in women receiving supplementation.6 More recently another study among women in French nursing homes noted a large but statistically non-significant reduction in hip, but not non-hip, fractures among those assigned calcium and vitamin D supplementation.7 The only trial that had fracture as the main end point was the original French nursing home study. It remains unknown whether these results can be generalised to populations outside of institutional care settings in France. Supplementation with calcium and vitamin D might be expected to prevent fractures not only through reductions in bone loss but by reducing falls. A recent systematic review found that vitamin D supplementation can reduce falls and falling by 22%.8
We assessed whether giving calcium and vitamin D supplements to community dwelling older women at increased risk of hip fracture would reduce their risk of any fracture.
Participants and methods
We identified women aged 70 and over who had at least one self reported risk factor for hip fracture: low bodyweight (< 58 kg), any previous fracture, maternal history of hip fracture, smoker, and poor or fair health. These risk factors were taken from a large population study in the United States9: we subsequently confirmed in a British cohort study that, apart from smoking, these risk factors predict the risk of hip and non-hip fractures.10 We assessed self reported calcium consumption through a brief 10 item questionnaire that was sent to the women along with questions on risk factors for fracture.
Women were excluded from the study if they could not give written consent or were receiving any calcium supplementation of more than 500 mg a day. We also excluded women with a history of kidney or bladder stones, renal failure, or hypercalcaemia.
Recruitment and randomisation
After a pilot study in the York area in September 1999, we began recruitment for the main trial in September 2001. We asked general practices across England to post information about the study, a consent form, and a questionnaire on risk factors for fracture to all women aged 70 and over. Women with cognitive impairment or a life expectancy of less than six months were to be excluded. Eligible women were asked to return the completed questionnaire to the relevant trial coordinating centres (Hertfordshire, Newcastle, or York).
Eligible women were randomised (stratified by practice) by computer at the York Trials Unit by an independent person with no knowledge of the participants' characteristics. We initially randomised in favour of the control group in a 2:1 ratio as this was hypothesised to be the most efficient allocation ratio given the study resources.11 We included research related costs (for example, extra staff), not the costs of the supplements, in the estimation only. Although a 2:1 ratio in favour of one arm may be considered extreme, the effect is minimal in terms of statistical power—for example, for a fixed sample size the power would be reduced from 80% to 75%. We increased our sample size to compensate for this reduction. A reanalysis of the trial's cost profile once recruitment had started showed that the optimum allocation ratio was 3:2. Towards the end of the study we therefore changed the allocation to 1:1.
Intervention and control groups
Before supplementation was started we sought written confirmation from the doctors that the participants had no known contraindications. Participants were also invited to see a nurse at their practice, who discussed the study and also checked for contraindications. Women who after randomisation were identified as having contraindications to calcium and vitamin D supplements were excluded from supplementation but were retained for follow-up and analysis on an intention to treat basis. The nurses gave participants general lifestyle advice on how to reduce their risk of fracture and six months supply of 1000 mg of calcium (calcium carbonate) and 800 IU of cholecalciferol (vitamin D3) as two tablets daily (Calcichew D3 Forte; Shire, Hampshire). Participants were recalled to see the practice nurse after six months and given a further supply of supplements if they wanted to continue with the study.
The control group were sent a leaflet with general advice on prevention of falls and on how to consume adequate calcium and vitamin D from dietary sources. The intervention group also received this leaflet.
Outcomes
The main outcome was fracture, excluding those of the digits, rib, face, and skull. Secondary outcomes included hip fracture; quality of life—as measured by the 12 item short form health survey questionnaire (SF-12)12 and the European quality of life instrument (EuroQol); death; visits to the doctor and hospital admissions; falls and fear of falling. Falls were self reported over the previous six months, and fear of falling was measured on a simple six point Likert scale.
Outcome data were mainly collected from questionnaires posted to participants every six months. Doctors were asked to confirm fractures in those women who reported a fracture in the previous six months. Information on fractures was also collected from the doctors of non-responders to the final questionnaire. For the principal analysis we included only confirmed fractures. Adherence was measured through self report every six months. We chose to report quality of life data at six and 12 months because of the reduction in follow-up rates with time for the quality of life questionnaires.
Sample size and statistical analysis
From previous work, and given a median follow-up period of 24 months, we presumed an all fracture rate of 10% among untreated participants.13 When two studies on calcium and vitamin D were combined in a random effects meta-analysis, the pooled reduction of fracture was 34%.5 6 We determined that to observe such a reduction in our population with 80% power (P = 0.05; two tailed) we would require 2855 participants to be allocated in a 2:1 ratio, allowing for a 20% dropout rate.
All participants were included in the analysis on an intention to treat basis. For our main analysis we used survival analysis to compare time to first fracture between the groups. We also undertook a logistic regression analysis adjusting for practice. We undertook subgroup analyses to compare rates for hip and wrist fracture between the two groups and secondary analyses with all reported fractures whether or not these had been confirmed. If a woman had more than one fracture we included only the first fracture in the analysis. We adjusted for practice because we changed the allocation ratio during the trial. In our unadjusted analysis we present the incidence of fracture by equally or unequally allocated groups as in any meta-analysis these need to be entered as two separate studies.
Pilot study
Between December 2000 and August 2001 we undertook a pilot trial at the York Centre to estimate recruitment rates. The 117 participants recruited in this pilot are included in the main trial report.
Results
Between September 2001 and November 2002 we recruited 3197 women in addition to the 117 participants recruited during the pilot trial (3314 in total). The recruitment rate of 7% instead of the presumed 5% allowed us to exceed our planned sample size by 16%.
Overall, 48 987 women registered with 107 general practices were invited to take part in our trial (fig 1). Of the 11 022 women who returned the questionnaire, 3078 were ineligible and 4490 did not want to take part, leaving 3454 women (7.0% of those originally invited). Table 1 shows the baseline characteristics of the participants. The intervention and contol groups were well balanced across all important predictors of fracture.
Fig 1 Flow of participants through trial. Adherence was estimated by subtracting those known to have died. Those who failed to return questionnaires were assumed not to be taking treatment
Table 1 Baseline characteristics of women receiving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) or only advice on diet or prevention of falls to prevent fractures. Values are percentages (numbers) unless stated otherwise
Over a median follow-up of 25 months, 149 confirmed fractures were reported, lower than anticipated. Time to fracture did not differ between the groups (fig 2) and we found no evidence of a benefit of supplementation in the prevention of fractures (table 2). When we took into account all reported fractures (including those not confirmed by a doctor) the results were not changed (adjusted odds ratio 1.60, 95% confidence interval 0.75 to 3.40).
Fig 2 Time to first fracture in women allocated calcium and vitamin D supplementation or only advice on diet and prevention of falls
Table 2 Odds of fracture in women receiving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) and those receiving only advice on diet and prevention of falls. Values are percentages (numbers) unless stated otherwise
We also examined the risk of falls, falling, and quality of life. We found no evidence of an effect on falls. After adjusting for practice, the odds ratio of a woman having a fall at six months was 0.99 (0.81 to 1.20). At 12 months we found no evidence that supplementation reduced falling (0.98, 0.79 to 1.20). We also found no differences in quality of life (table 3).
Table 3 Secondary outcomes in women reciving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) and those receiving only advice on diet and prevention of falls. Values are percentages (numbers) unless stated otherwise
Adherence
Rates for adherence at 12 months were about 63% when we included all women randomised but excluded those who had died. We compared women taking supplements with those in the control group to determine whether women who adhered to treatment might have had a reduced fracture rate. We found no evidence of any benefit (1.03, 0.68 to 1.56).
Discussion
Schurch MA, Rizzoli R, Mermillod B, Vasey H, Michel JP, Bonjour JP. A prospective study on the socio-economic aspects of fracture of the proximal femur. J Bone Miner Res 1996:11: 1935-42.
Barret-Connor E. The economic and human costs of osteoporotic fracture. Am J Med 1993:98(suppl 2a): S3-7.
Dolan P, Torgerson DJ. The cost of treating osteoporotic fractures in the United Kingdom female population. Osteoporos Int 1998;6: 11-7.
Grimley-Evans J, Seagroatt V, Goldacre MJ. Secular trends in proximal femoral fracture: Oxford record linkage study area and England 1968-86. J Epidemiol Community Health 1997;51: 424-9.
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327: 1637-42.
Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age and older. N Engl J Med 1997;337: 670-6.
Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 2002;13: 257-64.
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291: 1999-2006.
Eddy DM, Johnston CC, Cummings SR, Dawson-Hughes B, Lindsay R, Melton LJ, et al. Osteoporosis: cost-effectiveness analysis and review of the evidence for prevention, diagnosis and treatment. Osteoporos Int 1998(suppl 4).
Porthouse J, Birks YF, Torgerson DJ, Cockayne S, Puffer S, Watt I. Risk factors for fracture in a UK population: a prospective cohort study. Q J Med 2004;97: 569-74.
Torgerson DJ, Campbell MK. Unequal randomisation can improve the economic efficiency of clinical trials. J Health Ser Res Policy 1997;2: 81-5.
Iglesias CP, Birks YF, Torgerson DJ. Improving the measurement of quality of life of older people: the York SF12. Q J Med 2001;94: 695-8.
Birks YF, Porthouse J, Addie C, Loughney K, Saxon L, Baverstock M, et al. Randomised controlled trial of hip protectors among women living in the community. Osteoporos Int 2004;15: 701-6.
Larsen ER, Mosekilde L, Foldsprang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 2004;19: 370-8.
Donner A, Klar NS. Design and analysis of cluster randomisation trials in health research. New York: Hodder and Arnold, 2000.
MRC RECORD Trial Group. Randomised placebo-controlled trial of daily oral vitamin D and/or calcium for the secondary prevention of low-trauma fractures in the elderly. Lancet 2005 (in press).
Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomised, placebo-controlled clinical trial. Ann Intern Med 1996;124: 400-6.
Smith H, Anderson F, Raphael H, Crozier S, Cooper C. Effect of annual intramuscular vitamin D supplementation on fracture risk: population-based, randomised, double-blind, placebo-controlled trial. Osteoporos Int 2004;15(suppl 1): S8.
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: 469-72.
Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002;17: 709-15.
Bergmann M, Byers T, Freedman DS, Mokdad A. Validity of self-reported diagnoses leading to hospitalization: a comparison of self-reports with hospital records in a prospective study of American adults. Am J epidemiol 1998;147: 969-77.(Jill Porthouse, research fellow1, Sarah )
Correspondence to: D J Torgerson djt6@york.ac.uk
Objective To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
Design Pragmatic open randomised controlled trial.
Setting Practice nurse led clinics in primary care.
Participants 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
Intervention Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
Main outcome measures Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
Results 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
Conclusion We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture.
Registration ISRCTN26118436, controlled trials registry.
Low trauma fractures represent a major burden of illness and cost to society.1-3 This burden is likely to increase with ageing populations and because the age specific incidence of hip fracture seems to be increasing.4 Effective strategies are needed in a community setting to prevent the continuing rise in hip and other fractures and to reduce the associated excess morbidity and cost.
One relatively inexpensive method of reducing fracture rates might be supplementation with calcium and vitamin D. A randomised trial among female residents of French nursing homes showed significant reductions in both hip and non-hip fractures among those assigned supplementation with calcium and cholecaliferol (vitamin D3),5 and a study among community dwelling American men and women also noted a reduction in non-vertebral fractures in women receiving supplementation.6 More recently another study among women in French nursing homes noted a large but statistically non-significant reduction in hip, but not non-hip, fractures among those assigned calcium and vitamin D supplementation.7 The only trial that had fracture as the main end point was the original French nursing home study. It remains unknown whether these results can be generalised to populations outside of institutional care settings in France. Supplementation with calcium and vitamin D might be expected to prevent fractures not only through reductions in bone loss but by reducing falls. A recent systematic review found that vitamin D supplementation can reduce falls and falling by 22%.8
We assessed whether giving calcium and vitamin D supplements to community dwelling older women at increased risk of hip fracture would reduce their risk of any fracture.
Participants and methods
We identified women aged 70 and over who had at least one self reported risk factor for hip fracture: low bodyweight (< 58 kg), any previous fracture, maternal history of hip fracture, smoker, and poor or fair health. These risk factors were taken from a large population study in the United States9: we subsequently confirmed in a British cohort study that, apart from smoking, these risk factors predict the risk of hip and non-hip fractures.10 We assessed self reported calcium consumption through a brief 10 item questionnaire that was sent to the women along with questions on risk factors for fracture.
Women were excluded from the study if they could not give written consent or were receiving any calcium supplementation of more than 500 mg a day. We also excluded women with a history of kidney or bladder stones, renal failure, or hypercalcaemia.
Recruitment and randomisation
After a pilot study in the York area in September 1999, we began recruitment for the main trial in September 2001. We asked general practices across England to post information about the study, a consent form, and a questionnaire on risk factors for fracture to all women aged 70 and over. Women with cognitive impairment or a life expectancy of less than six months were to be excluded. Eligible women were asked to return the completed questionnaire to the relevant trial coordinating centres (Hertfordshire, Newcastle, or York).
Eligible women were randomised (stratified by practice) by computer at the York Trials Unit by an independent person with no knowledge of the participants' characteristics. We initially randomised in favour of the control group in a 2:1 ratio as this was hypothesised to be the most efficient allocation ratio given the study resources.11 We included research related costs (for example, extra staff), not the costs of the supplements, in the estimation only. Although a 2:1 ratio in favour of one arm may be considered extreme, the effect is minimal in terms of statistical power—for example, for a fixed sample size the power would be reduced from 80% to 75%. We increased our sample size to compensate for this reduction. A reanalysis of the trial's cost profile once recruitment had started showed that the optimum allocation ratio was 3:2. Towards the end of the study we therefore changed the allocation to 1:1.
Intervention and control groups
Before supplementation was started we sought written confirmation from the doctors that the participants had no known contraindications. Participants were also invited to see a nurse at their practice, who discussed the study and also checked for contraindications. Women who after randomisation were identified as having contraindications to calcium and vitamin D supplements were excluded from supplementation but were retained for follow-up and analysis on an intention to treat basis. The nurses gave participants general lifestyle advice on how to reduce their risk of fracture and six months supply of 1000 mg of calcium (calcium carbonate) and 800 IU of cholecalciferol (vitamin D3) as two tablets daily (Calcichew D3 Forte; Shire, Hampshire). Participants were recalled to see the practice nurse after six months and given a further supply of supplements if they wanted to continue with the study.
The control group were sent a leaflet with general advice on prevention of falls and on how to consume adequate calcium and vitamin D from dietary sources. The intervention group also received this leaflet.
Outcomes
The main outcome was fracture, excluding those of the digits, rib, face, and skull. Secondary outcomes included hip fracture; quality of life—as measured by the 12 item short form health survey questionnaire (SF-12)12 and the European quality of life instrument (EuroQol); death; visits to the doctor and hospital admissions; falls and fear of falling. Falls were self reported over the previous six months, and fear of falling was measured on a simple six point Likert scale.
Outcome data were mainly collected from questionnaires posted to participants every six months. Doctors were asked to confirm fractures in those women who reported a fracture in the previous six months. Information on fractures was also collected from the doctors of non-responders to the final questionnaire. For the principal analysis we included only confirmed fractures. Adherence was measured through self report every six months. We chose to report quality of life data at six and 12 months because of the reduction in follow-up rates with time for the quality of life questionnaires.
Sample size and statistical analysis
From previous work, and given a median follow-up period of 24 months, we presumed an all fracture rate of 10% among untreated participants.13 When two studies on calcium and vitamin D were combined in a random effects meta-analysis, the pooled reduction of fracture was 34%.5 6 We determined that to observe such a reduction in our population with 80% power (P = 0.05; two tailed) we would require 2855 participants to be allocated in a 2:1 ratio, allowing for a 20% dropout rate.
All participants were included in the analysis on an intention to treat basis. For our main analysis we used survival analysis to compare time to first fracture between the groups. We also undertook a logistic regression analysis adjusting for practice. We undertook subgroup analyses to compare rates for hip and wrist fracture between the two groups and secondary analyses with all reported fractures whether or not these had been confirmed. If a woman had more than one fracture we included only the first fracture in the analysis. We adjusted for practice because we changed the allocation ratio during the trial. In our unadjusted analysis we present the incidence of fracture by equally or unequally allocated groups as in any meta-analysis these need to be entered as two separate studies.
Pilot study
Between December 2000 and August 2001 we undertook a pilot trial at the York Centre to estimate recruitment rates. The 117 participants recruited in this pilot are included in the main trial report.
Results
Between September 2001 and November 2002 we recruited 3197 women in addition to the 117 participants recruited during the pilot trial (3314 in total). The recruitment rate of 7% instead of the presumed 5% allowed us to exceed our planned sample size by 16%.
Overall, 48 987 women registered with 107 general practices were invited to take part in our trial (fig 1). Of the 11 022 women who returned the questionnaire, 3078 were ineligible and 4490 did not want to take part, leaving 3454 women (7.0% of those originally invited). Table 1 shows the baseline characteristics of the participants. The intervention and contol groups were well balanced across all important predictors of fracture.
Fig 1 Flow of participants through trial. Adherence was estimated by subtracting those known to have died. Those who failed to return questionnaires were assumed not to be taking treatment
Table 1 Baseline characteristics of women receiving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) or only advice on diet or prevention of falls to prevent fractures. Values are percentages (numbers) unless stated otherwise
Over a median follow-up of 25 months, 149 confirmed fractures were reported, lower than anticipated. Time to fracture did not differ between the groups (fig 2) and we found no evidence of a benefit of supplementation in the prevention of fractures (table 2). When we took into account all reported fractures (including those not confirmed by a doctor) the results were not changed (adjusted odds ratio 1.60, 95% confidence interval 0.75 to 3.40).
Fig 2 Time to first fracture in women allocated calcium and vitamin D supplementation or only advice on diet and prevention of falls
Table 2 Odds of fracture in women receiving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) and those receiving only advice on diet and prevention of falls. Values are percentages (numbers) unless stated otherwise
We also examined the risk of falls, falling, and quality of life. We found no evidence of an effect on falls. After adjusting for practice, the odds ratio of a woman having a fall at six months was 0.99 (0.81 to 1.20). At 12 months we found no evidence that supplementation reduced falling (0.98, 0.79 to 1.20). We also found no differences in quality of life (table 3).
Table 3 Secondary outcomes in women reciving calcium and cholecalciferol (vitamin D3) supplementation (intervention group) and those receiving only advice on diet and prevention of falls. Values are percentages (numbers) unless stated otherwise
Adherence
Rates for adherence at 12 months were about 63% when we included all women randomised but excluded those who had died. We compared women taking supplements with those in the control group to determine whether women who adhered to treatment might have had a reduced fracture rate. We found no evidence of any benefit (1.03, 0.68 to 1.56).
Discussion
Schurch MA, Rizzoli R, Mermillod B, Vasey H, Michel JP, Bonjour JP. A prospective study on the socio-economic aspects of fracture of the proximal femur. J Bone Miner Res 1996:11: 1935-42.
Barret-Connor E. The economic and human costs of osteoporotic fracture. Am J Med 1993:98(suppl 2a): S3-7.
Dolan P, Torgerson DJ. The cost of treating osteoporotic fractures in the United Kingdom female population. Osteoporos Int 1998;6: 11-7.
Grimley-Evans J, Seagroatt V, Goldacre MJ. Secular trends in proximal femoral fracture: Oxford record linkage study area and England 1968-86. J Epidemiol Community Health 1997;51: 424-9.
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327: 1637-42.
Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age and older. N Engl J Med 1997;337: 670-6.
Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 2002;13: 257-64.
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291: 1999-2006.
Eddy DM, Johnston CC, Cummings SR, Dawson-Hughes B, Lindsay R, Melton LJ, et al. Osteoporosis: cost-effectiveness analysis and review of the evidence for prevention, diagnosis and treatment. Osteoporos Int 1998(suppl 4).
Porthouse J, Birks YF, Torgerson DJ, Cockayne S, Puffer S, Watt I. Risk factors for fracture in a UK population: a prospective cohort study. Q J Med 2004;97: 569-74.
Torgerson DJ, Campbell MK. Unequal randomisation can improve the economic efficiency of clinical trials. J Health Ser Res Policy 1997;2: 81-5.
Iglesias CP, Birks YF, Torgerson DJ. Improving the measurement of quality of life of older people: the York SF12. Q J Med 2001;94: 695-8.
Birks YF, Porthouse J, Addie C, Loughney K, Saxon L, Baverstock M, et al. Randomised controlled trial of hip protectors among women living in the community. Osteoporos Int 2004;15: 701-6.
Larsen ER, Mosekilde L, Foldsprang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 2004;19: 370-8.
Donner A, Klar NS. Design and analysis of cluster randomisation trials in health research. New York: Hodder and Arnold, 2000.
MRC RECORD Trial Group. Randomised placebo-controlled trial of daily oral vitamin D and/or calcium for the secondary prevention of low-trauma fractures in the elderly. Lancet 2005 (in press).
Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomised, placebo-controlled clinical trial. Ann Intern Med 1996;124: 400-6.
Smith H, Anderson F, Raphael H, Crozier S, Cooper C. Effect of annual intramuscular vitamin D supplementation on fracture risk: population-based, randomised, double-blind, placebo-controlled trial. Osteoporos Int 2004;15(suppl 1): S8.
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: 469-72.
Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002;17: 709-15.
Bergmann M, Byers T, Freedman DS, Mokdad A. Validity of self-reported diagnoses leading to hospitalization: a comparison of self-reports with hospital records in a prospective study of American adults. Am J epidemiol 1998;147: 969-77.(Jill Porthouse, research fellow1, Sarah )